Functional screening of primary DNMT3A-mutant AML cells in search for new therapeutic targets

Acute myeloid leukemia (AML) is a malignancy of the hematopoietic system caused by somatic mutations that accumulate in hematopoietic stem and progenitor cells. The cells are thereby transformed into leukemic stem cells (LSCs), which cannot be efficiently eliminated with the standard chemotherapy treatment. Thus, LSCs pose a risk of relapse for AML patients. There- fore, identification and characterization of LSCs is a major challenge in the field of AML research. Through next generation sequencing approaches the mutational spectrum of AML cells has been established and a continuous effort is being made to resolve the order of mutation acquisition and their functional consequences. In the subgroup of AML patients that bear a mutation in Nucleophosmin 1 (NPM1 ), a mutation in DNA-methyltransferase 3 A (DNMT3A) has been often found as a co-occurring event. Evidence suggests that this mutation arises early in leukemogene- sis and marks leukemic progenitors and stem cells. However, the functional consequences of this mutation are far from being understood. In this thesis work, I set out to unravel novel functional dependencies of the DNMT3A-mutant AML cells that can be exploited for therapeutic purposes. To nominate genes that are essential for the survival of primary AML cells, I performed a func- tional RNA interference-mediated drop out screen in 38 DNMT3A- and NPM1-mutant AML patient lines. The patients in this cohort were divided into two groups, based on the treatment outcome: an early relapse (ER) group and a long term remission (LTR) group. To nominate can- didate genes in each group, I have selected 12 screens with the highest data quality and performed a differential bioinformatic analysis. The analysis yielded 7 potential candidates, from which I initially validated three: Glucocorticoid modulatory element binding protein 1 (GMEB1), Mouse double minute 4 (MDM4) – both shared between the ER and the LTR groups – and Thioredoxin domain containing protein 9 (TXNDC9 ), which scored only in the ER group. Additional rounds of validation nominated MDM4 as the strongest candidate. To investigate the role of MDM4 in LSCs, I knocked it down in three patient samples and performed the long-term culture-initiating cell assay. However, the number of progenitor colonies that formed by the end of the assay was not enough for a statistical evaluation, probably due to the low frequency of long-term culture- initiating cells in the samples. Therefore, no conclusion regarding the functional dependency of LSCs on MDM4 could be made. However, a recent study suggested that loss of MDM4 causes cell cycle arrest and induces apoptosis in leukemic cell lines and primary cells, including progenitor populations, confirming the findings of this thesis. Nevertheless, the question about the role of MDM4 in NPM1 -mutant AML cells remains open. The NPM1 involvement in the p14Arf-MDM2- p53 pathway and the deregulation of this pathway caused by the NPM1 mutation indicate that MDM4 might poses special functions in NPM1 -mutant AML. Therefore, it should be investigated if MDM4 is a particularly suitable therapeutic target in AML with NPM1 mutation

Individual educational trajectories: from educational supermarket to sensemaking to blended values

Bringing the idea of students` individual educational trajectories into focus, Russian universities employ an ‘educational supermarket’ model and take for granted that universities are capable of incorporating any novelty. This paper proves the opposite, i.e. universities use specific ‘filters’ to minimize external influence. New filters introduction is able to destabilize the system and make it sensitive to outside cues. This phase, with its sensemaking potential, is the most efficient for building educational trajectories. However, this phase is short, for universities tend to reduce volatility and complexity. They are ‘autopoietic’. Genuine individualization stems from a person`s understanding of value that he or she can create over the trajectory of their lives, which is above autopoietic frames of one university. This paper discusses a shift in focus – from individualization to blended value – with the central premise that value is itself a ‘blend’ of economic, environmental, social, political, and personal factors. This notion shifts the focus from a university as the center for a person`s individualization to a university as an equal stakeholder and actor that identifies and maximizes blended value

