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{ "match": false, "comment": "Paths do not match", "expected" : { "method": "POST", "path": "/path/to/something", "query": "", "headers": {} }, "actual": { "method": "POST", "path": "/path/to/something/else", "query": "", "headers": {} } }

Q: Line segment / circle intersection - X value seems wrong? Major Edit I'm making a Breakout clone, and having difficulty with collision detection between a circle and line segment. Apologies, my earlier question was a result of frustration and no sleep :) Having read this post on collision detection I've re-written my collision code to the following: // Takes 2 points on a line, a circle centre, and a circle radius // Returns true is collision, false otherwise public Boolean DoesCollide(Vector2 a, Vector2 b, Vector2 c, float rad) { // First up, let's normalise our vectors so the circle is on the origin Vector2 normA = a - c; Vector2 normB = b - c; Vector2 d = normB - normA; // Want to solve as a quadratic equation, need 'a','b','c' components float aa = Vector2.Dot(d, d); float bb = 2 * (Vector2.Dot(normA, d)); float cc = Vector2.Dot(normA,normA)-(rad*rad); // Get determinant to see if LINE intersects double deter = Math.Pow(bb, 2.0) - 4 * aa * cc; if (deter > 0) { // Get t values (solve equation) to see if LINE SEGMENT intersects double t = (-bb - Math.Sqrt(deter)) / (2 * aa); double t2 = (-bb + Math.Sqrt(deter)) / (2 * aa); Boolean match = false; if (0.0 <= t && t <= 1.0) { // Interpolate to get collision point Vector2 collisionPoint = c + Vector2.Lerp(normA, normB, (float)t); match = true; } if (0.0 <= t2 && t2 <= 1.0) { Vector2 collisionPoint2 = c + Vector2.Lerp(normA, normB, (float)t2); match = true; } return match; } else return false; } However, I'm getting strange results for the X components of the collision points found 'on hit' - see the following debug output: Coll at {X:1033.931 Y:620}, t1 = 0.203759334390812, Normalised = {X:0.8576241 Y:0.5142772} Coll2 at {X:1052.069 Y:620}, t2 = 0.409877029245551, Normalised = {X:0.8615275 Y:0.5077109} Circ cent = {X:1043 Y:610}, rad = 13.5 As you can see, the X components are 10px either side of the circle centre, but the Y component (620) is the very topmost pixel of the top of the Breakout paddle. Surely here the X points can't be 20 pixels apart, given the location of the Y point? A: You are missing a stage before calculating t0 and t1. It should look more like this: float q; // Holds the solution to the quadratic equation if (bb >= 0) { q = (-bb - Math.Sqrt(deter)) / 2; } else { q = (-bb + Math.Sqrt(deter)) / 2; } float t0 = q / aa; float t1 = cc / q; After that, make sure t0 and t1 are sorted. [Edit] I made a small error with the determinant signs, note they are now reversed.

Top 15 Hottest Actresses of Hollywood 2017 Hollywood has been the epitome of beauty and glamour all over the world. It is the ultimate dream of every aspiring actors and actresses to set foot on this magical place. It is no surprise then, that it is also where you can find the hottest beauty on earth. And by hot we don’t just mean beauty and appeal. It’s a culmination of both which results to gorgeousness and attractiveness to the next level. Now, beauty is in the eye of the beholder, they say. But this list we got here is simply hard to dispute. Here is our own list of top 15 hottest Hollywood actresses for 2017. 15. Gal Gadot Not only can she capture hearts, she can also kick butts. This beauty served in the Israel Defense Force as a soldier for two years. She will be the first one to portray the role of Wonder Woman in a live action film. 14. Dakota Johnson Daughter of Hollywood royalty, she is making a name of her own after landing her lead role as Anastasia Steele in the steamy film trilogy Fifty Shades. She also took part in Black Mass and A Bigger Slash. She is one hot star to watch out for. 13. Jennifer Lawrence Her charming smile, bubbly personality and sexy body have captivated the whole world. She landed high-profile roles in movies such as Hunger Games series and Xmen, making her one of the highest paid actresses in Hollywood. 12. Marion Cotillard Her beauty is really fit for the silver screen. This French actress, singer-songwriter, musician and environmentalist were named the most Bankable French actress in 2015. From France to Hollywood big screen, she shows no slowing down. 11. Kiera Knightley This gorgeous English actress had an early start in show business acting as a child in her debut in 1995. She rose to international fame after playing Elizabeth Swann in the blockbuster series Pirates of the Caribbean. 10. Charlize Theron Aside from her excellent acting skills, her beautiful eyes have captivated Hollywood and the whole world. This beauty hailed from South Africa and the first one from her country to win an Oscar award. 9. Olivia Wilde It’s not hard to see why this actress and fashion model made it to our top list. She chose her screen name from the famous author, Oscar Wilde and was hailed as PETA sexiest celebrity in 2010. 8. Jessica Alba At a young age of 13, she began her TV and movie appearances. Now, she is one of the hottest Hollywood actresses and a businesswoman who founded her company back in 2012. Her first starring role in a major studio film was Honey in 2003. She became unstoppable ever since. 7. Emma Stone She recently starred alongside Ryan Gosling in the highly acclaimed La La Land, which billed her as one of the highest paid actresses in the world. She began acting as a child and grew up to be a gorgeous Hollywood actress. 6. Scarlett Johansson This very gorgeous actress has a huge male fan base and it is easy to see why. A four-time Golden Globe nominee, her most notable roles include The Avengers and just recently, Ghost in the Shell. 5. Megan Fox Revered as having a perfect face, she rose to fame after starring in The Transformers and Transformer 2. She also gave life to April O’Neill on the remake of Teenage Mutant Ninja Turtles in 2014 and 2016. Men can’t help drool over this sexy siren. 4. Mila Kunis This Ukranian beauty is always considered when coming up a list of the most gorgeous Hollywood celebrities. Who could forget her roles in Forgetting Sarah Marshall, Black Swan, and Friends with Benefits? This Hollywood hottie shows no sign of slowing down as her projects are lined up this year. 3. Beyonce Aside from being a record-breaking singer, this hot siren also starred in some Hollywood hit movies including Austin Powers in Goldmember, The Pink Panther, Dreamgirls and Obsessed. Having a body to die for and being multi-talented, we can’t just let have the list without her. 2. Angelina Jolie Everything about her face is incredibly sexy. This Oscar-winning actress and mom of six is a constant choice on every ‘hot’ list. Jolie has also been known to be involved in international charity projects and a full-fledged UN diplomat. 1. Natalie Portman Aside from her gorgeous looks and screaming attractiveness, this star is actually a smart cookie! She completed her degree in Psychology from Harvard, and is fluent in five languages. If that didn’t turn you on, perhaps these pictures of hers will.

Q: Why is "Nous sommes" used for days of the week? I've just been curious about this. Why is it that saying a day of the week, something like "It's monday" uses 'nous'? as in: Nous sommes lundi. Am I able to say it another way? is using: Aujourd'hui c'est lundi. / C'est lundi. an acceptable format for a day of the week? Furthermore, if that's the case, can I use On est lundi. in less formal contexts? I just want to know which of these is correct to use, and why it is that 'nous' is used pour les jours de la semaine. Merci! A: Nous sommes lundi is a slightly formal/written way to tell which day of the week it is. One can also say Nous sommes [le] lundi premier septembre. This French idiom can only be used in the first person plural. You can't say Je suis lundi or ils sont lundi because the current weekday is expected to be the same for everyone. The same idiom exists in Spanish: Estamos a lunes and Italian: Siamo [a] lunedì. In English, while "We are Monday" will sound very foreign, one can say "We are late", "We are on time" or "We are in September" which are close. Aujourd'hui, c'est lundi or simply c'est lundi are fully acceptable equivalents. On est lundi is a less formal and more common way to say nous sommes lundi.

--TEST-- testing anonymous inheritance --FILE-- <?php class Outer { protected $data; public function __construct($data) { $this->data = $data; } public function getArrayAccess() { /* create a proxy object implementing array access */ return new class($this->data) extends Outer implements ArrayAccess { public function offsetGet($offset) { return $this->data[$offset]; } public function offsetSet($offset, $data) { return ($this->data[$offset] = $data); } public function offsetUnset($offset) { unset($this->data[$offset]); } public function offsetExists($offset) { return isset($this->data[$offset]); } }; } } $outer = new Outer(array( rand(1, 100) )); /* not null because inheritance */ var_dump($outer->getArrayAccess()[0]); ?> --EXPECTF-- int(%d)

Fluticasone propionate hydrofluoroalkane inhalation aerosol in patients receiving inhaled corticosteroids. Inhaled corticosteroids (ICSs) delivered by metered-dose inhalers that contain chlorofluorocarbon propellants are being discontinued because of the harmful effects of chlorofluorocarbon on the ozone layer. Therefore, some metered-dose inhaler products are being reformulated with "ozone-friendly" hydrofluoroalkane propellants. To evaluate treatment with fluticasone propionate hydrofluoroalkane inhalation aerosol, 88, 220, and 440 microg twice daily, vs placebo in patients with asthma receiving an ICS. Randomized, double-blind, parallel-group, 12-week study. Mean morning predose percent predicted forced expiratory volume in 1 second increased by 2.2%, 3.2%, and 4.6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, compared with an 8.3% decrease for placebo (P < .001 vs placebo for all groups). Secondary pulmonary function end points and asthma symptoms showed similar improvements compared with placebo. Discontinuation from the study due to lack of efficacy was 50% in the placebo group and 11%, 10%, and 6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively. At week 12, the probability of remaining in the study was 0.89, 0.90, and 0.94 for the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, vs 0.45 for the placebo group (P < .001 for all). Changes in 24-hour urinary cortisol excretion rates were similar among treatment groups. Fluticasone propionate hydrofluoroalkane, previously shown to be a clinically suitable alternative to fluticasone propionate chlorofluorocarbon, was effective and well tolerated. The ability to switch from fluticasone propionate chlorofluorocarbon and other chlorofluorocarbon-containing ICSs to fluticasone propionate hydrofluoroalkane without sacrificing asthma control or tolerability will facilitate a smooth transition to this nonchlorofluorocarbon-containing medicinal.

International position paper on the appropriate use of uricosurics with the introduction of lesinurad. Over the last 70 years, pharmacotherapy in gout with urate-lowering drugs has consisted of four drugs only: In 1952, a mild uricosuric probenecid became available, the xanthine oxidase inhibitor Allopurinol in 1964, and the latter became the most frequently used urate-lowering drug worldwide; in the Eurozone, the uricosuric benzbromarone was welcomed in 1977. Only in 2002, the potent non-purine xanthine oxidase inhibitor febuxostat was introduced. In many countries, uricosurics such as probenecid and benzbromarone have not been available up to now, and these days, the new uricosuric lesinurad is the first uricosuric that may be introduced in these countries, which is the reason for describing the position this novel uricosuric deserves in treating gout. Recent literature will be shortly reviewed, and the current proposed position for lesinurad will be given as an aid for clinicians.

New York City Mayor Bill de Blasio declared Tuesday as "Morning Joe Day" in New York City to commemorate the 10-year anniversary of the MSNBC show. De Blasio, a Democrat, praised the show's hosts repeatedly during his time on the show before he gave Joe Scarborough, Mika Brzezinski and Willie Geist the proclamation and read what it said. De Blasio also said that the first time he witnessed a gripping, intelligent conversation on television was when he first watched Morning Joe in January 2008. "I turn on the TV early in the morning and I saw something I never saw before, which was an intelligent conversation that really gripped me," de Blasio said. Afterward, Geist joked that Donny Deutsch wanted a wallet-sized copy of the proclamation for the next time he was arrested to show to the police. Deutsch, who has routinely blasted President Donald Trump and even challenged him to a fight, then preceded to make a joke about what sounded like prostitution. "By the way, she told me a different story when I met her," Deutsch said.

The invention concerns a variable speed gear transmission comprising at least one gearwheel mounted through a rolling bearing on a transmission shaft, in which the gearwheel can be coupled to the transmission shaft through a coupling element, first cylindrical rolling elements being arranged in a cage in radial direction between an inner raceway formed on the transmission shaft and an outer raceway formed on a hub of the gearwheel, said cage comprising in pockets at least at three circumferential points, second cylindrical rolling elements having a slightly larger diameter than the first rolling elements. Gearwheels of the pre-cited type for variable speed gear transmissions, also called idler gears, are frequently arranged on the transmission shaft in split rolling bearing cages that expand under the effect of their inherent elasticity and come into play-free contact with the rolling elements. A cage of this type is known from DE 41 24 838 A1. In a no-load, unengaged condition, the bearing may not run kinematically under certain circumstances i.e., it may be subject to slippage. In the extreme case, the transmission shaft can come to a standstill and the idler gear may reach a speed of several hundred or several thousand rotations per minute. When the cage starts to rotate, the rolling elements are pressed against the outer raceway due to the centrifugal force so that the cage can reach approximately the same speed of rotation as the idler gear while, due to the operational clearance, the rolling elements can lose contact with the raceway of the transmission shaft. This results in a sliding movement of the rolling elements on the raceway of the transmission shaft that leads to increased wear and/or smearing in case of a sudden loading of the rolling elements. Efforts have been made to solve this problem by modifying the kinematics of the bearing during idling operation. One possibility of achieving this is to reduce the number of load-bearing rolling elements involved in idling operation. This results in a distribution of the weight of the idler gear among only a small number of rolling elements. Thus, for example, it is known from DE-OS 29 18 601 to mount shafts in a variable speed gear transmission through a bearing cage in which three circumferentially equally spaced pockets contain rolling elements having a larger diameter than the rest of the rolling elements. FIGS. 3 and 4 of this prior art document show a cage in which these larger diameter rolling elements are made in the form of hollow coiled wire cylinders. In DE 44 01 531 A1 an attempt is made to solve this problem, well known in the field of rolling bearings, by configuring needle rollers with an arcuate shape so that a radially elastically yielding arch is formed at their centers. It is also known from DE-OS 27 41 057 to configure a bearing so that it comprises a plurality of circumferentially spaced rolling elements whose enveloping circle diameter is smaller than the diameter of the shaft and that are deformable in radial direction. These rolling elements made of a plastic or of thin hollow steel bodies are arranged between the normal rolling elements and have a slightly larger diameter than these so that, in the installed state, they effect a pre-stressing of the bearing. A drawback of all the above solutions is that the rolling elements of larger diameter are of a different type from the remaining rolling elements and are very expensive to manufacture so that the total costs of the idler gear bearing are increased. It is an object of the invention to provide an idler gear bearing which possesses the property of elastic deformation of some of its rolling elements and still can be manufactured without extra fabrication costs. This and other objects and advantages of the invention will become obvious from the following detailed description. The invention achieves the above objects by the fact that the first and second rolling elements are of a same type, size ratios between the first and second rolling elements are defined so that, in an unloaded state, the larger diameter of the second rolling elements is such as to become equal to a diameter of the first rolling elements in an engaged state under radial loading, whereby a limit of elasticity of the second rolling elements having the larger diameter in the unloaded state is not exceeded. The provisions of the invention for the configuration of the idler gear bearing enable a simple but effective use of the law of elasticity for modifying the kinematics of the bearing. The invention utilizes the ability of the larger cylindrical rolling elements to reverse shape and volume variations brought about by outer forces or torques, in the present case by gear shifting, so that, in the engaged state under load, all the rolling elements have the same diameter while, in idling operation, the bearing comprises rolling elements of different diameters. It is quite obvious that the idler gear bearing of the invention having rolling elements of one and the same type is much simpler to manufacture than prior art bearings with different types of rolling elements. Moreover, the filling of rolling elements of the same type but with different diameters into the same bearing cage poses no problem from the fabrication point of view. According to further advantageous propositions of the invention, the diameter of the larger rolling elements is 2 to 5 xcexcm larger than the diameter of the rest of the rolling elements. The larger rolling elements and the rest of the rolling elements are arranged in alternating sequence with one another but it is also possible to arrange them in any other order. The invention will now be described with reference to one example of embodiment illustrated in the appended drawings.

This invention relates to an open wall storage assembly for use with unfinished walls and, in particular, a wall storage assembly for use in a wall region containing a plurality of vertical wall supports. In present day home construction, large areas of interior walls are left unfinished, typically in the basement and garage areas, although work rooms and laundry areas may be similarly unfinished. The homeowner desirous of utilizing this wall area typically provides shelving affixed to the exposed or internal surface of the vertical supports, thus providing storage which protrudes into the room area. A similar result obtains when closed wall storage assemblies such as cabinetry, are also affixed. Since these areas are frequently located in regions where space is at a premium, for example, the area adjacent customary automobile parking in garage facilities and areas adjacent the location of laundry equipment, the inability of the homeowner to effectively utilize the regions between vertical wall supports results in already crowded areas becoming further confined. While a variety of different shelving schemes and outwardly expandable cabinetry is available to promote storage in these areas, the homeowner is faced with a loss of room space especially where the cabinetry contains doors. Furthermore, the mounting of these storage assemblies on the relatively narrow face of the vertical support members utilized in house construction frequently requires the use of additional supporting structure underlying the assembly. This type of storage is characterized by the lack of utility of the region located within the wall between the vertical wall supports. In the construction of the typical house, it is common to find horizontal structural supports placed for fire break purposes and occasionally for structural rigidity between adjacent wall supports. If these members are present, the homeowner is reluctant to disturb them from both a structural and a fire retardant point of view. If these horizontal members are not present, the region between vertical supports and behind any such storage apparatus mounted on the narrow surfaces of the wall supports can act as a flue in the eventuality of fire along the base of the wall. Accordingly, it is a primary object of the present invention to provide an open wall storage assembly for use with unfinished walls which is readily installable by the homeowner and effectively utilizes the region between adjacent vertical wall supports heretofore ignored in the construction of storage means. Furthermore, the invention is characterized by a large area integral member which is utilized in surrounding engagement with adjacent vertical members and has flange members on the opposing vertical ends for affixation to the vertical wall supports. In the present invention, the individual installer can place the transverse shelving members at locations to fit his particular needs. Thus, the invention is located in heretofore unused areas in the support wall so as not to reduce the usable regions within the building.

import itertools from ..lang import sig from ..lang import H from ..lang import t from ..lang import L from ..lang import build_instance from ..lang import is_builtin from ..lang import List from ..lang import instance from ..Data.Functor import fmap from Applicative import Applicative class Monad(Applicative): """ The Monad class defines the basic operations over a monad, a concept from a branch of mathematics known as category theory. From the perspective of a Haskell programmer, however, it is best to think of a monad as an abstract datatype of actions. Dependencies: Functor, Applicative Attributes: bind, __rshift__ Minimal complete definition: bind """ @classmethod def make_instance(typeclass, cls, bind): bind = bind ** (H[(Monad, "m")]/ t("m", "a") >> (H/ "a" >> t("m", "b")) >> t("m", "b")) if not is_builtin(cls): def bind_wrap(s, o): return Monad[s].bind(s, o) cls.__rshift__ = bind_wrap build_instance(Monad, cls, {"bind":bind}) return @sig(H[(Monad, "m")]/ t("m", "a") >> (H/ "a" >> t("m", "b")) >> t("m", "b")) def bind(m, fn): """ bind :: Monad m => m a -> (a -> m b) -> m b Monadic bind. """ return Monad[m].bind(m, fn) @sig(H[(Monad, "m")]/ t("m", t("m", "a")) >> t("m", "a")) def join(m): """ join :: Monad m => m (m a) -> m a The join function is the conventional monad join operator. It is used to remove one level of monadic structure, projecting its bound argument into the outer level. """ __id = (lambda x: x) ** (H/ "a" >> "a") return bind(m, __id) @sig(H[(Monad, "m")]/ (H/ "a" >> "r") >> t("m", "a") >> t("m", "r")) def liftM(fn, m): """ liftM :: Monad m => (a1 -> r) -> m a1 -> m r Promote a function to a monad. """ return fmap(fn, m) instance(Monad, List).where( bind = lambda x, fn: L[itertools.chain.from_iterable(fmap(fn, x))] )

Kinetoplast DNA minicircles are inherited from both parents in genetic hybrids of Trypanosoma brucei. We have examined the inheritance of kinetoplast DNA (kDNA) in gentic crosses of trypanosomes. In 2 independent crosses of Trypanosoma brucei spp. trypanosomes, the kDNA maxicircles which carry the genes for mitochondrial biogenesis, were inherited from one parent only, as already found by other workers. However, the other component of kDNA, the minicircles, were inherited from both parents. This was demonstrated by Southern analysis using cloned minicircle probes. The inheritance of kDNA is therefore not uniparental. Our data point to fusion of the parental kinetoplast DNA networks during genetic exchange, with gradual loss of one or other parental maxicircle type due to random segregation of maxicircles at subsequent mitotic divisions. We infer that the first event of genetic exchange is fusion of parental trypanosomes (either haploid or diploid), followed at some point by fusion of the parental mitochondria.

High-definition remasters of Shenmue and Shenmue II will launch in 2017, according to “a trusted source close to Atlus USA” of blog and online retailer Rice Digital. The website reports that both games may be released together rather than separately, and are likely being geared up to launch before Shenmue III. While it doesn’t have any further information, the website said it was told it is “safe to assume a PC / Steam release,” and that there has not been any indication that the remasters will appear on any other platform. The author of the article previously leaked information that Atlus would publish The King of Fighters XIV a few days before its official announcement. Back in January, Sega registered a pair of Shenmue remaster-related domains in ShenmueHD.com and ShenmueRemastered.com. Prior to that, in May 2017, Sega said it was “investigating” working on remasters of Shenmue and Shenmue II. The long-anticipated sequel, Shenmue III, is in development at Ys Net and currently slated for release for PlayStation 4 and PC in December.

Corian, once considered the top-of-the kitchen counter upgrade, is being replaced in upscale homes by other solid-surface finishes. One of the hottest is granite, which adds rich luster to new kitchens in a range of dark colors, from gray to chocolate. Granite countertops are somewhat more expensive to install than Corian. Cost is why the least expensive choice, laminate, is still the most popular. Today, solid colors are out and patterns are in. People who can't have the real thing can choose a granite look-alike in any of a variety of colors. Also popular is a stipple finish, which may also be called a quarry or sparkle finish by different manufacturers. It may sparkle or shine and have a raised, bumpy feel. Despite competition, solid surface countertops such as Corian, Gibraltar and Fountainhead remain popular in some regions, in part because they are easy to clean. Fusing the sink and countertop eliminates raised lips and the need for caulking, so there's never dirt caught in the crevices. Another type of countertop that's prevalent in 49127, Michigan, is tile. While it has a sharp, clean look, it wears easily and can be difficult to keep clean because the grout lines deteriorate. The surface is also very hard, and if you drop a dish or a glass even from an inch or two, it will almost certainly break.

20 days of military operations in Aleppo and Idlib: 1,133 persons killed, nearly 400,000 civilians displaced, and 93 areas fall to regime forces 20 days of military operations in Aleppo and Idlib: 1,133 persons killed, nearly 400,000 civilians displaced, and 93 areas fall to regime forces The recent escalation of regime and Russian operations in both Idlib and Aleppo within the so-called “de-escalation” zone has accomplished its 20th consecutive day. Over the recent 20 days, the Syrian Observatory for Human Rights monitored the significant developments seen in the area of killing, displacement, destruction and shifts on the map of powers and influence. During the period between the 15th of January 2020 and the 4th of February 2020, SOHR activists documented the displacement of nearly 400,000 Syrian civilians from tens of cities, towns and villages within the southern and western countryside of Aleppo and the southern, eastern and south-eastern countryside of Idlib. This mass displacement comes as Syrian regime and Russia follow systematic policy to force civilians to flee their areas by stepping up aerial and ground bombardment, so that they can capture more areas. The problem now is that these people have no place to be sheltered in, if the regime forces advanced further into Idlib city which is the biggest residential community ever within a single area with 700,000 to 1,000,000 persons in. Most of the displaced people headed to the north-western countryside of Idlib near the Syrian border with Iskenderun, while some others headed to areas under control of the Turkish forces and their proxies in rural Aleppo. Some others try to infiltrate to the Turkish territory after paying large amounts of money to smugglers. Humanitarian catastrophe is continuing to deteriorate amid International Community’s inaction towards crimes by the Syrian regime and Russians against civilians in camps and those who are searching for a new safe haven. Turkey, the “de-escalation” guarantor, has had enough with mere publicity that polishes it as being an actor sympathetic towards the humanitarian catastrophe. Meanwhile, the Turkish border guard forces “Jandarma” continue to target and kill the Syrians who try to infiltrate into the Turkish territory. During the past 20 days, Observatory activists documented gross human losses reached 1,133 fatalities among civilians, soldiers, rebels and jihadis as a result of the intense aerial and ground bombardment, attacks, detonations and fierce battles in both Aleppo and Idlib. 47 children and 29 females among 135 civilians were killed in airstrikes by regime and Russian aircraft and ground fire on Idlib and Aleppo countryside, they were distributed as follows: By Russian jets: 94 civilians, including 37 children and 19 females By regime helicopters: three civilians, including one female By regime jets: 17 civilians, including eight children and four females By regime ground shelling: four civilians By factions ground shelling on regime-held areas in Aleppo city: 17 civilians, including two children and five females. 395 jihadis among 522 opposition fighters were also killed during the same period due to regime and Russian aerial and ground strikes and clashes, in addition to the killing of 476 regime soldiers and loyalists, including ten members of non-Syrian nationalities, as a result of attacks, detonations and clashes against opposition factions and jihadi groups. Backed and supervised by the Russians, regime forces launched a wide-scale military operation in both Idlib and Aleppo on January 24. This operation came under a cover of intense aerial and ground firepower represented by thousands of airstrikes, barrel bombs, rockets and artillery shells, which enabled the regime to capture 93 areas. In Idlib, regime forces captured 84 villages and towns: Telmans, Ma’ar Shmasha, Deir Sharqi, Deir Al-Gharbi, Ma’ar Shmarin, Ma’rata, Al-Ghadfa, Ma’ar Shourin Al-Za’alana, Al-Dana, Tal Sheikh, Sawami’e, Khirbet Mezyan, Masaran, Bsida, Taqana, Babolin, Kafr Bassin, Marhatat, Hamidia, Dar Al-Salaam, Salhia, Kafruma, Maarrat Al-Nu’man city, Wadi Al-Daif, Hantutin, Al-Jarrada, Al-Ruwayha and Al-Qahiryah, Khan al-Sobol town, Mardebseh, Al-Hartamiyah, Qamhana, Abu Juraif, Tal Khatrah, Tal Musaytif, Al-Kana’es, Karsyan, Hish, Kafr Mazdah, Jabbalah, Muqah, Al-Amudiyah, Armanya, Kafr Batikh, Dadikh, Luf, Anqarati, Jubas, Sannan, Zakkar, Tarnabeh and Al-Nayrab, Mardikh, Tal Mardikh, Kaddur, Al-Ruwayha, the Abandoned Battalion, Al-Balisah, Al-Wasitah, Kuwayris, Tal Al-Agher, Al-Mushayrafah, Tawil Al-Halib, Al-Raqim, Jadidat Al-Khatrah, Sheikh Idrees, Baj’as, Al-Rayyan, Tal Al-Rumman, Parisa, al-Hammamat, Tal al-Sultan, Om Sharshuh, al-Khashakhish, Tal Ibrahim, Jabal al-Taweel, Mas’adah, Ras Al-Ain, Shuha, Kafr Amim and Tal Rihan). Meanwhile, regime forces managed to take control of more nine areas in Aleppo: Khan Tuman, warehouses of Khan Tuman, Al-Khalidyah, Rajam, Hazmer Hills, Kherbet Kharas, Tal Al-Zaytun, Maarata, Al-Rashideen fifth sector and other positions and hills in both southern and western countryside of Aleppo. The regime forces advanced into all of these areas despite the recent Turkey’s movements and Turkish forces deployment in new areas.

Controlling the position of functional groups at the liquid/solid interface: impact of molecular symmetry and chirality. With the aim of controlling the position of functional groups in a substrate-supported monolayer, a new family of functionalized linear alkyl chains was designed and synthesized, aided by molecular mechanics and dynamics simulations of its two-dimensional self-assembly on graphite. The self-assembly of these amino functionalized diamides at the liquid/solid interface was investigated with scanning tunneling microscopy. Intermolecular hydrogen-bonding interactions involving amides, combined with the effect of molecular symmetry and chirality, were found to guide the self-assembly. Control of the relative position and orientation of the amine groups was achieved, in the case of enantiopure compounds. Interestingly, racemates led to both racemic conglomerate and solid solution formation, with a concomitant loss of positional and orientational control of the amino groups as a result.

Also: How Powerful Will the Tea Party be in 2012? On balance, do you think that divided government is good or bad? “In theory, it should be good and foster compromise, but House Republicans have shown they are incapable of flexibility and reason.” “If Republicans controlled everything it would be a total disaster.” ADVERTISEMENT “Can you imagine how bad things could be if the tea party controlled everything? Pre-WWII Italy comes to mind!” Bad “Divided government is proving to be a bad deal for the American people right now. But it doesn’t have to be this way.” “Democrats got the job done.” “You gotta be kidding! What about the 112th Congress is not clear?” “Track dollars donated to campaigns, however, and you’ll find there is truly little division in government. Wall Street sees no division here in Washington, as both parties are steadfastly in their pockets. Campaign finance reform anyone?” “Too much male chicken game going on here: The old-timers used to work it out. Now, the show horses are in charge.” Don't Miss Today's Top Stories Sign up form for the newsletter “No one is then accountable to the country.” “Bad when partisanship is so extreme.” “Bad this term.” Depends; neither “It’s certainly better than when Republicans run everything. Divided government can produce results, but it requires both sides to be willing to compromise—something we don’t see now in the Republican Party.” “Divided government is good if the alternative is full Republican control and bad if the alternative is full Democratic control.” “I’ve seen divided government when it’s been good, and I’ve seen it when it’s been bad. If the two sides in a divided government are committed to working to build consensus and find the middle on difficult issues, that divided government has the potential to be very good. That dynamic is not the one we’re witnessing today.” “Divided, OK. Dysfunction, no-no.” “There are times when divided government has moderated excesses and produced a positive policy blend. At present, however, with deep polarization and the Republicans beholden to their most extreme elements, it is dysfunctional and dangerous.” “Divided government can work if both sides are willing to compromise. Unfortunately, the House Republicans will not.” On balance, do you think that divided government is good or bad? Republicans (30 votes) Good: 77% Bad: 17% Depends; neither (volunteered): 7% Good “Parties get too arrogant when they control all branches.” “But it requires politicians to compromise. That is hazardous to one’s political survival these days. The politicians aren’t the problem with respect to compromise—the voters are.” “There’s a difference between a divided government and a divisive one. Most independents and rational people are OK with a somewhat-divided government so that real leaders can seek out balance and compromise. We saw what the Democrats did with full control of all three levers of government: an extreme agenda on spending and programs that caused serious backlash and brought in the GOP House.” “Good in theory, not always good in practice.” “The current so-called gridlock is simply the Republicans providing a firewall to keep [the Democrats from] digging us into fiscal oblivion. Just look back at the past totally controlled by a Dem Congress for proof.” “But history has proven that both options have had good and bad moments.” “We have a divided government by design. Our two-party system coupled with a bicameral legislature creates a bottleneck for a lot of bad legislation and gives us the opportunity to undo harmful laws.”

Q: Hive on Spark: Missing I'm running Hive 2.1.1, Spark 2.1.0 and Hadoop 2.7.3. I tried to build Spark following the Hive on Spark: Getting Started: ./dev/make-distribution.sh --name "hadoop2-without-hive" --tgz "-Pyarn,hadoop-provided,hadoop-2.7,parquet-provided" However, I couldn't find any spark-assembly jar files under the spark directory (find . -name "spark-assembly*.jar" returns nothing back). Instead of linking the spark-assembly jar to HIVE_HOME/lib, I tried export SPARK_HOME=/home/user/spark. I get the following Hive error in beeline: 0: jdbc:hive2://localhost:10000> set hive.execution.engine=spark; 0: jdbc:hive2://localhost:10000> insert into test (id, name) values (1, 'test1'); Error: Error running query: java.lang.NoClassDefFoundError: scala/collection/Iterable (state=,code=0) I think the error is caused by missing spark-assembly jars. How could I build / Where could I find those spark-assembly jar files? How could I fix the above error? Thank you! A: First of all, Spark will not build spark-assembly.jar from 2.0.0, but build all dependency jars to directory $SPARK_HOME/jars Besides, Hive does not support every version of Spark, actually it has a strong version compatibility restrictions to run Hive on Spark. Depends on which version of Hive you're using, you can always find out the corresponding Spark version in pom.xml file of Hive. For Hive 2.1.1, the spark version specified in pom.xml is: <spark.version>1.6.0</spark.version> As you already know that you need to build spark without hive support. I don't know why but the command in Hive on Spark - Getting Started does not work for me, finally I succeeded with following command: mvn -Pyarn -Phadoop-2.6 -Dscala-2.11 -DskipTests clean package And few other troubleshooting tips which I met before(Hope you're not going to meet): Starting Spark Master failed due to failed to find slf4f or hadoop related classes, run export SPARK_DIST_CLASSPATH=$(hadoop classpath) and try again Failed to load snappy native libs, which is caused by that there's no snappy dependency in classpath, or the snappy lib under hadoop classpath is not the correct version for Spark. You can download a correct version of snappy lib and put it under $SPARK_HOME/lib/, and run export SPARK_DIST_CLASSPATH=$SPARK_HOME/lib/*:$(hadoop classpath) and try again. Hope this could be helpful and everything goes well to you.

Q: C++ Virtual Destructor with Unresolved externals I have two classes.. template <class T> class Node { protected: Node() = default; virtual ~Node() = 0; Node(const T& data) noexcept; Node(const Node<T> & copy) noexcept; Node(Node<T> && copy) noexcept; Node<T> & operator=(const Node<T> & rhs) noexcept; Node<T> & operator=(Node<T> && rhs) noexcept; public: T & GetData() noexcept; T GetData() const noexcept; void SetData(const T & data) noexcept; private: T data_; }; template<class T> class ListNode : public Node<T> { public: ListNode() = default; ListNode(const T& data, ListNode<T> * next = nullptr, ListNode<T> * previous = nullptr) noexcept; ListNode(const ListNode<T> & copy) noexcept; ListNode(ListNode<T> && copy) noexcept; ~ListNode() override = default; ListNode<T> & operator=(const ListNode<T> & rhs) noexcept; ListNode<T> & operator=(ListNode<T> && rhs) noexcept; ListNode<T> * GetNext() noexcept; ListNode<T> * GetPrevious() noexcept; void SetNext(ListNode<T> * const next) noexcept; void SetPrevious(ListNode<T> * const previous) noexcept; private: ListNode<T> * next_; ListNode<T> * previous_; }; I get an "1 unresolved externals" error. In my previous experience this would usually mean something is wrong with virtual, override, or something like that. I've messed around with this code but can't make the error go away. Any advice? A: Derived destructors always implicitly invoke the base destructor at the end of their execution. You have code that is trying to invoke an abstract function. You need to give ~Node() a definition with an empty function body: virtual ~Node() {};

{ "name": "thread-list", "version": "0.1.0", "main": "./lib/main", "description": "View threads using React", "license": "GPL-3.0", "private": true, "engines": { "nylas": "*" } }

Q: play framework 2 promise status In play 2.1 I can execute a block of code asynchronously with Akka like this: Promise<Integer> promiseOfInt = Akka.future( new Callable<Integer>() { public Integer call() { return intensiveComputation(); } } ); How I can get status of this operation? For example: started, performed, completed, etc? A: There are three callbacks you could use onSuccess, onFailure and onComplete. See the "Callbacks" section here: http://doc.akka.io/docs/akka/2.1.0/scala/futures.html

v a prime number? False Suppose -206 = -t + 33. Is t prime? True Let d(z) = -11*z**3 + 3*z**2 + 7. Let m be d(-3). Suppose -2*o = 4*n - 158, 5*n - m = -4*o - 0*n. Is o a composite number? False Suppose -u - 2*u - 3 = 0. Let l be (3 - (4 + -2)) + u. Suppose l = 2*x - 3*i - 2 - 47, -4*i + 111 = 5*x. Is x composite? False Let z(c) = -c**3 - 5*c**2 - 6*c - 4. Let j be z(-4). Suppose j*k - 5*k = -45. Suppose k - 158 = -y. Is y a prime number? True Let x(o) = -81*o + 2. Is x(-1) a composite number? False Let b be (3 - -13)/((-4)/(-30)). Let u = -65 + b. Is u a prime number? False Let r = 1050 - 679. Is r prime? False Let o = 76 - -465. Is o composite? False Suppose 8 = 3*h - 4. Is (-19)/(-3 + h + -2) composite? False Suppose 4*q = -0*q + 136. Suppose 2*l + 8 = q. Is l a composite number? False Is 52*(1/4 - -3) composite? True Let z(r) = 4*r**2 + 0*r**2 - 3*r**2 - 6 - 4*r. Is z(11) a prime number? True Let i be 8 - (-2 - (1 - 1)). Let v = i + -7. Suppose 0 = -z - 2*z - 5*s + 43, -4*z = v*s - 39. Is z a composite number? True Let x(u) = u + 15. Let s be x(-7). Is 4/s + 105/2 prime? True Let n(h) = -419*h**3 + h**2 + h - 1. Is n(-2) composite? True Let w(g) = -g**3 - 6*g**2 + 6*g + 9. Is w(-8) a composite number? False Let j = 6 - 14. Let p(n) = -n - 4. Let w be p(j). Suppose -d = 2*o - 113, w*o = -d - 0*d + 229. Is o a composite number? True Let l(p) = p**3 - 5*p**2 + 6*p - 2. Let m be l(5). Suppose -m = 3*v - 5*v. Is v a composite number? True Let s be (-1815)/(-9) - 1/(-3). Suppose -4*x + w + s = 0, -4*w + 247 = 5*x - 16. Is x prime? False Suppose 5*j = 6*r - 4*r + 4, 5*j + 10 = -5*r. Let s = -9 - j. Is (-3)/s*3*21 composite? True Let h(x) = x**3 + 8*x**2 - 8*x + 13. Let n be h(-9). Suppose -n*k + 1876 = -0*k. Is k prime? False Let m be 2/(-6) + (-150)/9. Let n = 2 - m. Is n composite? False Suppose 0 = -5*m + q + q + 58, q - 6 = -m. Let d(i) = 11 - 11*i**2 - 15*i**3 + 12*i**3 + 4*i**3 + 10*i. Is d(m) a composite number? False Suppose -q = 7*q - 23368. Is q prime? False Let i(y) = 4*y**2 - 8*y. Let h be i(7). Suppose 0 = 4*f - 8*f + h. Is f prime? False Let l(c) = -c**2 + 2*c + 7. Let b be l(5). Let n(i) = -i**3 - 5*i**2 + 4*i + 3. Is n(b) a prime number? True Suppose 3*b = -0*b - v + 4, 3*b = 5*v + 34. Let s(j) = j + 5. Let g be s(4). Suppose 0 = b*q - g, 0*y - 3*q = 4*y - 517. Is y a composite number? False Let h(o) = -2 - 8 - 3*o**2 + 5*o + 10*o**2 - o. Is h(4) prime? False Let z = 0 - -1. Is 3 - z - -95 - 2 composite? True Let q(x) be the first derivative of x**3/3 - 5*x**2/2 + 3*x + 2. Let h be q(5). Let g(m) = 2*m. Is g(h) a composite number? True Let v = -6 + 6. Suppose 0 = -v*b + 3*b - 309. Is b composite? False Is (-199)/(-3) + 2/3 prime? True Suppose -5*k + 0*k - 715 = 0. Suppose -6*g + g = 1050. Let h = k - g. Is h composite? False Suppose 0 = -0*p + 4*p - 20. Let m be ((222/(-1))/(-3))/2. Suppose p*k - 28 - m = 0. Is k a composite number? False Let y(x) = -x**2 - 9*x + 4. Let i be y(-11). Let q be i/15*15/(-2). Let n = 13 + q. Is n a prime number? False Suppose 5*u = -2*b + 9541, -31527 = -5*b - u - 7617. Is b composite? False Let c(k) = 3 - 4*k**3 - k**2 + 4*k - 5*k - 2. Let b be 8/20 - 12/5. Is c(b) composite? False Let r be (-130)/(-18) + 2/(-9). Suppose -f + 10 = r. Suppose -242 = -3*i + 5*x, -4*x - 293 + 55 = -f*i. Is i prime? False Let g be ((-16)/6)/(10/(-45)). Suppose -2*i = i - g. Suppose -i*c + u = -41, -c - 4*u + 6 = -0*c. Is c prime? False Let w = 85 - 19. Suppose 26 = -4*i + w. Is i a prime number? False Let q be (-30)/12*(1 + -3). Suppose -3*w + q*m + 127 = 0, -m = 5*w - 0*w - 193. Is w a composite number? True Suppose -5*w - 4401 = -12676. Is w prime? False Suppose 3*b - 398 = -2*g - 0*g, 398 = 2*g + b. Is g a prime number? True Let r = -4 + 6. Suppose -r*x - 830 = -7*x. Is x composite? True Let b(p) = 30*p + 7. Is b(4) a composite number? False Let d be (1 - 0/(-2))*-1. Is 0/(-3) + d + 12 composite? False Let p be -1*2 - (-492)/3. Suppose -3*m = -3*j - m - 105, -5*j - m - p = 0. Let r = -20 - j. Is r a composite number? False Let f be 0*(-1)/(0 + -1). Suppose -52 = g - 5*g. Suppose j = -f*j + g. Is j a prime number? True Let g(n) = 39*n + 8. Let w be g(6). Suppose -6*h + w + 448 = 0. Is h composite? True Let a(l) = 87*l**2 + 4*l - 9. Is a(4) prime? True Suppose -v - 156 = 3*f - 5*f, f = -v + 75. Is f composite? True Let z(g) = -g**3 + g**2 + 5*g + 6. Let v be z(5). Let k be (4/(-5))/((-4)/730). Let q = v + k. Is q a prime number? False Suppose 0 = 5*y - 29 - 506. Let t = -64 + y. Is t composite? False Is (2122/4)/((-2)/(-4)) prime? True Let q = 399 + 52. Is q a prime number? False Let x = 732 - 439. Is x a prime number? True Let a(k) = k**3 + 5*k**2 + 2*k - 1. Suppose 0 = -5*t - 3*j + 26, 4*t + 4*j - 7 = 17. Suppose -t*x + 3*x - 2 = 0. Is a(x) a composite number? False Let k(x) = x - 1. Let i be k(-4). Let z = i - -3. Is (z + 21/9)*57 a composite number? False Is (-10)/(-25) - (-588)/5 prime? False Suppose 0*m - 22 = m. Let v = m - -36. Is v prime? False Let d(y) be the third derivative of y**5/60 - y**4/2 + 7*y**3/6 + 3*y**2. Let c be d(11). Is (-2)/c*(-3 + 47) prime? False Suppose b - 15 = -2*b. Is b/(50/6)*5 a composite number? False Let g be 5*(-3)/(-30)*54. Suppose -3*i = -0*i - 3. Suppose i = -2*h + g. Is h a composite number? False Let i(c) = -c**3 + 12*c**2 + c + 8. Let r be i(9). Suppose r = 2*n + 24. Is n composite? True Let l(w) = w**2 - 9*w + 3. Is l(13) composite? True Suppose 6*k = k + 265. Suppose -159 - k = m. Let a = m + 447. Is a a composite number? True Let f be (-272)/(-44) + (-2)/11. Suppose 0*r - 5*o - 42 = -2*r, 3*o = f. Suppose 2*b - r = 20. Is b composite? False Let b = 133 - 36. Is b composite? False Let v = 885 - -872. Is v composite? True Let t be 53*3*-1 + 0. Suppose 0 = 5*c - c - 36. Is (6/c)/((-2)/t) a composite number? False Suppose 4*w = -5*j + 593, -5*j + 0*j = 2*w - 309. Is w prime? False Suppose 167 = -h - 30. Suppose 5*o = 5*w - 655, o - 4*w + 18 = -110. Let i = o - h. Is i composite? True Suppose 8*a - 87 = 5*a. Is a/2*(-1 + 7) composite? True Let n(p) = -157*p**3 + 3*p**2 - 2*p + 3. Let c be 5/1 + -1 + 0. Let l(s) = 471*s**3 - 8*s**2 + 5*s - 8. Let a(d) = c*l(d) + 11*n(d). Is a(1) a prime number? True Suppose 4*g = 1952 + 1044. Is g a prime number? False Let o = -6 + 16. Suppose -15 = g + 3*u, 4*u = 5*g + 6*u + o. Suppose -3*t = -g*d - 3*d + 912, -5*t + 888 = 3*d. Is d composite? True Let q = 107 - 54. Suppose -3*v + 46 = -q. Is v composite? True Suppose 5*g = 3*o - 3, -7*g + 3*g + 4*o - 4 = 0. Let t(v) = -v + 13. Is t(g) a composite number? False Let f = 42 - 15. Suppose 0 = 5*t - 7 + f. Let x = 27 + t. Is x a composite number? False Suppose 0 = -3*p, 0*v - v = 3*p. Let n(f) = f - 74. Let y be n(v). Is y/5*1*-5 prime? False Let c = -25 - -36. Suppose 0 = -5*w + 1 - c. Let q = w - -69. Is q composite? False Is (4869 - -38) + (-4)/(-1) a composite number? True Is 3*907*(-6)/54*-3 a prime number? True Is (-11 + -4)*-1 + -1 a prime number? False Suppose g = 4*z + 346, g = -2*g - 5*z + 1123. Suppose 15 = 2*i + i. Is g/10 + 2/i a prime number? True Let d(y) = 28*y**2 - 5*y + 4. Is d(2) prime? False Is (331 - 3/2*2) + 3 prime? True Let y be 8/3*66/4. Suppose -y - 8 = -4*z. Is z composite? False Let m = 0 + 1. Let p be m + -3 + 2 + 2. Suppose -p*t - 2*u + 68 = 0, 3*u - 4*u - 32 = -t. Is t a prime number? False Let c(b) = 4*b**2 - 13*b + 4. Is c(9) prime? True Let c(a) = 2*a**2 - 2*a + 1. Let w be c(2). Let d = -2 - -6. Suppose w*k - 177 = -d*r, r = 5*k - 48 - 139. Is k composite? False Let k(l) = -65*l**3 - 2*l**2 + 1. Let y be k(1). Let m = -71 + 36. Let d = m - y. Is d composite? False Suppose -f = 2*i + 8, -2*i + 0*i = -f. Let d(g) = -2*g. Let a be d(i). Is 4/(-6)*(-282)/a a prime number? True Let t be (3 - 5) + (3 - 0). Suppose -t + 2 = c. Is (-44)/(-4)*1/c prime? True Let l(m) = m**3 - 4*m**2 - 2*m - 2. Let s be l(4). Let p be s/(-4)*(-2)/(-1). Suppose p*n - 140 = 25. Is n prime? False Suppose 3*a = -3*t - 18, 0*a + 3*a - 2*t = -38. Let h be (-123)/2*a/15. Suppose -4*f - 33 = 5*p - 87, -h = -4*p - f. Is p a composite number? True Let p be -10*(-1 + 14 + -3). Let d = p + 219. Is d a prime number? False Let r(l) = l**3 - 4*l**2 - 10*l + 7. Suppose -37 = -4*k - 13. Is r(k) prime? Tru

Almost everything she owned was in the van parked on Northwest 23rd PORTLAND, Ore. (KOIN) — A woman getting ready to start a new chapter of her life in Eugene has been hit with a huge setback. Madeline McKee has experienced a lot of heartache in the past 3 years. “It’s a lot of memories and a lot of stuff to sort through and so I was going to my hometown to breathe,” McKee said. She borrowed a van from a friend, packed it up and was ready to drive south in the morning. But someone stole the van carrying almost all of McKee’s belongings from Northwest 23rd Avenue and Northwest Savier Street overnight Monday. Among the things stolen were McKee’s antique bed and matress, her dresser with all her clothes and shoes, a nightstand with her daughter’s passport inside, her computer and paintings her artist sister made. At the last minute, she also decided to pack photos of loved ones she has recently lost — her mother and son, Henry. An undated photo of Madeline McKee and her son. (Courtesy of McKee) “Today is 5 months since he died and next week is his birthday — he would have been 15,” McKee said. “I thought, you know, what else can I lose?” The one thing she thankfully decided to leave in storage was her son’s ashes. She said the van was locked and she didn’t see broken glass around where it was. “My guess is that [the thief] will feel bad but they probably felt pretty desperate,” McKee said. The van is a white, 4-door 1995 Ford E-250 with windows in the back but no side windows and no rear-view mirror. There is also a sticker on the back that says “Girl Power.” “It’s just stuff but, you know, it was really important to me,” McKee said.

A Mississippi man has been sentenced to 30 years in prison for shooting and killing his wife after an argument over heating a pizza. Rankin County District Attorney John Bramlett Jr. tells media outlets that 54-year-old John Preston Finch was sentenced Thursday on second-degree murder charges. Finch was convicted of shooting Amy Renee Stewart on Dec. 31, 2016. Authorities say sheriff's deputies arrived at a house near Pelahatchie to find the door open and a blood-covered Finch standing over Stewart's body. Finch showed officers a single-barrel shotgun, initially saying the gun fired by accident. He later told deputies he and Stewart argued over the pizza, and Finch shot her.

Q: how can I minimize the distance from a given input distribution? I have a list of customers and each of them can be "activated" in four different ways: n= 1000 df = pd.DataFrame(list(range(0,n)), columns = ['Customer_ID']) df['A'] = np.random.randint(2, size=n) df['B'] = np.random.randint(2, size=n) df['C'] = np.random.randint(2, size=n) each customer can be activated either on "A" or on "B" or on "C" and only if the Boolean related to the type of activation is equal to 1. In input i have the count of the final activations. es: Target_A = 500 Target_B = 250 Target_C = 250 The random values in code are an input for the optimizer and represent the possibility or not to activate the client in that way. How can I associate the client with only one of those in order to respect the final targets? How can I minimize the distance between the count of real activation and the input data? A: Do you have any tested examples? I think this might work but not sure: import pandas as pd import numpy as np from pulp import LpProblem, LpVariable, LpMinimize, LpInteger, lpSum, value prob = LpProblem("problem", LpMinimize) n= 1000 df = pd.DataFrame(list(range(0,n)), columns = ['Customer_ID']) df['A'] = np.random.randint(2, size=n) df['B'] = np.random.randint(2, size=n) df['C'] = np.random.randint(2, size=n) Target_A = 500 Target_B = 250 Target_C = 250 A = LpVariable.dicts("A", range(0, n), lowBound=0, upBound=1, cat='Boolean') B = LpVariable.dicts("B", range(0, n), lowBound=0, upBound=1, cat='Boolean') C = LpVariable.dicts("C", range(0, n), lowBound=0, upBound=1, cat='Boolean') O1 = LpVariable("O1", cat='Integer') O2 = LpVariable("O2", cat='Integer') O3 = LpVariable("O3", cat='Integer') #objective prob += O1 + O2 + O3 #constraints prob += O1 >= Target_A - lpSum(A) prob += O1 >= lpSum(A) - Target_A prob += O2 >= Target_B - lpSum(B) prob += O2 >= lpSum(B) - Target_B prob += O3 >= Target_C - lpSum(C) prob += O3 >= lpSum(C) - Target_C for idx in range(0, n): prob += A[idx] + B[idx] + C[idx] <= 1 #cant activate more than 1 prob += A[idx] <= df['A'][idx] #cant activate if 0 prob += B[idx] <= df['B'][idx] prob += C[idx] <= df['C'][idx] prob.solve() print("difference:", prob.objective.value())

Howard reveals black and white love In a revealing interview, far removed from plastic Geordies like Carrick, Charlton, Bruce and Robson (see the common Manchester United denominator...) Steve Howard has talked ahead of his visit to SJP on Monday with Leicester about his love for Newcastle. Howard follows Brian Laws and Lee Clark in recent games as boyhood fans returning to Gallowgate and said: 'I played there (at SJP) when I was with Derby when we were in the Premier League and it was an amazing experience. My whole family was there and it was a very special day for all of us. I had two main ambitions and I fulfilled them both, to play at Wembley, which I did with Derby in the play-off final, and to play at St James' Park. All my family are born and bred in Newcastle in the Byker area and they are all mad keen Newcastle fans. I had a season ticket for a couple of years but I eventually had to give it up when I started playing on Saturdays. My dad took me to my first game when I was probably about eight years-old. I don't remember much about it except I was stood in the Gallowgate End of the ground and the atmosphere was amazing. My hero in those days was Peter Beardsley and then later on it was Alan Shearer. They are legends. Beardsley had amazing skills. He could produce something out of nothing. He had this little shimmy and you knew what was coming but the defenders still couldn't stop him. I was lucky enough to play with him at Hartlepool and he was an amazing professional. I grew up hearing all the stories about the Newcastle number nines and of Super Mac who was my dad's favourite player. My dad used to say he was a proper centre forward who could score from anywhere and could beat defenders up. The supporters are the most passionate I have ever experienced. They turn up week in, week out and they live and die for their football. That is all they talk about in Newcastle. Everywhere you go the talk is of football and Newcastle. They really love the game that much. I should go back more often than I do because I always enjoy going back up there. I was devastated when they went down last season. For a club like Newcastle to go down just proved you can't take anything for granted in football. Just because you are a big club like Newcastle doesn't mean you can drop your standards. I really felt for the fans who buy their tickets every week. The one hope I have is that they will sort out their problems and bounce back stronger than ever. The potential is massive at the club and I believe one day they will fulfil that potential. I think they should appoint Shearer as manager. He is the man to take the club forward and get them back into the Premier League. He will sort it all out.'

Various techniques of etching resist-imaged photomasks, silicon wafers or other semiconductor materials have been used in semiconductor fabrication processes. A wet etching technique conducted in an immersion tank is a practical high-throughput, flexible fabrication process. By properly selecting etchant chemicals, etch reactions with the target film are thermodynamically favored over reactions with other films. Desirable etch-rate ratios can usually be obtained. A wet etching method is especially suitable for the blanket etching of polysilicon, oxide, nitride and metal. The method is capable of providing the necessary etch selectivity, a damage-free interface and particle-contamination-free wafers. In more recently developed wet etching technology, automated robotic handling systems and ultra-pure chemicals have been used to further improve particle control and process consistency. A well-controlled wet etching technique is therefore the choice of etching process in VLSI and ULSI fabrication processes. One of the key criteria in carrying out a wet etching process is that the etch products must be soluble in the etchant solution and therefore, no contaminating particles are generated. In an immersion etching process, the volume of the etching tank should be large enough to create enough pressure on the wafer surface in order to dislodge hydrogen gas bubbles evolved during etching reactions; to ensure an accurate balance of the etchant components; to keep the concentration of the etchant relatively constant; and to reduce the number of times the etchant tank must be changed in a production environment. An etchant bath change creates expensive down time, and furthermore, the handling of highly hazardous corrosive materials should be rinimized from a safety standpoint. Wet etching is a frequently used technique for stripping photoresist films from silicon wafers where a complete removal of the resist images without adversely affecting the wafer surface is desired. The resist layer or images should be completely removed without leaving any residues, including contaminant particles that may have been present in the resist. The underlying surface of the photoresist layer should not be adversely affected, for instance, undesirable etching of the metal or oxide surface should be avoided. Liquid etchant strippers should produce reasonable bath yield in order to prevent redeposition of dissolved resist on the wafers. The etchant should completely dissolve the photoresist layer in a chemical reaction, and not just lifting or peeling so as to prevent redeposition. It is also desirable that the etching or stripping time should be reasonably short in order to permit a high wafer throughput. Sulfuric acid (H.sub.2 SO.sub.4) and mixtures of H.sub.2 SO.sub.4 with other oxidizing agents such as hydrogen peroxide (H.sub.2 O.sub.2) are widely used in stripping photoresist or in cleaning a wafer surface after the photoresist has been stripped by other means. For instance, a frequently used mixture is seven parts H.sub.2 SO.sub.4 to three parts of 30% H.sub.2 O.sub.2, or a mixture of 88% sulfuric acid and 12% nitric acid. Wafers to be stripped can be immersed in the mixtures at a temperature between about 100.degree. C. and about 150.degree. C. for 5.about.10 minutes and then subjected to a thorough rinse by deionized water and dried by dry nitrogen. Inorganic chemical resist strippers, such as the sulfuric acid mixtures, are very effective in the residual-free removal of highly postbaked resist. They are more effective than organic strippers and the longer the immersion time, the cleaner and more residue-free wafer surface can be obtained. A typical wet chemical treatment system 10 is shown in FIG. 1. The system has a wet chemical holding tank 12 comprises an inner tank 14 and an outer tank 16. As shown in FIG. 1, the inner tank 14 is usually positioned inside the outer tank 16 and that the sidewall 18 of the inner tank is lower than the sidewall 20 of the outer tank. This allows an operating mode where the inner tank is usually filled first with an etchant chemical through inlets 24 and 26. Inlet 26 to the inner tank 14 also serves as a drain and is connected to drain control valve 28 such that liquid can be drained through outlet 32. Similarly, outlet 34 is connected to the bottom of the outer tank 16 to drain the liquid etchant contained in the outer tank through a drain control valve 36 and the outlet 32. The wet chemical treatment system 10 also includes a recirculating means 40 which has an inlet 42 for receiving a fluid from outlet 34 of the outer tank 16 through passageway 46, and an outlet 44 for feeding to filter means 50. A frequently used recirculating means suitable for the wet chemical treatment system is a mechanical pump that is specially outfitted for transporting corrosive fluids. In such a pump, any components that are in contact with the fluid being pumped is constructed of stainless steel, a corrosion-resistant polymeric material such as Teflon, or a metal coated with a corrosive-resistant polymeric material. The passage tubing 46, the drain control valves 28, 36, and the outlets 26, 34 are similarly constructed of corrosion-resistant materials. The wet chemical treatment system 10 further includes a filter means 50 and a heater means 60. The liquid being pumped by the recirculating means 40 through outlet 44 and passage tubing 52 into inlets 54 and 56 of the filter means 50. The filter means 50 is capable of filtering out particulate contaminants in the wet chemical, especially those of metal particles, such that any contamination of the wafer situated in process tank 14 can be avoided. The filtered wet chemical exits the filter means at outlets 48 and 58 to enter into the heater means 60. In most wet chemical treatment processes, either for cleaning or for etching, the wet chemical can be more efficient in its cleaning or etching function when the temperature of the chemical is raised to above ambient temperature. For instance, for most etching and cleaning processes, a temperature of between about 100.degree. C. and about 150.degree. C. is found to be most suitable. The wet chemical enters the heater through inlet 62 and exits at outlet 66 to return the wet chemical to the inner tank 14 through inlets 24 and 26. The inner tank 14 can be filled with fresh chemicals when needed through a filling means 72 controlled by a fill control valve 74. In the operation of a wet chemical treatment system such as that shown in FIG. 1, the system is normally mounted on a raised floor (or a removable floor) in a semiconductor fabrication facility. A typical mounting method for a wet chemical treatment system is shown in FIGS. 2A and 2B. After the treatment system 10 is positioned on a raised floor 30 with a bottom bracket 38 contacting the floor, the treatment system 10 is fastened to the raised floor 30 by a welded angle 64. The welded angle 64, frequently made of a corrosion-resistant metal, such as stainless steel, is attached to the side frame 68 of the treatment system 10 by bolts 70. Collars 76 are used to secure bolts 70 in their mounting position. The welded angle 64 is further attached to the raised floor 30 by bolts 78 through a horizontal flange 80 of the angle. The thickness of the welded angle or of any other anchoring metal plate should be at least 1 cm. The raised floor is normally fabricated of a grating of aluminum which has a smooth top surface and a corrugated back (not shown). The raised floor 30 may also be fabricated of any other suitable material that has the necessary rigidity and lightweight characteristics for easier removal and installation. The raised floor 30 is positioned on top of an I-beam 82 which is in turn positioned on top of a second I-beam 84. Normally, there is no fastening provided between the raised floor 30 and the top surface 86 of the I-beam 82. The I-beam 82 may be fastened to the second I-beam 84 by any suitable mechanical means such as by bolts, or by welding. The bottom flange 88 of the second I-beam 84 may be fastened to a concrete slab floor 90 by bolts 92. A side view of the welded angle 64 for the wet chemical treatment system 10 is shown in FIG. 2B. In the mounting method shown in FIGS. 2A and 2B, the wet chemical treatment system 10 is only secured to the raised floor 30 that is essentially supported by I-beams that are mounted to a slab floor. The conventional mounting method therefore does not meet the seismic prevention standard that is normally required in fabrication facilities which may be subjected to earthquake damages. The problem can be more serious when the wet chemical treatment system is mounted on a higher floor in a fabrication facility where the effect of an earthquake is more severe. For instance, one of such seismic prevention regulations requires that all equipment foot/frame anchoring mechanism and accessories must be designed to survive a force of 0.35 g.times.2.36, i.e., a force magnified for a 4.sup.th floor installation. It is therefore an object of the present invention to provide a method for mounting a process machine on a removable floor that does not have the drawbacks or shortcomings of the conventional mounting methods. It is another object of the present invention to provide a method for mounting a process machine on a removable floor that meets seismic prevention regulation for the containment of corrosive chemicals in a wet chemical treatment system. It is a further object of the present invention to provide a method for mounting a process machine on a removable floor in a semiconductor fabrication facility such that the process machine can survive earthquakes having a force of 0.35 g.times.2.36. It is another further object of the present invention to provide a method for mounting a semiconductor process machine on a removable floor in a fabrication facility by providing an I-beam equipped with an extended upper flange for supporting the removable floor. It is still another object of the present invention to provide a method for mounting a semiconductor process machine on a removable floor in a fabrication facility by providing an I-beam that is equipped with an extended upper flange for supporting the removable floor and for fastening by mechanical means to the process machine through the removable floor. It is yet another object of the present invention to provide a method for mounting a semiconductor process machine on a removable floor in a fabrication facility by utilizing a modified I-beam for supporting the removable floor and for mounting directly to the process machine. It is still another further object of the present invention to provide an earthquake-proof mounting fixture for mounting a process machine on a removable floor by utilizing an I-beam modified with an extended upper flange for supporting the removable floor and for attaching directly to the process machine through the floor. It is yet another further object of the present invention to provide an earthquake-proof mounting fixture for mounting a process machine on a removable floor by providing an I-beam modified with an extended upper flange for attaching to an L-shaped bracket mounted on the process machine through apertures provided in the removable floor.

Social Media Governing bodies of the International Hydrological Programme IHP Intergovernmental Council The planning, definition of priorities, and supervision of the execution of International Hydrology Programme (IHP) are ensured by the Intergovernmental Council. The Council is composed of 36 UNESCO Member States elected by the General Conference of UNESCO at its ordinary sessions held every two years. Equitable geographical distribution and appropriate rotation of the representatives of the Member States are ensured in the composition of the Council. Each of UNESCO’s six electoral regions elects Member States for membership in the Council. The term of office of members of the Council is four years, and members are immediately eligible for re-election. To retain continuity, only half of the Council members are elected each second year for the four-year period, so that in each biennium half are newcomers and the other half have already acquired experience. The Council normally meets in plenary session once every two years. Extraordinary sessions may be convened under the conditions specified in the Rules of Procedure. IHP Bureau At the beginning of its first session following a session of the General Conference at which elections to the IHP Council have been held, the Council elects a chairperson and four vice-chairpersons. These, with the chairperson of the previous Bureau as ex-officio member, constitute the Council’s Bureau. The composition of the Bureau so formed reflects an equitable geographical distribution, each representing UNESCO’s six electoral regions. The members of the Bureau remain in office until a new Bureau has been elected. The IHP Bureau discharges, inter alia, the following duties: fix, in consultation with the Secretariat, the dates of the sessions of the Council and of its committees and working groups, in accordance with the general guidelines of the Council; prepare the sessions of the Council, in consultation with the Secretariat; supervise the implementation of the resolutions of the Council, and report at each session of the Council, on the status of implementation of the prescribed phases of project execution and, in particular, follow the activities of the Council’s committees and working groups; prepare for the Council all reports requested by the General Conference of UNESCO;

Catawba College signs 5 year deal with Adidas 2015-01-19T22:25:10Z2015-01-19T22:25:11Z SALISBURY, NC (WBTV) - From Catawba College: Catawba College and adidas® announced a five-year partnership in which the Portland, Oregon, based company will be the official athletic footwear, apparel and accessory brand of the Indians through the 2019-20 season, according to a press release provided to WBTV. The partnership will be implemented in concert with BrandRPM, a top team athletic dealer in the Carolinas. "Catawba's rich athletic tradition and consistent success make them a perfect fit for the adidas family," said Rohn Mulkey, adidas Team Sales Executive. "Our long-term partnership with the Indians highlights our commitment to U.S. college athletics. Catawba joins an impressive list of adidas schools includingKansas, Texas A&M, UCLA, Louisville, and most recently signed Arizona State and the University of Miami. "adidas has shown a sincere commitment to Catawba Athletics that is commensurate with the hard work displayed by our student-athletes, coaches, and sports programs.," saidLarry Leckonby, Catawba Athletic Director. “We are also excited to work with BrandRPM to execute the partnership -- they are a definite leader in the team dealer space with a huge emphasis on quality, service, and turn times.” “This is a significant addition for BrandRPM," stated BrandRPM President David Anderson. "Catawba College has one of the strongest traditions of athletic and academic excellence in the state as well as the region. We look forward to being the go-to organization for Catawba College's 18 varsity sports, student athletes, coaches, and staff.” It’s almost impossible to write stories about Santa without fears of ‘ruining the magic’ for any child that may be watching. But we found a way with this one. A Gaston County USPS carrier has opened mailboxes on his routes and found dozens of letters to Santa in the past month.

GameStop – Preorder Twilight Princess HD For Free CD Nintendo has just announced that GameStop will be carrying an exclusive Twilight Princess music sampler CD that customers will get for free when they preorder the game. Online customers will receive the CD when the game ships and customers who reserve in the store will receive the CD at the time they pick up the game. No word yet on how many tracks the CD will have, or what the arrangements will be. As a reminder, The Legend of Zelda: Twilight Princess HD will launch exclusively on the Wii U on March 4, 2016. If you’d like to take advantage of this offer, click here to go to GameStop’s page. Craig has been covering the video game industry since 1995. His work has been published across a wide spectrum of media sites. He’s currently the Editor-In-Chief of Nintendo Times and contributes to Gaming Age. Like this: Related Craig Majaski Craig has been covering the video game industry since 1995. His work has been published across a wide spectrum of media sites. He's currently the Editor-In-Chief of Nintendo Times and contributes to Gaming Age.

Staff Training Days at the University of Lausanne : University and Society, 18-21 June 2019 The International Relations office of the University of Lausanne is glad to announce the UNIL Staff training Days 2019, from 18 to 21 June 2019 around the theme: University and Society Programme The UNIL Staff Training Days are intended for administrative staff of international relations offices (on central or departmental level) working in connection with others locally and internationally. The programme aims to provide the participants with the following: Discuss and reflect on the role of University in Society and cities Develop soft and communication skills through workshops Exchange good practices to facilitate mobility Discuss collaboration in or out of the present and future Erasmus Explore the state of Europe through a discussion and visit to the Foundation Jean Monnet for Europe Have an insight on Lausanne as the Olympic Capital Discover the University of Lausanne's campus and infrastructures The intended programme is below. Modalities The number of participants is limited to 20 with a maximum of 2 people per institution. The selection will be made according to two criteria:

GLENDALE, Ariz. -- The night Arizona Cardinals right tackle Bobby Massie was arrested on two charges of DUI and DUI BAC over .08, he drove to the team's practice facility in the early hours of Jan. 31, the day before Super Bowl XLIX, in search of his tickets for the game. Massie has been suspended three games for violating the league's substance abuse policy, but he is appealing the suspension. According to a report released by the Tempe Police Department, Massie's blood alcohol concentration that night was .136 after a night of drinking at Sandbar, a restaurant and bar with a location in Chandler, Arizona, about 1.7 miles from the Cardinals' facility. When officers arrived, the report stated Massie had watery and bloodshot eyes, and his speech was slurred. He was also "unsteady" during field sobriety tests, which he ultimately failed, according to the report. Cardinals right tackle Bobby Massie had a blood alcohol content level of .136, according to the Tempe Police Department. Ross D. Franklin/AP He told officers he was at the facility to pick up his Super Bowl tickets. The Cardinals did not have a comment about Massie's arrest. Throughout the night, Massie was confused about where he was, making comments and asking questions about being in Virginia, his home state, according to the report. An officer said he repeatedly reminded Massie he was in Arizona. According to the report, a team security officer called police at 2:58 a.m. about a suspicious vehicle after Massie drove his 2015 white BMW into the team's secure parking lot and did not get out of the car. The security guard did not recognize Massie's car, which at the time had temporary plates, and "was unsure who" Massie was, according to statements in the report from officers on the scene. When officer Michael McCormick arrived on the scene, he noticed what looked like tears on Massie's face, according to the report. Massie said they were "because his college roommate was going to play in the Super Bowl." Massie admitted to McCormick that "I mean, I am a little f----d up." Over the course of the arrest, Massie told officers "I know I f----d up," the report said. At 3:43 a.m., Massie was arrested for DUI and transported to Tempe City Jail. According to the report, Massie told officers that he had been "f----d up" every day for the past 10 years. The report said that comment referred to alcohol but Massie told officers he does not have a drinking problem. He told officers he smoked marijuana but couldn't recall the last time he did. According to the report, Massie grew increasingly angered during processing, at one point yelling at an officer about "playing football" and asking that officer if he wanted to "play football." Massie was released around 5:40 a.m. in front of the Tempe City Jail to wait for a cab, the report said.

