An efficient platform for astrocyte differentiation from human induced pluripotent stem cells

Summary: Growing evidence implicates the importance of glia, particularly astrocytes, in neurological and psychiatric diseases. Here, we describe a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs), via a neural progenitor cell (NPC) intermediate. We evaluated this protocol across 42 NPC lines (derived from 30 individuals). Transcriptomic analysis demonstrated that hiPSC-astrocytes from four individuals are highly similar to primary human fetal astrocytes and characteristic of a non-reactive state. hiPSC-astrocytes respond to inflammatory stimulants, display phagocytic capacity, and enhance microglial phagocytosis. hiPSC-astrocytes also possess spontaneous calcium transient activity. Our protocol is a reproducible, straightforward (single medium), and rapid (<30 days) method to generate populations of hiPSC-astrocytes that can be used for neuron-astrocyte and microglia-astrocyte co-cultures for the study of neuropsychiatric disorders. : Brennand, Goate, and colleagues report a rapid and robust method for the differentiation of highly pure populations of replicative astrocytes from human induced pluripotent stem cells (hiPSCs) via a neural progenitor cell (NPC) intermediate. hiPSC-astrocytes resemble primary human fetal astrocytes, have a transcriptional signature consistent with a non-reactive state, respond to inflammatory stimulants, and enhance microglial phagocytosis. Keywords: human induced pluripotent stem cell, iPSC, astrocyt

Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2

Alzheimer\u27s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials

The Transformation of Architectural Styles in Soviet Art 1917–1922

Статья посвящена изменениям в архитектуре первой пятилетки Советской России – 1917–1922 годов. Это время глобальной реорганизации общества и образа жизни, кардинальных изменений в общественно-политических взглядах, трансляции новых ценностей и идеалов силами искусства. Градостроительство и архитектура одними из первых оказались в поле преобразований, поскольку вопрос строительства нового мира напрямую касался архитектурной формы и городского планирования. Архитектура выступает символическим воплощением этого нового мира и общества. Принципы социалистического строительства включали в себя особенности организации городской жизни, пространства города. В статье рассмотрены проекты А. В. Щусева («Новая Москва», 1918–1923 гг.) и С. С. Шестакова («Большая Москва», 1921–1925 гг.). В качестве репрезентативного типа нового общественного сооружения рассмотрен «дворец» как средоточие культурной, общественной и политической жизни трудящихся. Статья фиксирует ведущее положение конструктивизма как появившейся архитектурной традиции, и основным содержанием выступает анализ проекта «Памятника III Интернационалу» В. Е. Татлина как образа-символа нового строя и общего движения в построении коммунизмаThe article is devoted to changes in the architecture of the first five-year plan of Soviet Russia, 1917–1922. This is a time of global reorganization of society and lifestyle, fundamental changes in socio-political views, the transmission of new values and ideals by the forces of art. Urban planning and architecture were among the first to be in the field of transformation, since the issue of building a new world directly concerned the architectural form and urban planning. Architecture is a symbolic embodiment of this new world and society. The principles of socialist construction included the features of the organization of urban life, the space of the city. The article considers the projects of A. V. Shchusev (“New Moscow”, 1918–1923) and S. S. Shestakova (“Greater Moscow”, 1921–1925). As a representative type of a new public building, the “palace” is considered as the center of the cultural, social and political life of the working people. The article fixes the leading position of constructivism as an emerging architectural tradition, and the main content is the analysis of the project “Monument to the III International” by V. E. Tatlin as an image-symbol of the new system and the general movement in building communis