PECULIARITIES OF PSYCHOPHYSIOLOGICAL STATUS OF BIOLOGICAL AND MEDICAL SECOND-YEAR STUDENTS

The paper deals with psychophysiological features of biological and medical second-year students. Parameters of physical development and cardiovascular system were measured in 88 medical students (52 men and 36 women) and 89 biological students (36 men and 53 women). Peculiarities of psychoemotional status of the women, studying both in biological and medical universities, have been examined with the help of the standard methods. Underweight was detected in 1/3 men studying in medical university and in 1/4 men studying in biological university, in 1/5 women studying in both universities. In more than a half of cases, reduction of lung capacity and muscle strength of the hand was found in biological and medical students of both sexes. Cardiohemodinamic markers in all participants met the normative standards. Balanced state of intro-extroversive attitude, medium level of neuroticism and personal anxiety, hyperthymic type of character accentuation were revealed in most cases in women. At the same time, elevated levels of reactive anxiety and high risk of coronary-prone behavior was higher in women studying in medical university as compared to biological students. The paper discusses possible causes of mentioned specific differences and degree of physiological adequateness of the psychoemotional pattern in women studying in medical university

Results of the Primary Evaluation of Processes of Natural Self-cleaning of Lake Yanisyarvi As an Object of Fishing Value

The initial assessment of the processes of natural self-cleaning of the lakes of the Yanisyarvi basin was carried out. The morphological, physiological and biochemical characteristics of aquatic microflora were used as the main indicators of natural self-cleaning processes in the eco-system. The dominance of the anaerobic phase of self-purification due to the enzymatic activity of obligate and facultative anaerobes was described. The proportion of anaerobes controlling intra-water geochemical processes averaged 90%, and aerobes - 10%. The morphological component was represented by a wide variety, the presence of all morphotypes with the exception of crimped forms was noted. The study of tinctorial traits, isolated isolates made it possible to establish the predominance of representatives of the Gracilicutes department, whose number, depending on the sampling station, varied from 55 to 95%. The biochemical component of the study was performed on the basis of determining the activity of isolates in 8 groups of enzymes

«Большой террор» в современном британском романе

The mythological image of Russia in British fiction has been historically shaped and recurrently repeated for many centuries. Between the late 20th and the early 21st centuries the image of Russia and the Soviet Union was widely used by the authors of detective, adventure, etc. fiction, but it was also taken up by the leading British writers. The Great Terror of the Stalin epoch was described in a number of fiction and non-fiction books of the early 21st century. The author analyses novels of three British authors devoted to the topic: House of Meetings (2006) by Martin Amis, The Siege (2001) and The Betrayal (2010) by Helen Dunmore, and The Noise of Time (2016) by Julian Barnes. The three authors clearly show their profound knowledge of Russian and Soviet history and culture, but their points of view on them, as well as their estimation of the country’s future, are different. Both M. Amis and his protagonist are sure that the whole country is a “big zona” without any historical future. Conversely, H. Dunmore is sure that the great terror did not annihilate the country’s potential, and the sources of inspiration for the Russian people lie in the country’s great culture, great city (Leningrad), and great country. J. Barnes’s novel is a brief biography of D. Shostakovich, but it is also a reflection on an artist’s existence under totalitarian pressure. Thus, the three British writers look at a concrete period of Soviet history from different, sometimes opposite, points of view, and come to different conclusions.Британские писатели неоднократно обращались к образу России, который, как правило, носил в их произведениях мифологизированный характер. В конце XX — начале XXI в. российская и советская тема продолжает активно присутствовать в британских романах внешнего действия, но одновременно приходит в серьезные романы ведущих современных писателей. Тема «большого террора» начала активно разрабатываться в британской литературе, художественной и нехудожественной, в конце ХХ в. В статье рассматриваются романы трех ведущих британских писателей — «Дом свиданий» (2006) М. Эмиса, «Блокада» (2001) и «Измена» (2010) Х. Данмор и «Шум времени» (2016) Дж. Барнса, — посвященные сталинским репрессиям 1930–1950-х гг. Отмечается, что все три писателя глубоко знают русскую историю и культуру, однако их взгляды на советский период и на будущее России разнятся. Герой романа М. Эмиса, как и сам писатель, провозглашает, что вся страна — большая «зона», не имеющая исторической перспективы. Х. Данмор придерживается противоположной точки зрения: страшные репрессии не могут уничтожить потенциал народа, источниками силы которого становится великая русская культура, великий город (Ленинград) и великая страна. Роман Дж. Барнса — краткая художественная биография Д. Д. Шостаковича — становится размышлением на тему существования художника в условиях тоталитарного режима. Таким образом, конкретные события советской истории рассматриваются современными британскими писателями с разных точек зрения и приводят их к разным, иногда противоположным, выводам

