History.

Lisbon was laid out in 1851. It was named after Lisbon, the capital of Portugal.

Geography.

Lisbon is located at (41.920721, -91.388188).  According to the United States Census Bureau, the city has a total area of, all land.

Demographics.

2010 census.

As of the census of 2010, there were 2,152 people, 824 households, and 570 families living in the city. The population density was. There were 861 housing units at an average density of. The racial makeup of the city was 97.8% White, 0.5% African American, 0.2% Native American, 0.1% Asian, 0.1% from other races, and 1.3% from two or more races. Hispanic or Latino of any race were 1.2% of the population.  There were 824 households of which 40.3% had children under the age of 18 living with them, 55.0% were married couples living together, 9.7% had a female householder with no husband present, 4.5% had a male householder with no wife present, and 30.8% were non-families. 25.1% of all households were made up of individuals and 9.9% had someone living alone who was 65 years of age or older. The average household size was 2.61 and the average family size was 3.15.  The median age in the city was 36.4 years. 29.2% of residents were under the age of 18; 6.5% were between the ages of 18 and 24; 27% were from 25 to 44; 26.3% were from 45 to 64; and 11.1% were 65 years of age or older. The gender makeup of the city was 48.7% male and 51.3% female.

2000 census.

As of the census of 2000, there were 1,898 people, 728 households, and 516 families living in the city. The population density was 897.8 people per square mile (347.3/km2). There were 752 housing units at an average density of 355.7 per square mile (137.6/km2). The racial makeup of the city was 97.58% White, 0.37% African American, 0.32% Native American, 0.11% Asian, 0.11% from other races, and 1.53% from two or more races. Hispanic or Latino of any race were 0.95% of the population.  There were 728 households out of which 40.9% had children under the age of 18 living with them, 58.9% were married couples living together, 9.1% had a female householder with no husband present, and 29.1% were non-families.  Age spread: 30.1% under the age of 18, 8.1% from 18 to 24, 30.1% from 25 to 44, 21.4% from 45 to 64, and 10.2% who were 65 years of age or older. The median age was 34 years. For every 100 females, there were 100.8 males. For every 100 females age 18 and over, there were 94.4 males.  The median income for a household in the city was $45,139, and the median income for a family was $55,583. Males had a median income of $37,500 versus $24,432 for females. The per capita income for the city was $18,275. About 6.0% of families and 6.8% of the population were below the poverty line, including 8.2% of those under age 18 and 4.7% of those age 65 or over.

Lisbon is a city in Linn County, Iowa, United States, adjacent to the city of Mount Vernon. The population was 2,152 at the 2010 census. It is part of the Cedar Rapids Metropolitan Statistical Area.

Lisbon est une ville du comté de Linn, en Iowa, aux États-Unis. Elle est fondée en 1851 et incorporée le.


Religious scholar.

Granius wrote a book "De indigitamentis" ("On Forms of Address"), on the "indigitamenta", that is, those pontifical books that contained prayer formularies or lists of deity names as a reference for accurate invocations. Granius dedicated this work to Caesar, as his contemporary Varro did his "Antiquitates Divinae". The title of the book is taken from a citation in the 3rd-century grammarian Censorinus. Macrobius cites him jointly with Varro as an authority on a religious point.  Granius was used as a source on ancient Roman religion by the Church Fathers; Arnobius, for instance, refers to him as many as five times in his books "Contra Paganos", second in number only to Varro, equal to the famed Pythagorean scholar Nigidius Figulus, and more often than Cicero. Arnobius implies that he knows the works of Aristotle only indirectly, and cites Granius as his intermediary source at least once. Granius, he says, demonstrates that Minerva is Luna, and also identified the Novensiles with the Muses.  Granius maintained that the Genius and the Lar were one and the same. He shared the view of Varro that the "res divinae" for both Apollo and Father Liber were celebrated on Mount Parnassus. It is sometimes unclear whether references to "Flaccus" refer to him or to Verrius Flaccus.

Jurist.

Granius is cited as an authority in the "Digest" of Justinian, where he is said to have written a book on Papirian law ("Ius Papirianum") as ascribed to the 6th-century pontifex Papirius. A reference in Cicero to the Papirii dates the book to sometime after October 46 BC. The "ius Papirianum" dealt with the laws of the kings ("leges regiae"), which were sacred laws and required knowledge of pontifical records; therefore, the interests of Granius in legal and religious formulas should be seen as compatible. Granius recorded, for instance, that Numa Pompilius, in founding religious rites for the Romans, struck a deal with the gods to punish those who committed perjury. It may be that no collection of "leges regiae" existed earlier, and the idea that there was a "ius Papirianum" originated with the work of Granius at the beginning of Augustus' reign. He may thus be a more significant jurist than the extremely scant remains of his work would indicate.  The point of law cited in the "Digest" involves distinguishing a girlfriend ("amica") from a concubine as defined by law ("concubina"). Granius explained that "pellex" (found elsewhere as "paelex"), Greek "pallakis", had become the usual term for a woman sleeping regularly with a man who has a legal wife ("uxor"), but that formerly it referred to a live-in partner in lieu of a wife.  This Granius is sometimes identified with Granius Licinianus; the latter, however, is almost always dated to the time of Hadrian.

Granius Flaccus (active in the 1st century BC) was an antiquarian and scholar of Roman law and religion, probably in the time of Julius Caesar and Augustus.

Granius Flaccus (floruit ) est un antiquaire et érudit en droit et en religion romains. Il a peut-être vécu à l'époque de Jules César et Auguste.


Early years.

Marko Kropyvnytsky was born on May 7, 1840 in Bezhbayraky village (now Kropyvnytske), Kherson Governorate in a family of nobleman Luka Ivanovych Kropyvnytsky and Kapitolina Ivanivna (née Dubrovynska).

Creativity start.

In 1862 as an audit student, M. Kropyvnytsky attended classes at the Law Faculty of Kiev University. Deeply impressed by a melodrama he saw in Kiev Theatre, he wrote the play "Mykyta Starostenko, or You do know when disaster will awake" (). He later criticized this work as it was an attempt by inexperienced author. Now the play is known in the version, that has undergone numerous fundamental revisions. M. Kropyvnytsky had not completed his education for various reasons; yet he constantly complemented to his knowledge independently, especially after he moved to Elisavetgrad, where there was a library. There, he had a chance to get acquainted with Robert Owen, John Stuart Mill, Shakespeare, Byron, Goethe, Heine, Dumas, George Sand, Thackeray and many others. At the government service, he almost got no promotion, and often completely lost his earnings due to his devotion for art and amateur performances.  In 1871 Kropyvnytsky joined the troupe of professional actors, and agreed to work in the company of Count Morkov (Odessa). He gained a great theatrical experience after spending over ten years in the Russian theater troupe; he thoroughly studied the specific rules of theater genre and learned the place of theater in society.  In 1872 the Odessa newspaper "Novorossiysk Telegraph" published two musical comedies by M.Kropyvnytsky: "Reconciled" and "God will protect an orphan, or Unexpected Proposal".  In 1875 Kropyvnytsky went for tour in Galicia, where he worked as an actor and director of the theater company "Ruthenian talk"; he has made some effort to change the repertoire and artistic style of the theater in bringing it to the realism and national character.

Creating the Coryphee Theatre.

In 1881 the ban for Ukrainian theater was abolished; though there still were many limitations and restrictions, Ukrainian troupes emerged in Kiev, Kharkiv, Odessa. Yet these troupes did not satisfy Marko Kropyvnytsky, who sought for dramatic changes in scenic art. In 1882 he organized his own company, that in about a year merged with the Mykhailo Starytsky troupe, and Marko Kropyvnytsky became a leading director there. A new era in the history of Ukrainian professional theater began. Many famous actors played in Kropivnitskiy' troupe, such as: Maria Zankovetska, Mykola Sadovsky, later M.Sadovska-Barilotti, Panas Saksahansky, Ivan Karpenko-Kary.  At the beginning Kropivnitskiy wrote mainly comedy pieces: "Reconciled" (1869), "God will protect an orphan, or Unexpected Proposal" (1871), "Actor Sinitsa" (1871), "A revision" (1882), "Mustache" (1885) and others.

Later period.

In 1890s Kropivnitskiy called his pieces "pictures" not just once; "pictures of rural movement" ("Konon Blyskavychenko", 1902, "Tough Day", 1906), "pictures of rural life" ("Old bitch and young shoots», 1908) etc.  Even in his later years, forced by worsening health to settle in a farm House, Kropivnitskiy often travelled to participate in theatre performances, he continued writing plays. Kropivnitskiy bothered for organization of a school for farmers and their children, created two plays for children, using folk motifs ("Ivasik-Telesyk", "On the wave of the wand"), and worked on its staging at the farm.  Marko Kropyvnytsky died on 21 April 1910, on his way from Odessa, where he was on tour; he was buried in Kharkiv.

Legacy.

In July 2016 the city of Kirovohrad was renamed Kropyvnytskyi in his honour.  In 2008 Marko's grandson, Ihor Kropyvnytskyi said the following, "Created by Marko Kropyvnytskyi under conditions of a brutal national oppression, the professional theatre was one of main sources of cultural revival of the yoked nation during many years, particularly considering that many of our compatriots were illiterate at that time and were not able to read wonderful poetry and stories of Taras Shevchenko, Marko Vovchok, Ivan Franko and other Ukrainian writers. The Marko Kropyvnytskyi Theatre gave not only an extraordinary push for further development of Ukrainian culture, but also played a prominent socio-political role in the life of Ukrainians, became one of important spiritual foundations on which many decades later was built independent Ukrainian state".  About Kropyvnytskyi, Maksym Rylsky wrote the following, "Let's lower our foreheads: a genius was here, for people he worked and was tormented, so that the people would be treated just, so that the land would be green in garden's bloom" ().

Marko Kropyvnytskyi (, Marko Lukych Kropyvnytsky;, Mark Lukich Kropivnitskiy; May 7, 1840, Bezhbairaky village, Kherson Governorate – 21 April 1910, en route to Kharkiv) was a Ukrainian writer, dramaturge, composer, theatre actor and director. Over his career Kropyvnytskyi wrote 40 plays, played in over 500 roles of various repertoire, as well as wrote several songs.

Marko Kropyvnytsky est un écrivain ukrainien né le dans le village de Bejbaïraki (aujourd'hui ) dans le gouvernement de Kherson (Empire russe), et décédé le.