The Genre of the Soviet Poster in the Fine Arts of 1917–1922

Статья посвящена советскому плакату первой пятилетки Советской России – 1917–1922 гг. Плакат в рассматриваемый исследованием период выступает одним из главных жанров изобразительного искусства, именно он становится самым реагирующим на актуальные исторические события и перемены, а также принимает актуальные вызовы времени. В этом жанре активно ведется поиск адекватных форм выражения актуальных общественно-политических идей и внедрение в поле общественного сознания ценностей нового строящегося мира. Статья рассматривает как феномены плакатного искусства с 1917 по 1922 г. в целом, так и представляет анализ отдельных репрезентантов плаката этого времени. Методологической основой исследования выступает теория изобразительного искусства В. И. Жуковского и философско-искусствоведческий анализ. В качестве анализируемых репрезентантов авторами выбраны плакаты А. П. Апсита «На коня, пролетарий!» (1918 г.) и Д. С. Моора «Враг у ворот! Он несет рабство, голод и смерть!» (1919 г.). Исследование плакатов демонстрирует специфику сложения актуальных образов этого периода и своеобразие художественных идей данных произведенийThe article is devoted to the Soviet poster of the first five-year plan of Soviet Russia – 1917–1922. The poster in the period under consideration is one of the main genres of fine art, it is he who becomes the most responsive to current historical events and changes, and also accepts the actual challenges of the time. In this genre, an active search is being made for adequate forms of expression of current socio-political ideas and the introduction of the values of the new world under construction into the field of public consciousness. The article considers both the phenomena of poster art from 1917 to 1922 as a whole and presents an analysis of individual representatives of the poster of this time. The methodological basis of the study is the theory of fine arts by V. I. Zhukovsky and philosophical and art history analysis. The posters of A. P. Apsita “On the horse, proletarian!” (1918) and D. S. Moora “The enemy is at the gates! He brings slavery, hunger and death!” (1919). The study of posters demonstrates the specifics of the composition of actual images of this period and the originality of the artistic ideas of these work

The Image of Artificial Intelligence in Cinema: Transformations in the 1980s‑2010s

Статья посвящена актуальной теме образа искусственного интеллекта в кинематографе как осмысления отношения к внедрению высоких технологий в жизнь человека и как средства осмысления человеком не только искусственного интеллекта, но и самого себя. В качестве репрезентативных этапов авторами выбраны исторические периоды 1980–1990-х, 2000-х и 2010-х гг. Методологической основой исследования выступил и философско-искусствоведческий и сравнительный анализ кинофильмов. В качестве материала для исследования выбраны популярные в свое время и ставшие классикой киноленты: «Бегущий по лезвию» (Р. Скотт, 1981 г.), «Призрак в доспехах» (М. Осии, 1995 г.), «Искусственный разум» (С. Спилберг, 2001), «Прометей» (Р. Скотт, 2012), «Чужой: Завет» (Р. Скотт, 2017). Исследование показывает, что основными вопросами, которые поднимает кинематограф 1980–2010-х гг. в связи с образом искусственного интеллекта, можно назвать вопросы взаимодействия человека и созданного им андроида, характера их отношений, возможного равенства. Кинорепрезентанты демонстрируют актуальность тем степени признания человечности антропоморфного робота, его самосознания, статуса в человеческом обществе, этики отношений людей и машин. Образ искусственного интеллекта развивается от представлений о нем как о во многом равном человеку к репрезентации его как угрозы для положения человека в миреThe article is devoted to the actual topic of the image of artificial intelligence in cinematography as an understanding of the attitude to the introduction of high technologies in human life and as a means of understanding not only artificial intelligence, but also oneself. The historical periods of the 1980s – 1990s, 2000s and 2010s are chosen as representative stages. The methodological basis of the study was also a philosophical, art history and comparative analysis of films. As a material for the study, films that were popular in their time and became classics were chosen: «Blade Runner» (R. Scott, 1981), «Ghost in the Shell» (M. Oshii, 1995), «Artificial Intelligence» (S. Spielberg, 2001), «Prometheus» (R. Scott, 2012), «Alien: Covenant» (R. Scott, 2017). The study shows that the main questions that the cinema of the 1980s‑2010s raises in connection with the image of artificial intelligence can be called the issues of interaction between a person and the android he created, the nature of their relationship, and possible equality. Film representatives demonstrate the relevance of the degree of recognition of the humanity of an anthropomorphic robot, its self-awareness, status in human society, and the ethics of relations between people and machines. The image of artificial intelligence is developing from ideas about it as in many respects equal to a person to its representation as a threat to the position of a person in the worl

