ANALYSIS OF DOMAIN SPECIFICITY OF THE PROTECTIVE CHIMERIC ANTIBODY ch14D5a AGAINST GLYCOPROTEIN E OF TICK-BORNE ENCEPHALITIS VIRUS

A drug for the prevention and therapy of tick-borne encephalitis virus is being developed on the basis of the protective chimeric antibody ch14D5a. At the same time, the epitope recognized by this antibody on the surface of glycoprotein E has not been localized yet. The aim of this work was to identify the domain of glycoprotein E, to which the protective antibody ch14D5a binds. As a result, four recombinant variants of glycoprotein E were generated using the bacterial expression system: (1) the rE protein containing the domains D1, D2, and D3 of glycoprotein E; (2) the rED1+2 protein containing domains D1 and D2; (3) the rED3_301 protein, which is domain D3 of glycoprotein E, and (4) the rED3_294 protein comprising domain D3 and a hinge region connecting domains D1 and D3. The rED3_294 and rED3_301 proteins were obtained in soluble monomeric form. The rE and rED1+2 proteins were extracted from the inclusion bodies of Escherichia coli. Using Western blot analysis and surface plasmon resonance analysis, it was demonstrated that the protective chimeric antibody ch14D5a and its Fab fragment bound specifically to domain D3 of glycoprotein E. Since the antibodies recognizing epitopes on the surface of domain D3 do not tend to cause antibody-dependent enhancement of the infection as compared to antibodies directed to domains D1 and D2, the data obtained confirm the promise of using the antibody ch14D5a in the development of a therapeutic preparation against the tick-borne encephalitis virus

Salsalate treatment following traumatic brain injury reduces inflammation and promotes a neuroprotective and neurogenic transcriptional response with concomitant functional recovery

Neuroinflammation plays a critical role in the pathogenesis of traumatic brain injury (TBI). TBI induces rapid activation of astrocytes and microglia, infiltration of peripheral leukocytes, and secretion of inflammatory cytokines. In the context of modest or severe TBI, such inflammation contributes to tissue destruction and permanent brain damage. However, it is clear that the inflammatory response is also necessary to promote post-injury healing. To date, anti-inflammatory therapies, including the broad class of non-steroidal anti-inflammatory drugs (NSAIDs), have met with little success in treatment of TBI, perhaps because these drugs have inhibited both the tissue-damaging and repair-promoting aspects of the inflammatory response, or because inhibition of inflammation alone is insufficient to yield therapeutic benefit. Salsalate is an unacetylated salicylate with long history of use in limiting inflammation. This drug is known to block activation of NF-jB, and recent data suggest that salsalate has a number of additional biological activities, which may also contribute to its efficacy in treatment of human disease. Here, we show that salsalate potently blocks pro-inflammatory gene expression and nitrite secretion by microglia in vitro. Using the controlled cortical impact (CCI) model in mice, we find that salsalate has a broad antiinflammatory effect on in vivo TBI-induced gene expression, when administered post-injury. Interestingly, salsalate also elevates expression of genes associated with neuroprotection and neurogenesis, including the neuropeptides, oxytocin and thyrotropin releasing hormone. Histological analysis reveals salsalate-dependent decreases in numbers and activation-associated morphological changes in microglia/macrophages, proximal to the injury site. Flow cytometry data show that salsalate changes the kinetics of CCI-induced accumulation of various populations of CD11b-positive myeloid cells in the injured brain. Behavioral assays demonstrate that salsalate treatment promotes significant recovery of function following CCI. These pre-clinical data suggest that salsalate may show promise as a TBI therapy with a multifactorial mechanism of action to enhance functional recovery

The EDS1–PAD4–ADR1 node mediates Arabidopsis pattern-triggered immunity

Plants deploy cell-surface and intracellular leucine rich-repeat domain (LRR) immune receptors to detect pathogens1. LRR receptor kinases and LRR receptor proteins at the plasma membrane recognize microorganism-derived molecules to elicit pattern-triggered immunity (PTI), whereas nucleotide-binding LRR proteins detect microbial effectors inside cells to confer effector-triggered immunity (ETI). Although PTI and ETI are initiated in different host cell compartments, they rely on the transcriptional activation of similar sets of genes2, suggesting pathway convergence upstream of nuclear events. Here we report that PTI triggered by the Arabidopsis LRR receptor protein RLP23 requires signalling-competent dimers of the lipase-like proteins EDS1 and PAD4, and of ADR1 family helper nucleotide-binding LRRs, which are all components of ETI. The cell-surface LRR receptor kinase SOBIR1 links RLP23 with EDS1, PAD4 and ADR1 proteins, suggesting the formation of supramolecular complexes containing PTI receptors and transducers at the inner side of the plasma membrane. We detected similar evolutionary patterns in LRR receptor protein and nucleotide-binding LRR genes across Arabidopsis accessions; overall higher levels of variation in LRR receptor proteins than in LRR receptor kinases are consistent with distinct roles of these two receptor families in plant immunity. We propose that the EDS1–PAD4–ADR1 node is a convergence point for defence signalling cascades, activated by both surface-resident and intracellular LRR receptors, in conferring pathogen immunity