Description.

Aroeira 3 is a 400,000 year old "Homo heidelbergensis" hominid skull from the Middle Pleistocene which was discovered in the Aroeira cave, Portugal, and announced in spring 2017. It is the earliest human trace in Portugal.  Hominin fossils from this era are commonly classified as "H. heidelbergensis", a chronospecies that stands at the transition between "Homo erectus" and early Neanderthals. The Palaeolithic Acheulean culture, attributed to this and other finds in the Cave of Aroeira, is characterised by the production of Stone tools, notably the hand axe and the use of fire. The skull was damaged during the 2014 excavation from the hard conglomerate rock, but was restored in the following two years. It was only in 2017 that the description of the skull was published in the "Proceedings of the National Academy of Sciences of the United States of America" ("PNAS").

Features.

Aroeira 3 shows some of the features from similar skulls found in Europe, but their combination is unique. The over-eyelashes are continuous, as in the Bilzingsleben skull fragments of "Homo erectus bilzingslebensis". The mastoid of the temporal bone is short as in "Homo steinheimensis" from the gravel pit at Steinheim an der Murr. The large, triangular bony tap on the temporal bone near the auditory canal is also present in skull no. 5 from the site Sima de los Huesos in Spain, the best preserved "Homo heidelbergensis" skull in the world. The Aroeira 3 skull, however, differs from this and the "Homo steinheimensis" by the absence of essential features that also occur in the early Neanderthals.

Location.

The skull was found in a cave above the source of the Rio Almonda, a tributary of the Tagus, which lies in the karst landscape of the central limestone massif of the Portuguese Estremadura. The river forms an approximately 40-kilometer-long cut in the limestone massif with steep banks up to 70 meters in height. On these steep banks, there are various entrances to caves and cave systems that are partially collapsed or filled. Some caves have been excavated and explored. They are associated with human evolution during the Pleistocene and the cultural history during the Paleolithic. There are some cave systems used in the Upper Palaeolithic such as "Entrada Superior", "Entrada do Vale da Serra" and "Gruta da Aroeira". The Middle Palaeolithic is represented in the "Gruta da Oliveira". Late Palaeolithic developments of the Solutrean and Magdalenian cultures can be found in the "Galeria da Cisterna" and the "Lapa dos Coelhos".  Since 1978, the caves have been systematically explored, the first phase of the excavation work in the Cave of Aroeira lasted from 1998 until 2002. In addition to two early human teeth from the Acheulian industry (a canine and a molar, known as Aroeira 1 and Aroeira 2) were also found. The second phase of excavation, from 2013 to 2015, included the well-preserved skull Aroeira 3, but the hardness of the sediment in which it was embedded lead to damage during recovery and had it to be partially reconstructed.

Age.

The age was assessed by uranium–thorium dating, whereby the age of the outer layer of the adjacent stalagmite was found to be 406,000 years within a range of 30,000 years. This is the upper limit because the stalagmite was later buried by boulders and mud masses and stopped growing. Calcite crusts on the skull itself were dated to 390,000 years (± 14,000 years).

Aroeira 3 is a 400,000 year old "Homo heidelbergensis" hominid skull which was discovered in the Aroeira cave, Portugal. It is the earliest human trace in Portugal. "H. heidelbergensis" existed at the transition between "Homo erectus" and early Neanderthals and used both stone tools and fire. The skull was damaged during the 2014 excavation but was restored in the following two years. In 2017 the description of the skull was published in "PNAS". It is on display in the National Archaeology Museum (Lisbon).

Aroeira 3 est un crâne néandertalien ancien fragmentaire d'environ, découvert en 2014 dans la grotte d'Aroeira à Torres Novas au Portugal. Sa morphologie ne correspond à aucune autre forme de référence mais montre cependant quelques traits néandertaliens. Il s'ajoute à d'autres crânes contemporains aux caractéristiques propres comme ceux de Tautavel, de la Sima de los Huesos, de Ceprano, et confirme la diversité des groupes humains en Europe au Pléistocène moyen, au détriment d'un scénario d'évolution linéaire depuis "Homo heidelbergensis". Il était accompagné d'outils de pierre de mode 2 et d'os d'animaux calcinés, suggérant une maitrise du feu.


Etymology.

The first word of Kafr Zita, which is Kafr, is a Syriac word for "farm" or "village". The second word 'Zita' is another Syriac word which refers to olive oil. The village is known for cultivation of olives which is still until now one of the main crops of the village. Also pistachio became popular recently regarding to its better economic revenue.

History.

The ruins of a church dating to the Byzantine period in the 5th-century are located in Kafr Zita.  In the late Ottoman era between the 18th-19th centuries, the residents of Kafr Zita, which at that time was one of the largest villages in the area north of the Orontes River, were regularly in arrears for tax payment and had to obtain financial assistance.  During the period of the French Mandate in Syria, Kafr Zita, like many of the surrounding localities, was organized as a collective farming village. In 1975 the "nahiyah"s ("subdistricts") of Kafr Zita and Mhardeh were joined together to form the "mantiqah" ("district") of Mhardeh, with the latter as capital.  On 16 December 2012, during the Syrian uprising against the government of Bashar al-Assad that began in early 2011, government forces combating rebels bombed Kafr Zita, leaving three children dead, according to the Syrian Observatory for Human Rights (SOHR). On 20 December rebels claimed to have captured Kafr Zita and a string of other nearby towns during an offensive against government forces in the vicinity of Hama. In September 2013, Abu Shafiq checkpoint () which is between Kafr Zita and Morek, was captured by rebels. However, on 22 September 2014, it was reported that the rebels targeted the checkpoint. By early January 2014, the town was controlled by the Islamic State of Iraq and the Levant. However, later on, ISIL was removed from the town by the rebels.  On 20 August 2019, the Syrian Observatory for Human Rights reported that the rebel and Islamic factions including jihadi groups like a Hayat Tahrir al-Sham have withdrawn from Kafr Zita in north Hama province.

Demographics.

Kafr Zita's inhabitants are predominantly Sunni Muslim Mawalis. In the early 20th-century they, along with the inhabitants of nearby Suran, were still proud of their Mawali origins. The Mawali were non-Arab Muslim nomadic tribes who dominated the desert regions of northern Syria for centuries before being forced out to the vicinity of Hama and Aleppo in the 18th century by the Annizah, a Bedouin tribal confederation from the Najd region of the Arabian Peninsula.

Kafr Zita (, also spelled Kfar Zita, Kafr Zayta, Kfar Zeita, Keferzita or Kafr Zeita) is a town in northern Syria, administratively part of the Hama Governorate, located 30 kilometers north of Hama. Nearby localities include Kafr Nabudah and al-Habit to the northwest, Khan Shaykhun to the northeast, Mork to the east, Suran to the southeast, al-Lataminah, Halfaya and Mahardah to the south, Tremseh to the southwest and Kirnaz and Hayalin. According to the Syria Central Bureau of Statistics, Kafr Zita had a population of 17,052 in the 2004 census. It is also the center of a "nahiyah" ("subdistrict"), part of the Mhardeh District, that consists of seven localities with a combined population of 39,032 in 2004.

Kafr Zita est une ville syrienne situé dans le gouvernorat de Hama. Durant la guerre civile syrienne, Kafr Zita est une ville disputé entre les rebelles et les loyalistes. Elle est prise par les rebelles en.


Seasons.

In Argentina, the climate is divided into four, well defined seasons, those being winter, spring, summer and autumn.

Winter.

In winter (June–August), the northern parts of Argentina are generally warm, the central parts mild, and the southern parts cold with frequent frost and snow. The climate of the southern parts of the country is moderated by the surrounding oceans, resulting in cold weather that is less intense and prolonged than at comparable latitudes in the northern hemisphere. The northern parts of the country have the warmest temperatures, with an average

Spring.

Spring (September–November) is similar to autumn, with mild days and cool nights. During mid-October a large variety of wild and urban flora are in bloom. Temperatures range from in the north to in the center, and in most of Patagonia. Tierra del Fuego Province

Summer.

In summer (December–February), temperatures range from an average of in the north to a mean of in the center of the country except for the southeastern parts of Buenos Aires Province, where temperatures are cooler in summer due to the maritime influence. In the extreme south of the country, the temperature averages ; at very high altitudes, the average is below.  During summer, mean precipitation varies

Autumn.

Autumn (March–May) is generally mild. Some forests and vineyards display red and orange autumn foliage, especially in mid-April. Frost arrives notably earlier in the south and later in the north. Mean temperatures can exceed in the northern parts of the country, while they can touch in most of the central parts of the country, and less than at the higher altitudes. As autumn progresses, mean temperatures fall in all regions, with March warmer than May. In the north, mean temperatures range from in March to in May. In the central parts of the country,

Factors that influence the climate.

Different meteorological factors affect the Argentine climate. Some of these factors are local while others come from other countries.

Geographic factors.

The most important geographical factors that influence the climate of Argentina are latitude, elevation, and distance from the sea. With Argentina extending from 22S to 55S, there are differences in the amount of incoming solar radiation and the amount of daylight received in each season, which affects temperature. Thus, temperatures decrease from north to south due to the differences in latitudes.  Although the centre and the eastern parts of the country are mostly flat, the west is mountainous. Both the Andes and Sierras Pampeanas affect the climate of Argentina, leading to differences in temperature, pressure, and spatial distribution of precipitation depending on the topography and altitude. Here, the Andes exert an important influence on the climate. Owing to the higher altitudes of the Andes north of 40S, they completely block the normal westerly flow, preventing low pressure systems containing moisture from the Pacific Ocean from coming in. Thus, much of Argentina north of 40S is dominated by wind circulation patterns from the South Atlantic High. South of 40S, the Andes are lower in altitude, allowing much of Patagonia to be dominated by

Atmospheric Circulation.

The South Atlantic High and the South Pacific High both influence the pattern of winds and precipitations in Argentina. Owing to the greater high of the Andes at latitudes north of 40S, much of Argentina is dominated by wind circulation patterns from the South Atlantic High. The South Atlantic High transports moisture from the Atlantic Ocean to Argentina. This occurs throughout the year due to the atmospheric pressure being lower on land than in the ocean. Much of the north and central parts of the country are affected by the South Atlantic High, with a strong influence in the eastern parts than in the west. This is due to the eastern parts being more frequently affected by the South Atlantic High, causing precipitation to decrease westwards.  Throughout the

El Niño and La Niña.