Philosophy CarboneJS is a powerfull templating engine which works in all XML-based document. It can also convert your report to reliable PDFs and any other document formats. It uses a simple declarative programming language, which is not intrusive. You don't need to insert control flow code in your document such as if or for-loop markers. In computer science, declarative programming is a programming paradigm, a style of building the structure and elements of computer programs, that expresses the logic of a computation without describing its control flow.[1] Many languages applying this style attempt to minimize or eliminate side effects by describing what the program should accomplish in terms of the problem domain, rather than describing how to go about accomplishing it as a sequence of the programming language primitives[2] (the how being left up to the language's implementation). This is in contrast with imperative programming, in which algorithms are implemented in terms of explicit steps. source This way of programming provides more flexibility for travelling data. You can transform your orginal JSON array directly in the template. See examples: Moreover, the system is XML-agnostic. It means the template engine works on any valid XML-based documents, not only XML-documents created by Microsoft Office™, LibreOffice™ or OpenOffice™. CarboneJS finds automatically repetition patterns in your template. How it works? CarboneJS finds all markers {} in your document (xls, odt, docx, ...) and replaces these markers by datas. According to the syntax of your markers, you can make a lot of operations including Replacing a field Formatting data Repeating a document portion (a table row or anything else) Looping on unlimited nested arrays Conditionally displaying a data based on a test expression The syntax is easy to learn. It is like using a JSON Array or Object in Javascript. Combined with features of LibreOffice™ or MS Office™, you can easily create documents with: Graphics Headers, footers Automatically repeated table header across pages Insert computed field Page count ... How to read this documentation? This documentation is made for report designers. There are five parts sorted by level of complexity. Substitutions Each part of this documentation shows exactly what happens if you send Data (JSON Object) and a Template (handmade docx, odt, ...) to CarboneJS. Basic This is the most basic example. Do I need to explain it? Data { "firstname" : "John", "lastname" : "Doe" } Template Hello {d.firstname} {d.lastname} ! Result Hello John Doe ! Accessing sub-objects Of course, if your data contains sub-objects, you can access them using the Dot Notation to go deeper in the object tree. Data { "firstname" : "John", "type" : { "id" : 1, "name" : "human" } } Template {d.firstname} is a {d.type.name} Result John is a human Accessing arrays When data is an array of objects, you can access directly each object using the reserved word i, which represents the ith item of the array. CarboneJS uses zero-based arrays. The first item of an array is i=0. Data Template The movie of 1999 was {d[year=1999, meta.type="SF"].name} Result The movie of 1999 was Matrix Alias Aliases can be used to simplify the maintenance of your report avoiding code repetition or to insert markers somewhere in the document where special characters like square brackets are not allowed (worksheet names for exemple). Write {#... = ...} to define an alias Write {$...} to use this alias Aliases can be defined anywhere in the document, at the end, or at the beginning. They are parsed and removed by CarboneJS before rendering. Data { "name" : "Cars", "wheels" : 4 } Template {#myAlias = d.wheels} {d.name} need {$myAlias} wheels! Result Cars need 4 wheels! Parametrized Alias Aliases accept unlimited number of parameters between parentheses, like a function in many languages. Each parameter must start by $. Data Template {#mealOf($weekday) = d[weekday = $weekday].name} Tuesday, we eat {$mealOf(2)}. Result Tuesday, we eat fish. Repetitions CarboneJS can repeat a section (rows, title, pages...) of the document. We don't need to describe where the repetition starts and ends, we just need to design a "repetition example" in the template using the reserved key word i and i+1. CarboneJS will find automatically the pattern to repeat using the first row (i) as an example. The second row (i+1) is removed before rendering the result. Data Template {d[i].brand} Models {d[i].models[i].size} {d[i].models[i+1].size } {d[i+1].brand} Result Toyota Models Prius 2 Prius 3 Tesla Models S X As you may notice, it is useless to repeat completely the first paragraph twice in the template, only the title of the second paragraph is necessary to help CarboneJS detect where the repetition pattern of the main array ends {d.cars[i+1].brand}. Data Template Vehicles {d[type].brand} {d[type+1].brand} Result Vehicles car plane Iterate on multiple items In the previous example, only distinct rows were kept. If we want to keep all rows, and sort them by type in ascendant order, we can add the reserved iterator i. CarboneJS accepts multiple iterators separated by a comma. Conditioned output By default, condition formatters have a special behavior, the formatter's result is not propagated to the next formatter if the result of the condition is true. This enables test chaining You can change this behavior by setting the optional parameter continueOnSuccess. If continueOnSuccess=true, the result of the formatter will be passed to the next formatter like in the last line of the example below.

<div id="aboutme"> {% if AVATAR %} <p> <img width="100%" class="img-thumbnail" src="{{ SITEURL }}/{{ AVATAR }}"/> </p> {% endif %} {% if ABOUT_ME %} <p> <strong>{{ _('About') }} {{ AUTHOR }}</strong><br/> {{ ABOUT_ME }} </p> {% endif %} </div>

Tag: Nuns The Sisters of the Valley are “self-ordained” nuns that grow marijuana/hemp in California and sell cannabis based products. Last year, Christine Meeusen and 6 other members of the order claimed $750,000 in sales last year. Their best year since they started in 2015. The Sister’s mission is to empower women and provide what they call medical and healing products. What I think is perhaps more interesting than the fact that these nuns grow marijuana/hemp and sell cannabis based products, is that they are anti-religion. “We’re against religion, so we’re not a religion. We consider ourselves Beguine revivalists, and we reach back to pre-Christian practices.” Meeusen’s sister Kate told NBC. These nuns make it clear, despite their monikers, that they are not an order of the Catholic church. I’ve always held the position, as an agnostic, that I respect people’s belief in a higher power. In fact, I think people are better off believing in a higher power. My objection to religion has never been based merely on someone’s spiritual beliefs, but rather the oppressiveness of the religion that is attached to those beliefs. So these nuns are both confusing and intriguing to me. I’m not sure how you can be a nun and profess that you not only do not belong to a religion but also are anti-religion. It’s quite fascinating and it makes you think. (Well, it makes me think.) I think if more people renounced their religions and concentrated more on their relationship with whatever they perceive God to be, then the grip of religious-based oppression would weaken across the world. According to Lifeteen.org, a christian blog that aims to perpetuate the anti-progressive teachings of an ancient religion to children, claims that Marijuana is evil and you shouldn’t do it. Big surprise there. I never understood why the church was so against marijuana. Anti-marijuana rhetoric propagated by the church helped in creating a voodoo pharmacology based propaganda effort to subdue society into thinking it was evil. This fortifies a moral foundation that ultimately leads to the suppression of individual liberty. Did anyone in the church stop and think that maybe God wanted you to use this plant? The Sisters of the Valley did, and these nuns are pretty cool in my book.

Fullerton junior high teacher charged with molesting students Melissa Lindgren, 28, who taught at Nicholas Junior High School in Fullerton, faces multiple felony counts for allegedly assaulting three boys she met at the school. Melissa Lindgren, 28, who taught at Nicholas Junior High School in Fullerton, faces multiple felony counts for allegedly assaulting three boys she met at the school. (Orange County district attorney's office) Adolfo Flores A Fullerton junior high school math teacher was charged Tuesday with sexually assaulting and sending sexual text messages to three students. Melissa Lindgren, 28, who taught at Nicholas Junior High School, faces multiple felony counts on charges of assaulting three boys between the ages of 13 and 15 she met at the school, the Orange County district attorney's office said in a statement. The La Mirada resident is accused of sexually touching and kissing one boy while in a classroom, a second boy on the school campus and a third student in her car. Prosecutors said the crimes occured over a two-year period, ending this year. Prosecutors said Lindren also send sexual text messages to all three boys. Lindgren was arrested Feb. 21 after one of the victims came forward and the Fullerton Police Department launched an investigation. Lindgren is charged with five felony counts of lewd acts on a child, two felony counts of lewd acts on a child under 14 and three felony counts of distributing pornography to a minor. She faces a sentencing enhancement allegation for lewd acts on multiple children. If convicted she faces a maximum sentence of 16 years and four months in state prison, prosecutors said. Lindgren is free on $100,000 bail and is scheduled to be arraigned Wednesday morning.

Q: AutoHotkey - Zip called as a part of a path 1. I am in a certain folder called "2" where are different kind of files and the path looks like this: "C:\Users\Me\Desktop\Named_Folder\1\2" I want to put all those files in there in a Zip and how should the script look like so at the end the Zip would be called "Named_Folder", the same as the folder in the path ? Need to mention that the "Named_Folder" will have different name each time. So how to name the zip as two directories above. 2. Till now I have just found the script to put all those files in a zip: #IfWinActive ahk_class CabinetWClass Send ^a ; Select All Send, {AppsKey} ; Press the "context menu" key Sleep 100 Send n ; Select "Send to" with the "n" key Sleep 100 Send {Right} ; Open "Sent to" with the "right arrow" key Sleep 100 Send {Down} ; Select "Compressed (zipped) folder" with the "arrow down" key Sleep 100 Send {Enter} ; Execute "Compressed (zipped) folder" with the "Enter" key return And how the script should look like to combine the 1. and the 2. step ? With one letter shortcut. So at the end the result should look like this: Example 3. And then I would like to combine below two scripts (F2 F3 or even F1 if it changes anything) with one letter shortcut (4 first lines are from default AHK file): #NoEnv ; Recommended for performance and compatibility with future AutoHotkey releases. ; #Warn ; Enable warnings to assist with detecting common errors. SendMode Input ; Recommended for new scripts due to its superior speed and reliability. SetWorkingDir %A_ScriptDir% ; Ensures a consistent starting directory. #If WinActive("ahk_class CabinetWClass") ; explorer F1:: for window in ComObjCreate("Shell.Application").Windows try Fullpath := % window.Document.Folder.Self.Path ; IfExist, %Fullpath%\1\ Run, %Fullpath%\2 return F2:: for window in ComObjCreate("Shell.Application").Windows try Fullpath := % window.Document.Folder.Self.Path ; IfExist, %Fullpath%\1\2\ Run, %Fullpath%\1\2 return #If #IfWinActive ahk_class CabinetWClass F3:: for window in ComObjCreate("Shell.Application").Windows try Fullpath := % window.Document.Folder.Self.Path if (SubStr(Fullpath, -3) = "\1\2") { StringReplace, Fullpath, Fullpath, :, StringTrimRight, Fullpath, Fullpath, 4 StringSplit, folder_array, Fullpath, \, MsgBox, % folder_array%folder_array0% Send ^a ; Select All Send, {AppsKey} ; Press the "context menu" key Sleep 100 Send n ; Select "Send to" with the "n" key Sleep 100 Send {Right} ; Open "Sent to" with the "right arrow" key Sleep 100 Send {Down} ; Select "Compressed (zipped) folder" with the "arrow down" key Sleep 100 Send {Enter} ; Execute "Compressed (zipped) folder" with the "Enter" key Sleep 2000 ; wait 2 seconds SendInput, % folder_array%folder_array0% } return #IfWinActive 4. And then extract the zip (right click-->context menu-->Extract to "folder with the same name as zip" Context menu entry example So it creates a folder named "NAMED_FOLDER" with all the extracted content. I know that when I select the zip and press mouse right-button (to open context menu) and press letter "e" it works. 5. Then move this Zip and This new Extracted Folder to Desktop in a Folder "FINAL" And at the end to do all those 5 steps with one letter shortcut. That would do some voodoo magic for me which I really need for the workflow. A: #IfWinActive ahk_class CabinetWClass F4:: for window in ComObjCreate("Shell.Application").Windows try Fullpath := window.Document.Folder.Self.Path IfNotExist, %Fullpath%\1\2 { MsgBox, The folder "%Fullpath%\1\2" doesn't exist return } Run, %Fullpath%\1\2 WinWait, %Fullpath%\1\2 WinActivate, %Fullpath%\1\2 WinWaitActive,%Fullpath%\1\2 StringReplace, Fullpath2, Fullpath, :, StringSplit, folder_array, Fullpath2, \, FolderName = % folder_array%folder_array0% ; MsgBox, % folder_array%folder_array0% FileCopyDir %Fullpath%\1\2, %A_Desktop%\FINAL\%FolderName% ; Sleep 2000 ; wait 2 seconds Send ^a ; Select All Send, {AppsKey} ; Press the "context menu" key Sleep 100 Send n ; Select "Send to" with the "n" key Sleep 100 Send {Right} ; Open "Sent to" with the "right arrow" key Sleep 100 Send {Down} ; Select "Compressed (zipped) folder" with the "arrow down" key Sleep 100 Send {Enter} ; Execute "Compressed (zipped) folder" with the "Enter" key Sleep 2000 ; wait 2 seconds SendInput, % folder_array%folder_array0% Send {Enter} SetTimer, Move_ZIP, 500 return #IfWinActive Move_ZIP: IfExist, %Fullpath%\1\2\%FolderName%.zip { SetTimer, Move_ZIP, off FileMove, %Fullpath%\1\2\%FolderName%.zip, %A_Desktop%\FINAL } return or this: #IfWinActive ahk_class CabinetWClass F4:: for window in ComObjCreate("Shell.Application").Windows try Fullpath := window.Document.Folder.Self.Path IfNotExist, %Fullpath%\1\2 { MsgBox, The folder "%Fullpath%\1\2" doesn't exist return } Run, %Fullpath%\1\2 WinWait, %Fullpath%\1\2 WinActivate, %Fullpath%\1\2 WinWaitActive,%Fullpath%\1\2 StringReplace, Fullpath2, Fullpath, :, StringSplit, folder_array, Fullpath2, \, FolderName = % folder_array%folder_array0% ; MsgBox, % folder_array%folder_array0% ; Sleep 2000 ; wait 2 seconds Send ^a ; Select All Send, {AppsKey} ; Press the "context menu" key Sleep 100 Send n ; Select "Send to" with the "n" key Sleep 100 Send {Right} ; Open "Sent to" with the "right arrow" key Sleep 100 Send {Down} ; Select "Compressed (zipped) folder" with the "arrow down" key Sleep 100 Send {Enter} ; Execute "Compressed (zipped) folder" with the "Enter" key Sleep 2000 ; wait 2 seconds SendInput, % folder_array%folder_array0% Send {Enter} SetTimer, Move_ZIP, 500 return #IfWinActive Move_ZIP: FileCreateDir %A_Desktop%\FINAL IfExist, %Fullpath%\1\2\%FolderName%.zip { SetTimer, Move_ZIP, off FileMove, %Fullpath%\1\2\%FolderName%.zip, %A_Desktop%\FINAL Sleep 2000 ; wait 2 seconds SetTimer, CopyDir, 500 } return CopyDir: IfExist, %Fullpath%\1\2\%FolderName%.zip return SetTimer, CopyDir, off FileCopyDir %Fullpath%\1\2, %A_Desktop%\FINAL\%FolderName% return

Sewage sludge deriving from biofiltrationof municipal waste abound in soil processed organic substances and mineral fertilization components which may be used for fertil-ization of energy willow plantations. In the article the potential of natural utilization of sewage sludge and the patented device for injection dosage of sludge has been pre-sented. The device enables putting into soil mineral and organic fertilizers with loose consistency and their immediate covering by soil in order to reduce unpleasant smell and limit loss of volatile components of fertilizer.

Q: is there anything like _get_hovered in jsTree? using jsTreev pre 1 stable and hotkeys plugin. I have a function that is fired when 'return' is pressed. I want get text of the node that was hovered before pressing enter. This code $.jstree._focused().get_selected().text() works ONLY if I click the node with my mouse and then press enter. How can I get the text without using mouse? I was thinking that _get_hovered would be nice to have. when I use only keyboard the class for the node I am going to press enter changes and gets new class jstree-hovered. I thought I can use it somehow but I don't know how. A: You actually almost provided your own solution within your question: as jsTree (ever so nicely) adds the jstree-hovered class to the node that is currently being hovered over, all you need to do is find which node has this class from withing your "return" key event handling code. jQuery("#tree").jstree({ plugins: [ "themes","html_data","ui","crrm", "hotkeys" ], hotkeys: { "return" : function () { $hovered = $('#tree .jstree-hovered'); if ($hovered.length) { alert('Hovered node text: ' + $hovered.text()); } else { alert('No element was hovered over when return was pressed'); } } } }); Working example at http://jsfiddle.net/y7XVp/16/

Liu Xiao (fencer) Liu Xiao (born 8 November 1987, Anshan) is a Chinese fencer. At the 2012 Summer Olympics, he competed in the Men's sabre, but was defeated in the second round. References Category:Chinese male fencers Category:Living people Category:Olympic fencers of China Category:Fencers at the 2012 Summer Olympics Category:Asian Games medalists in fencing Category:Fencers at the 2010 Asian Games Category:1987 births Category:Asian Games gold medalists for China Category:Medalists at the 2010 Asian Games Category:Sportspeople from Anshan Category:Universiade medalists in fencing Category:Fencers from Liaoning Category:Universiade gold medalists for China

Improved method for the determination of anatoxin-a and two of its metabolites in blue-green algae using liquid chromatography with fluorescence detection. Anatoxin-a, a neurotoxin produced by blue-green algae (BGA) species, can cause death to exposed organisms. In North America, BGA are harvested and sold as food supplements, some of which contain elevated levels of other algal toxins, such as microcystins. Concern that elevated levels of anatoxin-a also may be present in BGA food supplements has led to the development of a simple method to determine the presence of anatoxin-a in BGA. Some researchers have successfully analyzed this compound using liquid chromatography with fluorescence detection by forming a fluorescent derivative with 4-fluoro-7-nitrobenzofurazan (NBD-F) in water and phytoplankton extracts. With this method, the background noise is high in BGA extracts due to the presence of co-extractives. Addition of o-phthaldialdehyde (OPA) and mercaptoethanol to the extract before addition of the NBD-F resulted in the successful removal of primary amines from the background noise when the NBD-F derivatives were detected with fluorescence. Improved chromatograms were obtained when extracts were cleaned up in this manner, leading to a lower detection limit (approximately 50 microg/kg) for anatoxin-a. The detection limits obtained for the 2 degradation products dihydroanatoxin-a and epoxyanatoxin-a in BGA extracts were similarly low (55 and 65 microg/kg, respectively).

Ketamine/xylazine/butorphanol: a new anesthetic combination for rabbits. Ketamine is often used in combination with tranquilizers to produce surgical anesthesia in rabbits. While generally effective, there is considerable variation in the depth and duration of anesthesia achieved with ketamine combinations. Butorphanol is a mixed agonist-antagonist opioid that is widely used in a variety of other species. In this study, the commonly used ketamine (35 mg/kg)/xylazine (5 mg/kg) combination is compared with ketamine (35 mg/kg)/xylazine (5 mg/kg)/butorphanol (0.1 mg/kg). Rabbits were anesthetized on consecutive weeks with one of the two regimens. Physiologic parameters including heart rate, respiratory rate, blood pressure and arterial blood gases (pH, PO2, PCO2) were measured throughout anesthesia. Loss of palpebral, pedal and righting reflexes were recorded and reflexes were subsequently evaluated. The addition of butorphanol prolonged reflex loss to 140% (X = 68 min +/- 20 SEM) of control for palpebral reflex; 506% (X = 52 min +/- 18 SEM) of control for pedal reflex; and 159% (X = 128 min +/- 21 SEM) of control for righting reflex. Addition of butorphanol to ketamine/xylazine resulted in mild alterations in the physiologic changes traditionally associated with this combination. Butorphanol can be safely added to the ketamine/xylazine combination in rabbits and results in moderate increases in the duration of reflex loss.

'The Game Plan' launches with 10 episodes ranging from teaching viewers how to get their music on Spotify to how and when they should start assembling a team. Spotify launched a new video series called The Game Plan on Wednesday (May 23) geared towards teaching artists and their teams how too better use the streaming service and advance their careers in the music industry. The series features Spotify employees, including global head of creator services Troy Carter and former global head of artist and label marketing (and current Universal Music Group executive vice president, creative) Dave Rocco, and artists such as Rick Ross, Little Dragon and Mike Posner, offering advice in quirky, easily digestible episodes. The first 10 installments were released on Wednesday with topics including "What Is Spotify for Artists?," "Building Your Artist Profile, "How to Read Your Data," "Engaging Your Audience," "Promoting Your Work," "Building Your Team" and more. "You can consider them the 101 basics that artists and their teams will need in order to navigate Spotify, get the most out of Spotify and succeed in the music industry in 2018," says Spotify's global head of creator marketing Dominik Sanya, teasing future episodes based on community and artist feedback. Sanya says that as streaming -- and Spotify specifically -- is changing the music industry, more people are looking to create careers making music and Spotify feels a responsibility to support that community with resources to succeed. The initial episodes of The Game Plan were mostly based off frequently asked questions, he explained, "whether it is in meetings or through customer support and public forums, so we figured why not actually make that available and not just from us but do it together with artists and develop it hand-in-hand with artists?" He added, "We're trying to be as transparent as possible in any aspect of what we're doing around Spotify for Artists, and offer easy access to information for all artists." The videos are the latest step in Spotify's editorial initiative for its Spotify for Artists program, which offers a data insights dashboard but also blog posts aimed at building community by telling creators' stories on the blog and providing best practices resources to its users. The Game Plan will be available on platform, as well as on the Spotify for Artists YouTube page. "The more information that's out there for artists and their teams to act on, the better we think they will do, the more music there's going to be out there and the less friction there is in the ecosystem," says Sanya. "I think it is just honestly a matter of making it easy for all of our partners to navigate this music industry that we're actually helping reshape together with them." Watch the The Game Plan series intro and first episode below, and check out the rest here.

Hospital restructuring and the epidemiology of hospital utilization: recent experience in Ontario. The author highlights changes in hospital utilization that have occurred in association with restructuring of Ontario hospitals. The basic features of the epidemiology of hospital utilization described link the analysis of the organizational and structural components of hospitals with a more comprehensive evaluation of the impacts of their restructuring and have implications for international comparative studies. Data from the Canadian Institute for Health Information and the Canadian census were analyzed to provide a population-based description of hospital utilization and care. These hospital data provided information on changes in the patterns of care that occurred during restructuring, based on hospital separations for the fiscal years 1991-1992 through 1995-1996. Analysis of hospital utilization patterns revealed a 30% decrease in the days of care provided per 1,000 population during the period, the result of declines in both the age-adjusted inpatient separation rates and average length of hospital stay. The shift of surgical treatment to outpatient settings contributed to the reduction in inpatient days of care. The decline in utilization was experienced unevenly across age groups, with the elderly experiencing less of the decline than did younger age groups. Individuals living in the poorest areas used more inpatient care than did those living in the richest areas, although the gap in utilization narrowed over the period. International comparisons of the epidemiology of hospital utilization and the impact of hospital restructuring will require the use of multiple data sources and the development of shared evaluative frameworks. Health data systems in Canada support the assessment of the broader impacts of hospital restructuring and offer a framework for developing research projects that can provide useful information on these important changes in health-care policy.

Share Product Description A perfect way to personalize your charm collection is with this Swarovski crystal briolette charm in light rose for October birthdays! This dazzling charm is topped with an antique gold clasp and hardware.

Polyploidy in spitz nevi: a not uncommon karyotypic abnormality identifiable by fluorescence in situ hybridization. Fluorescence in situ hybridization (FISH) often reveals imbalanced chromosomal gains in melanoma, whereas Spitz nevi typically have a normal complement of chromosomes. However, there may be a subset of Spitz nevi that are perfectly tetraploid by FISH analysis, and these cases may be confused diagnostically with melanoma. This study evaluates 41 cases of Spitz nevi that were histologically confirmed to be benign. Four of these lesions demonstrated polyploidy by FISH. Three of the 4 cases were from the same patient, a 17-year-old woman; 1 lesion was from the wrist, whereas the other 2 were from the buttocks. The other case was from a 14-year-old man from the ankle. All 4 cases that were polyploid were confirmed using a probe for the X chromosome. This article highlights the importance of polyploidy as a feature of some benign Spitz nevi.

Author's notes at bottom. ***PLEASE READ THIS!*** If you are reading this story, you need to know that it is a SERIES. That means that there are more stories before this one and to completely understand everything that is happening, you need to read the others first. DON'T LET ME GO: BROKEN PROMISES DON'T LET ME GO: INSANITY DON'T LET ME GO: ROSES DON'T LET ME GO: APPARITIONS DON'T LET ME GO: DEBAUCHERY The last one, Debauchery, is this one. I can't stop you from reading this first, but know that it won't make much since ^_^ ______________________________________________ Her words haunt me. I wonder why Queen Serenity couldn't have came to Usako and told her I was alright. Even if she didn't know where I was, at least let it be known I didn't die in the explosion. The pain that I see Usako go through day in and day out. Will that go away? There is an evil presence lurking, I can feel it. I wonder if Usako is strong enough in her state of mind to go against an enemy right now. I hope I can stay by her side - to help her. -Mamoru. ~~~~~~~~ Don't Let Me Go: Debauchery Chapter: 1 By: Bethany and Patch Edited by: Meara Rated: PG13 for violence Comments, suggestions, cheese cubes and Tiggers can be sent to us at [email protected] and [email protected] ~~~~~~~ ~*~ Four Days Later ~*~ Her body tossed and turned, sweat dripping from her bangs as she moved, writhing in bed. The sheets became a trap formed by a mastermind; twisting around to keep her legs from moving. With what felt like her last breath, Usagi screamed out the name of her protector, her saver, her lifeline. "MAMO-CHAN!!" The five seconds it took Mamoru to wake Usagi from her self-induced prison seemed like ages to the frightened girl. Her loud sobs filled the otherwise quiet room until they were muffled against a strong chest. "Usako, it's okay baby. I'm here, I'm right here," he soothed softly, stroking her back with one hand and holding her tightly with the opposite arm. Her weakened state only allowed her to hold his shirt loosely, her face pressed against the cotton of his shirt. "Mamo-chan? Are you really here? It was so.. so real. So horrible! I.. it hurts Mamo-chan, hurts!" Mamoru rained soft kisses on her head while checking to make sure he wasn't holding her too tightly or pressing against any of her broken ribs. "What hurts baby?" "My head... You're alive? But.. you were gone for so long." Another gush of fresh tears left her eyes and she sobbed louder into his shirt. "They told me you were dead, why did they lie to me, Mamo-chan? Why?" Mamoru could feel her pain through their soul-bond, feel her heartbreak and grief. It hurt worse than anything he had ever felt in his life. "Shhh... it's okay now. I'm here, I'm never leaving you again - never. Come on, you need to lay back down." Care- fully he helped her back onto her pillows, before climbing into the bed to lie beside her. Her breathing finally slowed until her chest rose and fell with soft movements. Mamoru ran his fingertips over her face and through her silver hair gently, reassuring her of his presence. His head dropped slightly as he strained to keep it propped up on his hand; making sure to watch over her so she couldn't fall into another nightmare. His eyes snapped shut before he caught them and opened them wide. ~*~ "Mamo-chan," a voice called in the back of his mind. His awareness returned slowly and reluctantly. "Mamo-chan!" "U...Usako...?" his lids felt too heavy to open completely. A soft hand ran over his face and cupped his check. "Baby, wake up." With all the strength he could manage, he opened his eyes and looked around. Silver hair was all around him, and baby blue eyes were looking at him with love. "Usako?" "Come on lazy bones, get up," she said in a sing-song voice full of happiness. That's when he noticed it. He had fallen asleep in the bed with her, and was now cuddled up against her petite form. But that isn't what really got him moving. It was those violet eyes on the other side of Usagi that were boring into him. And boy if looks could kill.... "Rei-chan?" "Get your ass up! You could have hurt her!" The look the Senshi of Mars gave him was not a gentle one as Mamoru gave a sleep induced mumble. "Leave him alone Rei-chan, he's tired," Usagi stated, running her soft palm over his forehead once more. "What's he doing in the bed with you anyway? Doesn't he realize that you have two broken ribs and not to mention numerous other injuries? Where are the doctors and nurses around here when you need them anyway?" Mamoru looked up, quite surprised at Usagi's tone of voice as she spoke. "The only thing that is hurting me right now is the loudness of your voice!" Rei looked just as surprised as Mamoru did. "I..." a blank looked crossed her face before she done something that both the Prince and Princess wished they had a tape recorder for. "Gomen nasai Usagi... I didn't mean to." Usagi blanched, obviously taken aback from Rei's apology. "It's..it's okay Rei-chan, just not so loud, ne?" Rei nodded before plopping down in a chair, watching Mamoru carefully rise off the bed and go into the adjoining bathroom. Minako burst in the room, Makoto and Haruka in tow. "Hidy hoe young lady, we hear you are being released today - care to comment?" Minako said, one hand over her ear like a reporter, and talking into her fist. "Yeah, give us the goods!" Haruka added, holding the cup up to Usagi's mouth. "You are getting out of the hell hole, what are YOU going to do first?" Makoto pushed Haruka aside and planted a wide grin on her face, "Ohh.. let me guess, I bet your going to Disney Land, ne Usagi-chan?" The princess couldn't help but laugh at her friends, they all were talking to each other, dicussing anything from hospital food to Usagi going home. Usagi looked across the room at Mamoru coming out of the bathroom, still scrubbing his palms over his face. She smiled slightly and he returned the gesture. In three quick strides he stood beside her and kissed her check. "Morning sunshine," he whispered lovingly in her ear. Usagi raised one of her hands up to brush some stray hairs from his forehead. "Morning baby." Their lips came closer together to touch just slightly... "AWWWWWWWWWW!" Makoto and Minako sighed, hearts in their eyes. "I'm going to be sick!" Haruka and Rei exclaimed, both looking rather annoyed. Mamoru blushed a beet red and moved back from Usagi, although still holding her hand tightly. "So, how long before we get out of here Usako?" Usagi sat up on the bed, still a little sore, and looked at the clock. "Mama should be here in about thirty minutes." Rei and Minako brought a suit case out and started packing away brushes, combs and the like while Makoto rattled on about the flowers that covered Usagi's entire room. The time passed quickly, and before she knew it a short woman with blue hair gushed in the room, a nurse and wheelchair behind her. "Okay honey, you are ready to go!" she exclaimed in a bubbly, although loving voice that belonged to mothers. The ride to the Tsukino residence was uneventful, unless you count the fact that they had to get a taxi to transport everyone and all of Usagi's flowers and balloons from the hospital to her house. Slowly Usagi rose from the passenger seat of the car and shooed away Mamoru who was anxiously standing in front of her to assist in getting her inside. Mamoru figured he'd have a heart attack or pick her up screaming and kicking to get in the house at the rate she was going. But Usagi wanted to do it herself and come hell or high water she would. With a little pain in her side she managed to get into the living room and sit. The stairs would have to wait for later. ~~~~~~~~~~~~~ Days later - Mamoru's Apartment ~~~~~~~~~~~~~ It puzzled him. This was one of few things in life that did. And, as he stared at her long *silver* hair, Mamoru connected that most things in life that did confuse him; had to do with Usagi. Was it his imagination, or just a conicenidence? Whatever the case may be, this beautiful flow of silver hair made his young Usako look more mature, better able to handle herself; she looked... like a Queen. "Usako?" Usagi looked up through thick lashes and smiled sweetly at him for a second before going back to painting a picture of a rabbit. "Hai, Mamo-chan?" No, Mamoru thought as she painted intently, she is still my beautiful Usako and Crystal Tokyo is still years off... isn't it? This bothered Mamoru, but he was hoping this was something that came of her thinking him dead- "Why is your hair silver?" Usagi stopped and put her paint brush down and looked at her hair. She wore a puzzled expression and shrugged. "Luna thinks it is a sign of my maturity - my mother's hair was silver." Mamoru nodded thoughtfully and ran his fingers through its thick mass. "You look beautiful." A pink blush tinted her cheeks and she bowed her head to continue painting. But that was not what Mamoru had in mind. Slowly Usagi watched a large hand take the brush from her smaller fingers and lay it aside. She stared at that invading hand to see what it's owner would do next. A tingle of excitement ran up her spine as it came dangerously close to touching her breast as it made it's way up her arm and to her neck. Mamoru had never ventured this far with Usagi before. He wanted to wait until she was emotionally ready and now seemed as good as time as any. Slowly he brought his lips to hers and gently leaned them both back on the floor. ~~~~~~~~~~~~~ He was being dragged by his arms through dark hallways as his knees scraped across the rough floor. His head hung between his shoulders and his hair was matted to his scalp. He didn't know how much more he could take. He was surprised he wasn't dead yet. But no, he had the will...to keep on living, to get back to Reika, his love. Reika... how was she? He had no idea how much time had passed and he desperately wished she was okay. The two men continued to pull him until they finally stopped. Motoki lifted his head slightly to get an idea of where they were. It was a cavernous room, and the only light source came from the torches that graced the black walls. Where the hell were they? After a moment, he was pulled forward again until they stopped once more and then thrown to the front. He flung out his hands to brace himself and then raised his head once more. His eyes grew wide at the sight that lay before him. A huge throne made of black marble sat before him, two tall torches on either side. A man sat on the throne but Motoki couldn't see it for it was partially hidden from the black hood that covered it. Motoki could see the man's beard but nothing else. He was dressed in a black robe with blood red lining. In front of the man, on the floor was a cauldron with flames of fire leaping into the air. It was a scene from someone's worst nightmare, Motoki was sure of that. His attention was brought back when the man stood up. "Furuhata Motoki. Welcome to my...humble abode," the man said, spreading his arms wide and smiling slightly. "You certainly haven't made me feel welcomed," Motoki spit out. "Your... treatment was necessary so that you understood what position you held here." "Why am I here? What do you want from me?" Motoki asked. He could feel sweat forming on his palms. He was terrified but he wasn't about to show it. "Ah, so we get down to business," the man said, and brought his hands up to lift his hood. Motoki gasped. The man...he had no eyes! They were white and sightless. A scar ran down one side of his face and he had long, straggly hair. The man grinned an ugly smile at Motoki's horrified reaction. "Do you like what you see? Sadly, there are consequences to certain actions, and this," he said pointing to his eyes, "was one of them. But, no matter. My name is Chronos, Leader of the Organization of Chronos. We are a secret society, using powers from the realm of the unknown to accomplish our goals. You have something I need." "What possession of yours could I *possibly* have?" Motoki asked, sarcasm thick in his voice. "The 10th Ring. You have it." "Nani? What are you talking about?" "Do not play games with me," Chronos warned, "You were looking for a wedding ring for your fiancee and had your friend, your dead friend now, look for it in America. He found one and found it so unique that before he sent it to you, he decided to do some investigating on it. Unfortunately...he wasn't able to finish that, as you now know," Chronos smiled mockingly. "You killed Mamoru?" Motoki asked in disbelief. But he recovered and charged at the man as pure hatred ran through his veins. "Bastard!" Chronos swung his arms and with a whoosh of air, Motoki was flung backwards and hit the hard ground with a sickening thud. He lay there, completely dazed and swallowed the urge to throw up. Kami only knew he *had* nothing to throw up. He saw the face of Chronos above him. "You underestimate me, boy," Chronos said, with a sneer of his lips. "Your friend did send you the ring and I want it." "What's it to you?" Motoki gasped out. Chronos turned around and walked a few steps away and Motoki had to raise his head to see him. He suddenly turned back again, his black robe flying about him. "I suppose I could tell you," he began in a bored tone, "it won't do you much good though. The ring that you have is known as the 10th Ring," he held up his hands and spread his fingers. Each finger had a gold ring with some kind of stone on it but one ring was missing; the last finger of his left hand bore no ring. "The ring belongs to me, it has always belonged to me until one of our *ex-members* stole it from us while we were in the middle of a... ritual." "Why is this ring so important?" Motoki asked suspiciously as he slowly got up. "It's quite simple, really. The 10th Ring completes the set of the Cattaras Rings. Its power is unimaginable and beyond this realm and without it the nine other rings are useless. With it, the Cattaras Rings are the greatest gift, or weapon, ever given to Earth," he stopped and then smiled at Motoki, his sightless eyes looking straight into Motoki's soul, "Shouldn't this be sounding familiar, Earth Prince? After all, we, the Organization of Chronos and these rings have existed as long as you have; have existed since the Silver Millennium." "Nani?" Motoki asked sharply, "I am no Earth Prince and I have no idea what this Silver Millenium is. What nonsense are you talking about?" gain Motoki felt himself thrown backwards and again he felt the pain roil through his body as he crashed against a wall. He couldn't understand why his body hadn't shut down a long time ago. He didn't think he would survive for much longer. He was surprised to find himself suspended against the wall and when he opened his eyes, Chronos was right in front of him although it seemed impossible considering the fact that Chronos had been on the other side of the room when Motoki had been thrown. "You dare to mock my words?" he breathed menacingly, "Do you think I don't know who you are? For so long, for so many milleniums I have waited to see you like this, crushed and near death before me but no, it cannot be. I must have that ring, and you will give it to me!" "Never!" Motoki managed, "I am not who you say I am, but even so, I would never give you the satisfaction of destroying this Earth Prince you speak about. Never!" Chronos stayed quiet and after a moment, a look of pure anger crossed his face and his eyes bore into Motoki's. Motoki felt him search his soul through those sightless eyes and whatever he found calmed him. "So, you are not the Earth Prince, I know that now. An inconvenience but no matter, I will have that ring from you, one way or the other." Motoki was terrified now. What did he mean by 'one way or the other?' "I believe you have a girlfriend, as one of my men told me. Reika, is it?" He walked to the cauldron and stared at the flames. Chanting, his eyes closed and he raised his face and arms. An image of Reika appeared within the flames and Motoki almost let out a choked sob of relief to see her alive and well. She was talking to Rei and she looked distressed. Don't worry, baby, he thought, I'll protect you. "It would be a pity to waste such a beautiful life," Chronos said, cocking his head slightly and staring at the image. "It would be a pity for you to see me destroy such goodness and heart. I could... break her neck so easily," his hand burst through the image causing it to disappear. "No!" Motoki yelled. He was still held against the wall and struggled to break free of his invisible bonds. "I'll kill you if you hurt her! I swear it!" Chronos threw back his head and laughed loudly. He stopped and brought his head back to look at Motoki. "Give me the ring." Motoki could only hang his head in defeat. ~~ Reika stood outside of Motoki's apartment complex looking up, her arms crossed against the slight chill in the air. "Oh Motoki, where are you?" she mumbled, sorrow laced in her voice. It had been about a week, an agonizing week since he had disappeared. A tear slipped down her cheek and she brushed it away. Usagi had Mamoru now, why couldn't she have Motoki? It wasn't fair. "Stop it!" she scolded herself. She was being selfish but it was just so hard. "I love you," she whispered. She looked up once more and gasped. As if in answer to her prayers, the light of his apartment had been turned on. She blinked a few times, not believing her eyes. It wasn't on a minute ago! She ran into the building and hit the elevator button. "C'mon, damn it, open up!" They doors opened and she rushed inside and then waited impatiently as they took her up to his floor. The doors opened once more and she ran out, her heart pounding as she ran down the hall- way. Thrusting the keys he had given her so long ago into the lock, she threw the door open. She inhaled sharply for there he stood, now facing her. She slowly walked into the apartment, the door forgotten behind her. She stopped when she stood in front of him. She said nothing, just stared at him, drinking in the site of him. Her eyes roved up to his face and she smiled through her tears... and then promptly fainted. ___________________ And there you have chapter 1! Drumroll please!! If you noticed, this chapter is a lot longer than our previous ones. It will continue to be this long if not longer from here on in. This is turning out to be a lot longer than either of us expected, and we hope you are enjoying ^_^ I'm sorry this wasn't out last week - I (Bethany) was suffering from major writer's block and I owe big thanks to Patch for putting up with me through it ^^; Thankfully I'm almost completely loose of it's grip and I can actually think straight when I look at the computer screen. HUGE thanks to everyone who has emailed us about this story, ***HUGS*** you guys have kept us going ^^ GIGANTIC THANKS to our editor, Meara! ***HUGS*** one million and six thank you's! Insert usual SM disclaimers that no one reads here... Thanks for reading - please, Please, PLEASE email us!!!!! We LOVE feedback!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! [email protected] & [email protected] Luva! Bethany Patch

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Somitic-vertebral correlation and vertebral levels in the human embryo. Somitic and vertebral interrelationships and levels were studied in 84 human embryos of stages 9-23 (3-8 postovulatory weeks). The first four somites are occipital, the occipitocervical junction is at somites 4/5, and eight somites are involved in the cervical region: X, Y, Z, and C. 3-7. By stage 17 the total number of occipitovertebral "units," namely 38 or 39, is attained. Resegmentation (Neugliederung) of sclerotomes is not supported. A new scheme of somitic/vertebral correlation is proposed in which somites and centra are in register. Differential growth of the regions of the vertebral column was calculated, and it was found that the percentages of the total column occupied by the various regions vary from one stage to another. The cervical and coccygeal regions decrease, the thoracic and lumbar regions increase, and the sacral region remains more or less constant during embryonic development. The following structures descend with reference to the vertebral column during the embryonic period proper: roots of lower limbs, thyroid gland and thymus, tracheal bifurcation, lungs, heart, diaphragm, abdominal arteries, mesonephroi, and suprarenal glands. The gonads may descend slightly. The scapulae and the separation point between the trachea and the esophagus remain at a fairly constant level. The metanephroi ascend. The migration of many of these structures (e.g., the heart, diaphragm, and metanephroi) is much more marked in the embryonic period than later although it continues during the fetal and postnatal periods. The conus medullaris ascends during the fetal period. Anomalies of migration that affect such organs as the thyroid gland, gonads, and metanephroi are discussed.

--- abstract: 'The orbital motion of non-contact double-lined spectroscopic binaries (SB2), with periods of a few tens of days to several years, holds unique accurate informations on individual stellar masses, that only long-term monitoring can unlock. The combination of radial velocity measurements from high-resolution spectrographs and astrometric measurements from high-precision interferometers allows the derivation of SB2 components masses down to the percent precision. Since 2010, we observed a large sample of SB2 with the SOPHIE spectrograph at the Observatoire de Haute-Provence, aiming at the derivation of orbital elements with sufficient accuracy to obtain masses of components with relative errors as low as 1% when the astrometric measurements of the Gaia satellite will be taken into account. In this paper we present the results from six years of observations of 14 SB2 systems with periods ranging from 33 to 4185days. Using the [todmor]{} algorithm we computed radial velocities from the spectra, and then derived the orbital elements of these binary systems. The minimum masses of the 28 stellar components are then obtained with a sample average accuracy of 1.0$\pm$0.2%. Combining the radial velocities with existing interferometric measurements, we derived the masses of the primary and secondary components of HIP 61100, HIP95995 and HIP101382 with relative errors for components (A,B) of respectively (2.0, 1.7)%, (3.7, 3.7)%, and (0.2, 0.1)%. Using the `Cesam2k` stellar evolution code, we could constrain the initial He-abundance, age and metallicity for HIP61100 and HIP95995.' author: - | F. Kiefer$^{1}$[^1], J.-L. Halbwachs$^{2}$, Y. Lebreton$^{3,4}$, C. Soubiran$^{5}$, F. Arenou$^{3}$, D. Pourbaix$^{6}$, B. Famaey$^{2}$, P. Guillout$^{2}$, R. Ibata$^{2}$ and T. Mazeh$^{7}$\ $^{1}$Institut d’Astrophysique de Paris,CNRS/UMR7095, 98bis boulevard Arago, 75014 Paris\ $^{2}$Université de Strasbourg, CNRS, Observatoire astronomique de Strasbourg, UMR 7550, 11 rue de l’Université, F-67000 Strasbourg, France\ $^{3}$LESIA, Observatoire de Paris, PSL Research University, CNRS UMR 8109, Université Pierre et Marie Curie, Université Paris Diderot,\ 5 Place Jules Janssen, F-92195 Meudon, France\ $^{4}$Institut de Physique de Rennes, Université de Rennes 1, CNRS UMR 6251, F-35042 Rennes, France\ $^{5}$Laboratoire d’astrophysique de Bordeaux, Univ. Bordeaux, CNRS, B18N, Allée Geoffroy Saint-Hilaire, F-33615 PESSAC\ $^{6}$FNRS, Institut d’Astronomie et d’Astrophysique, Université Libre de Bruxelles, boulevard du Triomphe, 1050 Bruxelles, Belgium\ $^{7}$School of Physics and Astronomy, Tel Aviv University, Tel Aviv 69978, Israel\ date: 'Accepted . Received 2017 ; in original form 2017' title: 'Masses of the components of SB2 binaries observed with [*Gaia*]{}. IV. Accurate SB2 orbits for 14 binaries, and masses of 3 binaries [^2]' --- \[firstpage\] binaries: spectroscopic, stars: fundamental parameters, stars: individual:HIP 61100, HIP 95995, HIP 101382 Introduction ============ Following the work of papers I-III [@Halb2014; @Halb2016; @Kiefer2016] we propose to measure masses of stars with an accuracy better than 1%. The loosely constrained single stars stellar evolution models still necessitate a confrontation to extremely accurate masses of stars. Non-contact binaries have the exclusive advantage to provide mass measurements of two separate objects with different masses but with the same age. They could thus provide a strong constraint on stellar models [@Torres2012]. To that end, we proposed in paper I [@Halb2014] to combine the high-resolution spectroscopy of the Spectrographe pour l’Observation des PHénomènes des Intérieurs Stellaires et des Exoplanètes (SOPHIE; Observatoire de Hautes-Provence) to the high-precision astrometry of the [*Gaia*]{} satellite on high-contrast large-period and bright spectroscopic binaries. SOPHIE provides radial velocities with an accuracy of a few tens of m s$^{-1}$, and [*Gaia*]{} will soon deliver photocenter positions with an accuracy of a few tens of microarcseconds. The combination of both will allow achieving better than 1% accuracy on binary masses. In paper I [@Halb2014], we selected a sample of 68 SB2s for which we expect to reach that level of precision. We have been observing these stars since 2010 with SOPHIE. A first result of our program was the detection of the secondary component in the spectra of 20 binaries which were previously known as single-lined (paperI). A second result was the determination of masses for two particular SB2s with accuracy between 0.26 and 2.4%, coupling astrometric measurements from PIONIER and radial velocities from SOPHIE (paperII; Halbwachs et al. 2015). In a third paper (paperIII; Kiefer et al. 2016), we derived projected masses (M $\sin^3i$) with precision better than 1.2% for the two components of 10 binaries, and the masses of the binary HIP87895 with an accuracy of $\sim $1% thanks to additional astrometric data. Here, we present the accurate orbits measured for 14 SB2s (Table \[tab:obs\]) with periods ranging from 33 to 4185 days. After 8 years of observations with SOPHIE, we collected a total of 203 spectra of these stars. A large number of previously published measurements is also available for each of these binaries in the SB9 catalog [@SB9]. Four of these targets were identified as new SB2s in paper I. We combined the radial velocity (RV) measurements and existing interferometric data for HIP61100, HIP95995 and HIP101382, to derive the masses of their components. This will enable us to validate the masses derived from our RVs and from Gaia astrometry, when the Gaia astrometric transits will be available. Meanwhile, in the present paper, these masses are confronted to evolutionary models. The observations are presented in Section \[sect:observations\]. The method of measurements of radial velocities from SOPHIE’s observations is explained in Section \[sect:RV\]. We derive the orbital solutions in Section \[sec:orbits\]. The derivation of the masses of HIP61100, HIP95995 and HIP101382 is presented in Section \[sec:masses\]. Finally, in Section \[sec:models\] we examine how they compare to stellar evolution models. Observations {#sect:observations} ============ The observations were performed at the T193 telescope of the Haute-Provence Observatory, with the SOPHIE spectrograph [@Perruchot2008]. SOPHIE is dedicated to the search of extrasolar planets, and, its high resolution ($R$$\sim $$75,000$) enables accurate stellar radial velocities to be measured for SB2 components. Since the beginning of the programme, we have accumulated 49 nights of observations in visitor mode. Before each observation run, ephemerides were derived from existing orbits provided by the SB9 catalogue [@SB9], and priority classes were assigned on the basis of the orbital phase and of the observations already performed. In addition, we obtained observations in service mode for a total duration of 7 nights; these observations were essentially used to complete the phase coverage of short-period binaries. The spectra were all reduced through SOPHIE’s pipeline, including localization of the orders on the frame, optimal order extraction, cosmic-ray rejection, wavelength calibration, flat-fielding and bias subtraction. Among all the observed SB2s, we have selected those which were satisfying two conditions: - They were observed over, at least, the part of the phase where the RVs of the components may be derived. Except for HIP 77122, a binary with a period of more than 11 years, the observations covered more than one period. - They received a minimum of 11 observations. This limit was set for statistical reasons (see *e.g.* paper III): Although an SB2 orbit could be derived in principle from only 6 of those observations, a minimum of 5 degrees-of-freedom on each component are needed for a reliable rescaling of the RV errorbars to the stochastic noise level, as explained in Section \[sec:orbits\]. Table \[tab:obs\] summarizes this information. [@l@[  ]{}l@[  ]{}c@[  ]{}c@[  ]{}c@[  ]{}c@[  ]{}c@[  ]{}l@]{} Name & Alt. name & V & Period$^a$ & $N_\text{spec}$ $^b$ & Span$^c$ & SNR$^d$\ HIP/HD & HD/BD &(mag.) & (day) & & (period) &\ \ &&&&&&\ HIP9121 & BD+41379 & 9.01 & 695 & 16 & 3.1 & 48\ HIP21946 & HD285970 & 9.86 & 56 & 11 & 34 & 54\ HIP38018 & HD61994 & 7.08 & 552 & 12 & 3.9 & 96\ HIP61100 & HD109011 & 8.10 & 1284 & 13 & 2.8 & 98\ HIP77122 & HD141335 & 8.95 & 4290 & 12 & 0.54 & 48\ HIP95995 & HD184467 & 6.59 & 494 & 14 & 4.3 & 145\ HIP100046 & HD193468 & 6.73 & 289 & 18 & 7.5 & 136\ HIP101382 & HD195987 & 7.09 & 57 & 18 & 45 & 101\ HIP116360 & HD221757 & 7.22 & 348 & 15 & 9.8 & 97\ HD98031 & BD+132380 & 8.40 & 271 & 15 & 7.9 & 48\ \ &&&&&&\ HIP7143 & HD9312 & 6.81 & 37 & 16 & 59 & 143\ HIP12472 & HD16646 & 8.10 & 329 & 13 & 6.7 & 90\ HIP48895 & HD86358 & 6.46 & 34 & 17 & 87 & 140\ HIP72706 & HD131208 & 7.61 & 84 & 13 & 18 & 97\ \ $^a$ The period values are taken from the SB9 catalogue [@SB9]. Except HIP3818 and HIP61100 [@Halb2003].\ $^b$ $ N_\text{spec}$ gives the number of spectra collected with SOPHIE.\ $^c$ Span is the total time span of the observation epochs used in the orbit derivation, counted in number of periods.\ $^d$ SNR is the median signal-to-noise ratio of all the SOPHIE spectra of a given star at 5550Å. \[tab:obs\] Radial velocity measurements {#sect:RV} ============================ The radial velocities of the components are derived using the TwO-Dimensional cross-CORrelation algorithm [todcor]{} [@zucker94; @zucker04]. It calculates the cross-correlation of an SB2 spectrum and two best-matching stellar atmosphere models, one for each component of the observed binary system. The radial velocities of both components are measured at the optimum of this two-dimensional cross-correlation function (CCF). More specifically we employed the multi-order version of [todcor]{} that is named [todmor]{} [@zucker04]. We redirect the readers to our preceding articles (paper I-III) for more details on this algorithm. All SOPHIE multi-orders spectra were first corrected for the blaze using the response function provided by SOPHIE’s pipeline; then for each of them, the pseudo-continuum was detrended using a p-percentile filter [paper II, @Hodg1985]. Finally, before deriving the RVs, a best-matching model spectrum is determined for both SB2 components of each star. Optimizing the model spectra ---------------------------- The theoretical spectra from the PHOENIX stellar atmosphere models [@Huss2013] optimized for best-matching of the components of all 14 SB2s are given in Table \[tab:stellpar\]. Contrary to the method presented in previous papers, instead of optimizing the CCF for all orders, we minimized the $\chi^2$ of the selected spectra compared to the PHOENIX models around the CaI line at $\sim$6120Å(order 33). This line is particularly sensitive to $T_\text{eff}$ and $\log g$ if conditions are close to LTE [@Drake1991; @Mashonkina2007]. Moreover being on the red side of the spectrum it offers the best conditions with respect to signal-to-noise and strength of the second component. We used the full order $\#$ 33, which also incorporates a few Fe lines. Compared to the previous method explained in paper III, which consisted in optimizing the CCF, the above method led to more reliable values of stellar parameters, with in particular less biased values of metallicity. We verified that the two methods give consistent, and equally satisfying, results on radial velocities measurements. We optimized the values of effective temperature $T_\text{eff}$, rotational broadening $v \sin i$, metallicity \[Fe/H\], surface gravity $\log(g)$, and flux ratio at $4916$Å, $\alpha$$=$$F_2/F_1$. For binaries on the main sequence, if $\alpha$ is too low ($\alpha$$<$$0.1$) and the secondary $\log g$ cannot be properly derived, we fixed its value with respect to $T_\text{eff}$, following the empirical relation $\log g = 12 - 2\log T_\text{eff}$, as derived from Fig. 1 of [@Angelov1996]. Each theoretical spectrum is convolved with the instrument line spread function, here modeled by a Gaussian, and pseudo-continuum detrended with the same techniques employed for detrending the observed spectra. The values of the stellar parameters, and their uncertainties, given in Table \[tab:stellpar\] are the average and standard deviation of the individual estimations. The 1$\sigma$ uncertainties do not include known systematics, see e.g. [@Torres2012]. To give a point of comparison, we measured the Sun’s parameters on SOPHIE spectra of Vesta and Ceres in Table \[tab:stellpar\]. Metallicity was found to be off by $-0.12$ dex, $\Delta T_{\text{eff},\odot}$$\sim $$60$K, and $\Delta\log(g)_\odot$$\sim $$0.1$. Given their small amplitude, and lacking an exhaustive analysis of benchmark stars spectra with this method, these errors could be considered as more realistic minimum uncertainties on $T_\text{eff}$, $\log(g)$ and \[Fe/H\], than the values given in Table \[tab:stellpar\]. Furthermore, the uncertainty on the effective temperatures is actually larger than this, since varying by hand metallicity in a $\pm$0.1dex range for a few targets, we found an amplitude of variations of $T_\text{eff}$ on the order of 100-200K. [@lrrrrr@]{} HIP & $^a$$ T_\text{eff,1}$ & $^b$$ \log g_1$ & $^c$$ V_1 \sin i_1$ & $^d$$ [\text{Fe/H}]$ & $\alpha$\ HD & $ T_\text{eff,2}$ & $ \log g_2$ & $ V_2 \sin i_2$& &\ & (K) & (dex) & (km s$^{-1}$) & (dex) & (flux ratio)\ HIP7143 & 5367 & 4.30 & 4.7 & 0.03 & 0.063\ & $\pm$166 & $\pm$0.13 & $\pm$0.6 & $\pm$0.03 & $\pm$0.013\ & 5150 & 4.6$_{\text{\tiny MS}}$ & $<$8 & &\ & $\pm$228 & & & &\ \ HIP9121 & 5789 & 4.40 & 2.7 & 0.11 & 0.083\ & $\pm$21 & $\pm$0.03 & $\pm$0.3 & $\pm$0.01 & $\pm$0.010\ & 4544 & 4.89 & $<$2 & &\ & $\pm$164 & $\pm$0.10 & & &\ \ HIP12472 & 6253 & 4.4$_{\text{\tiny MS}}$ & 10.5 & -0.86 & 0.037\ & $\pm$82 & & $\pm$0.3 & $\pm$0.12 & $\pm$0.012\ & 4802 & 4.6$_{\text{\tiny MS}}$ & $<$4 & &\ & $\pm$292 & & & &\ \ HIP21946 & 4680 & 4.72 & 4.0 & -0.13 & 0.035\ & $\pm$21 & $\pm$0.05 & $\pm$0.4 & $\pm$0.03 & $\pm$0.004\ & 4164 & 4.8$_{\text{\tiny MS}}$ & $<$10 & &\ & $\pm$110 & & & &\ \ HIP38018 & 5585 & 4.46 & 3.5 & -0.04 & 0.069\ & $\pm$13 & $\pm$0.04 & $\pm$0.2 & $\pm$0.06 & $\pm$0.011\ & 4484 & 4.7$_{\text{\tiny MS}}$ & $<$5 & &\ & $\pm$110 & & & &\ \ HIP48895 & 6186 & 4.30 & 74.1 & -0.59 & 0.253\ & $\pm$152 & $\pm$0.09 & $\pm$2.5 & $\pm$0.08 & $\pm$0.010\ & 5697 & 4.69 & 21.4 & &\ & $\pm$79 & $\pm$0.10 & $\pm$1.0 & &\ \ HIP61100 & 5105 & 4.75 & 5.7 & -0.14 & 0.229\ & $\pm$21 & $\pm$0.10 & $\pm$0.1 & $\pm$0.10 & $\pm$0.004\ & 4175 & 4.8 & 5.1 & &\ & $\pm$35 & $\pm$0.1 & $\pm$0.4 & &\ \ HIP72706 & 4524 & 3.27 & 4.3 & -0.13 & 0.099\ & $\pm$8 & $\pm$0.03 & $\pm$0.4 & $\pm$0.01 & $\pm$0.023\ & 5272 & 4.50 & 2.9 & &\ & $\pm$280 & $\pm$0.11 & $\pm$1.1 & &\ \ HIP77122 & 5638 & 4.22 & $<$4 & -1 & 0.195\ & $\pm$45 & $\pm$0.24 & & & $\pm$0.060\ & 5035 & 4.60 & $<$3 & &\ & $\pm$131 & $\pm$0.31 & & &\ \ HIP95995 & 5114 & 4.62 & 2.7 & -0.33 & 0.524\ & $\pm$11 & $\pm$0.05 & $\pm$0.3 & $\pm$0.01 & $\pm$0.083\ & 4705 & 4.67 & 2.7 & &\ & $\pm$101 & $\pm$0.05 & $\pm$1.0 & &\ \ HD98031 & 6018 & 4.55 & 2.4 & -0.13 & 0.236\ & $\pm$8 & $\pm$0.07 & $\pm$0.7 & $\pm$0.04 & $\pm$0.001\ & 5095 & 4.86 & $<$3 & &\ & $\pm$19 & $\pm$0.07 & & &\ \ HIP100046 & 6069 & 4.28 & 26.2 & -0.71 & 0.585\ & $\pm$53 & $\pm$0.21 & $\pm$1.0 & $\pm$0.06 & $\pm$0.016\ & 5623 & 4.36 & 13.7 & &\ & $\pm$43 & $\pm$0.21 & $\pm$0.5 & &\ \ HIP101382 & 5296 & 4.71 & 3.9 & -0.38 & 0.156\ & $\pm$19 & $\pm$0.03 & $\pm$0.3 & $\pm$0.01 & $\pm$0.005\ & 4360 & 4.97 & $<$2 & &\ & $\pm$87 & $\pm$0.04 & & &\ \ HIP116360 & 6227 & 4.37 & 4.3 & -0.21 & 0.624\ & $\pm$68 & $\pm$0.09 & $\pm$0.4 & $\pm$0.02 & $\pm$0.026\ & 5915 & 4.49 & 3.5 & &\ & $\pm$10 & $\pm$0.09 & $\pm$1.1 & &\ \ Sun & 5836 & 4.58 & 4.9 & -0.12 &\ & $\pm$40 & $\pm$0.10 & $\pm$0.2 & $\pm$0.04 &\ $^a$Minimum systematic uncertainties on T$_\text{eff}$ are about 100K.\ $^b$The MS subscript indicates that the $\log g$ did not converge to a realistic value ($>5$) and was fixed to be on the Main Sequence following $\log g = 12 - 2\log T_\text{eff}$ [@Angelov1996].\ $^c$When the $V \sin i$ is compatible with zero, we give the upper bound at the 1$\sigma$ limit; $V\sin i$=0 is used to derive the RVs.\ $^d$Given the systematic error on \[Fe/H\]$_\text{sun}$, a more reliable value of uncertainty on \[Fe/H\] should be at least 0.1dex. Deriving radial velocities -------------------------- We then applied [todmor]{} to all multi-order spectra of each target and determined the radial velocities of both components discarding all orders harboring strong telluric lines, following the method of paper III. In the cases where the S/N ratio and the secondary-to-primary flux ratio were large enough (SNR$>$90 and $\alpha$$>$$0.1$), we incorporated an enhancement on the 2D-CCF calculation. We employed the first-derivative of the spectra, rather than the spectra themselves. Using first derivative is equivalent to applying a linear filter on the spectra, filtering out low frequency components (like *e.g.* the continuum). Unfortunately, it enhances high frequency noise, and for that reason cannot be used on low S/N ratio spectra. We found that it greatly reduces systematics on RV measurements of those binaries with strong blend. Final velocities for each component are displayed in Table \[tab:RVs\]. They are used to derive the orbital solutions for the 14 SB2s in the next section. \ \ \ \ The SB2 orbits {#sec:orbits} ============== The orbits derived from the RVs in Table \[tab:RVs\] have too large residuals in relation to uncertainties. This is clear when the $F_2$ indicator of the goodness-of-fit (GOF) is calculated (see paper II, equation 1): the values are too large to obey a normal distribution, because the uncertainties were underestimated. This results in underestimating the uncertainties of the parameters of the orbit, but also in assigning erroneous weights to the RVs of each component. Deriving an SB2 orbital solution necessitates attributing realistic errors to each dataset properly. The correction process was already used in paper III, we refer the reader to that paper for explanations. The corrected errors express as follow with respect to initial errorbars $\sigma_{RV}$: $$\begin{aligned} \sigma^\text{corr}_{RV, 1} &= \varphi_1 \times \sqrt{\sigma_{RV, 1}^2 + \varepsilon_1^2} \label{eq:correction1}\\ \sigma^\text{corr}_{RV, 2} &= \varphi_2 \times \sqrt{\sigma_{RV, 2}^2 + \varepsilon_2^2} \label{eq:correction2}\end{aligned}$$ The correction terms $\varphi_1$, $\varphi_2$, $\varepsilon_1$ and $\varepsilon_2$ are given in Table \[tab:corsigRVprev\]. The references of previously published RVs are also displayed in this table, as well as the related correction terms. The orbital solutions of the 14 SB2s were derived twice: from the SOPHIE RVs alone, and also combining them with the previously published RVs. The results are presented on Table \[tab:orbSB2\]. Only the period, $P$, the time of periastron passage, $T_0$, and the SOPHIE offset $d_{n-p}$ were taken from the combined solution, since $P$ and $T_0$ are more accurate than in the SOPHIE solution. The eccentricity $e$, the center-of-mass velocity $\gamma$, the periastron longitude $\omega$, the RV amplitudes $K_1$ and $K_2$ and the deducted minimum masses and minimum semi-major axes were all taken from the SOPHIE solution. The primary offset $d_{2-1}$ also refers to this solution. The secondary component velocities are often shifted by up to a few 100m s$^{-1}$ compared primary’s velocities (paper II-III). This $d_{2-1}$ incorporates such shift as an additional parameter to the RV fit. ---------------------- -------------------------- --------------------- ----------------- --------------------- ----------------- --------------------- ----------------- --------------------- ----------------- HIP/HD Reference of previous RV $\varepsilon_{1,p}$ $\varphi_{1,p}$ $\varepsilon_{1,p}$ $\varphi_{2,p}$ $\varepsilon_{1,n}$ $\varphi_{1,n}$ $\varepsilon_{2,n}$ $\varphi_{2,n}$ km s$^{-1}$ km s$^{-1}$ km s$^{-1}$ km s$^{-1}$ HIP 7143 [@Katoh13] 0.017 1 $\ldots$ $\ldots$ 0.0129 0.947 0.1768 0.947 HIP 9121 [@Goldberg02] 0 0.599 0 3.962 0.0232 0.937 0.5146 0.937 HIP 12472 CGG95$^a$ 0 0.674 $\ldots$ $\ldots$ 0 1.049 0.2515 1.049 HIP 21946 HMU12$^a$ 0 1 0 1 0.0068 1.116 0.2676 1.116 HIP 38018 DM88$^a$ 0 1 $\ldots^b$ $\ldots^b$ 0.0338 0.921 0.2519 0.921 HIP 48895 [@Griffin06]$^c$ $\ldots$ $\ldots$ 0 1.409 1.4918 1.054 0.6993 1.054 HD 98031 [@Griffin05b] 0 0.316 0 0.822 0.0233 0.961 0.2224 0.961 HIP 61100 [@Halb2003] 0 0.7359 1.467 1 0.0196 1.021 0.1965 1.021 HIP 72706 [@Massarotti08] 0 1 $\ldots$ $\ldots$ 0.0267 1.208 0 1.208 HIP 77122 [@Goldberg02]$^d$ 0.770 1 3.416 1 0.0085 1.083 0.0993 1.083 HIP 95995 [@Pourbaix00] 0 1.070 0 1.060 0 0.489 0.0736 0.953 HIP 100046 [@Griffin05c]$^e$ 0 0.471 0 0.404 0.7031 1.060 0.0905 1.060 HIP 101382 [@Torres2002] 0 0.316 0 1.422 0.0206 0.938 0.0658 0.938 HIP 116360 [@Griffin05a] 0 0.325 0 0.433 0.0272 0.982 0.0238 0.982 \[tab:corsigRVprev\] ---------------------- -------------------------- --------------------- ----------------- --------------------- ----------------- --------------------- ----------------- --------------------- ----------------- $^a$ CGG95 = [@Carquillat95], HMU12 = [@Halb2012], DM88 = [@Duquennoy88]\ $^b$ The secondary component was marginally detected by DM88, but these measurements were so inaccurate that we prefer to ignore them.\ $^c$ [@Griffin06] derived the orbit of the secondary component, but not of the primary. He detected the primary component four times, but he didn’t take these measurements into account in the derivation of the orbit.\ $^d$ We have discarded the primary RV obtained by [@Goldberg02] for the epoch BJD=$2\,446\,604.810$.\ $^e$ The components of [@Griffin05b] are in the reverse position. ---------------- ---------------- -------------- --------------- --------------- -------------- --------------- ----------------------- -------------- ------- --------------- ------------------- -- -- -- HIP $P$ $T_0$(BJD) $e$ $V_0$ $\omega_1$ $K_1$ ${\cal M}_1 \sin^3 i$ $a_1 \sin i$ $N_1$ $d_{n-p}$ $\sigma(O_1-C_1)$ HD/BD $K_2$ ${\cal M}_2 \sin^3 i$ $a_2 \sin i$ $N_2$ $d_{2-1}$ $\sigma(O_2-C_2)$ (d) 2400000+ (km s$^{-1}$) ($^{\rm o}$) (km s$^{-1}$) (${\cal M}_\odot$) (Gm) (km s$^{-1}$) (km s$^{-1}$) HIP 7143 36.519182 56614.6542 0.14321 0.7726 203.418 34.9715 1.0971 17.3808 15 -2.7542 0.012 HD 9312 $\pm 0.000031$ $\pm 0.0057$ $\pm 0.00018$ $\pm 0.0040$ $\pm 0.073$ $\pm 0.0057$ $\pm0.0033$ $\pm 0.0028$ (12) $\pm 0.0085$ (0.019) 45.821 0.8373 22.773 15 0.490 0.173 $\pm 0.065$ $\pm0.0014$ $\pm 0.032$ $\pm 0.049$ HIP 9121 694.613 56921.910 0.56841 4.1302 313.220 15.108 1.003 118.725 16 0.338 0.020 BD +41 379 $\pm 0.022$ $\pm 0.069$ $\pm 0.00054$ $\pm 0.0068$ $\pm 0.081$ $\pm 0.012$ $\pm0.020$ $\pm 0.082$ (40) $\pm 0.097$ (0.517) 20.14 0.7524 158.3 16 0.070 0.452 $\pm 0.19$ $\pm0.0080$ $\pm 1.5$ (39) $\pm 0.135$ (3.52) HIP 12472 328.800 56891.43 0.1451 -4.929 354.28 12.341 0.6478 55.19 11 0.076 0.031 HD 16646 $\pm 0.020$ $\pm 0.72$ $\pm 0.0021$ $\pm 0.021$ $\pm 0.84$ $\pm 0.022$ $\pm0.0089$ $\pm 0.10$ (67) $\pm 0.102$ (0.861) 19.44 0.4112 86.94 11 0.383 0.274 $\pm 0.12$ $\pm0.0034$ $\pm 0.53$ $\pm 0.102$ HIP 21946 56.44365 56964.6923 0.35377 14.2337 191.221 26.7000 0.7515 19.3823 11 0.427 0.010 HD 285970 $\pm 0.00016$ $\pm 0.0079$ $\pm 0.00024$ $\pm 0.0064$ $\pm 0.067$ $\pm 0.0084$ $\pm0.0077$ $\pm 0.0066$ (38) $\pm 0.081$ (0.404) 37.78 0.5312 27.42 11 0.011 0.406 $\pm 0.18$ $\pm0.0030$ $\pm 0.13$ (3) $\pm 0.135$ (5.17) HIP 38018 553.206 57163.64 0.4276 -22.194 222.21 10.549 0.4676 72.54 12 0.400 0.024 HD 61994 $\pm 0.037$ $\pm 0.19$ $\pm 0.0012$ $\pm 0.011$ $\pm 0.22$ $\pm 0.015$ $\pm0.0067$ $\pm 0.11$ (17) $\pm 0.115$ (1.26) 15.85 0.3112 108.98 12 0.243 0.215 $\pm 0.10$ $\pm0.0026$ $\pm 0.70$ $\pm 0.078$ HIP 48895 33.71218 56574.65 0.0565 37.02 310.2 15.82 0.2373 7.32 17 -1.845 1.569 HD 86358 $\pm 0.00091$ $\pm 0.77$ $\pm 0.0087$ $\pm 0.40$ $\pm 8.9$ $\pm 0.51$ $\pm0.0070$ $\pm 0.24$ $\pm 0.381$ 31.06 0.1209 14.37 17 0.776 0.576 $\pm 0.26$ $\pm 0.0067$ $\pm 0.12$ (32) $\pm 0.465$ (1.67) HD 98031 271.265 56637.63 0.2216 68.664 213.63 6.8751 0.04309 24.996 14 -0.650 0.020 BD +13 2380 $\pm 0.017$ $\pm 0.37$ $\pm 0.0019$ $\pm 0.014$ $\pm 0.63$ $\pm 0.0088$ $\pm0.00083$ $\pm 0.033$ (65) $\pm 0.050$ (0.301) 7.742 0.03827 28.15 14 0.482 0.202 $\pm 0.072$ $\pm0.00039$ $\pm 0.26$ (65) $\pm 0.064$ (1.13) HIP 61100 1284.11 56493.58 0.5119 -9.722 244.75 9.615 0.5186 145.94 12 0.343 0.016 HD 109011 $\pm 0.14$ $\pm 0.37$ $\pm 0.0012$ $\pm 0.011$ $\pm 0.20$ $\pm 0.013$ $\pm0.0069$ $\pm 0.16$ (35) $\pm 0.065$ (0.361) 12.530 0.3980 190.2 12 0.122 0.203 $\pm 0.078$ $\pm0.0029$ $\pm 1.2$ (35) $\pm 0.065$ (2.44) HIP 72706 83.52955 56474.385 0.49100 -46.056 275.75 25.308 0.6218 25.328 12 0.107 0.022 HD 131208 $\pm 0.00085$ $\pm 0.036$ $\pm 0.00058$ $\pm 0.023$ $\pm 0.14$ $\pm 0.019$ $\pm0.0020$ $\pm 0.014$ (16) $\pm 0.091$ (0.388) 32.506 0.48411 32.532 12 0.622 0.123 $\pm 0.050$ $\pm0.00099$ $\pm 0.048$ $\pm 0.062$ HIP 77122$^a$ 4185.42 56423.36 0.94077 -46.5890 239.00 21.363 0.8507 416.92 11 0.111 0.011 HD 141335 $\pm 0.55$ $\pm 0.20$ $\pm 0.00021$ $\pm 0.0061$ $\pm 0.11$ $\pm 0.018$ $\pm0.0047$ $\pm 0.48$ (54) $\pm 0.108$ (0.816) 24.221 0.7503 472.7 11 0.426 0.112 $\pm 0.055$ $\pm0.0031$ $\pm 1.1$ (55) $\pm 0.038$ (3.42) HIP 95995 494.313 56549.487 0.38926 11.8933 180.300 9.4911 0.14399 59.424 13 0.592 0.0045 HD 184467 $\pm 0.012$ $\pm 0.046$ $\pm 0.00030$ $\pm 0.0018$ $\pm 0.043$ $\pm 0.0026$ $\pm0.00076$ $\pm 0.015$ (36) $\pm 0.106$ (0.596) 9.733 0.14041 60.94 13 0.112 0.067 $\pm 0.026$ $\pm0.00038$ $\pm 0.16$ (36) $\pm 0.021$ (0.860) HIP 100046 289.4669 56661.48 0.5704 -16.52 83.28 23.90 1.078 78.13 18 -1.410 0.750 HD 193468 $\pm 0.0076$ $\pm 0.13$ $\pm 0.0013$ $\pm 0.18$ $\pm 0.24$ $\pm 0.24$ $\pm0.011$ $\pm 0.79$ (70) $\pm 0.311$ (1.57) 26.031 0.990 85.11 18 0.017 0.079 $\pm 0.040$ $\pm0.020$ $\pm 0.11$ (70) $\pm 0.188$ (0.809) HIP 101382 57.32176 56627.3786 0.30514 -5.4108 357.195 28.8519 0.8088 21.6578 15 0.411 0.017 HD 195987 $\pm 0.00010$ $\pm 0.0075$ $\pm 0.00025$ $\pm 0.0057$ $\pm 0.064$ $\pm 0.0077$ $\pm0.0012$ $\pm 0.0056$ (73) $\pm 0.038$ (0.322) 36.697 0.63590 27.547 15 0.187 0.063 $\pm 0.025$ $\pm0.00058$ $\pm 0.019$ (73) $\pm 0.020$ (1.41) HIP 116360 348.0437 56641.395 0.43503 26.4670 359.664 20.362 1.0271 87.734 14 -1.147 0.023 HD 221757 $\pm 0.0054$ $\pm 0.050$ $\pm 0.00036$ $\pm 0.0086$ $\pm 0.068$ $\pm 0.014$ $\pm0.0015$ $\pm 0.057$ (52) $\pm 0.048$ (0.307) 21.874 0.9561 94.251 14 0.105 0.025 $\pm 0.013$ $\pm0.0015$ $\pm 0.055$ (52) $\pm 0.013$ (0.452) \[tab:orbSB2\] ---------------- ---------------- -------------- --------------- --------------- -------------- --------------- ----------------------- -------------- ------- --------------- ------------------- -- -- -- **$^a$ The elements were derived fixing $P$ to the value obtained taking the measurements of [@Goldberg02] into account.** Masses and parallaxes of HIP61100, HIP95995 and HIP101382 {#sec:masses} ========================================================= When a visual orbit can be derived properly, an SB2 system with measured RV can be fully determined. Especially, the inclination can be evaluated and allows deriving the absolute mass of the system and of its components. Moreover with measurements independent of the Hipparcos 2 catalogue [@vanLeeuwen07] it also allows verifying and correcting the Hippacos parallax taking into account the orbital motion. We found a visual orbit for 3 of the 14 SB2s presented in this paper; namely HIP61100, HIP95995 and HIP101382. HIP 61100 --------- Our RV measurements were combined to the speckle and interferometric observations used by [@Schlieder2016], which are summarized in Table \[tab:HIP61100-interfero\]. The uncertainties of the interferometric measurements were corrected by 0.71 in order to obtain a visual orbit with a GOF $F_2=0$. These measurements are combined with our RV measurements and led to the orbital elements given in Table \[tab:VB-elements\]. The apparent orbit and its residuals are presented in Fig. \[fig:HIP61100\]. Our results are not really different from the preceding ones of [@Schlieder2016], but slightly more accurate, with masses ${\mathcal M}_1$=(0.834$\pm$0.017)${\cal M}_\odot$ and ${\mathcal M}_2$=(0.640$\pm$0.011)${\cal M}_\odot$, improving the mass measurement accuracy for these stars by a factor of 2.5 compared to [@Masda2016]. Our estimation of the parallax in Table \[tab:VB-elements\], is more accurate, but compatible, with that given by the [*Hipparcos 2*]{} catalogue: $\varpi=(39.84 \pm 1.07)$ mas. However, this value was derived ignoring the orbital motion. A correction of the Hipparcos parallax was derived from the elements in Table \[tab:VB-elements\] and from the residuals of the Hipparcos astrometric solution. The new value is then $\varpi=(40.75 \pm 1.24)$ mas, in reasonable agreement with our result. No Tycho-Gaia Astrometric Solution [[*TGAS*]{} hereafter; see Michalik, Lindegren & Hobbs 2015; @GaiaDR1] is available for this star, probably because of its orbital motion. --------------- ---------- --------- ------------ ------------ -------------- $T$-2,400,000 $X$ $Y$ $\sigma_a$ $\sigma_b$ $\theta_a$ (BJD) (mas) (mas) (mas) (mas) ($^{\rm o}$) 52367.9$^a$ 41.031 -57.944 1.425 0.706 125.3 52978.4 -115.245 -25.349 2.053 1.425 102.4 53456.7 -19.661 -73.413 2.138 1.604 75.0 53460.6 -20.835 -75.166 2.138 2.031 74.5 53872.8 55.760 5.181 1.425 0.969 5.3 55344.1 -75.230 19.436 0.499 0.285 165.5 56405.2 64.134 -8.537 1.041 0.143 82.4 56653.2$^a$ -85.120 13.605 1.390 0.285 80.9 --------------- ---------- --------- ------------ ------------ -------------- : The interferometric measurements of HIP 61100, taken from Schlieder et al. (2016) and adapted to our purpose. $X$ is oriented to North and $Y$ to East. $\sigma_a$ and $\sigma_b$ are the semi-major axis and the semi-minor axis of the ellipsoid error, respectively; they are corrected as explained in the text. $\theta_a$ is the position angle of the major axis of the ellipsoid error. $X$, $Y$ and $\theta_a$ are for equinox 2000. \[tab:HIP61100-interfero\] $^a$ We have merged two measurements performed at the same epoch. HIP95995 -------- This star is the close visual binary MCA 56. [@Masda2016] combined RV measurements and the interferometric measurements provided by the Fourth Catalog of Interferometric Measurements of Binary Stars[^3] [Third catalogue: @Hartkopf01] to derive the masses of the components: ${\cal M}_1$=(0.89$\pm$0.08)${\cal M}_\odot$ and ${\cal M}_2$=(0.83$\pm$0.07)${\cal M}_\odot$. We found that the less accurate measurements in the “Fourth Catalog” were also the less reliable ones, since their errors are much larger than their uncertainties; therefore, we derived the visual orbit taking into account only the measurements with uncertainties smaller than 2 mas. These measurements are presented in Table \[tab:HIP95995-interfero\]. We applied to these uncertainties a correcting factor of 0.81 in order to get the apparent orbit with the GOF $F_2=0$. The combination of the relative positions with our RVs leads to the parameters in Table \[tab:VB-elements\]. The apparent orbit and its residuals are presented in Fig. \[fig:HIP95995\]. We found the masses ${\cal M}_1$=(0.833$\pm$0.031)${\cal M}_\odot$ and ${\cal M}_2$=(0.812$\pm$0.030)${\cal M}_\odot$ We found the parallax $\varpi=(56.10 \pm 0.81)$ mas, which is slightly different from that given in the [*Hipparcos 2*]{} catalogue: $\varpi=(58.96 \pm 0.65)$ mas. This is due to the orbital motion with a period close to one year: Correcting the Hipparcos parallax for this motion leads to $\varpi=(57.15 \pm 0.31)$ mas, in acceptable agreement with our result. The parallax from [*TGAS*]{} [@Michalik2015; @GaiaDR1] is $\varpi=(58.37 \pm 0.54)$ mas; the difference probably comes from the fact that the orbital motion was ignored in the calculation of [*TGAS*]{}. [@lccc@]{} & HIP61100 & HIP95995 & HIP101382\ $P$ (days) & 1285.31 $\pm$ 0.27 & 494.307 $\pm$ 0.012 & 57.32176 $\pm$ 0.00010$^a$\ $T_0$ (BJD-2400000) & 56492.13 $\pm$ 0.35 & 56549.505 $\pm$ 0.043 & 56627.3786 $\pm$ 0.0075$^a$\ $e$ & 0.51130 $\pm$ 0.00093 & 0.38933 $\pm$ 0.00029 & 0.43503 $\pm$ 0.00036$^a$\ $V_0$ (km s$^{-1}$) & -9.7113 $\pm$ 0.0096 & 11.8932 $\pm$ 0.0018 & -5.4108 $\pm$ 0.0057$^a$\ $\omega_1$ ($^{\rm o}$) & 244.50 $\pm$ 0.16 & 180.325 $\pm$ 0.041 & 357.195 $\pm$ 0.064$^a$\ $\Omega$($^{\rm o}$; eq. 2000) & 355.83 $\pm$ 0.24 & 245.72 $\pm$ 0.13 & 334.960 $\pm$ 0.070$^b$\ $i$ ($^{\rm o}$) & 58.63 $\pm$ 0.46 & 146.15 $\pm$ 0.46 & 99.364 $\pm$ 0.080$^b$\ $a$ (mas) & 102.19 & 81.03 & 15.378 $\pm$ 0.027$^b$\ ${\cal M}_1$ (${\cal M}_\odot$) & 0.834 $\pm$ 0.017 & 0.833 $\pm$ 0.031 & 0.8420 $\pm$ 0.0014\ ${\cal M}_2$ (${\cal M}_\odot$) & 0.640 $\pm$ 0.011 & 0.812 $\pm$ 0.030 & 0.66201 $\pm$ 0.00076\ $\varpi$ (mas) & 38.82 $\pm$ 0.23 & 56.10 $\pm$ 0.81 & 46.131 $\pm$ 0.084\ $d_{2-1}$ (km s$^{-1}$) & 0.097 $\pm$ 0.064 & 0.112 $\pm$ 0.021 & 0.187 $\pm$ 0.020$^a$\ $\sigma_{(o-c)\;VB}$ (mas) & 1.04 & 0.673 & -\ $\sigma_{(o-c)\;RV}$ (km s$^{-1}$) & 0.019, 0.202 & 0.0049, 0.066 & 0.017, 0.063$^a$\ \ $M_{A}$ (mag) & 4.06 $\pm$ 0.25$^d$ & 5.98 $\pm$ 0.02$^e$ & $\ldots$\ $M_{B}$ (mag) & 4.77 $\pm$ 0.27$^d$ & 6.24 $\pm$ 0.03$^e$ & $\ldots$\ $Y$ & $0.245-0.27$ & $0.245 - 0.279$ & $\ldots$\ age (Gyr) & 0.4$^c$ & $2.2 - 7.9$ & $\ldots$\ ${\rm [Fe/H]}$ (dex)& -0.17 & -0.33$~-~$-0.17 & $\ldots$\ \[tab:VB-elements\] $^a$ From Table \[tab:orbSB2\].\ $^b$ From the “Full Fit” solution of [@Torres2002].\ $^c$ Age of the UMA Group [@Jones2015]\ $^d$ K-band magnitude\ $^e$ V-band magnitude\ --------------- --------- --------- ------------ ------------ -------------- $T$-2,400,000 $X$ $Y$ $\sigma_a$ $\sigma_b$ $\theta_a$ (BJD) (mas) (mas) (mas) (mas) ($^{\rm o}$) 51097.8 -2.366 -49.944 1.628 0.497 87.3 51478.0 78.322 35.032 0.236 0.163 114.1 51865.3 52.047 99.172 0.814 0.472 62.3 52185.5 -46.283 44.203 0.993 0.814 46.3 52185.5 -45.654 46.268 1.009 0.814 44.6 53303.2 28.382 106.275 1.628 0.464 75.0 53896.0 73.586 73.492 0.814 0.586 44.9 --------------- --------- --------- ------------ ------------ -------------- : Same as Table \[tab:HIP61100-interfero\], but for HIP 95995. Only the positions more accurate than 2 mas are selected from the Fourth Catalogue of Interferometric Measurements of Binary Stars. \[tab:HIP95995-interfero\] HIP 101382 ---------- For this system, [@Torres2002] already derived the orbital elements from the combination of observations made at the Palomar Testbed Interferometer, with RV measurements. Unfortunately, they did not provide the positions of the secondary component with respect to the primary, so we cannot compute a combined orbit as for the two preceding binaries. However, comparing the elements of their “full fit” with those derived from our RVs, it appears that, expressed in unit of uncertainties, the discrepancies for period, periastron epoch, eccentricity and periastron longitude are -0.41, 0.91, 1.81 and 0.69 respectively. These values are all between -2 and +2, indicating a nice agreement between their elements and our solutions. With the inclination derived from their ”full fit”, we found the new masses: ${\cal M}_1$=(0.8420$\pm$0.0014)${\cal M}_\odot$ and ${\cal M}_2$=(0.66201$\pm$0.00076)${\cal M}_\odot$, improving the accuracy on these masses by a factor of 10 compared to [@Torres2002]. Moreover, we evaluated a new measurement of the parallax $\varpi=(46.131 \pm 0.084)$ mas. For comparison, the [*Hipparcos 2*]{} catalogue gives $(45.35 \pm 0.43)$ mas, which becomes $(45.31 \pm 0.44)$ mas when our orbital elements are applied to the residuals of the Hipparcos astrometric solution. The [*Hipparcos 2*]{} parallax is thus marginally compatible with ours, although slightly underestimated. The parallax from [*TGAS*]{} [@Michalik2015; @GaiaDR1] is $\varpi=(46.61 \pm 0.83)$ mas, in good agreement with our result, although the orbital motion was not taken into account in the calculation. Initial stellar parameters of HIP61100 and HIP95995 {#sec:models} =================================================== Having derived very accurate masses for HIP61100 and HIP95995 allowed us to characterize the two components of these binaries in terms of initial helium content and age. For that purpose, we modeled the two components following the stellar model optimisation method described in [@Lebreton2014]. We adopted the reference set of stellar input physics described in that paper and the [`Cesam2k`]{} stellar evolution code [@Morel2008]. The observational constraints considered for the models are the masses of the two components herebefore determined, their effective temperatures and luminosities, and the present metallicity of the primary component. We point out that we decided not to model HIP101382 because this binary system is enriched in $\alpha$-elements, with \[$\alpha\text{/Fe}$\]=$0.36$ [@Torres2002]. As discussed by [@Torres2002], a proper modeling would require to calculate new opacity tables which is beyond the scope of the present paper. In support of the previous estimation of stellar parameters given in Table \[tab:stellpar\], we used the code `iSpec` [@Blanco2014] to verify the primary stellar parameters. Results for HIP61100 and HIP95995 are discussed below and appended to Table \[tab:VB-elements\]. HIP61100 -------- To derive the luminosities of the components, we proceeded as follows. First, we used the system K band magnitude, $K$=5.662$\pm$0.020 from 2MASS [@Cutri2003], the magnitude difference of the two components in the K band, $\Delta K$=0.71$\pm$0.02 [@Schlieder2014], and the spectroscopic parallax derived in the present study. We obtained the absolute magnitudes $M_{K, A}$=4.06$\pm$0.25 and $M_{K, B}$=4.77$\pm$0.27mag. Then, in the calculation of the stellar models, we derived the luminosity using the bolometric corrections $BC_K(T_\mathrm{eff},\log g,\mathrm{[Fe/H]})$ of [@Casagrande2014]. The `iSpec` derivation gave $T_\text{eff}$=5049$\pm$43K, $\log g$=4.52$\pm$0.15dex, and \[Fe/H\]=-0.13$\pm$0.10, as consistent with what derived in Table \[tab:stellpar\]. Therefore, we constrained the stellar models with the effective temperatures of Table \[tab:stellpar\]. The choice of the metallicity is more delicate. We therefore considered three possible values of the metallicity ($\mathrm{[Fe/H]}$=-0.13, -0.18, -0.33dex) covering the range reported in the literature displayed in the SIMBAD database (Wenger et al. 2000).. We further assumed that the stars have a common origin and therefore share the same initial metallicity, helium abundance and age. Their initial helium abundance in mass fraction should be higher than the primordial value $Y_p$$\sim$0.245 [see e.g. @Peimbert2016; @Izotov2014]. Furthermore, according to [@King2003], the system is a bona-fide member of the UMA Group nucleus. Therefore, we assumed that the common age of the components is 400Myr, i.e. the age of the UMa group [@Jones2015]. The model optimisation provides the initial helium abundance for each star. The results are shown in Fig. \[fig:He\_abun\]. We first note that low values of the metallicity ($\mathrm{[Fe/H]}$=$-0.33$dex) can be excluded because they would lead to a sub-primordial initial helium abundance of the system. On the other hand, considering also the constraint that the two components have the same initial helium abundance, we find good compatibility with models on the higher metallicity case, with $\mathrm{[Fe/H]} \sim -0.15$, provided that the primary mass is on the lower bound and secondary mass on the upper bound of their confidence interval. Finally, we also explored the possibility that the stars have an age of 500Myr, as assumed by [@Schlieder2016] but did not find any satisfactory solution with the subsolar $\mathrm{[Fe/H]}$ values considered here. HIP95995 -------- To derive the luminosities, we took the parallax derived here, the system V band magnitude ($V$=6.607$\pm$0.010) from Tycho 2 [@Hog2000], and the magnitude difference of the two components in the $V$ band ($\Delta V$=0.26$\pm$0.03) which we calculated as the mean of interferometric values listed in Table 2 of [@Masda2016], but keeping the values with given error bars only. We obtained the absolute magnitudes $M_{V, A}$=5.98$\pm$0.02 and $M_{V, B}$=6.24$\pm$0.03mag. Then, we applied the bolometric corrections of [@Casagrande2014]. We did not include extinction, since it is usually expected to be very small for a star at less than 20 pc. The primary stellar parameters derived from `iSpec` are $T_\mathrm{eff}$=4972$\pm$32K and $\mathrm{ [Fe/H]}$=-0.45$\pm$0.27, in reasonable agreement with those derived in Table 2. Therefore, we constrained the stellar models with the effective temperatures of Table \[tab:stellpar\]. Since [@Casagrande2011] rather derived $\mathrm{ [Fe/H]}$=-0.17, we performed two sets of models, one with the metallicity determined here ($\mathrm{ [Fe/H]}$=-0.33) and one with $\mathrm{ [Fe/H]}$=-0.17. In the case of HIP 95995, we do not have constraints on the age. However, the star is classified as inactive by [@Gray2003] which is not in favor of young ages. Moreover, [@Casagrande2011] gives a rough estimation of the age of this system, 13.8$\pm$6Gyr. To model the system, we first optimized models of the primary component, adjusting the age, initial helium abundance and metallicity; and then we searched for a model of the secondary component by fixing its age and initial composition equal to those of the primary. Unfortunately, despite the improvement on the mass, the stellar model of HIP95995 remains rather poorly constrained, due to possible misestimation of the secondary’s stellar parameters. We thus eventually discarded the secondary’s constraint and only considered the contribution of the primary in the following. No acceptable solution (Y$>$Y$_\text{primordial}$ and age$>$1Gyr) is found for the upper part of the mass confidence interval (${\cal M}_A$$>$0.833${\cal M}_\odot$), and decreasing or increasing the metallicity still leads to reject the models. At ${\cal M}_A$=0.833${\cal M}_\odot$, the best models stand around $\mathrm{ [Fe/H]}$=-0.17; they lead to an age range $\sim$2.2-5.3Gyr and initial helium abundance $Y_0$=0.250-0.265. Finally, for ${\cal M}_A$$<$0.833${\cal M}_\odot$, the most suitable models have ages in the range 2.4-7.9 Gyr, initial helium abundance in the range 0.245-0.279, and metallicity between -0.17 and -0.33. Summary and conclusion {#sec:conclusion} ====================== Thanks to new SOPHIE spectra of 14 SB2s, four of which are newly identified SB2 (paper I), and the use of the [todmor]{} code, we derived new better accurate orbital solutions to the RV measurements of these binaries. The projected masses ${\cal M}\sin^3 i$ were calculated for all 14 SB2s, with an average accuracy of 1.0$\pm$0.2%, with extreme cases such as the rapid rotator HIP48898 with $\sigma({\cal M}\sin^3 i)$$\sim$4%, or HIP101382 with $\sigma({\cal M}\sin^3 i)$$\sim$0.12%. For HIP61100, HIP95995 and HIP101382, archival interferometric measurements allowed us to fully constraint the systems and derive masses for components (A,B) with accuracies respectively (2.0, 1.7)%, (3.7, 3.7)%, and (0.2, 0.1)%. The stellar evolution code `Cesam2k` [@Morel2008] applied to HIP61100 and HIP95995, led to constrain their age, metallicity and initial helium content. HIP61100 was found slightly overabundant in He with respect to primordial helium abundance, with $\mathrm{ [Fe/H]}\sim-0.15$dex and an age close to 400Myr, while HIP95995 was harder to constrain, assuming a relatively old star with age$>$1Gyr, and using only primary star’s mass and stellar parameters, led to a possible overabundance in He, with -0.33$<$\[Fe/H\]$<$0.17. Although we could not calculate stellar evolution models of HIP101382, the masses of the SB2 components that we derived reached the level of 0.1% accuracy. In the future, this star will likely become a reference for validating masses derived from [*Gaia*]{}. Added to the systems already published in papers II and III, we have now 6 binaries observed with SOPHIE and interferometric instruments which may be used to verify the masses that will be derived from [*Gaia*]{}. This number will continue to increase until the completion of the programme. Acknowledgments {#acknowledgments .unnumbered} =============== We sincerely thank the anonymous reviewer for his careful reading of our manuscript and valuable comments. This project was supported by the french INSU-CNRS “Programme National de Physique Stellaire”, “Action Spécifique [*Gaia*]{}”, and the Centre National des Etudes Spatiales (CNES). We are grateful to the staff of the Haute–Provence Observatory, and especially to Dr F. Bouchy, Dr H. Le Coroller, Dr M. Véron, and the night assistants, for their kind assistance. We made use of the SIMBAD database, operated at CDS, Strasbourg, France. This research has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant-agreement numbers 291352 (ERC) Angelov T., 1996, BABel, 154, 13 Blanco-Cuaresma S., Soubiran C., Heiter U., Jofr[é]{} P., 2014, A&A, 569, A111 Carquillat J.-M., Griffin R.F., Ginestet N., 1995, A&AS 109, 173 Casagrande L., Sch[ö]{}nrich R., Asplund M., Cassisi S., Ram[í]{}rez I., Mel[é]{}ndez J., Bensby T., Feltzing S., 2011, A&A, 530, A138 Casagrande L., VandenBerg D. A., 2014, MNRAS, 444, 392 Cutri R. M., et al., 2003, tmc..book, Drake J. J., 1991, MNRAS, 251, 369 et al. 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I., Torres G., Udry S., 2004, A&A, 424, 727 Schlieder J. E., et al., 2014, ApJ, 783, 27 Schlieder J.E., Skemer A.J., Maire A.-L., Desidera S., Hinz P. et al., 2016, AJ 818, 1 Torres G., Boden A.F., Latham D.W., Pan M., Stefanik R.P., 2002, AJ 124, 1716 Torres G., Fischer D. A., Sozzetti A., Buchhave L. A., Winn J. N., Holman M. J., Carter J. A., 2012, ApJ, 757, 161 van Leeuwen F., 2007, A&A 474, 653 Zucker S., Mazeh, T., 1994, ApJ, 420, 806 Zucker S., Mazeh T., Santos N. C., Udry S., Mayor M., 2004, A&A, 426, 695 \[lastpage\] [^1]: E-mail: [email protected] [^2]: based on observations performed at the Observatoire de Haute–Provence (CNRS), France [^3]: http://www.usno.navy.mil/USNO/astrometry/optical-IR-prod/wds/int4

