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This was no classic Masters, but it was certainly validation for Gerry Watson, the 35-year-old golf phenom from Baghdad, Florida.
Called Bubba since he was a baby in the hospital, he backed up his playoff win of two years ago by dominating the 78th staging of the Masters, here at Augusta National.
Judging by his performance, which was both strategic and entertaining, he has the tools to win several more Green Jackets and there won't really be a way to Bubba-proof the course.
The classic example was on the dogleg par-five 13th hole in the final round. Watson unleashed a towering, curving drive over the corner of the hole with such ferocity that TV viewers and spectators could only gasp at such a display of talent, smothered in brute force.
The drive was over 360 yards, on one of the most testing, iconic holes at Augusta National! Given the intensity with which the game is played at the top level and the circumstances (he was two shots ahead of playing partner Jordan Spieth, who had just bogeyed the par-three 12th), Watson brought "Amen Corner" to its knees.
Watson is built for success in the Masters and it would not be surprising to see him match Tiger Woods and Arnold Palmer's four respective victories before the decade is out.
The question is whether he will win any of the game's other three majors. He was beaten in a playoff for the 2010 PGA Championship by Germany's Martin Kaymer, so it's fair to suggest that he will contend in that tournament many more times.
However, his game is not suitable to a U.S. Open, which is the ultimate, grinding test of golf: placing a premium on straight driving and huge patience. Bubba doesn't favor straight hitting, and the relentless test of a U.S. Open setup would wear him down.
A British Open victory could possibly be in his future, but links golf is not a natural fit, while the uncertain bounces on that terrain would take some serious getting used to for the high-hitting American.
On CNN's Living Golf show, we've been very fortunate to spend precious time with Bubba, his caddy Ted Scott and his manager Jens Beck (check out the driving lesson he gave me in our above Masters preview and you'll get an insight into his natural gifts!)
Theirs is a small team, dedicated to getting their man in peak condition for the biggest championships. They timed this one to perfection.
Watson and Scott even played a round together in advance of the Masters, giving the caddy a priceless edge in working out their game plan, and an even greater appreciation of the course.
Bubba had the tools to win again at Augusta, but it was a true team effort in working out how to stamp their authority on the tournament and most importantly, eke out the victory.
Mission accomplished. Well done Bubba!
What do you think of Bubba's Masters triumph? Let Shane know on Twitter or comment below.
Bubba Watson worn autographed hat?
Golf has recently become a much more popular game to the world of sports. In recent years the game of golf has also seen an increase as a career choice, as golf programs and golf schools around the country make it that much easier to enter into the field.
James Parker


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You want a sample of what it's like to drive the newest, gen-five 911 GT3?
Here's one.
You're on the autobahn chasing a souped-up and slammed Audi through a violent rainstorm, eventually pushing that all-wheel-drive sedan out of the left lane just north of 130 mph. Now you're damn near cackling at what this car feels like. The rear-wheel-drive Porsche is pinned to the road, alive in your hands, yet quietly within its limits. It's so placid that pushing harder feels obvious, a blue-sky retort to the pelting deluge. It's a reaction that seems, in the moment, 100 percent natural. Almost matter of fact. Even though it completely ludicrous.
And so, you do it. You just go faster.
How about another?
Blasting through the Swabian Hills about an hour from Flacht, Germany, where Porsche houses about 60 staffers devoted solely to the production of GT cars for street and racing, you encounter every sort of country road you might find in Vermont. Two-laners become single-track. Or they're blasted and beaten by farm machinery. Or they're baby's bottom smooth. Some are serpentine; others, stiff-spine straight, gently undulating or predictably arced. Yes, outside a real racetrack, this is as good a place to tickle the capabilities of the 475-hp GT3.
Here you are, crawling up a switchback pass behind a tractor. Fifteen mph. You spy a narrow window and drop the hammer. First-through-third gears bounce off the 9000-rpm rev limiter and you're well beyond 100 mph in what feels like a blink (in reality it's just shy of nine seconds). Then, ahead of the next curve, you're hauling the car down to 30 mph even more quickly via its optional 410-millimeter front/390-millimeter rear carbon ceramic brakes. (This is the one part the GT3 shares with the outrageous 918.) Your eyes strain in their sockets. The seatbelt holds you against the g-forces. Your heart pounds.
Other cars are this capable. None may be this much fun. And likewise, there may be no other production car that simultaneously makes you feel so omnipotent at the wheel without being so "digital" as to remove driver skill from the equation entirely.
How Porsche achieved this is a few parts black magic, one part controversy, and a ridiculous helping of superb R&D. I'll explore all of the above, naturally stitched together with more raucous exploits.
The Engine—And How It Sounds
While the 991 GT3 shares a few parts with the current Carrera—such as crank case, timing chain, and alternator—this is almost an entirely new engine. Don't let the six-cylinder's 3.8-liter displacement fool you. Everything about the character of this engine is different vs. the prior GT3.
The makeover wasn't just about increasing redline (from 8400 to 9000 rpm), but also producing power at a higher rev range. That, in conjunction with tighter gearbox ratios—and all in concert with a freer revving engine—results in a motor that races toward seven grand the instant you punch the accelerator.
That's the goal. To keep everything simmering just below boiling. So while peak torque of 324 lb-ft arrives at 6250 rpm, the 475 horses aren't extracted until a roaring 8250, and it's the getting there that counts.
Part of that was simply shedding weight; the new engine is about 55 pounds lighter than the outgoing 435-hp GT3, with a catalogue of parts changes including a lighter oil pan separator, a carbon composite intake, and lighter headers.
Specific changes learned from racing include cylinder heads with separate valve controls via rocker arm. The benefits are multifaceted, but one primary aim was that the decreased mass allows for better wear and an especially quick-to-rev character.
Probably the most significant engineering change is direct fuel injection. While other 991 cars have it already, the system in use here is unique to the GT3.
Multi-hole injectors allow far higher pressures, up to 2900 PSI (versus 1740 PSI on the standard Carrera S). Translated, the result is both a broader performance range and what feels like more serious punch the deeper you're in the throttle.
Few motorcycles feel this free to rev. But the flip side is that this motor wants to rev. At idle it's gruff and a little cranky, like a bulldog straining at its leash. Past 911 motors have sounded cleaner, more placid in traffic.
But this engine wasn't built for traffic.
Bang into the gas, let the beast roar, and its true demeanor cooks through to the surface. If you're a bystander as the GT3 goes by at full tilt, you feel it in your bones. Feet vibrate on the sidewalk. Heads turn to see what's coming as the throaty rasp clangs off concrete buildings. Children stand by, gobsmacked. Their parents stare, slackjawed.
But...is the sound pretty?
No. Ferraris sound pretty. The GT3 sounds menacing and awesome. Lovelier music has been made from six-cylinders, but when you're at 4000 rpm and in a hurry, a quick tap-tap of the left paddle of the GT3's PDK gearbox will get you all the respect you need.
PDK Seven-Speed Transmission—And Why Nobody Should Complain
A lot has been made of the fact that the GT3 will only come with a single, automated manual gearbox, R&T has certainly made a lot of the debate.
Porsche's philosophy is pretty concise: No human can execute a manual gearbox change in 100 milliseconds, which is what the PDK enables. Not to mention, the PDK was adapted from GT racing cars for what Porsche describes as "torque overshoot," where, under full throttle, the engine won't be retarded to preserve the transmission during the demand for acceleration. That means the PDK withstands insane abuse.
Porsche has tested over 1000 full-throttle launch control starts in a row without failure. They've actually gone well beyond this point.
More pedestrian in nature is rev-matched downshifts, a given.
But whether you're upshifting, where gear changes are fantastically aggressive and bereft of power loss, or downshifting directly into the peak horsepower range (I managed downshifts into 7500 rpm without once seeing a refused shift), this transmission provides pure race responsiveness.
You can even achieve a clutch dump.
Yank both of the wheel-mounted aluminum shift paddles toward you at any speed and you're coasting in neutral. Let go and you're back in gear. This enables burnouts, sure, but more pragmatically, mid-turn adjustments are also feasible. For instance you can drop the clutch and then re-apply power as you come around during a drift to hook the car back up. You might want to be a very good driver to experiment with this ... or leave the standard stability control on as you work up to this brand of play.
Drifters with thick wallets, this is your cue to break into applause.
The GT3 grows more civilized with an auto mode, ideal for when you're stuck in traffic, but there's also a PDK Sport mode, which was uniquely designed for optimal down- and upshifts on the track. Gears are held right to redline, and upshifts are only executed when you've passed the horsepower peak.
You still want a manual? You're in the minority.
Porsche says worldwide demand for this car is beyond production capacity already. Even though it doesn't exist yet.
Technically, too, they say the free-revving engine pretty much demanded this gearbox because so much of the character was designed around incredibly fast shifts; in a dead straight the engine flies to redline so quickly you'd have a great deal of trouble executing clean shifts with a traditional gearbox.
Finally, Porsche says that only the PDK enabled a system called Torque Vectoring Plus, where an open (rather than traditional on/off differential) controls the application of power. I'll discuss that in more detail shortly.
Is Rear-Wheel Steering a Gimmick?
After a few hours in the GT3, including more than one U-turn to get un-lost, and dozens of rocket blasts down contorted intersections of country lanes mashing directly into highways, it's easy to laud the attributes of four-wheel steering.
Very simply, it has the effect of making the car feel shorter at slow speeds, turning the rears away from the direction of the fronts below 31 mph, so slow-speed radiuses get tighter.
Above 50 mph, the rears turn in concert with the fronts, virtually extending the length of the GT3 by a massive 20 inches.
That high-speed flight I executed in the pouring rain no doubt felt more stable because the rear of the car seemed to grow aft. There's surely a limit to how much stability can be gained, but one effect you feel is well-weighted but seemingly lighter steering at higher speeds. The car executes lane changes precisely and sharply, but without any dartiness.
And the steering itself?
Yes, it's electric. Don't go all hair-on-fire crazed. It's true that some of that magical Porsche steering "feel" is missing, but thanks to the rear-steer system, seat-of-the-pants feel is also added back.
This is especially the case when you hit the sweet spot decelerating into a 180-degree corkscrew. The front end bites and—911 traditionalists will never believe it—so does the BACK end! You can play village idiot and mash the throttle halfway around the bend and you'll be able to kick the rear wide, especially if you've disabled the stability control (two modes let you cut it partially out or kill ESC entirely).
But there's a massive set of countersteered Dunlop Sport Maxx tires behind you fighting to tighten the corner, not push you wide of the apex.
About the only time you'll sense something lost in the transition to the electric box is during low-speed straights, when on-center is perfectly weighted, but twitching slightly off center can feel faintly artificial.
Bigger, Badder
The 2014 Porsche 911 GT3 is 1.7 inches wider than a 911 Carrera S in the rear, and the wheelbase has grown 4.7 inches since the gen-four model.
While the body is based on the current 991 Carrera S, aluminum panels (roof, doors, engine lid, fenders) make the entire shell 13 percent lighter than the outgoing GT3, even while torsional rigidity shoots up 25 percent.
The car also sits about an inch and a half lower. In the U.S., there's an optional suspension-lifting switch to help avoid scraping the front apron on the deep curb cuts common to American driveways.
In case you missed it, there's a fixed, massive tail on the rear deck.
Functionally, Porsche says the lengthened lip helps increase downforce at the rear axle. The design is a combination of composite, fiberglass, and carbon fiber.
The front apron is also new. Larger vents increase air supply to the radiator, a wide spoiler lip increases downforce, and intakes funnel air beneath the car to provide additional downforce via diffusers, to prevent lift in the underbody where the undercarriage naturally lifts at the rear-mounted engine.
Suspension - More Compliant, And Also More Stable
If you just climb aboard the GT3 and drive off without fiddling with the suspension settings, you'll be treated to a surprisingly civilized ride. Yes, it sits lower, but suspension travel is increased, and the dampers default to a reasonable level of cushioning that's apt for even race-car speeds. Most of my testing was done in this mode, and even Porsche's own 7:25 lap time on the Nürburgring Nordschleife was achieved in this mode, because that's a notoriously bumpy track.
But if you intend to race (Porsche says 80 percent of its GT3 customers track their cars) there's a more aggressive Sport mode. Even so, it's not excessively brutal for well-paved roads. The adaptive suspension system wrings out more violent gyrations before they overly disturb the chassis.
Putting the Power Down
Porsche says the PDK was needed in part to be able to implement Torque Vectoring Plus (PTV Plus). This integrates a variable locking diff, as well as rear-wheel braking. In essence it's a constant balance of applying horsepower and selectively shortening turning circles. So in addition to rear-wheel steering, once you turn the steering wheel the inside rear wheel slows down slightly, effectively overdriving the outside rear wheel and pitching you more cleanly toward the intended apex.
Simultaneously, when exiting a turn the active differential can act on a continuum, rather than entirely locking up, sending us much available power to the ground based on grip, but preventing total mayhem. More succinctly, it makes you go faster.
Wheels—And Awesome Brakes
If you're going to buy the GT3, the one must-buy option is the carbon ceramic braking system. Yes, they're larger vs. the stock 380mm front/rear steel brakes, but mostly they're ridiculously confidence-inspiring. In the wet I found that at higher speeds just a soft application was needed to warm them ahead of very hard stopping. The thresholds are fantastically high, not only suitable for racing, but also for daily driving.
Porsche employs nine-inch 20-series tires on the front (245/35/ZR20) and massive, 12-inch rears (305/30/ZR20).
These are mounted to newly developed forged aluminum centerlock rims that manage to drop 2.2 pounds of unsprung weight per wheel despite being both wider and larger than the old car's equipment.
And even if you never intend to race, center-mounted wheels, especially these, just look really cool.
I already mentioned how this isn't the sexiest-sounding machine at idle. And by contrast, it's lion's-roar ferocious as it ascends toward redline.
Now tap the sport exhaust switch on the center console and raise the holy-shit factor to 11. The switch smites backpressure in the exhaust and as you climb toward peak torque, ultimate twist increases by up to 26 lb.-ft.
My recommendation: don't use the sport exhaust mode as you ply the roads of gated communities, lest the rent-a-cops deem you a menace to society.
Interior—Almost All Business
You won't ever confuse the GT3's interior for that of a Ferrari 458, but it's gorgeous if you believe in what Porsche stands for. The suede-wrapped steering wheel is perfectly shaped with "thumb-lock" slots above the T-shaped hub, the seating surfaces are grippy in suede, and door grab handles are likewise double-stitched in the same material. Aluminum accents grace the dash, and mildly highlight interior shapes.
And you can go after even more of a track look with rear cross bracing (there's no back seat regardless) and full race seats, complete with six-point harnesses.
Right now, you cannot order the car with sport bucket seats because they don't meet U.S. side airbag standards. You may not miss them. They only feature fore-aft rake, and there's no tilt. While excellent for aggressive driving, in traffic you might want more lumbar support or the ability to adjust height (shorter or taller drivers will need more adjustment for certain).
Functionally, even if there's less panache to this cabin than you'll find at the supercar level (don't forget that at $131,000 this car is technically fighting leagues above its class), it all works.
Often the flashier cabins at double or triple this price look stupendous (like the sunken living room of a show home), but they aren't all that functional.
The GT3 absolutely works.
From cockpit to transmission to outstanding engine and yet more spectacular brakes, in every regard this is an incredible piece of machinery. Maybe the best Porsche road car in the company's history. If you can afford one, we'd suggest buying one to find out.