The El Niño–Southern Oscillation leads to changes in the atmospheric circulation patterns (also known as teleconnections). Although the exact mechanisms are unknown, the impacts of the changes in atmospheric circulation patterns caused by the El Niño–Southern Oscillation are more clearly observed in the more humid eastern parts of the country (between Uruguay and southern Brazil). During El Niño events, precipitation is more higher than normal while during La Niña events, precipitation is lower than normal in the Pampas. In general, El Niño tends

Antarctic Oscillation.

The Antarctic Oscillation, also known as the Southern Hemisphere Annular Mode is the main factor in tropospheric circulation variability south of 20S and is characterized by pressure anomalies with one situated in the Antarctic and one situated in a band at around 40–50S around the globe. It mainly affects middle and high latitudes in the Southern Hemisphere. It is characterized by the north–south displacement of the westerly wind belt that circle around Antarctica. Such variation in the position of the westerly wind belt affects the intensity and position of cold fronts and mid latitude storm systems and is partly responsible for variation in precipitation in the southern parts of Argentina. The Antarctic

Indian Ocean Dipole.

The Indian Ocean Dipole is an atmospheric–oceanic phenomenon characterized by differences in sea surface temperatures between the eastern and western sections of the tropical Indian Ocean. Similar to the Antarctic Oscillation, the Indian Ocean Dipole is characterized by two phases: a positive and a negative phase. In the positive phase, the eastern section of the tropical Indian Ocean is

Regional climate.

In general, Argentina has four main climate types: warm, moderate, arid, and cold, all determined by the expanse across latitude, range in altitude, and relief features. The vast size, and wide range of altitudes, contribute to Argentina's diverse climate. Argentina possesses a wide variety of climatic regions ranging from subtropical in the north to subantarctic in the far south. Lying between those is the Pampas region, which features a mild and humid climate. Under the Köppen climate classification, Argentina has 11 different climate types: Humid Subtropical (Cfa, Cwa), moderate oceanic (Cfb), warm semi-arid (BSh), subtropical highland oceanic (Cwb), warm desert (BWh), cold semi–arid (BSk), cold desert (BWk), moderate Mediterranean (Csb), cold oceanic (Cfc), and tundra (ET). Consequently, there is a wide variety of biomes in the country, including subtropical rain forests, semi-arid and arid regions, temperate plains in the Pampas, and cold subantarctic in the south. However, despite the diversity of biomes, about two-thirds of Argentina is arid or semi-arid. Argentina is best divided into six distinct regions reflecting the climatic conditions of the country as a whole. From north to south, these regions are Northwest, Chaco, Northeast, Cuyo/Monte, Pampas, and Patagonia. Each climatic region has distinctive types of vegetation.

Mesopotamia.

The region of Mesopotamia includes the provinces of Misiones, Entre Ríos and Corrientes. has a subtropical climate with no dry season. Under the Köppen climate classification, it has a humid subtropical climate ("Cfa"). The main features of the climate are high temperatures and abundant rainfall throughout the year; this abundant rainfall makes water scarcity and extended periods of drought uncommon; most of the region has a positive water balance.  Average annual precipitation ranges from less than in the southern parts of the Province to approximately in the eastern parts. Precipitation is slightly higher in the summer than in the winter and generally decreases from east to west and from north to south. Summer precipitation levels range from a low of to a high

Chaco.

The Chaco region in the center-north completely includes the provinces of Chaco, and Formosa. Eastern parts of Jujuy Province, Salta Province, and Tucumán Province, and northern parts of Córdoba Province and Santa Fe Province are part of the region. As well, most of Santiago del Estero Province lies within the region. This region, located in the center-north has a subtropical climate with hot, humid summers and mild, dry winters. Under the Köppen climate classification, the west has a semi-arid climate ("Bs") while the east has a humid subtropical climate ("Cfa"). Chaco is one of the few natural regions in the world located between tropical and temperate latitudes that is not a desert. Precipitation and temperature are relatively homogeneous throughout the region.  Mean annual precipitation ranges from in the eastern parts

Northwest.

Northwest Argentina consists of the provinces of Catamarca, Jujuy, La Rioja, and western parts of Salta Province, and Tucumán Province. Although Santiago del Estero Province is part of northwest Argentina, much of the province lies in the Chaco region. Northwest Argentina is predominantly dry, hot, and subtropical. Owing to its rugged and varied topography, the region is climatically diverse, depending on the altitude, temperature and distribution of precipitation. Consequently, the vegetation will also differ. Under the Köppen climate classification, the region has five different climate types: semi–arid

Cuyo.

The Cuyo region includes the provinces of Mendoza, San Juan, and San Luis. Western parts of La Pampa Province (as shown in map) also belong in this region, having similar climatic and soil characteristics to it. It has an arid or a semi-arid climate. The region's wide range in latitude, combined with altitudes ranging from to nearly, means that it has a variety of different climate types. In general, most of the region has a temperate climate, with valleys at higher altitudes having a milder climate. At the highest altitudes (over ), icy conditions persist year round.  Average annual precipitation ranges from, though it is generally unpredictable. More than 85% of annual rainfall occurs from October to March, which constitutes the warm season. In contrast, the winter months are dry. Eastern and southeastern areas of the region receive more precipitation than the western areas since

Pampas.

The Pampas includes all of Buenos Aires Province, eastern and southern Córdoba Province, eastern La Pampa Province, and southern Santa Fe Province. It is subdivided into two parts: the humid Pampas to the east, and the dry/semi–arid Pampas to the west. The Pampas has land that is appropriate for agriculture and raising livestock. It is a mostly flat area, interrupted only by the Tandil and Ventana sierras in its southern portion. The climate of the Pampas is characterized as temperate and humid with

Patagonia.

Chubut, Neuquén, Río Negro, Santa Cruz, and Tierra del Fuego are the provinces that make up Patagonia. The Patagonian climate is classified as arid to semi-arid and temperate to cool temperate. One defining characteristic are the strong winds from the west which blow year round (stronger in summer than in winter), which favors evaporation and is a factor in making the region mostly arid. There are three major factors that influence the climate of the region: the Andes, the South Pacific High and South Atlantic High, and an

Statistics.

The average annual precipitation ranges from in the driest parts of Patagonia to over in the westernmost parts of Patagonia and the northeastern parts of the country. Mean annual temperatures range from

Extremes.

High.

In general, the highest temperatures in Argentina are recorded in the northern Chaco region where temperatures of have been recorded. According to the World Meteorological Organization, the highest temperature ever

Low.

Patagonia and the Puna region register the lowest temperatures in Argentina where temperatures lower than have been recorded. The lowest temperature ever recorded in Argentina and South America

Precipitation.

With an average annual precipitation of, Lago Frías in Río Negro Province is considered to be the wettest place in Argentina. Although an average annual precipitation of has been recorded in Lago Tromen in Neuquén Province, the validity of the data is dubious owing to fewer years of data. Lago Frías also has the record for wettest monthly precipitation in Argentina: of precipitation was recorded in May 1951. In contrast,

Natural disasters.

Floods.

Argentina's geomorphic characteristics make the country highly vulnerable to floods. These floods can damage infrastructure, cause loss of life, increase the risk of diseases, and negatively impact agricultural productivity, which is one of the main economic activities of the country. Many of the large Argentinean cities and agriculturally productive areas lie near rivers. The plains are at highest risk for flooding, particularly in the northeastern and central parts of the country, including Greater Buenos Aires. This is because these plains, which cover 35% of the land area in the country (including the Chaco and Pampean areas), are characterized by a flat landscape, which can impede proper water drainage. Both the Parana and Paraguay basins have a flat landscape and are

Droughts and dust storms.

Droughts are the most harmful natural disasters that are difficult to monitor, identify, analyse, and to manage. Events of droughts have considerable and serious negative impacts socially and economically. In the case of Argentina, it is highly dependent on rainfall in order to sustain production related to cereals and oilseeds. Argentina is highly dependent on water supplies originating outside its borders, making it highly vulnerable to changes in water supply due to climate change. In arid parts of the country, agricultural production is highly dependent on irrigation, making it vulnerable to droughts as they can reduce the availability of water which can negatively affect the commercial production of agricultural products or food security for smaller producers that depend on agriculture to feed their families. Droughts are frequent and devastating. Several years of droughts during the last decade have severely affected agricultural production and reduced economic growth. In 2018, a severe drought affected the country from the final months of 2017 to April 2018 was the worst in the last 50 years and one of the 10 most destructive climate related events in the world in 2018. Rainfall in some parts of the country were 50%

Tornadoes and severe weather.

Argentina experiences frequent tornadoes each year. Tornadoes occur in the South American "tornado alley" ("Spanish: Pasillo de los Tornados"), which includes the provinces of Entre Ríos, Córdoba Province, Santa Fe, La Pampa and Greater Buenos Aires. The frequency of tornadoes is similar to the one found in Tornado Alley in North America. However, there is no exact number of tornado occurrences per year, owing to the lack of data. These regions have the most frequent and intense mesoscale convective systems. Tornadoes

Snowstorms and cold waves.

Argentina regularly receives cold air from the south that can reach low latitudes owing to the influence of the Andes. Cold waves are usually accompanied with severe snowstorms or extremely cold conditions that can have a devastating impact on the country's economy.

Climate change.