Контакт культур и образ Японии в европейской литературе («Фрегат Паллада» И. А. Гончарова и «Тысяча осеней Якоба де Зута» Д. Митчелла)

This article studies the situation of contact between European and Japanese cultures and the image of Japan created in the classical work of Russian literature Frigate “Pallada” (1858) by I. Goncharov and in the novel The Thousand Autumns of Jacob de Zoet (2010) by David Mitchell, a contemporary British writer. The books were written during different periods of time, but they describe the same historical period and similar events; they both have documentary foundation. Special attention is paid to translators as characters of the books who play an important role in the plot development and provide intercultural communication. The research methodology combines methods of comparative literary criticism with a post-colonial approach, E. Said’s ideas about orientalism and ethnocentrism in particular. Comparative analysis of the two books demonstrates that the image of Japan created by the two writers has a number of similar features, which confirms its objective nature. Conversely, the authors’ perspectives and points of view of Japan differ drastically. The Russian writer looks at the Japanese down and from the outside; he considers “strangeness” and “childishness” to be their national features. Goncharov’s Eurocentric position is explained by several reasons: his knowledge of Japan was external, he was a civil servant, who cared mostly about the interests of Russia, and he represented an influential group of Eurocentric intelligentsia. D. Mitchell’s knowledge of Japan and its culture is deep and internal due to his biography. The English writer creates a bicultural novel in which the European and the Japanese worlds are equally significant. Thus, in the novel, the author offers a modern point of view on the world order and intercultural communication. В статье рассматривается ситуация контакта европейской и японской культур и образ Японии, созданный в классическом произведении русской литературы И. А. Гончарова «Фрегат Паллада» (1858) и в романе современного английского писателя Д. Митчелла «Тысяча осеней Якоба де Зута» (2010). Написанные в разное время, произведения повествуют об одном периоде и схожих событиях, обе книги имеют документальную историческую основу. Отдельное внимание уделяется героям-переводчикам, которые присутствуют в текстах двух произведений и выполняют важную роль при осуществлении межкультурного взаимодействия. Методология исследования включает в себя методы компаративного литературоведения, а также постулаты постколониальных исследований, в частности, идеи Э. Саида об ориентализме и этноцентризме. Сравнение и анализ текстов двух произведений показывает, что образ Японии, созданный двумя писателями, имеет ряд схожих черт, что подтверждает его объективный характер. С другой стороны, выраженная в текстах авторская точка зрения и взгляд на Японию отличаются кардинально. Для русского писателя это взгляд со стороны и сверху вниз, в японцах он отмечает «странность» и «детскость» как основные национальные черты. Гончаров стоит на позициях евроцентризма, что обусловлено рядом факторов: его знание Японии — внешнее, он государственный чиновник и заботится об интересах России, он представитель влиятельной группы отечественной интеллигенции. Знание Японии и ее культуры у Д. Митчелла глубокое и внутреннее в силу причин биографического характера. Английский писатель создает бикультурный роман, в котором европейский и японский мир одинаково значимы. Таким образом, в романе автор предлагает современную точку зрения на мироустройство и межкультурную коммуникацию

Dependence of the preparation method on the phase composition and particle size of the binary NiO–ZrO2 system oxides