Q: Determinar tempo e data de instalação de um aplicativo no Android É possível obter a data e o tempo exato que o seu usuário instalou o aplicativo? No iOS7+, você pode obter um recibo de quando o aplicativo foi baixado usando [NSBundle appStoreReceiptURL]. A: Obtendo o Tempo e Data de Instalação É possível obter o tempo e a data de instação da primeira vez que o aplicativo foi instalado através do packageManager: long installTime = context.getPackageManager() .getPackageInfo("com.some.package.name", 0) .firstInstallTime; E a sua respectiva versão: PackageInfo pInfo = getPackageManager().getPackageInfo(getPackageName(), 0); version = pInfo.versionName; Infelizmente, essa data é resetada sempre que o aplicativo for re-instalado. Se você usar o seguinte código PackageManager pm = context.getPackageManager(); ApplicationInfo appInfo = pm.getApplicationInfo("app.package.name", 0); String appFile = appInfo.sourceDir; long installed = new File(appFile).lastModified(); você conseguirá determinar a data de instalação do aplicativo no Android, mas o tempo irá sempre mudar quando ele for atualizado.

Abroskina Natalia Anatolievna,GVA Sawyer One of the top experts in the retail property management of Moscow market with 14 years of experience in operational management of 4 mixed-use complexes of total 130 000 sq.m. GBA. During her career in Colliers International Natalia was responsible for retail property facility management and she established business processes in 11 Shopping Centers in Moscow and in Regions. Nowadays in GVA Sawyer Natalia is responsible for retail properties’ occupancy issues and provides property management consulting for the Retail & Leisure Center Pobeda Plaza in Saratov. Shevchuk Elena Viktorovna, Vice-President for the Commercial Real Estate, Partner, GVA Sawyer Elena has over 17 years of working experience in the commercial real estate. Her customers were such global companies as Bloomberg, the Caspian Pipeline Consortium (CPC), Coca-Cola Soft Drink Consulting, Hoffmann-La Roche Ltd., Skadden, Arps, Slate, Meagher&Flom LLP, Rolf, Finn Flare, Comus, Volvo, LG etc. Has conducted tenant finding program in a number of Shopping Centers in Moscow and in Regions. Elena does training courses on Marketing for Commercial Real Estate in Moscow and St.Petersbug. Elena is a Member of the Expert Board of the Russian Guild of Property Managers and Developers concerning the certification issues for business centers in Moscow and also she is a Deputy Chairman of the Retail Real Estate Committee in the Russian Guild of Property Managers and Developers. PROGRAM: April, 26, 2018 (Thursday) Introduction: Property Management issues for the Shopping Centers in operation

Which weight will lift first as the rope is pulled? - brlewis http://friendfeed.com/rahsheen/b7e00bb3/which-weight-will-lift-first-as-rope-is-pulled ====== mkn I loved these pulley problems in statics. Assume the weights are resting on a surface, the pulleys and rope are massless, the pulleys are frictionless, and the system is maintained in quasi- equilibrium as the rope is pulled (steady state & small accelerations). In this case, the tension T in the rope is constant everywhere. Now, take a horizontal section through the ropes. ("Cut" them and replace the missing portions of the rope with the tension.) Each weight is experiencing an upward force of 2T. When 2T >= 20, or T = 10, weight A begins to rise. Once a hits a stop, T must be increased to just above 20 to get Weight B to rise. Similarly, T just above 30 causes C to rise after B stops. The "trick" with these pulley problems is to section the problem through the cables and show the tension, T. Then you've just got free body problems, in this case subject to the floor constraint. Oh, also, while the first weight is being lifted, the floor beneath weight B experiences 40 - 20 = 20 units of force, and the floor under C experiences 60 - 20 = 40 units of force. Once B is lifted, the floor under C experiences 60 - 40 = 20 units of force. (Presuming that the labels are weights, and not masses.) ~~~ lazyant "When ... T = 10, weight A begins to rise". No; the Tension the guy is supporting at rest is bigger than 10 (there are 2 other weights) so at T = 10 he would be moving backwards. He needs to apply a bit more than the tension at rest. (edit: this is for when all 3 weights are in the air, I see now some people see them in a floor that is not drawn) ~~~ brlewis The bottom of each weight is at about the same level as the bottom of the man's feet. A floor is the natural thing to assume. Otherwise it would be difficult to get them into this configuration. ~~~ leif A good way to think about this is to replace the man with a fourth weight, fixed to the rope (as opposed to a pulley). Now it should be clear that the weights would not rest in that configuration unless they were supported by a floor. ------ RiderOfGiraffes If the system is frictionless, the rope is weightless, and the weights are not supported, then the lighter weight will rise and the heavier weight(s) will fall. Therefore if the rope is pulled very slowly, the lighter weight will rise first. If the rope really is weightless and the pulleys really are fictionless (and inertialess) then it doesn't matter how hard or fast you pull, the lighter weight will rise first. This is at odds with your intuition simply because you have no (or insufficient) experience with weightless and frictionless environments. This is one reason why space is so bloody dangerous, in addition to the dangers posed by, say, diving, where similarly to space, your equipment has to work perfectly or you die. In the real world, pulling fast enough will make the closer weight rise first. The truth lies somewhere in between. ~~~ mcn >If the rope really is weightless and the pulleys really are fictionless (and inertialess) then it doesn't matter how hard or fast you pull, the lighter weight will rise first. I'm considering a thought experiments that make me believe that this is not the whole story. Imagine a two weight system set up similar to the original diagram in which the weights are the same weight, and the gravity is very little. Yanking on the rope I imagine them rising at the same speed. Now, we take a very small flake off of one weight and repeat the experiment. It seems clear that both weights will still rise from the start, just the lighter weight will rise at a faster speed. I think this should extend to three weights of any positive mass -- if you yank the rope fast enough (and it might be very fast) all three should rise from the start. ~~~ brlewis In your thought experiment you make the weight difference so small that otherwise insignificant factors (e.g. friction) take over. Go the opposite direction and make the weight difference enormous. ~~~ mcn Assuming no friction and given a fast tug of the rope I still don't think the near equal weight would hold still or sink while the other near equal weight flew up quickly. With the large weight difference, I think the required speed of pulling the rope to make them both rise just becomes impractically fast. Imagine the system in space - all the weights would move up, so they all have an upward force applied to them from the rope tugging. It's just a matter of pulling so fast that that upward force overcomes gravity. ------ cynicalkane Well, the diagram is impossible unless the weights are all resting on the floor, so let's assume they are. This system will find a steady state only at a local minimum of potential energy, so the lightest weight will be lifted before the heavier two get off the ground. ~~~ psycocoffey Assumptions: pulleys: idealized, massless, frictionless rope: idealized, massless, doesn't stretch weights: resting on ground. As tension is applied to the rope, Weight A will be lifted first, until it is lifted to the ceiling. Then Weight B, and finally Weight A. It helps to visualize Weight A as being massless. In that case, there would just be extra slack in the rope, and B&C would not move until the slack was taken in. ~~~ dkokelley * Then Weight B, and finally Weight A.* I believe you meant C, correct? ~~~ psycocoffey Yes, I meant C. Too late to go and fix it now. Good catch ------ hop This tricks people because it doesn't start out in static equilibrium. For it to look like this, the weights would have to be resting on a table to relieve the tension in the rope. If the man does nothing, the heaviest weight will fall and the lightest will rise. If it's frictionless and he starts pulling, the same thing will happen, only the lengths will lessen. ~~~ EventHorizon Could it not be in a meta stable equilibrium like this if the weights were of equal mass? The numbers of the weights are unit-less. We assume they represent the mass, but for all I know the number is the serial number of the weight. ~~~ hop For all we know, it could be in space, they could be heavily magnetized, 100m/s wind, .5 CoF in the pulleys, the rope could stretch, and the system could be traveling near the speed of light. ------ tankenmate I'm with Rider, if you view it as a "classic" physics class problem, ie weightless ropes and pulleys (and hence no angular inertia for the pulleys, and no inertia due to the ropes), and no friction, weight A would rise even without pulling the rope, weight B would remain static, and weight C would drop at the same rate that weight A would go up. If you pulled on the rope you could never make weight C go up faster than weight A until it hit the top and stopped moving. So the pulling bit is a red herring, as weight A would always hit the top before the other two, either pulling or holding it still. Assuming the weights are in kilograms you would have to let the rope go at a rate of 3.13 m/s (11.27 kph, 7 mph) to prevent weight A from rising. ~~~ tankenmate If you go with the weights on the floor model, then barrkel's comment a few below is correct. ------ JoeAltmaier Its not a static system; the question is unfair. ~~~ cynicalkane Why does that make it unfair? ~~~ lolipop1 Is the person currently pulling, are the weights on the ground, are the weigths currently moving to get into a stable position? Friction, weight of cord, acceleration, etc. etc. Any combination of the previous? Depending on your level with maths/physics you'll probably give different answers and make different assumptions. ~~~ cynicalkane In physics problems things are assumed idealized unless they aren't. Also, velocity doesn't matter here, and no math is required to solve the problem. ~~~ lolipop1 I didn't know physics problems are assumed to be idealized... When you build a bridge for example, will the physics try to be simplified to the max? (Honest question here). Velocity would matter -- it seems to me -- if there is friction and probably a few other factors included like elasticity. No? Personally, I always considered physicists to be applied mathematicians (not the other way around although I've seen physics problems thrown in university level math classes). That's why I put that there, so assuming a high level of math skills, you'd probably change your way of thinking quite a bit. ~~~ cynicalkane When you build a bridge, that's engineering, not physics. It's a physics convention that unspecified factors are assumed to be unimportant. If they were important, they would be specified. Anyway, it's implausible that the elasticity of the rope or the friction of the pulleys are going to matter. Unless you have really rusty pulleys, or something. ------ amalcon This reminds me of the airplane on the conveyor belt, in that the only confusion comes from the question being insufficiently specified. - Friction of the pulleys - Mass of the pulleys - Moment of inertia of the pulleys - Mass of the rope - Unit of mass of the weights - Is there a surface that the weights are resting on? - What's the local gravity like? - Others If we assume the things we're likely supposed to (rope mass, pulley friction, pulley mass and moment of inertia all insignificant, gravity tending down, resting on a surface), it's clear that the lightest weight will rise first. If, on the other hand, we make ridiculous assumptions (weights mass in AMU, in a no-gravity environment, high moment of inertia pulleys), then the "heavy" weight will lift first (because it's easier to lift the weight than to spin the pulleys). ~~~ brlewis The airplane on the conveyor belt is more interesting in this respect, in that different people have different ideas about how the question should be interpreted. For this question, I think everyone will agree on the likely expected assumptions. Incidentally, the mass of the rope doesn't affect the answer so long as it's uniform, and the mass of the pulleys doesn't matter so long as the pulleys directly attached to the weights all have the same mass. And once you assume the pulleys are frictionless, their moment of inertia doesn't affect the answer either. ~~~ amalcon True. The airplane problem had several things that were ambiguous; this problem only has things that are unspecified. ------ farmerbuzz I would love to see a video demonstration of the answer (my intuition was apparently wrong which would make a video that much more entertaining). ------ ck2 None. Instead he'll pull the ceiling down as they failed to screw it into the studs. ;-) ~~~ someone_here There's an elephant in the way? ------ lazyant The length of the rope is constant. For every weigh with a pulley the weigh moves 1/2 length unit for every length unit it's being pulled. Weights don't matter; C will go up first, then B then A (at a relative 1/2 length ratio). ~~~ lazyant funny the right answer being downvoted without reason ~~~ loup-vaillant You go against the consensus without a solid explanation. For instance, why don't the weights matter? Would they matter if they were respectively 1mg, 1kg, and 1megaton? ~~~ lazyant Fair enough. I gave the summarized version. I'll try to explain better. I'll only take basic classic mechanics assumptions: that the rope is of constant length (ie is like a cable that doesn't compress or expand). The framework is quasi-static classical mechanics; the results of the guy pulling slowly a little bit can solve the problem or be generalized (I won't consider the situation of the guy jerking quickly the rope etc). The guy's hand is under a calculable tension Tw that will be 60 units or whatever, it doesn't matter. The problem asks what happens when the guy pulls, so we suppose that he's not the one being pulled but he moves forward to the right. The tension Tg that he applies doesn't matter; as long as it's bigger than the one from the weights (Tg > Tw) he'll move the rope (we discard friction since he moves slowly or if you take into account friction he just needs more force, it doesn't matter). So the distribution of weights or their actual measure don't matter so far. (of course if you have a million tons and you blow the guy away weighs matter). Now since the cable/rope has constant length (there are no slacks etc since it's moving) when the guy pulls 1mm then than length needs to be taken from somewhere in the pulley systems. The effect of a pulley is to divide the length of rope you take in two (one has to go to the left vertical part of rope and the other one to the right one); this is why the tension in each side of a pulley is 1/2 of the total tension and you can pull with 1/2T a weight of T with a pulley. So with this we can straightforwardly calculate the tensions everywhere but we don't need that. So the that 1mm is taken from the system and the more pulleys the rope has to go through the less is taken (because of this 1/2 I explained above), so the weight closer to the guy (with less pulleys) will raise first, then the next one in the middle, then the next one etc; weighs don't matter. clarification update: poor conclusion wording: if weights are in the air all 3 weights go up at the same time but C will move more than B and B more than A. ~~~ cynicalkane When a weight is at rest, the tension in the rope must be less then or equal to half the weight. The problem asks which weight will be first to not be at rest. The answer should now be obvious. ~~~ lazyant When a weight is at rest the tension in the rope is _exactly_ half its weight. Problem asks which weight would be first to _raise_ (not "not be at rest" that could be going down) so that's why I'm supposing the guy can pull the whole thing. I'm also saying the first one is C (closer to guy). ~~~ cynicalkane The tension in the rope is greater than 30lbs, yet only one weight moves? I give up. ~~~ lazyant sorry; I made an edit with a clarification. Basically if the weights are at rest on the floor then mkn's answer is the correct one. If they are at rest on the air, then my answer is the correct one. ~~~ loup-vaillant No: <http://news.ycombinator.com/item?id=1659676> (this comment assumes that the weights are unsupported). ~~~ lazyant I supposed the system was at equilibrium without making the numbers. If it's not (as it seems) then sure, my reasoning is invalid and he's right, no problem.

Image caption Hustle follows the fortunes of a group of London confidence tricksters The creator of BBC One con artist drama Hustle has said its newly commissioned eighth series will be the last. But writer Tony Jordan did not rule out the possibility the show, which first aired in 2004, could be revived. "Do you allow the show to fade away or... quit while you're ahead?" he told Broadcast magazine. "You want to go out like James Dean in a fast car." A BBC spokesperson confirmed the next series of Hustle would be the last "with the current gang". But the corporation said it was "in discussions" about the programme's "continued life". The seventh series of Hustle, screened earlier this year, attracted an average audience of 6.3m viewers. The show, which stars Adrian Lester and Robert Vaughn, is made for the BBC by independent production company Kudos. Screenwriter Jordan acted as the lead storyliner on EastEnders for several years, and co-created time-travelling police drama Life on Mars.

Q: What are the conditions on using Eisenstein reduction of ternary quadratic forms? The ternary quadratic form $Q(x,y,z) = -3 x^2 + 3 x y + 3 x z - y^2 - y z - z^2$ is not positive definite. In Sage, using code found in this link, Q = TernaryQF([-3, -1, -1, -1, 3, 3]) Qr, m = Q.reduced_form_eisenstein() Qr Qr.is_eisenstein_reduced() nothing is returned by Sage. Why is nothing returned by Sage, what are the conditions on using Eisenstein reduction, what is a reference on Eisenstein reduction of ternary quadratic forms, and if $Q(x, y, z)$ does not satisfy the conditions for Eisenstein reduction, is there another appropriate reduction that might be used in such a case? A: your form is negative semidefinite, a binary form in disguise. Note that the determinant of the Hessian matrix of second partials is zero. In my standard order $$ x^2, y^2, z^2, yz, zx, xy $$ you have ordered coefficients $$ -3,-1,-1,-1,3,3 $$ This is $SL_3 \mathbb Z$ equivalent to $$ -1,-1,-1,1,1,1 $$ or $$ -\frac{1}{2} \left( (v-w)^2 + (w-u)^2 + (u-v)^2 \right) $$ by $$ x=u, \; y = u+v-w , z=w $$ This is also $$ - \frac{1}{4} (2u - v - w )^2 - \frac{3}{4} ( v - w )^2 $$ of deficient rank

This is the Pip-Boy 2000 MkVI from Fallout 76. Remixed from Victhor's amazing wip file by me into something printable, you will find his original F360 file at his thing linked under remix. Drop by his thing and leave a like! This Pip-Boy is a prop which currently does not have cavities for electronics, but thats not to say it never will (looking at you talented CAD modeller). Under files, you will find my F360 file if you want to edit anything and all the STLs. Simply print all the stls, they have been oriented to optimally print already, support needed in certain places. There are two versions of the "leatherBig" and "leatherSmall", the original does not have a hinge, the Velcro version is the file I used, its a sturdy, snug fit, but slightly inaccurate.There are also 2 versions of the mainscreen, the 'split' one is much easier to print, the 'whole' one is if you want to split it yourself. If you have any questions do feel free to leave a comment, i will answer all questions. I have included all the reference pictures I used and the "decals" which I simply scaled, printed, cut and pasted on the pipboy. P.S. there are a few minor inaccuracies to the real in-game model due to the game not being out yet and only working off of trailers, but I'd say its pretty damn close! My Print:Printed on my Original Prusa Mk2sABS, sanded then acetone smoothed.Airbrushed and handpainted.Epoxied all the pieces together.Used 2cm wide Velcro straps to hold everything on my arm.Glued a sponge on the "leatherBigVelcro" piece for a snug, comfortable fit on my arm, it's actually really hard to see when I'm wearing it. Shout out to the facebook group for the sustained interest! Thanks for reading! if you make it be sure to share, it would make my day! If you're going to decide to sell it on eBay or Etsy despite the licence at least tell me first and maybe drop me a tip.

AddCaptureCard The device path (/dev/video1) or device string (12345678-0) used to address the device. CardType (Required) Parameter Type: String The capture card type being created (HDHOMERUN, DEMO, etc.). DefaultInput (Required) Parameter Type: String The default physical input for the device being created (Component, MPEG2TS, Television, etc.). HostName (Required) Parameter Type: String The backend hostname which houses this new capture device. AudioDevice (Optional) Parameter Type: String The device path (/dev/dsp) or device string (ALSA:input) used to address the audio capture device. Usually only useful for framegrabber cards. VBIDevice (Optional) Parameter Type: String The device path (/dev/vbi1) used for VBI/CC capture. Usually only useful for a limited number of analog capture devices. AudioRateLimit (Optional) Parameter Type: Integer The maximum audio sampling rate for captured audio. Usually only useful for framegrabber cards. SkipBTAudio (Optional) Parameter Type: Boolean Used only for quirky BT878 DVB cards to prevent the backend adjusting their volume. DVBSWFilter (Optional) Parameter Type: Integer No longer used. Left as a parameter for legacy purposes. DVBSatType (Optional) Parameter Type: Integer No longer used. Left as a parameter for legacy purposes. DVBWaitForSeqStart (Optional) Parameter Type: Boolean Wait for the SEQ start header. Only useful for DVB capture devices. DVBOnDemand (Optional) Parameter Type: Boolean Only open the capture device when used for recording or EIT. Allow other programs to access the device when not actively used. Enabling can cause recording issues if multiple applications contend for the same device. DVBDiSEqCType (Optional) Parameter Type: Integer No longer used. Left as a parameter for legacy purposes. FirewireModel (Optional) Parameter Type: String The model of the firewire device, as defined in firewiredevices.cpp. Used to determine which AVC command set to use when changing channels and capturing. FirewireSpeed (Optional) Parameter Type: Integer Firewire speed to use. For firewire capture devices. FirewireConnection (Optional) Parameter Type: Integer The Firewire communication method to use. For firewire capture devices. SignalTimeout (Optional) Parameter Type: Integer Number of milliseconds to wait upon tuning a frequency before signal is found. If this timer expires, tuning has failed. ChannelTimeout (Optional) Parameter Type: Integer Number of milliseconds to wait upon finding signal before the desired channel is found. If this timer expires, tuning has failed. DVBTuningDelay (Optional) Parameter Type: Integer Workaround for quirky capture devices. Introduce a delay to the tuning process in milliseconds. Contrast (Optional) Parameter Type: Integer Used to adjust picture attributes on capture for framegrabber capture devices. Brightness (Optional) Parameter Type: Integer Used to adjust picture attributes on capture for framegrabber capture devices. Colour (Optional) Parameter Type: Integer Used to adjust picture attributes on capture for framegrabber capture devices. Hue (Optional) Parameter Type: Integer Used to adjust picture attributes on capture for framegrabber capture devices. DiSEqCId (Optional) Parameter Type: Integer Cross reference this device with a DiSEqC tree found in the diseqc_config table.

468 F.2d 1359 175 U.S.P.Q. 453 Harry P. LOCKLIN and Elmer J. Brant, General Partners, dbaRadiant Color Company, Plaintiffs-Appellants,v.DAY-GLO COLOR CORP., Defendant-Appellee.Harry P. LOCKLIN and Elmer J. Brant, General Partners, dbaRadiant Color Company, Plaintiffs-Appellees,v.DAY-GLO COLOR CORP., Defendant-Appellant. Nos. 26239 and 26266. United States Court of Appeals,Ninth Circuit. Oct. 6, 1972.Rehearing Denied Dec. 1, 1972. John R. Murtha (argued), San Francisco, Cal., for plaintiffs-appellants. Thomas V. Koykka (argued), Cleveland, Ohio, for defendant-appellee. Before LUMBARD,* MERRILL and KILKENNY, Circuit Judges. MERRILL, Circuit Judge: 1 This case has already been before the court three times. On the first occasion we upheld the validity of the Kazenas patent and found two resins manufactured and marketed by Locklin to be infringing. Locklin v. Switzer Bros., 299 F.2d 160 (9th Cir. 1961), cert. denied 369 U.S. 861, 82 S.Ct. 950, 8 L.Ed. 2d 18 (1962). On the second and third occasions we considered whether a resin known as "4-C" was also infringing. We held that it was. Locklin v. Switzer Bros., 348 F.2d 244 (9th Cir. 1965); Locklin v. Switzer Bros., 368 F.2d 553 (9th Cir. 1966) (per curiam), cert. denied, 386 U.S. 963, 87 S.Ct. 1029, 18 L. Ed.2d 112 (1967). 2 Following our decisions in these cases the matter was referred by the District Court to a master for an accounting to determine damages. The master heard evidence respecting damages suffered from the marketing of the three resins adjudicated to be infringing. Day-Glo (successor to Switzer Bros. by change of name) also sought damages suffered by Locklin's manufacture and marketing of other resin formulations asserted to be the equivalents of the adjudicated resins. The master found that these unadjudicated resins were thermosetting rather than thermoplastic, which would indicate that they were not infringing. He also found, however, that in this respect they were no different from the adjudicated resins-i. e., that the adjudicated resins themselves were thermosetting. He concluded, however, that since the adjudicated resins had been held to infringe, and since the unadjudicated resins were their equivalents, the unadjudicated resins must also be held to infringe. 3 The District Court rejected this conclusion. It held that damages should be calculated with respect to only the three adjudicated resins and awarded the sum of $238,000. 4 Both parties appeal from this judgment. We affirm. 5 Locklin contends that since the master determined that the adjudicated resins in truth are thermosetting rather than thermoplastic, we now, belatedly, in our search for the truth, know that they do not infringe the Kazenas patent and that we should accordingly correct the record on the basis of this new knowledge and reject an award of damages in connection with these resins. 6 We decline to re-examine our earlier adjudications. Res judicata applies and the right to damages follows as matter of law. See Carson Inv. Co. v. Anaconda Copper Mining Co., 26 F.2d 651 (9th Cir.) cert. denied 278 U.S. 635, 49 S.Ct. 32, 73 L.Ed. 551 (1928). 7 Day-Glo contends, in support of the master's ruling, that since res judicata precludes review of infringement as to the three adjudicated resins, and since the unadjudicated resins are every bit as "thermoplastic" as the adjudicated resins, we must hold the latter to be infringing also. 8 We disagree. The new resins may indeed be the equivalent of the infringing resins, but they have hardly been shown to be the equivalent of the patented resin. Res judicata may preclude us from taking a second look at the three adjudicated resins, but it does not require us to close our eyes to the new resins' lack of thermoplasticity and consequent lack of infringement. 9 Day-Glo asserts that res judicata should apply to the definitions of "thermosetting" and "thermoplastic" as used by us in our first decision and that Locklin is now advancing a new definition. We disagree. Our definition of a thermosetting resin, 299 F.2d at page 162, "an infusable 'thermoset' resin that no longer can be softened or fused by heating" applies to render the new resins noninfringing. It is new knowledge respecting the character of the resins and not a new definition that has created the present problem. 10 Both parties assert abuse of discretion in respect to their respective claims for exemplary damages and attorney fees in connection with the accounting proceedings. We find no abuse of discretion in denial of these claims. From the District Court findings, bad faith does not appear on either side nor does the record dictate such findings. 11 In one respect only do we disagree with the District Court. Attorney fees were awarded to Day-Glo in connection with the proceedings resulting in Locklin's being held in contempt for the marketing of its "4-C" resin. Such an award is proper only in exceptional cases, Pickering v. Holman, 459 F.2d 403 (9th Cir. 1972), and must be based on a finding of bad faith by the losing party or some similar consideration. Florida Brace Corp. v. Bartels, 332 F.2d 337 (9th Cir. 1964); Park-In-Theaters v. Perkins, 190 F.2d 137 (9th Cir. 1951). The District Court does not appear to have made such a finding, nor does the record seem to provide support for such a determination. Indeed, the ultimate result seems to speak to the contrary. 12 The District Court is reversed upon its award of attorney fees to Day-Glo in connection with the earlier contempt proceedings. 13 In all other respects judgment is affirmed. 14 No costs are awarded. * Honorable J. Edward Lumbard, Senior United States Circuit Judge, Second Circuit, sitting by designation

This invention relates to liquid compositions suitable as inks or toners for non-impact printing. The invention is particularly related to the manufacture of such liquid inks or toners. It has been recognised that certain properties of carrier fluids for inks or liquid developers are required for effective functioning in conventional electrostatic processes. Many of the physical requirements are mandatory, as known by those skilled in the art, but there are also other considerations, such as low toxicity, fire safety, low solvent power, low odour etc. For these reasons, isoparaffinic-hydrocarbons such as the Isopar(copyright) range manufactured by Exxon Corporation, the Shellsol(copyright) range manufactured by Shell Chemical and the Soltrol(copyright) range manufactured by Phillips Petroleum became the industry standards for liquid carriers. In more recent times, however, increased environmental concerns have placed these non-impact liquid processes under increasing pressure to further reduce or eliminate volatile emissions. Other carrier materials for inks or liquid developers have been investigated, and of these, silicone fluids are clearly liquids which combine all previously and currently desired properties for a modern ink and liquid toner carrier. In general, an electrostatic ink or liquid toner for developing electrostatic images is prepared by dispersing an inorganic or organic colorant such as iron oxide, carbon black, nigrosine, phthalocyanine blue, benzidine yellow, quinacridone pink and the like into a liquid vehicle which may contain dissolved or dispersed therein synthetic or naturally occurring polymers such as acrylics and their copolymers, alkyds, rosins, rosin esters, epoxies, polyvinyl acetate, styrene-butadiene, cyclised rubber, ethylene vinyl acetate copolymers, polyethylene, etc. Additionally, to impart or enhance an electrostatic charge on such dispersed particles, additives known as charge directors or charge control agents may be included. Such materials can be metallic soaps, fatty acids, lecithin, and the like. Silicone fluids have been used as a carrier for liquids for some time, for example, U.S. Pat. No. 3,105,821 to S. W. Johnson, and U.S. Pat. No. 3,053,688 to H. G. Greig. Both of these early patents recognised the virtues of silicone fluids, but the understanding of the functioning of liquid toners at that time was relatively empirical. More recently silicone fluids have again been recognised as desirable carrier fluids for liquid toners, as in for example U.S. Pat. No. 5,612,162 and U.S. Pat. No. 5,591,557, both to Lawson et al. More specifically, U.S. Pat. No. 5,612,162 to Lawson et al. discloses a composition and a method of forming a liquid developer or a constituent of a liquid developer for electrostatography comprising the steps of dispersing at least one monomer in silicone fluid and polymerizing the at least one monomer to form polymer particles in the silicone fluid. A homopolymer or a copolymer may be formed and a colorant, such as a pigment or dye, and a charge control agent may be added before or after the polymerisation. The disclosure further states that the liquid developer may further include a polymerisation stabiliser which is compatible with the silicone fluid. The stabiliser may be a silicone fluid such as dimethyl polysiloxane. It has been found that the high molecular weight, that is the 30,000 cSt and 60,000 cSt, dimethyl polysiloxane polymerisation stabilisers described in U.S. Pat. No. 5,612,162 that are compatible with silicone fluids, result in polymer dispersions that possess good suspension stability but poor fix strength, melt cohesion and adhesion properties. If the liquid carrier component of the polymer dispersions discussed in U.S. Pat. No. 5,612,162, which is removed by oven drying or centrifugation/filtration, the polymer spheres remaining can be analysed for fix performance. In this case, the non-volatile content of this formulation will upon heating/melting followed by cooling, produce a solid that possesses minimal adhesive and cohesive properties. The solidified polymer forms a xe2x80x9cchalky likexe2x80x9d resin that can be easily abraded or broken with minimal force. This property is obviously undesirable and when the polymer dispersion is formulated/incorporated into an ink jet ink for printing or liquid developer for electrostatography, the result is poor ink or liquid developer to substrate fix. It is the object of this invention to provide improved polymerisation stabilisers. It is a further objective of this invention to provide improved polymerisation stabilisers which result in the liquid ink or toner compositions exhibiting improved fix to a substrate.

*Escherichia coli*, the predominant facultative organism of the intestinal flora, can cause severe extra-intestinal infections, including infection of the kidney (pyelonephritis) or bloodstream (bacteremia). When it escapes from its usual habitat, *E*. *coli* can colonize the genital tract and, as a subsequent step, ascend to the bladder and kidneys. Ascending urinary tract infection (UTI) is well explained by tissue receptor--*E*. *coli* adhesins interactions. Several *E*. *coli* virulence factors, including toxins, are implicated in renal inflammatory injury and bacteremia, but the mechanisms of translocation from the renal system to the bloodstream is poorly understood. It is thought that the strains which cause extra-intestinal infections harbor virulence factors that enhance the ability of *E*. *coli* to cause systemic infection. While an increase in the occurrence of *E*. *coli* bacteremia and urosepsis has been reported in recent years, relatively few studies have investigated the characteristics of the *E*. *coli* strains causing bacteremia. In fact, reports on the association between the risk of bacteremia/septicemia and occurrence of *E*. *coli* virulence factors are contradictory. While some studies propose that P fimbriae and α-hemolysin are associated with the risk of bacteremia \[[@CR1]\], others indicate that there is no such association and that *E*. *coli* virulence factors do not differ between those isolated from bacteremia and those isolated from pyelonephritis \[[@CR2]\]. UTIs affect from 5 to 36 % of renal transplant (RT) patients. In these patients, UTI is a frequent cause of bacteremia, septicemia, and acute graft failure \[[@CR3]\]. *E*. *coli* is the most common etiologic agent of UTI in RT patients, as well as being the most frequent pathogen isolated from RT recipients with bacteremia \[[@CR4]\]. To date, only a few studies have been available regarding the phylogenetic and virulence characteristics of *E*. *coli* isolates causing UTI and bacteremia in severely immunosuppressed patients, such as RT recipients \[[@CR5]--[@CR7]\]. Uropathogenic *E*. *coli* (UPEC) strains have particular phenotypic features which facilitate their persistence in urinary tracts and differentiate them from the other pathogenic and commensal *E*. *coli* strains. UPEC strains encode a number of virulence factors which enable the bacteria to colonize the urinary tract and persist in the face of a highly effective host defense. UPEC isolates exhibit a high degree of genetic diversity, owing to the possession of specialized virulence genes located on mobile genetic elements, called pathogenicity islands \[[@CR8]\]. The virulence factors of *E*. *coli* which have been potentially implicated as important in establishing UTIs can be divided into two groups: (i) virulence factors associated with the surface of the bacterial cell and (ii) virulence factors which are secreted and exported to the site of action \[[@CR9]\]. The surface virulence factors of UPEC include a number of different types of adhesive organelles (fimbriae), which promote bacterial attachment to, and/or invasion of, host tissues within the urinary tract, namely, type 1, P, S, and Dr adhesins \[[@CR10]\]. For example, type 1 fimbriae mediate invasion of the bladder tissue, form intracellular bacterial communities, and are implicated in recurrent cystitis \[[@CR10]\]. P fimbriae induce acute inflammatory signaling and are associated with acute pyelonephritis, while Dr adhesins promote cellular invasion and are associated with chronic pyelonephritis \[[@CR11]\]. Interestingly, both adhesins are only carried by the same *E*. *coli* strain occasionally. The most important secreted virulence factors are a lipoprotein called α-hemolysin (HlyA), the cytotoxic necrotizing factor 1 (CNF1), and the uropathogenic specific protein (USP) \[[@CR12]\]. In addition, phylogenetic analyses have revealed that UPEC strains differ substantially from other *E*. *coli* strains. Pathogenic *E*. *coli* strains, including UPEC strains, mainly belong to phylogenetic group B2 and, to a lesser extent, group D, the 'high-virulence' groups, whereas isolates of groups A or B1, the 'low-virulence' groups, contain few virulence determinants and are usually regarded as commensals \[[@CR13]\]. The aim of this study was to gain insight into the phylogenetic distribution and virulence genes of *E*. *coli* isolates predisposing the translocation of *E*. *coli* from the urinary tract to the bloodstream in RT patients. We consider that the inconsistent findings on the association of individual virulence factors with the translocation to the bloodstream may result from the fact that *E*. *coli* require a battery of different adherence factors, in combination, in order to access the vascular bed. For example, we recently reported a case of maternal death owing to *E*. *coli* septicemia, where *E*. *coli* bearing both P and Dr adhesins spread from the kidney to the blood, causing lethal septic shock \[[@CR14]\]. To investigate *E*. *coli* factors predisposing RT patients with UTIs to bacteremia, we performed an analysis of individual *E*. *coli* virulence factors in RT versus non-RT bacteremia and then conducted a two-dimensional analysis of all the virulence factors in all the groups tested. The study population constituted 67 patients who had developed *E*. *coli* UTI and/or bacteremia and were hospitalized by the Department of Nephrology, Transplantology and Internal Diseases at the Gdańsk University of Medicine in Poland during the period from 2006 to 2009. The criteria for inclusion isolates in this study were based on the genotyping of isolates using the PCR MP and REA-PFGE methods \[[@CR15]\]. A total of 215 isolates were genotyped, of which 103 strains came from blood and 112 were isolated from urine. The strains isolated from the same material among particular patients identified as the same genotype were rejected from the study. The genetic criteria for urinary tract and bloodstream transmission of the *E*. *coli* isolate were that of identical fingerprint profiles with at least one identical genotype isolated from the urine and the blood. A total of 77 *E*. *coli* isolates met the inclusion criteria and they were divided into four groups: (I) 44 blood isolates from non-RT patients with positive urine culture and bacteremia, (II) 19 blood isolates from RT patients with positive urine culture and bacteremia, (III) six isolates from non-RT patients with positive urine culture but no bacteremia, and (IV) eight isolates from RT patients with positive urine culture but no bacteremia. Multiplex PCR-based methods were used to determine the presence of six virulence factors genes, as previously described \[[@CR16]\]. They included *fimG*/*fimH* (genes of type 1 fimbriae), *sfaD*/*sfaE* (genes of S fimbriae), *papC* (gene of P fimbriae), *hlyA* (gene encoding α-hemolysin), *cnf1* (gene encoding cytotoxic necrotizing factor 1), and *usp* (gene encoding uropathogenic specific protein). The isolates were also examined by PCR assay for the presence of the genes encoding fimbriae of the Dr family, *afa*/*dra(B-C)*, as described previously \[[@CR17]\]. Statistical analysis of the results was carried out using a Chi-square test. The probability threshold *p*-value was assumed to be at the level of 0.05. The one-dimensional analysis (Table [1](#Tab1){ref-type="table"}) carried out on the pool of selected strains from all patients shows that bacteriocin Usp was the most frequently occurring virulence factor. Gene *usp* was carried by 90 % of the bacteremia strains which were able to translocate to the blood (groups I and II) and 71 % among strains with no bacteremia and no translocation (groups III and IV). Despite its higher frequency in blood, the presence of the *usp* gene was not statistically significant (*p* = 0.551). The occurrence of only two individual factors, P fimbriae (*p* = 0.006) and α-hemolysin (*p* = 0.007), out of the seven virulence factors being investigated was statistically more frequent among *E*. *coli* isolates from bacteremia. The one-dimensional analysis thus suggests that P fimbriae and α-hemolysin are the virulence factors which may predispose *E*. *coli* strains to migrate from the urinary tract to the bloodstream. Surprisingly, the occurrence of Dr adhesin among all the bacteremic *E*. *coli* (80 %) and in the RT patients (53 %) was both very high and much higher than previously reported \[[@CR2]\]. Despite the overall high frequency, the blood isolates from RT patients were characterized by a lower rate of individual virulence genes, such as, for example, Dr adhesins (*p* = 0.03). A high frequency of genes coding S fimbriae (70 %) was also observed, but there was no difference between the groups being tested.Table 1Unidirectional analysis of PCR-based detection *n* = of genes encoding the examined *E*. *coli* virulence factorsVirulence factor^a^Translocation groups I + II (*n* = 63) vs. no translocation groups III + IV (*n* = 14)RT translocation group II (*n* = 19) vs. non-RT translocation group I (*n* = 44)RT total groups II + IV (*n* = 27) vs. non-RT total groups I + III (*n* = 50)%*p*-value%*p*-value%*p*-valueP62/21**0.006**58/640.66744/600.191S71/500.12174/700.79570/660.696cnf46/360.48237/500.33637/480.355usp90/710.55184/930.26678/920.076fim76/570.14868/800.34159/800.051hly46/7**0.007**37/500.33630/440.217dr71/640.59753/80**0.030**52/80**0.010**Group I translocation non-RT \[blood(+)/urine(+)\] 44 *E*. *coli*Group II translocation RT \[blood(+)/urine(+)\] 19 *E*. *coli*Group III no translocation non-RT \[blood(−)/urine(+)\] 6 *E*. *coli*Group IV no translocation RT \[blood(−)/urine(+)\] 8 *E*. *coli*^a^ *P* P fimbriae (*papC*), *S* S fimbriae (*sfaD*/*sfaE*), *cnf* cytotoxic necrotizing factor (*cnf1*), *usp* bacteriocin usp, *fim* type 1 fimbriae (*fimG*/*fimH*), *hly* α-hemolysin (*hlyA*), *dr* Dr fimbriae (*afa*/*dra* B--C) As pathogenic *E*. *coli* often carry multiple adherence factors, a two-dimensional data analysis was performed (Table [2](#Tab2){ref-type="table"}). Consistent with our hypothesis, a combination of two adherence factors was associated with bacteremia/translocation to the blood. This included combinations of P + Dr and S + Dr, but not type 1 + Dr (*p*-values 0.022, 0.036, and 0.452, respectively). We observed that the strains which carry genes coding type 1 fimbriae and α-hemolysin simultaneously were also associated with bacteremia (*p* = 0.005). This suggests that a combination of this kind could also be a predictive factor for the risk of translocation. The two-dimensional analysis demonstrated that the strain's blood transmission was not statistically associated with the presence of such virulence factors as a cytotoxic necrotizing factor coexisting with P, S, Dr, or type 1 fimbriae or with bacteriocin Usp (*p*-values 0.237, 0.276, 0.384, 0.199, and 0.481, respectively). The risk of translocation was also not correlated with the coexistence of Dr fimbriae and bacteriocin Usp or type 1 fimbriae (*p* = 0.384 and *p* = 0.24, respectively). In contrast to bacteremia versus non-bacteremia, where significant differences were observed, we identified no significant differences between *E*. *coli* virulence factors from RT and non-RT patients. The reason for the lower frequency of Dr adhesins in RT patients is not clear and may be associated with immunosuppression or, perhaps, the stage of renal disease and/or function, which may require independent evaluation.Table 2Two-dimensional analysis of the coexistence of two genes encoding virulence factors among the investigated *E*. *coli* isolatesVirulence factor^a^Translocation groups I + II (*n* = 63) vs. no translocation groups III + IV (*n* = 14)RT translocation group II (*n* = 19) vs. non-RT translocation group I (*n* = 44)RT total groups II + IV (*n* = 27) vs. non-RT total groups I + III (*n* = 50)%*p*-value%*p* value%*p* valueP + S56/21**0.021**53/570.75941/540.267P + cnf138/210.23726/430.20622/420.083P + usp62/21**0.006**59/640.66744/600.191P + fim48/7**0.005**42/500.56530/460.162P + hly38/7**0.025**37/390.89330/340.696P + dr48/14**0.022**32/550.09426/50**0.041**S + cnf44/290.27637/480.42533/460.282S + usp70/430.05674/681.66267/640.815S + fim59/21**0.011**58/590.92948/540.624S + hly38/7**0.025**32/410.48426/360.368S + dr52/21**0.036**37/590.10533/540.083cnf + usp46/360.48137/500.33637/480.355cnf + fim40/210.19932/430.38830/400.367cnf + hly35/70.04021/410.12919/360.110cnf + dr33/210.38416/410.05219/380.078usp + fim76/500.05068/800.34159/780.082usp + hly46/7**0.007**37/500.33630/440.217usp + dr67/500.24047/75**0.033**44/74**0.010**fim + hly38/0**0.005**26/430.20619/380.078fim + dr54/430.45237/610.07330/64**0.004**hly + dr38/7**0.025**21/450.06719/400.055^a^ *P* P fimbriae (*papC*), *S* S fimbriae (*sfaD*/*sfaE*), *cnf* cytotoxic necrotizing factor (*cnf1*), *usp* bacteriocin usp (*usp*), *fim* type 1 fimbriae (*fimG*/*fimH*), *hly* α-hemolysin (*hlyA*), *dr* Dr fimbriae (*afa*/*dra* B--C) The phylogenetic group analysis was determined by a triplex PCR assay performed with a combination of three DNA markers (*chuA*, *yjaA*, and the DNA fragment *TSPE4*.*C2*), as previously described \[[@CR18]\]. As expected, group B2 was associated with the presence of classic virulence factor genes, whereas group B1 isolates had the lowest virulence factor score. In our analysis, phylogenetic *E*. *coli* groups A, B1, B2, and D for the RT recipients' isolates being tested (groups II and IV) accounted for 0 %, 33 %, 57 %, and 10 % of the isolates, respectively. In the isolates from the non-RT patients (groups I and III), phylogenetic groups A, B1, B2, and D accounted for 0 %, 16 %, 84 %, and 0 %, respectively. The shift from group B2 toward group B1 observed could, thus, account for the lower frequency of virulence factor genes among RT isolates when compared with those from non-RT patients. To summarize, in this paper, we have reported that *E*. *coli* translocation to the bloodstream was associated with a high frequency combination of two adherence factors, namely, P, and Dr, S, or Type 1 adhesins. P mediates acute inflammatory signaling, while Dr, S, and Type 1 may mediate tissue invasion. This observation implies that *E*. *coli* bearing P fimbriae with the capacity to cause severe inflammatory response and an adhesin which can mediate tissue invasion may establish an effective translocation strategy for passing all tissue barriers in order to access the bloodstream and cause bacteremia. An unrecognized combination of P and Dr adhesins may contribute to the establishment of a clonal group of a super-pathogenic *E*. *coli*, which, if combined with resistance to antibiotics, may represent a new trend in the evolution of uropathogens. This work was supported by the Polish Ministry of Science and Higher Education Grant No. N401331239, awarded to A.Ś and in part by U54 RR026140 (NCRR)/U54 MD007593 (NIMHD). Conflict of interest {#d30e1649} ==================== The authors declare that they have no conflict of interest.