subset: commoncrawl


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Princess Kay of the Milky Way an NDSU student
FALCON HEIGHTS, Minn. - A young northwestern Minnesota woman received a chilly and warm reception Thursday, hours after receiving the coveted Princess Kay of the Milky Way crown.
FALCON HEIGHTS, Minn. - A young northwestern Minnesota woman received a chilly and warm reception Thursday, hours after receiving the coveted Princess Kay of the Milky Way crown.
The reception was warm for MarJenna McWilliam because Princess Kay candidates always rally around the winner.
It was chilly because she spent most of Thursday in a 40-degree rotating, glass-walled Minnesota State Fair refrigerator.
The 20-year-old Winger woman is the 60th Princess Kay, the state's most visible dairy ambassador. Part of the tradition is for the winner to sit about six hours on the fair's opening day in the refrigerated room built for artist Linda Christensen to sculpt the princess's head out of a 90-pound butter block (and do the same for other Princess Kay finalists each of the fair's remaining 11 days).
For the first several hours, Christensen worked with the butter head facing her, and McWilliam could not see the work. Hundreds of onlookers in the Dairy Building got sneak peeks at the butter face, but it wasn't until after 1 p.m. that Christensen turned the sculpture around so the model could see it.
"It looks pretty cool," McWilliam said, an appropriate comment given her refrigerated state.
After a brief afternoon break to appear in the fair parade with a sleeveless dress, McWilliam returned to the chill, wearing her winter coat in August.
Like for most Princess Kay contestants, her day in the cooler was a dream come true. The woman who has been at the fair every year of her life said she watched Christensen (now in her 42nd year of sculpting dairy royalty) turn butter into works of art "multiple times."
McWilliam said she admired Christensen's work over the years. "How could you not? The idea of getting a head carved in 90 pounds of butter is just an amazing idea."
It is an honor few northwestern Minnesota women have known.
Princess Kay officials said records indicate that the last princess from north of Interstate 94 was Jennifer Kinnunen Schlauderaff of Wadena in 1998. Diane Schroeder Dunn was princess in 1958 when she lived in Polk County, where McWilliam lives.
Even rarer is for a Princess Kay to attend North Dakota State University. No one from the Fargo school has been the princess in the past 20 years and Princess Kay officials said no one recalls someone from there ever wearing the crown.
McWilliam has NDSU company at the fair. Katelyn Blackwelder, 20, of Chokio in Big Stone County and Sarah Paskewitz, 19, of Browerville in Todd County also attend NDSU and, as finalists, will see their likenesses also carved in butter -- and take them home when the fair ends.
Going to school in Fargo while representing Minnesota dairy is fine for McWilliam, she said, because she prefers to attend a school close to home. "It makes it easier to go home on the weekend to see the cows."
Her parents, Bruce and LaVonne McWilliam, have reduced their dairy herd to eight cows, but the princess said that she would like to be able to keep cows once she graduates from NDSU and becomes an English teacher. "I cannot imagine my life not ever having a cow again."
During her reign, McWilliam said, her goal is to deliver "a positive image" about dairy.
"I'm just hoping to get the point across in schools about how important dairy products are to their diets and getting across to their parents that dairy products are healthy for you and they are never something you should cut out of your diet," she said.
Also, she plans to educate the public about "milk imitators," products such as those made from soy beans and almonds. "They do not have the same essential ingredients and fortified calcium that milk does."