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function

Regulation of Amyloid Precursor Protein Processing by Serotonin Signaling

<div><p>Proteolytic processing of the amyloid precursor protein (APP) by the β- and γ-secretases releases the amyloid-β peptide (Aβ), which deposits in senile plaques and contributes to the etiology of Alzheimer's disease (AD). The α-secretase cleaves APP in the Aβ peptide sequence to generate soluble APPα (sAPPα). Upregulation of α-secretase activity through the 5-hydroxytryptamine 4 (5-HT₄) receptor has been shown to reduce Aβ production, amyloid plaque load and to improve cognitive impairment in transgenic mouse models of AD. Consequently, activation of 5-HT₄ receptors following agonist stimulation is considered to be a therapeutic strategy for AD treatment; however, the signaling cascade involved in 5-HT₄ receptor-stimulated proteolysis of APP remains to be determined. Here we used chemical and siRNA inhibition to identify the proteins which mediate 5-HT_4d receptor-stimulated α-secretase activity in the SH-SY5Y human neuronal cell line. We show that G protein and Src dependent activation of phospholipase C are required for α-secretase activity, while, unexpectedly, adenylyl cyclase and cAMP are not involved. Further elucidation of the signaling pathway indicates that inositol triphosphate phosphorylation and casein kinase 2 activation is also a prerequisite for α-secretase activity. Our findings provide a novel route to explore the treatment of AD through 5-HT₄ receptor-induced α-secretase activation.</p></div

Digital Art Studies: A Possible Typology of Art Databases

Неотъемлемой частью научных исследований в области искусствознания в настоящее время являются цифровые базы данных. Применение информационно- коммуникационных технологий, развитие информационно-аналитических систем в искусствоведении связаны с масштабностью задач, которые могут решить эти средства систематизации. Актуализируется использование методов искусственного интеллекта для создания, каталогизации, проведения качественного и количественного анализа произведений искусства. Специализированные искусствоведческие базы прочно заняли свою нишу в процессе проверки подлинности и поиске утерянных произведений искусства. В настоящем исследовании были проанализированы отечественные и международные базы данных по искусству, в том числе EBSCO, WEB Gallery Of Art, Цифровая коллекция Государственного Эрмитажа и т.д. В результате обзора репрезентативных баз данных и интерактивных платформ искусствоведческого контента в статье приводится возможная типология на основе рассмотренных баз данных по искусству. Методологическим основанием настоящего исследования выступили источниковедческий метод для поиска цифровых коллекций, баз данных по искусству, методы сравнительного анализа, типологизацииDigital databases are currently an integral part of scientific research in the art studies field. The use of information and communication technologies, the information development and analytical systems in art criticism are associated with the scale of the tasks that these means of systematization can solve. The use of artificial intelligence methods for the creation, cataloging, qualitative and quantitative art works analysis is being updated. Specialized art history databases have firmly occupied their niche in the process of authenticating and searching for lost works of art. In this study, domestic and international databases on art were analyzed, including EBSCO, WEB Gallery Of Art, Digital Collection of the State Hermitage Museum, etc. As a review result of representative databases and interactive platforms of art history content, the article presents a possible typology based on the considered art databases. The methodological basis of this research is the source-based method for searching digital collections, databases on art, methods of comparative analysis, typologizatio

Schematic representation of the proposed 5-HT_4d receptor-stimulated signaling pathway leading to increased sAPPα production.

<p>The proteins involved in 5-HT_4d receptor-mediated non-amyloidogenic APP shedding are shown with green circles while orange circles and red characters indicate proteins or second messengers that were tested but were ineffective in modulating 5-HT_4d receptor-stimulated sAPPα release. The dotted lines with the question marks indicate remaining areas of investigation for further elucidation of the molecular mechanism of α-secretase activation. cAMP-dependent pathway of α-secretase induction was previously reported and is depicted as a plausible way for 5-HT_4d receptor-mediated sAPPα release <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087014#pone.0087014-Maillet1" target="_blank">[15]</a>.</p