According to the national government and scientists, climate change is predicted to have a significant effect on the climate of Argentina. There has been an increase in annual precipitation in almost all of Argentina during the 20th century, particularly in the northeast and the center of the country, where agricultural production has expanded to the west by more than in areas that were previously too dry during middle of the 20th century. In contrast, the Andean part of Patagonia, along with the Cuyo region, has seen a decrease in precipitation, leading to a reduction in river flow in the last 100 years. These trends were observed with an increase in the river–stream flows in most of the country, excluding rivers originating from the Andes, and an increase in extreme precipitation events that led to considerable socioeconomic losses. The increase in precipitation has led to more variability in precipitation from year to year in the northern parts of the country, with a higher risk of prolonged droughts.  Mean temperatures have increased by between 1901 and 2012, slightly lower than the global average. Temperatures in the Andean part of Patagonia have increased by more than, which has caused the retreat of almost all of the glaciers. This is affecting water availability to the arid areas of the country that depend on glacier meltwater. Higher temperatures can reduce winter snowfall, causing river flow to decrease, which in turn can reduce hydroelectric energy production; losses of up to 40% have been observed. In the last half of the 20th century, the lack of snow in the highest peaks in the Cuyo region has impacted agriculture and viticulture production due to the decrease in available water in the rivers. Outside of Patagonia, mean temperatures have increased at a slower rate since the increase in minimum temperatures is counteracted by the decrease in maximum temperatures. There has been a decrease in the number of days with frost, and there have been increases in the frequency of hot nights and heat waves throughout the country.  Within the next two or three decades (2016–2035), mean temperatures are predicted to increase by under the two scenarios (RCP 4.5 and RCP 8.5) from the IPCC Fifth Assessment Report. In both scenarios, the projected warming will be more pronounced during the summer months. The predicted trend for precipitation is not as clear as the one for temperature. In the northern and central regions, precipitation is predicted to increase while in most of central–western Argentina and Patagonia, precipitation is predicted to decrease. Because Argentina is potentially vulnerable to climate change, such projected changes based on the models could exacerbate current problems or create new problems associated with climate change in Argentina.  Scientists predict that glaciers will continue to recede and melt or, in some areas, disappear. It is also predicted that the Cuyo region could face a potential water crisis due to an increase in water demand caused by a reduction in river streamflows. In northern Patagonia, a similar situation is projected in which there will be a negative impact on fruit and vegetable growing owing to a reduction in the river flow in the Colorado and Chubut rivers. In the north and central parts of the country, the higher temperatures and lower precipitation projected for this region will lead to higher evaporation, intensifying droughts and leading to desertification. Heat waves could become more frequent and intense, negatively impacting agricultural production while placing more demand on energy needs. Intense precipitation could become more common, increasing the likelihood of suffering from events such as flooding, since most of its population lives in urban areas near a body of water (rivers, lakes and oceans). Climate change could extend the habitats of vectors carrying tropical diseases such as malaria southwards. Though most of the coastal regions of Argentina will not suffer permanent flooding associated with sea level rise, it is predicted that storm surges will become more frequent in coastal areas, affecting locations such as Buenos Aires.

The climate of Argentina is a vastly complex subject, as the vast size of the country and wide variation in altitude make for a wide range of climate types. Summers are the warmest and wettest season in most of the country except in most of Patagonia where it is the driest season. Winters are normally mild in the north, cool in the center and cold in the southern parts experiencing frequent frost and snow. Because southern parts of the country are moderated by the surrounding oceans, the cold is less intense and prolonged than areas at similar latitudes in the northern hemisphere. Spring and autumn are transition seasons that generally feature mild weather.

Le climat de l'Argentine est différent selon les régions, son climat principal est le climat subtropical humide, mais d'autres sont aussi bien présents, comme le climat désertique en Patagonie, le climat semi-aride, le climat océanique ou celui de la toundra dans la Terre de Feu.


Music video.

The music video for the single was directed by John Downer and utilised stop motion animation, a technique used in the videos for Gabriel's earlier hits "Sledgehammer" and "Big Time". The work was painstaking, especially for Gabriel himself who was required to lie still for hours at a time over the course of several days. The video won the Grammy Award for Best Short Form Music Video in 1993. The woman in the video is played by Francesca Gonshaw.  The video is largely an exploration of the issues in his personal life at the time, the end of his relationship with Rosanna Arquette, his desire to reconnect with his daughter and the self-healing he was looking for in therapy.  In the video, Gabriel is displayed in a variety of disturbing imagery, including being buried alive, consumed by an overgrowth of foliage (thanks to a gruelling stop-motion process) and flying into a rage while trying to swat a wasp (after being stung). This time, Gabriel returned to stop motion and claymation that had served him so well in the 1980s, forgoing the computer graphics used in "Steam".  Initially, the word "DIG" forms in the grass while dark imagery plays. Gabriel morphs into a skeleton while at the same time trying to excavate himself. Ultimately, the viewers are left with a gleam of hope as mushrooms sprout to form the word "HELP," followed by "HEAL" in blooming flowers after Gabriel has emerged from underground, now clad in white.  The Secret World Live version of the song is far more intense than the studio version. This is due to a chaotic blend of high pitched distorted guitar (by guitarist David Rhodes), as well as occasional jarring synth bass stabs (Tony Levin) and an expansive performance by Manu Katché on the drums. Gabriel wore a special "helmet" with a video camera attached in an antennae-like way, showing in great detail his facial expressions, while moving in time with the music. This is used to create a particularly grotesque image of Gabriel, most prominent during the "freak-out" sequence in which the camera is pointed down Gabriel's throat.

Track listings.

CD maxi  7" single  All songs written by Peter Gabriel.

Personnel.

Additional musicians

"Digging in the Dirt" is a 1992 song by British musician Peter Gabriel. It was the first single taken from his sixth studio album, "Us". The song was a minor hit on the US "Billboard" Hot 100, peaking at number 52, but it topped both the "Billboard" Modern Rock Tracks and Album Rock Tracks charts. The song was moderately successful on the UK Singles Chart, where it peaked at number 24, and it reached the top 10 in Canada, Portugal and Sweden.

Ce titre marque le retour de Peter Gabriel après six années d'absence. Il indique que le thème de la chanson concerne l'introspection (). Il a été qualifié de genre.


History.

Patterson was laid out in 1872. It derives its name from Alexander Pattison, the original owner of the town site, but the name was misspelled on the plat and stuck.

Geography.

Patterson is located at (41.348815, -93.880684), along the Middle River.  According to the United States Census Bureau, the city has a total area of, all of it land.

Demographics.

2010 census.

As of the census of 2010, there were 130 people in 57 households, including 37 families, in the city. The population density was. There were 66 housing units at an average density of. The racial makeup of the city was 99.2% White and 0.8% Pacific Islander.  Of the 57 households 29.8% had children under the age of 18 living with them, 47.4% were married couples living together, 7.0% had a female householder with no husband present, 10.5% had a male householder with no wife present, and 35.1% were non-families. 29.8% of households were one person and 10.5% were one person aged 65 or older. The average household size was 2.28 and the average family size was 2.84.  The median age was 43 years. 22.3% of residents were under the age of 18; 3.8% were between the ages of 18 and 24; 30% were from 25 to 44; 21.5% were from 45 to 64; and 22.3% were 65 or older. The gender makeup of the city was 52.3% male and 47.7% female.

2000 census.

As of the census of 2000, there were 126 people in 58 households, including 33 families, in the city. The population density was 635.1 people per square mile (243.2/km). There were 67 housing units at an average density of 337.7 per square mile (129.3/km). The racial makeup of the city was 100.00% White.  Of the 58 households 20.7% had children under the age of 18 living with them, 51.7% were married couples living together, 3.4% had a female householder with no husband present, and 41.4% were non-families. 27.6% of households were one person and 6.9% were one person aged 65 or older. The average household size was 2.17 and the average family size was 2.74.  The age distribution was 16.7% under the age of 18, 12.7% from 18 to 24, 24.6% from 25 to 44, 34.1% from 45 to 64, and 11.9% 65 or older. The median age was 42 years. For every 100 females, there were 129.1 males. For every 100 females age 18 and over, there were 118.8 males.  The median household income was $47,500 and the median family income was $52,500. Males had a median income of $31,607 versus $24,375 for females. The per capita income for the city was $21,457. There were no families and 1.4% of the population living below the poverty line, including no under eighteens and none of those over 64.

Patterson is a city in Madison County, Iowa, United States. The population was 130 at the 2010 census. It is part of the Des Moines–West Des Moines Metropolitan Statistical Area.

Patterson est une ville du comté de Madison, en Iowa, aux États-Unis. Elle est fondée en 1872 et incorporée le.


Opinion polling for the 2017 French legislative election

Liste de sondages sur les élections législatives françaises de 2017

Graphical summary.

The averages in the graphs below were constructed using polls listed below conducted by the nine major French pollsters. The graphs are smoothed 14-day weighted moving averages, using only the most recent poll conducted by any given pollster within that range (each poll weighted based on recency).  No total for Europe Ecology – The Greens (EELV) was provided by the Ministry of the Interior in the 2017 legislative elections. According to statistics compiled by Laurent de Boissieu, 454 EELV candidates collected 3.41% of the vote in the first round.

First round.

The comparison for the French Communist Party and La France Insoumise with 2012 is made against the Left Front. Before their unification under the umbrella of the Union of Democrats and Independents, the New Centre, Radical Party, and Centrist Alliance were counted individually in 2012, and are included in the miscellaneous right total for that year, which would otherwise be 3.51%.

Second round seat projections.

Projections marked with an asterisk (*) were constructed for 535 out of 577 constituencies, including only metropolitan France only and excluding Corsica as well as overseas territories and residents.  The comparison for the French Communist Party and La France Insoumise with 2012 is made against the Left Front. Before their unification under the umbrella of the Union of Democrats and Independents, the New Centre, Radical Party, and Centrist Alliance were counted individually in 2012, and are included in the miscellaneous right total for that year, which would otherwise be 15.

By second round configuration.

By first round vote.

In each case, results were based on interviews in which respondents were presented with a list of candidates in their constituency.

By constituency.

First round.

Hauts-de-Seine's 9th.

The campaign of Marie-Laure Godin commissioned and released a PollingVox survey in this constituency, after which the campaign of Thierry Solère published an Ifop poll contradicting its findings.

Second round.

Hauts-de-Seine's 9th.

Pre-2017 polling.

First round.

Before their unification under the umbrella of the Union of Democrats and Independents, the New Centre, Radical Party, and Centrist Alliance were counted individually in 2012, and are included in the miscellaneous right total for that year, which would otherwise be 3.51%. The total for miscellaneous candidates in 2012 also includes regionalist, ecologist, and far-right candidates who were not counted separately in the CSA poll, and would otherwise be 0.52%.

Second round seat projections.

Before their unification under the umbrella of the Union of Democrats and Independents, the New Centre, Radical Party, and Centrist Alliance were counted individually in 2012, and are included in the miscellaneous right total for that year, which would otherwise be 15. The total for miscellaneous candidates in 2012 also includes regionalist and far-right candidates who were not counted separately in the CSA poll, and would otherwise be 0.