Was studied how preparation method influences phase composition, oxide particle size and catalytic activity of the binary NiO–ZrO2 systems. The processes taking place under the thermal influence while NiO–ZrO2 catalysts are formed from precursors, obtained using a variety of methods, were determinated using the methods of simultaneous TGA-DTG/DSC analysis and XFA. Was studied the influence of the precursor preparation method upon the catalysts' phase composition, sizes of the nickel oxide and zirconium dioxide particles. The research revealed that preparation of precursor using coprecipitation method makes it possible to obtain a binary system, where nickel oxide has minimal size, determined by CSR, and monoclinic phase prevails in ZrO2, after heating it to 800 °C. The research unearthed that the catalyst exhibiting maximal catalytic activity by deep oxidation of methane is nickel oxide-zirconium dioxide, containing equal amounts of monoclinic and tetragonal phases of ZrO2

Региональные средства массовой информации от самоцензуры к мифотворчеству

This article aims to solve the following scientific problem: to study the ways of interaction between mass media, audience and authorities used in regional practice. The relevance and scientific significance of solving the above-mentioned problem lies in the fact that modern mass media exist in a dynamically changing social space. The main objective is to determine how fully events of the political and public life of a country or region are reflected in the daily practice of regional mass media. Based on the analysis of print media, the authors of the article consider the authenticity, completeness and objectivity of the information worldview created by journalists of the Arkhangelsk Region. The contractual mechanism of information services used by authorities forces journalists to resort to self-censorship and non-disclosure of socially important information, which leads to the creation of media myths and the loss of professionalism, as well as changes essential characteristics of journalism. It is indicated that it is much more dangerous for this profession to consciously distort the reflected reality by emphasizing some events or certain aspects of the displayed phenomena and concealing others, i.e. manipulating mass consciousness through non-disclosure. Non-disclosure not only erases, destroys and eliminates facts, but also creates a mythical, distorted and unreliable information worldview.Este artículo pretende resolver el siguiente problema científico: estudiar las formas de interacción entre los medios de comunicación, el público y las autoridades utilizadas en la práctica regional. La relevancia y el significado científico de resolver el problema mencionado radica en el hecho de que los medios de comunicación modernos existen en un espacio social que cambia dinámicamente. El objetivo principal es determinar cómo se reflejan plenamente los eventos de la vida política y pública de un país o región en la práctica diaria de los medios de comunicación regionales. Sobre la base del análisis de los medios impresos, los autores del artículo consideran la autenticidad, integridad y objetividad de la visión del mundo de la información creada por los periodistas de la región de Arkhangelsk. El mecanismo contractual de los servicios de información utilizados por las autoridades obliga a los periodistas a recurrir a la autocensura y la no divulgación de información socialmente importante, lo que lleva a la creación de mitos mediáticos y la pérdida de profesionalismo, así como a cambios en las características esenciales del periodismo. Se indica que para esta profesión es mucho más peligroso distorsionar conscientemente la realidad reflejada al enfatizar algunos eventos o ciertos aspectos de los fenómenos mostrados y ocultar otros, es decir, manipular la conciencia de masas a través de la no divulgación. La no divulgación no solo borra, destruye y elimina hechos, sino que también crea una visión del mundo de la información mítica, distorsionada y no confiable.Научная проблема, на решение которой направлена данная работа, ― исследование способов взаимодействия средств массовой информации, аудитории и власти, применяемых в региональной практике. Актуальность и научная значимость решения проблемы состоит в том, что современные СМИ существуют в условиях динамично изменяющегося социального пространства. Цель работы – определить, насколько полно отражаются события политической и общественной жизни страны и региона в повседневной практике региональных СМИ. На основе анализа печатных изданий рассматривается достоверность, полнота и объективность информационной картины мира, создаваемой журналистами СМИ Архангельской области. Договорный механизм информационного обслуживания органов власти вынуждает журналистов прибегать к самоцензуре и замалчиванию общественно важных сведений, что приводит к созданию медиамифов и утрате профессионализма, меняет сущностные характеристики журналистики. Указывается, что намного опаснее для профессии сознательное искажение отражаемой реальности путем акцентирования, подчеркивания одних событий или отдельных сторон отображаемых явлений и замалчивания других, то есть манипулирования массовым сознанием путем умолчаний. Умолчание не только вычеркивает, уничтожает, устраняет факты, но и творит, создавая мифическую, искаженную, недостоверную информационную картину мира