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ReMax Southern Shores Sells Homes in Loris, South Carolina
Loris is located in Horry County, about 20 minutes from North Myrtle Beach and five minutes from the North Carolina border. Loris began as a railroad town, serving the area's rapidly-growing timber and turpentine industries. The small town experienced tremendous growth after the Civil War and was incorporated on July 26, 1902.
Loris is in the northern part of Horry County and offers incredible commercial opportunities as well as residential and investment property. Choose a large lot in a neighborhood or opt for a horse farm with acres and acres of pasture. The local airport accommodates private and corporate aircraft, while the renowned Loris Healthcare System operates a state-of-the-art hospital and wellness center. These creature comforts make Loris, South Carolina a very attractive option when you are considering purchasing property in the Myrtle Beach area.
Loris is known for its annual Loris Bog-Off Festival, which is held the third weekend of October. Chicken Bog is a South Carolina favorite consisting of rice, chicken, sausage, and seasonings. In addition to the bog-off, the event also includes live music, fireworks, and children's activities. If you're wondering how to make Chicken Bog, just watch the following video!
Why contact a RE/MAX Southern Shores real estate agent?
First of all because RE/MAX Southern Shores agents are the #1 selling agents in the entire Grand Strand area! And an agent who knows the Loris market as well as the regional real estate market will be able to find exactly the RIGHT property for you at the RIGHT price.
We've designed the RE/MAX Southern Shores search page for Loris, South Carolina real estate, so that you can find a highly qualified and agent and investigate properties independently. You can input specific criteria to search all of Loris Real Estate to get an idea of the home styles, price ranges, and desired amenities that are available. Then, call RE/MAX Southern Shores at 843-839-0200 to speak with an agent. RE/MAX Southern Shores agents are licensed in both North and South Carolina and specialize in Loris Real Estate. They can help you find the home, condo, vacation home, investment property, or land that is RIGHT for you!
If you have any questions, please contact our office where our Loris SC Real Estate agents are available to assist with all your Loris South Carolina Real Estate needs. We'll help you navigate through the extensive list of Loris Real Estate properties to find the right one! We have three offices to better meet your needs, each of which has expert, trained, customer-oriented agents waiting to help you with all your Real Estate needs. Call RE/MAX Southern Shores today at 843-839-0200 to make your dreams a reality!
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A variant of the Nokia Lumia 820 Windows Phone 8 handset, dubbed the Lumia 822, will be coming to Verizon for $99.99 with a two-year contract. The Lumia 820 series are the more modest counterparts to the higher-end Lumia 920, all of which are slated for official announcements with prices and release dates later today.
Like the Lumia 820, the Lumia 822 packs a dual-core 1.5GHz Snapdragon S4 processor, 1GB of RAM, and 8-megapixel camera, but will have 16GB of storage built-in as opposed to the 820's 8GB. The 822 also has a significantly longer battery life, offering 11.7 hours of talk time, compared to the 820's 7.5 hours.
The Lumia 822 and 820 both have a 4.3-inch 800x480 display, but the 822's face is rounder, and it's a bit thicker than the 820 at 11.2 millimeters to the 820's 9.9 millimeters. The Lumia 820 will also come in a range of colors including red, yellow, cyan and purple, while the 822 will stick to grayscale: white, gray, or black.
The Lumia 822 is $99.99 on a two-year contract with Verizon. Microsoft and Nokia have yet to announce a release date for any of the phones in the Lumia line, but rumor has it that November 12 will be the day for the 822, with November 2 for the Lumia 920 and 820. HTC's range of Windows Phone 8 devices are slated for November and likely won't follow far behind.
Ars will be on the ground in San Francisco Monday afternoon liveblogging Microsoft's Windows Phone 8 event to bring you up-to-the-minute info on the launch of the devices and platform.


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David Gregory Named New Host of Meet the Press
NBC has named David Gregory the official replacement host of their Sunday morning show Meet the Press, in which politicos and reporters of all sorts chat about Issues and then cry a little and then do some whippets and take a nap.
The seat was left vacant when longtime host Tim Russert died early this summer, with Tom Brokaw acting as interim host until now. Gregory is the Chief White House Correspondent for NBC News, and is married to Beth Wilkinson, a former Fannie Mae executive and the lawyer who got Timothy McVeigh executed. So, um, good work everybody! Watch a clip of Gregory hard at work, below.


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User:Steven J. Koch/Articles to read
From OpenWetWareJump to navigationJump to search
Articles can be added either by categorizing other pages, or by just manually adding below. (So far, just manual is enabled.)
- http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004612 "Dissection of Kinesin's Processivity" Sarah Adio1, Johann Jaud1, Bettina Ebbing1, Matthias Rief1,2, Günther Woehlke1*
- PMID 16604065 "Individual dimers of the mitotic kinesin motor Eg5 step processively and support substantial loads in vitro." Valentine MT, Fordyce PM, Krzysiak TC, Gilbert SP, Block SM. Nat Cell Biol 2006 May 8(5):470-6
- PMID 17035506 "The distance that kinesin-1 holds its cargo from the microtubule surface measured by fluorescence interference contrast microscopy." http://www.pnas.org/content/103/43/15812.full.pdf+html
- PMID 16100275 Radial compression of microtubules and the mechanism of action of taxol and associated proteins. Needleman DJ, Ojeda-Lopez MA, Raviv U, Ewert K, Miller HP, Wilson L, Safinya CR. Materials Department, University of California, Santa Barbara, CA 93106, USA. Microtubules (MTs) are hollow cylindrical polymers composed of alphabeta-tubulin heterodimers that align head-to-tail in the MT wall, forming linear protofilaments that interact laterally. We introduce a probe of the interprotofilament interactions within MTs and show that this technique gives insight into the mechanisms by which MT-associated proteins (MAPs) and taxol stabilize MTs. In addition, we present further measurements of the mechanical properties of MT walls, MT-MT interactions, and the entry of polymers into the MT lumen. These results are obtained from a synchrotron small angle x-ray diffraction (SAXRD) study of MTs under osmotic stress. Above a critical osmotic pressure, P(cr), we observe rectangular bundles of MTs whose cross sections have buckled to a noncircular shape; further increases in pressure continue to distort MTs elastically. The P(cr) of approximately 600 Pa provides, for the first time, a measure of the bending modulus of the interprotofilament bond within an MT. The presence of neuronal MAPs greatly increases P(cr), whereas surprisingly, the cancer chemotherapeutic drug taxol, which suppresses MT dynamics and inhibits MT depolymerization, does not affect the interprotofilament interactions. This SAXRD-osmotic stress technique, which has enabled measurements of the mechanical properties of MTs, should find broad application for studying interactions between MTs and of MTs with MAPs and MT-associated drugs.
- PMID 7698310 Phase separation in cytoplasm, due to macromolecular crowding, is the basis for microcompartmentation. Walter H, Brooks DE.Laboratory of Chemical Biology 151, Veterans Affairs Medical Center, Long Beach, CA 90822-5201. "The macromolecular diversity and concentrations in the fluid phase of cytoplasm constitute conditions necessary and sufficient for aqueous phase separation. Consequences of phase separation in cytoplasm, including its 'compartmentation', are inferred from analogies with the physicochemical properties of aqueous two-phase systems and with the partitioning behavior of biomaterials in them."
Myosin / osmotic pressure
- http://www.mdpi.org/ijms/papers/i9081435.pdf Enrico Grazi *Department of Biochemistry and Molecular Biology, Ferrara University, Via Borsari 46, 44100 Ferrara, ItalyReceived: 4 Jun 2008; in revised form: 29 July 2008 / Accepted: 30 July 2008 / Published: 18 August 2008 Review: Water and Muscle Contraction Int. J. Mol. Sci. 2008 , 9 , 1435-1452 (PDF format, 155K); DOI: 10.3390/ijms9081435