This page lists public opinion polls conducted for the 2017 French legislative elections, which were held in two rounds on 11 and 18 June 2017.

Cette page dresse la liste des sondages d'opinions relatifs aux élections législatives françaises de 2017. Tous les sondages de cette liste, sauf mention contraire, se conforment aux règles de la Commission des sondages et appliquent la méthode dite des quotas.


Biography.

Her father was Robert Pearsall Smith, her mother Hannah Whitall Smith. She studied at the Harvard Annex in 1884-1885. Here Mary met the Irish barrister Benjamin "Frank" Conn Costelloe, whom she married in 1885, having converted to Catholicism. This marriage was the occasion for the whole family, including her brother Logan Pearsall Smith and sister Alys Pearsall Smith to move to England in 1888. However, already in 1892 the couple separated, though Frank would not agree to divorce.  Mary had two daughters with Frank Costelloe; Ray Strachey and Karin Stephen. Through the latter Mary was related by marriage to the Bloomsbury Group of English artists and literary figures, as her son-in-law Adrian Stephen was Virginia Woolf's brother.  In 1888 in London she made the acquaintance of Bernard Berenson. With a dissatisfying marriage, she became an authority on art history and she took up in Italy with Berenson. Berenson developed a reputation as an art expert and it is believed Bernard's work were substantially helped by Mary. Their/His book "The Venetion Painters of the Renaissance" was published in 1894 and it is said that it was Mary's mother who asked that Mary not take credit for her work.  They eventually married in 1900 after her first husband died, although they both had affairs and Mary believed this was because they liked to hurt each other.  Her US lecture tours were instrumental in developing an interest in Italian Renaissance art among wealthy American collectors during the first decade of the twentieth century.  Subsequently, Berenson brought together a social circle at "Villa I Tatti", the Berenson home, and developed its gardens. She hosted some of the most celebrated personalities of the period, including Edith Wharton, Gertrude Stein, Gabriele D'Annunzio, John Maynard Keynes, and Isabella Gardner.  By 1927 Mary tired of entertaining, and left the duty of hosting to the couple's librarian Elizabeth Mariano. Mariano was one of Bernard's lovers, and Mary would much later write to give permission for Mariano to marry Bernard. In later life she was plagued by illness and by 1935 she was largely invalided. In 1940 she lost her eldest daughter to surgery complications, and she had to be left behind by her husband (being a Jew under Nazi rule) under the care of Mariano's sister.

See also.

Women in the art history field

Mary Berenson (1864 in Pennsylvania – 1945), née Mary Whitall Smith, was an art historian, now thought to have had a large hand in some of the writings of her second husband, Bernard Berenson.

Mary Berenson, née Mary Whitall Smith en Pennsylvanie en 1864 et morte le, est une historienne de l'art américaine. Son nom et celui de Bernard Berenson sont attachés à la villa I Tatti, à Florence, siège de The Harvard Center for Italian Renaissance Studies.


Geography.

New Sharon is located at (41.469314, -92.650838).  According to the United States Census Bureau, the city has a total area of, all of it land.

Demographics.

2010 census.

As of the census of 2010, there were 1,293 people, 538 households, and 368 families living in the city. The population density was. There were 590 housing units at an average density of. The racial makeup of the city was 99.1% White, 0.4% Native American, and 0.5% from two or more races. Hispanic or Latino of any race were 0.3% of the population.  There were 538 households of which 30.5% had children under the age of 18 living with them, 57.8% were married couples living together, 7.1% had a female householder with no husband present, 3.5% had a male householder with no wife present, and 31.6% were non-families. 27.7% of all households were made up of individuals and 13.7% had someone living alone who was 65 years of age or older. The average household size was 2.40 and the average family size was 2.90.  The median age in the city was 41.8 years. 25.2% of residents were under the age of 18; 6.4% were between the ages of 18 and 24; 22% were from 25 to 44; 28.2% were from 45 to 64; and 18.1% were 65 years of age or older. The gender makeup of the city was 48.5% male and 51.5% female.

2000 census.

As of the census of 2000, there were 1,301 people, 540 households, and 361 families living in the city. The population density was 1,390.9 people per square mile (534.4/km2). There were 575 housing units at an average density of 614.7 per square mile (236.2/km2). The racial makeup of the city was 98.92% White, 0.08% Native American, 0.54% Asian, 0.15% Pacific Islander, and 0.31% from two or more races. Hispanic or Latino of any race were 0.69% of the population.  There were 540 households out of which 30.7% had children under the age of 18 living with them, 56.9% were married couples living together, 8.1% had a female householder with no husband present, and 33.1% were non-families. 30.7% of all households were made up of individuals and 17.8% had someone living alone who was 65 years of age or older. The average household size was 2.30 and the average family size was 2.87.  In the city, the population was spread out with 23.9% under the age of 18, 7.8% from 18 to 24, 23.9% from 25 to 44, 19.9% from 45 to 64, and 24.4% who were 65 years of age or older. The median age was 41 years. For every 100 females, there were 84.0 males. For every 100 females age 18 and over, there were 82.3 males.  The median income for a household in the city was $36,125, and the median income for a family was $42,829. Males had a median income of $33,125 versus $21,739 for females. The per capita income for the city was $17,280. About 7.8% of families and 10.0% of the population were below the poverty line, including 15.4% of those under age 18 and 8.7% of those age 65 or over.

Government.

New Sharon is governed by a Mayor-City Council form of government. The residents elect five at-large council members and one mayor. Each serving a four-year term. The current Mayor of New Sharon is Keri Lamberson.

Education.

New Sharon is home to North Mahaska Community School District schools. North Mahaska Community School District is a rural school district serving nearly 600 students in grades Pre-K through 12th. Located adjacent to the schools is the North Mahaska Community School District Early Childhood education center which opened in 2009. This houses pre-school classes for 3 & 4 year olds as well as the Sunshine and Smiles Daycare Center.

New Sharon is a city in Mahaska County, Iowa, United States. The population was 1,293 at the 2010 census. The first building was erected in 1856 by Edward Quaintance.

New Sharon est une ville du comté de Mahaska, en Iowa, aux États-Unis. Elle est créée en 1856 par "Edward Quaintance" et incorporée en 1871.


Life.

Maria Anna was a daughter of Prince Adam Kazimierz Czartoryski and Countess Isabella von Flemming. She spent her childhood in the Blue Palace in Warsaw and Powązki. In 1782 she moved with her parents to Puławy.  Since 1784 to 1793 Maria was married to Duke Louis of Württemberg, who became the Hetman of the Lithuanian Army in the 1792 war against Russia. Maria divorced him when his betrayal of the Polish-Lithuanian Commonwealth became known. Maria's only son, Duke Adam of Württemberg, remained with his father and was raised in an atmosphere prejudiced against his mother and Poland.  Following her divorce, Maria lived mostly in Warsaw, and since 1798 to 1804 spent winters in Vienna and summers at Puławy. Between 1808-1816 she hosted her literary salon in Warsaw (Blue Saturdays). Her guests included Julian Ursyn Niemcewicz. She attended meetings of the Xs Society (Towarzystwo Iksów). In 1816 she published "Malvina, or the Heart's Intuition", considered Poland's first psychological novel.  Charmed with the picturesque village of Pilica she bought it and remodelled its landscape garden. She built a palace and a Catholic church. The park in Pilica was considered among the most beautiful in Europe, and rivalled other parks in Poland: Powązki (established by Maria's mother) and Helena Radziwiłł's Arkadia. Maria hired Franciszek Lessel as her land agent.  Maria Wirtemberska was an active philanthropist. She provided education and published calendars for the peasantry.  Following the November Uprising Maria moved to Sieniawa, then in Galicia. In 1837 she moved to Paris, where she lived with her brother, Adam Jerzy Czartoryski.

Princess Maria Czartoryska, also formerly known as Duchess Maria, Duchess Louis of Württemberg (March 15, 1768, Warsaw – October 21, 1854, Paris), was a Polish noble, writer, and philanthropist.

Maria Anna Wirtemberska née Czartoryska le à Varsovie et morte le à Paris, est une écrivaine, salonnière, philanthrope et princesse polonaise de la famille Czartoryski.


Production.

The first step in the production of CAR-T cells is the isolation of T cells from human blood. CAR-T cells may be manufactured either from the patient's own blood, known as an autologous treatment, or from the blood of a healthy donor, known as an allogeneic treatment. The manufacturing process is the same in both cases; only the choice of initial blood donor is different.  First, leukocytes are isolated using a blood cell separator in a process known as leukocyte apheresis. Peripheral blood mononuclear cells (PBMC) are then separated and collected. The products of leukocyte apheresis are then transferred to a cell-processing center. In the cell processing center, specific T cells are stimulated so that they will actively proliferate and expand to large numbers. To drive their expansion, T cells are typically treated with the cytokine interleukin 2 (IL-2) and anti-CD3 antibodies.  The expanded T cells are purified and then transduced with a gene encoding the engineered CAR via a retroviral vector, typically either an integrating gammaretrovirus (RV) or a lentiviral (LV) vector. These vectors are very safe in modern times due to a partial deletion of the U3 region. The new gene editing tool CRISPR/Cas9 has recently been used instead of retroviral vectors to integrate the CAR gene into specific sites in the genome.  The patient undergoes lymphodepletion chemotherapy prior to the introduction of the engineered CAR-T cells. The depletion of the number of circulating leukocytes in the patient upregulates the number of cytokines that are produced and reduces competition for resources, which helps to promote the expansion of the engineered CAR-T cells.

Cancer treatment.

T cells are genetically engineered to express chimeric antigen receptors specifically directed toward antigens on a patient's tumor cells, then infused into the patient where they attack and kill the cancer cells. Adoptive transfer of T cells expressing CARs is a promising anti-cancer therapeutic, because CAR-modified T cells can be engineered to target virtually any tumor associated antigen.  Early CAR-T cell research has focused on blood cancers. The first approved treatments use CARs that target the antigen CD19, present in B-cell-derived cancers such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). There are also efforts underway to engineer CARs targeting many other blood cancer antigens, including CD30 in refractory Hodgkin's lymphoma; CD33, CD123, and FLT3 in acute myeloid leukemia (AML); and BCMA in multiple myeloma.  Solid tumors have presented a more difficult target. Identification of good antigens has been challenging: such antigens must be highly expressed on the majority of cancer cells, but largely absent on normal tissues. CAR-T cells are also not trafficked efficiently into the center of solid tumor masses, and the hostile tumor microenvironment suppresses T cell activity.