Attitudes to animal-assisted therapy with farm animals among health staff and farmers. Green care is a concept that involves the use of farm animals, plants, gardens or the landscape in cooperation with health institutions for different target groups of clients. The present study aimed at examining psychiatric therapists' (n = 60) and farmers' (n = 15) knowledge, experience and attitudes to Green care and animal-assisted therapy (AAT) with farm animals for people with psychiatric disorders. Most respondents had some or large knowledge about Green care, but experience with Green care was generally low in both groups. Both farmers and therapists believed that AAT with farm animals could contribute positively to therapy to a large or very large extent, with farmers being significantly more positive. Most of the therapists thought that AAT with farm animals contributes to increased skills in interactions with other humans, with female therapists being more positive than males. Two-thirds of the therapists believed that AAT with farm animals to a large extent could contribute better to mental health than other types of occupational therapy. There were no differences in attitudes to AAT between psychiatrists/psychologists and psychiatric nurses. This study confirms the marked potential of offering AAT services with farm animals for psychiatric patients by documenting positive attitudes to it among psychiatric therapists.

All relevant data are within the paper and its Supporting Information files. Introduction {#sec005} ============ 'Empiric tuberculosis (TB) treatment'- defined as the administration of TB treatment to persons being evaluated for TB who do not have laboratory evidence of TB---is advised by WHO guidelines in resource-limited settings when ambulant HIV-positive persons with two negative sputum smear microscopy tests and chest radiography findings compatible with TB do not respond to broad-spectrum antimicrobial therapy\[[@pone.0191608.ref001]\]. While empiric TB treatment is not without risks (unnecessary administration of TB drugs with potential for adverse effects or delay in the diagnosis of conditions other than TB), it is appropriate in a context where the pre-test probability of TB is high, diagnostics have inadequate sensitivity and/or the consequences of withholding TB treatment are serious\[[@pone.0191608.ref002]\]. In South Africa, the National Department of Health (NDoH) provides algorithms for TB diagnosis which advise additional investigations when initial sputum smear microscopy or Xpert MTB/RIF (Xpert) tests for TB are negative and persons under investigation are co-infected with HIV\[[@pone.0191608.ref003]\]. These algorithms indicate that clinicians may commence TB treatment for HIV-positive persons when two sputum smear microscopy tests or a single sputum Xpert are negative for *Mycobacterium tuberculosis*, chest radiograph findings are compatible with TB, and symptoms do not respond to broad spectrum antibiotics. Neither the extent, nor the circumstances under which empiric TB treatment is administered in primary health care (PHC) settings in South Africa are well described. We have previously demonstrated poor adherence to the algorithms for TB diagnosis in a cluster-randomised, pragmatic trial (XTEND) that evaluated Xpert *vs* smear microscopy for the diagnosis of TB\[[@pone.0191608.ref004]\]. Using data from XTEND, in which we followed over 4,000 persons undergoing TB investigations by PHC nurses for six months, we identified persons receiving empiric TB treatment and describe their pathways to treatment initiation, including results of investigations, health seeking efforts and time to treatment start. Study population and methods {#sec006} ============================ The XTEND trial--study design and TB investigation procedures {#sec007} ------------------------------------------------------------- The XTEND (Xpert for TB---Evaluating a New Diagnostic) study was a pragmatic, two-arm, parallel, cluster-randomised trial evaluating the effect on mortality of Xpert implementation *vs* smear microscopy for the diagnosis of TB amongst persons being evaluated for TB in PHC facilities in South Africa\[[@pone.0191608.ref005]\]. Twenty laboratories servicing 40 PHCs across four provinces were randomised to receive Xpert as described\[[@pone.0191608.ref005]\]. XTEND study staff enrolled a systematic sample of clinic attendees being evaluated for TB. Personal identifiers, demographic and clinical data relevant to TB and mortality risk were collected at enrolment. XTEND study staff had no influence on clinical investigations nor management decisions made by PHC staff. At six months post enrolment, XTEND study staff abstracted data from patients' clinic records, obtained participants' sputum results and conducted patient interviews. XTEND study methods are described more completely elsewhere\[[@pone.0191608.ref005]\]. At participating clinics, nurses identified persons who required investigation for TB according to local screening practice. When initial sputum test results (Xpert or smear microscopy) were negative for TB, further investigations (sputum mycobacterial culture, chest radiography and therapeutic trial of antibiotics) or referral to hospital were made at the discretion of the PHC nurse according to routine local practice\[[@pone.0191608.ref003], [@pone.0191608.ref006]\]. In clinics using Xpert, the NDoH had recently trained nurses in the use of the Xpert algorithm for TB diagnosis\[[@pone.0191608.ref003]\], while in clinics using smear microscopy, no additional training was given as part of XTEND trial procedures. Inclusion criteria for the secondary data analysis and case definitions {#sec008} ----------------------------------------------------------------------- Participants in the XTEND study with negative initial sputum results (smear microscopy or Xpert) at enrolment who were started on TB treatment during any stage of the 6-month follow-up were included in the analysis. Participants were defined as 'index test negative' if sputum tests conducted within four days of enrolment (two smear microscopy tests or one Xpert) were negative for TB. Participants who had a TB treatment prescription in their clinic notes or reported having started TB treatment at six-month patient interview were regarded has having started TB treatment. Positive HIV status was ascertained through self-report, or any of a documented HIV positive test, any CD4 count, HIV viral load test or ART prescription in the clinic record. For these eligible XTEND participants, the course of events leading to TB treatment initiation was reconstructed from data sources described above; this substudy entailed additional record review at a later timepoint compared to that undertaken in the main XTEND analysis. Through evaluation of participants' pathways, the reasons for TB treatment initiation of participants were inferred according to [Table 1](#pone.0191608.t001){ref-type="table"}. Participants whose reason for TB treatment initiation was 'clinical assessment' or 'chest radiography findings compatible with TB' were defined as receiving empiric TB treatment. 10.1371/journal.pone.0191608.t001 ###### Criteria used to infer the reason for TB treatment start amongst persons enrolled in the XTEND trial who had a negative sputum test for TB at enrolment by Xpert or smear microscopy, but who were started on TB treatment during the six month period after enrolment. {#pone.0191608.t001g} -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Criteria used to infer the reason for TB treatment start Inferred reason for TB treatment start Was TB treatment given empirically? ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------ A sputum specimen collected at PHC after enrolment was positive for TB by at least one of smear microscopy, Xpert or culture\ Positive laboratory sputum test for TB No     AND\     Sputum results were available to PHC clinicians at the time of TB treatment start (as defined by collection date of the sputum preceded the TB treatment start date by a minimum of 2 days (smear microscopy or Xpert) or 14 days \[culture\])\     WITH OR WITHOUT\     Chest radiography and/or referral to higher level of care Extra-pulmonary TB diagnosed at a higher level of care (including pleural TB, TB of lymph nodes or miliary/disseminated TB)\ Extra-pulmonary TB No for the purposes of this analysis, but uncertain as clinical notes not available for review     AND\     No documented positive laboratory test (smear microscopy, Xpert or culture) at the time of TB treatment start\     WITH OR WITHOUT\     Chest radiography No documented positive laboratory test (smear microscopy, Xpert or culture) at the time of TB treatment start\ Clinical assessment Yes     AND\     No evidence of chest radiography\     AND\     No referral to a higher level of care Chest radiography documented within 7 days prior to TB treatment start\ Chest radiography findings compatible with TB Yes     AND\     No positive smear microscopy, Xpert or sputum culture results for *M*. *tuberculosis* were available before TB treatment initiation (within 2 days of the sputum collection date (smear microscopy or Xpert) or within 14 days (culture) Consultation at a hospital out-patient clinic or hospital admission at or immediately prior to TB treatment start\ Assessment at a higher level of care leading to TB treatment initiation No for the purposes of this analysis, but uncertain as clinical notes not available for review     AND\     No positive smear microscopy, Xpert or sputum culture results for *M*. *tuberculosis* were available before TB treatment initiation (within 2 days of the sputum collection date (smear microscopy or Xpert) or within 14 days (culture)\     AND\     No documentation that a chest radiograph had been taken or requested at PHC Insufficient data and/or patient pathway could not be reliably reconstructed No reason assigned Uncertain -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Institutional and ethical review {#sec009} -------------------------------- The XTEND protocol and this secondary data analysis received formal approval following review by the Human Sciences Research Ethics Committee (HREC) of the University of the Witwatersrand in 2011 (M110827), the London School of Hygiene & Tropical Medicine, the University of Cape Town and WHO. All XTEND participants provided written (name or thumbprint) informed consent for participation. In this secondary analysis which was approved by the University of the Witwatersrand in 2013 (M140486), all data were fully anonymized prior to analysis. Results {#sec010} ======= Amongst 4,656 XTEND participants, 541 (12%)\[[@pone.0191608.ref005]\] initiated TB treatment by six months of follow up of whom 167 (31%) were index test negative at enrolment, and were started on TB treatment during 6 months of follow-up. The median age was 37 years (31--45 years) and 79/167 (49%) were female. HIV status was positive at or before enrolment amongst 120/167 (72%). Regarding TB symptoms cough, fever, sweats or weight loss, the majority (109, 65%) had 2 or more weeks of symptoms prior to enrolment, and 3 or 4 symptoms (103, 62%) vs 1--2 or none. The median number of health seeking visits prior to enrolment was 1 (IQR = 0--2) with the majority having sought help from a public clinic (126, 75%). [Table 2](#pone.0191608.t002){ref-type="table"} describes the characteristics of: 1) all XTEND participants with negative sputum tests for tuberculosis at enrolment; 2) the subgroup who were started on TB treatment on an empiric basis; and 3) the subgroup with subsequent microbiological confirmation of tuberculosis. As some participants who were started on empiric TB treatment were subsequently found to have microbiologically confirmed TB, subgroups 2) and 3) are not mutually exclusive. [**Fig** 1](#pone.0191608.g001){ref-type="fig"}. depicts reasons for TB treatment start which were: 1) a positive sputum test for TB taken after enrolment (n = 49, 29%); 2) presumed chest radiography findings compatible with TB (n = 63, 38%); 3) clinical assessment suggestive of TB (n = 19, 11%); 4) following assessment at or admission to a higher level of care (n = 19, 11%), and 5) a diagnosis of extra-pulmonary TB (EPTB) made at a higher level of care (n = 9, 5%) or 6) reasons unclear (n = 8, 5%). A total of 82/167 (49%) were initiated on TB treatment empirically (I.e. did not have bacteriological confirmation when TB treatment was started), representing 15% (82/541) of treatment initiations in the entire XTEND cohort. Amongst 167 participants started on TB treatment, 60 (36%) had a subsequent positive sputum test for TB at PHC level (smear microscopy, Xpert or culture, before or after starting TB treatment ([**Fig** 1](#pone.0191608.g001){ref-type="fig"}). The remaining 107/541 (20%) XTEND participants were treated for TB without any microbiological confirmation of TB at PHC level (though the participants started at a higher level of care may have had laboratory tests confirming TB). Amongst 167 participants with negative TB tests at enrolment who were subsequently started on TB treatment, 113 (68%) were in the smear microscopy arm of the XTEND trial. {#pone.0191608.g001} 10.1371/journal.pone.0191608.t002 ###### Characteristics of XTEND participants with negative sputum tests for tuberculosis by smear microscopy or Xpert at enrolment into XTEND who were subsequently started on TB treatment during the 6-month follow-up (n = 167). Sub-groups 1 (empirically treated participants) and sub-group 2 (participants with microbiologically-confirmed TB) are not mutually exclusive as some participants who were started on empiric TB treatment were subsequently found to have microbiologically confirmed TB. {#pone.0191608.t002g} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- All participants with negative sputum index results at enrolment who were subsequently started on TB treatment\ --------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------- ------------- ------------- **Characteristics at enrolment**     Female gender, n (%) 79 (47) 39 (48) 25 (41)     Age in years, median (IQR) 37 (31--45) 36 (30--45) 37 (31--43)     Residing in a rural area, n (%) 72 (43) 32 (39) 27 (45)     HIV status at enrolment         HIV positive before or at enrolment/HIV status known, n/N, (%) 120/137 (88) 59/78 (76) 46/50 (92)         on ART, among those HIV positive, n/N (%) 30/120 (25) 10/59 (17) 14/46 (30)     Previous TB, n (%) 41 (25) 22/82 (27) 16 (26)     Karnofsky score \<80, n (%) 41 (25) 46/82 (47) 16 (27)     Body mass index \<18.5, kg/m^2^, n (%) 23 (14) 9 (11) 11 (18)     XTEND study arm         Smear microscopy 113 (68) 61 (74) 43 (72)         Xpert 54 (32) 21 (26) 17 (28) **Health seeking behaviour and symptoms prior to and at enrolment**     Participants with duration of symptoms \> 2 weeks prior to enrolment, n (%) 109 (65) 47 (57) 14 (23)     Enrolment visit was first health seeking visit for TB symptoms, n (%) 111 (66) 43 (52) 30 (50)     Visits to health care provider prior to enrolment, median (IQR) 1 (0--2) 1.5 (1--3) 1 (0--2)     Provider from whom participant first sought help for presenting symptoms         Public clinic, n, % 126 (75) 66 (80) 46 (77)         Pharmacy, n (%) 20 (12) 8 (10) 9 (15)         Private doctor/other, n(%) 15 (9) 5 (7) 5 (8)         Public Hospital, n (%) 5 (3) 3 (5) 0         Traditional healer, n (%) 1 (1) 0 0     Reason for visit to PHC at which enrolment took place         TB symptoms, n (%) 140 (84) 71 (87) 51 (85)         HIV testing or routine visit, n (%) 15 (9) 8 (8) 5(8)         Chronic disease routine visit/other, n (%) 12 (7) 3 (4) 4 (7)     Number of symptoms at enrolment         None, n (%) 3 (2) 1 (1) 2 (3)         1--2, n (%) 61 (37) 29 (35) 22 (37)         3--4, n (%) 103 (62) 52 (64) 36 (60) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- \* A subset of the group n = 167 who met the definition for empiric TB treatment initiation as defined in [Table 1](#pone.0191608.t001){ref-type="table"}. Eleven had a subsequent positive microbiology test on sputum. \# A subset of the group n = 167 who had a positive Xpert or smear microscopy or culture result before [or]{.ul} after TB treatment start. Eleven were started on TB treatment empirically. IQR = interquartile range, PHC = primary health clinic Pathways to TB treatment, visits to health care providers and vital status at 6 months of follow-up {#sec011} --------------------------------------------------------------------------------------------------- From enrolment to TB treatment start, the 167 participants completed 529 visits to health care providers to address TB symptoms including the enrolment visit, repeat visits to the same or different providers and the visit culminating in TB treatment start---a median of 3 visits per participant (interquartile range \[IQR\] 2--4). [Table 3](#pone.0191608.t003){ref-type="table"} summarises TB investigations, treatment initiation and vital status at 6 months follow up for all XTEND participants with negative sputum tests for tuberculosis and amongst the subgroups--those who were started on TB treatment on an empiric basis, and those who had subsequent microbiological confirmation of TB. Evidence for adherence to algorithms for TB investigation (any of documented chest radiography, sputum culture or referral to hospital) was found in 106 (63%). Documented or undocumented (self-reported) chest radiography was reported in 87/167 (52%). Sputum was submitted for culture amongst 64/167 (38%) participants of which 37/64 (58%) were positive for *M*. *tuberculosis*. TB treatment was started a median of 3.9 weeks (IQR 1.4--11 weeks) after enrolment amongst persons started empirically, and 8.6 weeks after enrolment amongst persons with microbiologically confirmed TB. Amongst 37 persons with culture-confirmed TB, 15 (41%) were initiated on TB treatment \>8 weeks after sputum submission (median 15.6, range 8.4 to 31.7 weeks). **[Fig 2](#pone.0191608.g002){ref-type="fig"}** summarises the pathways to TB treatment during 6 months of follow-up grouped by place of TB treatment start and omitting multiple visits to the same provider. Amongst those who were started on TB treatment at their enrolment clinic and did not make use of other providers (n = 71), more than a third (26, 37%) made at least two subsequent visits to their enrolment clinic prior to TB treatment initiation. Amongst 60 participants who were initiated on TB treatment following assessment at a higher level of care, only 21 (33%) had a documented referral in the PHC notes. Over the 6 months of follow up, 12/167 (7%) participants died, of whom 11 were in the smear microscopy arm. Death occurred a median of 9 weeks (range 3--34 weeks) after enrolment and a median 3 weeks (range 0.8--10 weeks) after TB treatment initiation. {#pone.0191608.g002} 10.1371/journal.pone.0191608.t003 ###### TB investigations, treatment initiation and vital status at 6 months follow up of XTEND participants with negative sputum tests for tuberculosis by smear microscopy or Xpert who were subsequently started on TB treatment during the 6-month follow-up (n = 167). Sub-groups 1 (empirically treated participants) and sub-group 2 (participants with microbiologically-confirmed TB) are not mutually exclusive as some participants who were started on empiric TB treatment were subsequently found to have microbiologically confirmed TB. {#pone.0191608.t003g} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- All participants with negative sputum index results at enrolment who were subsequently started on TB treatment\ -------------------------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------- --------------- ------------------ **Investigations for TB initiated by PHC staff after enrolment in XTEND**     Sputum culture done, n (%) 64 (38) 23 (28) 42 (70)     Documented chest radiography, n (%) 58 (35) 51 (62) 9 (15)     Undocumented chest radiography, n (%) (patient reported at interview) 29 (17) 10 (11) 6 (10)     Any admission to hospital, n (%) 27 (22) 70 (85) 9 (15) Algorithm followed (any of documented CXR, culture, or referral for hospital), n (%) 106 (63) 58 (71) 45 (75) **TB treatment initiation** Reason for TB treatment start (as defined in [Table 1](#pone.0191608.t001){ref-type="table"})     Clinical assessment compatible with TB, n (%) 19 (11) 19 (23) 1 (2)     Chest radiography compatible with TB (documented or undocumented), n (%) 63 (38) 63 (77) 10 (17)     Positive sputum test for TB^z^, n (%) 49 (29) 0 45 (75)     Extra-pulmonary TB diagnosed at higher level of care, n (%) 9 (5) 0 2 (3)     Assessment at a higher level of care leading to TB treatment initiation, n (%) 19 (11) 0 2 (3)     Unclear^y^, n (%) 8 (5) 0 0 TB treatment started 'empirically' (i.e. without laboratory confirmation at the time of TB treatment start), n (%) 82 (49) 82 (100) 11 (19) Time from enrolment to TB treatment start in weeks, median (IQR) 5.7(2.1--12.1) 3.9 (1.4--11) 8.57 (3.9--15.3) Place of TB treatment start     Original clinic, n (%) 97 (58) 55 (67) 38 (63)     Another PHC clinic, n (%) 8 (5) 2 (2) 5 (8)     Private GP, n (%) 2 (1) 2 (2) 0     Hospital (OPD or ward), n (%) 60 (36) 23 (29) 17 (28) **Laboratory results, ART care and outcome** Microbiologically-confirmed TB     Any microbiological confirmation, n (%) 60 (36) 11 (13) 60 (100)     Positive smear microscopy, n (%) 12 (7) 5 (6) 12 (20)     Positive Xpert, n (%) 11 (6) 3 (4) 11 (18)     Positive culture, n (%) 37 (22) 3 (4) 37 (62) **HIV testing and ART initiation** Final HIV and ART status (after 6 months of follow up)     HIV positive, n (%) 129 (77) 65 (79) 49 (82)         HIV positive and on ART, n (%) 109 (65) 56 (68) 43 (72)     HIV negative (documented negative result), n (%) 30 (18) 15 (18) 10 (17)     Unknown, n (%) 8 (5) 2 (2) 1 (2) Timing of TB treatment in relation to ART amongst HIV positive participants who were on ART at enrolment or initiated ART during follow-up     TB Rx start before ART, n/N (%) 46/109 (42) 29/56 (52) 18/43 (42)     TB start within 3 months after ART, n/N (%) 19/109 (17) 8/56 (14) 8/43 (19)     TB start \>3months after ART, n/N (%) 44/109 (40) 20/56 (36) 17/43 (39) Death during follow-up, n (%) 12 (7) 5 (6) 3 (5) ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- \*A subset of the group n = 167 who were started on TB treatment who met the definition for empiric TB treatment initiation as defined in [Table 1](#pone.0191608.t001){ref-type="table"} ^1^empiric = without a positive microbiology test at the time of TB treatment start; \#A subset of the group n = 167 who had negative sputum result(s) at enrolment but after further investigation had a positive Xpert or smear microscopy or culture result. Some cases in this group (n = 11) are also amongst those that were started on TB treatment empirically as defined in [Table 1](#pone.0191608.t001){ref-type="table"}; PHC = primary health clinic, GP = general practitioner/private doctor, OPD = out patient department), CXR = chest X ray, IQR = interquartile range, ART = antiretroviral therapy; HIV care among participants with negative TB tests at enrolment who were subsequently started on TB treatment {#sec012} ------------------------------------------------------------------------------------------------------------- Amongst 167 participants, 120 were documented to be HIV positive and 30 on ART at or before enrolment and an additional 9 tested HIV positive during the 6 months of follow up. Amongst all HIV positive participants, 79 (61%) initiated ART during follow-up, with 109 on ART by 6 months post enrolment. Amongst 129 HIV-positive persons initiated on TB treatment, microbiologically-confirmed TB was diagnosed in 49 (43%), of whom 18 (37%) had started TB treatment before ART initiation. Eight (15%) HIV-positive participants with microbiologically-confirmed-TB started treatment within 3 months after ART initiation and 18 (35%) started TB treatment three or more months after ART initiation. Discussion {#sec013} ========== In a prospective observational cohort of over 4,000 persons, of whom over 60% were HIV positive, investigated for TB at the discretion of clinic staff in South African PHC facilities\[[@pone.0191608.ref005]\], and amongst whom 541 (12%) initiated TB treatment, we report infrequent use of empiric TB treatment (15%, 82/541). Chest radiography was the leading investigation prompting empiric TB treatment initiation. This, and our observation of repeated health-seeking attempts at different providers and delayed TB treatment start when TB diagnosis amongst persons initially Xpert- or smear-negative was made by sputum culture highlight 1) the importance of chest radiography as a follow-on diagnostic test for tuberculosis even in the Xpert era, and 2) the need to strengthen PHC TB diagnostic processes including improved diagnostic tests, adherence to diagnostic algorithms, and follow-up of patients who remain symptomatic, or at high risk of death (those with unknown HIV status or HIV+ and not on ART)\[[@pone.0191608.ref005]\]. Our previous finding of poor adherence to TB diagnostic algorithms\[[@pone.0191608.ref004]\] and in this analysis, low frequency of empiric TB treatment initiation in a predominantly nurse-managed, PHC TB treatment programme demonstrate an on-going reliance on sputum TB diagnostic tests. While empiric TB treatment, delivered as per WHO guidelines for the management of smear-negative TB\[[@pone.0191608.ref001]\], is a rational and evidence-based intervention that reduces mortality amongst HIV-positive persons with negative initial sputum tests for tuberculosis\[[@pone.0191608.ref007]--[@pone.0191608.ref009]\], in a predominantly nurse-managed TB control programme we and others\[[@pone.0191608.ref010]--[@pone.0191608.ref012]\] have found that it may not be widely prescribed. Adherence to algorithms for TB diagnosis amongst persons with negative initial sputum TB tests is not always optimal\[[@pone.0191608.ref011], [@pone.0191608.ref013]\] nor possible. Chest radiography remains inaccessible for many, even in South Africa, and requires interpretation by doctors and functioning health referral networks. Access to sputum culture is often limited. Multiple visits to health facilities are required leading to increased patient costs\[[@pone.0191608.ref014], [@pone.0191608.ref015]\], and follow up of patients may be limited. Initiation of TB treatment on the basis of clinical assessment alone, while appropriate in certain contexts\[[@pone.0191608.ref016]\], is infrequently prescribed. These observations, together with autopsy data showing that the most frequent cause of death amongst HIV-positive persons is undiagnosed tuberculosis\[[@pone.0191608.ref017]--[@pone.0191608.ref019]\], suggest that empiric TB treatment could appropriately be more frequently prescribed amongst HIV-positive persons. In our evaluation, the reliance on chest radiography as the reason for TB treatment initiation amongst persons being evaluated for TB with negative Xpert sputum tests is in keeping with findings from studies evaluating routine TB screening\[[@pone.0191608.ref020], [@pone.0191608.ref021]\] and diagnostic algorithms using Xpert\[[@pone.0191608.ref022]--[@pone.0191608.ref025]\]. In the TB-NEAT evaluation of Xpert, where all participants received smear microscopy or Xpert, and chest radiography and sputum culture, TB treatment was initiated empirically on the basis of chest radiographic findings in 313 (51%) of all 611 persons initiated on TB treatment\[[@pone.0191608.ref026]\]. In a multi-centre, individually randomised trial of Xpert vs smear-microscopy with pragmatic implementation of further diagnostic tests, liberal use of chest radiography was a major factor driving empiric TB treatment initiation\[[@pone.0191608.ref013]\]. We observed that empiric TB treatment was frequently initiated following a visit to hospital or during admission, but only a third of persons had a documented referral suggesting that the majority of patients self-referred to a higher level of care. This suggests that patients may lack faith in the ability of clinics to assist them, and that PHC facilities miss opportunities to conduct further investigations. Naidoo et al\[[@pone.0191608.ref027]\] reported poor perceptions of public sector services amongst South African TB patients. Further, weak case management such as failure to adhere to testing algorithms\[[@pone.0191608.ref027], [@pone.0191608.ref028]\] and sputum results not being available\[[@pone.0191608.ref027]\] may lead to missed opportunities to conduct additional investigations and delay TB treatment start\[[@pone.0191608.ref015]\]. Our observation of delayed treatment start amongst persons diagnosed by culture suggests failure to promptly recall patients with positive results, a finding reported by others\[[@pone.0191608.ref027]\]. Ultimately, health system performance including district and facility level support, continuity and quality of care provide the context for TB case management and impact directly on TB programme outcomes\[[@pone.0191608.ref029]\]. Churchyard\[[@pone.0191608.ref005]\], Creswell\[[@pone.0191608.ref030]\] and others\[[@pone.0191608.ref031], [@pone.0191608.ref032]\] attribute the failure of Xpert to improve patient outcomes, despite the improved sensitivity of Xpert to health system weaknesses in the TB and HIV continuum of care, with missed opportunities to diagnose and link persons into TB treatment. Our findings underscore the need for highly sensitive TB diagnostic tests. Currently available diagnostic assays include the Xpert MTB/RIF Ultra cartridge, the loop-mediated amplification (LAMP) assay and urine lipoarabinomannan (LAM) tests. While Xpert MTB/RIF Ultra has demonstrated improved sensitivity\[[@pone.0191608.ref033]\], and a potential impact on mortality in high TB/HIV prevalent regions\[[@pone.0191608.ref034]\], the assay has a marginal reduction in specificity especially amongst persons with a prior TB treatment history\[[@pone.0191608.ref035]\]. The WHO advises that the LAMP assay may be used as a replacement for or follow-on test after smear-microscopy, but should not replace Xpert MTB/RIF where this is available\[[@pone.0191608.ref036]\]. The currently-available urine LAM assay has limited clinical applicability, and is recommended for use amongst persons with HIV infection and low CD4 counts (\<100 cells/μl)\[[@pone.0191608.ref037]\]. The strength of our evaluation arises through the pragmatic XTEND study design with implementation of TB diagnosis in a real-world setting in 40 PHCs across four South African provinces, allowing follow up of persons investigated for TB for 6 months after submitting sputum for TB investigation. Our findings may be limited by possible poor clinical record keeping at clinics. We were not able to conduct patient record review at referral hospitals. In addition, the XTEND study design did not allow for confirmation of TB diagnoses amongst all participants, and so it was not possible to confirm TB diagnoses amongst persons who did not have sputum submitted for TB culture, or who died during follow-up. Conclusions {#sec014} =========== In this secondary data analysis of a cohort of symptomatic persons investigated for TB at primary health care level and followed up for 6 months, we observed uncommon use of empiric TB treatment, reliance on chest radiography and self-referral to hospital to initiate TB treatment when initial sputum tests were negative. In the context of high rates of death due to autopsy-confirmed previously undiagnosed TB in the South African context, our findings underscore the importance of highly sensitive TB diagnostics and strong health systems to support TB diagnosis in this setting. Supporting information {#sec015} ====================== ###### Pathways from enrolment to end of follow up of 167 persons who were index sputum test negative for TB at enrolment, but who were started on TB treatment during 6 months of follow up. (XLSX) ###### Click here for additional data file. The authors would like to acknowledge the contribution of the XTEND Investigators (Wendy Stevens, Lerole Mametja, Violet Chihota, Mark Nicol, Linda Erasmus, Norbert Ndjeka, Lindiwe Mvusi, Anna Vassall, Edina Sinanovic, Helen Cox, Christopher Dye) for their analysis and interpretation of the XTEND study; the staff of the XTEND study for their contribution towards data collection and commitment towards the study, and the persons who gave consent to participate in the XTEND study. [^1]: **Competing Interests:**The authors have declared that no competing interests exist.

Franklin Junior High School (Brainerd, Minnesota) Franklin Junior High School is a historic former school building in Brainerd, Minnesota, United States. The core sections were built in 1932 and extensions were added on in 1954 and 1962. The school closed in 2005. In 2008 the building reopened as the Franklin Arts Center, which leases residential, work, and commercial space to local artists. The building was listed on the National Register of Historic Places in 2009 for having local significance in the theme of architecture. It was nominated for reflecting the research-based national standards for middle school design as they evolved through the first half of the 20th century. Novel, early-century features apparent in the original section include large windows for maximum sunlight, an auditorium and gymnasium designed to accommodate large community events, and rooms for specialized instruction in music, science, and vocational training. The later sections show new preferences adopted after World War II, most noticeably smaller classroom windows and a reliance on artificial lighting. Description The historic core of Franklin Junior High School, built in 1932, resembles a stubby arrow. The two classroom wings meet at a right angle with a prominent, angled-off main entry facing southwest. Extending at a 45-degree angle to the northeast is a third wing containing the auditorium and gymnasium. New additions in 1954 extended all three wings, particularly the two classroom wings. A further expansion in 1962 extended the north wing, bringing the school's total floorspace from in its original configuration to about . The building has a brick and reinforced concrete structure. The exterior is dark red-brown brick with trim of smooth limestone quarried near Mankato, Minnesota. A belt course of stone trim extends continuously just under the ground floor windows. The second-floor windows have stone lintels. The building's primary façade is the southwest corner, which is angled at 45 degrees. The main entrance is set into a stone entryway featuring a segmental arch topped by a parapet and flanked by a pair of tall piers each sporting a bronze lantern. Large windows on the second floor are topped by a series of stone lancet arches supported by stone corbels. The roofline is defined by a brick parapet which sports a medallion of pattened bricks in the very center. Projecting stone bay windows define the façade's ground floor corners. The 1954 additions use brick and stone similar to the original section. An entry door in the middle of the west and south façades indicates the corners of the original construction. A recessed bay on the west façade with another entry door defines the start of the 1962 addition. Interior The front entrance leads into a ground level foyer with administrative offices to the side and stairs to the second floor. Beyond the foyer, where the building's three wings come together, is the school's 500-seat auditorium. The north and east wings contain classrooms on either side of central halls. The northeast wing extends behind the auditorium stage and contains a gymnasium as well as a basement-level cafeteria and boiler room. Directly over the main entrance, on the second floor, was the school library. The ground floor of one classroom wing housed industrial arts workshops for boys while the other offered home economics classes for girls. The gymnasium was also originally divided in two for sex-segregated instruction. Although the architectural style of the school's exterior is Collegiate Gothic, the interior has simple details in the Streamline Moderne mode popular in the early 1930s. The foyer is tiled, while there were terrazzo floors in the hallways and maple wood flooring in the classrooms and gym. The terrazzo continues in the hallways of the later additions, but the walls are covered in ceramic tile and the classrooms are floored with vinyl tile. History Education experts began promoting separate middle schools in the early 20th century as they began recognizing seventh and eighth grade as an important transitional period. Previously these grades were included in primary school but tended to be too focused on review of previously taught material and left students ill-prepared for the high school environment, leading to a high drop-out rate. When Brainerd's high school building was destroyed by fire in 1928, the city took the opportunity to propose building a middle school in addition to a new high school. Voters approved both projects when they appeared on the ballot. By the time the two contracts went up for bid, the Great Depression had set in and construction work was scarce (federal New Deal funding for building projects would not appear for another few years). 14 architectural firms competed for Brainerd's two school bids, and the commission went to Croft & Boerner of Minneapolis. Concerned about losing jobs to outsiders, a delegation of local craftsmen lobbied the Board of Education for the construction labor to be drawn from Brainerd residents. Croft and Boerner's design drew on the established best practices for American junior high schools. These favored H-, I-, or L-shaped layouts and flat roofs, fireproofing, large windows for natural light in classrooms, good air circulation, a well-stocked library, science laboratories, and specialized rooms for music, industrial, and vocational training. Auditoriums and gyms were often planned to serve the larger community as public event spaces. Croft and Boerner's design included an auditorium stage that could be opened up to the gymnasium behind it for additional seating. A growing student population led to expansion of the school in 1954. The design, by Minneapolis architect Hubert Swanson, once again reflected the latest standards, which had evolved since the 1930s. Most notable is a reversal in opinions about windows, driven in part by improvements in artificial lighting. Where maximum sunlight and air circulation had once been deemed essential, fluorescent lighting was now considered preferable and large windows a distraction. An increased emphasis on physical education prompted an expansion of the gymnasium and improvements to the sports field northeast of the school. A further addition to the north wing was designed by the Brainerd-based firm of Stengen, Hendrickson, and McNutt in 1962. Adaptive reuse By the 2000s Franklin Junior High School was getting too small again for its student body, but the state funds that had previously helped the city expand the existing building had been eliminated. Brainerd was obliged to build a new junior high, and Franklin closed in 2005. Hoping to find an adaptive reuse for Franklin, the school district contacted Artspace Projects, Inc, a national non-profit organization specializing in converting older buildings into art centers. Artspace formally purchased the building in 2008 and completed renovations later that year. Now known as the Franklin Arts Center, the building leases space to arts organizations and rents out residential and work studios to artists. The school district retains access to the auditorium, gymnasium, and athletic field for sports programs and community events. To preserve the building's historic feel, state rules forbid major alterations to the exterior or the hallways with their rows of lockers and built-in cabinets. See also National Register of Historic Places listings in Crow Wing County, Minnesota References External links Franklin Arts Center Category:1932 establishments in Minnesota Category:Defunct schools in Minnesota Category:Former school buildings in the United States Category:Gothic Revival architecture in Minnesota Category:National Register of Historic Places in Crow Wing County, Minnesota Category:School buildings completed in 1932 Category:School buildings completed in 1954 Category:School buildings on the National Register of Historic Places in Minnesota Category:Schools in Crow Wing County, Minnesota

Thyme There are few things more comforting than having a real French Onion Soup – slowly cooked, caramelized onions that turn mellow and sweet in a broth laced with white wine and Cognac. And to finish it off – crunchy baked … Readmore +

All relevant data are within the paper and its Supporting Information files. Introduction {#sec001} ============ Oxaliplatin, a platinum-based drug, is used as the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. However, oxaliplatin is associated with acute and chronic peripheral neuropathies \[[@pone.0225586.ref001], [@pone.0225586.ref002]\]. Oxaliplatin-induced acute neuropathy is characterized by acral paresthesia that is enhanced by exposure to cold. Furthermore, cumulative oxaliplatin dose can cause chronic neuropathy, which includes pain, paresthesia, hypoesthesia, dysesthesia, and changes in proprioception. Therefore, oxaliplatin-induced neuropathic pain is a major clinical side-effect that can influence the treatment as well as the quality of life. Pain results from the activation of a subset of sensory neurons termed nociceptors. Under physiological conditions, activation of unmyelinated (C-fiber) and myelinated (Aδ-fiber) nociceptive afferent fibers indicates potential tissue damage, which is reflected in the high thresholds of nociceptors for mechanical, thermal, and chemical stimuli; these neurotransmissions are attributed to ion channels, neurotransmitters, and intracellular signaling \[[@pone.0225586.ref003], [@pone.0225586.ref004]\]. These conditions change dramatically in neuropathic pain states, including chemotherapy-induced peripheral neuropathy (CIPN). Understanding the changes that occur in neuropathic pain is vital to identify new therapeutic targets and develop novel analgesics \[[@pone.0225586.ref004]\]. Recently, it has been reported that oxaliplatin-induced acute paresthesia is induced by voltage-dependent sodium channel (Na~V~1.6) dysfunction \[[@pone.0225586.ref005]--[@pone.0225586.ref007]\] and upregulation of transient receptor potential (TRP) channels, TRPM8 and TRPA1 \[[@pone.0225586.ref008]--[@pone.0225586.ref011]\], which are temperature-sensitive channels. However, the pathophysiology of oxaliplatin-induced neuropathic pain as a chronic neuropathy has not yet been clearly established. Mitogen-activated protein kinases (MAPKs) signaling cascade is known to be involved in the regulation of cellular functions such as cell differentiation, proliferation, and apoptosis \[[@pone.0225586.ref012], [@pone.0225586.ref013]\]. MAPKs, such as extracellular signal-regulated kinase (ERK), p38 kinase, and c-jun N-terminal kinase (JNK), have been linked with the development of pain \[[@pone.0225586.ref012], [@pone.0225586.ref013]\]. Furthermore, it has recently been reported that the modulation of MAPKs activation is associated with oxaliplatin-induced apoptosis in cultured dorsal root ganglion (DRG) neurons \[[@pone.0225586.ref014], [@pone.0225586.ref015]\]. Therefore, the aim of the current study was to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We investigated whether MAPKs were modulated by oxaliplatin in the rat DRG and found that oxaliplatin treatment up-regulates ERK phosphorylation in rat DRG and induced chronic neuropathic pain. We also demonstrated that administration of an ERK inhibitor inhibits oxaliplatin-induced neuropathic pain. Thus, our study suggests a novel mechanism by which oxaliplatin treatment can influence MAPKs signaling and contribute to chronic neuropathy. Materials and methods {#sec002} ===================== Animals {#sec003} ------- Six-week-old male Sprague Dawley rats (Kudo, Japan) weighing approximately 200--250 g were used in the study. All rats were individually housed in a temperature- and humidity-controlled environment with a 12-hour light-dark cycle and were permitted free access to food and water. The study was conducted in strict accordance with the guidelines for Proper Conduct of Animal Experiments (Science Council of Japan). The experiments were approved by the Experimental Animal Care and Use Committee of University of Miyazaki (Permit Number: 2015--528). All efforts were made to minimize the number of animals used and their suffering. Pharmacological treatments {#sec004} -------------------------- In the first series of experiments, we investigated the intracellular molecular alterations in DRG. Oxaliplatin (4 mg kg^-1^ of body weight; Sigma-Aldrich, St. Louis, MO, USA) or vehicle (5% glucose) was injected intraperitoneally (i.p.) twice a week for 4 weeks \[[@pone.0225586.ref016]\]. Oxaliplatin was prepared in 5% glucose to a final concentration of 2 mg ml^-1^. von Frey test was conducted before and 1 week after each oxaliplatin or vehicle treatment. On day 28, at the end of the last behavioral test, L4-L6 DRGs were dissected from each group and intracellular molecules including ERK were measured using western blot analysis. In the second series of experiments, we investigated the effects of ERK inhibitor on oxaliplatin-induced neuropathy. Rats were anesthetized with an intraperitoneal injection of a combination anesthetic (0.375 mg kg^-1^ of medetomidine, 2.0 mg kg^-1^ of midazolam, and 2.5 mg kg^-1^ of butorphanol). A PE-10 polyethylene catheter (Becton-Dickinson, Sparks, MD, USA) was inserted into the subarachnoid space through the atlanto-occipital membrane and pushed to the region of lumbar enlargement \[[@pone.0225586.ref017]\]. An osmotic pressure pump (ALZET model 2004, DURECT, Cupertino, CA, USA; total volume of the pump: 200 μl, drug infusion: 0.25 μl hour^-1^ for 4 weeks) was connected to the catheter and placed subcutaneously on the back \[[@pone.0225586.ref018]\]. Immediately after surgery, the operating surgeon regularly observed animals until they were ambulatory. Furthermore, the animals\' appearance, movement, and appetite were observed daily for one week after surgery. ERK inhibitor PD98059 (6 μg day^-1^; Sigma-Aldrich, St. Louis, MO, USA) or vehicle \[20% dimethyl sulfoxide (DMSO)\] was injected intrathecally (i.t.) for 4 weeks with the osmotic pressure pump. PD98059 was dissolved in 20% DMSO to a final concentration of 1 μg μl^-1^. One week after the pump placement, oxaliplatin (4 mg kg^-1^) or vehicle (5% glucose) was injected i.p. twice a week for 3 weeks. The sham-operated (Sham) mice underwent a similar surgical procedure except for pump placement and drug treatments. von Frey test was conducted before pump placement, and before and 1 week after each oxaliplatin or vehicle treatment. On day 28 of pump placement, at the end of the last behavioral test, L4-L6 DRGs were dissected from each group and intracellular levels of various molecules were measured using western blot analysis. von Frey test {#sec005} ------------- Mechanical sensitivity was examined by testing the paw withdrawal threshold using the von Frey (VF) filaments (Stoelting, Wood Dale, IL, USA). Briefly, each rat was placed in a 20 cm × 20 cm suspended chamber on a metallic mesh floor. After an acclimation period of 30 minutes, a series of calibrated VF filaments were applied perpendicularly to the plantar surface of the right and left hind paws with sufficient force to bend the filament for 5 seconds. Brisk withdrawal or paw flinching was considered as a positive response. In the absence of a response, the filament of next greater force was applied. After a positive response, the filament of next lower force was applied. The tactile stimulus producing a 50% likelihood of withdrawal response was calculated using the up-down method \[[@pone.0225586.ref019]\]. von Frey test was conducted before an osmotic pressure pump placement, and before and 1 week after each intraperitoneal oxaliplatin or vehicle treatment for 4 weeks. Western blot analysis {#sec006} --------------------- On day 28 of intraperitoneal treatment or pump placement, all rats were euthanized with sevoflurane exposure and the L4-L6 DRGs from each group were quickly dissected for further analysis. Briefly, the collected DRGs were mechanically homogenized in ice-cold lysis buffer composed of 1% Triton X-100, 150 mM NaCl, 1 mM EDTA, and 20 mM Tris-HCl, pH 7.5, with added Protease and Phosphatase Inhibitor Cocktails (Roche Diagnostics, Mannheim, Germany) and centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant was collected and stored at -80°C until use. The total protein content was determined in each sample using the Bradford method-based protein assay kit, with bovine serum albumin (BSA) as standard (Aproscience, Naruto, Japan). The supernatants were solubilized in 2× SDS electrophoresis sample buffer and heated at 98°C for 5 minutes. Equal amount of proteins (7.0--7.5 μg per lane) were separated by SDS-12% polyacrylamide gel electrophoresis (PAGE) and transferred onto a polyvinylidene difluoride (PVDF) membrane (Immobilon-P, Merck Millipore, Burlington, MA, USA). The membrane was then incubated with a blocking solution \[5% BSA in Tween-Tris-buffered saline (10 mM Tris-HCl, pH 7.4, 150 mM NaCl, and 0.1% Tween-20)\] and further incubated overnight at 4°C in Can Get Signal Solution-1 (TOYOBO, Osaka, Japan) with rabbit anti-ERK polyclonal antibody (1:2000, K-23, Santa Cruz, Dallas, TX, USA), mouse anti-p-ERK monoclonal antibody (1:2000, E-4, Santa Cruz), rabbit anti-p38 monoclonal antibody (1:2000, D13E1, Cell Signaling Technology, MA, USA), rabbit anti-p-p38 monoclonal antibody (Thr180/Tyr182) (1:2000, D3F9, Cell Signaling Technology), rabbit anti-JNK polyclonal antibody (1:2000, D-2, Santa Cruz), mouse anti-p-JNK monoclonal antibody (1:2000, Santa Cruz), rabbit anti-BDNF polyclonal antibody (1:2000, ab226843, Abcam, Cambridge, UK) or mouse anti-β-actin monoclonal antibody (1:2000, A1978, Sigma-Aldrich, St. Louis, MO, USA). After repeated washing, the immunoreactive bands were developed using Can Get Signal Solution-2 with horseradish peroxidase-conjugated anti-rabbit antibody (1:5000, GE Healthcare Japan Corporation, Tokyo, Japan) or anti-mouse antibody (1:5000, Santa Cruz), then visualized using an enhanced chemiluminescence detection system reagent (Amersham ECL-prime, GE Healthcare Japan Corporation), and captured in a LAS-3000 Luminoimage analyzer (Fuji Film, Tokyo, Japan). A commercially available molecular weight marker (Amersham ECL rainbow marker--full range, GE Healthcare Japan Corporation), consisting of proteins of molecular weight 12 to 225 kDa, was used as a reference for each molecular weight. The densities of protein blots were quantified using ImageJ \[[@pone.0225586.ref020]\] and the protein levels were normalized to β-actin levels. Statistical analysis {#sec007} -------------------- For behavioral experiments, the hindpaw data within each group were analyzed using one-way repeated measures analysis of variance (ANOVA) followed by Bonferroni post hoc analysis. Comparisons between two means of the hindpaw data and western blot data were performed by Welch's test and Student's t-test, respectively. The results were presented as mean ± SEM (for von Frey test) or ± SD (for western blot analysis). *P* \< 0.05 was considered as significant. The statistics software used was JMP 11 (SAS Institute, Inc., Cary, NC, USA) for Macintosh. Results {#sec008} ======= Mechanical allodynia in a rat model of oxaliplatin-induced neuropathic pain {#sec009} --------------------------------------------------------------------------- The oxaliplatin treatment (4 mg kg^-1^, twice a week for 4 weeks) induced increased pain behavior in the rat model \[[@pone.0225586.ref016]\]. [Fig 1](#pone.0225586.g001){ref-type="fig"} shows that the paw withdrawal thresholds measured with VF filaments to the non-noxious mechanical stimulus at 3 and 4 weeks after oxaliplatin treatment were significantly lower than the vehicle treatment (4.4 ± 1.0 g vs. 16.0 ± 4.1 g; *P* = 0.046 and 4.4 ± 0.7 g vs. 14.8 ± 3.1 g; *P* = 0.027, respectively). {#pone.0225586.g001} Oxaliplatin treatment up-regulates ERK phosphorylation in rat DRG neurons {#sec010} ------------------------------------------------------------------------- The modulation of MAPKs activation, including ERK, p38 kinase, and JNK pathways, have not only been linked with the development of pain \[[@pone.0225586.ref012], [@pone.0225586.ref013]\], but also with the oxaliplatin-induced apoptosis in DRG \[[@pone.0225586.ref014], [@pone.0225586.ref015]\]. Western blot analyses of different MAPKs in the DRG of oxaliplatin-treated rats as compared to vehicle-treated rats are illustrated in Figs [2](#pone.0225586.g002){ref-type="fig"}--[4](#pone.0225586.g004){ref-type="fig"}. Although no difference was observed in the total ERK1/2 levels between oxaliplatin and vehicle treatment groups, p-ERK1/2 was found to be up-regulated up to 4.5-fold (447.6 ± 273.6%, *P* = 0.0029) in DRG of oxaliplatin-induced neuropathic pain rat model ([Fig 2](#pone.0225586.g002){ref-type="fig"}). On the other hand, no change was observed in the phosphorylation and protein levels of p38 and JNK between oxaliplatin and vehicle treatment groups (Figs [3](#pone.0225586.g003){ref-type="fig"} and [4](#pone.0225586.g004){ref-type="fig"}). {#pone.0225586.g002} {#pone.0225586.g003} {#pone.0225586.g004} Oxaliplatin treatment increases brain-derived neurotrophic factor (BDNF) levels in rat DRG {#sec011} ------------------------------------------------------------------------------------------ BDNF is not only a nerve growth factor, but also a neurotransmitter of nociceptive fibers in the dorsal horn of the spinal cord. In the spinal nerve ligation (SNL) model of neuropathic pain, BDNF expression was found to be up-regulated in the rat spinal dorsal horn \[[@pone.0225586.ref021]\]. BDNF expression was also up-regulated in DRG in lumbar 5 ventral root transection model of neuropathic pain \[[@pone.0225586.ref021]\]. In our study, BDNF levels were increased in DRG of oxaliplatin-induced neuropathic pain rat model (115.8 ± 23.4%, *P* = 0.047) ([Fig 5](#pone.0225586.g005){ref-type="fig"}). {#pone.0225586.g005} Effects of ERK inhibitor on oxaliplatin-induced neuropathic pain {#sec012} ---------------------------------------------------------------- [Fig 6](#pone.0225586.g006){ref-type="fig"} shows that ERK inhibitor PD98059 (6 μg day^-1^) injected intrathecally inhibited oxaliplatin-induced mechanical allodynia. The paw withdrawal thresholds in the oxaliplatin and PD98059 treatment group were mostly maintained from baseline and were significantly higher than the oxaliplatin and vehicle treatment group at 3 weeks after oxaliplatin treatment (OX + PD98059: 15.2 ± 2.9 g and Sham: 16.2 ± 2.6 g vs. OX + Veh: 4.8 ± 0.8 g; *P* = 0.021 and *P* = 0.01, respectively). Concomitantly, PD98059 also inhibited oxaliplatin-induced upregulation of ERK phosphorylation in DRG (OX + PD98059: 147.6 ± 47.6%,vs. OX + Veh: 402.9 ± 251.2%, *P* = 0.0094) ([Fig 7](#pone.0225586.g007){ref-type="fig"}). {#pone.0225586.g006} {#pone.0225586.g007} Discussion {#sec013} ========== Platinum-based drugs are the first-line chemotherapy for different cancers. Platinum derivatives such as oxaliplatin and cisplatin act as cytotoxins on tumor cells by forming platinum-DNA adducts, thus leading the tumor cells to programmed cell death. These platinum derivatives induce Chemotherapy-Induced Peripheral Neuropathy (CIPN) as one of the clinical side-effects \[[@pone.0225586.ref001], [@pone.0225586.ref002]\]. In an *in-vitro* study, treatment of cultured DRG neurons from E15 rat embryos with toxic doses of oxaliplatin or cisplatin induced a dose-dependent neuronal apoptosis by phosphorylating and inactivating the anti-apoptotic protein Bcl-2 and increasing the levels of the pro-apoptotic protein Bax \[[@pone.0225586.ref014]\]. Furthermore, studies have shown that these platinum derivatives modulate different MAPKs \[[@pone.0225586.ref013]\]. MAPKs are vital for intracellular signal transduction and play critical roles in regulation of neural plasticity and inflammatory responses \[[@pone.0225586.ref012], [@pone.0225586.ref013]\]. This family of kinases consists of three key members: ERK, p38, and JNK. Accumulating evidence shows that the activation of MAPKs can induce the synthesis of pronociceptive mediators via distinct molecular and cellular mechanisms, resulting in the enhancement and prolongation of pain \[[@pone.0225586.ref012], [@pone.0225586.ref013]\]. The platinum derivatives phosphorylate and activate p38 while they reduce the levels of active and total JNK. Both oxaliplatin and cisplatin have shown to activate ERKs during early stages (4--8 hours after treatment), although they behave differently at later stages \[[@pone.0225586.ref014]\]. Moreover, by using specific inhibitors of the different MAPKs, it has been demonstrated that the platinum-induced neuronal apoptosis is mediated by early p38 and ERK1/2 activation \[[@pone.0225586.ref014]\]. In *in-vivo* studies, oxaliplatin has shown to increase p38 phosphorylation at 0.5 and 4 hours after the treatment \[[@pone.0225586.ref022]\], or protein kinase C (PKC) phosphorylation, ERK1/2 phosphorylation, and c-fos expression on day 14 after the treatment \[[@pone.0225586.ref023]\], in the spinal cord of oxaliplatin-induced neuropathy mouse model. These results and our findings suggest a role for MAPKs including ERK in the generation and development of oxaliplatin-induced peripheral neuropathy. Electrophysiological studies in patients undergoing oxaliplatin-treatment demonstrated nerve hyperexcitability in both peripheral motor \[[@pone.0225586.ref024]\] and sensory axons \[[@pone.0225586.ref025]\]. Furthermore, electrophysiological *in-vitro* studies in isolated peripheral nerve segments indicated that the hyperexcitability is characterized by an increase in the duration of the compound A-fiber action potential and the emergence of after-activity persisting over several tens of milliseconds \[[@pone.0225586.ref026]--[@pone.0225586.ref029]\]. A modulating effect on both voltage-dependent sodium channels and delayed rectifier potassium channels has been demonstrated during oxaliplatin administration to the myelinated axons in frog nerves \[[@pone.0225586.ref030]\] and to the neuronal cells in cell culture \[[@pone.0225586.ref031]\]. Thus, abnormal Na^+^ channel and/or K^+^ channel function has been highlighted as a possible mechanism of oxaliplatin-induced neuropathy. However, focusing on Na^+^ channel subtypes, Na~V~1.7, Na~V~1.8, and Na~V~1.9, expressed in the DRG, conditional knockout mice established using the Na~V~1.7^Advill^ line, which eliminates Na~V~1.7 expression in all the DRG neurons, and the Na~V~1.7^Wnt1^ line, which lacks Na~V~1.7 expression in the DRG and sympathetic ganglion neurons, both Na~V~1.7^Advill^ and Na~V~1.7^Wnt1^ mice developed mechanical and cold allodynia normally following oxaliplatin treatment \[[@pone.0225586.ref032]\]. In addition, global deletion of Na~V~1.3, Na~V~1.8, or Na~V~1.9 also did not attenuate either mechanical or cold allodynia in oxaliplatin-induced neuropathy. Furthermore, in our study, the expression levels of Na~V~1.7, Na~V~1.8, and Na~V~1.9 were not altered in the DRG of oxaliplatin treated rats compared to non-treated rats ([S1 Fig](#pone.0225586.s001){ref-type="supplementary-material"} and [S2 Fig](#pone.0225586.s002){ref-type="supplementary-material"}). These findings suggest that the expression of the voltage-dependent Na^+^ channel subtypes Na~V~1.3, Na~V~1.7, Na~V~1.8, and Na~V~1.9 is not required for the development of oxaliplatin-induced neuropathy. So, how does abnormal Na^+^ current lead to the development of nerve hyperexcitability? Firstly, Na^+^ channel subtypes other than Na~V~1.3, Na~V~1.7, Na~V~1.8, and Na~V~1.9 could contribute to oxaliplatin-induced nerve hyperexcitability. Indeed, a recent study revealed that the expression of Na~V~1.6 was dramatically increased in the DRG in oxaliplatin-induced CIPN model rats \[[@pone.0225586.ref033]\]. Furthermore, the agomir of miR-30b, a microRNA implicated in neuropathic pain, cancer, and neurodegenerative diseases, can downregulate Na~V~1.6 and alleviate oxaliplatin-induced mechanical allodynia and cold hypersensitivity \[[@pone.0225586.ref033]\]. Secondly, the cytokines and chemokines associated with altering intracellular signaling could modify Na^+^ current, which is conducive to nerve hyperexcitability. Recently accumulated evidence has shown that oxaliplatin treatment increases pro- and anti-inflammatory cytokines and chemokines \[[@pone.0225586.ref034]--[@pone.0225586.ref040]\]. Oxaliplatin injection enhanced the mRNA levels of cytokines including tissue necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and chemokines including monocyte chemoattractant protein-1 (MCP-1, also referred to as C-C chemokine ligand (CCL) 2) and monocyte inflammatory protein-1 (MIP-1α, also referred to as CCL3) in the spinal dorsal horn \[[@pone.0225586.ref034]\]. Melatonin attenuates pain hypersensitivity by inhibition of TNF-α in oxaliplatin-induced neuropathy \[[@pone.0225586.ref033]\]. CCL2 and its receptor CCR2 have also been shown to be increased in the DRG after oxaliplatin administration, in parallel with the development of mechanical hypersensitivity \[[@pone.0225586.ref035], [@pone.0225586.ref036]\]. Wang et al. have reported that oxaliplatin treatment up-regulates NF-κB and induces neuronal hyperexcitability in DRG \[[@pone.0225586.ref037]\]. This neuronal hyperexcitability was inhibited by NF-κB inhibitors. Oxaliplatin-induced pain has also been shown to be accompanied with the upregulation of PI3K-mTOR and mTOR-mediated signals as well as IL-1β, IL-6, and TNF-α in DRG. As PI3K or mTOR signal was inhibited, mechanical and cold hypersensitivity were attenuated in oxaliplatin treated rats, and the levels of proinflammatory cytokines also decreased \[[@pone.0225586.ref038]\]. The upregulation of pro-inflammatory cytokines and membrane pro-inflammatory cytokine receptors in the midbrain periaqueductal gray, which has an inhibitory or excitatory control on pain transmission via the rostral ventromedial medulla, projecting to the spinal dorsal horn, of oxaliplatin treated rats is likely to impair the descending inhibitory pathways in regulation of pain transmission and thereby, contribute to the development of neuropathic pain after the administration of chemotherapeutic oxaliplatin \[[@pone.0225586.ref039]\]. These reports suggest that the mechanism of development of oxaliplatin-induced neuropathy resembles inflammatory pain. Furthermore, Huang et al. and Liu et al. have reported an increase in the levels of TNF-α, NF-κB, and phosphorylation of ERK in the spinal cord and DRG of an oxaliplatin-induced peripheral neuropathy rat model and a lumber disk herniation rat model \[[@pone.0225586.ref036], [@pone.0225586.ref040]\]. Previous studies have demonstrated that TNF-α enhances TTX-R Na^+^ currents via TNFR1 and the p38 pathway in the cultured DRG neurons within 1 minute of the onset of TNF-α application (peak effect within 3--5 minutes) \[[@pone.0225586.ref041]\], as well as via the p38 pathway in the uninjured DRG neurons after L5-ventral root transection (VRT) *in vivo* \[[@pone.0225586.ref042]\]. The phosphorylated ERK1 lowers the activation threshold, making it easier to open Na~V~1.7 channel in response to weak stimuli \[[@pone.0225586.ref043]\]. We have also reported that veratridine-induced ^22^Na^+^ influx was inhibited by the inhibitors of ERK and p38, indicating that the basal constitutive activities of ERK and p38 may prime Na~V~1.7 to open \[[@pone.0225586.ref044]\]. These findings suggest that oxaliplatin-induced neuroinflammation and inflammatory mediators would evolve abnormal Na^+^ channel currents via MAPK including ERK phosphorylation, and thus, lead to the development of neuropathy. Conclusions {#sec014} =========== Oxaliplatin administration induces chronic mechanical allodynia in rats. The phosphorylation of ERK is upregulated in the DRG of oxaliplatin-induced neuropathic pain rat model, whereas other MAPKs, p38, and JNK are not altered. ERK inhibitor impedes mechanical allodynia by inhibiting oxaliplatin-induced upregulation of ERK phosphorylation. Thus, the findings from the present study may provide a better understanding of the intracellular molecular alterations in the development of oxaliplatin-induced neuropathic pain and help in designing effective therapeutics. Supporting information {#sec015} ====================== ###### The protein levels of Na~V~1.7, Na~V~1.8, and Na~V~1.9 in oxaliplatin-treated rat DRG. Typical western blots of Na~V~1.7, Na~V~1.8, and Na~V~1.9 are shown. These images suggested that there was no difference in Na~V~1.7, Na~V~1.8, and Na~V~1.9 protein levels between oxaliplatin and vehicle treatment groups. (TIFF) ###### Click here for additional data file. ###### The mRNA levels of Na~V~1.7, Na~V~1.8, and Na~V~1.9 in oxaliplatin-treated rat DRG. Typical polymerase chain reaction (PCR) gel images of Na~V~1.7, Na~V~1.8, and Na~V~1.9 are shown. These images suggested that there was no difference in Na~V~1.7, Na~V~1.8, and Na~V~1.9 mRNA expression levels between oxaliplatin and vehicle treatment groups. (TIFF) ###### Click here for additional data file. ###### Expanded views of western blots and PCR used in Figs [2](#pone.0225586.g002){ref-type="fig"}--[5](#pone.0225586.g005){ref-type="fig"}, [7](#pone.0225586.g007){ref-type="fig"}, [S1](#pone.0225586.s001){ref-type="supplementary-material"} and [S2](#pone.0225586.s002){ref-type="supplementary-material"}. (TIFF) ###### Click here for additional data file. This study is attributed to the Department of Anesthesiology, Faculty of Medicine, University of Miyazaki. The authors would like to thank Noriko Hidaka, Mio Kurogi, and Toshiko Watanabe for their technical and secretarial assistance in this study. The authors would like to thank Editage ([www.editage.jp](http://www.editage.jp/)) for English language editing. 10.1371/journal.pone.0225586.r001 Decision Letter 0 Gallyas, Jr. Ferenc Section Editor © 2019 Ferenc Gallyas, Jr. 2019 Ferenc Gallyas, Jr. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 22 Aug 2019 PONE-D-19-17881 Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain PLOS ONE Dear Dr. MARUTA, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. 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At this time, we request that you  please report additional details in your Methods section regarding animal care, as per our editorial guidelines: a\) Please describe any steps taken to minimize animal suffering and distress, such as by administering analgesics, b\) Please include the method of sacrifice and c\) Please describe the post-operative care received by the animals, including the frequency of monitoring and the criteria used to assess animal health and well-being. Thank you for your attention to these requests. \[Note: HTML markup is below. Please do not edit.\] Reviewers\' comments: Reviewer\'s Responses to Questions **Comments to the Author** 1\. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer \#1: Partly Reviewer \#2: Partly \*\*\*\*\*\*\*\*\*\* 2\. Has the statistical analysis been performed appropriately and rigorously? Reviewer \#1: No Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 3\. Have the authors made all data underlying the findings in their manuscript fully available? The [PLOS Data policy](http://www.plosone.org/static/policies.action#sharing) requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data---e.g. participant privacy or use of data from a third party---those must be specified. Reviewer \#1: Yes Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 4\. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer \#1: Yes Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 5\. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer \#1: In the current manuscript, the authors investigate the factors underlying the neuropathy development following oxaliplatin treatment in rats. This phenotype is seen after 3-4 weeks of treatment. The authors propose that upregulation of ERK phosphorylation in rat DRG neurons is responsible for generating this pain phenotype. They use ERK inhibition in combination with the evaluation of mechanical pain and western blot analysis to show that this mechanism may be responsible for the oxaliplatin-induced neuropathic pain. The data are conciseness and supportive, the study is well written and the conclusions are broadly reasonable. To improve the paper the authors should consider the following points: 1\. The authors need to increase the sample size to ascertain that this time course of the incidence of mechanical allodynia in oxaliplatin group respect to vehicle group is not related to the small sample size -i.e. n=5 per group. The control group show a high variability These results will provide crucial information to the interpretation of the current data set (Fig1). 2\. The authors should include more information that clarifies and justifies their statistical analyses. Specify the statistical methods performed in the figure legends and include the significance values in manuscript text. Please also provide all vehicle group values (mean +/- SD) which are used to relative the oxaliplatin group values, and F and P-values for each individual factor for all statistic performed. 3\. For the ERK inhibition experiments on oxaliplatin-induced neuropathic pain, important further controls include sham rats that receive vehicle and ERK inhibitor in behavioral test and western blot. While this represents significant additional experiments, it would help interpret the existing main findings. 4\. There have been previous reports of acute oxaliplatin administration already contributes to mechanical hyperalgesia (peripheral neuropathic pain) in DRG involving different mechanisms (Huang et al., 2018; Illias et al., 2018) - perhaps this should be integrated in their discussion. Reviewer \#2: This paper studied the factors contributing to the induction of chemotherapy-induced peripheral neuropathy (CIPN), using the platinum based chemotherapeutic agent, oxaliplatin. The authors used a rat model of oxaliplatin-induced neuropathic pain to evaluate the role of different mitogen-activated protein kinase (MAPK) pathways in the dorsal root ganglia of the lumbar spinal cord segment. The authors were specifically interested in studying the expression of ERK in the DRG, and the effect oxaliplatin treatment had on ERK phosphorylation in relation to the onset of mechanical allodynia. The results from these experiments report that oxaliplatin induces phosphorylation of EDK, and that delivering an ERK inhibitor inhibited oxaliplatin-induced ERK phosphorylation and blocked the onset of mechanical allodynia. This paper provides great insight on the pathology underlying the development of cancer induced neuropathic pain. A lot of research in the pain field has focused on other models of chronic pain, such as diabetic neuropathy and peripheral nerve injury, but mechanisms underlying cancer therapeutic induced neuropathic pain are still not understood. I believe that these findings would contribute to furthering our knowledge on the pathology driving chronic pain caused by anti-cancer agents. There are questions and comments that should be addressed, before moving forward. Abstract/Introduction: • Lines 29-30: The statement \"we aimed to understand the factors involved in the development and maintenance of chronic neuropathy elicited by oxaliplatin treatment\" is misleading. The pathology underlying, both, the development and maintenance of chronic pain is a complex, multi-phase process involving changes in peripheral and central nervous system. The design of this study focused on the mechanism driving the onset of mechanical allodynia in relation to the effect oxaliplatin treatment had on the expression of p-ERK within the DRG, rather than the process of transitioning from acute to chronic pain. Clarifying the aim will strengthen the conclusions made by the authors, and help readers better interpret the data presented in each experiment. This statement is also made again in lines 68-70. • Lines 49-60: Background information is introduced only on sodium ion channels and TRP channels, indicating their role in temperature hypersensitivity. A brief overview of current literature on mechanoreceptors in pain models should be introduced to reinforce that the author\'s are specifically studying mechanical allodynia because it\'s pathophysiology is poorly understood in this model of chronic pain. Methods: • Lines 87-112: Why was there a difference in duration of treatment between experiments 1 and 2? Do you have data comparing p-ERK/ERK expression in animals receiving treatment for 3 weeks versus animals receiving treatment for 4 weeks? • Lines 107-108: The sham procedure is unclear. Did sham animals receive any i.p. or i.t. treatment, or were they naïve? Results: • The figure legends indicate values are expressed as mean +/- SD, but the values aren\'t reported in the results sections, figure legends, or on the graphs. • The number of animals assigned to each treatment group should be reported on all the graphs. • Lines 228-241: The mechanical allodynia measurements from the sham group need to be included in Figure 6 and incorporated into the statistical analysis. The sham behavioral data should be presented in this figure in order compare all three groups in Figure 7. Discussion: • Lines 285-289: The authors expand on the findings from previous studies concerning the involvement of voltage dependent sodium channel subtypes in the pathophysiology of oxaliplatin-induced neuropathy. The author\'s findings from the experiments on Na1.7, Na1.8, and Na1.9 expression in the DRG are consistent with the literature, but recent studies have reported that Na1.6 expression in the DRG contributes to the onset of oxaplatin induced neuropathic pain. The reports characterize Na1.6 in the DRG for its role in pain behavior as well as having abnormal spontaneous neuronal activity following nerve injury. Evidence from these studies show that directly targeting Na1.6 in the DRG alleviates oxaplatin induced mechanical allodynia and cold hypersensitivity. These studies should be reviewed and interpreted in the context of this study in the final paragraph of the discussion. Overall, I thought this was a very well executed study that will contribute to the CIPN research community. After these points are addressed, I believe the manuscript will be ready to move forward in the review process as it satisfies the PLOS ONE criteria for publication. \*\*\*\*\*\*\*\*\*\* 6\. PLOS authors have the option to publish the peer review history of their article ([what does this mean?](https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history)). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. **Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our [Privacy Policy](https://www.plos.org/privacy-policy). Reviewer \#1: No Reviewer \#2: No \[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files to be viewed.\] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, <https://pacev2.apexcovantage.com/>. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at <[email protected]>. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0225586.r002 Author response to Decision Letter 0 2 Oct 2019 Dear Reviewer \#1 (Manuscript ID: PONE-D-19-17881; Title: Upregulation of ERK phosphorylation...) Thank you for your valuable comments on our paper. In response to your comments, we have extensively revised our paper, as shown below in a point-by-point manner. Points 1 & 2. Reviewer \#1 pointed out that the sample size of the behavioral experiments, especially in the vehicle group, were small and that more information about the data and statistical analysis should be provided. Considering this, we reviewed our statistical analysis. First, we must apologize for a miscalculation of SEM from SD. SEM = SD / √n (n = number of sample size), so SD / √5 was correct, but we miscalculated by using SD / √3. We have now revised all the SEM data. Second, in the comparisons between two groups of the hind paw data from the behavioral experiments, the F test shows P \< 0.05, thus in this revised version of the manuscript we have used Welch's test, not Student's t-test. In addition, we have added the statistical methods in the figure legends, and we have provided the P-value in manuscript text when there are significant differences. Regarding sample size, we do not think that we need more samples. We agree that if the sample size of vehicle group were increased, the SD and SEM would likely be narrower (because variability would become low). However, we think that as there were already statistical significances, we should minimize the number of animals used in each experiment. Reviewer \#1 stated that we should provide all vehicle group values (mean ± SD) which are used to relative the oxaliplatin group values. In our present study, western blot data were calculated as percentages of the control blot density, which was expressed as 100% (control meant vehicle or sham group in each experiment) on each membrane. The blot data were presented as means of these percentages ± SD. We consider this to be a common way to present expression analysis from western blots. For example, in figure 2 (A), the p-ERK level of oxaliplatin group was 447.6 ± 273.6% as a percentage of the vehicle, whereas the densities of protein blots quantified by ImageJ in the vehicle vs. oxaliplatin were 0.31 ± 0.19 vs. 0.96 ± 0.37, respectively. However, we consider that the calculation of densities is inaccurate in our present study, because we did not use an internal standard (e.g. the same DRG sample) on each membrane. Thus, we could not normalize the densities of the blots on each membrane. Point 3. Reviewer \#1 pointed out that for the ERK inhibition experiments, sham rats receiving vehicle (5% glucose) i.p. and ERK inhibitor i.t. (Veh + PD98059) should be used, because it would help interpret our findings. Of course, we also considered whether a Veh + PD98059 group was needed or not when designing the experiments. We researched previous studies in which similar ERK inhibition experiments were performed. Some studies (marked below with\*) did not use a Veh + PD98059 group. When there was a Veh + inhibitor treatment group, the ERK inhibitor did not affect the behavioral test (marked below with\*\*). Furthermore, in our present study, Figure 6 & 7 show that the ERK inhibitor clearly inhibits ERK phosphorylation in DRG and oxaliplatin-induced mechanical allodynia. Therefore, we decided not to use a Veh + PD98059 group. \*(1) Cao Y, Li K, Fu KY, Xie QF, Chiang CY, Sessle BJ. Central sensitization and MAPKs are involved in occlusal interference-induced facial pain in rats. J Pain. 2013;14:793-807. (2) Wang XW, Li TT, Zhao J, Mao-Ying QL, Zhang H, Hu S, Li Q, Mi WL, Wu GC, Zhang YQ, Wang YQ. Extracellular signal-regulated kinase activation in spinal astrocytes and microglia contributes to cancer-induced bone pain in rats. Neuroscience. 2012;217:172-181. (3) Yoon SY, Kwon SG, Kim YH, Yeo JH, Ko HG, Roh DH, Kaang BK, Beitz AJ, Lee JH, Oh SB. A critical role of spinal Shank2 proteins in NMDA-induced pain hypersensitivity. Mol Pain. 2017;13:1744806916688902. \*\*(1) Sanna MD, Mello T, Ghelardini C, Galeotti N. Inhibition of spinal ERK1/2-c-JUN signaling pathway counteracts the development of low doses morphine-induced hyperalgesia. Eur J Pharmacol. 2015;764:271-277. (2) Xing F, Kong C, Bai L, Qian J, Yuan J, Li Z, Zhang W, Xu JT. CXCL12/CXCR4 signaling mediated ERK1/2 activation in spinal cord contributes to the pathogenesis of postsurgical pain in rats. Mol Pain. 2017;13:1744806917718753. Point 4. Reviewer \#1 pointed out that the reports of Huang et al. 2018 and Illias et al. 2018 should be integrated into the discussion. Therefore, we added a discussion of these reports (lines 331-333 and lines 347-349). We also added these reports to reference list (35 and 36). We felt that Reviewer \#1 emphasized acute oxaliplatin administration. There are various oxaliplatin administration methods that produce oxaliplatin-induced mechanical allodynia. In some methods, single or short administration of oxaliplatin produces mechanical allodynia in the early phase, such as thermal hyperalgesia. We chose a method similar to the clinical administration and mechanical allodynia onset for humans. In our present report, we did not refer to the variation of mechanical allodynia due to the differences in the oxaliplatin administration methods. Dear Reviewer \#2 (Manuscript ID: PONE-D-19-17881; Title: Upregulation of ERK phosphorylation...) Thank you for your valuable comments on our paper. In response to your comments, we have extensively revised our paper, as shown below point-by-point manner. Abstract/Introduction: Lines 29-30 & 68-70: We agree your suggestion and revise the sentence from "development and maintenance" to "generation" (line 30 and line 78). Lines 49-60: Reviewer \#2 pointed out that mechanoreceptors in pain model should be introduced to reinforce that we studied oxaliplatin-induced mechanical allodynia, not thermal hyperalgesia. However, neuropathic pain is caused not only by mechanoreceptors, so we added some sentences about the potential mechanisms of neuropathic pain (lines 57-64) in the introduction and added the following reports to the references (3. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9:807-819. and 4. St John Smith E. Advances in understanding nociception and neuropathic pain. J Neurol. 2018;265:231-238.). Lines 87-112: Reviewer \#2 pointed out the difference in treatment duration between experiment 1 and 2. We used an ALZET osmotic pressure pump for continuous injection of PD98059. We could find an ideal pump for our experiments (size, infusion rate, and infusion duration), however, this pump can only continue to infuse the drug for 4 weeks. Therefore, we had to choose the data in animals receiving oxaliplatin treatment for 3 weeks, in which the paw withdrawal thresholds were significantly lower than vehicle treatment. Lines 107-108: Reviewer\#2 pointed out that the sham procedure is unclear. However, we already described "The sham-operated (Sham) mice underwent a similar surgical procedure except for pump placement and drug treatments" in Method section (line 119-120). Therefore, the sham-operated mice (Sham) did not receive any i.p. or i.t. treatment. Results: We changed the sentences from "Values are expressed" to "All data are calculated" in each figure legend. We also added the values in manuscripts text when there are significant differences. The number of animals assigned to each treatment group are already described in the figure legends, but not reported on the graphs. Therefore, we added the number on each graph. Lines 228-241: We did not show the sham group in Figure 6, because the hind paw data of the sham group was not altered compared with the OX + PD98059 group and we were afraid that Figure 6 would become too busy and difficult to interpret. However, we agree with the reviewer\'s comment and have added the sham group in Figure 6. Discussion: Lines 285-289: We found a recent report that the expression of NaV1.6 in DRG was increased in oxaliplatin-induced CIPN model rats. We review this study in the discussion (lines 317-324) and have added this report to the references (33. Li L, Shao J, Wang J, Liu Y, Zhang Y, Zhang M, Zhang J, Ren X, Su S, Li Y, Cao J, Zang W. MiR-30b-5p attenuates oxaliplatin-induced peripheral neuropathic pain through the voltage-gated sodium channel NaV1.6 in rats. Neuropharmacology. 2019;153:111-120.). ###### Submitted filename: Response to Reviewers.docx ###### Click here for additional data file. 10.1371/journal.pone.0225586.r003 Decision Letter 1 Gallyas, Jr. Ferenc Section Editor © 2019 Ferenc Gallyas, Jr. 2019 Ferenc Gallyas, Jr. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 29 Oct 2019 PONE-D-19-17881R1 Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain PLOS ONE Dear Dr. MARUTA, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE's publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please address the statistical analysis issues raised by reviewer\#1. We would appreciate receiving your revised manuscript by Dec 13 2019 11:59PM. When you are ready to submit your revision, log on to <https://www.editorialmanager.com/pone/> and select the \'Submissions Needing Revision\' folder to locate your manuscript file. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: <http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols> Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled \'Response to Reviewers\'.A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled \'Revised Manuscript with Track Changes\'.An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled \'Manuscript\'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Ferenc Gallyas, Jr., Ph.D., D.Sc. Academic Editor PLOS ONE \[Note: HTML markup is below. Please do not edit.\] Reviewers\' comments: Reviewer\'s Responses to Questions **Comments to the Author** 1\. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the "Comments to the Author" section, enter your conflict of interest statement in the "Confidential to Editor" section, and submit your \"Accept\" recommendation. Reviewer \#1: (No Response) Reviewer \#2: All comments have been addressed \*\*\*\*\*\*\*\*\*\* 2\. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer \#1: Partly Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 3\. Has the statistical analysis been performed appropriately and rigorously? Reviewer \#1: No Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 4\. Have the authors made all data underlying the findings in their manuscript fully available? The [PLOS Data policy](http://www.plosone.org/static/policies.action#sharing) requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data---e.g. participant privacy or use of data from a third party---those must be specified. Reviewer \#1: Yes Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 5\. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer \#1: Yes Reviewer \#2: Yes \*\*\*\*\*\*\*\*\*\* 6\. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer \#1: Comments to authors: In the revised manuscript, the authors have adequately revised the manuscript and addressed important questions regarding the experimental results and analysis. But if possible, I would still like to address some point that were raised in the review: 1\) In the behavioral experiments, in the comparisons between time points of the hind paw data is recommendable to perform a repeated measures ANOVA. 2\) In western blot experiments, I agree with the authors that calculating data as percentages of control blot density (expressed as 100%) is a common way of representation. What I pointed out in the previous review is to express somehow the variance within the control group, since although it is considered 100%, it is an average of measures with SD. The protein density data quantified in ImageJ for experimental and control groups would support the levels of significance expressed in the figures (above suggested supplementary table). Also, because I understand that the statistical analysis has been carried out with these data. According to the authors, I consider that methodologically the most adequate quantification has not been performed due to the absence of internal standard. However, if it is possible to normalize the density of protein blots of each membrane with respect to the background of each of them. Have you been considered in the analysis? Reviewer \#2: (No Response) \*\*\*\*\*\*\*\*\*\* 7\. PLOS authors have the option to publish the peer review history of their article ([what does this mean?](https://journals.plos.org/plosone/s/editorial-and-peer-review-process#loc-peer-review-history)). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. **Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our [Privacy Policy](https://www.plos.org/privacy-policy). Reviewer \#1: No Reviewer \#2: Yes: Zach LaMacchia \[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link \"View Attachments\". If this link does not appear, there are no attachment files to be viewed.\] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, <https://pacev2.apexcovantage.com/>. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at <[email protected]>. Please note that Supporting Information files do not need this step. 10.1371/journal.pone.0225586.r004 Author response to Decision Letter 1 4 Nov 2019 Dear Reviewer \#1 (Manuscript ID: PONE-D-19-17881; Title: Upregulation of ERK phosphorylation...) Thank you for your valuable comments on our paper. In response to your comments, we have extensively revised our paper, as shown below in a point-by-point manner. Points 1. Reviewer \#1 pointed out that in the comparisons between time points of the hind paw data is recommendable to perform a repeated measures ANOVA. So, we used one-way repeated ANOVA. OX group in Figure 1 and OX + Vehicle group in Figure 6 were significantly changed according to time (p = 0.0003 and p = 0.0039, respectively). We revised the sentences in statistical methods and Figure legends (lines 175, 195, and 260). Point 2. Reviewer \#1 pointed out that to express somehow the variance within the control group, since although it is considered 100%, it is an average of measures with SD; and if it is possible to normalize the density of protein blots of each membrane with respect to the background of each of them. Of course, the density of protein blots in control group must have the variance. We tried to use the background density as an internal standard. For example, in figure 2 (A), the p-ERK level of oxaliplatin group was 447.6 ± 273.6% as a percentage of the vehicle, whereas the densities of protein blots quantified by ImageJ in the vehicle vs. oxaliplatin were 0.31 ± 0.19 vs. 0.96 ± 0.37 (p = 0.0006), respectively; and when using the background density as an internal standard, the densities of protein blots in the vehicle vs. oxaliplatin were 0.46 ± 0.32 vs. 1.39 ± 0.65 (p = 0.003), respectively. This way to use the background density as an internal standard seems good and we are grateful for Reviewer \#1's valuable advice. However, we have some concerns that this way might depend on how to set background and we do not know whether there is consensus in the use of the background density as an internal standard. We consider that using same sample as an internal standard on each membrane is better, if the variance of control is needed to be expressed. So, in this study, we would like to keep to express the calculating data as percentages of control blot density (expressed as 100%). ###### Submitted filename: Response to Reviewers.docx ###### Click here for additional data file. 10.1371/journal.pone.0225586.r005 Decision Letter 2 Gallyas, Jr. Ferenc Section Editor © 2019 Ferenc Gallyas, Jr. 2019 Ferenc Gallyas, Jr. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 8 Nov 2019 Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain PONE-D-19-17881R2 Dear Dr. MARUTA, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. 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Section Editor PLOS ONE Additional Editor Comments (optional): Reviewers\' comments: 10.1371/journal.pone.0225586.r006 Acceptance letter Gallyas, Jr. Ferenc Section Editor © 2019 Ferenc Gallyas, Jr. 2019 Ferenc Gallyas, Jr. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 13 Nov 2019 PONE-D-19-17881R2 Upregulation of ERK phosphorylation in rat dorsal root ganglion neurons contributes to oxaliplatin-induced chronic neuropathic pain Dear Dr. MARUTA: I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact <[email protected]>. For any other questions or concerns, please email <[email protected]>. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Ferenc Gallyas, Jr. Section Editor PLOS ONE [^1]: **Competing Interests:**The authors have declared that no competing interests exist.