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Why I hate the myth of the suffering artist — It is absurd and insulting to assume artists are assisted by despair or hunger in a way that, say, plumbers are not. (Via @ce_murphy.)
Copying Is Not Theft — Hmmm…
The Bacon Coffin — For when John Scalzi becomes a vampire. (Via my Dad.)
Boston University scientists discover evidence humans used fire 1 million years ago
We Can Survive Killer Asteroids — But It Won't Be Easy — Duck! And cover!
Programmable 'smart sand' can assume any shape — If you don't think this is cool, you are dead to me.
Future telescope array drives development of exabyte processing
Flying car completes its first test flight, could be on sale by end of the year — 1970 called, they want their future back. Now, where's my jetpack?
Oil Scare Turns FedEx On To Energy Efficiency — Electric vehicles? Come on. Any Republican can tell you that's total Kenyan Muslim socialism. Even when one of American's leading companies is doing the investing.
Gay pride flag raised at a US base in Afghanistan — Go, go, go!
Charlie debunks 2012 nonsense — Why does this even need debunking? As profoundly counterfactual and willfully ignorant as evolution denial and climate change denial are, at least I can see where they're coming from in a cultural and political sense. But 2012 paranoia?
Wisconsin Planned Parenthood attacked with 'explosive device' — Remember kids, according to the Republican party, it's not terrorism if good conservative white people are doing the bombing and the killing.
Six dead in shooting at Oakland university; suspect arrested in Alameda — Thank god for the NRA and the GOP standing up for everyone's right to their defense of essential liberties.
A Return to... You Call This Sanity? — Scrivener's Error is interesting on ebooks and the politics of education. To start with, if you call anything that does not meet your preconceived notion from the hard Right "liberal" — including centrist positions a liberal might well call "conservative" — you're going to get a rather distorted picture. Then, too, exactly how does one judge the political orientation of introductory calculus-based physics? Is it a "liberal-oriented" course if it includes "modern physics"? How about if you offer a non-calculus-based alternative that mentions energy production as an example for study? Is a linguistics course that includes consideration of non-Western languages inherently "liberal", especially if it is not based on Latin and ancient Greek?
Permitted handguns will be allowed in RNC's 'clean zone' — oping to head off violent protesters during the Republican National Convention, Mayor Bob Buckhorn has proposed a litany of items that will be considered security threats during the week-long event. The list runs from air pistols to water pistols and also includes items such as masks, plastic or metal pipe and string more than six inches long. Conspicuously absent from the list of potential weapons: Firearms. Nice to see that conservative America still has its priorities straight. (Via
Social issues are not the Republican Party's problem – the gender gap is about healthcare, not sex — A British perspective, with a strong conservative bias.
Republicans are causing a moral crisis in America — It's hard to point to a single priority of the Republican Party these days that isn't steeped in moral failing while being dressed up in moral righteousness. [...] It is a very strange thing that the people who lecture most fervently about morality are those who are most willing to fight for policies that are so immoral. This is an emperor-has-no-clothes argument, one I've been making for years in vain given the conservative dominance of the "liberal" media and our political discourse.
Pink Slime Economics — [A] lasting budget deal can only work if both parties can be counted on to be both responsible and honest — and House Republicans have just demonstrated, as clearly as anyone could wish, that they are neither. This is news how?
Pressure grows for Rick Santorum to drop out as Obama surges in polls — Mitt Romney expected to win Tuesday primaries as GOP eager to end contest and shift campaign against the president. Amazingly enough, bugfuck conservative lunacy doesn't poll well with people who haven't already drunk the Kool-Aid. I know this will come as a shock to many Republican voters, but their worldview as expressed by Santorum is neither rational nor popular.
Obama Cautions Against 'Judicial Activism' On Health Care — "Ultimately I'm confident the Supreme Court will not take what would be an unprecedented, extraordinary step of overturning a law that was passed by a strong majority of a democratically elected congress," Obama said at a Rose Garden press conference. "And I just remind conservative commentators that for years, what we've heard is the biggest problem on the bench was judicial activism or a lack of judicial restraint. An unelected group of people would somehow overturn a duly constituted and passed law. Well, this is a good example. And I'm pretty confident this court will recognize that and not take that step." Silly president, assuming the remotest intellectual consistency or good faith from Republicans. It's only judicial activism when conservatives disagree with the outcome. Legislation from the bench is fine when it supports the conservative worldview.
?otd: Do you ever ever ever wanna be young again?
Writing time yesterday: 4.25 hours (2.75 hours of reviewing existing draft of Their Currents Turn Awry, added 1,300 words; 1.5 hours of WRPA)
Body movement: 30 minute stationary bike ride
Hours slept: 7.75 (solid)
Weight: 238.6
Currently reading: The Bone Doll's Twin by Lynn Flewelling


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A very quiet, peaceful piano and celesta piece with themes of Christmas and innocence. A simple pattern played out on the piano gets joined by a movement of slow chords underneath, building an emotional crescendo before ending with a twinkle of positivity. For a christmassy, peaceful, or moving feel.
Includes MP3 & WAV format.


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OPINION: Internet freedom may be thing of past after Snowden, NSA
MUNICH – Edward Snowden's supporters have portrayed him as the champion of Internet freedom.
But when senior European and American experts privately discuss the future of cyberspace, their fear is that the Internet may be closing, post-Snowden, rather than opening. "We may be the last generation to take joy from the Internet," because of new boundaries and protectionism, as one American glumly put it.
Privacy advocates would argue that any dangers ahead are the fault of the pervasive surveillance systems of the U.S. National Security Agency, rather than Snowden's revelation of them. I'll leave that chicken-and-egg puzzle for historians.
But it begs the question of how to prevent the anti-NSA backlash from shattering the relatively free and open Internet that has transformed the world – and which the NSA (and other security services) exploited. Unfortunately, the cure here could be worse than the disease, in terms of reduced access, cyber-security and even privacy.
As a starting point, Americans need to understand just how angry Europeans are about the NSA's invasion of their personal space. Secretary of State John Kerry cheerily told the Munich Security Conference last weekend that he foresees a "trans-Atlantic renaissance," with new trade and diplomatic agreements. For now, such talk is just whistling past the NSA graveyard.
"People in Washington don't realize how serious feelings on this side of the Atlantic are," argued one prominent European politician at a high-level private dinner here hosted by the Atlantic Council to discuss cyber issues.
He predicted flatly that American companies would lose an estimated $28 billion to $32 billion in revenues to European cloud-computing companies that will market "NSA-proof" data storage.
This boom for Euro-cloud companies is understandable, in terms of corporate opportunism. But it could build fences around European servers that might turn the global information superhighway into a series of bottlenecks and on-off ramps.
The Internet governance issue is fraught, too. For the last several decades, basic standards and architecture have been managed by a private body known as ICANN. But this group, though passionate about privacy, is now seen as American-dominated, and therefore contaminated. An alternative would give more oversight to the U.N.'s International Telecommunication Union. The leading candidate to head the ITU next is a Chinese official, Houlin Zhao, the group's deputy secretary-general.
Protecting data networks may actually be harder in the post-Snowden environment, argued both Europeans and Americans. That's because sophisticated cyber-protection involves cooperation between agencies such as the NSA (and its foreign counterparts) and private Internet service providers. Such contacts are now anathema.
Another paradox is that indignation about American snooping may make it easier for Russian and Chinese security services to spy on their own people and conduct cyber-espionage. "The Russians and Chinese will talk about sovereignty and non-interference in cyberspace, which is a proxy for their control agenda," argued one cyber expert.
"The Snowden disclosures are being used to renationalize the Internet and roll back changes that have weakened government control of information," argues Stewart Baker, a former NSA lawyer who writes an influential blog on cyber issues.
Many Europeans told me President Barack Obama made a good start with his speech last month outlining new rules for the NSA, especially in his willingness to provide some version of a global Fourth Amendment.
One European argued that privacy rights should be reciprocal – the U.S. should offer protections to countries that grant such rights to their own citizens, as well as Americans.
But one senior European politician warned that if his fellow citizens can't sue in U.S. courts to enforce their new privacy rights, then the European Union will withdraw its so-called "safe harbor" protection for American technology companies.
The NSA revelations have tapped what another top European official called "a fundamental anti-Americanism and mistrust of the U.S."
He noted that if Europeans question the new post-Snowden call for limits and boundaries, they are accused of being NSA's lackeys. "Where's the pushback from the U.S.?" he asks plaintively.
In this tempest of anti-NSA feeling, one of the bravest speeches at Munich was given by German President Joachim Gauck. "We rightly complain when allies overstep the mark when they use electronic surveillance to detect threats. And yet, we prefer to remain reliant on them and hesitate to improve our own surveillance capacities," he said.
A loose interpretation of his underlying message would be: Get real, fellow Europeans. Protecting cyberspace is more complicated than bashing the NSA. ¦


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While cleaning up my very old mail, I came across some of the 1st mails I sent related to GNOME, and, a bit late though, I wish to celebrate my 10th anniversary as a GNOME user and developer. I started as a user in 1998, and after some hacking training (on my free time, since my job at that time was nothing related to free software), I came to announce version 0.1 of gnome-sql, which was later on integrated with the already existing GNOME-DB project.
In all these years, I've worked on several projects (GNOME-DB, Evolution, Control Center, openSUSE GNOME packaging and integration mainly), and, most important, I've met a lot of great people, and, fortunately, the future looks even more exciting (more news on this soon), so looking forward to my 20th anniversary 🙂


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Ask Dog Lady: Adjusting to love beyond the dog
Dear Dog Lady,
I am a single woman, never married, 50-ish. Almost six years ago, I adopted a puppy and my dog changed my life. I know you've heard it all before, but my Muggles, a rescue Husky/Lab mix, got me out of myself enough to meet a real man. I'm still adjusting.
Recently, a friend called and invited me and my "beloved" for dinner. I thought she was really sweet to include Muggles because many dog-less friends make it clear they do not want animals in their homes.
Imagine my surprise when Muggles and I showed up and my friend groaned as she opened the door. "You brought your dog?" she asked in disbelief. "I told you to bring your `beloved.' I meant your new boyfriend."
I was rattled. I haven't yet told my guy that Muggles is still uppermost in my mind as my "beloved." I fear I've lived with my dog for so long I can't allow a human into my heart. What do you think?
Dear Ann,
Tell your man about the incident and keep your sense of humor. Such a confession about how you mentally misplaced his invitation to the dinner will inevitably bring you two closer together.
There is nothing wrong with you. You have just lived with a dog for more human years than with a person. One of your most attractive qualities is your affection for your pet, although your bond with Muggles could be a mystery to your new boyfriend if he isn't a "dog person." The more time he spends with you and your dog, the more he will understand.
You're working out a new romantic dynamic. Don't rush. Remember when you got your puppy? It probably took months for you to adjust to Muggles. So it is with your human sweetheart. There will be tension but communication, understanding, biscuits, and laughter will help you grow into any relationship.
Dear Dog Lady,
My 9-year-old collie pants all the time. I have spent close to $7,000 on different vets. Her heart and lungs are OK. She does not have Cushing's disease and we had nose biopsies showing she had a nose bacteria, which we gave her meds for. The veterinarians are at a loss. I know you are not a vet, but I was wondering if any of your readers have experienced this problem with any of their dogs. I don't know how to proceed from here. Can this panting, even when it is moderate temperature, be normal in some dogs?
Dear Marilyn,
Your sweet collie has been poked, prodded, medicated and biopsied up and down the wazoo. You deserve praise for seeking out veterinary care and paying the bills. Now, let her relax. Often, when a dog pants and appears anxious, the best cure is a good walk in the sunshine, a run in the park and a marathon sniff in an odoriferous venue. Your collie needs fresh air away from the doctor's office.
Monica Collins offers advice on dogs, life and love. Her Web site is www.askdoglady.com. Contact her at firstname.lastname@example.com.