Clinical studies and FDA approvals.

The first two FDA-approved CAR-T therapies both target the CD19 antigen, which is found on many types of B-cell cancers. Tisagenlecleucel (Kymriah / Novartis) is approved to treat relapsed/refractory B-cell precursor acute lymphoblastic leukemia (ALL), while axicabtagene ciloleucel (Yescarta / Kite Pharma) is approved to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL).  As of March 2019, there were around 364 ongoing clinical trials happening globally involving CAR-T cells. The majority of those trials target blood cancers: CAR-T therapies account for more than half of all trials for hematological malignancies. CD19 continues to be the most popular antigen target, followed by BCMA (commonly expressed in multiple myeloma). In 2016, studies began to explore the viability of other antigens, such as CD20. Trials for solid tumors are less dominated by CAR-T, with about half of cell therapy-based trials involving other platforms such as NK cells.  Although the initial clinical remission rates after CAR-T cell therapy in all patients are as high as 90%, long term survival rates are much lower. The cause is typically the emergence of leukemia cells that do not express CD19 and so evade recognition by the CD19–CAR T cells, a phenomenon known as antigen escape. Preclinical studies developing CAR-T cells with dual targeting of CD19 plus CD22 or CD19 plus CD20 have demonstrated promise, and trials studying bispecific targeting to circumvent CD19 down-regulation are ongoing.

Safety concerns.

CAR-T cells are undoubtedly a major breakthrough in cancer treatment. However, there are serious side effects that result from CAR-T cells being introduced into the body, including cytokine release syndrome and neurological toxicity. Because it is a relatively new treatment, there is little data about the long-term effects of CAR-T cell therapy. There are still concerns about long-term patient survival, as well as pregnancy complications in female patients treated with CAR-T cells.  The most common issue after treatment with CAR-T cells is cytokine release syndrome (CRS), a condition in which the immune system is activated and releases an increased number of inflammatory cytokines. The clinical manifestation of this syndrome resembles sepsis with high fever, fatigue, myalgia, nausea, capillary leakages, tachycardia and other cardiac dysfunction, liver failure, and kidney impairment. CRS occurs in almost all patients treated with CAR-T cell therapy; in fact, the presence of CRS is a diagnostic marker that indicates the CAR-T cells are working as intended to kill the cancer cells. Note, however, that a higher grade of CRS severity does not correlate with an increased response to the treatment, but rather higher disease burden.  Neurological toxicity is also often associated with CAR-T cell treatment. The underlying mechanism is poorly understood, and may or may not be related to CRS. Clinical manifestations include delirium, the partial loss of the ability to speak coherently while still having the ability to interpret language (expressive aphasia), lowered alertness (obtundation), and seizures. During some clinical trials deaths caused by neurotoxicity have occurred. The main cause of death from neurotoxicity is cerebral edema. In a study carried out by Juno Therapeutics, Inc., five patients enrolled in the trial died as a result of cerebral edema. Two of the patients were treated with cyclophosphamide alone and the remaining three were treated with a combination of cyclophosphamide and fludarabine. In another clinical trial sponsored by the Fred Hutchinson Cancer Research Center, there was one reported case of irreversible and fatal neurological toxicity 122 days after the administration of CAR-T cells.  Anaphylaxis is an expected side effect, as the CAR is made with a foreign monoclonal antibody and as a result, provokes an immune response.  On-target/off-tumor recognition occurs when the CAR-T cell recognizes the correct antigen, but the antigen is expressed on healthy, non-pathogenic tissue. This results in the CAR-T cells attacking non-tumor tissue, such as healthy B cells that express CD19. The severity of this adverse effect can vary from B-cell aplasia, which can be treated with supporting infusions, to extreme toxicity leading to death.  There is also the unlikely possibility that the engineered CAR-T cells will themselves become transformed into cancerous cells through insertional mutagenesis, due to the viral vector inserting the CAR gene into a tumor suppressor or oncogene in the host T cell's genome. Some retroviral (RV) vectors carry a lower risk than lentiviral (LV) vectors. However, both have the potential to be oncogenic. Genomic sequencing analysis of CAR insertion sites in T cells has been established for better understanding of CAR T cell function and persistence in vivo.

Receptor structure.

Chimeric antigen receptors combine many facets of normal T cell activation into a single protein. They link an extracellular antigen recognition domain to an intracellular signalling domain, which activates the T cell when an antigen is bound. CARs are composed of four regions: an antigen recognition domain, an extracellular hinge region, a transmembrane domain, and an intracellular T-cell signaling domain.

Antigen recognition domain.

The antigen recognition domain is exposed to the outside of the cell, in the ectodomain portion of the receptor. It interacts with potential target molecules and is responsible for targeting the CAR-T cell to any cell expressing a matching molecule.  The antigen recognition domain is typically derived from the variable regions of a monoclonal antibody linked together as a single-chain variable fragment (scFv). An scFv is a chimeric protein made up of the light (V) and heavy (V) chains of immunoglobins, connected with a short linker peptide. These V and V regions are selected in advance for their binding ability to the target antigen (such as CD19). The linker between the two chains consists of hydrophilic residues with stretches of glycine and serine in it for flexibility as well as stretches of glutamate and lysine for added solubility. Single domain antibodies (e.g. V, VH) have been engineered and developed as antigen recognition domains in the CAR format due to their high transduction efficiency in T cells.  In addition to antibody fragments, non‐antibody‐based approaches have also been used to direct CAR specificity, usually taking advantage of ligand/receptor pairs that normally bind to each other. Cytokines, innate immune receptors, TNF receptors, growth factors, and structural proteins have all been successfully used as CAR antigen recognition domains.

Hinge region.

The hinge, also called a spacer, is a small structural domain that sits between the antigen recognition region and the cell's outer membrane. An ideal hinge enhances the flexibility of the scFv receptor head, reducing the spatial constraints between the CAR and its target antigen. This promotes antigen binding and synapse formation between the CAR-T cells and target cells. Hinge sequences are often based on membrane-proximal regions from other immune molecules including IgG, CD8, and CD28.

Transmembrane domain.

The transmembrane domain is a structural component, consisting of a hydrophobic alpha helix that spans the cell membrane. It anchors the CAR to the plasma membrane, bridging the extracellular hinge and antigen recognition domains with the intracellular signaling region. This domain is essential for the stability of the receptor as a whole. Generally, the transmembrane domain from the most membrane-proximal component of the endodomain is used, but different transmembrane domains result in different receptor stability. The CD28 transmembrane domain is known to result in a highly expressed, stable receptor.  Using the CD3-zeta transmembrane domain is not recommended, as it can result in incorporation of the artificial TCR into the native TCR.

Intracellular T-cell signaling domain.

The intracellular T-cell signaling domain lies in the receptor's endodomain, inside the cell. After an antigen is bound to the external antigen recognition domain, CAR receptors cluster together and transmit an activation signal. Then the internal cytoplasmic end of the receptor perpetuates signaling inside the T cell.  Normal T cell activation relies on the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) present in the cytoplasmic domain of CD3-zeta. To mimic this process, CD3-zeta's cytoplasmic domain is commonly used as the main CAR endodomain component. Other ITAM-containing domains have also been tried, but are not as effective.  T cells also require co-stimulatory molecules in addition to CD3 signaling in order to persist after activation. For this reason, the endodomains of CAR receptors typically also include one or more chimeric domains from co-stimulatory proteins. Signaling domains from a wide variety of co-stimulatory molecules have been successfully tested, including CD28, CD27, CD134 (OX40), and CD137 (4‐1BB).

Evolution of CAR design.

The first CAR-T cells were developed in 1987 by Yoshikazu Kuwana et al. followed in 1989 by Gideon Gross and Zelig Eshhar at Weizmann Institute, Israel. The sophistication of the engineered CAR receptors has grown over time, and are referred to as first, second, third, or fourth generation CARs depending on their composition.  First generation CARs are composed of an extracellular binding domain, a hinge region, a transmembrane domain, and one or more intracellular signaling domains. The extracellular binding domain contains a single-chain variable fragment (scFv) derived from tumor antigen‐reactive antibodies that usually has a high specificity to a specific tumor antigen. All CARs contain the CD3ζ chain domain as the intracellular signaling domain, which is the primary transmitter of T cell activation signals.  Second generation CARs add a co‐stimulatory domain, like CD28 or 4‐1BB. The involvement of these intracellular signaling domains improve T cell proliferation, cytokine secretion, resistance to apoptosis, and in vivo persistence.  Third generation CARs combine multiple co-stimulatory domains, such as CD28-41BB or CD28-OX40, to augment T cell activity. Preclinical data show the third-generation CARs exhibit improved effector functions and better in vivo persistence as compared to second‐generation CARs.  Fourth generation CARs (also known as TRUCKs or armored CARs) further add factors that enhance T cell expansion, persistence, and anti‐tumoral activity. This can include cytokines, such is IL-2, IL-5, IL-12 and co‐stimulatory ligands.

Control mechanisms.