Shuttered St. Joe’s College clears final debt, settles Sodexo’s $1.3 million fraud lawsuit Sodexo claimed in federal court that St. Joe’s leaders knew college was about to close, even as they allowed the food service company to renovate a campus student center The campus of Saint Joseph's College in Rensselaer on Monday, Feb. 6, 2017. The college is suspending operations at the end of the semester due to financial issues.(Photo: Meghan Holden/Journal & Courier) RENSSELAER, Ind. – One more lingering burden weighing on the rebirth of Saint Joseph’s College, which halted operations more than a year ago, was lifted Friday when the former, four-year liberal arts school announced it had settled a $1.3 million lawsuit filed by a food service company over renovations the college ordered even when it was on the verge of financial collapse. Sodexo Group filed a federal suit in August, accusing St. Joe’s of fraud, fraudulent concealment and breach of contract, claiming that the college knew more than it was letting on in the summer of 2016 when the food service company was sinking $1.3 million into the school’s student center renovations in exchange for a 10-year management contract. Sodexo claimed in the lawsuit that it finished renovations weeks before St. Joe’s leaders, dealing with millions in debt and the threat of losing academic accreditation, announced in late 2016 that it would close after the spring 2017 semester. In the suit – one frustrated St. Joe’s alumni had been watching closely to get to the bottom of why their alma mater closed with little warning – Sodexo seemed aimed to prove that the college’s leaders “knowingly and deliberately failed to disclose the facts” about St. Joe’s $27 million debt and deep tuition discounts offered to students to stave off dropping enrollment. On Friday, Michael Kohlman, chief information officer at St. Joe’s, said the college had reached “an equitable agreement” with Sodexo to drop the lawsuit before it went to trial. The terms of the settlement, Kohlman said, were confidential. “We’re settling the bill,” Kohlman said. “It’s greater than zero, but it’s not for the amount Sodexo was suing for.” Attorneys for Sodexo, based in Indianapolis and Washington, D.C., did not immediately return calls seeking their side on the settlement. Kohlman said that unlike a settlement in September, when St. Joe’s restructured its $27 million debt on a Farm Credit Services loan, the college will not have to give up any of its land holdings. That means St. Joe’s will keep its core campus along U.S. 231 in Rensselaer, the administrative building called Drexel Hall across the highway and thousands of acres in income-producing property known as the Waugh Farm in nearby White County. Fr. Larry Hemmelgarn, chairman of the St. Joe’s board of trustees, said the Sodexo lawsuit was the last of the college’s potential debts, making Friday a significant milestone in efforts to revive the school in some fashion. “It has been a huge challenge trying to plan for the future without having our debts resolved,” Hemmelgarn said in statement released by St. Joe’s. “Now we know what resources we have available as we work to rebuild programs for Saint Joseph’s College at Rensselaer. With the help of our alumni, we can now create a sustainable model for the future.” Sodexo’s lawsuit claimed former St. Joe’s President Robert Pastoor and Spencer Conroy, the college’s former controller, knew of the school’s dire financial situation when they brought the company into the 10-year contract and the renovations. The suit claimed Sodexo officials had no way to tell that the college was in such a jam or had been deferring maintenance on the campus for years. In February 2017, Pastoor told the J&C that St. Joe’s finances were no secret and that students, faculty, staff, alumni and the Rensselaer community should have heard the warnings he’d been giving about the college’s challenges. That contention was roundly debated at the time, as alumni and others said they were blindsided when St. Joe’s trustees moved in late 2016 to close the college by the end of the school year. Pastoor left in spring 2017. Those with St. Joe’s ties have been digging around for better explanations ever since. Kohlman dismissed the notion the St. Joe’s was anxious to avoid the Sodexo case for fear of revealing college secrets. “I personally don’t see that as part of the calculus,” Kohlman said. “I think the sole motivation was truly finding some equitable number with Sodexo. We owed money to them. This put them in a place where they could be satisfied, and it put us in a place where, quite honestly, we felt we could move forward.” In October, Fr. Barry Fischer, St. Joe’s rector and part of the 127-year-old school’s “Phoenix Team,” and Daniel Elsener, Marian University president, announced an agreement that puts the St. Joe name – along with $1.5 million in St. Joe scholarship money – toward a two-year college Marian plans to open in July 2019 near the Indianapolis campus. The two-year school will be called Saint Joseph’s College of Marian University-Indianapolis. Elsener and Fischer said at the time that depending on how that program does, Marian’s two-year degree efforts could take root on St. Joe’s Rensselaer campus at some point. What’s next? Kohlman said St. Joe’s plans to outline a new capital campaign by the end of December. He said letters would go to alumni in the coming weeks. Did the Sodexo settlement need to be done before that could happen? “We really wanted it to be done,” Kohlman said. "It’s not like we weren’t continuing to look at things like: What was the fundraising going to look like? What’s a capital campaign going to look like? What’s an organization plan going to be for this campus, and how do you fit that into the community?" Kohlman said. "That ambiguity of knowing we had one major, potentially organizational-killing debt out there, we didn’t want to move into a phase where we’re talking to alumni until we had all those off the checklist." Reach Dave Bangert at 765-420-5258 or at [email protected]. Follow on Twitter: @davebangert.

Clearwater Lake (Manitoba) Clearwater Lake is a lake in Manitoba, Canada. It is the main geographical feature of Manitoba's Clearwater Lake Provincial Park, located northeast of The Pas in western Manitoba. References Category:Lakes of Manitoba

Pigmented villonodular synovitis of the temporomandibular joint. The first case of pigmented villonodular synovitis of the temporomandibular joint in a Chinese patient is reported. The clinicopathological features are described and the presentation as a parotid mass is emphasized. This rare tumour requires a high clinical suspicion for diagnosis. For removal, meticulous dissection of tumour and facial nerve is necessary.

Q: Non-enterprise uses for WCF? I'm interested in gaining a better understanding of WCF. Of course, I can read books and tutorials about it, but it seems that a better way would be to actually come up with some project idea (either open-source or a startup) which would actually benefit from using WCF, and then build it using WCF. What are your ideas for small-scale projects which might benefit from WCF? A: A hosted service that a mobile device (such as a WP7 or iPhone) could connect with to retrieve data A: I'm not sure it is really a matter of scale that drives a decision to use WCF. If a learning project is all you are interested in, then take a normal idea for a project, and turn the entire data access layer into WCF calls. This should give you a fair understanding of all the little nooks and crannies of WCF, and allow you to fail in a controlled manner. That way you can make decisions in the future about when are where it is best to apply a service boundary using WCF. As was already mentioned, anything to do with the web can benefit tremendously from WCF. Heck, you could build a pure JavaScript and HTML 5 application using WCF without ever touching ASP.Net.

Interstitial fluid pressure in free vascularized skin flaps of the rat epigastrium. The purpose of this study was to observe the magnitude and time course of changes in tissue edema in experimental free flaps. Thirty female Sprague Dawley rats underwent elevation and orthoptic transplantation of free epigastric skin flaps. Using a modified "wick in needle" technique, interstitial fluid pressure (IFP) was measured in the flaps at various times up to 2 weeks postoperatively. Increases in IFP to positive values were seen by 12 hours. IFP remained elevated for 3 to 5 days, after which they gradually returned to control values by 2 weeks. This is the first study to follow the time course and magnitude of changes in IFP and edema in free flaps. It is a useful animal model by which the hemodynamic effects of physical and pharmacological manipulation of flaps can be studied.

--- abstract: 'Chinese is one of the most widely used languages in the world, yet online handwritten Chinese character recognition (OLHCCR) remains challenging. To recognize Chinese characters, one popular choice is to adopt the 2D convolutional neural network (2D-CNN) on the extracted feature images, and another one is to employ the recurrent neural network (RNN) or 1D-CNN on the time-series features. Instead of viewing characters as either static images or temporal trajectories, here we propose to represent characters as geometric graphs, retaining both spatial structures and temporal orders. Accordingly, we propose a novel spatial graph convolution network (SGCN) to effectively classify those character graphs for the first time. Specifically, our SGCN incorporates the local neighbourhood information via spatial graph convolutions and further learns the global shape properties with a hierarchical residual structure. Experiments on IAHCC-UCAS2016, ICDAR-2013, and UNIPEN datasets demonstrate that the SGCN can achieve comparable recognition performance with the state-of-the-art methods for character recognition.' author: - Ji Gan$^1$ - Weiqiang Wang$^1$ - | Ke Lu$^{2}$$^1$ School of Computer Science and Technology, University of Chinese Academy of Sciences\ $^2$School of Engineering Science, UCAS [email protected], [email protected], [email protected] bibliography: - 'arxiv.bib' title: | Characters as Graphs: Recognizing Online Handwritten Chinese Characters\ via Spatial Graph Convolutional Network --- {height="8.5cm"} Introduction ============ Chinese characters are among the oldest written languages in the world, which nowadays have been widely used in many Asian countries such as China, Japan, and Korea. Although handwritten Chinese characters can be well recognized by most humans, it remains a challenging issue for computers due to the complex shape structures, a large number of category, and great writing style variations. Therefore, automatic online handwritten Chinese character recognition (OLHCCR) has been widely studied in the past decades for the development of human intelligence. Traditional methods for OLHCCR generally require to design effective hand-crafted features, upon which classification is performed via traditional machine learning algorithms like the modified quadratic discriminate function (MQDF) [@liu2013online]. With the great success of deep learning techniques, an overwhelming trend is that deep neural networks have gradually dominated the field of OLHCCR [@yin2013icdar; @zhang2017online; @zhang2018drawing], outperforming traditional methods with a large margin. The latest most popular choice for OHLCCR is to adopt the convolutional neural network (CNN) on feature images [@yin2013icdar; @zhang2017online], which converts the problem of character recognition into the image classification. To adopt 2D-CNN for OLHCCR, the most intuitive way is to render handwriting trajectories as static images. To further incorporate the temporal information of handwriting, it is important to utilize the domain-specific knowledge for extracting directional feature images [@zhang2017online], which improves the recognition accuracy. However, we argue that it is not an ideal solution to represent handwriting as images. Specifically, different from natural images with varied colours and rich content, the character images are typically black-and-white binary-valued, which only provide response values for strokes while leaving large blank areas as background. Therefore, such character images typically contain significant redundant information than natural images. Moreover, transforming 1D trajectories into 2D images increases the data dimension, and thus it may result in huge computational consumption and heavy demand for extra parameters. Recent advances [@zhang2018drawing; @gan2018anew] show that OLHCCR also can be effectively addressed by applying the recurrent neural network (RNN) or 1D-CNN on temporal trajectories, avoiding extracting image-like representations. However, the RNN remains less amenable to parallelization and suffers low computational speed due to its recurrent computation mechanism; yet the 1D-CNN requires to stack extremely deep layers for learning long-term dependencies of long sequences due to the locality of convolutions. Moreover, since both networks only focus on exploiting temporal information of sequences, it makes them unsuitable for the scenarios that temporal information is lacked or disturbed. Instead of viewing characters as either images or trajectories, here we propose to represent characters as geometric graphs, naturally retaining both spatial structures and temporal orders. Accordingly, we propose a novel spatial graph convolution network (SGCN) to effectively classify those unstructured graphs as shown in Fig. \[fig:detailed\_gcn\]. Particularly, we demonstrate that the graph representation has its unique advantages: (1) compared with images, graphs provide a similar natural visual representation, yet graphs keep the essential information with more compact forms. This may lead to much lower computation complexity and fewer model parameters when performing convolutions; (2) compared with trajectories, graphs can store the temporal orders of sequences within the directed edges, but graphs further explicitly reveal the geometric structures. As a result, when the temporal information is lacked, graphs are more discriminative than trajectories and thus can be applied to the more strict scenarios. Our contributions are summarized as follows: - We propose a compact and efficient geometric graph representation for online handwritten characters, which naturally retains the spatial structures and temporal orders by viewing characters as graphs. - We propose a novel spatial graph convolutional network (SGCN) for OLHCCR for the first time. The proposed method is largely different from the latest popular methods including the 2D-CNN on feature images, and the LSTM or 1D-CNN on temporal trajectories. - The proposed graph-based architecture is fully end-to-end, requiring no human efforts once graphs are constructed. Moreover, it is the first time to verify the effectiveness of SGCN for the large category pattern recognition (nearly four thousands different classes). - Experiments are conducted on benchmark datasets (including IAHCC-UCAS2016, ICDAR-2013, and UNIPEN), which demonstrate that the SGCN is very competitive with the state-of-the-art methods for OLHCCR. Related Work ============ #### Online Handwritten Chinese Character Recognition OLHCCR has attracted great interests over the past decades, and tremendous achievements have been witnessed in recent years. Specifically, [@liu2013online] proposed a standard machine learning-based framework for OLHCCR, which first extracts hand-crafted features from the normalized characters and then performs classification with the modified quadratic discriminate function (MQDF). As an alternative to MQDF, [@qu2018air] recently introduced the sparse representation based classification for air-written Chinese characters. With the great impact of deep learning, the CNN has been gradually applied for OLHCCR [@yin2013icdar], which regards character recognition as image classification. Furthermore, [@zhang2017online] proposed to incorporate traditional domain-specific knowledge for extracting feature images, thus further improving the recognition performance of CNN. However, this method faces two problems: (1) the complex domain-specific knowledge for extracting feature images and (2) demand for huge computation and large parameters after increasing the data dimension. Instead of transforming online trajectories into image-like representations, [@zhang2018drawing] proposed to directly apply the recurrent neural network (RNN) on temporal trajectories, avoiding the complex domain-specific knowledge for extracting feature images. Unfortunately, the RNN remains less amenable to parallelization and suffers low computational speed for long sequences. Instead, [@gan2018anew] proposed to directly classify temporal trajectories with the 1D-CNN, which empirically runs faster than the RNN for long sequences. However, to exploit long-term dependencies of sequences, the 1D-CNN requires to stack extremely deep layers due to the locality of convolutions. Moreover, both the RNN and 1D-CNN only focus on sequential learning, and thus they are unsuitable for the scenarios that temporal information is lacked (such as the offline HCCR). Rather than viewing characters as static images or temporal trajectories, here we propose to represent characters as geometric graphs. Accordingly, a spatial graph convolutional network (SGCN) is proposed for character recognition for the first time, addressing OLHCCR in a novel perspective. #### Convolution on Graphs Although the traditional CNN has achieved great success in many domains, it is limited to processing images with regular grid structures. Instead, recent advances have generalized convolutions on irregular unstructured graphs, which can be divided into two broad categories: the spectral methods [@kipf2016semi; @Micha2016fastgcn; @yu2018spatio] and spatial methods [@monti2017geo; @fey2018splinecnn; @wang2019dynamic]. The spectral methods typically apply the Fourier transform on graphs, converting the graph convolution into multiplication in the spectral domain. However, the spectral methods require the input graphs to have the identical structures; and worse still, the spectral convolution only encodes the connectivity of nodes but ignores their geometric information. On the contrary, the spatial methods perform convolutions to aggregate local neighbourhoods of graph nodes in the spatial domain via the weighted sum, where the edge weights are dynamically calculated depending on the local geometry. Therefore, our work follows the spirit of spatial graph convolutions to fully exploit the spatial geometric properties of character graphs. Moreover, we are among the first to verify the effectiveness of spatial graph convolution for the large category pattern classification (which involves nearly four thousand classes). Methodology =========== Our goal is to represent online handwritten characters as sparse geometric graphs and then perform convolutions on the constructed graphs for the final classification. The overview of the spatial graph convolutional network (SGCN) for character recognition is illustrated in Fig. \[fig:detailed\_gcn\], and the details of each part will be described in the following section. Graph Construction ------------------ ![Graph construction. From left to right: original & normalized trajectories, and directed & undirected graphes respectively.[]{data-label="fig:graph_construction"}](graph_construction.png){height="2.2cm"} Handwriting typically contains rich diversity of writing styles, and it also suffers from large variations in spatial sizes as well as locations. Therefore, it is important to normalize handwritten characters to reduce those variations for extracting reliable features. Similar to  [@zhang2018drawing], each character is firstly normalized into a standard $xy$-coordinate system with its shape unchanged. Moreover, each handwriting stroke is further re-sampled into the same interval. After the normalization, we obtain a point sequence of the length $N$ with absolute coordinates as $[[x_1, y_1],\dots,[x_i, y_i],\dots,[x_N, y_N]]$. As shown in Fig. \[fig:graph\_construction\], we propose to construct a direct geometric graph $\mathbb{G}=(\mathbf{V}, \mathbf{E}, \mathbf{P})$ from the given point sequence of length $N$, where $\mathbf{V}$ denotes the node-set, $\mathbf{E}$ denotes the edge-set, and $\mathbf{P}$ denotes the coordinate-set of all nodes. In the graph, each point is corresponding to a node entity $v_i$, and the node-set $\mathbf{V}=\{v_i|i=1,\dots,N\}$ includes all the sampling points in the given sequence, where $\mathbf{V} \in \mathbb{R}^{N\times 1}$. Accordingly, the absolute coordinate $[x_i, y_i]$ of each node $v_i$ is stored in $\mathbf{P}=\{p_i|i=1,\dots,T\}$, where $\mathbf{P} \in \mathbb{R}^{N \times2}$. Moreover, the edge-set $\mathbf{E}=\{(i, j)|v_j \rightarrow v_i\}$ is constructed depending on the node connectivity, where $v_j \rightarrow v_i$ denotes that $v_j$ points to $v_i$ and $\mathbf{E} \in \mathbb{|R|}^{|\mathbf{E}|\times2}$. Additionally, $|\mathbf{E}| \ll N^2$ in a sparse graph. Lastly, the remaining issue is how to define effective features for each node $v_i$, and we will discuss this next. Feature Extraction Module ------------------------- Once the directed graph $\mathbb{G}=(\mathbf{V}, \mathbf{E}, \mathbf{P})$ is constructed from the trajectory, the spatial structure of character is stored in the position-set $\mathbf{P}$ and the temporal information is embedded in the set of directed edges $\mathbf{E}$. Intuitively, we define features of node $v_i$ to retain both spatial and temporal information, i.e., f([v\_i]{})=\[x\_i, y\_i, x\_i, y\_i, \_i, \_i\], where $[x_i, y_i]$ denotes the absolute coordinate, $[\Delta x_i,\Delta y_i]$ denotes the writing offset, and $\theta_i$ denotes the writing direction of node $v_i$. Particularly, we regard $[x_i, y_i]$ as the spatial features and $[\Delta x_i, \Delta y_i, \sin \theta_i, \cos \theta_i]$ as the temporal features. It should be noted that all those features can be computed from the directed graph $\mathbb{G}$ with differentiable operations, and thus we can integrate the feature extraction into the back-propagation procedure rather than the pre-processing stage. After that, we add self-connections for all the nodes and further transform the directed graph into the undirected one. This eventually leads the graph convolution to fully incorporate information from the node $v_i$ and all its neighbourhoods. ![Convolution operations: (left) Conventional convolution, (middle) Dynamic graph convolution, (right) Spline convolution kernel. In addition, the self-connection is ignored for simplicity.[]{data-label="fig:graph_convs"}](gconv.pdf){height="2.cm"} Spatial Graph Convolution -------------------------  \[subsec:sgn\] Formally, the convolution at the position $p=[x, y]$ of a 2D grid image (or a single feature map) $\mathbf{F}$ can be defined as $$\label{eq:1} \mathbf{F}*g(x, y)=\iint \limits_{(\delta_x, \delta_y) \in \mathbf{G}}{\mathbf{F}(x - \delta_x, y-\delta_y)\mathbf{g}(\delta_x, \delta_y)} {d \delta_x d\delta_y},$$ where $\mathbf{G}$ denotes the local region that centred around the position $p$ of $\mathbf{F}$, $[\delta_x, \delta_y]$ denotes the coordinate offset to the center position $p$, and $\mathbf{g}$ denotes the convolutional kernel. As shown in Fig \[fig:graph\_convs\] (left), when $\mathbf{F}$ is represented as the irregular 2D grid structure (i.g. an image), the convolution kernel $\mathbf{g}$ is easy to be implemented with a $k \times k$ learnable matrix, where $k$ is well-known as the kernel size. However, it is not straightforward to directly apply the convolution to the unstructured graphs, since the structures of local regions at different positions in a graph can be largely different (i.g. Fig \[fig:graph\_convs\] (middle)). Considering that the convolution aggregates information from the local neighbourhoods, the convolution at the node $v_i$ of graph $\mathbb{G}$ can be defined as $$\label{eq:2} \mathbf{F}*g(v_i)=\frac{1}{|\mathcal{N}(v_i)|} \sum_{v_j \in \mathcal{N}(v_i)}f(v_j)\mathbf{g}(u(i,j)),$$ where $f(v_j)$ denotes features of the node $v_j$, $\mathbf{F}=\{f(v_i)|i=1,\dots,N\}$, $\mathcal{N}(v_i)$ denotes the neighbourhood nodes of $v_i$, and $u(i,j)=(p_j - p_i)$ denotes the coordinate offsets from $v_j$ to $v_i$. Particularly, the term $\frac{1}{|\mathcal{N}(v_i)|}$ normalizes the cardinality of the corresponding subset. In graphs, the coordinate offsets $u(i,j)$ can be any possible values at different local regions; therefore, the remaining issue is how to define the spatial convolution kernel $\mathbf{g}$ for handling the irregular local structures. Institutively, the basic idea is to fit a continuous function (i.e. a curve surface) depending on the distribution of $u(i,j)$ to approximate the convolution kernel $\mathbf{g}(\mathbf{u})$, where $\mathbf{u}=\{u(i,j)|i=1,\dots,N; v_j \in \mathcal{N}(v_i);u(i,j)=(p_j - p_i)\}$. Fortunately, many spatial convolution kernels recently have been proposed [@monti2017geo; @fey2018splinecnn; @wang2019dynamic], and among them, [@fey2018splinecnn] is demonstrated to perform the best in many scenarios. Hence, the spline graph convolution kernel (as shown in Fig \[fig:graph\_convs\] (right)) is adopted in our work, which can be formally defined as $$\label{eq:2} \mathbf{g(u)}=\sum_{p \in \mathbf{P}}{w_p \mathbf{B}_p(\mathbf{u})},$$ where $\mathbf{P}$ is the Cartesian product of the ${B}$-spline bases, $\mathbf{B}_p$ is the ${B}$-spline function, and $w_p$ is the trainable parameters to control the height of ${B}$-spline surface. More details of ${B}$-spline convolutional kernel can refer to [@fey2018splinecnn]. Spatial Transform Network ------------------------- Since the geometric structure $\mathbf{P}$ of graph $\mathbb{G}$ is corresponding to the absolute coordinates of all the points, the node features as well as graph convolutions are not invariant to the certain geometric transformations of graphs (i.g. the rotation, scaling, and translation). Inspired by [@qi2017pointnet], the spatial transform network (STN) is utilized to align the input graph into a canonical coordinate system before feature extraction. Specifically, we first encode the geometric structure $\mathbf{P} \in \mathbb{R}^{|N|\times2}$ into a high-dimensional feature vector $\mathbf{h} \in \mathbb{R}^{1 \times d}$as $$\label{eq:3} \mathbf{h}=\max \mathcal{M}(\mathbf{P}),$$ where $\mathcal{M}$ denotes a multi-layered perceptron (MLP). After that, we estimate a transform matrix $\mathbf{T}$ based on the embedded vector $\mathbf{h}$. In our task, we further constrain $\mathbf{T}$ to be the similarity transform for simplicity and stability, i.e., $$\label{eq:4} \mathbf{T}=\begin{bmatrix} s \cdot \cos \theta & - s \cdot \sin \theta & \Delta x \\s \cdot \sin \theta & s\cdot \cos \theta &\Delta y\end{bmatrix},$$ where $\theta$ denotes the rotation angle, $s$ denotes the scale, and $[\Delta x, \Delta y]$ denotes the transition of $xy$-coordinates, which can be calculated as $$\begin{aligned} \label{eq:5} [\tilde{\theta}, \tilde{s}, \Delta x, \Delta y]&=& \mathcal{M}(\mathbf{h}), \\ \theta = \pi \cdot \tanh \tilde{\theta}&,& s = \exp(\tanh(\tilde{s})),\end{aligned}$$ Therefore, the aligned geometric structure $\mathbf{\tilde{P}}$ is computed as $$\label{eq:6} \mathbf{\tilde{P}}=\begin{bmatrix} \mathbf{P}& \mathbf{1}\end{bmatrix} \mathbf{T}',$$ Furthermore, This idea can be further extended to the node features $\mathbf{F} \in \mathbb{R}^{|N|\times d}$ as $$\begin{aligned} \label{eq:6} \mathbf{h}&=&\max \mathcal{M}(\mathbf{F}),\\ \mathbf{T}&=& \mathcal{R}( \mathcal{M}(\mathbf{h})),\\ \mathbf{\tilde{F}}&=&\mathbf{F}\mathbf{T},\end{aligned}$$ where $\mathcal{R}$ reshapes the 1-dimensional $d\times d$ vector into a square matrix, and the feature transform matrix $\mathbf{T}$ is not constrained here. Ideally, this STN aligns the intermediate features into a latent canonical space and thus helps learn the geometric invariant features, essentially benefiting the final classification. Hierarchical Residual Structure ------------------------------- ![Configurations of our SGCN for OLHCCR. In the figure, “Rs-GCB (32)” denotes a Rs-CGB module with 32 output channels, “FC (160)” denotes a fully-connected layer with 160 output neurons, and “MLP” denotes a three-layered perceptron respectively.[]{data-label="fig:gcn_arch"}](gcn_configs.pdf){height="5.2cm"} Traditional graph neural networks (GNNs) are inherently flattened and cannot learn the hierarchical representation of graphs [@Micha2016fastgcn; @li2019deepgcns], since GNNs (i) lack the effective and efficient pooling for coarsening unstructured graphs and (ii) also suffer from the gradient vanishing and over-smoothing problems when stacking more layers. As a result, this limitation makes GNNs especially problematic for graph classification (which associates a label with an entire graph). To address this problem, a hierarchical residual structure is adopted for our SGCN, which is capable of fully incorporating the local neighbourhood information and exploiting the global shape properties. To this end, the following two key ideas are introduced for our SGCN: - Cluster-based Pooling [@Micha2016fastgcn] derives a clustering on all the graph nodes and then aggregates the nodes of the same cluster with new computed coordinates, which eventually results in a coarsen graph. - Residual Learning [@he2016deep; @li2019deepgcns] adds shortcut connections between the input and output of graph convolutions, which empirically enables the reliably converge in training deep networks. As shown in Fig. \[fig:gcn\_arch\] (a), the proposed SGCN follows the standard hierarchical residual structure of conventional deep CNNs, where the figure (b) details the spatial transform network (STN) and (c) details the residual graph convolutional block (Rs-GCB). Additionally, each convolutional layer follows with the batch normalization [@ioffe2015batch] and PReLU [@he2015delving] for better convergence, and the dropout [@Srivastava2014Dropout] is also utilized for good generalization. Finally, the SGCN is trained end-to-end by minimizing the $\mathbb{L}_2$ normalized cross-entropy [@wang2018cosface]. Complexity Analysis of Graph Convolution ---------------------------------------- Here we compare the computation complexity of convolutions on images and graphs for the task of OLHCCR. Generally, both images and graphs can be represented as graphs with their nodes and edges, i.e., $\mathbb{G}=(\mathbf{V}, \mathbf{E})$. Then, the complexity of a single channel convolution on a graph $\mathbb{G}$ should be $\mathcal{O}(|\mathbf{V}||\bar{\mathbf{E}}|)$, where $|\bar{\mathbf{E}}|$ denotes the average number of edges for each node, i.e., $|\bar{\mathbf{E}}|=\frac{1}{|\mathbf{V}|}\sum_{v_i \in \mathbf{V}}|\mathcal{N}(v_i)|$. Specifically, for an image with the height $H$ and weight $W$, we get $|\mathbf{V}|=HW$ and $|\bar{\mathbf{E}}|=9$ (i.e. eight neighbourhoods and itself); for a sparse character graph, we can safely assume that $|\bar{\mathbf{E}}|\approx3$ (i.e. the former point and subsequent points in temporal order and itself), since most of the nodes are not the intersection points. As a result, the convolution complexity comparison between the image and graph should be $r \approx \mathcal{O}(\frac{3NH}{|\mathbf{V}_g|})$, where $\mathbf{V}_g$ denotes the node-set of the graph. Empirically, to achieve comparable accuracy for OLHCCR, the resolution of an input image is typically fixed to $64\times64$, while a character graph only contains nearly 100 nodes on average. On this condition, the convolution complexity of images is much more expensive than that of character graphs. Experiments =========== Datasets -------- Online handwritten Chinese character datasets are as follows: - [**IAHCC-UCAS2016**]{} [@qu2018data] is a public in-air handwritten Chinese character dataset, where each character is written in the midair within a single stroke. The dataset contains totally 431,825 samples covering 3755 Chinese characters (level-1 set of GB2312-80), where each class contains 115 different samples. Similar to previous works [@qu2018air], 92 samples per class are chosen as the training set, and the remaining as the test set. - [**ICDAR-2013**]{} [@yin2013icdar] is the most popular dataset of online handwritten Chinese characters that collected by the CASIA institution. For the OLHCCR task, the sub-datasets CASIA-OLHWDB 1.0 & 1.1 are used as the training set, which contains 2,693,183 samples; and the ICDAR-2013 competition sub-dataset is used as the test set, which contains 224,590 samples of 3755 character classes (level-1 set of GB2312-80). Implementation Details ---------------------- The whole architecture is entirely based on the PyTorch [@paszkepytorch] deep learning platform. In experiments, the detailed configuration of our spatial graph convolutional network for OLHCCR is shown in Fig. \[fig:gcn\_arch\], where the kernel size of each spline convolution is set as 3. Moreover, the dropout probability is set as 0.2 for each “Rs-GCB” module during training. The whole network is optimized via ADAM algorithm [@kingma2014adam] with a batch size of 128. Furthermore, the initial learning rate is set at 0.002 and then decayed by $\times$ 0.1 when the performance stops improving. Finally, the training process is terminated when the model reaches the convergence. All the experiments are conducted on a Dell workstation with an Intel(R) Xeon(R) CPU E5-2630 v4 @ 2.20GHz, 32 GB RAM, and two NVIDIA Quadro P5000 GPUs. Results with Varying Depths & Widths ------------------------------------ ----- --- ------------- ---------- --------- ---------- Training Storage Accuracy (h) (MB) (%) \#1 1 1.0$\times$ 3.0 3.73 96.33 \#2 1 1.5$\times$ 4.4 5.09 96.68 \#3 2 1.0$\times$ 4.7 4.99 96.84 \#4 2 1.5$\times$ 7.6 7.92 96.99 \#5 3 1.0$\times$ 6.6 6.17 96.85 \#6 3 1.5$\times$ 10.4 10.56 96.98 ----- --- ------------- ---------- --------- ---------- : Accuracies of SGCNs with varying block depths and widths on IAHCC-UCAS2016, i.g.“\#3” corresponds to the SGCN in Fig. \[fig:gcn\_arch\].[]{data-label="tab:vary_configs"} To investigate the effectiveness of the proposed method for OLHCCR, we fully compare the performance of SGCNs with varying depths and widths as shown in Table \[tab:vary\_configs\]. Additionally, we mainly search different network configurations on the small dataset (i.g. IAHCC-UCAS2016), hoping that the well-performed SGN architecture can be successfully transferred to the large dataset (i.g. ICDAR-2013). Specifically, during the comparison, different SGCNs follow the same structure as shown in Fig. \[fig:gcn\_arch\] but with different numbers of convolutional layers and channels in each “Rs-GCB” module. For example, “SGCN-\#3” in Table \[tab:vary\_configs\] is corresponding to the SGCN in Fig. \[fig:gcn\_arch\], and “SGCN-\#4” expands the width of “SGCN-\#3” by $\times$1.5. As shown in Table \[tab:vary\_configs\], either increasing the network depth or expanding its width can improve the recognition accuracy, however, both strategies correspondingly demand much more parameters and training time. Moreover, this accuracy improvement tends to become marginal when the model is sufficiently deep. In general, we prefer to choose the “SGCN-\#3” and “SGCN-\#4” for OLHCTR as the trade-off among the accuracy, storage, and training time. Ablation Study -------------- To fully analyze the effectiveness of each part in SGCN, we conduct the detailed ablation study of “SCGN-\#3” on IAHCC-UCAS2016 dataset as shown in Table \[tab:ablation\_study\]. ------------------------------ ---------- --------- --------- ----------------------------------- (l)[1-2]{}(l)[3-4]{} Spatial Temporal Input Feature (%) 95.95$^{\downarrow\textbf{0.89}}$ $\surd$ $\surd$ 96.22$^{\downarrow\textbf{0.62}}$ $\surd$ $\surd$ $\surd$ 96.53$^{\downarrow\textbf{0.31}}$ $\surd$ $\surd$ $\surd$ 96.49$^{\downarrow\textbf{0.35}}$ $\surd$ $\surd$ 96.35$^{\downarrow\textbf{0.49}}$ $\surd$ $\surd$ $\surd$ 96.42$^{\downarrow\textbf{0.42}}$ $\surd$ $\surd$ $\surd$ 96.75$^{\downarrow\textbf{0.09}}$ $\surd$ $\surd$ $\surd$ $\surd$  **96.84** ------------------------------ ---------- --------- --------- ----------------------------------- : Ablation study of SGCN-$\#$3 on IAHCC-UCAS2016.[]{data-label="tab:ablation_study"} ------------------------- --------- --------- --------- (lr)[2-4]{} [1a]{} [1b]{} [1c]{} HMM + DTW         [@Bahlmann2004thew] LSTM         [@Hochreiter1997Long] 1D-CNN         [@Iwana2019dwa] DWA 1D-CNN         [@Iwana2019dwa] Google Hybrids         [@Keysers2017multi] SGCN \[Ours\] *98.76* *96.33* *95.52* ------------------------- --------- --------- --------- : Classification accuracies of digits and letters on UNIPEN.[]{data-label="tab:unipen_results"} #### Node Feature Analysis We first analyze the effectiveness of different node features. As shown in Table \[tab:ablation\_study\], if no features are provided for graph nodes (i.e. features of all nodes are set into the same value), the SGCN still achieves a slightly good accuracy. This indicates that the graph representations well retain the geometric properties of characters, and the spatial graph convolution can also exploit their spatial structures via the local neighbourhoods aggregation and hierarchical structure learning. Moreover, the recognition accuracy will increase if we explicitly assign either spatial features (i.e. the absolute coordinates) or temporal features (i.e. writing offsets & directions) to the graph nodes. Finally, the SGCN achieves the best result by combining both spatial and temporal features, demonstrating the necessity of feature extraction. #### Spatial Transformation Analysis We further analyze the effectiveness of spatial transformation (ST) for inputs and features. We notice that ST for inputs does not bring a noticeable accuracy improvement for character recognition, which reveals that (1) variations in scales and positions can be effectively addressed by pre-processing and (2) the SGCN is robust to the small rotations of characters. On the contrary, a significant accuracy increase is observed when the ST is adopted in the feature space. This may indicate that the ST transforms high dimensional features into the latent canonical forms, and thus it helps learn the geometric invariant features. This eventually benefits the final classification. #### Extension to Digits and Letters To demonstrate that the SGCN is language-independent, we evaluate the SGCN on the UNIPEN dataset  [@guyon1994unipen], which consists of the isolated digits (**1a**), upper case (**1b**) and lower case English letters (**1c**) respectively. Moreover, the detailed configuration of SGCN for UNIPEN is “STN $\rightarrow$ FeatLayer $\rightarrow$ Rs-GCB(32) $\rightarrow$ Pooling $\rightarrow$ STN $\rightarrow$ Rs-GCB(64) $\rightarrow$ Pooling $\rightarrow$ Global-Average$\rightarrow$FC(128) $\rightarrow$ Softmax”. As shown in Table \[tab:unipen\_results\], the SGCN achieves comparable accuracies compared with previous methods on the UNIPEN datasets. This indicates that the SGCN is not limited to Chinese characters and it also can be extended to other languages easily. Benchmarking Results -------------------- [rlrr]{} & &Storage&Accuracy\ &&(MB)& (%)\ MQDF&[@liu2013online]&188.35 & 89.96\ LSROPC&[@qu2018air]& 68.04& 91.01\ DMap-CNN&[@qu2018data]& 20.2& 92.81\ 2D-CNN&[@gan2020comp]& 15.5& 95.33\ GRU&[@ren2017end]& *7.03* &92.50\ Attn-GRU&[@ren2019recog]&8.71 &93.18\ 1D-CNN&[@gan2018anew]& 8.09& [96.78]{}\ SGCN-\#3 &\[Ours\] &[**4.99**]{} &*96.84*\ SGCN-\#4 &\[Ours\] &[7.92]{} &[**96.99**]{}\ ---------- ----------------------- ---------- ----------- Storage Accuracy (MB) (%) Human [@yin2013icdar] N/A 95.19 DLQDF [@liu2013online] 120.0 95.31 VO3-CNN [@yin2013icdar] 87.60 96.87 DS-CNN [@yang2016dropsample] 15.0 97.23 UWarwick [@yin2013icdar] 37.80 97.39 DMap-CNN [@zhang2017online] 23.50 97.55 Attn-GRU [@ren2019recog] *7.01* 97.30 LSTM [@zhang2018drawing] 10.38 *97.76* 1D-CNN [@gan2018anew] 8.05 **97.86** SGCN-\#3 \[Ours\] **4.99** [97.34]{} SGCN-\#4 \[Ours\] [7.92]{} [97.55]{} ---------- ----------------------- ---------- ----------- : Comparison of classification accuracies for online handwritten Chinese characters on ICDAR-2013.[]{data-label="tab:icdar_results"} Lastly, we fully compare the SGCN with previous methods on benchmark datasets (including IAHCC-UCAS2016 and ICDAR-2013) as listed in Table \[tab:iahcc\_results\] and Table \[tab:icdar\_results\]. Particularly, we notice that the SGCN on graphs requires much fewer parameters than the 2D-CNN on feature images to achieve comparable accuracy. Moreover, the SGCN also achieves comparable accuracies and similar storages compared with the 1D-CNN or RNN on temporal features; however, the accuracy of the SGCN does not heavily rely on the temporal information (as shown in Table \[tab:ablation\_study\]), while the 1D-CNN and RNN will not work for classification when temporal orders of trajectories are lacked or disturbed. Overall, experiments demonstrate that the SGCN is comparable with the state-of-the-art methods, yet the SGCN not only has its unique advantages but also addresses OLHCCR in a completely different perspective . Conclusion ========== In this paper, we have proposed a novel spatial graph convolutional network (SGCN) for OLHCCR, upon which characters are viewed as geometric graphs. This is largely different from the latest popular methods including the 2D-CNN, 1D-CNN, and LSTM, thus addressing character recognition in a novel perspective. Experiments on benchmarks demonstrate the effectiveness of SGCN for OLHCCR. In future work, we plan to (1) design new graph convolution kernels for better performance and (2) extend our SGCN to offline HCCR.

Theranostic lipid nanoparticles for cancer medicine. Disease heterogeneity within and between patients necessitates a patient-focused approach to cancer treatment. This exigency forms the basis for the medical practice termed personalized medicine. An emerging, important component of personalized medicine is theranostics. Theranostics describes the co-delivery of therapeutic and imaging agents in a single formulation. Co-delivery enables noninvasive, real-time visualization of drug fate, including drug pharmacokinetic and biodistribution profiles and intratumoral accumulation. These technological advances assist drug development and ultimately may translate to improved treatment planning at the bedside. Nanocarriers are advantageous for theranostics as their size and versatility enables integration of multiple functional components in a single platform. This chapter focuses on recent developments in advanced lipid theranostic nanomedicine from the perspective of the "all-in-one" or the "one-for-all" approach. The design paradigm of "all-in-one" is the most common approach for assembling theranostic lipid nanoparticles, where the advantages of theranostics are achieved by combining multiple components that each possesses a specific singular function for therapeutic activity or imaging contrast. We will review lipoprotein nanoparticles and liposomes as representatives of the "all-in-one" approach. Complementary to the "all-in-one" approach is the emerging paradigm of the "one-for-all" approach where nanoparticle components are intrinsically multifunctional. We will discuss the "one-for-all" approach using porphysomes as a representative. We will further discuss how the concept of "one-for-all" might overcome the regulatory hurdles facing theranostic lipid nanomedicine.

The University of Texas Southwestern Medical Center in Dallas has initiated a major expansion in its NMR faculty and facilities. To drive this program, the University has committed over $5M for purchase of additional instruments, construction of state-of-the-art facilities, hiring of dedicated support personnel and appointment of senior faculty. Integral to this program is the purchase of an 800 MHz spectrometer equipped with a cryoprobe to support new research initiatives that cannot be carried out on lower field instruments, and funds are requested to assist in this endeavor. This instrument will support the research of 30 users in the four principal NMR groups in the Departments of Biochemistry and Pharmacology, plus numerous collaborators and minor users within and outside the university. Research using the instrument will address central questions in a broad range of biological areas, including molecular mechanisms of neurotransmitter release and constitutive intracellular membrane traffic, control of actin cytoskeletal architecture and dynamics through integrated signaling networks, regulation of cellular hypoxia responses and circadian cycling, and molecular mechanisms of a mitotic checkpoint that ensures the high-fidelity segregation of chromosomes in mitosis. Specific structural/biophysical problems in these areas include studies of the calcium sensor, synaptotagmin, and its interaction with SNARE proteins, essential components of the membrane fusion machinery; the activation mechanism of the 240 kDa Arp2/3 complex, the central actin nucleating machine in the cell, the biophysical foundations of signal integration by autoinhibitory proteins; the ability of PAS domains to control biological function through changes in protein structure and dynamics induced by natural and non-natural ligands; competition for the mitotic checkpoint protein Mad2 by its upstream regulator, Mad1, and its downstream target, Cdc20. These studies will require NMR analyses of multi-component systems ranging in size from 15-250 kDa, and will involve innovative use of CRIPT/TROSY methods, lanthanide-assisted magnetic field alignment, multi-field dynamics studies and analysis of very dilute solutions, necessitating maximum field strength and sensitivity. In summary, an 800 MHz spectrometer at UT Southwestern will foster cutting edge science in important biological areas that will expand the boundaries of NMR methods to large and/or complex systems. The instrument will be strongly supported by the University, and administered through a detailed plan that ensures efficient use and maintenance, specific mechanisms for training new users and dissemination of results to the larger communitv.

At the close of this program in Timor Leste’s Viqueque region, Manuel says his family is better off all around. “We don’t have to buy as much in the market so it’s a saving for us. And, a few months ago, I sold some of my harvest and earned enough to cover my family’s basic needs. I also bought some equipment to improve and expand my planting area,” he says. Another farmer, who only used to be able to grow enough for five months, says, “Nearly a year after harvest, we still have food.” Manuel says he is getting greater yields of improved-quality maize and has learned to dry it and protect it from pests and mold by storing it in airtight containers like water bottles. Besides maize and rice, he plants a wider variety of foods – beans, taro root, cassava, papaya – for better nutrition. According to the program’s final report, all of the farmers who took part in the training are using one or more of the environmentally-friendly farming techniques they learned. At the start of the program, maize yielded around 1,036 pounds per hectare (2.5 acres). Everyone met or exceeded the target of 1,343 lbs./hectare, some harvesting as much as 2,320. And, by drying and storing maize in airtight containers – instead of hanging it in unprotected sheaves outdoors – their losses to mold and pests are minimal. Local partner staff and extension workers from the Ministry of Agriculture live and farm in the same villages as program participants, and will continue to model improved farming and storage techniques on their own land. The Ministry of Agriculture will continue to assist farmers with seed, training, moisture testing and new ideas. Caption: Manuel’s great results from improved seed and environmentally-friendly farming

import {createHash, createHmac, pbkdf2Sync, randomBytes, timingSafeEqual} from 'crypto'; import {MongoAuth} from './auth'; import {t} from '@deepkit/type'; import {MongoClientConfig} from '../../client'; import {BaseResponse, Command} from '../command'; import {MongoError} from '../../error'; import * as saslprep from 'saslprep'; class SaslStartCommand extends t.class({ saslStart: t.literal(1), $db: t.string, mechanism: t.string, payload: t.type(Uint8Array), autoAuthorize: t.literal(1), options: { skipEmptyExchange: t.literal(true) } }) { } class SaslStartResponse extends t.class({ conversationId: t.number, payload: t.type(Uint8Array), done: t.boolean, }, {extend: BaseResponse}) { } class SaslContinueCommand extends t.class({ saslContinue: t.literal(1), $db: t.string, conversationId: t.number, payload: t.type(Buffer), }) { } class SaslContinueResponse extends t.class({ conversationId: t.literal(1), payload: t.type(Uint8Array), done: t.boolean, }, {extend: BaseResponse}) { } function H(method: string, text: Buffer) { return createHash(method).update(text).digest(); } function HMAC(method: string, key: Buffer, text: Buffer | string) { return createHmac(method, key).update(text).digest(); } function cleanUsername(username: string) { return username.replace('=', '=3D').replace(',', '=2C'); } function passwordDigest(u: string, p: string) { if (p.length === 0) throw new MongoError('password cannot be empty'); const md5 = createHash('md5'); md5.update(`${u}:mongo:${p}`, 'utf8'); //lgtm[js/weak-cryptographic-algorithm] lgtm[js/insufficient-password-hash] return md5.digest('hex'); } function HI(data: string, salt: Buffer, iterations: number, cryptoAlgorithm: string) { if (cryptoAlgorithm !== 'sha1' && cryptoAlgorithm !== 'sha256') { throw new MongoError(`Invalid crypto algorithm ${cryptoAlgorithm}`); } //should we implement a cache like the original driver? return pbkdf2Sync( data, salt, iterations, cryptoAlgorithm === 'sha1' ? 20 : 32, cryptoAlgorithm ); } function xor(a: Buffer, b: Buffer) { const length = Math.max(a.length, b.length); const buffer = Buffer.alloc(length); for (let i = 0; i < length; i++) buffer[i] = a[i] ^ b[i]; return buffer; } export abstract class ScramAuth implements MongoAuth { protected nonce = randomBytes(24); protected cryptoMethod: string; protected constructor(protected mechanism: 'SCRAM-SHA-1' | 'SCRAM-SHA-256') { this.cryptoMethod = this.mechanism === 'SCRAM-SHA-1' ? 'sha1' : 'sha256'; } async auth(command: Command, config: MongoClientConfig): Promise<void> { const username = cleanUsername(config.authUser || ''); const password = config.authPassword || ''; const startResponse = await command.sendAndWait(SaslStartCommand, { saslStart: 1, $db: config.getAuthSource(), mechanism: this.mechanism, payload: Buffer.concat([Buffer.from('n,,', 'utf8'), this.clientFirstMessageBare(username, this.nonce)]), autoAuthorize: 1, options: {skipEmptyExchange: true} }, SaslStartResponse); const processedPassword = this.mechanism === 'SCRAM-SHA-256' ? saslprep(password) : passwordDigest(username, password); const payloadAsString = Buffer.from(startResponse.payload).toString('utf8'); const payloadStart = this.parseStartPayload(payloadAsString); const withoutProof = `c=biws,r=${payloadStart.r}`; const saltedPassword = HI( processedPassword, Buffer.from(payloadStart.s, 'base64'), payloadStart.i, this.cryptoMethod ); const clientKey = HMAC(this.cryptoMethod, saltedPassword, 'Client Key'); const serverKey = HMAC(this.cryptoMethod, saltedPassword, 'Server Key'); const storedKey = H(this.cryptoMethod, clientKey); const authMessage = [ this.clientFirstMessageBare(username, this.nonce), payloadAsString, withoutProof ].join(','); const clientSignature = HMAC(this.cryptoMethod, storedKey, authMessage); const clientProof = `p=${xor(clientKey, clientSignature).toString('base64')}`; const clientFinal = [withoutProof, clientProof].join(','); const serverSignature = HMAC(this.cryptoMethod, serverKey, authMessage); const continueResponse = await command.sendAndWait(SaslContinueCommand, { saslContinue: 1, $db: config.getAuthSource(), conversationId: startResponse.conversationId, payload: Buffer.from(clientFinal) }, SaslContinueResponse); const payloadContinueString = Buffer.from(continueResponse.payload).toString('utf8'); const payloadContinue = this.parseContinuePayload(payloadContinueString); if (!timingSafeEqual(Buffer.from(payloadContinue.v, 'base64'), serverSignature)) { throw new MongoError('Server returned an invalid signature'); } if (continueResponse.done) return; //not done yet, fire an empty round const continueResponse2 = await command.sendAndWait(SaslContinueCommand, { saslContinue: 1, $db: config.getAuthSource(), conversationId: startResponse.conversationId, payload: Buffer.alloc(0) }, SaslContinueResponse); if (continueResponse2.done) return; throw new MongoError('Sasl reached end and never never acknowledged a done.'); } //e.g. "r=fyko+d2lbbFgONRv9qkxdawLHo+Vgk7qvUOKUwuWLIWg4l/9SraGMHEE,s=rQ9ZY3MntBeuP3E1TDVC4w==,i=10000" protected parseStartPayload(payload: string) { const result = {r: '', s: '', i: 0}; for (const pair of payload.split(',')) { const firstSign = pair.indexOf('='); const name = pair.substr(0, firstSign); const value = pair.substr(firstSign + 1); result[name] = name === 'i' ? parseInt(value, 10) : value; } if (result.i < 4096) throw new MongoError(`Server returned an invalid iteration count ${result.i}`); if (result.r.startsWith('nonce')) throw new MongoError(`Server returned an invalid nonce: ${result.r}`); return result; } //e.g. "v=UMWeI25JD1yNYZRMpZ4VHvhZ9e0=" protected parseContinuePayload(payload: string) { const result = {v: ''}; for (const pair of payload.split(',')) { const firstSign = pair.indexOf('='); const name = pair.substr(0, firstSign); result[name] = pair.substr(firstSign + 1); } return result; } protected clientFirstMessageBare(username: string, nonce: Buffer) { // NOTE: This is done b/c Javascript uses UTF-16, but the server is hashing in UTF-8. // Since the username is not sasl-prep-d, we need to do this here. return Buffer.from(`n=${username},r=${nonce.toString('base64')}`, 'utf8'); } } export class Sha1ScramAuth extends ScramAuth { constructor() { super('SCRAM-SHA-1'); } } export class Sha256ScramAuth extends ScramAuth { constructor() { super('SCRAM-SHA-256'); } }

Q: Best practice for which Response Code to use for invalid requests? There are a few sites that are linking back to mine, but they are invalid URLs; content that I've never had on my site. I know that for content I have moved I should be using 301 and content that I have deleted I should be using a 410. But for something like this, I don't foresee those sites coming back and correcting their links, one of which is in the footer of a persons signature on a forum in China. Do I just send the 410 and let it be? A: The correct response code to use for such requests is 404, and that is also what Apache will send by default.

Critics Are Trashing the Warcraft Movie and Rogue One Keeps Getting Better - Up At Noon Live!

Financial Highlights for the Third Quarter Ended September 30, 2015 Revenues operating income for the third quarter increased 3% to $6.6 million, compared to $6.4 million in the same period last year. On a constant currency basis, excluding the negative impact from the erosion of foreign exchange rates (mainly resulting from the devaluation of the Euro and Japanese Yen versus the U.S Dollar), non-GAAP operating income would have reflected an increase of 10% year over year to $7.1 million. Operating income decreased 5% to $5.3 million, compared to $5.6 million in the same period last year to a record-breaking result of $47.8 million. Non-GAAP operating income for the second quarter increased 7% to $6.5 million, compared to $6.0 million in the same period last year. Excluding the impact of erosion of foreign exchange rates (mainly resulting from the devaluation of the Euro and Japanese Yen versus the U.S Dollar), non-GAAP operating income would have reflected an increase of 16% year over year to $7.0 million. Non-GAAP operating margin increased by 40 basis points to 15.2%, up from 14.8% in same period last year. Operating income for the second quarter increased 5% to $5.4 million, compared to $5.1 million in the same period last year. Non-GAAP net income for the third quarter increased 14% to $5.7 million, or $0.13 per fully diluted share, compared to $5.0 million, or $0.11 per fully diluted share in the same period last year. On a constant currency basis, excluding the negative impact from the erosion of foreign exchange rates (including the devaluation of cash balances denominated mainly in New Israeli Shekels, Euros, and Japanese Yen against the US Dollar), non-GAAP net income would have reflected an increase of 23% year over year to $6.2 million, or $0.14 per fully diluted share. Net income for the third quarter amounted to $4.2 million (or $0.09 per fully diluted share), compared to $4.2 million (or $0.10 per fully diluted share) in the same period last year. Financial Highlights for the Nine-Month Period Ended September 30, 2015 Revenues for the first nine months of 2015 increased 5% to a record of $128.2 million compared to $121.8 million in the same period last year. Revenues were negatively impacted by the devaluation of the New Israeli Shekel, Euro and Japanese Yen against the U.S Dollar by 10%, 18% and 15%, respectively. On a constant currency basis, excluding the negative impact from the erosion of foreign exchange rates, revenues for the first nine months would have reflected an increase of 12% year over year to a record of $135.9 million. Non-GAAP operating income for the first nine months of 2015 increased 5% to $19.8 million compared to $18.9 million in the same period last year. On a constant currency basis, excluding the negative impact from the erosion of foreign exchange rates (mainly resulting from the devaluation of the Euro and Japanese Yen versus the U.S Dollar), non-GAAP operating income would have reflected an increase of 13% year over year to $21.4 million. Operating income for the first nine months of 2015 decreased 1% to $16.5 million compared to $16.7 million in the same period last year. Non-GAAP net income for the first nine months of 2015 increased 9% to $16.1 million (or $0.36 per fully diluted share) compared to $14.7 million (or $0.34 per fully diluted share) in the same period last year. On a constant currency basis, excluding the negative impact from the erosion of foreign exchange rates (including the devaluation of cash balances denominated mainly in New Israeli Shekels, Euros, and Japanese Yen against the US Dollar amounting to $0.9 million), non-GAAP net income would have reflected an increase of 26% year over year to $18.6 million (or $0.42 per fully diluted share). Net income for the first nine months of 2015 decreased 1% to $12.5 million (or $0.28 per fully diluted share), compared to $12.6 million (or $0.29 per fully diluted share) in the same period last year. Total cash, cash equivalents and short-term investments as of September 30, 2015, amounted to $80.9 million. Comments of Management Guy Bernstein, Chief Executive Officer of Magic Software Enterprises, said, “We are pleased to report record-breaking quarterly revenues of $45.3 million. We are continuing to see solid demand for our software and professional services from all regions, demonstrating the relevance of our enterprise mobility, cloud integration and Big Data solutions as companies move forward with digital transformations.” “Our focus on operational discipline while enriching our offerings and enlarging our customer base has enabled us to maintain non-GAAP operating margins of over 15% despite foreign currency devaluations and a changing revenue mix. We are maintaining our revenue guidance of $166 million to $173 million for the full-year 2015, reflecting a 7% to 11% growth rate on a constant currency basis.” Conference Call Details Magic’s Management will host an interactive conference today, November 11, at 10:00 am Eastern Time (7:00 am Pacific Time, 17:00 Israel Time). On the call, management will review and discuss the results, and will also be available to answer investors’ questions. To participate, please call one of the following teleconferencing numbers. Please begin placing your calls at least 10 minutes before the conference call commences. If you are unable to connect using the toll-free numbers, call the international dial-in number. NORTH AMERICA: 1.888.668.9141 UK: 0 800 917 5108 ISRAEL: 03.918.0650 INTERNATIONAL: +972.3.918.0650 For those unable to listen to the live call, a replay of the call will be available for three months from the day after the call under the investor relations section of Magic’s website. About Magic Software Enterprises Magic Software Enterprises Ltd. (NASDAQ and TASE: MGIC) is a global provider of mobile and cloud-enabled application and business integration platforms. Forward Looking Statements Some of the statements in this press release may constitute “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities and Exchange Act of 1934 and the United States Private Securities Litigation Reform Act of 1995. Words such as "will," "expects," "believes" and similar expressions are used to identify these forward-looking statements (although not all forward-looking statements include such words). These forward-looking statements, which may include, without limitation, projections regarding our future performance and financial condition, are made on the basis of management’s current views and assumptions with respect to future events. Any forward-looking statement is not a guarantee of future performance and actual results could differ materially from those contained in the forward-looking statement. These statements speak only as of the date they were made, and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise. We operate in a changing environment. New risks emerge from time to time and it is not possible for us to predict all risks that may affect us. For more information regarding these risks and uncertainties as well as certain additional risks that we face, you should refer to the Risk Factors detailed in our Annual Report on Form 20-F for the year ended December 31, 2013 and subsequent reports and registration statements filed from time to time with the Securities and Exchange Commission. Magic is a registered trademark of Magic Software Enterprises Ltd. All other product and company names mentioned herein are for identification purposes only and are the property of, and might be trademarks of, their respective owners.