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Q: Yesterday I was driving home and a spark plug blew right out of the cylinder head. The car was towed to the shop where I'd had a tuneup the day before -- which included changing the spark plugs. The mechanic said he could repair the threads, but my uncle says the cylinder head is ruined and the mechanic should replace it at his expense. The car has about 100,000 miles. Thoughts?
A: There are a number of ways to repair stripped threads. In fact, it may be possible to simply chase the old threads with a tap and clean them up. Or, as illustrated, you can insert a Helicoil. There are several types of repair inserts, but we prefer Helicoils. I'd give your mechanic a shot at fixing the threads before I held his feet to the fire. When a spark plug has had a chance to marry a cylinder head for 100,000 miles, it's not uncommon for the aluminum threads to come out of the head with the plug. (I pull and inspect plugs every couple of years and reinstall them with a small dab of antiseize compound, but that's another column.)
A proper thread repair should last as long as the life of the car. This type of repair can be used for almost any threaded fastener, by the way. And that includes cast-iron, steel and aluminum parts. Warning: Installing a Helicoil or other threaded insert looks simple -- but it's not. Any readers out there who wish to attempt it might want to practice a couple of times on scrap parts.
More From Popular Mechanics
Start by threading the special Helicoil tap into the remaining threads in the head. This is to ensure the new threads are concentric and parallel with the originals. Continue threading the tap in to cut the new, oversize threads. To avoid getting aluminum chips in the cylinder when retapping the threads, you should coat the tap with grease. The chips will stick to the grease and come back out with the tap. Back out the chip-laden tap, and clean up any remaining chips.
I've also filled the cylinder (before tapping the hole) with oil-soaked clothesline to catch any chips -- but that was in a racing engine with a squish band only a few thousandths of an inch deep. Street engines with a more normal compression ratio should be fine if you are careful, and blow the chips out with compressed air. Mostly, you don't want any chips to find their way out the exhaust port and wind up in the catalytic converter.
Now you can thread the appropriate-length coil over the installation mandrel. There's a raised flat on the mandrel that will catch on the tang in the coil, allowing you to thread the coil into your new threads. The coil is a little bit bigger than the threads, which will keep it in place when you're finished. The tang will pull the coil into place from the inner end. Once the coil is in place, remove the mandrel.
Now, use a pair of needle-nose pliers to break the tang off. It's prescored to break off cleanly and easily. Do NOT drop the tang into the cylinder! A few aluminum chips will not damage your engine, but a 1/2-in.-long piece of sharp stainless steel wire will tattoo the top of your piston and the combustion chamber before it finally gets out past the exhaust valve.


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Ed here: I read all these as they first appeared in paperback. They're a lot of fun and foreshadow his gifts as a great op novelist.
Early Crichton Novels to Be Released as e-Books
By THE ASSOCIATED PRESS
NEW YORK — Ten early novels that Michael Crichton wrote under pen names while he was in medical school are coming out as e-books.
Open Road Integrated Media announced Thursday that it was releasing the first e-editions of "A Case of Need," ''Odds On" and other suspense thrillers.
Crichton wrote the books while studying at Harvard Medical School in the 1960s under pen names including John Lange, Jeffery Hudson and Michael Douglas.
Open Road CEO Jane Friedman published many of Crichton's books while she was an executive at Alfred A. Knopf and HarperCollins.
Crichton's many best-sellers have included "Rising Sun," ''Jurassic Park" and "Disclosure." He died in 2008 at age 66.
Other novels being released as e-books by Open Road include "Easy Go" and "Zero Cool."


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French Trade Commission
Business France is the national agency supporting the international development of the French economy, responsible for fostering export growth by French businesses, as well as promoting and facilitating international investment in France.
It promotes France's companies, business image and nationwide attractiveness as an investment location, and also runs the V.I.E international internship program.
Founded on January 1, 2015 through a merger between Ubifrance and the Invest in France Agency, Business France has 1,500 personnel, both in France and in 70 countries throughout the world, who work with a network of public- and private-sector partners.


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empirica provides research and consultancy enabling our clients in the public and private sectors internationally to succeed in innovation with new information and communication technology.
Demographic change, chronic diseases and personalised care demand new approaches to health and social care delivery. The safety, sustainability, and cost-efficiency of our care systems need to be improved. The application of advanced ICT and medico-technical innovations can make a major contribution towards achieving these goals.
With people living longer than before, but also with changing behaviours and expectations, our society and the place and role of older people in it changes constantly. Care providers, employers and civil society have to keep abreast of those changes. Supporting them in addressing the challenges arising from this is one of our core competencies.
Fostering talent is key to competitiveness and to employment. We help exploit innovation in skills enhancement, design organisational innovations and help policy and private sector clients to match education and training with technological development and evolving requirements of learners and employers.
Building a society open for everyone requires a sensitivity for justice, a creative mind and strategic thinking. We help organisations and decision makers to address the challenges of inclusiveness and develop innovative ways and tools to make society more equal.
Governments, enterprises and research organisations need to define research and innovation concepts to find solutions for pressing economic and societal challenges. empirica supports R&I actors through collecting and analysing representative data, organising events and developing recommendations for strategic action.
empirica works with cities, utilities, researchers and service providers across Europe on innovative means to improve energy efficiency in public and private buildings. We coordinate large projects and offer evaluation, business analysis and solution consulting.


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The Port Pub, built by friends and owned by community shareholders, welcomes you. Named by EnRoute Magazine as one of Canada's top 10 Bars & Patios, enjoy good cheer and wonderful locally-produced food and drink, in an idyllic location in Port Williams, Nova Scotia.
The Port Pub and Bistro, situated on the banks of the Cornwallis River, is one of the first gastropubs in Nova Scotia. The Pub was purposefully designed and built as a gastropub by local tradesmen and showcases a unique architectural design. You can enjoy beautiful Annapolis Valley views from both within the pub or outside on our waterside deck.
Your food is prepared in our kitchen from local produce within season. We feature our own micro-brewed beers produced on site and an adventurous drink selection.


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Happy Release Day to
Artifacts by Pete Catalano!
Join us in celebrating this new release from Tantrum Books!
Enter the giveaway found at the end of the post.
Happy Book Birthday, Pete!
It's funny how one little letter can change a person's life. Jax and his friends have been planning the summer of a lifetime at Camp Runamuck. However, when one of them is facing summer at a school desk for failing English, they watch those plans crash and burn!
At the last moment they're given a way out.
An extra credit assignment to find several fake artifacts for a fairy tale display their teacher is presenting at the local library.
Thinking they've hit the easiest-extra-credit-ever jackpot, they begin rummaging through any piles of junk they can find. As they start putting the clues together, they realize that what they're really searching for is one authentic artifact that can rewrite fairy tales!
Enlisting the aid of the Lost Boys, Jax and his friends battle fairy tale villains to see who can get their hand, or their hook, on it first.
Artifacts by Pete Catalano Release Date: May 17, 2016 Publisher: Tantrum Boooks
BAM | Google Play | Chapters | Amazon | B&N | Kobo | TBD | iBooks
Pete Catalano's books are written for kids of all ages — and adults who secretly never grew up. He lives in Charlotte, NC with his adorably funny wife and two neurotic dogs. Pete was a theatre major in college and tries to keep the 'suspension of disbelief' in his life as much as he can.
Website | Twitter | Facebook | Pinterest |Goodreads
Complete the Rafflecopter below for a chance to win!