Adding a synthetic control mechanism to engineered T cells allows doctors to precisely control the persistence or activity of the T cells in the patient's body, with the goal of reducing toxic side effects. The major control techniques trigger T cell death or limit T cell activation, and often regulate the T cells via a separate drug that can be introduced or withheld as needed.  Suicide genes: Genetically modified T cells are engineered to include one or more genes that can induce apoptosis when activated by an extracellular molecule. Herpes simplex virus thymidine kinase (HSV-TK) and inducible caspase 9 (iCasp9) are two types of suicide genes that have been integrated into CAR-T cells. In the iCasp9 system, the suicide gene complex has two elements: a mutated FK506-binding protein with high specificity to the small molecule rimiducid/AP1903, and a gene encoding a pro-domain-deleted human caspase 9. Dosing the patient with rimiducid activates the suicide system, leading to rapid apoptosis of the genetically modified T cells. Although both the HSV-TK and iCasp9 systems demonstrate a noticeable function as a safety switch in clinical trials, some defects limit their application. HSV-TK is virus-derived and may be immunogenic to humans. It is also currently unclear whether the suicide gene strategies will act quickly enough in all situations to halt dangerous off-tumor cytotoxicity.  Dual-antigen receptor: CAR-T cells are engineered to express two tumor-associated antigen receptors at the same time, reducing the likelihood that the T cells will attack non-tumor cells. Dual-antigen receptor CAR-T cells have been reported to have less intense side effects. An in vivo study in mice shows that dual-receptor CAR-T cells effectively eradicated prostate cancer and achieved complete long-term survival.  ON-switch: In this system, CAR-T cells can only function in the presence of both tumor antigen and a benign exogenous molecule. To achieve this, the CAR-T cell's engineered chimeric antigen receptor is split into two separate proteins that must come together in order to function. The first receptor protein typically contains the extracellular antigen binding domain, while the second protein contains the downstream signaling elements and co-stimulatory molecules (such as CD3ζ and 4-1BB). In the presence of an exogenous molecule (such as a rapamycin analog), the binding and signaling proteins dimerize together, allowing the CAR-T cells to attack the tumor.  Bispecific molecules as switches: Bispecific molecules target both a tumor-associated antigen and the CD3 molecule on the surface of T cells. This ensures that the T cells cannot become activated unless they are in close physical proximity to a tumor cell. The anti-CD20/CD3 bispecific molecule shows high specificity to both malignant B cells and cancer cells in mice. FITC is another bifunctional molecule used in this strategy. FITC can redirect and regulate the activity of the FITC-specific CAR-T cells toward tumor cells with folate receptors.

Small molecule drug conjugates adaptor technology.

SMDCs (small molecule drug conjugates) platform in immuno-oncology is an experimental approach that makes possible the engineering of a single universal CAR T cell, which binds with extraordinarily high affinity to a benign molecule designated as fluorescein isothiocyanate (FITC). These cells are then used to treat various cancer types when co-administered with bispecific SMDC adaptor molecules. These unique bispecific adaptors are constructed with a FITC molecule and a tumor-homing molecule to precisely bridge the universal CAR T cell with the cancer cells, which causes localized T cell activation. Anti-tumor activity in mice is induced only when both the universal CAR T cells plus the correct antigen-specific adaptor molecules are present. Anti-tumor activity and toxicity can be controlled by adjusting the administered adaptor molecule dosing. Treatment of antigenically heterogeneous tumors can be achieved by administration of a mixture of the desired antigen-specific adaptors.  There are several challenges of current CAR T cell therapies, such as:

Chimeric antigen receptor T cells (also known as CAR T cells) are T cells that have been genetically engineered to produce an artificial T-cell receptor for use in immunotherapy.

Un récepteur antigénique chimérique (de l'anglais "chimeric antigen receptor" ou CAR) est une molécule créée en laboratoire pour permettre aux cellules immunitaires de reconnaître et de cibler des protéines présentes à la surface d'autres cellules, par exemple présentes à la surface de cellules tumorales.


Biography.

Ernst Wilhelm Förstemann was born in Danzig as the son of the mathematician Wilhelm August Förstemann. His family was originally from Nordhausen. From 1831 to 1840 he was educated at the local grammar school, where his father was a teacher of Mathematics. In 1840 Förstemann went to study Comparative linguistics at the Humboldt University of Berlin but moved to Halle (Saale) in 1841, where he continued his studies at the Martin Luther University of Halle-Wittenberg. During his years at university, Förstemann was particularly furthered by Karl Lachmann, Franz Bopp and August Friedrich Pott.  Upon his return from Halle, Förstemann was appointed assistant teacher at the Danzig grammar school and also worked as a private tutor until 1848. In 1845 he took the "Staatsexamen" in Berlin. Förstemann was also the only contestant in a competition hosted by Jacob Grimm that required a list of names that were in use in Germany until the year of 1100. Although he only submitted a draft, he won the prize and was encouraged by Grimm to publish the completed work in 1858.  When Förstemann was offered a position as librarian at the Fürst zu Stolberg-Wernigerodesche Bibliothek in 1851, he gave up his position at Danzig and went to Wernigerode. Also, he added about 20.000 volumes to the library's holdings. In addition to his work as librarian, Förstemann also accepted a teaching assignment at the local grammar school.  In 1865 Förstemann was invited to Dresden by the widow of Frederick William IV of Prussia, where he succeeded Gustav Klemm as chief librarian at the Royal Public Library (now the Saxon State Library), which contained the Dresden Codex. Förstemann reorganized the library and began to work on a new catalogue. Förstemann resigned in 1887, aged 65, in favour of the less strenuous task of overseeing the King's private library and the library of the Sekundogenitur (Dresden). For his services Förstemann received the Albert Order in 1892. In the following years, Förstemann prepared an edition of the Maya manuscript as well as several treatises on it. His services in behalf of the reorganization of the library were most important. In 1894 he deciphered the Maya numbering systems.  In 1899, Förstemann retired and moved to Charlottenburg one year later, where he died on 4 November 1906.

Ernst Wilhelm Förstemann (Danzig, 18 September 1822 – Charlottenburg, 4 November 1906) was a German historian, mathematician, doctor of linguistics, librarian, and director of the Saxon State Library () in Dresden. He is known as a founder of onomastics and folk etymology studies in Germany, and also for his seminal contributions made in the early years of Mayanist research, towards the decipherment and understanding of calendrical elements in the pre-Columbian Maya script.

Ernst Wilhelm Förstemann, né le à Dantzig (Prusse-Occidentale, actuellement en Pologne) et mort le à Charlottenbourg Berlin), est un bibliothécaire, linguiste, historien et mathématicien allemand qui fut directeur de la (en allemand : "Sächsische Landesbibliothek") à Dresde.


Career.

Ward was educated privately and at Newcastle Church High School. She contested Morpeth in 1924 and 1929 without success and was elected to the House of Commons in 1931 for Wallsend, defeating Labour's Margaret Bondfield. A strong advocate for Tyneside industry and social conditions, she lost her seat in the 1945 general election, which Labour won by a landslide.  In 1950, Ward returned to Parliament for Tynemouth, again defeating a female incumbent, Grace Colman. An active backbencher, she introduced the bill that became the Rights of Entry (Gas and Electricity Boards) Act, 1954. She promoted a Bill to pay pocket money to the elderly living in institutions.  Ward worked with Charlotte Bentley who led the "National Association of State Enrolled "Assistant" Nurses". Her private member's bill passed through parliament to remove the demeaning word "assistant" from the State Enrolled Nurses's job title. This was the Nurses (Amendment) Act, 1961 and the following year there followed the Penalties for Drunkenness Act, 1962. She served on the Public Accounts Committee from 1964.  She is remembered in some quarters for an incident which caused amusement on both sides of the House when she threatened to "poke" the then Labour Prime Minister Harold Wilson. Having received an evasive answer to a parliamentary question, she responded with the words: "I will poke the Prime Minister. I will poke him until I get a response."  Ward retired from the Commons in February 1974, having served a total of almost 38 years. She was the longest-serving female MP (although she would not have been Mother of the House because there was always a longer continuously-serving sitting MP as a result of the gap in her tenure) until that record was broken by Gwyneth Dunwoody in 2007. Aged 79 at her retirement, Ward was at that time also the oldest-ever serving female Member of Parliament and the oldest-ever woman to be re-elected, records not broken until Ann Clwyd achieved both in 2017.

Honours.

She was created a life peer as Baroness Ward of North Tyneside, of North Tyneside in the County of Tyne and Wear, on 23 January 1975.  Ward was appointed a Commander of the Order of the British Empire (CBE) in 1929 and promoted to Dame Commander (DBE) in 1955, and was appointed a Companion of Honour in 1973.

Irene Mary Bewick Ward, Baroness Ward of North Tyneside, (23 February 1895 – 26 April 1980) was a British Conservative politician. She was a long-serving female Member of Parliament (MP).

Irene Mary Bewick Ward, baronne Ward of North Tyneside, née le et morte le, est une femme politique britannique conservatrice, membre du Parlement pour la circonscription de Wallsend entre 1931 et 1945 puis pour celle de Tynemouth entre 1950 et 1974.


Biography.

Early life.

Before the Romanian Revolution, Cristian Popescu was the head waiter at a seaside restaurant. In 1990, he opened his own restaurant named "Restaurantul Ciocârlia (""Nightingale Restaurant"")" on the Dâmbovița River quay in Bucharest. Popescu joined the Party of Social Democracy in Romania in 1994 after the youth wing of the party started congregating in his restaurant.  He began studying at the Dimitre Gusti High School in Bucharest in 1991, at the age of 28, graduating four years later. He later continued his studies at the University of Petroșani, which he graduated in 2002.

Local councilor.

In 2000, he was elected member of the General Council of Bucharest on the lists of the Social Democratic Party, becoming also an inspector at the Sector 6 city hall. In 2004, he was elected councilor for Bucharest's Sector 6.  He quit the Social-Democrats and joined the Christian Democratic National Peasants' Party, then the National Democratic Bloc, a small party created by trade unionists of "Blocul Național Sindical" ("National Union Bloc") and allied with Greater Romania Party and finally joined the Conservative party.  Following the election of Bucharest Mayor Traian Băsescu as President of Romania, a by-election was held to replace the now-vacant function. Popescu was a candidate representing the National Democratic Bloc, gaining 37,985 votes, or 8,71%.  In 2007, obtained his driving license in Pitești, Argeș County after temporarily moving his domicile to Priboieni. Following a fraud and corruption investigation, the authorities decided to cancel his driving license, together with hundreds other licenses. Journalists noted that moving his domicile without resigning from his function as member of the local council is illegal. Additionally, while a resident in Priboieni, he registered a Cadillac in Bucharest, for which he was criminally prosecuted.  Popescu Piedone founded an NGO named "Asociația pentru Protecția Cetățeanului" ("Association for the Protection of the Citizen"), which drew criticism after receiving donations from the State Lottery, a state-owned company managed by a fellow Conservative Party member.  His assumed moniker, "Piedone" (Italian for "big foot") is taken from the Spaghetti Western character by that name starred by Bud Spencer. In 2006, Popescu legally changed his name to include "Piedone".

Mayor of Bucharest's sector 4.

