Generierung eines Mausmodells für Mastozytose durch kontrollierte Ausprägung eines mutierten, konstitutiv aktiven Kit-Rezeptors

Mastozytose ist eine seltene Erkrankung, die durch abnormale Zahlen von Mastzellen in Haut und innerern Organen gekennzeichnet ist. Die Erkrankung, die durch eine starke Variation bezüglich ihrer klinischen Manifestationen charakterisiert ist, konnte mit (meist) somatischen Mutationen des Kit-Genes assoziert werden, die zur konstitutiven, Ligand-unabhängigen Aktivierung der Rezeptortyrosinkinase Kit führen. Der Kit-Signalweg kontrolliert Differenzierung, Proliferation und Überleben von hämatopoetischen Vorläuferzellen und Mastzellen. Die klinische Ausprägung der Erkrankung scheint wesentlich durch das Differenzierungsstadium der vom ursprünglichen Mutationsereignis getroffenen Zelle abzuhängen. Ziel der Arbeit war die Generierung eines Tiermodells für Mastozytose, bei dem die Ausprägung eines mutierten Kit-Rezeptors zeitlich und räumlich kontrollierbar ist. In ein "bacterial artificial chromosome", das die gesamte Sequenz des Kit-Gens und weite flankierende Bereiche enthielt, wurde die aktivierende Punktmutation KitD814V, das murine Homolog der am häufigsten in Mastozytosepatienten beobachteten Mutation KitD816V, eingebracht. Eine konditionale Expression des transgenen KitD814Vflox-Allels wurde durch Cre/loxP-mediierte Exzision eines im ersten Intron platzierten Stopp-Elementes ermöglicht. Das Konstrukt wurde durch Pronukleusinjektion in das murine Genom eingeführt. Die Expression des mutierten Kit in adulten Tieren, unter anderem in hämatopoetischen Vorläuferzellen, führte zu rascher, progressiver Mastzellinfiltration der Haut und war häufig von einer B-Zellneoplasie und fokaler Colitis begleitet. Beschränkung der KitD814V Expression auf reife Mastzellen resultierte in vergleichbarer Mastzellhyperplasie und Colitis, die sich jedoch deutlich langsamer entwickelten. Die embryonale Expression des konstitutiv aktiven Kit-Transgens führte zu einer massiv gesteigerten Erythropoese und perinataler Lethalität. Die wenigen überlebenden Tiere entwickelten ebenfalls eine starke Mastzellhyperplasie und Darmentzündung. Die Ergebnisse zeigen, dass KitD814V-Effekte stark vom Entwicklungszeitpunkt und Differenzierungsstadium der Zelle abhängen, in welcher die Mutation auftritt

Under pressure: The influence of time limits on human exploration

How does time pressure influence attitudes towards uncertainty? When time is limited, do people engage in different exploration strategies? We study human exploration in a range of four-armed bandit tasks with different reward distributions and manipulate the available time for each decision (limited vs. unlimited). Through multiple behavioral and model-based analyses, we show that reactions towards uncertainty are influenced by time pressure. Specifically, participants seek out uncertain options when time is unlimited, but avoid uncertainty under time pressure. Moreover, larger relative differences in uncertainty between options slowed down reaction times and dampened the drift rate of a linear ballistic accumulator model. These results shed new light on the differential effect of uncertainty and time pressure on human exploration

Проектирование релейной защиты линии электропередачи 220 кВ ПС «Крохалевская» – ПС «Ново-Анжерская» Кузбасской ЭЭС

Выпускная квалификационная работа содержит 93 страницы, 12 рисунков, 15 таблиц, 30 источников, 3 приложения. Ключевые слова: Дистанционная защита, токовая защита нулевой последовательности, максимальная токовая защита, релейная защита, линия электропередач. Объектом разработки является релейная защита линии электропередач. Цель работы – выбор и расчет уставок срабатывания релейной защиты линии электропередач. В процессе работы проводились замеры электрических величин с помощью программно-вычислительного комплекса и расчеты необходимых параметров по соответствующим выражениям. Полученными результатами являются значения уставок срабатывания и коэффициентов чувствительности. Область применения: непосредственная установка защит и задание ее параметров.Final qualifying work consists of 93 pages, 12 figures, 15 tables, 30 sources, 3 application. Keywords: distance protection, current protection of zero sequence, overcurrent protection, relay protection, power line. The object is the development of relay protection of power lines. Purpose – the choice and calculation of settings of actuation of relay protection of power lines. In the process the work was carried out measurements of electrical quantities using the software-computing complex calculations and the necessary parameters on the relevant terms. The results obtained are set values of the response and sensitivity coefficients. Application scope: direct installation of protections and setting its parameters

Open Power System Data - Frictionless data for electricity system modelling

The quality of electricity system modelling heavily depends on the input data used. Although a lot of data is publicly available, it is often dispersed, tedious to process and partly contains errors. We argue that a central provision of input data for modelling has the character of a public good: it reduces overall societal costs for quantitative energy research as redundant work is avoided, and it improves transparency and reproducibility in electricity system modelling. This paper describes the Open Power System Data platform that aims at realising the efficiency and quality gains of centralised data provision by collecting, checking, processing, aggregating, documenting and publishing data required by most modellers. We conclude that the platform can provide substantial benefits to energy system analysis by raising efficiency of data pre-processing, providing a method for making data pre-processing for energy system modelling traceable, flexible and reproducible and improving the quality of original data published by data providers.Comment: This is the postprint version of the articl

The stem/progenitor landscape is reshaped in a mouse model of essential thrombocythemia and causes excess megakaryocyte production

Frameshift mutations in CALR (calreticulin) are associated with essential thrombocythemia (ET), but the stages at and mechanisms by which mutant CALR drives transformation remain incompletely defined. Here, we use single-cell approaches to examine the hematopoietic stem/progenitor cell landscape in a mouse model of mutant CALR-driven ET. We identify a trajectory linking hematopoietic stem cells (HSCs) with megakaryocytes and prospectively identify a previously unknown intermediate population that is overrepresented in the disease state. We also show that mutant CALR drives transformation primarily from the earliest stem cell compartment, with some contribution from megakaryocyte progenitors. Last, relative to wild-type HSCs, mutant CALR HSCs show increases in JAK-STAT signaling, the unfolded protein response, cell cycle, and a previously undescribed up-regulation of cholesterol biosynthesis. Overall, we have identified a novel megakaryocyte-biased cell population that is increased in a mouse model of ET and described transcriptomic changes linking CALR mutations to increased HSC proliferation and megakaryopoiesis

Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway

Mutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition. Thus, therapeutic approaches involving hypomethylating agents, ascorbic acid, and isoform-specific PI3K inhibitors are likely to be useful for treating patients with TET2 and KIT mutations