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Yura Transitional Button Tufted Loveseat in Beige
Yura Transitional Button Tufted Loveseat in Beige
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Our casual shipping window is 2 to 10 business days for most of our products within the contiguous United States.
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Orders to Alaska and Hawaii will most likely incur additional freight charges and the responsibility of the customer.
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Hey blog readers,
It's November in Wisconsin... can you guess what that means? Yep, snow! Tons of it, and it's not even Thanksgiving yet! I mean, I love snow, but when it comes this early, all it does is make me want it to be Winter break even MORE. I'm going to have a heck of a time walking to class tomorrow...
Okay moving on...
More From Seventeen
I went to St. Olaf College this weekend to visit my friend Chelsea, and all I can say is wow... never underestimate a private school. It was honestly just as much fun, if not MORE fun than my public school. I mean, although St. Olaf is a tiny school, there was always something going on, and I didn't get bored once the entire weekend. (Which could be partly due to the fact that when Chelsea and I are together we're never bored anyway.) But really, it was ablast
. Basically, my weekend was a mixture of huge parties (I'm talking over 400 people!), late night pizza, boys, dancing, movies, more parties, more late night pizza, more boys... and the list goes on and on.
Anywho, I thought it'd be a cool idea to talk about what I noticed to be the
pros and cons of private school college life. [Besides what you read in the pamphlets and on university websites] I thought it might be helpful to the readers out there who are having a hard time deciding if a private school is the right fit for them. Where to begin... I think I'll make a chart!
Pros of a Private School
-Smaller campus; easier to walk to classes/cafeteria
-Fewer people; more recognizable faces
-Fewer parties, which makes every party HUGE because the entire student body is there
-WAY. BIGGER. DORM ROOMS. So much more room!
-Much shorter cafeteria lines; better quality of food
Cons of a Private School:
-Smaller campus; not a lot of places to go -Fewer people; fewer new faces -Fewer parties; not a lot of options -Way bigger dorm rooms; more expensive room and board -Better quality of food, but less variety
I know it's not tons of information, but hey, I was only there for one super short weekend, I mean come on what do you expect? And really, even though the reasons might seem small and silly, they actually do make a big difference.
Hopefully that helped, talk to you next week!
Have any questions/comments about private school campuses? Share/Ask in the comment section below!


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Some thoughts to fill the space between AACR and ASCO (and the attendant frenzied biopharma/biotech IO deals).
Classical immune responses are composed of both innate and adaptive arms that coordinate to drive productive immunity, immunological expansion, persistence and resolution, and in some cases, immunological memory. The differences depend on the "quality" of the immune response, in the sense that the immunity is influenced by different cell types, cytokines, growth factors and other mediators, all of which utilize diverse intracellular signaling cascades to (usually) coordinate and control the immune response. Examples of dysregulated immune responses include autoimmunity, chronic inflammation, and ineffective immunity. The latter underlies the failure of the immune system to identify and destroy tumor cells.
Let's look at an immune response as seen by an immunologist, in this case to a viral infection:
Of note are the wide variety of cell types involved, a requirement for MHC class I and II responses, the presence of antibodies, the potential role of the complement cascade, direct lysis by NK cells, and the potentially complex roles played by macrophages and other myeloid cells.
In the immune checkpoint field we have seen the impact of very specific signals on the ability of the T cell immune response to remain productive. Thus, the protein CTLA4 serves to blunt de novo responses to (in this case) tumor antigens, while the protein PD-1 serves to halt ongoing immune responses by restricting B cell expansion in the secondary lymphoid organs (spleen, lymph nodes and Peyer's Patches) and by restricting T cell activity at the site of the immune response, thus, in the tumor itself. Approved and late stage drugs in the immune checkpoint space are those that target the CTLA4 and PD-1 pathways, as has been reviewed ad nauseum. Since CTLA4 and PD-1 block T cell-mediated immune responses at different stages it is not surprising that they have additive or synergistic activity when both are targeted. Immune checkpoint combinations have been extensively reviewed as well.
We'll not review those subjects again today.
If we step back from those approved drugs and look at other pathways, it is helpful to look for hints that we can reset a productive immune response by reengaging the innate and adaptive immune systems, perhaps by targeting the diverse cell types and/or pathways alluded to above.
One source of productive intelligence comes from the immune checkpoint field itself, and its' never-ending quest to uncover new pathways that control immune responses. Indeed, entire companies are built on the promise of yet to be appreciated signals that modify immunity: Compugen may be the best known of these. It is fair to say however that we remain unclear how best to use the portfolio of checkpoint modulators we already have in hand, so perhaps we can look for hints there to start.
New targets to sift through include the activating TNF receptor (TNFR) family proteins, notably 4-1BB, OX40, and GITR; also CD40, CD27, TNFRSF25, HVEM and others. As discussed in earlier posts this is a tricky field, and antibodies to these receptors have to be made just so, otherwise they will have the capacity to signal aberrantly either because the bind to the wrong epitope, or they mediate inappropriate Fc-receptor engagement (more on FcRs later). At Biogen we showed many years ago that "fiddling" with the properties of anti-TNFR antibodies can profoundly alter their activity, and using simplistic screens of "agonist" activity often led to drug development disaster. Other groups (Immunex, Amgen, Zymogenetics, etc) made very similar findings. Careful work is now being done in the labs of companies who have taken the time to learn such lessons, including Amgen and Roche/Genentech, but also BioNovion in Amsterdam (the step-child of Organon, the company the originally created pembrolizumab), Enumeral in Cambridge US, Pelican Therapeutics, and perhaps Celldex and GITR Inc (I've not studied their signaling data). Of note, GITR Inc has been quietly advancing it's agonist anti-GITR antibody in Phase 1, having recently completed their 8th dose cohort without any signs of toxicity. Of course this won't mean much unless they see efficacy, but that will come in the expansion cohort and in Phase 2 trials. GITR is a popular target, with a new program out of Wayne Marasco's lab at the Dana Farber Cancer Institute licensed to Coronado and Tg Therapeutics. There are many more programs remaining in stealth for now.
More worrisome are some of the legacy antibodies that made it into the clinic at pharma companies, as the mechanisms of action of some of these agonist antibodies are perhaps less well understood. But lets for the sake of argument assume that a correctly made anti-TNFR agonist antibody panel is at hand, where would we start, and why? One obvious issue we confront is that the functions of many of these receptors overlap, while the kinetics of their expression may differ. So I'd start by creating a product profile, and work backward from there.
An ideal TNFR target would complement the immune checkpoint inhibitors, an anti-CTLA4 antibody or a PD-1 pathway antagonist, and also broaden the immune response, because, as stated above, the immune system has multiple arms and systems, and we want the most productive response to the tumor that we can generate. While cogent arguments can be made for all of the targets mentioned, at the moment 4-1BB stands as a clear frontrunner for our attention.
4-1BB is an activating receptor for not only T cells but also NK cells, and in this regard the target provides us with an opportunity to recruit NK cells to the immune response. Of note, it has been demonstrated by Ron Levy and Holbrook Khort at Stanford that engagement of activating Fc receptors on NK cells upregulates 4-1BB expression on those cells. This gives us a hint of how to productively combine antibody therapy with anti-4-1BB agonism. Stanford is already conducting such trials. Furthermore we can look to the adjacent field of CAR T therapeutics and find that CAR T constructs containing 4-1BB signaling motifs (that will engage the relevant signaling pathway) confer upon those CAR T cells persistence, longevity and T cell memory – that jewel in the crown of anti-tumor immunity that can promise a cure. 4-1BB-containing CAR T constructs developed at the University of Pennsylvania by Carl June and colleagues are the backbone of the Novartis CAR T platform. It is a stretch to claim that the artificial CAR T construct will predict similar activity for an appropriately engineered anti-4-1BB agonist antibody, but it is suggestive enough to give us some hope that we may see the innate immune system (via NK cells) and an adaptive memory immune response (via activated T cells) both engaged in controlling a tumor. Pfizer and Bristol Myers Squibb have the most advanced anti-4-1BB agonist antibody programs; we'll see if these are indeed best-in-class therapeutics as other programs advance.
Agonism of OX40, GITR, CD27, TNFRSF25 and HVEM will also activate T cells, and some careful work has been done by Taylor Schreiber at Pelican to rank order the impact of these receptors of CD8+ T cell memory (the kind we want to attack tumors). In these studies TNFRSF25 clearly is critical to support CD8 T cell recall responses, and may provide yet another means of inducing immune memory in the tumor setting. Similar claims have been made for OX40 and CD27. Jedd Wolchok and colleagues recently reviewed the field for Clinical Cancer Research if you wish to read further.
Looking again beyond T cells another very intriguing candidate TNFR is CD40. This activating receptor is expressed on B cells, dendritic cells, macrophages and other cell types involved in immune responses – it's ligand (CD40L) is normally expressed on activated T cells. Roche/Genentech and Pfizer have clinical stage agonist anti-CD40 programs in their immuno-oncology portfolios. Agonist anti-CD40 antibodies would be expected to activated macrophages and dendritic cells, thus increasing the expression of MHC molecules, costimulatory proteins (e.g. B7-1 and B7-2) and adhesion proteins like VCAM-1 and ICAM-1 that facilitate cell:cell interactions and promote robust immune responses.
I mentioned above that interaction of antibodies with Fc receptors modulates immune cell activity. In the case of anti-CD40 antibodies, Pfizer and Roche have made IgG2 isotype antibodies, meaning they will have only weak interaction with FcRs and will not activate the complement cascade. Thus all of the activity of the antibody should be mediated by it's binding to CD40. Two other agonist anti-CD40 antibodies in development are weaker agonists, although it is unclear why this is so; much remains to be learned regarding the ideal epitope(s) to target and the best possible FcR engagement on human cells. Robert Vonderheide and Martin Glennie tackled this subject in a nice review in Clinical Cancer Research in 2013 and Ross Stewart from Medimmune did likewise for the Journal of ImmunoTherapy of Cancer, so I won't go on about it here except to say that it has been hypothesized that crosslinking via FcgRIIb mediates agonist activity (in the mouse). Vonderheide has also shown that anti-CD40 antibodies can synergize with chemotherapy, likely due to the stimulation of macrophages and dendritic cells in the presence of tumor antigens. Synergy with anti-CTLA4 has been demonstrated in preclinical models.
One of the more interesting CD40 agonist antibodies recently developed comes from Alligator Biosciences of Lund, Sweden. This antibody, ADC-1013, is beautifully characterized in their published work and various posters, including selection for picomolar affinity and activity at the low pH characteristic of the tumor microenvironment (see work by Thomas Tötterman, Peter Ellmark and colleagues). In conversation the Alligator scientists have stated that the antibody signals canonically, i.e. through the expected NF-kB signaling cascade. That would be a physiologic signal and a good sign indeed that the antibody was selected appropriately. Not surprisingly, this company is in discussion with biopharma/biotech companies about partnering the program.
Given the impact of various antibody/FcR engagement on the activity of antibodies, it is worth a quick mention that Roghanian et al have just published a paper in Cancer Cell showing that antibodies designed to block the inhibitory FcR, FcgRIIB, enhance the activity of depleting antibodies such as rituximab. Thus we again highlight the importance of this sometimes overlooked feature of antibody activity. Here is their graphical abstract:
The idea is that engagement of the inhibitory FcR reduces the effectiveness of the (in this case) depleting antibody.
Ok, moving on.
Not all signaling has to be canonical to be effective, and in the case of CD40 we see this when we again turn to CAR T cells. Just to be clear, T cells do not normally express CD40, and so it is somewhat unusual to see a CAR T construct containing CD3 (that's normal) but also CD40. We might guess that there is a novel patent strategy at work here by Bellicum, the company that is developing the CAR construct. The stated goal of having a CD40 intracellular domain is precisely to recruit NF-kB, as we just discussed for 4-1BB. Furthermore, the Bellicum CAR T construct contains a signaling domain from MYD88, and signaling molecule downstream of innate immune receptors such as the TLRs that signal via IRAK1 and IRAK4 to trigger downstream signaling via NF-kB and other pathways.
Here is Bellicum's cartoon:
If we look through Bellicum's presentations (see their website) we see that they claim increased T cell proliferation, cytokine secretion, persistence, and the development of long-term memory T cells. That's a long detour around 4-1BB but appears very effective.
The impact of innate immune signaling via typical TLR-triggered cascades brings us to the world of pattern-recognition receptors, and an area of research explored extensively by use of TLR agonists in tumor therapy. Perhaps the most notable recent entrant in this field is the protein STING. This pathway of innate immune response led to adaptive T cell responses in a manner dependent on type I interferons, which are innate immune system cytokines. STING signals through IRF3 and TBK1, not MYD88, so it is a parallel innate response pathway. Much of the work has come out of a multi-lab effort at the University of Chicago and has stimulated great interest in a therapeutic that might be induce T cell priming and also engage innate immunity. STING agonists have been identified by the University of Chicago, Aduro Biotech, Tekmira and others; the Aduro program is already partnered with Novartis. They published very interesting data on a STING agonist formulated as a vaccine in Science Translational Medicine on April 15th (2 weeks ago). Let's remember however that we spent several decades waiting for TLR agonists to become useful, so integration of these novel pathways may take a bit of time.
This emerging mass of data suggest that the best combinations will not necessarily be those that combine T cell immune checkpoints (anti-CTLA4 + anti-PD-1 + anti-XYZ) but rather those that combine modulators of distinct arms of the immune system. Recent moves by biopharma to secure various mediators of innate immunity (see Innate Pharma's recent deals) and mediators of the immunosuppressive tumor microenvironment (see the IDO deals and the interest in Halozyme's enzymatic approach) suggest that biopharma and biotech strategists are thinking along the same lines.