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652 So.2d 211 (1994) Vernda Kay HICKS, as administratrix of the Estate of John William Hicks, deceased v. COMMERCIAL UNION INSURANCE COMPANY, et al. 1921934. Supreme Court of Alabama. August 26, 1994. Rehearing Denied December 16, 1994. *213 Bayless E. Biles of Wilkins, Bankester, Biles & Wynne, Bay Minette, L.A. Marsal of Seale, Marsal & Seale, Mobile, for appellant. *214 Vaughan Drinkard, Jr. and Winn Faulk of Drinkard, Ulmer & Hicks, Mobile, for Thaxton, Inc. and Hy-Tech Machine, Inc. Vincent A. Noletto, Jr. and Thomas H. Nolan, Jr. of Brown, Hudgens, P.C., Mobile, for Commercial Union Ins. Co. and Samuel Flood. PER CURIAM. Vernda Kay Hicks, as administratrix of the estate of John Williams Hicks, appeals from a summary judgment in favor of the defendants Thaxton, Inc., Hy-Tech Machine, Inc., Samuel Flood, and Commercial Union Insurance Company. Vernda Hicks brought this action for damages against these four defendants and against three co-employees of John Hicks,[1] alleging negligence, intentional or willful wrongful conduct, and liability under the Alabama Extended Manufacturer's Liability Doctrine ("AEMLD"), in connection with the discharge of a pipe plug or pipe stopper, attached to a highly pressurized container or vessel, which struck John Hicks in the head, killing him instantly. With regard to Thaxton, Inc., and its "affiliate," Hy-Tech Machine, Inc. (together referred to hereinafter as "Thaxton"), Vernda Hicks alleged that the pipe stopper and its component parts, which Thaxton had designed and manufactured, were "defective," as that term is used in our cases applying the AEMLD. With regard to Samuel Flood and his employer, Commercial Union Insurance Company, Vernda Hicks alleged that Commercial Union, through Flood, had breached a duty to exercise reasonable care to ensure safety during the testing of the vessel, during which testing John Hicks was killed. The issues are (1) Whether a genuine issue of material fact exists as to whether the pipe stopper was defective; (2) Whether a genuine issue of fact exists as to whether the condition of the pipe stopper had been substantially altered when it was used in the testing of the vessel; (3) Whether the evidence indicated that John Hicks was contributorily negligent as a matter of law; (4) Whether it indicated that John Hicks voluntarily assumed the risk of death, as a matter of law; and (5) Whether the plaintiff presented substantial evidence that Commercial Union and its agent Flood had assumed a duty to exercise reasonable care to inspect the pipe stopper for safety. A summary judgment is proper only when the court concludes that there is no genuine issue of material fact and that the movant is entitled to a judgment as a matter of law, Rule 56, Ala.R.Civ.P. On a motion for a summary judgment, when the movant makes a prima facie showing that no genuine issue of material fact exists, the burden shifts to the nonmovant to present substantial evidence creating a genuine issue of material fact. Rule 56(e); § 12-21-12, Ala.Code 1975. The court views the evidence most favorably to the nonmovant and resolves all reasonable doubts concerning the existence of a genuine issue of material fact against the movant. Specialty Container Mfg., Inc. v. Rusken Packaging, Inc., 572 So.2d 403, 404 (Ala. 1990). John Hicks had been employed by Taylor-Wharton/Plant City Steel Company ("Taylor-Wharton") and its predecessor Union Carbide since 1977. Taylor-Wharton manufactures boilers or "vessels," which store pressurized gasses such as oxygen, nitrogen, and hydrogen. John Hicks conducted hydrostatic pressure tests of vessels manufactured by Taylor-Wharton. In a hydrostatic pressure test, water is placed into the vessel being tested, and the vessel is then pressurized to determine whether the vessel properly maintains its structural stability under such pressure. During such a test, the vessel is inspected for leaks and other conditions that may affect its compliance with standards of the Boiler and Pressure Vessel Code ("Code") of the American Society of Mechanical Engineers ("ASME"); such compliance is necessary for the manufacturer to obtain ASME certification of its vessel. The vessel John Hicks was testing when he was killed had been designed and manufactured to meet ASME standards. *215 For a vessel to receive ASME certification, which signifies that a vessel complies with ASME standards, a representative of an authorized ASME inspection agency must be present at the testing of the vessel. Commercial Union was an authorized inspection agency; under a written contract between it and Taylor-Wharton, Samuel Flood, an inspector employed by Commercial Union, regularly witnessed the testing of vessels manufactured by Taylor-Wharton at Taylor-Wharton's manufacturing facility. On May 15, 1990, Michael Onderdonk, a Taylor-Wharton employee, prepared a 6,000-gallon vessel for testing by the next work shift. When the shift changed, Onderdonk left, and Hicks arrive to conduct the hydrostatic test. Pursuant to the ASME Code, John Hicks began the test by pressurizing the vessel to 433 pounds per square inch. Samuel Flood was present, along with Lee Hull, another Taylor-Wharton employee. After about two minutes, a pipe stopper on the vessel dislodged and shot toward John Hicks, who at that moment was walking in front of it. The pipe stopper, which weighed 2.8 pounds, was travelling 71 feet per second when it struck John Hicks in the head; it went through John Hicks's hard hat, killing him instantly. Pipe stoppers cover the opening of pipes extending from vessels for the purpose of pressurizing vessels for testing. A pipe stopper contains four "jaws," which secure the pipe stopper to the pipe extending from the vessel by expanding with increased pressure. As the pressure increases, the jaws expand and grip the inside of the pipe. The jaws are manufactured in sets. Although the jaws within a set are apparently uniform in size, the size of the jaws of different sets varies slightly. Because these sets of jaws differ slightly in size, the jaws of a set are all marked by the same letter, e.g., "A," "B," or "C." The jaws easily detach from the pipe stopper itself, and the jaws of different sets are interchangeable. An "o-ring" and a neoprene seal hold the jaws on the pipe stopper. The o-ring and the seal deteriorate with use, and the pipe stopper is designed to permit their replacement. Thaxton markets "o-ring kits" to replace the o-ring and the seal after they deteriorate. To replace the o-ring and the seal, it is necessary to remove the jaws from the pipe stopper. The circuit court entered a summary judgment in favor of all of the defendants. With regard to the AEMLD claims against Thaxton, the circuit court held that Vernda Hicks had failed to present substantial evidence 1) that the pipe stopper was defective; 2) that the condition of the plug had not been substantially altered; and 3) that Thaxton had failed to adequately provide certain warnings. The circuit court held further that John Hicks had been contributorily negligent, as a matter of law; that John Hicks had assumed the risk of death, as a matter of law; and that the doctrine of res ipsa loquitur was not applicable to these facts. With regard to the claims against Flood and Commercial Union, the circuit court held that in Commercial Union's contract with Taylor-Wharton to provide inspection services, Commercial Union had not assumed a duty to ensure that the testing of vessels was conducted safely. I. The Claims Against Thaxton and Hy-Tech In arguing that the circuit court erred in entering the summary judgment in favor of Thaxton and Hy-Tech as to her AEMLD claim, Vernda Hicks contends first that a genuine issue of material fact exists as to whether the pipe stopper was "defective" within the terms of the AEMLD. In order to establish liability under the AEMLD, a plaintiff must show the following: "(1) he suffered injury or damages to himself or his property by one who sells a product in a defective condition unreasonably dangerous to the plaintiff as the ultimate user or consumer, if "(a) the seller is engaged in the business of selling such a product, and "(b) it is expected to and does reach the user or consumer without substantial change in the condition in which it is sold." Kelly v. M. Trigg Enterprises, Inc., 605 So.2d 1185, 1191 (Ala.1992) (quoting earlier cases); Caterpillar Tractor Co. v. Ford, 406 *216 So.2d 854, 855 (Ala.1981). "Liability under the AEMLD turns upon whether a product is unreasonably dangerous when put to its intended use." Koehring Cranes & Excavators, Inc. v. Livingston, 597 So.2d 1354 (Ala. 1992); Casrell v. Altec Indus., Inc., 335 So.2d 128, 133 (Ala.1976). This Court has further stated: "`The manufacturer of a product which may be reasonably anticipated to be dangerous if used in a way which he should reasonably foresee it would be used is under a duty to exercise reasonable care to give reasonable and adequate warnings of any dangers known to him, or which in the exercise of reasonable care he should have known and which the user of the product obviously could not discover. Reasonable care means that degree of care which a reasonably prudent person would exercise under the same circumstances.'" Bean v. BIC Corp., 597 So.2d 1350, 1353 (Ala.1992) (quoting Dunn v. Wixom Brothers, 493 So.2d 1356, 1360 (Ala.1986) (quoting Alabama Pattern Jury Instructions (Civil), 32.07, and stating that A.P.J.I. 32.07 was a correct statement of the law)). In opposition to the summary judgment motion filed by Thaxton, Vernda Hicks submitted the deposition testimony of Fred A. Lewter III and J. Albert McEarchern, Jr., two engineering experts, regarding the Thaxton pipe stopper, its jaws, and the instructions and warnings that accompanied the product. After conducting numerous hydrostatic tests using the pipe stopper and jaws that had failed and led to the death of John Hicks, and other pipe stoppers manufactured by Thaxton, Lewter and McEarchern concluded generally that, although this fact is not readily discernible, the jaws from different sets were not uniform in size; that the jaws were easily detachable from the pipe stopper; that the jaws from different sets were interchangeable; that a pipe stopper with jaws from different sets does not function properly and has a strong propensity to dislodge during a hydrostatic test; that the jaws of the pipe stopper recovered after the accident were mismatched; and that the mismatching of the jaws in the pipe stopper was a cause contributing to the accident. On the basis of these findings, the experts concluded that the pipe stopper was unreasonably dangerous. For example, McEarchern stated: "[The mismatching of the jaws] was a factor in what caused this plug to come out.... ". . . . "... [T]here is a serious potential for mismatching even if you keep the `E's' and `X's' together. So, there is a definite defect here in the concept of this design in the fact that it is very easy to mix up or confuse these. And nowhere in the instructions does it tell you not to. ". . . . "... [I]f you had a tool box full of these, I mean these inevitably come apart when you throw them in a box. I mean, it's very easy for this o-ring to come off and I won't do it here or I will end up with them all over the floor. But, it is very easy when you throw these in a tool box for these to become a pile of parts. ". . . . "... [I]t is very easy to mismatch them. ". . . . "Unless you are warned not to." Lewter and McEarchern concluded that Thaxton should clearly and conspicuously mark the jaws so that they would not be easily mismatched and concluded that the instructions accompanying the pipe stopper should be amended to warn against mismatching. Lewter and McEarchern also concluded that the pipe stopper was unreasonably dangerous because its design did not include a "gag" or safety chain to prevent it from flying loose if it dislodged. Thaxton marketing literature states that gags should be used as an "additional safety precaution" in certain types of pressure testing; however, this literature did not list hydrostatic testing as one of the types in which a gag should be used. Lewter concluded that a gag or safety chain should be attached to the plugs during all types of pressure tests, including hydrostatic tests. Thaxton argues that the evidence presented does not create a genuine issue of material *217 fact as to whether the pipe stopper was sold in a defective condition. Relying on Onderdonk's deposition testimony that he properly attached the pipe stopper and did not mismatch the jaws on the pipe stopper before the accident, Thaxton argues, in effect, that the tests conducted by the plaintiff's experts, in which the pipe stopper with the mismatched jaws became dislodged, are not probative or material because, when conducting these tests, the plaintiff's experts did not tighten the hex nut, which attached the pipe stopper to the vessel, with sufficient torque. In their deposition testimony, however, both of the plaintiff's experts concluded that, contrary to the opinion of Thaxton employees, torque applied to the hex nut did not significantly affect the ability of the pipe stopper to hold in place under pressure. Further, the conflict between Onderdonk's testimony that he did not mismatch the jaws in the pipe stopper that later became dislodged and killed John Hicks, and Lewter and McEarchern's testimony that the jaws recovered from the scene of the accident were mismatched simply creates another genuine issue of fact for the jury. Relying on the operating instructions that accompanied the pipe stopper when it was sold, Thaxton contends that it provided an adequate warning of the risk of harm to which John Hicks was exposed. The relevant part of the operating instructions states: "BEFORE USE, A SPECIAL WORD OF CAUTION—Thaxton, Inc., engineers and manufactures a superior testing product, but pressure testing is generally recognized as an inherently hazardous operation, hence general safety precautions should be observed: check rating and overall condition of all connections, flanges, valves, and other testing equipment against planned testing pressure. Vent all air if hydrostatic testing and provide a remote or automatic pressure control away from the test assembly. Do not stand in front of test plug or other enclosure while the test is in progress." (Emphasis added.) Because Taylor-Wharton received this warning and because, Thaxton says, a manufacturer may rely on an employer to convey such warnings and instructions to its employees who use the product, Thaxton contends that even if the pipe stopper was defective, as the plaintiff alleged, John Hicks was adequately warned of the danger that led to his death, specifically the danger posed by standing in front of the plug during a test. Without commenting on the merit of Thaxton's argument that a warning given to an employer is somehow deemed, as a matter of law, to have been given to its employees who use the product, we hold that the testimony presented by the plaintiff's experts at least creates a genuine issue of material fact regarding the adequacy of the warning in the instructions accompanying the pipe stopper manufactured by Thaxton. Whether the provision of the operating instructions warning users not to stand in front of the pipe stopper during a test adequately apprises users of the risk of injury and death presented by the mismatching of the jaws of a pipe stopper is a question of fact for the jury. Citing Ford Motor Co. v. Rodgers, 337 So.2d 736 (Ala.1976), Thaxton also argues that it had no duty to warn because, it says, the danger that a pipe stopper could become dislodged during a hydrostatic test was common knowledge among the employees of Taylor-Wharton. Thus, Thaxton contends, the presence of the warnings recommended by the plaintiff's experts would not have supplied the users of the pipe stopper with any information that the management and employees of Taylor-Wharton did not already have. Although the testimony of the Taylor-Wharton employees raises an inference that the danger posed by a pipe stopper's slipping loose was commonly known, that evidence does not create an undisputed inference that users of the pipe stopper knew that mismatching the jaws of the pipe stopper would greatly increase the propensity of the pipe stopper to dislodge during a hydrostatic test. With regard to the issue of defectiveness, Thaxton argues, last, that the pipe stopper is unavoidably unsafe and that Vernda Hicks failed to show how Thaxton could have designed the pipe stopper differently so as to avoid the risk of its failure. This argument, *218 however, ignores the considerable and specific testimony of the plaintiff's experts regarding changes in design that would have eliminated or greatly reduced not only of the risk of failure but also, more importantly, the risk of injury and death. We conclude that Vernda Hicks presented substantial evidence from which an impartial trier of fact could reasonably infer that the pipe stopper, as manufactured and sold by Thaxton, was "defective" within the terms of the AEMLD. Vernda Hicks argues also that a genuine issue of fact exists as to whether the condition of the plug used in the hydrostatic test had been substantially altered. In Sears, Roebuck & Co. v. Harris, 630 So.2d 1018, 1027 (Ala.1993), cert. denied, ___ U.S. ___, 114 S.Ct. 2135, 128 L.Ed.2d 865 (1994), the Court stated the following applicable legal principles: "An essential element of an AEMLD claim is proof that the product reached the consumer without substantial change in the condition in which it was sold. Clarke Indus., Inc. v. Home Indemn. Co., 591 So.2d 458, 462 (Ala.1991); see also Caterpillar Tractor Co. v. Ford, 406 So.2d 854 (Ala.1981). However, the mere fact that a product has been altered or modified does not necessarily relieve the manufacturer or seller of liability. Johnson v. Niagara Machine & Tool Works, 555 So.2d 88, 91 (Ala.1989). A manufacturer or seller remains liable if the alteration or modification did not in fact cause the injury, Johnson, 555 So.2d at 91 (quoting Industrial Chem. & Fiberglass Corp. v. Hartford Acc. & Indemn. Co., 475 So.2d 472, 476 (Ala. 1985)); Bullen v. Roto Finishing Systems, 435 So.2d 1256 (Ala.1983); Brown v. Terry, 375 So.2d 457 (Ala.1979), or if the alteration or modification was reasonably foreseeable to the manufacturer or seller, Clarke Indus., 591 So.2d at 462; Beloit Corp. v. Harrell, 339 So.2d 992 (Ala.1976)." Thaxton contends that Vernda Hicks did not present sufficient evidence that it sold the pipe stopper with mismatched jaws and that if the pipe stopper that dislodged and killed John Hicks had mismatched jaws, it did so because an employee of Taylor-Wharton had mismatched them. Any such mismatching of the jaws of the pipe stopper, Thaxton argues, constituted a substantial alteration of its product, and that alteration, it says, was not reasonably foreseeable. No evidence shows that Thaxton sold the pipe stopper to Taylor-Wharton with mismatched jaws. Circumstantial evidence tends to show that the jaws were mismatched at the manufacturing facility of Taylor-Wharton. Although the mismatching of the jaws of the pipe stopper is undisputedly a substantial alteration of the product, a genuine issue of fact exists as to whether that substantial alteration was reasonably foreseeable to Thaxton. Vernda Hicks presented substantial evidence from which an impartial trier of fact could reasonably infer that Thaxton could have reasonably foreseen that the jaws of the pipe stopper could easily be mismatched during the productive life of the product. Thaxton markets "o-ring kits" for the purpose of replacing the pipe stopper's o-ring and neoprene seal when they deteriorate or wear out. Vernda Hicks also produced testimony from George Piel, vice president of Thaxton, who stated: "Q.... You all advertise the sale of a neoprene seal after the heavy parts of the product reach the user, do you not? "[Piel]: We sell seal kits, yes, sir. "Q. Seal kits. And you also advertised the o-ring? "[Piel]: Yes, sir. That is part of the seal kit. "Q. Once the o-ring is destroyed or used up for its life expectancy and once the neoprene seal is used up for its life expectancy, is there anything to hold those jaws next to the mandrel so they are not mismatched? "[Piel]: No, sir." We hold that Vernda Hicks presented substantial evidence from which an impartial trier of fact could reasonably infer that the alleged substantial alteration, i.e., the mismatching of the jaws, was reasonably foreseeable to the manufacturer Thaxton. Finally, Vernda Hicks argues that the circuit court erred in entering the summary *219 judgment in favor of Thaxton and Hy-Tech on the ground that John Hicks misused the pipe stopper, was contributorily negligent, and assumed the risk of injury—all, as a matter of law. "`When asserting misuse as a defense under [the] AEMLD, the defendant must establish that the plaintiff used the product in some manner different from that intended by the manufacturer. Stated differently, the plaintiff's misuse of the product must not have been `reasonably foreseeable by the seller or manufacturer.'" Kelly v. M. Trigg Enterprises, Inc., 605 So.2d 1185, 1192 (Ala.1992) (quoting Edward C. Martin, Alabama's Extended Manufacturer's Liability Doctrine (AEMLD), 13 Am.J.Trial Advoc. 983, 1040 (1990)), quoted in Sears, Roebuck & Co., 630 So.2d at 1028. These principles apply to the use of the product by the plaintiff or the plaintiff's decedent as they do to the use of the product by third parties. Kelly, 605 So.2d at 1192. Ordinarily, whether someone misused an allegedly defective product is a factual issue for the jury. Sears, Roebuck & Co., 630 So.2d at 1028; Kelly, 605 So.2d at 1192; Banner Welders, Inc. v. Knighton, 425 So.2d 441, 448 (Ala.1982); Beloit Corp. v. Harrell, 339 So.2d 992, 997 (Ala.1976). Thaxton contends that the pipe stopper was misused either by one or more employees of Taylor-Wharton, who altered the pipe stopper by mismatching its jaws, or by John Hicks, who failed to examine the adequacy of the pipe stopper before the test commenced. We hold, however, that there are genuine issues of fact for the jury as to Thaxton's affirmative defense of product misuse. First, there are the issues whether John Hicks or any other employee of Taylor-Wharton misused the pipe stopper by mismatching its jaws and by not inspecting it properly before beginning the test. Second, if a jury finds that another employee of Taylor-Wharton, or John Hicks himself, misused the pipe stopper, then there arises the issue whether these alleged misuses of the product were reasonably foreseeable to Thaxton. Thaxton has simply not conclusively shown that the pipe stopper, if it was not being used properly, was being used in a way that was not reasonably foreseeable. Vernda Hicks argues also that the evidence fails to show that John Hicks was contributorily negligent as a matter of law. She argues first that contributory negligence is no longer an affirmative defense under the AEMLD after Dennis v. American Honda Motor Co., 585 So.2d 1336 (Ala.1991). However, this Court has decided in General Motors, Inc. v. Saint, 646 So.2d 564 (Ala.1994), and in Campbell v. Cutler Hammer, Inc., 646 So.2d 573 (Ala.1994), that contributory negligence remains an affirmative defense under the AEMLD. The standard for determining whether a person was contributorily negligent as a matter of law has been stated as follows: "In order to sustain a finding of contributory negligence as a matter of law, there must be a finding that the plaintiff put himself in danger's way, Mackintosh Co. v. Wells, 218 Ala. 260, 118 So. 276 (1928), and a finding that the plaintiff appreciated the danger confronted, Wilson v. Alabama Power Co., 495 So.2d 48 (Ala.1986); Marquis v. Marquis, 480 So.2d 1213 (Ala.1985); Baptist Medical Center v. Byars, 289 Ala. 713, 271 So.2d 847 (1972); Mackintosh Co. v. Wells, supra. Moreover, it must be demonstrated that the plaintiff's appreciation of the danger was a conscious appreciation at the moment the incident occurred. Marquis v. Marquis, supra; Elba Wood Products, Inc. v. Brackin [356 So.2d 119 (Ala.1978)]. Mere `heedlessness' is insufficient to warrant a finding of contributory negligence as a matter of law. Decatur Light, Power & Fuel Co. v. Newsom, 179 Ala. 127, 59 So. 615 (1912)." Central Alabama Electric Co-op. v. Tapley, 546 So.2d 371, 381 (Ala.1989), quoted in Smith v. U.S. Construction Co., 602 So.2d 349, 350-51 (Ala.1992); Empiregas, Inc. of Belle Mina v. Suggs, 567 So.2d 271, 273 (Ala.1990). Viewing the evidence in favor of the nonmovant and resolving all doubts in her favor, we hold that the circumstantial evidence presents a genuine issue of material *220 fact as to whether at the time John Hicks placed himself in danger, he had a conscious appreciation of the danger posed by the possibility that the pipe stopper would dislodge and hit him. Although employees of Taylor-Wharton testified in deposition that employees at the Taylor-Wharton manufacturing facility were commonly aware of the danger of blow-outs, no such blow-out had occurred in more than a decade. Undisputed testimony showed that John Hicks conducted on average of two tests each working day. The circumstantial evidence does not conclusively show that John Hicks specifically appreciated the risk of harm or death at the time of the accident. Evidence of mere heedlessness is alone insufficient to warrant a finding of contributory negligence as a matter of law. Last, Vernda Hicks argues that a genuine issue of fact exists as to whether John Hicks assumed the risk of harm or death as a matter of law. We acknowledge that in defining the affirmative defense of assumption of the risk under the AEMLD, the cases have not been altogether consistent and that in some cases the Court has intimated that assumption of the risk is a form of contributory negligence. However, for purposes of this appeal, we resort to the definition of assumption of the risk stated in Atkins v. American Motors Corp., 335 So.2d 134 (Ala.1976): "`If the user or consumer discovers the defect and is aware of the danger, and nevertheless proceeds unreasonably to make use of the product and is injured by it, he is barred from recovery.'" 335 So.2d at 143 (quoting Restatement (Second) of Torts § 402A, comment n (1965). In an AEMLD action, whether the injured person assumed the risk of injury or death is ordinarily a question of fact for the jury. Atkins, 335 So.2d at 143. Thaxton contends that, considering John Hicks's knowledge of and his long experience with the hydrostatic testing, the Court must concluded that, as a matter of law, John Hicks assumed the risk of injury by standing in front of the pipe stopper during the test. We hold, however, that the circumstantial evidence presented by Vernda Hicks and Thaxton creates a genuine issue of material fact as to whether, at the time of the accident, John Hicks was specifically aware of the danger posed by the pipe stopper and whether he voluntarily and intelligently assumed the risk of death by standing in front of the pipe stopper during the test. We conclude, therefore, that genuine issues of material fact exist as to the affirmative defenses of product misuse, contributory negligence, and assumption of the risk, asserted by Thaxton and Hy-Tech. II. The Claim Against Commercial Union and Flood With regard to the claim of negligence against Commercial Union and Flood, the issue is whether in its contract with Taylor-Wharton, Commercial Union and its agent Flood assumed a duty to inspect the pipe stopper to determine whether it was properly secured to the vessel and that its jaws were not mismatched. Vernda Hicks argues that under the terms of the inspection agreement between Taylor-Wharton and Commercial Union and provisions of the ASME Code incorporated therein, Flood, as the agent of Commercial Union, had a duty to inspect the pipe stopper before the commencement of the hydrostatic test. In addition to the terms of the inspection services contract and the ASME Code, Vernda Hicks also relies on the deposition testimony of Wayne McCain, an expert who testified that under the ASME Code Flood had a duty to inspect the pipe stopper. Commercial Union argues generally that under the terms of the contract itself and in accordance with the testimony of its own experts, Flood had no duty as its agent to inspect the pipe stopper. Commercial Union insists that, although Vernda Hicks wants to characterize Flood as a safety inspector, under the terms of the contract and the ASME Code the duty of Commercial Union and Flood to inspect extended only to determining whether a vessel met ASME standards of quality. Vernda Hicks relies implicitly on the following general, common law principle: "`Alabama clearly recognizes the doctrine that one who volunteers to act, though under no duty to do so, is thereafter *221 charged with the duty of acting with due care and is liable for negligence in connection therewith.'" Columbia Engineering Int'l, Ltd. v. Espey, 429 So.2d 955, 966 (Ala.1983) (quoting Dailey v. City of Birmingham, 378 So.2d 728, 729 (Ala.1979)). Because there was before the Court no evidence that during testing at the Taylor-Wharton facility Commercial Union or its agents ever actually inspected vessels, pipe stoppers, or any other testing equipment for safety, Vernda Hicks must show that Commercial undertook to do so under the provisions of its contract with Taylor-Wharton. Under the contract between Taylor-Wharton and Commercial Union, Commercial Union agreed to "provide manufacturer, at the fabricating facility listed above or at the vendor's premises or field erection sites, inspection services meeting the requirements of the Boiler and Pressure Vessel Code of the American Society of Mechanical Engineers, hereinafter referred to as the `Code,' and the requirements of the National Board of Boiler and Pressure Vessel Inspectors for Shop Inspection, Testing and Certification." Section UG-99 of the ASME Code deals with the conduct of a "standard hydrostatic test." Vernda Hicks bases her argument in part on paragraph (j) of § UG-99: "(j) Before applying pressure, the test equipment shall be examined to see that it is tight and that all low pressure filling lines and other appurtenances that should not be subjected to the test pressure have been disconnected." (Emphasis added.) Vernda Hicks submitted the expert testimony of Wayne McCain, who concluded that Flood was negligent in allowing the hydrostatic test to proceed with a defective pipe stopper. McCain testified also that a pipe stopper attached to a vessel during a hydrostatic test is at the time of the test a part of the vessel and that, therefore, the pipe stopper that killed John Hicks should have been inspected by Flood before the test. Commercial Union contends that Taylor-Wharton, not Flood, was responsible for examining the vessel. Commercial Union and Flood submitted expert testimony indicating that Flood was not a "safety inspector" for Taylor-Wharton and indicating that his sole responsibility was to inspect Taylor-Wharton boilers and vessels for compliance with ASME standards of quality. Commercial Union and Flood also submitted testimony that Taylor-Wharton, not Flood, was responsible for employee safety during the hydrostatic tests. Because Commercial Union contractually undertook to provide inspection services to Taylor-Wharton in accordance with the ASME Code, the provisions of the ASME Code determine whether Commercial Union had a duty to inspect the pipe stopper. The ASME Code variously states the respective duties of both the manufacturer and the inspecting authority. Paragraph (j) of § UG-99, however, does not stipulate whether the manufacturer or the inspector has the duty to examine the test equipment and determine that it is "tight" before pressurizing the vessel for the test. Because the ASME Code does not clearly specify whether the manufacturer or the inspector must perform the examination provided by paragraph (j) and because it is not clear whether the duty to examine the vessel to determine that it is "tight" encompasses a duty to inspect pipe stoppers, we hold that the conflicting expert testimony on this issue submitted by Commercial Union and Vernda Hicks creates a genuine issue of material fact as to whether Commercial Union and Flood owed the alleged duty of reasonable care. Therefore, the summary judgment was improper as to Commercial Union and Flood. As to the affirmative defense of contributory negligence asserted by Commercial Union and Flood, we conclude, as we have concluded with regard to Thaxton's assertion of this defense, that the circumstantial evidence is insufficient to warrant a finding that John Hicks was contributorily negligent as a matter of law. Based on the foregoing, we reverse the summary judgment in favor of Thaxton, Inc., *222 Hy-Tech Machine, Inc., Commercial Union, and Flood. REVERSED AND REMANDED. MADDOX, ALMON, SHORES, HOUSTON, STEAGALL and KENNEDY, JJ., concur. INGRAM, J., concurs in the result. HORNSBY, C.J., and COOK, J., concur in part and dissent in part. INGRAM, Justice (concurring in the result). I concur in the result reached by the majority in this case. It is clear that there are several genuine issues of material fact concerning Mr. Hicks's death that must be resolved by the jury. However, I disagree with the principles outlined in the majority's discussion of the affirmative defenses available to Thaxton relating to Mr. Hicks's interaction with the plug. Contrary to the majority's opinion, I believe that Thaxton should not be allowed to assert contributory negligence as a defense to Mrs. Hicks' AEMLD claim. Further, I believe that the majority, in its discussion of the product misuse defense, should have noted the important issue of the manufacturer's intention. Finally, the majority, while quoting the definition of the assumption of the risk defense given in Atkins v. American Motors Corp., 335 So.2d 134 (Ala.1976), does not address the reasonableness of Mr. Hicks's actions in encountering the dangerous plug; it is my opinion that the plaintiff's reasonableness is an essential element of the assumption of risk defense under the AEMLD. Contributory negligence as an AEMLD affirmative defense In Casrell v. Altec Industries, Inc., 335 So.2d 128 (Ala.1976) and Atkins, supra, the Court produced the Alabama Extended Manufacturer's Liability Doctrine (AEMLD). In those cases, the Court attempted to develop a products liability doctrine that would "level the playing field" for consumers attempting to recover for injuries resulting from defective products. For far too long in Alabama, delinquent manufacturers of defective products were shielded by the problems that warranty and negligence law posed for injured consumers seeking recompense. The complexities of discovery and proof in products liability cases, particularly in negligence cases, made proving the manufacturer's liability almost insurmountably difficult. These difficulties grew with the advent of mass media advertising and subtle merchandising, wherein manufacturers convey a sense of safety and quality to consumers who rely upon those manufacturers to produce safe, nondefective products. In retrospect, it is clear that the Atkins court did not go far enough in its efforts to protect the consumers of Alabama from unreasonable risks occurring from inferior products. The Atkins Court, although basing the AEMLD upon Restatement (Second) of Torts § 402A (1965), retained the concept of fault-based recovery through its theory of "negligence as a matter of law"; that is, the sale of a defective product is itself indicative of negligence on the manufacturer's part. That theory alone would not have tainted Alabama's products liability law.[2] However, this Court's subsequent interpretations of Atkins have left open a corridor for manufacturers to maintain the contributory negligence defense as a total bar against recovery. See General Motors Corp. v. Saint, 646 So.2d 564 (Ala.1994) (Ingram, J., dissenting); Campbell v. Cutler Hammer, Inc., 646 So.2d 573 (Ala.1994) (Ingram, J., dissenting). The Saint and Cutler Hammer cases threaten the *223 progressive step taken by the Court in Dennis v. American Honda Motor Co., 585 So.2d 1336 (Ala.1991), whereby contributory negligence relating to accident causation was held as an invalid AEMLD defense. This is so, even though the Atkins Court noted that AEMLD permitted the contributory negligence defense only "in proper cases (e.g., plaintiff's misuse of the product)." Atkins, 335 So.2d at 143 (emphasis added). As I stated in my dissent in Saint, I believe that the doctrine of contributory negligence should be abandoned as a viable defense in products liability cases. While I believe that contributory negligence is a severely outmoded concept when applied in ordinary negligence cases, see Simmons v. Central Concrete Products Co., 619 So.2d 1335 (Ala.1993) (Ingram, J., dissenting), it is even more clear that there should be no place for contributory negligence where a consumer is injured by a defective product. I believe that the purpose of the AEMLD is to protect the consumer from risks that have been created by a defective product. Therefore, I disagree with the majority's holding that allows Thaxton to assert the defense of contributory negligence in this case. Product misuse as an AEMLD affirmative defense I also disagree with the majority's interpretation of the product misuse defense. We have held that a misuse of a product occurs when a plaintiff utilizes the product "in some manner different from that intended by the manufacturer"; the misuse "must not have been `reasonably foreseeable by the seller or manufacturer.'" Kelly v. M. Trigg Enterprises, Inc., 605 So.2d 1185 (Ala.1992). For other definitions of product misuse corresponding to this Court's holding in M. Trigg Enterprises, see the Restatement (Second) of Torts § 402A Cmt. h ("A product is not [defective] when it is safe for normal handling and consumption. If [injury] results from abnormal handling.... abnormal preparation.... [or] abnormal consumption, the seller is not liable"); W. Prosser and W. Keeton, The Law of Torts § 102 (5th ed. 1984) (misuse is a utilization different from what was intended, and it is unforeseeable misuse in that the utilization could not have been reasonably anticipated by the manufacturer); L. Frumer and M. Friedman, Products Liability § 15.01 (1984) (misuse is the abnormal or unintended use of the product if that use was not reasonably foreseeable). Product misuse, by definition, concerns an action taken by a person in utilizing the product in question which was both unintended and unforeseeable by the manufacturer. A court should look to both of these issues in determining whether the plaintiff's utilization of the product falls under the product misuse defense. A manufacturer may not intend for a product to be utilized in a certain manner; however, if that utilization was foreseeable, the product misuse defense does not bar recovery. Of course, if the product was intended for a certain purpose or purposes and is utilized for the intended purpose or purposes, that utilization is foreseeable, and does not bar recovery. Only if the utilization of the product was both unintended by the manufacturer and was not reasonably foreseeable by that manufacturer, will the product misuse defense bar the plaintiff's recovery in an AEMLD action. This two-pronged definition of the product misuse defense corresponds with the Court's holding in both M. Trigg Enterprises and Atkins, wherein the Court held that the gravamen of an AEMLD action is that the plaintiff was injured by a defective product while putting the product "to its intended use." Atkins, 335 So.2d at 139. In my opinion, the questions as to Mr. Hicks's alleged misuse of the Thaxton plug must encompass both the manufacturer's intention for the use of the product and the manufacturer's ability to foresee that use. The majority, however, correctly defines product misuse but limits its application of that defense to that use that was not "reasonably foreseeable" by the manufacturer. 652 So.2d at 219. I believe, following M. Trigg Enterprises, that the manufacturer's intention must first be determined. If it can be shown that Thaxton intended for the plug to used in the manner in which it was used in this case, then the question of foreseeability would need not arise; there would be no product misuse defense available. Clearly, *224 as stated above, if a manufacturer intends for its product be used in a certain manner, then it would also be foreseeable to that manufacturer that such use would occur. Assumption of the risk as an AEMLD affirmative defense Finally, I disagree with the majority's view of assumption of the risk under the AEMLD. This Court has held that, to establish assumption of the risk as an affirmative defense in an AEMLD action, the defendant must show that the plaintiff had knowledge of the danger at hand, and made a voluntary and deliberate choice to assume that known danger. Dennis, supra. The majority, although citing Atkins in its discussion of the assumption of the risk defense, appears to follow the assumption of the risk definition of Dennis. Under the assumption of the risk defense as defined in Dennis, there is no distinction between assumption of the risk in products liability cases and assumption of the risk in ordinary negligence cases. However, as the majority notes, the Atkins Court adopted the following language from Restatement (Second) of Torts § 402A in defining assumption of the risk under the AEMLD: "If the user or consumer discovers the defect and is aware of the danger, and nevertheless proceeds unreasonably to make use of the product and is injured by it, he is barred from recovery." Atkins, 335 So.2d at 143 (emphasis added). The language of Atkins defining the assumption of the risk defense under the AEMLD differs from the Dennis definition of the assumption of the risk defense. A plain reading of the Atkins Court's definition indicates that an element of reasonableness should exist in the AEMLD defense of assumption of the risk. Therefore, following the language in Atkins, I believe that, for Thaxton to establish assumption of the risk in this AEMLD case, it should be required to show the following: first, that Mr. Hicks actually had knowledge of and appreciated the particular risk or danger; second, that Mr. Hicks voluntarily encountered the risk while realizing the danger; and third, that Mr. Hicks's decision to voluntarily encounter the known risk was unreasonable. An AEMLD defendant, when faced by a prima facie showing that it sent a defective product into the stream of commerce and was thus negligent as a matter of law should not be allowed to escape liability because the plaintiff exposed himself to a danger negligently created by the defendant, if that choice was reasonable under the circumstances. Under the AEMLD assumption of the risk defense, I believe that several factors should enter the inquiry as to whether the decision to voluntarily encounter the danger was reasonable. These factors include the conditions under which the plaintiff made the decision and the amount of time that he had to make the decision. The circumstances surrounding the plaintiff's interaction with the product must be taken into account. For example, as in the instant case, a worker whose job requires exposure to danger and who, while working, is injured by a dangerous, defective tool of his trade can rarely be said to have assumed the risk of danger as a matter of law. I believe that the "voluntariness" with which a worker who is assigned to a dangerous machine encounters that danger is often illusory. The majority does not apply the reasonableness element stated in Atkins to the facts of this case. In my opinion, the jury should not only make an inquiry into whether Mr. Hicks's encounter of the danger created by the Thaxton plug was knowledgeable and voluntary. Instead, the jury should be able to consider whether Mr. Hicks's actions were reasonable under the circumstances of his inherently dangerous work. Too often, the worker's "choices" in encountering danger on the job are made for him by the circumstances of his work. The Court should follow its own language of Atkins to direct the jury to consider the reasonableness of the plaintiff's action under the surrounding circumstances. As I stated above, I agree with the majority that the jury, not the trial judge, should determine whether Thaxton should be held liable for Mr. Hicks's death. However, as it stands today, products liability law in Alabama simply does not meet the needs of the *225 consumers of Alabama, who deserve a better opportunity to receive compensation for their injuries that stem from defective products. HORNSBY, Chief Justice (concurring in part and dissenting in part): I concur with the Court's opinion in all respects except its application of the doctrine of contributory negligence to the AEMLD claim. See my dissent in General Motors Corp. v. Saint, 646 So.2d 564 (Ala.1994). COOK J., concurs. NOTES [1] These defendants were Michael W. Onderdonk, Lloyd Lee Hull, and Asa Joseph Schram. The circuit court later entered a summary judgment in their favor. Vernda Hicks does not appeal from that judgment. [2] There would be little difference between § 402A strict liability and the Atkins Court's theory of negligence as a matter of law, if contributory negligence was struck from the list of AEMLD available defenses. "In essence, strict liability ... is not different from negligence per se. Selling a dangerously unsafe product is the equivalent of negligence regardless of the defendant's conduct in letting it become unsafe.... Thus, a court which appears to be taking the radical step of changing from negligence to strict liability for products is really doing nothing more than adopting a rule that selling a dangerously unsafe chattel is negligence within itself." J. Wade, Strict Tort Liability of Manufacturers, 19 Sw.L.J. 5, 14 (1965).

Oscillatory potentials and light microscopic changes demonstrate an interaction between zinc and taurine in the developing rat retina. Our objective was to investigate whether zinc interacts with taurine to influence the development of retinal structure and function. Virgin female Sprague-Dawley rats were bred overnight and assigned to one of four treatments in a 2 x 2 factorial design with two levels of zinc (50 micrograms/g through gestation and 50 micrograms/g after parturition; 15 micrograms/g through gestation and 7.5 micrograms/g after parturition) and two levels of taurine (2 or 0 mumol/g). The control diet contained 50 micrograms/g zinc and 2 mumol/g taurine. Guanidinoethyl sulfonate (10 g/L), a taurine transport inhibitor, was added to the drinking water of the rats receiving 0 mumol/g taurine. At postnatal d 23, male pups (n = 10) were weaned onto their respective diets. Pup eyes were examined by biomicroscope and indirect ophthalmoscope at 4 and 7 wk; retinal folds and choroidal atrophy were detected in the pups deficient in zinc and taurine. Analysis of plasma zinc and tibial zinc concentrations revealed a significant interaction in these tissues (P < 0.05). Dark-adapted oscillatory potentials (OP) were recorded at 7.5-8.5 wk. Two-way ANOVA showed a significant interaction between zinc and taurine for OP2 and OP3 amplitudes; marginal zinc deficiency decreased the amplitude of the OP only when rats were also deficient in taurine. A significant depressing effect of marginal zinc deficiency was noted for OP1 amplitude. Taurine deficiency significantly depressed the amplitude of OP1 and OP4. Histological examination of the retinas from rats deficient in both zinc and taurine revealed photoreceptor degeneration and confirmed retinal dysplasia. These data provide evidence for an interaction between zinc and taurine in retinal morphology and function.

package mstypes import ( "encoding/binary" "gopkg.in/jcmturner/rpc.v0/ndr" ) // GroupMembership implements https://msdn.microsoft.com/en-us/library/cc237945.aspx // RelativeID : A 32-bit unsigned integer that contains the RID of a particular group. // The possible values for the Attributes flags are identical to those specified in KERB_SID_AND_ATTRIBUTES type GroupMembership struct { RelativeID uint32 Attributes uint32 } // ReadGroupMembership reads a GroupMembership from the bytes slice. func ReadGroupMembership(b *[]byte, p *int, e *binary.ByteOrder) GroupMembership { r := ndr.ReadUint32(b, p, e) a := ndr.ReadUint32(b, p, e) return GroupMembership{ RelativeID: r, Attributes: a, } } // DomainGroupMembership implements https://msdn.microsoft.com/en-us/library/hh536344.aspx // DomainId: A SID structure that contains the SID for the domain.This member is used in conjunction with the GroupIds members to create group SIDs for the device. // GroupCount: A 32-bit unsigned integer that contains the number of groups within the domain to which the account belongs. // GroupIds: A pointer to a list of GROUP_MEMBERSHIP structures that contain the groups to which the account belongs in the domain. The number of groups in this list MUST be equal to GroupCount. type DomainGroupMembership struct { DomainID RPCSID GroupCount uint32 GroupIDs []GroupMembership // Size is value of GroupCount } // ReadDomainGroupMembership reads a DomainGroupMembership from the bytes slice. func ReadDomainGroupMembership(b *[]byte, p *int, e *binary.ByteOrder) (DomainGroupMembership, error) { d, err := ReadRPCSID(b, p, e) if err != nil { return DomainGroupMembership{}, err } c := ndr.ReadUint32(b, p, e) g := make([]GroupMembership, c, c) for i := range g { g[i] = ReadGroupMembership(b, p, e) } return DomainGroupMembership{ DomainID: d, GroupCount: c, GroupIDs: g, }, nil }