The Conservative Party's candidate for mayor in the 2008 local election in Sector 4, Popescu Piedone won the elections against PD-L's Radu Silaghi.  Before the 2012 Romanian local election, Popescu negotiated with the National Union for the Progress of Romania (UNPR) to be their candidate. He resigned in September 2011 from being the prime-vice-president of the Conservative Party and president of its Bucharest branch. In October 2012, he announced that he would run on the Conservative Party ticket, but the following month, he announced that he would run on the UNPR side. Romanian MP Elena Udrea announced that Popescu Piedone would be the coordinator of the UNPR - PD-L campaign. A few months later, in March 2012, Piedone decided to run on a Social Liberal Union ticket.  Popescu Piedone was reelected in the June 2012 elections, gaining 80.36% of the votes in Sector 4.  His Conservative Party merged with the Liberal Reformist Party to form the Alliance of Liberals and Democrats (ALDE) and in July 2015, Popescu Piedone resigned ALDE, joining UNPR, as he claimed he has "a beautiful friendship" with its leader, Gabriel Oprea. In September 2015, he announced that he would run again for Sector 4 mayorship from the National Union for the Progress of Romania.  A criminal complaint by the Save Bucharest Association related to the demolition of a building belonging to a heritage protected area was admitted by the Sector 4 court, with Piedone being officially criminally charged in August 2015. The case involves a building belonging to the Samurcășești Monastery which was demolished in order to be replaced a 5-floors building in association with a real estate investor.  On October 30, 2015, the Colectiv nightclub fire killed dozens of people. Since the nightclub had been authorized by mayor Piedone, protesters demanded his resignation, which he did on November 4.  The National Anticorruption Directorate began investigating the case and they arrested Popescu Piedone on November 6 on charges of abuse of power for not respecting the fire safety laws when authorizing the nightclub.  In April 2016, Popescu Piedone registered as a candidate for the Sector 4 mayorship in the 2016 local elections, but his candidacy was contested by an association of the victims in the Colective nightclub fire. The judges of Bucharest Tribunal decided to disallow him from becoming a candidate.

Cristian Popescu Piedone (born February 15, 1963) is a Romanian politician who has served as mayor of Bucharest's Sector 4 from 2008 until the November 4, 2015, when he resigned following the Colectiv nightclub fire and the subsequent 2015 Romanian protests.

Cristian Popescu Piedone (né le ) est un homme politique roumain qui a servi en tant que maire du Secteur 4 de Bucarest de 2008 jusqu'au, date à laquelle il a démissionné à la suite de l'incendie de la discothèque Colectiv et des manifestations en Roumanie qui ont suivi ce drame.


Story.

Max, the protagonist of "Max & the Magic Marker", arrives home from school one day and finds his younger brother Felix playing in his room and smashing his beloved toys. Being annoyed by his little brother Max searches online on the search engine website "Giggle" (a parody of Google) for a way to get rid of Felix. He immediately stumbles upon a spell which promises to make his brother disappear. Inadvertently reading the spell out loud opens up a mysterious portal from which a giant claw emerges and kidnaps his little brother Felix. Realizing the consequences of his actions, Max jumps without hesitation into the portal to rescue Felix and enters a magical and hostile world controlled by the evil lord Mustacho and his henchmen.

Gameplay.

In its core "Max: The Curse of Brotherhood" is a physics-based puzzle/platformer and set in a 2.5D environment with a free and cinematic camera. The game has 7 chapters and 20 levels in total. All levels are connected so the game feels like one long journey. Besides platforming, the gameplay twist is the magic marker which introduces a creative and open approach to how puzzles can be solved. Throughout the game the magic marker will gain different powers.

Reception.

"Max: The Curse of Brotherhood" received mixed to positive reviews, with an aggregated score of 72/100 from Metacritic.  Gamesradar praised the inventive and well-balanced puzzle design, gorgeous visuals and beautiful environments providing a fresh and charming experience on the platformer genre. Destructoid also commended its visuals which are "Pixar-esque" charming and loved the mix of cerebral puzzles combined with thrilling action sequences in a memorable world. Edge described it as a memorable and enjoyable platformer with ingenious puzzles and steady flow of new sights. But they remark that the game "stretches the controls beyond their comfort zone" and criticize the limit of freedom to draw whatever and wherever you want. GameSpot loved its lush environments and attractive art design combined with an appealing story and protagonist. Regarding the puzzles they found them initially intriguing but they tend to get repetitive and therefore predictable over the course of the game.  Game Informer wrote that the game's central conceit was a "gimmick that simply doesn't work all that well", and for that reason, they did not expect players to advance to the end of the game. They added that the Xbox One controller was not precise enough for the puzzles. They commended the final puzzle. Kotaku did not recommend the game, which they compared to a larger version of the iPhone game. They praised the game's humor and background art, but complained that the game's drawing mechanics were needlessly difficult at times and extended the game's length in undesirable ways. Hardcore Gamer criticized the game for not breaking any new ground and failing to utilize the features of the Kinect for the drawing mechanics, while praising its voice acting, sound effects and soundtrack. GameZone stated that it is hard to recommend Max: The Curse of Brotherhood to fans of platformers, since the game presents such infuriating mechanics. However, they praised the visuals, calling them, "freaking gorgeous," and commended the detailed environments, which, "coupled with the brilliant lighting make it look like an interactive Pixar movie."

Max: The Curse of Brotherhood is a puzzle-platform video game developed by Press Play for Xbox One, Microsoft Windows, Xbox 360, Nintendo Switch and later on PlayStation 4. The game was announced during Microsoft's E3 2013 press event. It is a sequel to Press Play's previous work, the 2010 game "Max & the Magic Marker".

Max: The Curse of Brotherhood est un jeu vidéo de plates-formes et de réflexion développé et édité par Press Play, sorti en 2013 sur Windows, Xbox 360 et Xbox One.


Biography.

Hans Jørgen Hammer was born in Copenhagen to Johanne (née Bistrup) and Peder Pedersen Hammer, a shipmaster. A younger brother, William Hammer (1821–1889), also became a painter. As a boy Hammer displayed an aptitude for drawing, and he received his first training from the Norwegian-Danish master Jon Gulsen Berg (1783–1864), a court painter and wallpaper designer.  Hammer was admitted to the Royal Danish Academy of Fine Arts as an apprentice in 1828. His development was slow, and in 1835 he worked as an assistant to a decoration painter. In 1836 he trained at the Plaster Replica School, and he began exhibiting his works in 1838. In 1840 he advanced to the Model School, and from 1841 to 1843 he studied with Christoffer Wilhelm Eckersberg, who would remain a friend and mentor. Like many Academy students, Hammer was strongly influenced by Niels Laurits Høyen, an early avatar of the National Romantic movement who championed a new Nordic understanding of culture and art, advising students to eschew travel to foreign lands and urging them to portray the Danish people of humble agricultural origins in rural settings where folkways were as yet untouched by industrialization. In 1842 Hammer was awarded the Academy's Small Silver Medal, and in 1843 he graduated from the Academy with a Large Silver Medal. In 1845 he entered the Neuhausen Art Competition with "Farmers Return Home from the Field with the Final Sheaves of Grain". While the painting did not win the prize, it was purchased for the Royal Painting Collection. In 1847 he won the Neuhausen Prize with "Farmboys and Girls Gather for Outdoor Merrymaking on a Holiday Afternoon", also purchased for the Royal Painting Collection.  Hammer's career was interrupted in 1848 by the outbreak of Denmark's Three Years' War with Prussia over hegemony in the Duchy of Schleswig. He volunteered and was commissioned as a lieutenant in March 1849. In the years following Denmark's fragile victory, he remained on active duty with the rank of captain before shifting to the reserves and finally leaving the service entirely in 1860.  Prior to the war Hammer had been encouraged to apply for a stipend to cover the expense of a sojourn in Italy, and finally at the age of 41 he traveled there with the financial support of the Academy of Fine Arts. The paintings he produced in Italy in 1856–57 and immediately thereafter had considerable public appeal. "A Square in Ariccia after Sunset" (1862) with its striking coloration was highly praised and purchased for the Royal Painting Collection. Highlights among his later works are "Den lille Axsamlerske" (1866) and "The Postman with the Long-Awaited Letter" (1877). He delved into national history with "Jens Baggesen and Count Schimmelmann" (1872, painted in two copies) and "Count Gert and Niels Ebbesen" (unfinished, despite extensive preparatory studies), and he also illustrated works of Hans Christian Andersen, Adam Oehlenschläger, and Christian Winther.  In 1862 he was decorated a knight of the Order of the Dannebrog, and in 1874 he was named a member of the Academy of Fine Arts. He traveled to the United States in 1874–75 to visit relatives and also visited Skagen in 1875, painting motifs in both locales. He also traveled to the Centennial Exposition in Philadelphia in 1876. He was decorated a knight of the Order of St. Olav in 1877 and was awarded a travel stipend from the Carl Andreas Anker Legacy in 1879. Hammer came close to dying of anemia, but he recovered and was able to travel to Italy for a second time in 1881–82. That winter he caught a cold and succumbed to fever, and he is buried in Rome's Protestant Cemetery. Hammer, who never married, was described by contemporary art historian Philip Weilbach as serious, diligent, and thoughtful, but also somewhat labored and tentative. A perfectionist streak is said to have curtailed his productivity and hampered his creativity.  His likeness is preserved in a portrait by Constantin Hansen (1863), a woodcut after a Bertel Christian Budtz Müller studio photograph, and various self-portraits, including one drawn in pencil and held by the Frederiksborg Museum. A number of his drawings and engravings are held by the Royal Collection of Graphic Art, the ARoS Aarhus Kunstmuseum, the Roskilde Museum, the Randers Museum of Art, the Vejle Museum of Art, and the Museet på Koldinghus. His paintings are in the Fuglsang Art Museum on Lolland, the Bornholm Art Museum, the Sorø Art Museum, the Museum of Modern Art in Aalborg and, in Copenhagen, in the National Gallery, the Hirschsprung Collection, the Rosenborg Collections, the City Museum, and the M/S Maritime Museum of Denmark.

External links.

Peter Nørgaard Larsen, "H. J. Hammer", "Kunstindeks Danmark".<br> Hammer's gravestone in Rome's Protestant Cemetery

Hans Jørgen Hammer (29 December 1815 – 28 January 1882) was a genre, landscape, and portrait painter of the Golden Age of Danish painting. In addition, he served for eleven years as a military officer.

Hans Jørgen Hammer, né le à Copenhague dans la région du Hovedstaden et mort le à Rome dans la région du Latium, est un peintre danois associé à l'âge d'or danois.