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Just last week we gave you the news about SailDrone's historic unmanned voyage from 'frisco to Hawaii. With their safety-orange drone safely tied down, we're getting project designer and leader Richard Jenkins on the line for another great SA Innerview.
Whether you're a tech freak, a RC sailboat lover, or just a lover of all things dronish, get your questions in about this potentially revolutionary little sailboat here, and Mr. Clean will make sure the good ones get asked in our video Skype chat. Deadline for questions: Friday at 1300 GMT. Saildrone photos with more here.


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Mamiya Announces $1,000 Trade-in Program for the New RZ33 Medium Format Digital Camera
Photographers who purchase a new Mamiya RZ33 camera kit between July 2010 and September 30, 2010 can trade in their existing RZ67 or RB67 camera body
Elmsford, NY (PRWEB) July 8, 2010 — Mamiya announces today a new trade-in program created to make its new Mamiya RZ33 digital camera kit even more affordable. Designed specifically for existing owners of Mamiya RB67 and RZ67 film-based camera systems, this new trade-in program allows photographers to update their equipment to the latest digital version of the legendary Mamiya RZ system at an exceptionally reasonable price.
From July 2010 until September 30, 2010, photographers who purchase a new Mamiya RZ33 digital camera kit can trade in their existing RZ67 or RB67 camera body for a credit of US $1,000 towards the purchase of their new Mamiya RZ33. There is a limit of one trade-in per RZ33 purchased.
"The positive response to the announcement of the new Mamiya RZ33 digital camera kit has been overwhelming among existing Mamiya RB and RZ owners," says Mamiya Product Marketing Manager Mike Edwards. "Photographers are eager to update their equipment to the new digital RZ33, but still want to make good use of their previous RB or RZ67 camera body. Our new trade-in program gives these photographers the perfect way to do this, and makes transitioning to the new Mamiya RZ digital system even more affordable."
About the Mamiya RZ33
The Mamiya RZ33 is a new large-sensor digital camera kit featuring a high performance 33 megapixel CCD sensor. This new camera advances the long adored Mamiya RZ line to a new level, bringing the famous ease-of-use and versatility of the Mamiya RZ camera system to the large-sensor digital arena. With no cables necessary, RZ33 users simply add their favorite razor sharp RZ lens and a CF card, and they are ready to produce large, detailed, and gorgeous images. The RZ33 leverages the large availability of lenses and accessories from the previous generations of the Mamiya RZ67 family, allowing photographers to utilize premium-level equipment they already own.
Pricing and Availability
The new Mamiya RZ33 digital camera kit, including Capture One and Leaf Capture software, will be available in the U.S. this month for US $17,990. Photographers taking advantage of the US $1,000 trade-in program will simply coordinate the trade-in with their authorized Mamiya Digital Dealer at the time of the new RZ33 transaction.
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FORMER MANCHESTER UNITED coach Rene Meulensteen does not expect Louis van Gaal to wave a magic wand and quickly fix the club's problems.
After fresh optimism at Old Trafford during the close-season, United were brought back to earth on Saturday as Swansea City recorded a surprise 2-1 win.
Van Gaal's side began that game in a new 3-4-1-2 formation but the Dutchman was forced to revert to a more traditional 4-4-1-1 after the break, which saw United improve but ultimately fall short.
For Meulensteen, the manager's indecision on the opening weekend of the Premier League season shows United are still some way off the finished article and he called for the club's fans to be patient as Van Gaal embarks on a rebuilding process.
"This is not going to be a quick fix," Meulensteen – first-team coach under Alex Ferguson at the club – told Talksport.
"They have still got two weeks to go in this transfer window.
"They definitely need to maximise the opportunities in this window and probably do something in January as well. This process will take a long, long time.
"We need to strengthen at the back, we need to strengthen in midfield and that is foremost the two areas they need to look at.
"In my opinion, they need to bring in at least four top players to crank up the level."
United have signed Luke Shaw and Ander Herrera during the close-season but have failed to sign the likes of Arturo Vidal, Mats Hummels and Marcos Rojo, despite repeated links.