This article corresponds to Petrosky, A. L. 2018. Digest: Extra‐pair mating and inbreeding avoidance in a socially monogamous fairy‐wren. Evolution. <https://doi.org/10.1111/evo.13526>. It is often expected that inbreeding depression should generate selection to avoid inbreeding (Pusey [1987](#evo13496-bib-0057){ref-type="ref"}; Blouin and Blouin [1988](#evo13496-bib-0009){ref-type="ref"}; Tregenza and Wedell [2000](#evo13496-bib-0070){ref-type="ref"}; Szulkin et al. [2013](#evo13496-bib-0067){ref-type="ref"}). In particular, inbreeding avoidance has frequently been suggested as an explanation for female infidelity in socially monogamous species. If individuals are likely to be socially paired with a relative, extra‐pair paternity (EPP) may have adaptive advantages if it reduces rates of inbreeding (Blomqvist et al. [2002](#evo13496-bib-0008){ref-type="ref"}; Foerster et al. [2003](#evo13496-bib-0028){ref-type="ref"}). The expectation that inbreeding depression is ubiquitous in diploids (Lynch and Walsh [1998](#evo13496-bib-0049){ref-type="ref"}) and the difficulties inherent in explaining the occurrence of EPP (Griffith et al. [2002](#evo13496-bib-0032){ref-type="ref"}; Westneat and Stewart [2003](#evo13496-bib-0074){ref-type="ref"}; Arnqvist and Kirkpatrick [2005](#evo13496-bib-0003){ref-type="ref"}; Forstmeier et al. [2014](#evo13496-bib-0030){ref-type="ref"}) have jointly strengthened the appeal of this "inbreeding‐avoidance hypothesis" for the occurrence of extra‐pair reproduction. However, quantifying the relevant parameters in empirical studies is challenging, and so our understanding of several key aspects of the interplay between inbreeding and infidelity in natural populations is still limited. Here, we use data from a long‐term study to investigate the effects of exceptionally high rates of extra‐pair paternity on inbreeding and inbreeding depression in a passerine bird. Three assumptions are necessary to support the notion that extra‐pair mating occurs to facilitate inbreeding avoidance: (1) that inbreeding depression is present; (2) that infidelity increases with kinship to social mate; and (3) that infidelity reduces the chances of inbreeding. We emphasize that while these assumptions are necessary for there to be adaptive benefits of inbreeding avoidance *via* EPP (i.e., these will not occur without the assumptions being met), they may not be sufficient (i.e., the assumptions being met does not inevitably guarantee the outcome). In particular, with regard to (1), the existence of inbreeding depression may not inevitably select for inbreeding avoidance because of the potential inclusive fitness benefits of inbreeding (through increased reproductive success of relatives; e.g., Bengtsson [1978](#evo13496-bib-0006){ref-type="ref"}; Parker [1979](#evo13496-bib-0054){ref-type="ref"}; Kokko and Ots [2006](#evo13496-bib-0042){ref-type="ref"}; Duthie and Reid [2015](#evo13496-bib-0026){ref-type="ref"}, [2016](#evo13496-bib-0027){ref-type="ref"}). Increased, rather than decreased, rates of inbreeding *via* extra‐pair paternity may even be adaptive if inbreeding depression is sufficiently mild (Lehtonen and Kokko [2015](#evo13496-bib-0048){ref-type="ref"}). Further, the overall benefits of inbreeding avoidance will also depend on the potential costs of any avoidance mechanisms (Koenig et al. [1999](#evo13496-bib-0041){ref-type="ref"}; Lehmann and Perrin [2003](#evo13496-bib-0047){ref-type="ref"}). The selection pressures on the alternative mating strategies of inbreeding avoidance, inbreeding preference or random mating will therefore depend on the relative magnitudes of inbreeding depression, the benefits to inclusive fitness of inbreeding, and the costs of inbreeding avoidance (Szulkin et al. [2013](#evo13496-bib-0067){ref-type="ref"}; Duthie and Reid [2016](#evo13496-bib-0027){ref-type="ref"}; Duthie et al. [2016a](#evo13496-bib-0024){ref-type="ref"}). However, in setting out a necessary (if not sufficient) set of conditions, assumptions (1)---(3) provide a useful framework for evaluating the plausibility of inbreeding avoidance *via* extra‐pair paternity. Studies of wild populations will be especially valuable for evaluation of mating patterns and inbreeding, because laboratory studies may not be able to recreate natural patterns of mate choice, and also because inbreeding depression may change with environmental conditions (Crnokrak and Roff [1999](#evo13496-bib-0019){ref-type="ref"}; Joron and Brakefield [2003](#evo13496-bib-0037){ref-type="ref"}; Szulkin and Sheldon [2007](#evo13496-bib-0066){ref-type="ref"}). Studies to date have provided evidence from wild populations for each of the three assumptions outlined above. For example, Keller and Waller ([2002](#evo13496-bib-0038){ref-type="ref"}) review evidence for inbreeding depression in the wild (assumption 1); Leclaire et al. ([2013](#evo13496-bib-0046){ref-type="ref"}) and Arct et al. ([2015](#evo13496-bib-0001){ref-type="ref"}) review evidence across species for relatedness to the social mate increasing EPP (assumption 2); and Foerster et al. ([2003](#evo13496-bib-0028){ref-type="ref"}) and Reid et al. ([2015b](#evo13496-bib-0060){ref-type="ref"}) document reduced inbreeding coefficients as a result of infidelity in two passerine bird species. However, comprehensive tests of all three assumptions within a single study system are scarce. One notable exception is the work on a Canadian population of song sparrows (*Melospiza melodia*), where evidence combined across several papers covers all three assumptions (assumption 1: e.g., Taylor et al. [2010](#evo13496-bib-0069){ref-type="ref"}; assumptions 2 and 3: Reid et al. [2015a](#evo13496-bib-0059){ref-type="ref"},[b](#evo13496-bib-0060){ref-type="ref"},[c](#evo13496-bib-0061){ref-type="ref"}). However, the song sparrow study involves a small, isolated island population where high levels of relatedness between individuals are expected and observed. Equivalent studies of systems with other characteristics will therefore be required for any indication of the generality of these patterns. The scarcity of comprehensive empirical studies of the role of extra‐pair (EP) reproduction in facilitating inbreeding avoidance may be partially due to the inherent difficulty of quantifying inbreeding and inbreeding depression in the wild. Analyses of inbreeding require estimates of relatedness between individuals, but in socially monogamous systems, social pedigrees based on the observed parental behavior cannot provide accurate estimates of relatedness when infidelity is present, meaning that genetic information of some form is ideally required. Several studies of associations between extra‐pair mating and relatedness (assumption 2) have used genetic rather than social data, but these are typically based on assessing inbreeding from heterozygosity at a handful of molecular markers, typically microsatellites (e.g., Smith et al. [2005](#evo13496-bib-0063){ref-type="ref"}; Foerster et al. [2006](#evo13496-bib-0029){ref-type="ref"}). This is potentially problematic as heterozygosity at a small number of markers may be only weakly correlated with genome‐wide heterozygosity: just as it is now clear that inbreeding depression cannot reliably be estimated from correlations between heterozygosity of a few markers and trait values (Balloux et al. [2004](#evo13496-bib-0004){ref-type="ref"}; Slate et al. [2004](#evo13496-bib-0062){ref-type="ref"}; Szulkin et al. [2010](#evo13496-bib-0064){ref-type="ref"}), studies that use a low number of markers to test for inbreeding avoidance through EP matings may not be able to estimate relevant levels of relatedness sufficiently accurately. Furthermore, estimates of inbreeding and relatedness may be marker dependent (Wang [2014](#evo13496-bib-0072){ref-type="ref"}), and using the same markers to evaluate both paternity and heterozygosity may lead to false positives when assessing the role of heterozygosity in mate choice (Wetzel and Westneat [2009](#evo13496-bib-0075){ref-type="ref"}). These issues mean that genetically informed pedigrees and/or high‐density genomic data are required for accurate estimates of relatedness, inbreeding, and inbreeding depression (Pemberton [2004](#evo13496-bib-0055){ref-type="ref"}; Harrison et al. [2013](#evo13496-bib-0034){ref-type="ref"}), and hence, for accurate tests of the hypothesis of inbreeding avoidance through EP reproduction in the wild. The dynamics of inbreeding, inbreeding depression, and infidelity may also be shaped by the social environment of individuals, in particular the number and characteristics of conspecifics with which they interact (Koenig and Haydock [2004](#evo13496-bib-0040){ref-type="ref"}). In cooperatively breeding species that live in groups of closely related individuals, group composition may affect mating patterns and change any effects of inbreeding depression on offspring development. The social environment may affect the chances that an individual inbreeds: the likelihood that relatives will be socially paired may be higher in cooperative breeders where close adult kin are tolerated in the social group, than in other social systems. The hypothesis of inbreeding avoidance through EP matings assumes that extra‐pair partners will be less‐closely related than social partners. However, this may not be so if the closest available alternative mate is equally related----a scenario that can readily occur in cooperatively breeding groups. Thus, immediate social environment may play an important role in shaping inbreeding and infidelity patterns. There is also a general expectation that inbreeding depression may vary with environmental conditions (e.g., Miller [1994](#evo13496-bib-0050){ref-type="ref"}; Armbruster and Reed [2005](#evo13496-bib-0002){ref-type="ref"}; Fox and Reed [2010](#evo13496-bib-0031){ref-type="ref"}), although detecting inbreeding‐environment interactions has been difficult in wild populations (Pemberton et al. [2017](#evo13496-bib-0056){ref-type="ref"}). We might thus also expect inbreeding depression to vary with social environment. Recent theoretical work suggests parents should invest more care into inbred offspring to counteract the reduced viability of such offspring (Duthie et al. [2016b](#evo13496-bib-0025){ref-type="ref"})----by extension, if assisted parents in cooperatively breeding species can rely on helpers to provide additional care for offspring, potentially lessening the effects of inbreeding depression, selection against inbreeding could be reduced. Whether this occurs in natural populations is not yet clear: for example, a recent study of inbreeding in meerkats (Nielsen et al. [2012](#evo13496-bib-0053){ref-type="ref"}) found positive effects of helpers but negative effects of inbreeding depression on offspring growth, but did not find evidence that helpers mitigated the negative effects of inbreeding depression. However, such associations may play an important role in the impact of social environment on inbreeding‐infidelity dynamics. In this article, we investigate the intraspecific relationship between inbreeding and infidelity, and its interaction with the social environment. Our study species, the superb fairy‐wren (*Malurus cyaneus)*, is socially monogamous but has exceptionally high levels of female infidelity, effectively making it the least faithful species of the least faithful bird genus (Cockburn et al. [2016](#evo13496-bib-0014){ref-type="ref"}). We used data from a long‐term study of a wild population in south‐east Australia, including a genetically based pedigree to estimate levels of inbreeding and inbreeding depression. Superb fairy‐wrens are characterized by substantial variation in levels of cooperative breeding. About half (54.5%) of breeding attempts in the population involve just a single pair of breeding adults, whereas the other half are helped by up to four (exceptionally rarely five) male subordinates (or "helpers"), frequently sons from previous breeding attempts (61.8% of all helpers are sons of the breeding female). This cooperative breeding increases the chances of social pairing between relatives: helper males form a stable queue, and may inherit the dominant position and thus pair socially with their mother (Cockburn et al. [2008b](#evo13496-bib-0016){ref-type="ref"}). Individual females will therefore experience different social environments, dependent on whether they are breeding just as a pair or are accompanied by helpers, and whether they are socially paired to their son or not. The current study is motivated by the observation that mothers never produce offspring with their sons, either when socially paired to their sons as the dominant pair on a territory or when the sons are acting as helpers to their mother (Cockburn et al. [2003](#evo13496-bib-0017){ref-type="ref"}). This suggests fairy‐wrens use extra‐pair reproduction to avoid close inbreeding. Furthermore, mother--son pairs show no behavioral interest in each other as potential mates (A. Cockburn, pers. obs.). However, whether the three assumptions underlying the inbreeding‐avoidance hypothesis outlined above all hold, and whether inbreeding avoidance extends to other levels of relatedness, is not known. Recently, Brouwer et al. ([2017](#evo13496-bib-0012){ref-type="ref"}) explored multiple possible explanations for extra‐pair reproduction across the fairy‐wren (Maluridae) family. In support of inbreeding‐avoidance, studies of four other fairy‐wren species reported higher infidelity when social partners are more closely related (splendid fairy‐wrens, Brooker et al. [1990](#evo13496-bib-0010){ref-type="ref"}; Tarvin et al. [2005](#evo13496-bib-0068){ref-type="ref"}; red‐winged, Brouwer et al. [2011](#evo13496-bib-0011){ref-type="ref"}; red‐backed, Varian‐Ramos and Webster [2012](#evo13496-bib-0071){ref-type="ref"}; purple‐crowned, Kingma et al. [2013](#evo13496-bib-0039){ref-type="ref"}). However, these conclusions are all based on estimates of relatedness from microsatellite markers, rather than pedigree‐based knowledge of identity of close relatives. Furthermore, despite invoking the inbreeding‐avoidance hypothesis, these analyses do not assess inbreeding depression for offspring traits (with the exception of Kingma et al. ([2013](#evo13496-bib-0039){ref-type="ref"}) finding evidence of hatching failure) or the implications of infidelity for inbreeding levels in the offspring. Our aims in this study were fivefold. Firstly, we used 26 years of multigenerational genetic pedigree data to quantify the frequency of inbreeding in superb fairy‐wrens, and to identify particular routes by which it might occur. We then tested the three assumptions of the hypothesis that extra‐pair reproduction facilitates inbreeding avoidance by: (1) assessing inbreeding depression in two offspring traits, nestling mass, and fledgling survival; (2) testing whether females who were socially paired to a relative were more likely to be unfaithful, extending the previous documentation of 100% infidelity in mother‐son pairings (Cockburn et al. [2003](#evo13496-bib-0017){ref-type="ref"}) to consider all possible levels of kinship between social partners. Then, (3) we quantified the overall effects of infidelity on the probability of offspring being inbred, testing whether extra‐pair offspring were less likely to be inbred than within‐pair offspring, and comparing observed levels of inbreeding with those that would have occurred had females always been entirely faithful. Finally, we assessed the impact of the social environment on each of these four aspects, by considering whether effects were mediated by the number of helpers in all analyses. Materials and Methods {#evo13496-sec-0020} ===================== STUDY SYSTEM {#evo13496-sec-0030} ------------ The colour‐banded population of superb fairy‐wrens (*Malurus cyaneus*) in and around the Australian National Botanic Gardens, Canberra, Australia (35°16 S, 149°06 E) has been intensively monitored since 1988 (Cockburn et al. [2003](#evo13496-bib-0017){ref-type="ref"}). The study site measures ∼60 ha, contains 60--90 territories/year, and is surrounded by unmonitored superb fairy‐wren territories; the study population is thus a sample of a much larger population with free movement across its boundaries. In this article, we use data from years 1988--2013. All study population birds were censused throughout the year (Cockburn et al. [2003](#evo13496-bib-0017){ref-type="ref"}), with data collected on group composition, social pairings, fates, and reproductive performance of individuals. Females can successfully raise up to three broods in a single season (between August and March each year), with each brood containing 3--4 young (Cockburn et al. [2008c](#evo13496-bib-0018){ref-type="ref"}). However, because predation rates are high, as many as eight clutches may be initiated in a season (Cockburn et al. [2008c](#evo13496-bib-0018){ref-type="ref"}). Nestlings were banded 5--8 days after hatching. A blood sample was taken at the same time, and microsatellite genotyping was used to assign parentage to all individuals (Double et al. [1997](#evo13496-bib-0022){ref-type="ref"}); for paternity assignment details see the Supplementary Information (SI). Since we tested the association between the number of helpers and EPP rates, it is worth noting that the large majority of extra‐pair paternity is extra‐group (i.e., involving a male on a different territory, in a different social group). Helpers gain little paternity within their social group, although many gain substantial reproductive success through extra‐group matings (Double and Cockburn [2003](#evo13496-bib-0021){ref-type="ref"}). In particular, helpers only gain within‐group paternity when their mother is no longer the breeding female, because she has either died or divorced her social partner to move to another territory, and so has then been replaced as breeder by an unrelated female (Cockburn et al. [2003](#evo13496-bib-0017){ref-type="ref"}). Furthermore, if the breeding female is socially paired with her son, all other helpers on the territory will most likely also be her sons (Cockburn et al. [2008b](#evo13496-bib-0016){ref-type="ref"}), leaving the female with no outbred mating opportunities on the territory. SECTION 1: PEDIGREE RECONSTRUCTION AND QUANTIFYING LEVELS OF INBREEDING {#evo13496-sec-0040} ----------------------------------------------------------------------- We used eight exceptionally polymorphic microsatellite loci and a stepwise process to assign paternities while taking into account the structure of our population; this allows identification of sires with near 100% certainty. Further details are provided in the SI. Using the parentage data, we constructed a multigenerational pedigree for individuals sampled between 1988 and 2013: this pedigree had maximum depth of 15 generations. We estimated inbreeding coefficients (*f*) from the pedigree for individuals for whom the identities of both genetic parents and at least one grandparent were known (*n* = 4431). Note that inbreeding between distant relatives could have been underestimated for individuals with less complete pedigree data. We therefore provide details of the effect of restricting to higher numbers of known grandparents on the sample sizes and inbreeding rates in the SI (Table [S1](#evo13496-supl-0001){ref-type="supplementary-material"}). For each social pair (i.e., for each territory, the breeding female, and the dominant male---always the oldest male on the territory), we calculated a kinship coefficient (*k~SOC~*), and for each female‐EP male pair that produced extra‐pair offspring (EPO), we also calculated a kinship coefficient (*k~EP~*). The kinship coefficient between two individuals is defined as the probability that homologous alleles sampled from two individuals are identical by descent (Wright [1922](#evo13496-bib-0076){ref-type="ref"}), and is equal to the inbreeding coefficient of offspring that would be produced by these individuals. Throughout, we distinguish between the "genetic father," meaning the male who sired a particular offspring, and the "social father," meaning the male who was dominant on the territory at the time that the offspring was hatched, and who may or may not have been the genetic father. The variables fitted in the statistical models described below varied depending on the model, thus sample sizes for individual models varied and are given alongside the model results. All analyses were carried out in *R* version 3.3.1 (Development Core Team [2011](#evo13496-bib-0020){ref-type="ref"}). See SI for general information on individual/parent numbers in our main dataset. SECTION 2: INBREEDING DEPRESSION {#evo13496-sec-0050} -------------------------------- We estimated inbreeding depression in nestling mass and in fledgling survival. ### Inbreeding depression in nestling mass {#evo13496-sec-0060} We fitted a linear‐mixed effects animal model using the R package *ASReml‐R* version 3 (Butler et al. [2009](#evo13496-bib-0013){ref-type="ref"}), with *nestling mass* (continuous) as the response variable, with Gaussian errors. An animal model (i.e., incorporating an additive genetic effect; Kruuk [2004](#evo13496-bib-0043){ref-type="ref"}) was fitted to avoid any potential bias of estimates of inbreeding depression by not accounting for heritable genetic effects (Becker et al. [2016](#evo13496-bib-0005){ref-type="ref"}), and to provide an estimate of the heritability of nestling mass. Significance of fixed effects was assessed using Wald statistics (with critical level of *P* \< 0.05). **Fixed effects**: The *inbreeding coefficient* of each individual was fitted to test for potential inbreeding depression. We also fitted: *number of helpers* (as a three‐level factor: 0, 1, and 2+; where 2+ level consisted mainly of two helpers with some pairs assisted by three or four helpers; Kruuk et al. [2015](#evo13496-bib-0044){ref-type="ref"}); *brood size* (the number of nestlings, 3--5), to account for the variation in the amount of care provided to the individual nestlings; and *sex of nestling* (male, female), to account for differences in size between males and females. *Nestling age* at measurement (continuous, in days; as a quadratic function) was fitted because pragmatic considerations meant that nestlings were weighed at different ages (days 5--8) and hence at different stages of their development. We fitted a two‐level factor (pre‐1992, 1992+) to account for the introduction of a new weighing protocol in 1992, which changed the time of day at which nestlings were weighed (Kruuk et al. [2015](#evo13496-bib-0044){ref-type="ref"}). **Random effects**: We fitted *nest ID* to account for any similarities across multiple offspring from the same brood; an *additive genetic effect* (with covariance structure determined by the pedigree) to test for covariance between relatives (Kruuk [2004](#evo13496-bib-0043){ref-type="ref"}); and a multilevel factor of *cohort* to represent interannual variation (1988--2013: the "2013" cohort incorporates nestlings from August 2013 through to March 2014 etc.). Finally, we represented intraannual temporal variation across the breeding season by fitting a multilevel factor of *hatch date interval* (split into 12 two‐week intervals, between 23 September and 15 March). The above model was run using the R package *ASReml‐R*, as the response required Gaussian errors. All following models were run using the R package *MCMCglmm* (Hadfield [2010](#evo13496-bib-0033){ref-type="ref"}) to allow for binomial errors. For all the *MCMCglmm* models the effective sample sizes for specific parameters varied due to autocorrelation, but we ensured that they were always above 1000. We considered terms to be statistically significant based on 95% CIs (credible intervals) not spanning 0 and *pMCMC* values (the number of simulations greater or smaller than 0 corrected for number of *MCMC* samples) calculated by *MCMCglmm* being \<0.05. Details of model settings, such as the number of iterations, burn‐in, thinning interval, and priors for each model can be found in the SI. ### Inbreeding depression in survival {#evo13496-sec-0070} We investigated survival from fledging to independence (from 12 to 41 days, see the SI for details on how these bounds were chosen). We ran two generalized linear‐mixed effects animal models using the *MCMCglmm* package. We first tested whether inbreeding affected survival, and then investigated whether any effect of inbreeding acted through body mass, by including mass as a covariate in the analysis. *Survival* was modeled as a binary (0/1) response variable, with binomial errors. **Fixed effects**: *Inbreeding coefficient, number of helpers, brood size*, and an *individual\'s sex* were fitted as described above (with *nestling mass* as an additional covariate in one of the models). **Random effects**: *Nest ID, additive genetic effect, cohort*, and *hatch date interval* were fitted as described above. We added in an interaction between the inbreeding coefficient and the number of helpers, to test whether helpers could mitigate the effects of inbreeding depression (see SI). SECTION 3: EFFECTS OF KINSHIP BETWEEN SOCIAL PARTNERS ON INFIDELITY {#evo13496-sec-0080} ------------------------------------------------------------------- We tested whether patterns of EPP were associated with either kinship between social partners (*k~SOC~*) and/or social environment, specifically the number of helpers at the nest. We used the proportion of EPO in each brood (as an index of infidelity) to investigate factors affecting a female\'s likelihood of producing extra‐pair young. It is possible that inbreeding depression in early embryo/nestling survival could bias later estimates of the extent of EPP in pairs where social partners are related. If all WPO die due to inbreeding depression, the clutch will appear to be composed entirely of EPO and rates of EPP will be overestimated (Reid [2015](#evo13496-bib-0058){ref-type="ref"}; Reid et al. [2015b](#evo13496-bib-0060){ref-type="ref"}). To assess whether such "selective disappearance" affected our estimates, we tested whether kinship between the social partners affected clutch size and/or survival of nestlings prior to measurement age. We found that *k~SOC~* was not associated with either clutch size or survival to measurement (Table [S2](#evo13496-supl-0001){ref-type="supplementary-material"}). (Note that this analysis also provided a test of inbreeding depression in early survival, but that this test was indirect; highly accurate assessment of early inbreeding depression is difficult. See SI for details.) When assessing EPP levels, cases of mother--son pairings required special consideration. As described above, both behavioral and genetic analyses indicate that mothers and their sons never mate, even when socially paired, suggesting strong inbreeding avoidance in these pairings. We therefore ran two versions of our models: (a) using all available data; and (b) excluding mother--son pairings. This allowed us to test whether the results were disproportionately affected by the special case of mother--son pairings, without restricting exploration of the effects of kinship and the social environment beyond the mother--son pairings. To test the effect of kinship between social partners on infidelity we fitted binomial generalized linear‐mixed models in *MCMCglmm*, with the proportion of EPO in a brood (defined by the numbers of extra‐ *vs*. within‐pair offspring) as a response variable, and binomial errors; these models were by definition fitted at the level of the brood rather than individual nestlings. **Fixed effects**: *Kinship* (continuous) was fitted to test whether the probability of offspring being sired by an extra‐pair male varied with the kinship between the female and her social mate (*k~SOC~*). The *number of helpers* (0, 1, and 2+) was fitted to test whether the social environment affected the probability of extra‐pair reproduction. Additionally, the *mother\'s age* and the *social father\'s age* (two‐level factors: one‐year‐old, older) were fitted to account for potential effects of differences in experience. **Random effects**: *Mother ID* and *social father ID* were fitted to account for the multiple observations on specific females and males (social fathers). *Cohort* was fitted as above. We then fitted both of the models of EPP rates with an interaction between the *k~SOC~* and the number of helpers, to test for the role of social environment (see SI). SECTION 4: EFFECTS OF INFIDELITY ON INBREEDING {#evo13496-sec-0090} ---------------------------------------------- This final section tested the consequences of EPP for the probability of offspring being inbred. Due to the high proportion of zeros (94.5%) among the estimated inbreeding coefficients, the inbreeding coefficient did not fit any standard distribution for a continuous covariate. We therefore used a two‐step process: first we fitted a model with a binomial response of whether an individual offspring was inbred (*f* \> 0) or not (*f* = 0), and then we fitted a model with a continuous response, but only considering inbred individuals (*f* \> 0) (see Huisman et al. [2016](#evo13496-bib-0035){ref-type="ref"} for a similar two‐stage analysis). The models were fitted excluding mother--son pairings to avoid any bias stemming from those special cases. Additionally, because the number of helpers affects rates of EPP (Cockburn et al. [2016](#evo13496-bib-0014){ref-type="ref"} and references therein, and see below), we did not fit the number of helpers in these models, given the potential confounding effects between the two. **Step 1**. We fitted a binomial generalised linear‐mixed model using *MCMCglmm*, with the *inbreeding status* of every offspring as a response (two‐level factor: inbred *vs*. outbred, where an inbred individual had *f* \> 0). **Fixed effects**: We fitted *within‐pair status*, that is whether an offspring was the result of within‐pair (WP) or extra‐pair (EP) reproduction, as a two‐level factor. **Random effects**: *Nest ID* and *cohort* were fitted as above.**Step 2**. We tested what determined the magnitude of the inbreeding coefficient amongst those nestlings that were inbred, that is had *f* \> 0. We fitted a linear mixed model using *MCMCglmm*, with log‐transformed inbreeding coefficient as the response variable, and Gaussian errors. We used only the inbred individuals (*f* \> 0) in this model. **Fixed effects**: We fitted *within‐pair status* (a two‐level factor: WP *vs*. EP). **Random effects**: *Nest ID* and *cohort* were fitted as above. As a final step, we asked what level of inbreeding would have occurred if there had never been any extra‐pair reproduction. To do this, we constructed an artificial social "faithful" pedigree to represent the relatedness patterns that would have occurred had all females always been faithful and their social mates were always the genetic fathers of all their offspring. Comparing the inbreeding coefficients that would have resulted if this pedigree were real with the actual observed inbreeding coefficients allowed us to judge the overall impact of infidelity on inbreeding in the population. In order for the *MCMCglmm* models to run satisfactorily, it was necessary to truncate the latent variables for models in this section (J. Hadfield, pers. comm.); see SI for details. RESULTS {#evo13496-sec-0100} ======= SECTION 1: PEDIGREE RECONSTRUCTION AND LEVELS OF INBREEDING {#evo13496-sec-0110} ----------------------------------------------------------- Kinship between superb fairy‐wren social partners (*k~SOC~*) ranged from zero to 0.25, with the latter category consisting entirely of pairings between mothers and sons; the mean *k~SOC~* across 863 unique social pairings was 0.0129 (*median* = 0). Only 10.5% of social pairings were incestuous (*k~SOC~* \> 0), with mother--son pairings accounting for 4.2% of all social pairings (Table [1](#evo13496-tbl-0001){ref-type="table"}A). ###### Distribution of kinship between social partners and of inbreeding coefficients \(A\) Kinship between social partners (brood level) Broods % (*n*) ---------------------------------------------------------------------------------- ----------------------- ------------------- All: $k_{soc} > 0$ 10.5% (183/1745) High: $k_{soc} \geq 0.25$ 4.2% (73/1745) Moderate: $0.125 \leq k_{soc} < 0.25$ 0.7% (12/1745) Low: $k_{soc} < 0.125$ 5.6% (98/1745) Male social partner Female social partner Broods % (*n*) **High**: $k_{soc} \geq 0.25$    son Mother 4.2% (73/1745) **Moderate**: $0.125 \leq k_{soc} < 0.25$    Paternal half‐brother Paternal half‐sister 0.2% (4/1745)    Maternal half‐brother Maternal half‐sister 0.2% (4/1745)    Grandson Maternal grandmother 0.2% (4/1745) \(B\) Inbreeding coefficient (individual level) Individuals % (*n*) All: $f > 0$ 5.5% (245/4431) High: $f \geq 0.25$ 0.0% (0/4431) Moderate: $0.125 \leq f < 0.25$ [†](#evo13496-tbl1-note-0001){ref-type="fn"} 0.3% (14/4431) Low: $f < 0.125$ 5.2% (231/4431) Male parent Female parent Individuals % (n) **Moderate**: $0.125 \leq f < 0.25$ [†](#evo13496-tbl1-note-0001){ref-type="fn"}    Paternal half‐brother Paternal half‐sister 0.09% (4/4431)    Maternal half‐brother Maternal half‐sister 0.02% (1/4431)    Grandson Paternal grandmother 0.05% (2/4431)    Grandson Maternal grandmother 0.1% (5/4431)    Paternal grandfather Granddaughter 0.05% (2/4431) † For consistency with (A), we refer to "moderate" inbreeding as $0.125 \leq f < 0.25$, but in practice all individuals in this category were *f* = 0.125. \(A\) Percentage of broods for which the social parents were relatives (*k~SOC~* \> 0) (out of *n* = 1745 broods), then split into high, moderate, or low levels of *k~SOC~*, and followed by details of individual cases where *k~SOC~* ≥ 0.125; and (B) percentage of inbred offspring, considering the inbreeding coefficient (*f* \> 0) at the individual level (out of *n* = 4431 individuals), then split into high, moderate, or low levels of *f*, followed by details of individual cases where *f* ≥ 0.125. John Wiley & Sons, Ltd. Inbreeding appeared rare: of the 4431 offspring with at least one grandparent known, only 5.5% were inbred (i.e., had *f* \> 0) (Table [1](#evo13496-tbl-0001){ref-type="table"}B). There were no individuals with *f* = 0.25 (as would result from reproduction between a parent and offspring or from a full‐sibling pairing). The maximum inbreeding coefficient observed was *f* = 0.125, and occurred *via* a variety of routes (Table [1](#evo13496-tbl-0001){ref-type="table"}B). Tighter pedigree restrictions lead to an increased overall frequency of inbreeding, due to tighter restrictions generally resulting in the exclusion of "outbred" (*f* = 0) individuals (Table [S1](#evo13496-supl-0001){ref-type="supplementary-material"}). This increase was particularly prominent when maternal grandparents were included in the restriction: a requirement of at least three known grandparents corresponded to a frequency of inbred individuals of 18.2%. SECTION 2: INBREEDING DEPRESSION ON NESTLING MASS AND SURVIVAL {#evo13496-sec-0120} -------------------------------------------------------------- Nestling mass declined with inbreeding coefficient, providing evidence for inbreeding depression (Table [2](#evo13496-tbl-0002){ref-type="table"}, Fig. [1](#evo13496-fig-0001){ref-type="fig"}A): the mean observed mass for nestlings with *f * = 0.125 was ∼10% lower than the mean observed mass for nestlings with *f* = 0 (see Table [S9](#evo13496-supl-0001){ref-type="supplementary-material"} for predicted nestling mass across different *f* values). In line with previous results (Kruuk et al. [2015](#evo13496-bib-0044){ref-type="ref"}), we also found that: males were heavier than females; nestlings from smaller broods were heavier than those from larger broods; those from broods assisted by helpers were heavier than those from unassisted broods; and, unsurprisingly, nestling mass increased with the age at which they were measured (Table [2](#evo13496-tbl-0002){ref-type="table"}). Additionally, the heritability of nestling mass was estimated as 18.9% (±3.2% SE). However, the social environment had no effect on the realization of inbreeding depression (*P* = 0.98; Table [S3](#evo13496-supl-0001){ref-type="supplementary-material"}A). ###### Test for inbreeding depression **Nestling mass (g)** **Survival from fledging to 41 days** -------------------------- ----------------------- --------------------------------------- ----------------------- ----------- ----------------------- ----------- Intercept −3.83 (1.21) **0.008** −0.92 (−3.02, 1.18) 0.364 1.41 (0.14, 2.73) **0.035** 1992 (1992 + , pre‐1992) \<**0.001**    pre‐1992 0.62 (0.12) Nestling age 2.16 (0.35) \<**0.001** Nestling age^2^ −0.09 (0.03) \<**0.001** Brood size −0.05 (0.02) **0.012** −0.17 (−0.45, 0.13) 0.257 −0.20 (−0.48, 0.11) 0.194 Sex (female, male) \<**0.001**    Male 0.15 (0.02) −0.08 (−0.38, 0.18) 0.595 −0.02 (−0.30, 0.26) 0.881 Mass 0.33 (0.07, 0.55) **0.004** Helpers (0, 1, 2 + ) \<**0.001**    1 helper 0.09 (0.04) 0.26 (−0.24, 0.73) 0.278 0.29 (−0.16, 0.78) 0.223    2+ helpers 0.20 (0.04) 0.33 (−0.20, 0.93) 0.252 0.40 (−0.14, 0.91) 0.146 Inbreeding coefficient −3.64 (1.26) **0.004** −6.92 (−27.45, 13.83) 0.497 −5.33 (−24.35, 16.00) 0.590 **Random effects** **Variance (SE)** **Posterior mean** **Posterior mean** **(95% CI)** **(95% CI)** Nest ID 0.23 (0.01) 6.53 (4.68, 8.76) 6.37 (4.48, 8.31) Hatch date 0.01 (0.01) 2.54 (0.60, 5.78) 2.67 (0.54, 5.89) Cohort 0.01 (0.01) 0.30 (8.91^−5^, 0.70) 0.32 (2.27^−5^, 0.75) Additive genetic effect 0.10 (0.02) 1.54 (0.17, 3.10) 1.48 (0.22, 3.00) Residual variance 0.19 (0.01) n/a n/a Sample size 4167 3187 3200 Effects of inbreeding coefficient *f* on (A) nestling mass; and on survival from fledging to 41 days fitted (B) with nestling mass (corrected for change in protocol in 1992 and for nestling age at measurement) included as a covariate, and (C) without nestling mass included. There was no support for an interaction between the inbreeding coefficient and number of helpers, thus the interaction was dropped from the models and simple models are presented above; for models with interaction see Table [S3](#evo13496-supl-0001){ref-type="supplementary-material"}. (Note that the precise form of output differs for the *ASReml‐R* model in (A) versus the *MCMCglmm* models in (B)/(C).) John Wiley & Sons, Ltd. {#evo13496-fig-0001} In contrast, there was no evidence of inbreeding depression for survival, whether or not nestling mass was included in the model: the probability of a fledgling surviving to independence was not affected by its inbreeding coefficient. Heavier individuals did survive better (Fig. [1](#evo13496-fig-0001){ref-type="fig"}B, Table [2](#evo13496-tbl-0002){ref-type="table"}), but none of the other variables modeled were associated with changes in survival (Table [2](#evo13496-tbl-0002){ref-type="table"}). As above, we found no statistical support for an interaction between the effect of inbreeding on nestling mass and the number of helpers (Table [S3](#evo13496-supl-0001){ref-type="supplementary-material"}). SECTION 3: EFFECTS OF KINSHIP BETWEEN SOCIAL PARTNERS ON THE LEVELS OF EXTRA‐PAIR REPRODUCTION {#evo13496-sec-0130} ---------------------------------------------------------------------------------------------- Out of the 4431 individuals with known parents and at least one known grandparent, 2704 (61%) were extra‐pair, and out of the total 1745 broods, 1445 (82.8%) had at least one extra‐pair offspring. Considering the full dataset including the mother--son pairings, the proportion of EPO in the brood increased with increasing kinship, *k~SOC~* (Fig. [2](#evo13496-fig-0002){ref-type="fig"}, Table [3](#evo13496-tbl-0003){ref-type="table"}A). However, *k~SOC~* had no effect on EPO frequency when the mother--son pairings were removed (Fig. [2](#evo13496-fig-0002){ref-type="fig"}, Table [3](#evo13496-tbl-0003){ref-type="table"}B), indicating that its effect on infidelity rates was driven by the special case of mother--son pairings, where infidelity was 100%. Outside of the mother--son pairings, the mean percentage of EPO per brood was 73.3%. The proportion of EPO also increased with increasing helper number, regardless of whether mother--son pairings were included in the model or not. However, the effects of *k~SOC~* were not modulated by the number of helpers (Table [S4](#evo13496-supl-0001){ref-type="supplementary-material"}). Mother\'s age and social father\'s age also had no effect in either model (Table [3](#evo13496-tbl-0003){ref-type="table"}). {#evo13496-fig-0002} ###### Effects of kinship between the social male and female and the effects of helpers on the proportion of extra‐pair offspring in the brood Proportion of extra‐pair offspring in the brood -------------------------------- ------------------------------------------------- ------------- ------------------------- ------------- Intercept 0.47 (0.11, 0.84) **0.017** 0.49 (0.13, 0.88) **0.009** Mother age (1yo, older) older 0.16 (−0.12, 0.42) 0.248 0.13 (−0.15, 0.39) 0.356 Social father age (1yo, older) older −0.16 (−0.55, 0.20) 0.400 −0.13 (−0.53, 0.25) 0.522 Helpers (0, 1, 2+)    1 helper 0.53 (0.24, 0.82) **0.004** 0.55 (0.23, 0.81) **0.002**    2+ helpers 1.17 (0.78, 1.55) \<**0.001** 1.17 (0.82, 1.58) \<**0.001** Kinship 18.69 (13.65, 24.29) \<**0.001** −1.19 (−11.04, 9.41) 0.807 Random effects Posterior mean (95% CI) Posterior mean (95% CI) Mother ID 0.73 (0.33, 1.15) 0.69 (0.30, 1.09) Social father ID 0.71 (0.33, 1.07) 0.72 (0.40, 1.12) Cohort 0.02 (5.36^−09^, 0.06) 0.02 (9.73^−09^, 0.06) Residual variance 1.85 (1.35, 2.33) 1.82 (1.38, 2.36) Sample size 1473 1421 Models were run **(A)** on all data, including mother--son pairings; and **(B)** excluding mother--son pairings and any offspring produced by females socially paired to their sons. John Wiley & Sons, Ltd. SECTION 4: EFFECTS OF INFIDELITY ON THE PROBABILITY OF OFFSPRING BEING INBRED {#evo13496-sec-0140} ----------------------------------------------------------------------------- Kinship between females and their extra‐pair partners (*k~EP~*) ranged from zero up to 0.125 (Table [1](#evo13496-tbl-0001){ref-type="table"}A), with the highest value representing three extra‐pair pairings that occurred between grandmothers and grandsons, and one extra‐pair pairing between granddaughter and grandfather; the mean *k~EP~* across 1197 unique extra‐pair pairings was 0.0012 (*median*  =  0). Infidelity reduced inbreeding: if all females had been faithful to their social partners throughout the study period, 10.4% of all individuals in the population would be inbred (*f* \> 0) compared to the observed 5.5% (Table [4](#evo13496-tbl-0004){ref-type="table"}; Fisher\'s exact test: *P* \< 0.001). Excluding mother--son pairings, these frequencies become 9.3% *vs*. 4.5% (Fisher\'s exact test: *P* \< 0.001). ###### Numbers and percentages of inbred and outbred within‐ and extra‐pair offspring Inbred Outbred Row total ------------------- -------- --------- ----------- Within‐pair 130 1597 1727 7.5% 92.5% Extra‐pair 115 2589 2704 4.3% 95.8% Observed total 245 4186 4431 5.5% 94.5% If faithful total 459 3972 4431 10.4% 89.6% Figures for inbred and outbred offspring if all females were always faithful to their social partners, that is with no extra‐pair offspring present in the population ("if faithful total") are also given for comparison. Percentages are presented per row and rounded to 1 decimal place. Any individual with inbreeding coefficient *f* \> 0 was classified as inbred. John Wiley & Sons, Ltd. Table [4](#evo13496-tbl-0004){ref-type="table"} shows the frequency of inbred (*f* \> 0) *vs*. outbred (*f* = 0) individuals in relation to their extra‐pair *vs*. within‐pair status: there were more inbred WPO than EPO (Fisher\'s exact test: *P* \< 0.001). Moreover, this was the case regardless of pedigree restrictions applied (Table [S5](#evo13496-supl-0001){ref-type="supplementary-material"}). The mixed model confirmed that EPO were less likely to be inbred than WPO (Table [5](#evo13496-tbl-0005){ref-type="table"}), while the number of helpers had no effect on inbreeding status (Table [S8](#evo13496-supl-0001){ref-type="supplementary-material"}). These results were also consistent across different pedigree restrictions (Table [S6](#evo13496-supl-0001){ref-type="supplementary-material"}). Furthermore, the second step of this analysis showed that amongst inbred offspring (*f* \> 0), EPO had lower inbreeding coefficients than WPO (Table [6](#evo13496-tbl-0006){ref-type="table"}). ###### Effects of within‐pair status of an offspring (whether it was within‐pair, WP, or extra‐pair, EP) on the offspring\'s inbreeding status (whether it was inbred, with *f* \> 0, or outbred, with *f* = 0), using a binomial‐mixed model run in *MCMCglmm* Inbreeding status of an individual ----------------------------- ------------------------------------ ------------- Intercept −9.83 (−10.80, −8.91) \<**0.001** Within‐pair status (EP, WP) WP 1.36 (0.70, 1.98) \<**0.001** **Random effects** **Posterior mean (95% CI)** Nest ID 25.12 (21.11, 29.51) Cohort 2.55 (0.46, 5.23) Sample size 4283 The model was run without mother--son pairings. John Wiley & Sons, Ltd. ###### Effects of within‐pair status of an inbred (*i.e*., *f* \> 0) offspring (whether it was within‐pair, WP, or extra‐pair, EP) on the offspring\'s level of inbreeding *f* (continuous), using a linear mixed model run in *MCMCglmm* Inbreeding level of an individual ----------------------------- ----------------------------------- ------------- Intercept −4.99 (−5.70, −4.26) \<**0.001** Within‐pair status (EP, WP) WP 0.50 (0.17, 0.77) \<**0.001** **Random effects** **Posterior mean (95% CI)** Nest ID 4.02 (2.86, 5.17) Cohort 1.63 (0.29, 3.32) Residual variance 0.15 (0.11, 0.18) Sample size 245 The model was run without mother--son pairings. John Wiley & Sons, Ltd. DISCUSSION {#evo13496-sec-0150} ========== Our study explored the associations between, and the effects of, inbreeding, kinship, and infidelity in a wild population of a cooperatively breeding bird. We found some support for each of the three key assumptions outlined in the Introduction as necessary for the hypothesis that extra‐pair reproduction is driven by inbreeding avoidance. Thus we found **(1)** evidence of inbreeding depression in nestling mass; **(2)** that increased kinship between social partners was associated with a higher frequency of extra‐pair offspring in the brood; and **(3)** that extra‐pair offspring were less likely to be inbred than within‐pair offspring, and when inbred, they had lower inbreeding coefficients than within‐pair offspring. However, detailed analysis revealed that kinship‐infidelity results were context‐specific: the frequency of extra‐pair offspring only increased with kinship when considering mother--son pairs. Given that only 4.2% of broods had mother--son pairs as social parents, our results suggest that the inbreeding‐avoidance hypothesis cannot explain the widespread occurrence of extra‐pair reproduction in our system. We also found no evidence that any of these aspects were affected by the social environment. We discuss each of these points in turn below. INBREEDING AND INBREEDING DEPRESSION {#evo13496-sec-0160} ------------------------------------ Both social pairing between close relatives and moderate‐level inbreeding were rare in our population: only 4.9% of pairs had *k~SOC~* ≥ 0.125 and only 0.3% of individuals had *f* between 0.125 and 0.25 (Table [1](#evo13496-tbl-0001){ref-type="table"}). There was no high‐level inbreeding (*f* ≥ 0.25). The *overall* frequency of incestuous pairings and of inbreeding events were 10.5% (*k~SOC~* \> 0) and 5.5% (*f* \> 0), respectively. These overall frequencies increased with tighter restrictions on the pedigree to 24.6% incestuous pairs and 18.2% inbred offspring for 3+ known grandparents, and to 28.5% incestuous pairs and 21.5% inbred offspring with four grandparents known (Table [S1](#evo13496-supl-0001){ref-type="supplementary-material"}). The increased frequency presumably reflects, in part, the exclusion of pairs/individuals erroneously assigned *k~SOC~* = 0 and *f* = 0 because their ancestry information was not sufficient to identify lower levels of relatedness/inbreeding: without a perfectly complete pedigree, inbreeding between distant relatives may not be detected, leading to an underestimation of the overall occurrence of inbreeding. However, the steep increase beyond 2+ known grandparents is likely predominately due to biasing the dataset toward females who have dispersed shorter distances from their natal territory, as our ability to sample all grandparents was often restricted to these females. These short‐dispersing females will be more likely to encounter male relatives as partners than females dispersing over longer distances (in superb fairy‐wrens female dispersal is obligatory (Mulder [1995](#evo13496-bib-0051){ref-type="ref"})). Our results therefore indicate that inbreeding and social pairing between close relatives were rare in this population. The overall levels detected were nevertheless comparable to several other bird populations (reviewed in Kruuk et al. [2002](#evo13496-bib-0045){ref-type="ref"}). For instance, in a British great tit population, only 1.3% of pairings were between first‐ or second‐order relatives (Szulkin et al. [2007](#evo13496-bib-0065){ref-type="ref"}), whereas in our superb fairy‐wren population it was 4.9% of pairings (high/moderate *k~SOC~*, Table [1](#evo13496-tbl-0001){ref-type="table"}A). In contrast, the Mandarte Island song sparrows have substantially higher frequency of closely related pairings: 21.4% of pairings were between first‐ or second‐order relatives (Reid et al. [2015c](#evo13496-bib-0061){ref-type="ref"}). We note also that theory suggests that under certain conditions father--daughter pairings may be more likely than mother--son pairings (Waser et al. [1986](#evo13496-bib-0073){ref-type="ref"}). However, in superb fairy‐wrens, obligate female dispersal means that females never pair with their social fathers and so the only feasible social pairing of close/familiar relatives in this system are mother--son pairings (all of *k~SOC~*  =  0.25 cases here). While a female could conceivably disperse and pair/mate with her extra‐group sire, we have never observed this. Such pairings may be unlikely in this system due to the dispersal distances typically being too large to facilitate father--daughter contact. As a result, we do not see offspring resulting from pairings between females and their fathers. We found evidence for inbreeding depression in nestling mass, of magnitude comparable to other studies (e.g., Soay sheep on the islands of St. Kilda (Berenos et al. [2016](#evo13496-bib-0007){ref-type="ref"})). However, although nestling mass positively affected survival, there was no evidence for inbreeding depression in survival. Inbred offspring with *f* = 0.125 surviving to fledging were on average 6.5% lighter than outbred offspring (*f* = 0.125: mean observed nestling mass ∼6.6 g; *f* = 0: mean observed nestling mass ∼ 7.0 g). The average survival of fledglings with nestling mass 6.5--6.7 g was 54%, while for fledglings with nestling mass 6.9--7.1 g it was 58%. Therefore, all else being equal, a reduction in nestling mass should have translated into ∼4% reduction in survival for inbred fledglings (*f* = 0.125), but this was not evident from our survival models (in which estimates suggested inbreeding depression in survival, but 95% CIs spanned 0). Due to the rarity of inbreeding events between close relatives, the lack of statistical support for inbreeding depression in survival may be due, in part, to a lack of statistical power, but these calculations suggest that any reduction in survival within this period may not be large. We did not test for inbreeding depression in adult traits due to the low number of inbred adult birds. Thus detecting inbreeding depression may be easier in populations with higher levels of inbreeding. It may also be facilitated by use of high‐density genomic marker data, which can reveal variation in genome‐wide heterozygosity among individuals classified as *f* =  0 with a pedigree analysis (Huisman et al. [2016](#evo13496-bib-0035){ref-type="ref"}). Regardless, our analyses here do not indicate strong inbreeding depression in survival in this population. Two further caveats are worth pointing out with regard to interpretation of the estimated occurrence of inbreeding depression. Firstly, it is of course difficult to ascertain how the level of inbreeding depression observed during the period of this study may compare to the severity of inbreeding depression in the past, and thus difficult to infer past selection pressures against inbred individuals. Second, while inbreeding depression of some form is necessary for inbreeding avoidance to provide a plausible explanation for extra‐pair paternity, it would need to be sufficiently strong for the adaptive benefits of inbreeding avoidance to counter any costs and any potential inclusive fitness benefits of inbreeding (Szulkin et al. [2013](#evo13496-bib-0067){ref-type="ref"}; Duthie and Reid [2016](#evo13496-bib-0027){ref-type="ref"}; Duthie et al. [2016a](#evo13496-bib-0024){ref-type="ref"}). INFIDELITY VARIATION WITH KINSHIP {#evo13496-sec-0170} --------------------------------- Our analyses confirmed Cockburn et al.'s (2003) results: mother--son pairings resulted in absolute infidelity by the female, with no WPO produced by such pairings. These results appear robust to "selective disappearance" as we found no evidence for reduced clutch size and/or survival to measurement age, as would happen if EPO were more likely to survive to measurement than WPO due to inbreeding depression (Reid et al. [2015b](#evo13496-bib-0060){ref-type="ref"}). However, there was no evidence of inbreeding avoidance through extra‐pair reproduction in cases other than the mother--son pairs, who were the social parents of 4.2% of the observed broods. This, together with behavioral data indicating that all females seek extra‐pair copulations throughout the breeding season (Cockburn et al. [2016](#evo13496-bib-0014){ref-type="ref"}), suggests that the main reason for extra‐pair reproduction for the majority of the females in our study is *not* inbreeding avoidance. The lack of a simple population‐wide relationship between *k~SOC~* and infidelity indicates that explanations for infidelity can be context‐dependent. Brouwer et al. ([2017](#evo13496-bib-0012){ref-type="ref"}) recently showed that explanations for infidelity patterns in the fairy‐wren family vary depending on the level of analysis and the spatiotemporal scale used. In our study, only females in mother--son pairings avoided inbreeding through increased infidelity, and the hypothesis of inbreeding avoidance through EP reproduction was not supported for other females. Yet, studies typically investigate this hypothesis at a population‐level, often assuming that a simple relationship, or lack thereof, between kinship and infidelity is evidence for the existence of a population‐wide explanation for infidelity. Even across other species of Maluridae, several studies have shown higher infidelity in incestuous pairs (Brooker et al. [1990](#evo13496-bib-0010){ref-type="ref"}; Tarvin et al. [2005](#evo13496-bib-0068){ref-type="ref"}; Brouwer et al. [2011](#evo13496-bib-0011){ref-type="ref"}; Varian‐Ramos and Webster [2012](#evo13496-bib-0071){ref-type="ref"}; Kingma et al. [2013](#evo13496-bib-0039){ref-type="ref"}), but we note that where relatedness between social partners is assessed by genetic markers, it is not possible to distinguish certain types of relationships, such as mother--son pairings, for which different strategies may apply. Thus we suggest that care is needed when interpreting *overall* relationships between kinship and infidelity as evidence of a *general* inbreeding avoidance "strategy" applicable to all individuals in a population. Our data suggest that such relationships may vary and that very different patterns in a relatively small number of individuals, not necessarily representative of the whole population, could drive the results of an analysis. Furthermore, evidence suggests that, in general, bird species can only recognise kin when there is strong contextual evidence of relationship, such as having been raised in the same nest (Nakagawa and Waas [2004](#evo13496-bib-0052){ref-type="ref"}; Ihle and Forstmeier [2013](#evo13496-bib-0036){ref-type="ref"}). It would seem unlikely that females are able to distinguish kin, beyond close/familiar relatives, from nonkin, and thus unlikely that they would actively allocate paternity based on kinship to a less‐closely related social partner. Close relatives, such as nuclear family members and familiar individuals (e.g., a female\'s offspring, nest mates), may present a special case that should potentially be considered separately from more distant relatives in these types of studies. INFIDELITY REDUCES INBREEDING {#evo13496-sec-0180} ----------------------------- The levels of inbreeding we detected were low: 94.3% of our inbred individuals had inbreeding levels of *f* \< 0.125. Yet, we found that EPO were more likely to be outbred than WPO, even after the exclusion of the mother--son pairings, and that amongst inbred offspring, EPO had lower inbreeding coefficients than WPO. These results demonstrate that differences in inbreeding status and inbreeding levels between WPO and EPO can arise even without a relationship between kinship (*k~SOC~*) and infidelity (we found none when mother--son pairings were excluded). Due to the lack of a relationship between kinship and infidelity beyond the mother--son pairings, active mate choice for less‐related males seems unlikely to be explaining the difference in inbreeding status between WPO and EPO. What is driving this relationship? We suggest it is likely to be linked to the demographic and/or spatial structure of the population: females may be, on average, less closely related to males in another group, several territories away, than they are to their social partners. Potentially, this pattern could be linked to nonrandom formation and/or persistence of more‐related----than expected by chance----social pairs (Reid et al. [2015c](#evo13496-bib-0061){ref-type="ref"}), kin structure, that is relatedness between individuals varying with distance (Nakagawa and Waas [2004](#evo13496-bib-0052){ref-type="ref"}; Foerster et al. [2006](#evo13496-bib-0029){ref-type="ref"}), or constraints on mate availability (Duthie et al. [2016a](#evo13496-bib-0024){ref-type="ref"}). A more detailed analysis will be required to understand whether the spatial and/or temporal distribution of mates can explain the pattern we observe. ASSESSMENT OF THE INBREEDING AVOIDANCE EXPLANATION FOR EXTRA‐PAIR PATERNITY {#evo13496-sec-0190} --------------------------------------------------------------------------- At a first glance all three assumptions necessary for the hypothesis of inbreeding avoidance through EP reproduction----inbreeding depression, increase in EPP when social partners are related, and a reduction in inbreeding *via* infidelity----were met in our study system. However, dissecting the infidelity‐kinship relationship we found that there was no population‐wide pattern, and that the effect of kinship on infidelity was driven entirely by mother--son pairs. Looking beyond such pairings, the risk of mating with relatives appeared too low and the degree of kin recognition required too fine‐scale for inbreeding avoidance to serve as a plausible explanation for EPP in this system. Given that only 0.7% of pairings involved moderate kinship levels (0.125 ≤ *k~SOC~* \< 0.25), that is at a level that could be relevant to female choice, it seems highly unlikely that a complex behaviour such as extra‐pair reproduction would occur in the vast majority of breeding events just to mitigate this small risk of inbreeding: behavioral evidence suggests that females always seek EP copulations *via* extra‐territorial forays (Cockburn et al. [2016](#evo13496-bib-0014){ref-type="ref"}), and 82.8% of broods have at least one EP offspring. It therefore seems likely that other explanations for extra‐pair reproduction, such as choice of a preferred male in light of restricted social partner choice (e.g., choosing males with earlier moult date (Dunn and Cockburn [1999](#evo13496-bib-0023){ref-type="ref"}; Cockburn et al. [2008a](#evo13496-bib-0015){ref-type="ref"})), are more plausible. Our study therefore illustrates the need to test all components of the hypothesis of inbreeding avoidance through EP reproduction explicitly: specifically, relationships between kinship and infidelity, as well as differences between WPO and EPO need to be assessed in detail. SOCIAL ENVIRONMENT {#evo13496-sec-0200} ------------------ The social environment influenced patterns of infidelity, but not the occurrence or consequences of inbreeding. It had a strong influence on infidelity rates, with females assisted by helpers producing more EPO, predominantly sired by males outside of the entire social group (95% of the EPO were extra‐group offspring; G.K. Hajduk, unpubl. data); in particular, for reasons that are not entirely clear, the number of unrelated helpers is the best predictor of levels of extra‐group paternity (G.K. Hajduk, unpubl. data). However, the presence of helpers did not affect the probability of offspring in a nest being inbred (Table [S8](#evo13496-supl-0001){ref-type="supplementary-material"}). Furthermore, while nestlings from broods assisted by helpers were heavier than those from unassisted broods (as in Kruuk et al. [2015](#evo13496-bib-0044){ref-type="ref"}), there was no evidence that the presence of helpers affected the occurrence or magnitude of inbreeding depression (Table [2](#evo13496-tbl-0002){ref-type="table"}; Table [S3](#evo13496-supl-0001){ref-type="supplementary-material"}). These results fit with the general impression that it may be difficult to detect interactions of inbreeding depression with environmental conditions in natural populations (Pemberton et al. [2017](#evo13496-bib-0056){ref-type="ref"}). However, it is possible that we were simply unable to find support for interactions with inbreeding depression in our study population due to the rarity of inbreeding events. Conclusions {#evo13496-sec-0210} =========== Our study used multigenerational pedigree data from a long‐term individual‐based study of a wild population to investigate patterns of inbreeding and inbreeding depression, as well as causes and consequences of extra‐pair reproduction. We showed that the relationship between kinship and infidelity may be complex, context‐dependent and not necessarily population‐wide, and that results can be easily driven by a small sample of individuals----in this case mother--son pairings. Additionally, we showed that within‐pair and extra‐pair offspring can differ in their probability of being inbred, even when infidelity occurs for reasons apparently unrelated to inbreeding avoidance. Furthermore, the social environment affected infidelity rates, but did not affect the probability of offspring being inbred or inbreeding depression. Overall, our study demonstrates how the social system of a population may affect mating patterns and their consequences in multiple complex ways, and also illustrates the value of long‐term pedigree data for providing insights into core aspects of evolutionary biology. CONFLICT OF INTEREST {#evo13496-sec-0240} ==================== The authors declare no conflict of interests. {#evo13496-sec-0260} Associate Editor: E. Derryberry Handling Editor: M. Servedio Supporting information ====================== ###### **Table S1**. Pedigree restrictions on number of known grandparents affected not only the sample size, but also the rates of incestuous pairings between social partners (*k~SOC~* \> 0) and inbreeding (*f* \> 0). **Table S2**. Effects of kinship between the social male and female and the effects of helpers on (a) clutch size, and (b) hatchability/survival of offspring to measurement age. Output from *MCMCglmm* models: sample sizes are number of broods across 26 cohorts. **Table S3**. Test for inbreeding depression and the effects of social environment on the magnitude of inbreeding depression (an interaction between the inbreeding coefficient and number of helpers). **Table S4**. Effects of kinship between the social male and female and the effects of helpers on the proportion of extra‐pair offspring in the brood, including an interaction between *k~SOC~* and helpers. **Table S5**. Effects of pedigree restrictions on numbers and percentages of inbred and outbred within‐ and extra‐pair offspring. **Table S6**. Pedigree restrictions: effects of within‐pair status of an individual (whether it was within‐pair, WP, or extra‐pair, EP) on the individual\'s inbreeding status (whether it was inbred, with *f* \> 0, or outbred, with *f* = 0), using binomial mixed models run in *MCMCglmm*. **Table S7**. Pedigree restrictions: effects of within‐pair status of an individual (whether it was within‐pair, WP, or extra‐pair, EP) on the individual\'s inbreeding status (whether it was inbred, with *f* ≥ 0.0625, or outbred, with *f* \< 0.0625), using binomial mixed models run in *MCMCglmm*. **Table S8**. Effects of social environment ‐ number of helpers -- on the probability of offspring being inbred. **Table S9**. Predicted nestling mass (g) for increasing levels of inbreeding (standard errors in brackets). ###### Click here for additional data file. Data collection: H.L.O., A.C., and N.M. Planning of analyses: G.K.H., L.E.B.K., A.C., and C.A.W. Data analysis: G.K.H. Drafting of the article: G.K.H. and L.E.B.K. Revising of the article: G.K.H., L.E.B.K., C.A.W., and A.C. Approval of final manuscript: all. G.K.H. was supported by the U.K. Natural Environment Research Council (Grant NE/L002558/1) through the University of Edinburgh\'s E3 Doctoral Training Partnership. The long‐term research has been facilitated by Discovery Project grants from the Australian Research Council to A.C. and L.K., and L.K. was funded by an ARC Future Fellowship. Data collection was greatly assisted by the Australian National Botanic Gardens (Canberra, ACT), and many field assistants. We thank Jarrod Hadfield for invaluable help with the *MCMCglmm* package; Matt Bell for discussions and Lyanne Brouwer for helpful comments on the manuscript. The doi for our data is <https://doi.org/10.5061/dryad.5fb633t>.

NEW YORK (AP) — The Latest on Time”s Up calling for a probe into the Manhattan District Attorney”s office (all times local): 8:40 p.m. The Manhattan district attorney”s office says a review of how prosecutors handled a 2015 sex abuse case against Harvey Weinstein will show the investigation was handled properly. New York”s governor on Monday directed the state”s attorney general to review a decision not to prosecute the disgraced media mogul after an Italian model told police that he groped her. The woman caught Weinstein apologizing on tape during a sting operation, but the DA”s office declined to prosecute the case. Spokesman Danny Frost says the DA”s office will provide the attorney general with any information necessary. Gov. Andrew Cuomo made the directive on Monday, hours after Time”s Up, an initiative started by Hollywood industry women, asked for the review. In a statement, the Democratic governor asked that the review be conducted “in a way that does not interfere with the current investigation.” ___ 8 p.m. New York”s governor has directed the state attorney general to review the 2015 decision by the Manhattan district attorney”s office not to prosecute a sex abuse case against Harvey Weinstein. An initiative started by Hollywood industry women had called for Gov. Andrew Cuomo (KWOH”-moh) to investigate the DA”s office after a New York magazine published an article about the case involving an Italian model who said Weinstein groped her. Time”s Up says an investigation is necessary to protect the integrity of the office. Police have said the case should have been prosecuted; the district attorney”s office disagreed. In a statement, the Democratic governor asked that the review be conducted “in a way that does not interfere with the current investigation.” The Manhattan DA”s office says a criminal investigation into Weinstein is active and ongoing. ___ 3:30 p.m. The Manhattan District Attorney”s office says a criminal investigation into Harvey Weinstein is active and ongoing and a commitment to justice in sexual abuse cases is “unwavering.” The comments by spokesman Danny Frost Monday came as the Time”s Up initiative called for the governor to investigate the district attorney”s office for refusing to prosecute the disgraced media mogul in 2015. Police have said the case should”ve been prosecuted; the district attorney”s office disagreed. Frost says the sex crimes unit is a national leader in the investigating and prosecution of sex crimes. Police and prosecutors may disagree sometimes, but never at the expense of justice. Time”s Up was started by women in Hollywood. The statement from the group came after New York magazine published an article about the 2015 case involving an Italian model who said Weinstein groped her. ___ 1:30 p.m. An initiative started by Hollywood industry women is calling for New York”s governor to investigate the Manhattan district attorney”s office over a decision in 2015 not to prosecute a sex abuse case against Harvey Weinstein. Time”s Up says a report in New York magazine is disturbing because it suggests the district attorney”s office may have been improperly influenced by Weinstein and sought to intimidate an Italian model who accused the disgraced media mogul of groping her. She secretly recorded him in a police sting. The district attorney”s office decided there wasn”t enough evidence to prosecute. Time”s Up says an investigation is necessary to protect the integrity of the office.

Hymn/Song Information Crown Him with many crowns The Lamb Crown Him with many crowns, The Lamb upon His throne; Hark! how the heavenly anthem drowns All music but its own: Awake, my soul, and sing Of Him who died for thee, And hail Him as thy chosen King Through all eternity. Crown Him the Son of God Before the worlds began; And ye who tread where He hath trod, Crown Him the Son of Man, Who every grief hath known That wrings the human breast, And takes and bears them for His own, That all in Him may rest. Crown Him the Virgin's Son, The God incarnate born, Whose arm those crimson trophies won Which now His brow adorn; Fruit of the mystic rose, As of that rose the stem; The root whence mercy ever flows, The Babe of Bethlehem. Crown Him the Lord of Love. Behold His hands and side, Rich wounds, yet visible above, In beauty glorified. No angel in the sky Can fully bear that sight, But downward bends his wondering eye At mysteries so bright! Crown Him the Lord of life, Who triumphed o'er the grave, And rose victorious in the strife, For those He came to save: His glories now we sing, Who died and rose on high, Who died eternal life to bring, And lives that death may die. Crown Him the Lord of peace, Whose power a scepter sways From pole to pole, that wars may cease, and all be prayer and praise. His reign shall know no end, and round His piercèd feet Fair flowers of paradise extend their fragrance ever sweet. Crown Him the Lord of heaven, One with the Father known One with the Spirit through Him given From yonder glorious throne. To Thee be endless praise, For Thou for us hast died; Be Thou, O Lord, through endless days Adored and magnified. Crown Him the Lord of heaven, Enthroned in worlds above; Crown Him the King to whom is given The wondrous name of love: All hail, Redeemer, hail! For Thou has died for me; Thy praise shall never, never fail, Throughout eternity. Crown Him the Lord of lords, who over all doth reign, Who once on earth, the incarnate Word, for ransomed sinners slain, Now lives in realms of light, where saints with angels sing Their songs before Him day and night, their God, Redeemer, King. Crown Him the Lord of years, the Potentate of time, Creator of the rolling spheres, ineffably sublime. All hail, Redeemer, hail! For Thou has died for me; Thy praise and glory shall not fail throughout eternity.

Introduction {#sec1} ============ When individuals prioritize themselves over their communities, the consequences can damage global economies, scientific institutions and the planet. Philosophers and scientists have debated the origins of human prosociality for centuries ([@ref13]). The study of cooperation has evolved beyond philosophy and consumed the energy of scientists across numerous disciplines, from primatology to economics ([@ref7]; [@ref14]). To better understand the nature of cooperation, we took an interdisciplinary approach that combined neuroeconomics, social and personality psychology, and cognitive neuroscience. We examined the neural systems that guide cooperation in groups, and how these systems are shaped by social norms and individual differences. For many years, *prosocial restraint* models asserted that cooperation stems from deliberate restraint of selfish impulses ([@ref58]; [@ref15]; [@ref31]). More recently, *prosocial intuition* models have argued that cooperation stems from intuition, whereas deliberation always maximizes self-interest ([@ref50]; [@ref48]). Both models carve the mind into two core processes: intuition (i.e. rapid, automatic, reflexive mental processing) and deliberation (i.e. delayed, controlled, reflective processing). They differ on the role these processes play in promoting selfish *vs* collective interest. Despite extensive research on this issue, studies of the mental processes underlying cooperation have yielded mixed evidence for existing theoretical models ([@ref6]; [@ref49]). To help reconcile these issues, we considered an alternative approach to cooperation. *Value-based decision* models argue that the cooperative decisions hinge on preferences that vary between individuals and situations. According to this approach, the neural systems involved in storing, representing and learning value play a role in all decisions, whether they are motor actions, food preferences or cooperative behavior ([@ref9]; [@ref38]; [@ref33]). By specifying the conditions under which cooperation requires effortful deliberation, value-based models explain when (and for whom) interventions to boost cooperation will be most effective. Furthermore, these models can reconcile opposing predictions from prosocial restraint and prosocial intuition models. For instance, consider two car drivers (one prosocial and the other selfish) who witness a collision and decide to pull over and help. Although the driver with prosocial preferences might find the decision to pull over easy, the selfish driver might find the decision hard. Understanding the value each individual places on human welfare may determine which processes produce cooperation. Research on human cooperation often involves social dilemmas, such as the public goods game (PGG). In this economic game, players can make monetary contributions to their group that get multiplied and distributed equally (including to players who keep all their money for themselves). It is in the group's collective interest if all players contribute, but it is in each individual's self-interest to contribute nothing and reap the benefits of other's generosity (i.e. free-riding). Consistent with the prosocial intuition model, faster decisions have been associated with larger group contributions in a PGG, suggesting intuitive cooperation ([@ref50]). However, value-based models posit that longer decisions reflect decision-conflict during choices in which the agent is close to being indifferent between options ([@ref16]). In addition, prosocial individuals (i.e. those who generally help others) are faster to cooperate than free-ride (i.e. prioritize themselves over the group), whereas selfish individuals are faster to free-ride than cooperate ([@ref29]; [@ref32]). Thus, individual differences in prosociality shape which mental computations steer cooperation ([@ref63], [@ref64]). The value-based approach also contends that situational factors shift these mental computations. Increasing the cost of cooperation renders selfish decisions faster and less conflicted ([@ref32]). Therefore, descriptive norms (i.e. perceptions of typical social behavior) may also shape cooperation. Humans have strong needs for belonging and tendencies toward conformity ([@ref1]; [@ref10]; [@ref3]), and norms can increase prosocial behavior ([@ref45]) as well as the intrinsic value of socially preferred stimuli ([@ref66]). Indeed, one's cooperation is related to the mean levels of cooperation of others around ([@ref57]). As a result, it may take more effort to defy group norms---cooperating when others are selfish or free-riding when others are generous. In sum, whether people are faster to cooperate or free-ride depends on their prosocial tendencies and context. We examined whether neural regions involved in decision-making show a similar pattern. While early evidence from neuroimaging studies implicated the ventromedial prefrontal cortex (vmPFC) in affective evaluations ([@ref4]; [@ref56]; [@ref35]), the vmPFC is now widely considered a hub for value-based decision-making. For instance, activity in vmPFC is proportional to the expected value that would be obtained by taking an action ([@ref30]; [@ref38]). In contrast, the dorsolateral prefrontal cortex (dlPFC) is associated with executive function and supports goal pursuit ([@ref8]). Indeed, dlPFC damage impairs executive functions like working memory, reasoning and self-regulation ([@ref67]). Functional connectivity between dlPFC and vmPFC is thought to reflect modulation of value during goal-directed decisions ([@ref26]). Moreover, the connectivity of these regions hinges on individual preferences (e.g. healthy eating among dieters; [@ref26]) and context (e.g. regulating cravings; [@ref28]). In sum, vmPFC activation reflects expected value whereas dlPFC may index overcoming prepotent response tendencies ([@ref2]), decision difficulty ([@ref55]) and goal-directed modulation of vmPFC's expected value signal ([@ref52]). This suggests that individuals' prosociality and the social contexts in which they are embedded should determine the value of cooperation. According to the value-based approach, we should observe greater vmPFC activity during choices that align with one's prosocial tendency since value computations will be higher. Likewise, we should observe dlPFC-vmPFC connectivity during choices that conflict with this tendency, since the dlPFC will need to modulate value signals in the vmPFC to steer decision-making. In this manner, fMRI can provide insight into group-based cooperation. Indeed, past research has found roles for vmPFC and dlPFC in cooperation consistent with a value-based approach ([@ref47]). For instance, people show greater activation in vmPFC when mutually cooperating in a Prisoner's Dilemma ([@ref53], [@ref54]) or when inferring cooperative intentions in others ([@ref11]). However, people show enhanced dlPFC activity when cooperating in a Prisoner's Dilemma with someone who typically defects ([@ref59]) or when trusting out-group members in a Trust Game ([@ref27])---situations that might require modulating prepotent value representations. Moreover, a recent study found that patients with dlPFC damage were less likely to cooperate in a Public Goods Game ([@ref65]), again highlighting that dlPFC can contribute to cooperative choice. To clarify the contributions of these regions in group-based cooperation, we examined here how individual differences and social norms shape vmPFC and dlPFC activity during contributions to public goods. Current research {#sec2} ---------------- We examined two variables that could influence the neural computations underlying cooperation: (1) prosocial tendencies and (2) descriptive norms. We measured brain activity while participants played one-shot PGGs ostensibly with other university students. Prosocial tendencies were measured as the proportion of cooperative PGG decisions made by each participant ([@ref32]). To test that PGG decisions reflected broader individual differences in prosociality, we further measured giving in a dictator game (see Supplemental Section S7). We created prosocial and antisocial social norms by manipulating the feedback from the other university students in the PGG (see [Figure 1](#f1){ref-type="fig"}). To verify these norms, we asked participants to estimate how often students cooperated at each university. These estimates indexed individual differences in norm detection. ![Public goods game with descriptive norm manipulation. (a) At the beginning of each block, participants were instructed, 'You will now encounter students from University \[X/Y\]' with one of the corresponding emblems shown. The base rates were fixed for each university such that 30% of students cooperated in one university (antisocial) whereas 70% of students cooperated in the other (prosocial). Participants alternated between antisocial and prosocial schools (order counterbalanced) for a total of four blocks with 25 trials within each block. **(b)** Each trial consisted of a decision phase (4 s) and a feedback phase (7 s) that was broken down into three stages: (1) each student's contribution to the public pot, (2) the pot multiplying by two and (3) each student's earnings after the pot is evenly divided four ways. Students who gave to the pot were always pictured in blue whereas students who kept their money were displayed in yellow. ITI and ISI durations were jittered in order to dissociate neural activity between decision and outcome phases.](nsaa055f1){#f1} We tested four hypotheses derived from the value-based approach: (VB~H1~) prosocial tendencies will moderate the relative contribution of vmPFC and dlPFC, such that choices aligned with one's tendency (i.e. selfish participants free-riding or prosocial participants cooperating) will elicit greater vmPFC responses whereas (VB~H2~) choices that conflict with one's tendency (e.g. selfish participants cooperating or prosocial participants free-riding) will elicit greater dlPFC-vmPFC connectivity. Social context should moderate activity in these regions, such that (VB~H3~) deviating from group norms (i.e. cooperating with free-riders or free-riding against cooperators) will elicit greater dlPFC-vmPFC connectivity whereas (VB~H4~) complying with group norms (e.g. cooperating with cooperators or free-riding against other free-riders) will elicit greater vmPFC activity. Methods {#sec3} ======= Participants {#sec4} ------------ Our target sample was 45--50 participants. Forty-seven university students (32 female) were recruited (via online posters) from the New York City area and paid \$20 (or two research credit hours). Students (*M* = 20.85, *SD* = 2.60) spanned across 16 north-eastern colleges. All participants were right-handed, healthy, had normal or corrected-to-normal vision, and had no history of psychiatric diagnoses, neurological or metabolic illnesses. The study was approved by the review board of New York University. We report how we determined sample size, all data exclusions, all manipulations and all measures. Five participants were excluded from analyses, leaving a sample of 42 participants. Participants were excluded if they met at least one of the criteria defined prior to data collection: (1) moving at least 3 mm across all scan sessions and (2) reporting suspicion (during debriefing) that their decisions could actually affect the payment of other participants. One participant was excluded due to criterion 1 (\>5 mm motion in each scan session), and four participants were excluded due to criterion 2. Procedure {#sec5} ========= Public goods game {#sec6} ----------------- Participants received instructions on how to play a PGG, including four practice trials and a thorough comprehension quiz. In each round, participants were given \$8.00, which they could either keep for themselves or contribute to benefit the group. Players interacted in groups of four and contributions were doubled and split equally by all group members. On each trial, participants were given 4 s to make a decision and received no payment on trials where no response was recorded. After each choice, participants were shown feedback about the other players' decisions and resulting payouts. An intertrial interval (ITI) signaled the beginning of each round and a fixation cross interstimulus interval (ISI) separated the decision and feedback stages ([Figure 1B](#f1){ref-type="fig"}). ITIs and ISIs were jittered 1--8 s using a Poisson distribution and randomized between participants. Participants were instructed they would never encounter the same player more than once such that each trial resembled a one-shot PGG. Before beginning the game, we informed participants that the other players' decisions were based on previous responses from students attending two universities whose identities we had concealed (labeled University X and University Y; [Figure 1A](#f1){ref-type="fig"}). Participants were further instructed that students from one university were more likely to give their money (prosocial school) whereas students from the other university were more likely to keep their money (antisocial school). We did not specify which university was prosocial and antisocial. Participants alternated between playing with students from the prosocial and antisocial schools across four blocks for a total of 100 trials. The identity of the universities and the order they were encountered were counterbalanced across participants. In reality, we adjusted the base rates such that players from each university gave 70% (prosocial) or 30% (antisocial) of the time. Of the 50 trials playing with the prosocial university, for instance, participants encountered 105 'givers' (out of 150 students) with the following feedback distribution: 0 givers (2 trials), 1 giver (10 trials), 2 givers (20 trials) and 3 givers (18 trials). Earnings across all trials were averaged and paid to participants after the study. Prosocial tendencies were computed for each participant by computing their mean level of cooperation (i.e. the proportion of trials they decided to give). Two survey measures were collected and analyzed for exploratory analyses reported in the supplement: emotional ratings for each PGG outcome (see Supplementary Sec. S1) and group identification with each university ([@ref60]) (see Supplementary Sec. S2). Additional survey measures were collected at the end of the study but are not included in the present analyses[^1^](#fn1){ref-type="fn"}. Dictator game {#sec7} ------------- As an independent measure of prosociality, participants played two dictator games upon exiting the scanner: one with a student from the prosocial school and one with a student from the antisocial school. Participants could allocate anywhere from \$0.00---\$1.00 to each student using a slider bar. The amount given to both groups was averaged into an overall measure of prosociality. At the end of the study, participants were informed that no students were actually going to be paid and they were paid the full \$2.00 they were originally endowed with (regardless of their actual allotment). Explicit estimation {#sec8} ------------------- We next assessed the extent to which students' explicitly learned the social norms. Using a slider bar, participants estimated the percentage of students that cooperated from each school. We took the difference between these scores for each participant to compute a measure of norm detection (i.e. the extent to which students from the prosocial school cooperated more often than the antisocial school). Positive scores indicate students who (correctly) remembered the prosocial school giving more often whereas negative scores indicate students who (incorrectly) remembered the antisocial school giving more often. Behavioral analyses {#sec9} ------------------- Analyses of cooperative behavior were conducted using generalized estimating equations ([@ref39]) (GEE) with an exchangeable correlation structure clustered on each participant[^2^](#fn2){ref-type="fn"}. These procedures account for repeated measures in a regression framework and were implemented using the geepack package ([@ref25]) in R ([@ref12]). We used logistic regression with cooperation operationalized as a binary outcome for each trial (0 = Keep, 1 = Give). Parametric tests were only conducted on measures where we observed insufficient evidence for non-normality (α = 0.05; Shapiro--Wilk test). Otherwise, bootstrap confidence intervals were computed with 10 000 simulations. fMRI data acquisition {#sec10} --------------------- Functional imaging was conducted using a Siemens (Erlangen, Germany) 3.0 Tesla Allegra head-only MRI scanner. Functional images were acquired using a customized multi-echo EPI sequence developed by the NYU Center for Brain Imaging to mitigate the effects of susceptibility artifacts in medial temporal and ventromedial regions (TR = 2000 ms; TE = 15 ms; Flip Angle = 82°; 34 3 mm slices with a 0.45 mm gap for whole-brain coverage, Matrix = 64 × 80; FOV = 192 × 240 mm; Acquisition voxel size = 3 × 3 × 3.45 mm). This sequence has been described in detail in prior work ([@ref24]). Each volume comprised 34 axial slices collected in an interleaved-ascending manner and parallel to the AC-PC line. Data were collected in four sessions, 225 volumes each (7 min and 30 sec). Six scans were acquired at the start of each run and dropped from analysis to allow magnet equilibration. During this time, participants were told which university they would be playing with. Finally, whole-brain high-resolution structural scans (T1-weighted, MPRAGE, 1 × 1 × 1 mm resolution) were acquired from all participants, coregistered with their mean EPI images and averaged together to permit anatomical localization of the functional activations at the group level. fMRI data pre-processing {#sec11} ------------------------ Image analysis was performed using SPM12. Images were corrected for slice-time acquisition and realigned to correct for participant motion, coregistered to structural images, transformed to conform to the default T1 Montreal Neurological Institute (MNI) brain interpolated to 3 × 3 × 3 mm, smoothed using a Gaussian kernel with a full-width-at-half-maximum of 6-mm, corrected for artifacts using the ArtRepair toolbox ([@ref41]) and detrended using the LMGS toolbox ([@ref40]). The blood-oxygenation-level-dependent (BOLD) signal was modeled using a canonical hemodynamic response function. A general linear model (GLM) included (1) onset of give decisions, (2) onset of keep decisions, (3) onset of feedback after give decisions and (4) onset of feedback after keep decisions. Reaction times were entered for decision epoch durations, such that each trial was modeled as having a duration of the participant's reaction time ([@ref23]). Further regressors of no interest included (5) onsets of choice epochs for missed trials (i.e. non-responses), (6) feedback epochs for missed trials, as well as six movement parameters from the realignment stage. A high-pass filter with cutoff period of 128 s was used. To analyze the impact of prosocial tendencies, first-level contrasts for Give \> Keep were generated and entered into a second-level random effects analysis along with each participant's mean cooperation (i.e. proportion of give decisions) as an interaction term. To analyze the impact of descriptive norms, first-level contrasts for Give \> Keep were generated separately for each of the four scanner sessions. Norm-level contrasts were computed for each participant by averaging session contrasts corresponding to each norm and then subtracting the antisocial contrast from the prosocial contrast. These contrasts were then entered into second-level random effects analyses. For a psychophysiological interaction (PPI) analysis of overall choice, vmPFC activity served as a physiological variable, choice type (free-riding *vs* giving) served as a psychological variable, and the interaction of these variables was examined; individual differences in prosociality served as a moderator in a second-level analysis. For a PPI analysis of norm congruence, vmPFC activity served as a physiological variable, choice type (congruent with norm *vs* deviant from norm) served as a psychological variable, and the interaction of these variables was examined; individual differences in norm detection served as a moderator in a second-level analysis. Based on past work, our hypotheses targeted specific regions of interest (ROIs): the vmPFC and the dlPFC. To constrain our analysis to these regions, we used existing ROI masks for vmPFC and dlPFC based on prior work ([@ref65]). These ROIs were constructed with the MarsBar toolbox by combining corresponding structures from the Harvard--Oxford Maximum Probability Atlases ([@ref20]) (see [Supplementary Figure S6](#sup1){ref-type="supplementary-material"}). The vmPFC ROI consisted of the frontal pole, frontal medial cortex, paracingulate gyrus, subcallosal cortex, constrained by rectangular prism X = \[−14, 14\], Y = \[10, 80\], Z = \[−35, 0\]. The dlPFC ROI consisted of the frontal pole, inferior frontal gyrus and middle frontal gyrus, constrained by bilateral rectangular prism X = \[−60, −30 (L); 30, 60 (R)\], Y = \[20, 70\], Z = \[5, 55\]. Small-volume corrections were conducted using these ROI masks. Unless otherwise noted, all analyses were corrected for multiple comparisons using a voxel-wise height threshold of *P* \< 0.001 combined with an appropriate cluster extent to maintain a family-wise error (FWE) rate of *P* \< 0.05, using Gaussian random field theory as implemented in SPM ([@ref21]). ROI effect size estimation {#sec12} -------------------------- Given the difficulty of drawing conclusions from null results, we conducted the following procedure to estimate effect sizes for non-significant contrasts. Using Marsbar, we first extracted each subject's average betas (i.e. predicted amplitude) for each contrast within each ROI mask. We then computed the mean amplitude across 10 000 bootstrapped simulations and report the 95% confidence interval of the resulting distribution of means. Computational model {#sec13} ------------------- We fit a computational model that estimated participants' trial-by-trial expectations about the number of expected givers on each round. This model assumed participants chose to give or keep based on (1) a constant term and (2) the number of expected givers on a given round:$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}\begin{equation*} p{G}_t=\frac{1}{1+{e}^{\left(-c+-\beta \times G\right)}} \end{equation*}\end{document}$$where $\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}${pG}_t$\end{document}$ is the probability of giving on trial *t, c* is a constant term, $\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\beta$\end{document}$ is a weight on the expected number of givers for that trial and $\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$G$\end{document}$ is the expected number of givers. Separate estimates of *G* were held for each university. On each trial, *G* was updated for the relevant university using a delta-learning rule:$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}\begin{equation*} {G}_t={G}_{t-1}+\alpha \delta \end{equation*}\end{document}$$where $\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$ \alpha$\end{document}$ is a learning rate parameter and $\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\delta$\end{document}$ is a prediction error related to the expected number of givers:$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}\begin{equation*} \updelta= Number\ of\ Givers\ - G\end{equation*}\end{document}$$ The number of givers was rescaled to range from −1 to 1, so that the constant term would be interpretable at the mean number of givers. Finally, given that the proportion of givers in each group did not change over time, participants could learn the contingencies relatively early on. We therefore allowed the learning rate to decay over time with a decay parameter *d* between 0 and 1 ([@ref43]):$$\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}\begin{equation*} {\alpha}_t={\alpha}_{t-1}\times d \end{equation*}\end{document}$$ This model was fit using maximum likelihood estimation. We applied parameters derived from the model to each participant's data to compute trial-by-trial estimates for the expected number of givers for each participant (see Supplementary Sec. S5 for more details on the modeling approach and [Supplementary Table S2](#sup1){ref-type="supplementary-material"} for parameter estimates). This time series was entered as a parametric modulator of choice, using the same first-level fMRI GLM described in the primary analysis. This analysis was whole-brain corrected for multiple comparisons. Data availability {#sec14} ----------------- All relevant and deidentified, pre-processed data and materials have been made publicly available at the following OSF link: (<https://osf.io/hfngs/>). Results {#sec15} ======= Behavioral Results {#sec16} ------------------ *Prosocial tendencies.* On average, participants cooperated on 33.57% of the trials (SD = 28.40%). Nonetheless, there were large individual differences between participants, ranging from one participant who always cooperated to seven free-riders who chose to keep on all 100 trials (see [Supplementary Figure S1](#sup1){ref-type="supplementary-material"}). Reaction times did not vary between giving and keeping or between norm condition. However, RTs did depend on individual differences in prosocial tendencies, such that cooperation tended to be faster among prosocial participants (see Supplementary Sec. S3). *Descriptive norms*. To ensure participants encoded the descriptive norm manipulation, we conducted a paired *t*-test to assess whether participants estimated different rates of cooperation between the schools (i.e. norm detection). Participants noticed that students from the prosocial school cooperated more often (*M* = 54.71%, *SD* = 23.37%) than students from the antisocial school (*M* = 32.10%, *SD* = 21.30%), suggesting they learned that group norms differed, *t*(41) = 4.34, *d* = 0.67, *P* \< .001 (see [Supplementary Figure S3](#sup1){ref-type="supplementary-material"}). In turn, descriptive norms impacted cooperation. Participants were more likely to cooperate with students from the prosocial school (*M* = 40.42%, *SD* = 49.08%) than the antisocial school (*M* = 24.08%, *SD* = 42.77%; Odds ratio = 2.15, Wald *χ*^2^(1) = 26.4, *P* \< 0.001; see Supplementary Sec. S3 for reaction time analysis). Moreover, norm compliance (i.e. preferential cooperation with the prosocial *vs* antisocial school) was associated with norm detection (*M* = 22.62%, *SD* = 33.77%; *r*(40) = 0.36, bootstrapped 95% CI: \[0.12, 0.55\]): participants who correctly recalled greater cooperation from the prosocial school were more cooperative towards the prosocial school. Neuroimaging results {#sec17} -------------------- *Overall cooperation*. We first tested whether cooperation and defection overall were associated with neural activation in vmPFC and dlPFC. Such findings could be consistent with models asserting that intuition drives cooperation and deliberation promotes self-interest (prosocial intuition; [@ref50], [@ref51]) or that humans are impulsively selfish and require self-control to cooperate (prosocial restraint; [@ref58]; [@ref31]). We tested the first prosocial restraint hypothesis by examining whether the mean signal within vmPFC (defined through an anatomical region of interest; see Methods) was higher during free-riding as opposed to cooperation (i.e. Give \> Keep). Therefore, seven participants with invariant decisions (i.e. cooperating or free-riding on every trial) were excluded from this analysis, leaving 35 participants. No significant vmPFC activation was observed in this contrast at thresholds with small volume corrections (*p*~voxel~ \< 0.001; *p*~cluster~ \< 0.05). We then examined whether dlPFC activity increased during cooperation *vs* free-riding (i.e. Keep \> Give), but observed no significant difference. We reversed these contrasts to test the two prosocial intuition hypotheses: vmPFC is more active when cooperating (i.e. Keep \> Give) and dlPFC activity increases during free-riding (i.e. Give \> Keep). However, we did not observe significant differences for these contrasts. Bootstrapped 95% confidence intervals of the signal change for cooperative (relative to selfish) choices indicated that mean vmPFC signal may increase up to 0.387% or decrease up to 0.474% whereas mean dlPFC signal may increase up to 0.224% or decrease up to 0.173%. Thus, we found insufficient evidence that these regions were differentially recruited for cooperation or free-riding. These results were not consistent with simplified prosocial restraint or prosocial intuition models of cooperation. Thus, we examined whether activation in these regions depends on cooperative tendencies and social norms. *Prosocial tendencies.* According to the value-based approaches, vmPFC should be more responsive during choices aligned with one's prosocial tendencies: selfish participants should display greater vmPFC responses when free-riding and prosocial participants should display greater vmPFC responses when cooperating (see VB~H1~). This is because vmPFC has been found to represent the difference in value between chosen *vs* unchosen options ([@ref5]; [@ref42]; [@ref24]). As a result, vmPFC activity should be higher for a prosocial participant when giving (i.e. when relative value is higher) than when keeping (i.e. when relative value is lower). For a free-riding participant, the reverse should be true. To test this hypothesis, we entered each participant's mean cooperation into a second-level GLM as an estimate of prosociality, and then tested the interaction between prosociality and decision type (i.e. cooperate *vs* free-ride)[^3^](#fn3){ref-type="fn"}. We observed a cluster of vmPFC for the interaction of Prosociality x Decision, *t*(33) = 4.99, *k* = 53, *p*~cluster~ \< 0.001 ([Figure 2A and B](#f6){ref-type="fig"}; see [Supplementary Table S1](#sup1){ref-type="supplementary-material"})[^4^](#fn4){ref-type="fn"}. Consistent with value-based approach, decisions that aligned with one's prosociality elicited greater vmPFC activity: free-riders had more vmPFC activity when free-riding, whereas cooperators had greater vmPFC activity when cooperating. {#f6} We examined whether prosociality moderated dlPFC activity during choices that *conflicted* with prosociality (i.e. selfish participants cooperating or cooperative participants free-riding). For this prosociality × decision interaction, we observed two clusters within right dlPFC (both with equal cluster sizes, *k =* 13*, p*~cluster~ *=* 0.050). More prosocial participants showed greater right dlPFC activity when free-riding whereas participants with selfish tendencies showed greater activity when cooperating (see [Figure 2C](#f6){ref-type="fig"}). Moreover, we obtained the same findings when using a self-report measure of cooperative preferences that was not derived from behavior and was not specific to either norm context. Specifically, after the main task, participants reported how positively and negatively they felt upon giving and keeping; when using relative positive affect during giving *vs* keeping as an alternative measure of individual cooperative preference, we observed the same patterns of activation in vmPFC and dlPFC described above (see Supplemental Figure S5, and Supplementary Sec. S1). Some value-based models also assert that dlPFC and vmPFC become temporally correlated when making more difficult, goal-directed choices (see VB~H2~). To test this prediction, we examined whether functional connectivity between dlPFC-vmPFC was moderated by prosociality. We conducted a psychophysiological interaction (PPI) analysis with the right dlPFC cluster for non-dominant choices ([Figure 2C](#f6){ref-type="fig"}) and the vmPFC cluster for dominant choices as a seed region ([Figure 2A](#f6){ref-type="fig"}). We examined connectivity as a function of cooperative *vs* free-riding decisions, with prosociality serving as an individual difference. Cooperative participants showed greater right dlPFC-vmPFC connectivity when free-riding, whereas selfish participants showed greater connectivity when cooperating, *r*(33) = −0.23, bootstrapped 95% CI: \[−0.56, −0.04\], *t*~R~ = −2.00 ([Figure 2D](#f6){ref-type="fig"})[^5^](#fn5){ref-type="fn"}. In other words, participants showed greater dlPFC-vmPFC connectivity when making choices that ran counter to their prosociality, consistent with the value-based approach. *Social norms.* If norms amplify the value of conformity ([@ref44]), then a value-based approach would predict greater dlPFC-vmPFC connectivity when choosing to deviate from norms (i.e. cooperating in antisocial groups or free-riding in prosocial groups; see VB~H3~). We tested this prediction by conducting another PPI analysis with the dominant choice vmPFC cluster ([Figure 2A](#f6){ref-type="fig"}) as the seed region and the non-dominant choice dlPFC cluster ([Figure 2C](#f6){ref-type="fig"}). We contrasted deviant *vs* compliant decisions (i.e. cooperating with the prosocial group and free-riding with the antisocial group *vs* free-riding with the prosocial group and cooperating with the antisocial group)[^6^](#fn6){ref-type="fn"}. We did not observe any significant connectivity changes across decision type: bootstrapped confidence intervals for deviant (*vs* compliant) choices indicated mean dlPFC connectivity may increase up to 0.172% or decrease up to 0.189%. Our measure of norm detection indicated that not all participants learned the group norms. Since this norm-detection measure was positively associated with behavioral norm compliance, it seemed possible that norms modulated dlPFC-vmPFC connectivity in a manner dependent on how participants perceived the norms. To test this possibility, we conducted an exploratory analysis similar to our individual difference analysis above: we entered individual differences in norm detection as a predictor in the second-level GLM. We observed a positive correlation between norm detection and dlPFC-vmPFC connectivity: participants who correctly perceived the norms elicited greater right dlPFC-vmPFC connectivity when deviating from the group, *r*(33) = 0.50, bootstrapped 95% CI: \[0.22, 0.69\], *t*~R~ = 2.90 ([Figure 3](#f16){ref-type="fig"}). This suggests that vmPFC and dlPFC are more functionally correlated when (a) participants who correctly perceived norms deviated from actual group norms and (b) participants who incorrectly perceived norms complied with group norms, thus deviating from their *perceived* norms. That is, participants who incorrectly perceived norms showed greater vmPFC-dlPFC connectivity when deviating from their *subjectively* perceived norms, much as participants who correctly perceived norms showed greater vmPFC-dlPFC connectivity when deviating from the *objective* norms. {#f16} We examined whether this connectivity predicted norm compliance (i.e. preferential cooperation with the prosocial *vs* antisocial school). We observed an interaction whereby participants with greater right dlPFC-vmPFC connectivity during deviant decisions engaged in greater norm-compliant cooperation, OR = 1.97, 95% CI = \[1.26, 3.10\], Wald *χ*^2^(1) =8.72, *P* = 0.003. This suggests that vmPFC and dlPFC are more functionally correlated when (a) norm-compliant participants deviate from norms and (b) non-compliant participants comply with norms; the latter finding may reflect the fact that non-compliance was correlated with incorrect perceptions of norms, as reported above. We did not observe a relationship between group norms and vmPFC activity (see Supplementary Sec. S6). *Evolving expectations*. Adapting to norms requires people to update and deploy expectations about how others will cooperate. We therefore tested whether neural activity during choice reflected expectations about others' cooperation. We fit participant choices to a computational model of learning and choice, which assumed that people updated an estimate of average cooperation for each group following feedback on each trial. Estimates were updated with a prediction error, or the discrepancy between the actual and expected number of cooperators on each trial. This model allowed us to estimate, in a trial-by-trial manner, the number of givers participants expected while making decisions and analyze whether any neural regions tracked this quantity during choice. Increased expectation of givers during choice was associated with activation near the right temporoparietal junction ([Figure 4](#f17){ref-type="fig"}). Given this region's purported role in theory of mind tasks ([@ref22]), this may reflect increased social cognitive processing during choices where others were expected to cooperate. If so, internalizing social norms may play a key role in future cooperation---a form of social prediction. It also suggests participants dynamically tracked expectations related to norms during decision-making. {#f17} Discussion {#sec18} ========== Value-based models contend that psychological processes supporting cooperation may hinge on idiosyncratic preferences as well as contextual factors that shift these preferences ([@ref32]; [@ref47]). Consistent with this approach, we find that vmPFC and dlPFC activity during cooperation depends upon individual differences in prosociality and sensitivity to social norms. Specifically, prosocial participants elicited greater vmPFC activity when cooperating as well as heightened right dlPFC activity and dlPFC-vmPFC connectivity when free-riding. Self-serving participants showed the reverse pattern. Thus, neither the vmPFC nor the dlPFC exhibited a consistent role in cooperation, but instead showed greater activation when people acted consistently or inconsistently with their prosocial tendencies, respectively. These findings are consistent with the idea that vmPFC activity reflects a decision value that can be modulated by dlPFC ([@ref52]). In contrast, prominent models rooted in dual-process frameworks argue that cooperation is either reflexive (*prosocial intuition* models) or primarily stems from deliberate self-control (*prosocial restraint* models). Past neuroimaging work rooted in dual-process tradition associated vmPFC with intuitive processing and dlPFC with deliberative processing. Thus, the *prosocial restraint model* implied free-riding would be associated with vmPFC activity and cooperation would be associated with dlPFC activity. In contrast, the *prosocial intuition model* implied cooperation would be associated with greater vmPFC activity and free-riding would be associated with greater dlPFC activity. When adopting this interpretation of vmPFC and dlPFC, our data still suggest that prosocial participants are intuitive cooperators, which conflicts with prosocial restraint models, and that selfish participants are deliberative cooperators, which conflicts with prosocial intuition models. Thus, our findings support a value-based interpretation of vmPFC and dlPFC activity or require a more flexible dual-process model that can account for the moderating roles of prosociality and norms. The current research further indicates that norms shape cooperation. Participants who were most attentive to norms aligned their behavior with norms and showed greater right dlPFC-vmPFC connectivity when deviating from norms, whereas the least attentive participants showed the reverse pattern. Curiously, we found no clear evidence that decisions to conform were more valued than decisions to deviate. This conflicts with work suggesting social norms boost the value of norm compliance ([@ref44]). Instead, our findings suggest that norm compliance can also stem from increased functional connectivity between vmPFC and dlPFC. Our findings raise questions about how people model the dynamic shifts in norms that vary over time and between groups. We fit a computational model of learning to understand how people represent the cooperation expected from each group. Expectation of givers during decision-making was associated with activation in a region near the right temporoparietal junction---a region related to theory of mind ([@ref22]). This finding comports well with recent work ([@ref46]) and suggests that social cognitive systems may interface with the construction of value to guide decisions. The present research highlights two important factors that modulate the neuro-cognitive processes guiding cooperation: prosociality and social norms. Rather than neural activity in vmPFC *always* reflecting either prosocial or selfish behavior, the value of cooperation may be lower among selfish individuals or in selfish environments. The notion that cooperation necessarily stems from reflexive intuitions ignores the possibility that some individuals value the outcomes of others. This idea coheres with evidence that selfish participants more often cooperate by mistake, whereas prosocial participants accidentally prioritize their self-interest ([@ref29]). Thus, intuition may trigger cooperative mistakes from selfish participants but deter prosocial participants from second guessing their cooperation. Conclusion {#sec19} ========== In conclusion, more flexible models are needed to specify when, and for whom, cooperation is intuitive or deliberative. This study highlights the advantage of social neuroscience methods for disambiguating the decision-making processes that guide prosocial behavior. The present findings are largely inconsistent with models that assume one mental process always supports cooperation but are consistent with a value-based approach to understanding cooperation. Although our focus on dlPFC and vmPFC helped constrain our hypotheses, cooperation is complex and draws on a widely distributed network of neural systems implicated in prosocial behavior ([@ref34]; [@ref17]; [@ref18]; [@ref29]; [@ref19]). For instance, other reward-related regions, such as caudate, are involved in prosocial choices ([@ref36]) and may show differential patterns of activation across individuals with strong *vs* weak prosocial preferences. Similarly, as evidence accumulates that moral decisions rely on more dynamic, distributed and multi-faceted neurocognitive processing ([@ref61]), more flexible models of value-based decision-making appear to offer a fruitful account for prosociality. Supplementary Material ====================== ###### Click here for additional data file. We thank E. Owens for assistance with data collection, and members of the New York University Social Perception and Evaluation Laboratory for comments on the manuscript. This work was funded by the New York University Center for Brain Imaging and the US National Science Foundation grant \#1349089 awarded to J.V.B., grant \#1606959 awarded to L.H., and graduate research fellowship awarded to J.W. There are no conflicts of interest to declare. These include the Levenson Self-Report Psychopathy Scale ([@ref37]), Groupiness Scale (Dunham & Van Bavel, unpublished), Social Value Orientation ([@ref62]), and additional demographic information (e.g. political ideology, socioeconomic status, etc.) Unlike traditional OLS regression, GEE parameter estimates are typically evaluated using a Wald *χ*^2^ distribution with 1 degree of freedom. See Krajbich et al., (2015) for or a similar analytic strategy with behavioral data. The *t* statistic reported for this contrast (as well as all subsequent contrasts) refers to the peak voxel within the cluster. We use the *t*~R~ notation to indicate *t* statistics calculated using the robust linear regression procedure with an M estimator available in the MASS package ([@ref01]) for R ([@ref12]). One additional participant was excluded from this analysis because they never cooperated when playing with the antisocial students. This left thirty four valid participants in all fMRI analyses involving descriptive norms.

Missouri State Senator Maria Chappelle-Nadal hoped for the assassination of President Trump in a Facebook comment on Thursday then deleted it in a panic. She even acknowledged she would get a visit from the Secret Service for her comment. Maria Chappelle-Nadal’s Facebook comment was so egregious that even ABC News reported on the story. Then on Thursday Chappelle-Nadal tweeted out a Holocaust threat to Jewish Missouri Governor Eric Greitens. On Friday Missouri Lt. Governor Mike Parsons told Senator Chappelle-Nadal to step down or be removed from office. TRENDING: BREAKING: Omaha Bar Owner Charged For Killing Rioter Who Attacked Him and His Business Has Committed Suicide Now this… Maria Chappelle-Nadal finally issued a tearful apology on Sunday in a Facebook interview that streamed live. Chappelle-Nadal said her judge and her jury is my Lord Jesus Christ. Here’s some video of Sen. Chappelle-Nadal’s remarks in Ferguson today. #moleg pic.twitter.com/ByMhEfvlvx — Celeste Bott (@celestebott) August 20, 2017 Now this… A petition was launched on Change.org to remove Maria Chapppelle-Nadal from office AND arrest her. The petition already has over 9,000 signatures. From the petition.

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package com.htmessage.fanxinht.acitivity.moments; import android.app.Activity; import android.content.Intent; import android.view.LayoutInflater; import android.view.View; import android.view.ViewGroup; import android.widget.BaseAdapter; import android.widget.ImageView; import android.widget.RelativeLayout; import android.widget.TextView; import com.alibaba.fastjson.JSONObject; import com.bumptech.glide.Glide; import com.bumptech.glide.load.engine.DiskCacheStrategy; import com.htmessage.fanxinht.HTApp; import com.htmessage.fanxinht.HTConstant; import com.htmessage.fanxinht.R; import com.htmessage.fanxinht.acitivity.moments.widget.MomentsItemView; import com.htmessage.fanxinht.domain.MomentsMessage; import com.htmessage.fanxinht.domain.MomentsMessageDao; import java.util.ArrayList; import java.util.HashMap; import java.util.List; import java.util.Map; public class MomentsAdapter extends BaseAdapter { private Activity context; private List<JSONObject> jsonArray; private MomentsMessageDao momentsMessageDao; private RelativeLayout re_unread; private ImageView iv_moment_bg; private String backgroud = ""; private String serverTime; public MomentsAdapter(Activity context1, List<JSONObject> jsonArray, String backgroud) { this.context = context1; this.jsonArray = jsonArray; momentsMessageDao = new MomentsMessageDao(context1); this.backgroud = backgroud; } @Override public int getCount() { return jsonArray.size() + 1; } @Override public JSONObject getItem(int position) { if (position == 0) { return null; } else { return jsonArray.get(position - 1); } } @Override public long getItemId(int position) { return position; } @Override public int getItemViewType(int position) { if (position == 0) { return 0; } else { return 1; } } @Override public int getViewTypeCount() { return 2; } @Override public View getView(final int position, View convertView, ViewGroup parent) { if (getItemViewType(position) == 0) { convertView = LayoutInflater.from(context).inflate(R.layout.item_moments_header, null, false); ImageView iv_avatar = (ImageView) convertView.findViewById(R.id.iv_avatar); re_unread = (RelativeLayout) convertView.findViewById(R.id.re_unread); iv_moment_bg = (ImageView) convertView.findViewById(R.id.iv_moment_bg); initHeaderView(); Glide.with(context).load(HTApp.getInstance().getUserJson().getString(HTConstant.JSON_KEY_AVATAR)).diskCacheStrategy(DiskCacheStrategy.ALL).placeholder(R.drawable.default_avatar).error(R.drawable.default_avatar).into(iv_avatar); iv_moment_bg.setOnClickListener(new View.OnClickListener() { @Override public void onClick(View v) { if (adapterListener != null) { adapterListener.onMomentTopBackGroundClock(); } } }); setBackground(backgroud); } else { if (convertView == null) { convertView = LayoutInflater.from(context).inflate(R.layout.item_moments, parent, false); } ViewHolder holder = (ViewHolder) convertView.getTag(); if (holder == null) { holder = new ViewHolder(); holder.momentsItemView = (MomentsItemView) convertView.findViewById(R.id.main); convertView.setTag(holder); } JSONObject json = jsonArray.get(position - 1); final int realPosition = position - 1; // = new MomentsItemView(context); holder.momentsItemView.initView(json, getServerTime()); holder.momentsItemView.setOnMenuClickListener(new MomentsItemView.OnMenuClickListener() { @Override public void onUserClicked(String userId) { if (adapterListener != null) { adapterListener.onUserClicked(realPosition, userId); } } @Override public void onGoodIconClicked(String aid) { if (adapterListener != null) { adapterListener.onPraised(realPosition, aid); } } @Override public void onCommentIconClicked(String aid) { if (adapterListener != null) { adapterListener.onCommented(realPosition, aid); } } @Override public void onCancelGoodClicked(String aid) { if (adapterListener != null) { adapterListener.onCancelPraised(realPosition, aid); } } @Override public void onCommentDeleteCilcked(String cid) { if (adapterListener != null) { adapterListener.onCommentDelete(realPosition, cid); } } @Override public void onDeleted(String aid) { if (adapterListener != null) { adapterListener.onDeleted(realPosition, aid); } } @Override public void onImageListClicked(int index, ArrayList<String> images) { if (adapterListener != null) { adapterListener.onImageClicked(realPosition, index, images); } } }); setItemView(realPosition, (MomentsItemView) convertView); } return convertView; } private class ViewHolder { MomentsItemView momentsItemView; } public void setBackground(String url) { this.backgroud=url; if (iv_moment_bg == null) { return; } Glide.with(context).load(url).diskCacheStrategy(DiskCacheStrategy.ALL).placeholder(R.drawable.bg_moments_header).error(R.drawable.bg_moments_header).into(iv_moment_bg); } public void initHeaderView() { if (re_unread == null) { return; } int count = momentsMessageDao.getUnreadMoments(); if (count > 0) { MomentsMessage momentsMessage = momentsMessageDao.getLastMomentsMessage(); re_unread.setVisibility(View.VISIBLE); re_unread.setOnClickListener(new View.OnClickListener() { @Override public void onClick(View v) { context.startActivity(new Intent(context, MomentsNoticeActivity.class)); } }); ImageView imageView = (ImageView) re_unread.findViewById(R.id.msg_avatar); TextView tvCount = (TextView) re_unread.findViewById(R.id.tv_count); tvCount.setText(count + context.getString(R.string.msg_count)); Glide.with(context).load(momentsMessage.getUserAvatar()).placeholder(R.drawable.default_avatar).diskCacheStrategy(DiskCacheStrategy.ALL).into(imageView); } else { re_unread.setVisibility(View.GONE); } } public void hideHeaderView() { if (re_unread == null) { return; } re_unread.setVisibility(View.GONE); } private Map<Integer, MomentsItemView> views = new HashMap<>(); public MomentsItemView getItemView(int position) { return views.get(position); } private void setItemView(int position, MomentsItemView momentsItemView) { views.put(position, momentsItemView); } public void setServerTime(String serverTime) { this.serverTime = serverTime; } public String getServerTime() { return serverTime; } private AdapterListener adapterListener; public void setListener(AdapterListener adapterListener) { this.adapterListener = adapterListener; } }

alculate the remainder when t(-16) is divided by r. 0 Let a be (-2)/(-4) - 1/(-2). Let t be -72 - ((-1)/a + -1). Let v = 109 + t. What is the remainder when v is divided by 14? 11 Calculate the remainder when (-6 - -10) + 2 + 218 is divided by 80. 64 Suppose 0 = -2*c + c + 4. Let t(b) = 4*b - 5. What is the remainder when 74 is divided by t(c)? 8 What is the remainder when 35 is divided by 3/(49/(-14)*(-9)/273)? 9 Let g(m) be the first derivative of -m**2 - 32*m - 9. Calculate the remainder when 54 is divided by g(-23). 12 Let h(p) = -4*p - 4. Let b be h(-3). Suppose -b*c + 422 = -226. What is the remainder when c is divided by 28? 25 Suppose -4*a + 0*a = 3*g - 20, 0 = -2*g - 4*a + 16. Suppose -5*w = -20, g*w = 4*o - o - 101. Let s = -126 - -140. What is the remainder when o is divided by s? 11 Suppose -6*f + 13 = -2*f + 5*n, -f + n = -10. Let g(r) = 5*r + 13. What is the remainder when 141 is divided by g(f)? 45 Suppose 5*u + 18 = -2, 2*u + 1 = g. Let z = -4 - g. Suppose -40 = -5*w - 5*p, 3*w - z*p = w - 4. Calculate the remainder when 6 is divided by w. 2 Let h(i) = 2 - 3*i**2 + i**2 + i**2 - 3 + 16*i. Let v = 34 + -21. Calculate the remainder when h(13) is divided by v. 12 Suppose -5*g + 5*u + 295 = 0, g - 6*u = -9*u + 47. Calculate the remainder when g is divided by 11. 1 Suppose 0 = 46*a - 21*a - 5300. What is the remainder when a is divided by 7? 2 Let l(g) = -6*g + 7. Let v(y) = -y. Let p(u) = -l(u) + 3*v(u). What is the remainder when 40 is divided by p(7)? 12 Let n(v) = 10*v + 69. What is the remainder when n(0) is divided by 6? 3 Let k(r) be the first derivative of r**3/3 - r**2/2 + 127*r + 41. Calculate the remainder when k(0) is divided by 16. 15 Suppose 34*t = 4062 - 1512. What is the remainder when t is divided by 13? 10 Let k(z) = 2*z + 15. Let i be ((-4)/6)/(5/(-3 - -48)). Calculate the remainder when 20 is divided by k(i). 2 Suppose 3*p + 30 = -42. Let s = p + 36. What is the remainder when 15 is divided by s? 3 Let x = 9167 - 8983. Let q = 75 + -44. Calculate the remainder when x is divided by q. 29 Let n be (50/(-10))/(1/(-2)). Let k = -6 + n. Suppose k*j = 6*j - 10. Calculate the remainder when 7 is divided by j. 2 Let c(x) = 625*x + 59. What is the remainder when c(3) is divided by 43? 42 Let m(b) = 36*b**3 + 9*b**2 - b - 5. Let v(g) = 73*g**3 + 19*g**2 - 2*g - 11. Let r(d) = 13*m(d) - 6*v(d). Calculate the remainder when r(2) is divided by 23. 21 Let j = -37 + 53. Suppose -5*a + a = -j, 0 = -5*i - 5*a + 50. What is the remainder when i is divided by 3? 0 Suppose 5*p = 2*p + 30. Calculate the remainder when 23 is divided by p. 3 Suppose 0*w + 6*w + 54 = 0. Let r = 11 + w. Suppose r*f - 44 = 10. Calculate the remainder when f is divided by 7. 6 Let o(m) = m**3 + 14*m**2 + 3*m - 58. What is the remainder when 271 is divided by o(-13)? 55 Let m = 4 - -29. What is the remainder when 361 is divided by m? 31 Let g = -5 + 15. Suppose 0 = h - 0*h - i + 196, -4*i = 5*h + 953. Let x = h + 212. Calculate the remainder when x is divided by g. 9 Let m = 7 + -5. Let x = -114 + 123. Calculate the remainder when 16/(m/(2/1)) is divided by x. 7 Suppose 8 = 2*o, 5*q - o - o - 42 = 0. Suppose 0 = 3*n + 4*b - 22, -5*b + q*b = 3*n - 40. Let t = n - 1. Calculate the remainder when 34 is divided by t. 7 Calculate the remainder when 2/(-4) + (-168)/(-16) is divided by (-7)/(-2) + (-11)/22. 1 Let j(w) = w**3 + 5*w**2 - 9*w - 6. Suppose 0 = 5*h + 31 - 1. Calculate the remainder when j(h) is divided by (9 + -4)/5*5. 2 Let t(h) = -3*h + 19. Let z be t(6). Suppose 5 = -n + 18. Calculate the remainder when 24 - (z - -1 - 1) is divided by n. 10 Let n = -120 + 123. Suppose 2*w - 28 = -5*s, 87 = 5*w + s + n*s. Calculate the remainder when 56 is divided by w. 18 Let r = 1826 + -1751. What is the remainder when r is divided by (-2)/(-4) - (-74)/4? 18 Let p be 1/((11/54)/11). Let c = 84 - p. Let n(u) = 12*u**2 - 5*u - 4. What is the remainder when n(-3) is divided by c? 29 Let c = 16 + -23. Let u(o) be the second derivative of o**5/20 + o**4/2 - 4*o**3/3 + 3*o**2 + 9*o. What is the remainder when 51 is divided by u(c)? 12 Let p(u) = u**3 - 13*u**2 + 45*u + 29. What is the remainder when 418 is divided by p(9)? 88 Suppose 2*h - 10 = -2*k, h - 3*k + 5*k = 2. What is the remainder when 56 is divided by h? 0 Let i(w) = 9*w - 3. Let h(x) = x**2 - 2*x + 4. Let c be h(0). Suppose z = -c*z + 40. Calculate the remainder when i(2) is divided by z. 7 Suppose 2*y - 175 = 113. Suppose -9*x + y = -45. What is the remainder when x is divided by 6? 3 Let k(d) = -3*d**2 + 4*d + 8. Let w be k(5). Let g = w - -89. What is the remainder when g is divided by 22? 20 Suppose 52*n = -d + 56*n + 45, -3*d - 3*n + 165 = 0. Calculate the remainder when 369 is divided by d. 51 Let s(d) = -22*d - 381. Calculate the remainder when 119 is divided by s(-18). 14 Let g be ((-365)/75 - -5) + (-806)/(-30). Let h = 3 + -3. Suppose h = -0*f + f, -2*f = -x + g. Calculate the remainder when x is divided by 6. 3 Suppose 0 = -m + 5*m - 156. Calculate the remainder when m is divided by (-297)/(-45) - 4/(-10). 4 Suppose -b + 5*b - 73 = 5*j, -3*b + j = -41. Let x = b - 8. Let t(a) = 2*a**3 - a**2 - 2. Calculate the remainder when t(2) is divided by x. 2 What is the remainder when 384 is divided by ((-1)/(-2))/(7/1358)? 93 Suppose -65*u - 5*l + 46 = -64*u, -4*u = -3*l - 161. Calculate the remainder when 405 is divided by u. 36 Let y = 756 + -702. Calculate the remainder when 169 is divided by y. 7 Suppose 3*h - 5*b - 45 = -0*h, 4*h = 3*b + 49. Let z(i) = i**2 - 9*i - 10. Let t be z(h). Suppose t - 34 = -2*r. What is the remainder when r is divided by 6? 5 Let g = -32 - -59. Let c be (6/4)/((-6)/40). Let n = 0 - c. What is the remainder when g is divided by n? 7 Suppose -5*a - 20 = 0, a = 5*g - 3*a - 46. Calculate the remainder when g is divided by (8 + (2 - 5))*1. 1 Suppose 3*q = -f + 11, 2*f + f - 4*q = 20. What is the remainder when 48 is divided by (0 - -1)/(f/136)? 14 Let p = -33 + 35. Suppose 58 = 2*d + 2*v + p*v, 10 = 2*v. What is the remainder when 29 is divided by d? 10 Suppose 0 = -c - 1 + 3. Suppose -13 = -2*r - 5, t + 2*r - 14 = 0. Calculate the remainder when t is divided by ((0 - -3) + c)*1. 1 Let y(v) = -7*v**3 - 9*v**2 - 5*v - 9. Let s(f) = 11*f**3 + 14*f**2 + 8*f + 14. Let q(l) = -5*s(l) - 8*y(l). What is the remainder when q(4) is divided by 25? 23 Let f = -1 - -4. Let s(c) = 7*c - 97. Let z be s(14). Let i = f + z. What is the remainder when 7 is divided by i? 3 Let d be 282 + 5 - (-3)/1. Suppose -13*l + 61 = -d. Calculate the remainder when l is divided by 7. 6 Let k = -34 - -110. Suppose 144 + k = 4*q. Calculate the remainder when q is divided by 29. 26 Let t(j) = -j + 22. What is the remainder when 54 is divided by t(6)? 6 Suppose 3*s + 4*g - 415 = 0, 15*s - 697 = 10*s - 4*g. What is the remainder when s is divided by 33? 9 Suppose -7*o + 701 = -1196. Calculate the remainder when o is divided by 85. 16 Suppose -2*n - 21 = -5*n. Suppose 11*q - 6*q - l = -103, q = 3*l - 15. Calculate the remainder when 33 is divided by 12/q + 130/n. 15 Let w(n) = 3*n**2 + 8*n - 9. Let k = -20 - -62. Calculate the remainder when w(-7) is divided by k. 40 Suppose -8 = 3*c + p - 171, -4*p - 37 = -c. What is the remainder when c is divided by 15? 8 Let d = -771 - -879. Suppose 2*w + t = 6*w - 149, -3*t = 3. What is the remainder when d is divided by w? 34 Let x(s) = -s + 1. Let z(a) = 4*a + 19. Let h(j) = 3*x(j) + z(j). Calculate the remainder when h(-13) is divided by 8/28 - 52/(-14). 1 Let o(g) = 10*g + 45. Calculate the remainder when 176 is divided by o(0). 41 Let g = 53 - 83. Calculate the remainder when 255 is divided by -1*((-86)/3)/((-20)/g). 40 Let x(y) be the first derivative of y**4/4 + 7*y**3/3 + y**2 - y + 2. Let t be x(-7). Let l = t - -22. What is the remainder when 27 is divided by l? 6 Let x = 64 - 195. Let q = -66 - x. What is the remainder when q is divided by 35? 30 Let l = -5 + 10. Suppose -8 = -l*d - 13. What is the remainder when 15 is divided by (12/10)/(d/(-5))? 3 Suppose 219 = 5*p + 4*g - 2*g, -3*p + 4*g = -121. Let h(u) = 2*u**2 - 367*u + 1807. Calculate the remainder when p is divided by h(5). 21 Suppose 8*c - 1260 = -12*c. What is the remainder when 64 is divided by c? 1 L

/* * Copyright (c) 2004, Swedish Institute of Computer Science. * All rights reserved. * * Redistribution and use in source and binary forms, with or without * modification, are permitted provided that the following conditions * are met: * 1. Redistributions of source code must retain the above copyright * notice, this list of conditions and the following disclaimer. * 2. Redistributions in binary form must reproduce the above copyright * notice, this list of conditions and the following disclaimer in the * documentation and/or other materials provided with the distribution. * 3. Neither the name of the Institute nor the names of its contributors * may be used to endorse or promote products derived from this software * without specific prior written permission. * * THIS SOFTWARE IS PROVIDED BY THE INSTITUTE AND CONTRIBUTORS ``AS IS'' AND * ANY EXPRESS OR IMPLIED WARRANTIES, INCLUDING, BUT NOT LIMITED TO, THE * IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE * ARE DISCLAIMED. IN NO EVENT SHALL THE INSTITUTE OR CONTRIBUTORS BE LIABLE * FOR ANY DIRECT, INDIRECT, INCIDENTAL, SPECIAL, EXEMPLARY, OR CONSEQUENTIAL * DAMAGES (INCLUDING, BUT NOT LIMITED TO, PROCUREMENT OF SUBSTITUTE GOODS * OR SERVICES; LOSS OF USE, DATA, OR PROFITS; OR BUSINESS INTERRUPTION) * HOWEVER CAUSED AND ON ANY THEORY OF LIABILITY, WHETHER IN CONTRACT, STRICT * LIABILITY, OR TORT (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY * OUT OF THE USE OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF * SUCH DAMAGE. * * This file is part of the Contiki operating system. * * Author: Adam Dunkels <[email protected]> * */ /** * \file * CFS header file. * \author * Adam Dunkels <[email protected]> * */ /** * \addtogroup sys * @{ */ /** * \defgroup cfs The Contiki file system interface * * The Contiki file system interface (CFS) defines an abstract API for * reading directories and for reading and writing files. The CFS API * is intentionally simple. The CFS API is modeled after the POSIX * file API, and slightly simplified. * * @{ */ #ifndef CFS_H_ #define CFS_H_ #include "contiki.h" #ifndef CFS_CONF_OFFSET_TYPE typedef int cfs_offset_t; #else typedef CFS_CONF_OFFSET_TYPE cfs_offset_t; #endif struct cfs_dir { /* Iteration state, which is implementation-defined and should not be accessed externally. */ char state[32]; }; struct cfs_dirent { char name[32]; cfs_offset_t size; }; /** * Specify that cfs_open() should open a file for reading. * * This constant indicates to cfs_open() that a file should be opened * for reading. CFS_WRITE should be used if the file is opened for * writing, and CFS_READ + CFS_WRITE indicates that the file is opened * for both reading and writing. * * \sa cfs_open() */ #ifndef CFS_READ #define CFS_READ 1 #endif /** * Specify that cfs_open() should open a file for writing. * * This constant indicates to cfs_open() that a file should be opened * for writing. CFS_READ should be used if the file is opened for * reading, and CFS_READ + CFS_WRITE indicates that the file is opened * for both reading and writing. * * \sa cfs_open() */ #ifndef CFS_WRITE #define CFS_WRITE 2 #endif /** * Specify that cfs_open() should append written data to the file rather than overwriting it. * * This constant indicates to cfs_open() that a file that should be * opened for writing gets written data appended to the end of the * file. The default behaviour (without CFS_APPEND) is that the file * is overwritten with the new data. * * \sa cfs_open() */ #ifndef CFS_APPEND #define CFS_APPEND 4 #endif /** * Specify that cfs_seek() should compute the offset from the beginning of the file. * * \sa cfs_seek() */ #ifndef CFS_SEEK_SET #define CFS_SEEK_SET 0 #endif /** * Specify that cfs_seek() should compute the offset from the current position of the file pointer. * * \sa cfs_seek() */ #ifndef CFS_SEEK_CUR #define CFS_SEEK_CUR 1 #endif /** * Specify that cfs_seek() should compute the offset from the end of the file. * * \sa cfs_seek() */ #ifndef CFS_SEEK_END #define CFS_SEEK_END 2 #endif /** * \brief Open a file. * \param name The name of the file. * \param flags CFS_READ, or CFS_WRITE/CFS_APPEND, or both. * \return A file descriptor, if the file could be opened, or -1 if * the file could not be opened. * * This function opens a file and returns a file * descriptor for the opened file. If the file could not * be opened, the function returns -1. The function can * open a file for reading or writing, or both. * * An opened file must be closed with cfs_close(). * * \sa CFS_READ * \sa CFS_WRITE * \sa cfs_close() */ #ifndef cfs_open CCIF int cfs_open(const char *name, int flags); #endif /** * \brief Close an open file. * \param fd The file descriptor of the open file. * * This function closes a file that has previously been * opened with cfs_open(). */ #ifndef cfs_close CCIF void cfs_close(int fd); #endif /** * \brief Read data from an open file. * \param fd The file descriptor of the open file. * \param buf The buffer in which data should be read from the file. * \param len The number of bytes that should be read. * \return The number of bytes that was actually read from the file. * * This function reads data from an open file into a * buffer. The file must have first been opened with * cfs_open() and the CFS_READ flag. */ #ifndef cfs_read CCIF int cfs_read(int fd, void *buf, unsigned int len); #endif /** * \brief Write data to an open file. * \param fd The file descriptor of the open file. * \param buf The buffer from which data should be written to the file. * \param len The number of bytes that should be written. * \return The number of bytes that was actually written to the file. * * This function reads writes data from a memory buffer to * an open file. The file must have been opened with * cfs_open() and the CFS_WRITE flag. */ #ifndef cfs_write CCIF int cfs_write(int fd, const void *buf, unsigned int len); #endif /** * \brief Seek to a specified position in an open file. * \param fd The file descriptor of the open file. * \param offset A position, either relative or absolute, in the file. * \param whence Determines how to interpret the offset parameter. * \return The new position in the file, or (cfs_offset_t)-1 if the seek failed. * * This function moves the file position to the specified * position in the file. The next byte that is read from * or written to the file will be at the position given * determined by the combination of the offset parameter * and the whence parameter. * * \sa CFS_SEEK_CUR * \sa CFS_SEEK_END * \sa CFS_SEEK_SET */ #ifndef cfs_seek CCIF cfs_offset_t cfs_seek(int fd, cfs_offset_t offset, int whence); #endif /** * \brief Remove a file. * \param name The name of the file. * \retval 0 If the file was removed. * \return -1 If the file could not be removed or if it doesn't exist. */ #ifndef cfs_remove CCIF int cfs_remove(const char *name); #endif /** * \brief Open a directory for reading directory entries. * \param dirp A pointer to a struct cfs_dir that is filled in by the function. * \param name The name of the directory. * \return 0 or -1 if the directory could not be opened. * * \sa cfs_readdir() * \sa cfs_closedir() */ #ifndef cfs_opendir CCIF int cfs_opendir(struct cfs_dir *dirp, const char *name); #endif /** * \brief Read a directory entry * \param dirp A pointer to a struct cfs_dir that has been opened with cfs_opendir(). * \param dirent A pointer to a struct cfs_dirent that is filled in by cfs_readdir() * \retval 0 If a directory entry was read. * \retval -1 If no more directory entries can be read. * * \sa cfs_opendir() * \sa cfs_closedir() */ #ifndef cfs_readdir CCIF int cfs_readdir(struct cfs_dir *dirp, struct cfs_dirent *dirent); #endif /** * \brief Close a directory opened with cfs_opendir(). * \param dirp A pointer to a struct cfs_dir that has been opened with cfs_opendir(). * * \sa cfs_opendir() * \sa cfs_readdir() */ #ifndef cfs_closedir CCIF void cfs_closedir(struct cfs_dir *dirp); #endif #endif /* CFS_H_ */ /** @} */ /** @} */

open Core module Bench = Core_bench.Bench module Test = Bench.Test let size = 10_000 let alist = List.init size ~f:(fun i -> (i, i)) let of_alist_exn () = ignore ((Int.Map.of_alist_exn alist) : int Int.Map.t) let of_sorted_array () = let sorted_array = Array.init size ~f:(fun i -> (i, i)) in ignore (Int.Map.of_sorted_array sorted_array) let map = Int.Map.of_alist_exn alist let iter () = Map.iteri map ~f:(fun ~key:_ ~data:_ -> ()) let iter2 () = Map.iter2 map map ~f:(fun ~key:_ ~data:_ -> ()) let iter2_naive () = let iter2 a b ~f = Map.iteri a ~f:(fun ~key ~data:_ -> match Map.find b key with | None -> f `Left | Some _ -> f `Both ) in iter2 map map ~f:ignore let add_with_set = assert(not (Int.Map.mem map size)); fun () -> ignore (Map.set map ~key:size ~data:size) ;; let add_with_add = assert(not (Int.Map.mem map size)); fun () -> ignore (Map.add map ~key:size ~data:size) ;; let add_duplicate = let map = Map.set map ~key:size ~data:size in assert(Int.Map.mem map size); fun () -> ignore (Map.add map ~key:size ~data:size) ;; let remove = let deep_key = fst (Map.min_elt_exn map) in fun () -> ignore (Map.remove map deep_key) ;; let old_map_merge t1 t2 ~f = let all_keys = List.dedup_and_sort ~compare (List.append (Map.keys t1) (Map.keys t2)) in List.fold ~init:Map.Poly.empty all_keys ~f:(fun t key -> let z = match Map.find t1 key, Map.find t2 key with | None, None -> assert false | None, Some v2 -> `Right v2 | Some v1, None -> `Left v1 | Some v1, Some v2 -> `Both (v1, v2) in match f ~key z with | None -> t | Some data -> Map.set t ~key ~data) ;; let merge_test do_merge = let map2 = Int.Map.of_alist_exn (List.init size ~f:(fun i -> 2*i, 2*i)) in fun () -> ignore ( do_merge map map2 ~f:(fun ~key:_ x -> match x with | `Left a -> Some a | `Right a -> Some a | `Both (a, b) -> Some (a + b))) ;; let gen_diff_test m ~number_of_diff ~diff = let gen_pair i = sprintf "%6d" i, sprintf "%6d" (i+1) in let map1 = String.Map.of_alist_exn (List.init m ~f:gen_pair) in let map2 = let gen_pair i = gen_pair (i * 16856431 mod m) in List.fold (List.init number_of_diff ~f:gen_pair) ~init:map1 ~f:(fun acc (key, data) -> Map.set acc ~key ~data) in fun () -> let (_ : _ list) = diff map1 map2 ~data_equal:String.equal in () ;; let diff_by_iter2 map1 map2 ~data_equal = let results = ref [] in Map.iter2 map1 map2 ~f:(fun ~key ~data -> match data with | `Left _ -> results := (key, None) :: !results | `Right v -> results := (key, Some v) :: !results | `Both (v1, v2) -> if not (data_equal v1 v2) then results := (key, Some v2) :: !results ); !results ;; let command = let symmetric_diff t1 t2 ~data_equal = Map.symmetric_diff t1 t2 ~data_equal |> Sequence.to_list in Bench.make_command [ Test.create ~name:"Map.of_alist_exn" of_alist_exn; Test.create ~name:"Map.of_sorted_array" of_sorted_array; Test.create ~name:"Map.add reporting duplicate" add_duplicate; Test.create ~name:"Map.set adding a new element" add_with_set; Test.create ~name:"Map.add" add_with_add; Test.create ~name:"Map.iteri" iter; Test.create ~name:"Map.iter2" iter2; Test.create ~name:"Map.iter2_naive" iter2; Test.create ~name:"Map.remove" remove; Test.create ~name:"Map.merge (new)" (merge_test Map.merge); Test.create ~name:"Map.merge (old)" (merge_test old_map_merge); Test.create ~name:"Map.symmetric_diff-10" (gen_diff_test 100_000 ~number_of_diff:10 ~diff:symmetric_diff); Test.create ~name:"Map.symmetric_diff-100" (gen_diff_test 100_000 ~number_of_diff:100 ~diff:symmetric_diff); Test.create ~name:"Map.symmetric_diff-1000" (gen_diff_test 100_000 ~number_of_diff:1000 ~diff:symmetric_diff); Test.create ~name:"Map.symmetric_diff_by_iter2-10" (gen_diff_test 100_000 ~number_of_diff:10 ~diff:diff_by_iter2); Test.create ~name:"Map.symmetric_diff_by_iter2-100" (gen_diff_test 100_000 ~number_of_diff:100 ~diff:diff_by_iter2); Test.create ~name:"Map.symmetric_diff_by_iter2-1000" (gen_diff_test 100_000 ~number_of_diff:1000 ~diff:diff_by_iter2) ] ;; let () = Command.run command

/******************************************************************************* * Copyright (c) 2000, 2016 IBM Corp. and others * * This program and the accompanying materials are made available under * the terms of the Eclipse Public License 2.0 which accompanies this * distribution and is available at https://www.eclipse.org/legal/epl-2.0/ * or the Apache License, Version 2.0 which accompanies this distribution and * is available at https://www.apache.org/licenses/LICENSE-2.0. * * This Source Code may also be made available under the following * Secondary Licenses when the conditions for such availability set * forth in the Eclipse Public License, v. 2.0 are satisfied: GNU * General Public License, version 2 with the GNU Classpath * Exception [1] and GNU General Public License, version 2 with the * OpenJDK Assembly Exception [2]. * * [1] https://www.gnu.org/software/classpath/license.html * [2] http://openjdk.java.net/legal/assembly-exception.html * * SPDX-License-Identifier: EPL-2.0 OR Apache-2.0 OR GPL-2.0 WITH Classpath-exception-2.0 OR LicenseRef-GPL-2.0 WITH Assembly-exception *******************************************************************************/ #ifndef J9_X86_LINKAGE_INCL #define J9_X86_LINKAGE_INCL /* * The following #define and typedef must appear before any #includes in this file */ #ifndef J9_LINKAGE_CONNECTOR #define J9_LINKAGE_CONNECTOR namespace J9 { namespace X86 { class Linkage; } } namespace J9 { typedef J9::X86::Linkage LinkageConnector; } #endif #include "codegen/OMRLinkage.hpp" namespace J9 { namespace X86 { class OMR_EXTENSIBLE Linkage : public OMR::LinkageConnector { public: Linkage(TR::CodeGenerator *cg) : OMR::LinkageConnector(cg) {} void alignOffset(uint32_t &stackIndex, int32_t localObjectAlignment); void alignLocalObjectWithCollectedFields(uint32_t & stackIndex); void alignLocalObjectWithoutCollectedFields(uint32_t & stackIndex); }; } // namespace X86 } // namespace J9 #endif

When the new coaching staff came onboard last season it appeared they had no place for Taiwan Jones. He seemed to be in the thick of the competition at running back in the preseason only to fall out of favor due to ball security issues. As the season went on, Darren McFadden went down injured and the team opted for Mike Goodson as the primary back. Then Mike Goodson went down but instead of going with Jones, the team opted to go with Marcel Reece and newly activated undrafted rookie Jeremy Stewart. It was painfully clear coaches didn't trust him to handle the ball and he was rendered without a role on this team. Near the end of the season, I posed the question to Taiwan about whether he had considered trying his hand at cornerback. It was a position he had played in high school so it seemed like an interesting thought. His response was interesting and, though I didn't know at the time, turned out to be a bit of foreshadowing for him actually being switched to cornerback. The switch was a risky one for Taiwan. It was not usual that players make such a change successfully and if things didn't go well, it would mean his departure from this team. But it was a risk he was willing to take because with the way things were going at his current position, he was already on the outside looking in. Many fans and NFL minds alike wrote Jones off or simply didn't give him much of a thought at all. He was buried on the depth chart at cornerback and looked as if he was on a slow march to being among those cleaning out their lockers on cutdown day. His number 22 seemed destined to be shifted to Tracy Porter who was forced to give up the number 24 to Charles Woodson before training camp. But Taiwan wouldn't be giving up his number. Porter now wears number 23. How did he do it? He made himself into arguably the best special teams gunners in the NFL. He currently sits third in the NFL with 11 special teams tackles. He has also forced a fumble on special teams and in the past four games the coaches have entrusted him to return kicks again. Now, just a couple months from when many expected to see his name among the final roster cuts, we see his name on a Pro Bowl ballot. I caught up with him on Friday to ask him what he thought about his sudden Pro Bowl rumblings. "I think it's pretty cool," Jones said of his Pro Bowl notice. "It definitely was one of my goals coming into the season and I worked hard for it every day, so for others to take notice it feels pretty good." "I really believed it, every day, every time I stepped on the field my mindset is to make a difference. I don't want to be one of those guys who's just out there, I don't wanna just be here to fill the roster, I wanna make a difference and be productive. My role being special teams, I'm able to make a difference and seeing them happy when I do so makes me work that much harder." For Taiwan, it's a culmination of his hard work and sacrifice for the sake of making his NFL career any way they'll let him. "It's a privilege to be in the NFL so I hope it'll be a long career," said Jones. "That's pretty much my goal, stay in the league a while. His goals have shifted from the starry eyed young hopeful who the Raiders chose in round five of the 2011 draft. Now, he can see making a nice long career as a special teamer. And he had guidance from a guy who went through a similar NFL experience as he did, moving from being a running back to special teams maven. "When I first came in, one of the guys that took me under his wing was Rock Cartwright," Jones continued. "He spent ten plus years in the league just on special teams so I had a lot of influence by him. He pretty much told me, ‘don't get discouraged that you're not playing running back'. It's always our dream to be a starter at something but God's got a different plan for everybody." Taiwan Jones' journey to this point fits right in with some of those we have heard from other current Raiders who have had the fortitude to overcome their obstacles and carve out their niche. If he keeps it up, that niche will lead him to Hawaii in January. To vote for this year's Pro Bowl, click here. http://www.nfl.com/probowl/ballot

A “Lethal Weapon 5” is reportedly in the works with Mel Gibson and Danny Glover rumored to return to their starring roles in the franchise. Deadline reported the original “Lethal Weapon” director, Richard Donner was teaming up with Glover and Gibson once again and would also return to direct the film. ‘STRANGER THINGS’ STAR CHARLIE HEATON DENIED ENTRY INTO US AFTER COCAINE FOUND IN BAGGAGE Warner Bros., the studio that put out the franchise’s other films, was reportedly slated to sign on to the next movie. The first film, released in 1987, followed Glover, a veteran cop, partnered with a younger, daring officer, Gibson, who work together to solve crime. The two officers, who were very different, go from disliking one another to having a close friendship. TAYLOR SWIFT FANS SAY SINGER’S ‘READY FOR IT’ MUSIC VIDEO A JAB AT CALVIN HARRIS The movie went on to gross more than $120 million and spawn three successful sequels. Glover and Gibson have not starred in a “Lethal Weapon” movie since the fourth film released in 1998. The movies also led to a television series named after the franchise. The show was in its second season and stars Damon Wayons and Clayne Crawford.

Ontario Highway 17 King's Highway 17, more commonly known as Highway 17, is a provincially maintained highway and the primary route of the Trans-Canada Highway through the Canadian province of Ontario. It begins at the Manitoba boundary, west of Kenora, and the main section ends where Highway 417 begins just west of Arnprior. A small disconnected signed section of the highway still remains within the Ottawa Region between County Road 29 and Grants Side Rd. This makes it Ontario's longest highway. The highway once extended even farther to the Quebec boundary in East Hawkesbury with a peak length of about . However, a section of Highway 17 "disappeared" when the Ottawa section of it was upgraded to the freeway Highway 417 in 1971. Highway 17 was not re-routed through Ottawa, nor did it share numbering with Highway 417 to rectify the discontinuity, even though Highway 417 formed a direct link between the western and eastern sections of Highway 17. However, from East Hawkesbury to Ottawa, Highway 17 retained the Trans-Canada Highway routing and signs until it met up again and merged with Highway 417 until 1997 when Highway 17 through Ottawa was downgraded. The Trans-Canada Highway designation now extends along all of Highway 417. Ontario Highway 17 is a very important part of the national highway system in Canada, as it is the sole highway linking the eastern and western regions of the country. Although other small roads connect the province of Ontario with the province of Manitoba, it is the only major highway that links the two, making it a crucial section of Canada's primary commercial and leisure route for all traffic travelling between Canada's largest cities, from Toronto and Montreal in the east to Calgary and Vancouver in the west. History Beginnings With the establishment of the provincial highway network on February 26, 1920, the Department of Public Highways, predecessor to today's Ministry of Transportation of Ontario, sought to establish a network of reliable roads through the southern part of the province. Through July and August 1920, a highway east of Ottawa to Pointe-Fortune at the Quebec boundary, known as the Montreal Road, was assumed by the department. This original routing of Highway 17 followed what is now Montreal Road, St Joseph Boulevard, and the Old Montreal Road eastward out of Ottawa; McTeer Rd past Cumberland; DeLaBaie Rd and Laurier Street through Rockland; Regional Road 55 (Old Highway 17 through Clarence, Principale St through Wendover) and Regional Road 26 (Old Highway 17) between Wendover and Plantagenet; Villeneuve Rd east of Plantagenet; Blue Corner Road and Bay Road (Regional Road 24) to L'Original; John Street, Pharand Street, and Main Street (Regional Road 4) to Hawkesbury; Front Rd along the shore of the Ottawa River from Hawkesbury to Chute-a-Blondeau and Des Outaouais Rd just west of Pointe-Fortune, and Regional Road 17 elsewhere. A portion of this original highway was lost when the completion of the Carillon Generating Station in 1964 raised the water level of the Ottawa River north of Voyageur Provincial Park. West of Ottawa, a route was assumed to Arnprior on October 6, following today's Carling Avenue, March Road and Donald B. Munro Drive between Ottawa and Kinburn, and Kinburn Side Road and Madawaska Boulevard between Kinburn and Arnprior. On June 15, 1921, the highway was extended to Pembroke via Renfrew, Cobden, and Beachburg. The entire route between Pembroke and Pointe-Fortune became known as Highway 17 in the summer of 1925. Although the jurisdiction of the soon-to-become Department of Highways did not extend beyond Pembroke, a rough trail continued to North Bay, and a trunk road constructed by the Department of Northern Development beyond there to Sault Ste. Marie by 1923, roughly following the route of Highway 17 today. The Pembroke and Mattawan Road Colonization Road was constructed between 1853 and 1874 to encourage settlement in the Upper Ottawa Valley. Between Mattawa and North Bay, many aboriginals and early settlers made use of the Mattawa River, the headwaters of which lie just north of Lake Nipissing. From there they would travel down the French River into Georgian Bay and onwards to Lake Superior. Highway 17 between Mattawa and Sault Ste. Marie roughly traces this early voyageur route. Northern development and the Lakehead Following World War I, discussions of a cross-continental road through Canada became vocal and construction of such a route was underway in several places. However, funding for this work was soon halted as the government distributed funding to projects that were believed to be more important than the luxury of the new road. The most significant accomplishment of this work was the Nipigon Highway between Thunder Bay and Nipigon, opened in 1924. With the signing of the Department of Northern Development (DND) Act in 1926, construction resumed on improving many northern roads; the Ferguson Highway was the main project to begin as a result of the act. The onset of the Great Depression would result in federally funded relief projects being signed with provinces in late 1930. Thousands of men were hired to construct highways in remote areas of the province from temporary camps, named Bennett Camps after then-Prime Minister R. B. Bennett. This provided the necessary labour to open road links through vast expanses of wilderness in a relatively short period of time. Beginning in 1931, certain routes were designated as the Trans-Canada Highway, including the route between Sault Ste. Marie and the Quebec boundary as well as the planned connection to Thunder Bay and Winnipeg. By June 1931, planning for the route of the highway was complete, and work underway on the new link between Thunder Bay and Winnipeg that would roughly parallel the Canadian Pacific Railway. The first section to open was between the Manitoba town of Whitemouth and Kenora. On Dominion Day (July 1) 1932, an inter-provincial ceremony was held in Kenora to dedicate the new route. The next link would connect the road through the Kenora with the rough road connecting Vermilion Bay, Dryden and Dyment. This section opened in early 1933. From the east, construction proceeded at a similar pace, although through much more barren expanses of forests and lakes. By the end of 1932, construction had proceeded from Thunder Bay through Upsala to English River. A gap was all that remained, between Dyment and English River. On June 4, 1934, crews cleared the last section of forest separating Thunder Bay from Winnipeg. However, it would require another year of rock blasting and construction to make the route navigable by vehicles. On July 1, 1935, a multi-day motorcade celebration was held to officially open the new highway. A convoy of vehicles travelled from Thunder Bay to Winnipeg along the route, resting overnight in Kenora before completing the two-day journey. By the end of 1935, numerous factors combined which resulted in the termination of the highway camps. The federal government of R. B. Bennett used Section 98 of the Criminal Code in 1931 to arrest several leaders of the Communist Party of Canada. However, the lack of evidence and protests would eventually lead to the early release of the men, much to the embarrassment of the government. The men, with public support behind them, headed north to highway camps, where mounting tensions due to low wages, poor conditions, lacklustre food, isolation, and military-like discipline resulted in organized labour strikes. Funding was pulled from the Trans-Canada Highway in 1936. On April 1, 1937, the DND was absorbed into the Department of Highways, and the road west of Pembroke became an extension of Highway 17. At this point, the highway from Sault Ste. Marie to the Quebec boundary was long. Portions were paved at this point: east of Sault Ste. Marie, west of Blind River, through Sudbury, east of Sturgeon Falls, through Mattawa, and from Chalk River to Quebec; the remainder was a gravel road. The highway between the Manitoba boundary and Nipigon was , mostly gravel-surfaced. The only significant exceptions were in the Kenora and Thunder Bay areas. Before the outbreak of World War II in 1939, a new bridge spanning the Nipigon River was completed alongside a highway eastward to Schreiber. Both were opened together ceremoniously on September 24, 1937. When the war began, construction on Highway 17 halted, with effort instead focused on the simpler northern route via Geraldton and Hearst. The Gap Following the war, construction on the missing segment of Highway 17 between Schreiber and Sault Ste. Marie proceeded slowly; the completion of Highway 11 between Nipigon and Hearst already provided a road between the east and west. However, in 1949 the federal government signed the Trans Canada Highway Act, which provided up to a 90% subsidy to provinces to complete their portion of the highway to the required standards. Two portions of Ontario's route were eligible for this subsidy: Highway 69 between Parry Sound and Sudbury, and Highway 17 along the north shore of Lake Superior. Amongst some of the most difficult terrain encountered in Canada, engineers blasted 2,087,234 cubic metres (2,730,000 cubic yards) of rock, removed 5,982,641 cubic metres (7,825,000 cubic yards) of earth, and cleared of forest in order to bridge the of wilderness known as "the Gap". The Gap was completed and opened to traffic on September 17, 1960, uniting the two segments and completing the route of Highway 17 from the Manitoba border to the Quebec border. The Queensway During the 1950s, the Greber Plan called for the creation of numerous parkways and divided highways through the growing city of Ottawa. One of these, known as The Queensway, was a grade-separated freeway that would bypass the urban alignment of Highway 17. The Greber Plan was produced by Jacques Gréber under the direction of Prime Minister William Lyon Mackenzie King in the late 1940s. Although Gréber had been corresponding with King as early as 1936, World War II halted any plans from reaching fruition at that time. Following the war, Gréber was again contacted and his expertise requested. He arrived on October 2, 1945, and began working almost immediately. The Greber Plan, as it came to be known, was released in 1950 and presented to the House of Commons on May 22, 1951. The plan called for the complete reorganization of Ottawa's road and rail network, and included amongst the numerous parkways was an east to west expressway along what was then a Canadian National Railway line. With the rail lines removed, construction of the new expressway got underway in 1957 when Queen Elizabeth visited Ottawa to open the first session of the 23rd Parliament. On October 15, the Queen detonated dynamite charges from the Hurdman Bridge, which now overlooks the highway as it crosses the Rideau River, and formally dedicated the new project as the Queensway. At the ceremony, premier Leslie Frost indicated that the entire project would cost C$31 million and emphasized the importance of the link to the Trans-Canada Highway. The Queensway was constructed in four phases, each opening independently: phase one, from Alta Vista Drive (now Riverside Drive) east to Highway 17 (Montreal Road); phase two, from Highway 7 and Highway 15 (Richmond Road) to Carling Avenue; phase three, from Carling Avenue to O'Connor Street; and, phase four, from O'Connor Street to Alta Vista Drive, crossing the Rideau Canal and Rideau River. Phase one opened to traffic on November 25, 1960, extending up to the Rideau River. On the western side of Ottawa, phase two opened a year later in October 1961. The central section presented the greatest challenge, as an embankment was built to create grade-separations. In addition, the structures over the Rideau Canal and river required several years of construction. On May 15, 1964, the majority of the third phase was ceremonially opened. completing the Carling Avenue interchange and extending the freeway as far as Bronson Avenue. Several months later, on September 17 the short but complicated section east to O'Connor Street was opened. This left only phase four, the central section of the Queensway, which was opened in three segments. On November 26, 1965, the structures over the Rideau Canal were opened to traffic. At the same time, the westbound lanes of the Queensway were extended to Concord Street, located west of the Nicholas Street interchange. The interchange opened on January 1, 1966, allowing travel in both directions over the canal. The final segment, linking the two section of the Queensway, was placed into service on October 28, 1966. Following this, the Highway 17 designation was applied along the Queensway and the old routing renumbered as Highway 17B. Bypasses and upgrades Although it was completed from Manitoba to Quebec in 1960, many upgrades to the original routing of Highway 17 had and would take place over the years. In addition to bypasses around almost every urban centre it encountered, many original sections have been downloaded to regional and local jurisdiction or decommissioned entirely to lay abandoned in the forest. Of special note is reroutings in the Ottawa Valley – where the highway follows very little of the original routing – and around Thunder Bay, where it has undergone several reroutings and upgrades since the 1920s. In the following section, upgrades are listed from west to east due to complex chronologies. Thunder Bay The original routing of Highway 17 travelled into Port Arthur along the Dawson Road, now Highway 102. Nipigon Highway 17 originally entered Red Rock along what is now Highway 628 before turning north alongside the Nipigon River north to Nipigon. Sault Ste. Marie Although the route into and out of Sault Ste. Marie has remained generally the same, Highway 17 has been rerouted through the city numerous times. In addition, to the east of the city, the route has been redirected onto a four lane at-grade expressway around Echo Bay. Espanola Sudbury The route of Highway 17 in Sudbury currently follows the Southwest and Southeast Bypasses through the south end of the city. Prior to the completion of this route, the highway followed what is now Municipal Road 55 through the downtown core. North Bay Upper Ottawa Valley Construction of the Renfrew Bypass began in June 1974, and continued for three years, opening in 1977. Ottawa Lower Ottawa Valley Elsewhere The last gravel stretches of Highway 17, between Kenora and Dryden and north of Batchawana Bay, were paved in 1964. Downloads On April 1, 1997, the Ministry of Transportation of Ontario (MTO) transferred the responsibility of maintenance and upkeep along of Highway 17 east of "the split" with Highway 417 to Trim Road (Regional Road 57), a process commonly referred to as downloading. The Region of Ottawa–Carleton designated the road as Regional Road 174. Despite the protests of the region that the route served a provincial purpose, a second round of transfers saw Highway 17 within Ottawa downloaded entirely on January 1, 1998. An additional was added to the length of Regional Road 174. The highway was also downloaded within the United Counties of Prescott and Russell, where it was redesignated as County Road 17. The result of these transfers was the truncation of Highway 17 at the western end of Highway 417, while the Trans-Canada Highway designation was taken from the former Highway 17 and applied to Highway 417. Route description Highway 17 crosses some of the most remote regions of Ontario. Although there are several settlements established throughout its length, the distance between gas stations can often exceed several hundred kilometres. Despite the isolation of the highway, it is well-travelled throughout its length. The section of Highway 17 north of Lake Superior is regarded as one of the most scenic drives in the province. Manitoba to Nipigon Highway 17 begins at the boundary between Ontario and Manitoba, where a large installation greets drivers in both directions. The highway is two lanes wide and travels over and between the surface features of the Canadian Shield; further west into Manitoba the highway widens into a four-lane divided expressway. To the east, the highway travels through thick boreal forest towards Keewatin, where the Kenora Bypass, Highway 17A, splits to the north. Through the town of Kenora, Highway 17 is signed but maintained under a connecting link agreement between the town and the province. Full provincial maintenance resumes at the eastern town limits. Further east, the highway merges with the Kenora Bypass. It meets the northern terminus of Highway 71, then makes a gradual eastward journey through the lake-dotted Kenora District to the town of Dryden. Here the highway encounters one of the few agriculturally-sustainable areas of northern Ontario. The highway begins to zig-zag southeasterly, passing through several minor settlements before entering the mining town of Ignace. Shortly thereafter, it begins to curve to the south. It meets Highway 11 east of the Manitoba boundary. The two highways travel concurrently towards Thunder Bay at the western Lakehead of Lake Superior. Though it originally travelled through what was then the twin-cities, the highway bypasses to the northwest on the at-grade Thunder Bay Expressway. Nipigon to Sudbury Within Nipigon, Highway 11 and Highway 17 cross the Nipigon River on the Nipigon River Bridge. Along with the railway crossing immediately to the south, and another on the northern shore of Lake Nipigon, this forms the narrowest bottleneck in Canada between the Atlantic and Pacific oceans. On the eastern shore of the river, Highway 11 separates and travels north towards Geraldton and Hearst. Highway 17 continues east along the northern shore of Lake Superior. Near White River, the highway enters Algoma District and turns southward. It meets the western terminus of Highway 101 near Wawa, which provides for a shorter route to Sudbury via the Sultan Industrial Road. South of Wawa, the highway enters Lake Superior Provincial Park. After proceeding through several mountain ranges, and crossing numerous rivers and the Montreal River Hill, the highway enters Sault Ste. Marie. Here a border crossing into the United States is provided via the Sault Ste. Marie International Bridge, which connects with I-75 in Michigan. As the highway exits Sault Ste. Marie to the east, a newly constructed segment of four-lane divided highway branches north; Highway 17B (one of two remaining business routes of Highway 17 in service) continues east through Garden River. The divided highway bypasses Garden River and passes east of Echo Bay before curving south and merging with Highway 17B. Shortly thereafter, it turns to the east and travels along the North Channel of Lake Huron towards Sudbury, passing through numerous small towns, including Thessalon, Blind River, Massey and McKerrow. At Sudbury, the highway widens into a freeway through the Walden area of the city until reaching the Southwest / Southeast Bypass at Lively, where it narrows again to a Super 2 road. This segment is currently undergoing an environmental assessment, with plans to upgrade it to a full freeway in the next ten years. Sudbury to Arnprior Highway 17 passes to the south of the urban centre of Sudbury. It meets Highway 69 at an interchange. At this interchange, the Southwest and Southeast Bypasses meet, and for just over a kilometre, Highway 17 is a divided four-lane freeway. The Super 2 continues northeast to meet the original alignment of Highway 17 east of downtown Sudbury. Here it turns east and travels through the city's outlying neighbourhoods of Coniston and Wahnapitae; a new freeway alignment of this route is currently in the planning stages. The highway route passes through the rural municipalities of Markstay-Warren and West Nipissing before reaching North Bay, where it follows an undivided four-lane expressway alignment, with reduced but not full control of access, through the city of North Bay; as of 2012, early preparations have taken place for a freeway conversion and realignment of this segment. For 4.1 kilometres from Algonquin Avenue to the Twin Lakes area, the route is once again concurrent with Highway 11. At the northern end of this concurrency, Highway 11 travels north and wraps westward and south to Nipigon; at the southern end, it continues southward towards Toronto, while Highway 17 turns east toward the Ottawa Valley. An at-grade intersection with Highway 63 is located at approximately the midpoint of the concurrency. East of North Bay, Highway 17 meets Highway 94, thereafter travelling alongside the Mattawa River to its confluence with the Ottawa River in Mattawa, where it meets Highway 533 at a roundabout. The highway then parallels the Ottawa River through a mountainous region, first passing through the villages of Stonecliffe and Rolphton before arriving in Deep River, a planned community developed as part of the Manhattan Project. It then passes through Chalk River and enters Canadian Forces Base Petawawa. Beginning at the southern end of the army base, Highway 17 follows the Pembroke Bypass, bypassing west of Petawawa and Pembroke, where it intersects Highway 41. The bypass ends at Renfrew County Road 40, north of Muskrat Lake. The highway then travels south through the town of Cobden. It follows a bypass east of Renfrew and meets Highway 60. Highway 17 curves east and passes north of Alexander Stewart Provincial Park. Approximately west of Scheel Drive, west of Arnprior, the highway divides and widens to four lanes, at which point Highway 417 begins. A disconnected section of the highway (known as Old Highway 17) still exists within the Ottawa Region between Regional Road 29 and Grants Side Rd, travelling directly parallel to Highway 417. However, it is likely to be downgraded and possibly absorbed as part of Regional Road 117. Business routes Highway 17 used to have a number of business routes, all but one of which have been decommissioned. All were at one time the primary route of Highway 17 through their respective locations, and were given the business route designation following the construction or designation of a newer bypass alignment. Highway 17B (Ottawa) Highway 17B (North Bay) Highway 17B (Thessalon) Highway 17B (Sault Ste. Marie) Highway 17B (Thunder Bay) Future With all route planning studies now completed on Highways 11 and 69/400, in the latter half of the 2000s, the Ministry of Transportation's planning branch began undertaking more active preparations for the eventual conversion of Highway 17 to freeway. Although no comprehensive conversion plan is currently in place, planning and construction projects are now underway at a number of locations along the highway. Sault Ste. Marie MPP David Orazietti has spearheaded a petition to have the entire highway four-laned from Arnprior to Sault Ste. Marie, similar to the campaign previously undertaken by his caucus colleague Rick Bartolucci regarding the extension of Highway 400. Cheryl Gallant, the federal Member of Parliament for Renfrew—Nipissing—Pembroke, has also advocated the four-laning of the highway through the Ottawa Valley toward North Bay, and ultimately the entire length of the highway throughout Northern Ontario. A 2009 study commissioned by the forestry trade magazine The Working Forest, titled "A Vision for Ontario’s Trans Canada Highway, North Bay to the Manitoba Border", determined that it would cost the Ontario government $600 million per year over 25 years to convert the entire length of both Highway 17 and Highway 11 to freeway, suggesting that a comprehensive plan would be affordable and achievable if the provincial and federal governments could reach a cost-sharing agreement. Renfrew County Studies are underway on the extension of Highway 417 through the Ottawa Valley region from its current terminus at Arnprior to Petawawa. From Arnprior to Haley Station and from Meath to Petawawa, the proposed freeway route largely follows the existing alignment — in these areas, the current highway route largely avoids existing communities, and thus a second set of lanes can be easily added alongside the existing route. Within the township of Whitewater Region, however, a new alignment is planned several kilometres east of the existing road in order to bypass communities such as Cobden. In August 2017, the Ministry of Transportation formally confirmed that detail design studies have commenced on the next westward extension of Highway 417, from the existing terminus at Scheel Drive in Arnprior to three kilometres west of the Bruce Street intersection at Renfrew. North Bay Planning studies have been completed for the conversion of Highway 17's alignment through North Bay, which is currently a four-lane expressway with partial but not full control of access, into a full freeway. The plan will include an interchange with a new alignment of Highway 11, which would replace the existing Algonquin Avenue segment. In the city, the four-laned route will follow the existing highway route from the western city limits to Meighen Avenue, and then a new alignment from there to the eastbound Highway 11/17 interchange. The bypassed portion of the current route will be realigned to connect with Lansdowne Avenue. This alignment, nicknamed "Route 6", has been planned since the 1970s; although minor adjustments to the plan have been made since, as of 2017 the ministry has not announced an official construction schedule. Studies commenced on an extension of the four-lane route easterly to Bonfield in early 2011, and from Eau Claire Station to the Nipissing District-Renfrew County boundary in early 2012; further studies on the routes from Bonfield to Eau Claire Station and from North Bay to Cache Bay are expected to begin at a later date. Sudbury As the extension of Highway 400 approaches Sudbury, the MTO began a route planning and environmental assessment study on Highway 17 easterly from Highway 69 to Markstay in 2010; studies for the segment from Highway 69 westerly to the existing freeway in Walden were completed in 2007. The current route plan involves twinning the existing Southeast Bypass to its terminus, along with the construction of a new four-lane route north of Coniston and Wahnapitae. Original plans called for a new multi-level interchange with Highway 69 in the Lake Laurentian Conservation Area. However, public consultation has since removed this proposal from the route planning process; all of the plans currently under consideration involve converting the existing alignment of Highway 69 to a full freeway which would meet Highway 17 at the existing interchange. Preliminary route planning studies have also been completed on the freeway's westerly extension to McKerrow, near Espanola, but no construction schedule has been announced to date. However, the first phase of this route, extending the existing freeway from Municipal Road 55 in Sudbury for six kilometres farther west through the Den-Lou neighbourhood, is currently in the detail design phase. Sault Ste. Marie At Sault Ste. Marie, the expressway segment currently ends six kilometres short of its eventual terminus at Black Road and Second Line, as an agreement has yet to be reached with the Batchawana First Nation regarding land use through Rankin. The completion date for this segment is not currently known. In the interim, highway traffic travels between the expressway and the current highway alignment through Sault Ste. Marie by means of the previously planned northerly extension of Trunk Road. The former segment of Highway 17 through Garden River was initially redesignated as part of Highway 638, although the Garden River First Nation disputed this designation and insisted that the highway be renamed Highway 17B. As of February 2009, the former route is now designated as Highway 17B. In February 2010, Garden River's band council publicly warned that they would consider imposing tolls on the routes of both Highway 17 and Highway 17B through their territory if the provincial government did not assist the council with a funding shortfall of approximately $1 million. In February 2011, the Ministry of Transportation announced that the expressway's current level intersection at Highway 638 in Echo Bay will be upgraded to a full interchange. Thunder Bay and Kenora Construction started in 2004 on a westerly extension of Thunder Bay's Harbour Expressway, from the Thunder Bay Expressway to Vibert Road, intended to serve as a new alignment for Highways 11 and 17. In July 2008 the federal and provincial governments announced a $6.2 billion infrastructure program that makes the four-laning of Hwys. 11 and 17 near Kenora and Thunder Bay a priority. Engineering work on twinning 11/17 between Nipigon and Thunder Bay was to begin in 2008. On May 1, 2009 the federal and provincial government announced that twinning of Highway 11/17 would begin in 2010. On May 15, 2009, the federal and provincial government announced that twinning of Highway 17 at the Manitoba/Ontario boundary easterly toward Kenora would also begin in 2010. Major intersections Notes References Sources Bibliography External links Trans Canada Highway distance charts, road conditions, maps Highway 17 photos and information Google Maps: Highway 17 route 017 Ontario 017 Category:Lake Superior Circle Tour Category:Roads in Greater Sudbury Category:Roads in Thunder Bay Category:Transport in Dryden, Ontario Category:Transport in Kenora Category:Transport in North Bay, Ontario Category:Transport in Sault Ste. Marie, Ontario

Q: Absolutely convergent sequence, but no measure Let $(X, \mathcal A)$ a measure space, $\mu : \mathcal A \rightarrow (- \infty, \infty)$ a map with the following properties: (i) $\mu(\emptyset) = 0$ (ii) For all pairwise disjoint families $(A_j)$ with $A_j \in \mathcal A$, $\sum \mu(A_j)$ converges absolutely and $\mu ( \cup A_j) = \sum \mu(A_j)$. Then it does not necessarily follow that $|\mu|: \mathcal A \rightarrow [0, \infty)$ is a measure. But why? A: Consider $X=\mathbb{R}$ and $\mu=\delta_1-\delta_0,$ were $\delta_x$ is dirac mass at $x$. Then, $\mu$ clearly satisfies the given, but $|\mu|(\{0\})=|\mu|(\{1\})=1,$ while $|\mu|(\{0,1\})=|1-1|=0,$ so even finite additivity might fail.

The OA type TV Show network Netflix If you've been taken with Netflix's new sci-fi drama The OA — co-created by and starring Brit Marling as a young blind woman who disappears and returns years later with her sight restored — you're clearly not the only one. In the month since its release, fans and theorists alike have taken to Reddit to parse out the enigmatic series — down to the tiniest of details. And while it's something Marling and co-creator Zal Batmanglij anticipated, Marling explained on this week's episode of EW's What to Watch podcast how the collaborators were still surprised by just how deep the digging went. "Some of the research people do — it's amazing. Someone found right away the one mine in North America that's 8,000 feet deep, which is the location that we had been inspired by based on this Harper's article," she said of the location of her character's captivity. "So that part of it is fantastic, the sort of forensic aspect of fandom. We did, in the beginning, in collaboration with Alex DiGerlando the production designer, who really is sort of the third Musketeer in terms of storytelling with Zal and I, we felt like, How do we make a show that can stand up to that kind of scrutiny? Because now you can stop and start, you can watch it three times, you can screengrab and share it and be on Reddit. So you have to have a narrative that's robust enough to live up to that expectation. So we really tried to think about that and make sure every image and every frame was honest, and if we should get more than one season out, you could go back and watch the first season again and go, It was all there." Speaking of a second season, Marling and Batmanglij do have a road map, but whether they'll get to take the journey is another question. "The truth is, before Zal and I started doing this, we thought you could potentially get caught up in doing something like this for many years. So you better be sure all those years of your life are going to be interesting, so that's why we spent a good year and a half upfront before we even wrote the first chapter, designing the labyrinth and making sure there was something at its center that would feel worthwhile to arrive at," Marling said. "So there is a there there, but whether or not we'll be able to get there is another question. But we always had an intention for where a second season would start and where it would end. it was important to know all those things upfront. So I guess we'll just have to see if we get to tell it." Marling had much more to say about The OA, including how they cast Inside Out star Phyllis Smith, learning all the "movements," and researching high school life (which might have been the scariest part of all!). Listen below to hear the full What to Watch podcast episode – and don't forget to subscribe for the latest TV news and exclusives each week. <iframe src="https://art19.com/shows/ews-what-to-watch/episodes/021c0785-2c21-4f98-aaf0-0e6534743489/embed?theme=light-gray-blue" scrolling="no" width="100%" height="460" frameborder="0" class="" allowfullscreen="" resize="0" replace_attributes="1" name=""></iframe>wMõç¾;yÞ=ïÏ8ëvõënv{ן{ΚqÞ^ã}

EMBED >More News Videos Possible surveillance video of a deadly hit-and-run involving Marion 'Suge' Knight was posted online. LOS ANGELES (KABC) -- Former rap mogul Marion "Suge" Knight was sentenced Thursday to 28 years in state prison for killing one man and injuring another with his truck outside a Compton burger stand in 2015.Knight, wearing a large cross and orange jail attire, showed no emotion as loved ones of the deceased victim addressed the court and described 55-year-old Terry Carter as a deeply devoted husband, father, grandfather and friend.Knight, the 53-year-old co-founder of Death Row Records, struck a surprise plea deal with prosecutors Sept. 20, just days before he was set to face trial for murder and attempted murder. Once dubbed "the most feared man in hip-hop," Knight instead agreed to a prison sentence of nearly 30 years.Probation is not on the table for Knight, who will have to serve at least 23 years of his 28-year sentence.The sentence marks a low point in a precipitous fall for the onetime music impresario, who reached the peak of his career in the mid-1990s. At the time, he was releasing platinum-selling records from Dr. Dre, Snoop Dogg and Tupac Shakur.Knight was part of an acrimonious, public feud between East Coast and West Coast rappers. Shakur was a passenger in Knight's BMW sedan when he was killed in a drive-by shooting in Las Vegas in 1996.Knight had felony convictions for armed robbery and assault. He lost control of the legendary Death Row label after it was forced into bankruptcy.He got into an altercation with longtime rival Cle "Bone" Sloan in January 2015. Sloan was a consultant on the N.W.A. biopic film "Straight Outta Compton."In an incident captured on dramatic surveillance video , Knight backed his truck into Sloan, who was injured, then drove it forward and struck Carter, who later died from his injuries. Defense attorneys claimed it was an act of self-defense because Knight thought one of the men had a gun.Voluntary manslaughter would normally bring a sentence of 11 years in prison, but Knight's conviction along with his previous felonies triggers California's three strikes law. That doubles the manslaughter sentence and adds an extra six years.The agreement also clears Knight in two other cases, both from 2014. He was accused of stealing a camera from a woman and of sending threatening text messages to "Straight Outta Compton" director F. Gary Gray.