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As cinemagoers and telly watchers we are used to accomplished adaptations of fictions born on the page. Whether it's the BBC's latest Jane Austen costume drama or blockbusters like the Harry Potter series, we consume creations transformed from the page to the screen all the time. We are also accustomed to the fictionalisation and cinematic imaginings of happenings from history, with one of film's latest trends being the increasing use of exciting events from the recent past. The likes of The Social Network and 127 Hours brought books about modern, real lives to the big screen.
But we are less used to films based on academic and extensively researched works of non-fiction. There is of course the occasional box office hit based on a lucky scholar's lengthy biography or surprisingly successful history. However it's rare for such books to be huge hits in print via Amazon, Waterstones or WH Smith, let alone dominate in theatres. It normally takes a strong following of the book to persuade producers that the appetite is there for a lucrative movie. Or a particularly juicy subject matter, ripe for controversial or intriguing expansion and exploration.
In the case of A Most Dangerous Method by John Kerr there is certainly the potential for controversy. His book, released in the early 1990s and based on new evidence, charts the relationship between commonly recognised pioneers of psychoanalysis, Carl Jung and Sigmund Freud, which is controversial enough in itself. But its way into the world of intellectual competition and mental instability is the papers of Sabina Spielrein. She was a Russian patient of Jung's, taken to a clinic in Zurich in 1904 at the age of 18. Her habits included "ill concealed masturbation". And she and Jung had an affair.
As if that were not a sufficiently saucy and shocking cocktail, the nature of the affair remains scandalous even now. Jung was trying to drive forward a new profession and ensure its respect as a science and as a medical treatment. And yet he had an affair with one of his patients. An affair directly linked to his treatment and his probing of her condition. She was beaten as a child by her father and this sexually excited her. It doesn't take much to imagine what she and Jung got up to. Sadomasochism enters the mix.
An official trailer for A Dangerous Method, David Cronenberg's adaptation of Christopher Hampton's play, The Talking Cure (which was based on Kerr's original novel), is now online. You can watch it here: http://www.youtube.com/watch?v=uZ7JKmcLTsI&feature=player_embedded
It stars Cronenberg's usual partner in crime Viggo Mortensen as Freud, Michael Fassbender as Jung and Keira Knightley as Spielrein. Disappointingly for fans of Cronenberg and Mortensen's previous collaborations, the story appears to focus on Jung, with Freud relegated to a secondary figure. The weight of the narrative therefore falls on rising star Fassbender, who also stars in a new Jane Eyre adaptation out later this year, and his chemistry with Knightley. Disappointingly for fans of history and good storytelling, Knightley's role, from the trailer at least, appears to be that of kinky sex slave.
Even the slightest research into Kerr's original work uncovers just how fascinating a story, a true story, he set out to tell. Spielrein was treated by Jung and she had some kind of sexual affair with him, although it may never have been consummated. She went onto graduate as a doctor and pursued her own career in psychoanalysis, playing a key role in bringing its breakthroughs back to Russia. She was treated by Freud but always remained attached to Jung.
Not only did Kerr tell this remarkable story with "verve devices" of storytelling and "scholarly precisions", according a 1994 review in The Independent, but his book had a serious point. Aside from being part of a tantalising love triangle complicated by genius and a battle for the soul of a groundbreaking science, Sabina Spielrein sheds light on who was the more influential man; Jung or Freud. Kerr argues that Freud's thinking was of its time and not revolutionary. In any case many of Freud's and Jung's ideas are recognised as plain wrong and outdated today but if one was more important in laying the true foundations of psychoanalysis, Kerr argues it was Jung. He helped create Freud's reputation and was the "engine" of the profession's growth.
Of course this is just Kerr's opinion but it is backed by thorough research and is genuinely interesting. The trailer for A Dangerous Method focused on psychoanalysis for its first 40 seconds, before throwing Knightley into the mix as over the top, loony eye candy for Fassbender to drool over. The dialogue, from Fassbender, Knightley and Vincent Cassel, becomes shamelessly erotic; "never repress anything"/"I want you to punish me"/" why should we put so much effort into suppressing our most basic natural instincts". Surely Cronenberg hasn't wasted his time on soft porn with period detail?
Probably not. It's probably just the marketing approach of the trailer. And there are positives and great potential to be found within its brief runtime. The focus on Jung suggests that the general intellectual thrust of Kerr's book, that Jung was more instrumental than Freud, will remain (although Mortensen does seem to be portrayed as an infrequent but superior wise figure). Cronenberg is hardly known for costumed drama and after the hard hitting History of Violence and Eastern Promises, we can expect something knew from him in this genre. There is also little wrong with well acted desire and I'm sure the full performances won't disappoint.
The fact remains though that those behind the trailer for A Dangerous Method are following that age old principle of advertising; sex sells. The prospect of charismatic and fit X-Men star Fassbender having forbidden romps with a kinky and crazy Keira Knightley will interest millions, whilst Jung's professional friendship and battles with Freud will lure considerably less. There is nothing wrong with humanising great figures from the past; it's what great stories do and it can bring fact to life. But there is something wrong with completely destroying the intentions of a source born of one writer's hard work. Even if the final film tells Sabina Spielrein's full story and is truer to Kerr's revisionist study, it will have sold some sensational half truths to tempt people to see it.


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Attributes of crude oil at U.S. refineries vary by region
Note: PADDs (Petroleum Administration for Defense Districts) are geographic aggregations that allow regional analysis of petroleum markets.
Note: Sweet refers to the absence of hydrogen sulfide (H2S) in crude oil, which typically corresponds to low sulfur content. Sour refers to high H2S content, and a typically high sulfur content.
Crude oil has unique qualities and commands different prices depending on these qualities. In addition to quality considerations, location and local refining capability influence a crude's value. Two key characteristics of crude oil are density and sulfur content. Density ranges from light to heavy, while sulfur content is characterized as sweet or sour. The purchase costs of various crude oils depend mainly on density and sulfur content, and other factors such as location and transportation costs.
Refining capacity in the Gulf Coast has large secondary conversion capacity including hydrocrackers, cokers, and desulfurization units. These units enable the processing of heavy, high sulfur (sour) crude oils like Mexican Maya that typically sell at a discount to light, low sulfur (sweet) crudes like Brent and Louisiana Light Sweet. Many East Coast refineries have less secondary conversion capacity, and in general they process crude oil with lower sulfur content and a lighter density. This lighter, lower sulfur crude oil commands a premium price on world markets.
In recent years, crude production has risen dramatically in Canada (heavy, sour crude) and the United States (high-quality light, sweet crude), providing these types of oil to U.S. refiners. The new U.S. production often sells at a discount to poorer quality crudes because of storage and transportation constraints. Refineries across the country are developing strategies to acquire the new domestic crude streams to replace more expensive imports of high-quality crude oil. Gulf Coast refiners are also seeking more access to Canadian crudes to replace declining supplies of heavy, sour crudes from Mexico and Venezuela (Venezuelan crudes, while heavy, tend to have lower sulfur content than Maya).
Tags: Canada, crude oil, Gulf Coast, oil/petroleum, production/supply, refining


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On the battlefield of the future, a wounded soldier could be scooped up by a robot, placed in a specially equipped drone, and then flown to the closest manned-medical center, where he or she is diagnosed with automated equipment that can deliver treatment without human intervention. Of course, that brings up the question: If robots can do all that, will there be human soldiers on the battlefield?
Air Mobility Command, the military command in charge of aeromedical evacuation of wounded troops, recently announced that it was looking to commission a study on the future of evacuating soldiers from the battlefield. The Pentagon is asking government contractors, as well as their own engineers, to come up with ideas for technologies to be deployed not for the next military conflict, but looking three decades into the future. "The results of the study should be imaginative and revolutionary, not simply evolutionary," Air Mobility Command said in its release, which ticks off robotics, suspended animation, and even spaceflight as a few of the potential ways wounded troops could be evacuated in the future. The military says it is looking for "science fact, not science fiction." So speculating on the nature of future warfare, such as the possibility of remote-controlled battles, is okay, but the concepts must be "reasonable."
Brig. Gen. Bart O. Iddins, Command Surgeon for Headquarters Air Mobility Command, says this move is simply part of long-term strategic planning. That said, he acknowledged the unusual nature of this approach, which seems to conjure up images of robots placing soldiers in hibernation pods. "While strategic planning studies are common across the armed forces, this study is the first of its kind focused specifically on patient movement and en route casualty care," Iddins says.
More From Popular Mechanics
So what might the future look like? One major area of development is evacuation by UAV. NATO has a task force, called Research Technology Group 184, which is looking at how to create an unmanned air ambulance. Germany, Israel, the United States, and the United Kingdom are all taking part, looking at the types of unmanned air vehicles that could be used as well as the legal and certification requirements that would be needed. There are any number of unmanned aircraft, both current and future, that could be used for medical evacuation, including the K-MAX, the Little Bird, and the Fire-X.
There are also aircraft under development with aeromedical evacuation in mind, like the AirMule, developed by the Israeli firm Urban Aeronautics. The AirMule is a vertical takeoff and landing aircraft that uses internal lift rotors, allowing it to land in urban areas inaccessible to helicopters. The idea is that a medic or someone on the battlefield could call for the AirMule, which would be dispatched like a taxi and travel to the injured soldier guided by GPS, then land gudied by a laser designation or perhaps a beacon signal. The company expects to demonstrate a fully autonomous flight test by the end of this year, which would involve having the aircraft take off, travel, land, and return. The aircraft will be ready to be deployed at the end of 2015, according Janina Frankel-Yoeli, the company's vice president for marketing.
Illustration of the AirMule.
"The most likely initial customer will be the Israeli Defense Forces," she says. But, she adds, "it's not likely that [the] first thing they would use it for is medical evacuation." It's still too early for the military to accept loading a patient on an unmanned aircraft, Frankel-Yoeli says. "Initially it would be for cargo delivery."
There are also any number of research projects looking at robotic rescue, such as the U.S. Army-funded Battlefield Extraction Assist Robot (BEAR), a humanoid robot that would literally scoop up a casualty in its arms and carry him or her away from the battlefield, avoiding the need to put human lives in danger. Iddins says there are also advances underway in the realm of handheld diagnostics and automated life support.
And, of course, the military really is looking at suspended animation. "[A]n artificially induced 'hibernation-like' state is another promising medical intervention in which a trauma victim's physiologic deterioration is dramatically slowed or 'suspended' in order to buy time during evacuation to a higher level of medical care," Iddins says. This work is more than theoretical, DARPA is already funding university experiments with pigs to see if this sort of hibernation state would be useful for humans.
This study, Iddins says, is not designed to lead directly to selecting or funding any specific technologies. So don't count on suspended animation quiet yet. "[I]t is important to realize," says Iddins, "that the results of this initial futures study may indicate the need for further study and investigation." However, he says, "[R]obotic-assisted surgery is already commonplace, and robotic battlefield treatment and battlefield extraction of casualties is on the horizon."