Matrix metalloproteinases in lung biology

Despite much information on their catalytic properties and gene regulation, we actually know very little of what matrix metalloproteinases (MMPs) do in tissues. The catalytic activity of these enzymes has been implicated to function in normal lung biology by participating in branching morphogenesis, homeostasis, and repair, among other events. Overexpression of MMPs, however, has also been blamed for much of the tissue destruction associated with lung inflammation and disease. Beyond their role in the turnover and degradation of extracellular matrix proteins, MMPs also process, activate, and deactivate a variety of soluble factors, and seldom is it readily apparent by presence alone if a specific proteinase in an inflammatory setting is contributing to a reparative or disease process. An important goal of MMP research will be to identify the actual substrates upon which specific enzymes act. This information, in turn, will lead to a clearer understanding of how these extracellular proteinases function in lung development, repair, and disease

NADPH oxidase elevations in pyramidal neurons drive psychosocial stress-induced neuropathology

Oxidative stress is thought to be involved in the development of behavioral and histopathological alterations in animal models of psychosis. Here we investigate the causal contribution of reactive oxygen species generation by the phagocyte NADPH oxidase NOX2 to neuropathological alterations in a rat model of chronic psychosocial stress. In rats exposed to social isolation, the earliest neuropathological alterations were signs of oxidative stress and appearance of NOX2. Alterations in behavior, increase in glutamate levels and loss of parvalbumin were detectable after 4 weeks of social isolation. The expression of the NOX2 subunit p47phox was markedly increased in pyramidal neurons of isolated rats, but below detection threshold in GABAergic neurons, astrocytes and microglia. Rats with a loss of function mutation in the NOX2 subunit p47phox were protected from behavioral and neuropathological alterations induced by social isolation. To test reversibility, we applied the antioxidant/NOX inhibitor apocynin after initiation of social isolation for a time period of 3 weeks. Apocynin reversed behavioral alterations fully when applied after 4 weeks of social isolation, but only partially after 7 weeks. Our results demonstrate that social isolation induces rapid elevations of the NOX2 complex in the brain. Expression of the enzyme complex was strongest in pyramidal neurons and a loss of function mutation prevented neuropathology induced by social isolation. Finally, at least at early stages, pharmacological targeting of NOX2 activity might reverse behavioral alterations

The Effect of a Paired Lab on Course Completion and Grades in Nonmajors Introductory Biology

This paper explores the effect of a paired lab course on students’ course outcomes in nonmajors introductory biology at the University of Alaska Anchorage. We compare course completion and final grades for 10,793 students (3736 who simultaneously enrolled in the lab and 7057 who did not). Unconditionally, students who self-select into the lab are more likely to complete the course and to earn a higher grade than students who do not. However, when we condition on observable course, academic, and demographic characteristics, we find much of this difference in student performance outcomes is attributable to selection bias, rather than an effect of the lab itself. The data and discussion challenge the misconception that labs serve as recitations for lecture content, noting that the learning objectives of science labs should be more clearly articulated and assessed independent of lecture course outcomes. This paper explores the effect of a paired lab course on students’ course outcomes in introductory biology for nonmajors at the University of Alaska Anchorage (UAA), a large, open-enrollment, 4-year university. We compare outcomes for 10,793 students, 3736 who simultaneously enrolled in the lab and 7057 who did not, and analyze the degree to which they select into the lab on observable characteristics to explore the following research questions: 1. Are students who take a paired lab more likely to complete the lecture component (i.e., receive a final grade as opposed to withdrawing or receiving an Incomplete)? 2. Are students who take a paired lab more likely to receive a higher grade in the lecture component? 3. Does the laboratory experience differently affect course outcomes for students in specific demographic subgroups (e.g., gender, race, high school urbanicity, age, prior academic performance, and socioeconomic status)

Проблемные аспекты культурной политики в современной Туве

The article is devoted to the analysis of the cultural politics in Tuva and is focused on the problematic aspects of its current development. It is the result of reflection on personal participation in the cultural policy making in the Tyva Republic, followed by the report and its subsequent discussion (within the Forum “Tuva of Future: Strategy for Change”, 28-30 June 2017, Kyzyl) through the application of historical-comparative, structural-typological and participant observation’s methods. According to the author, a major challenge for the development of culture industry of Tuva is that in the Soviet period it was the institutional model chosen for regional cultural development, while the region experiences the lack of human resources. Ethnic culture of the post-Soviet stage in the Tuvan history is characterized by the self-isolation concerning the value aspect. The implementation of the cluster institutional models and the effective use of the Tuva cultural brand, which is an eco-exo-ethnocultural synthesis, can contribute to the solution of the cultural policy problems. The research results can be applied in the development of concepts and Republican target programs of the Tuva cultural development. The prospect may be finding the optimal balance of conservative and innovative tendencies. The imbalance between ethnic culture and national culture in the contemporary cultural life of the Republic should be oriented towards the national (Russian) identity and its understandingПредлагаемое исследование посвящено анализу культурной политики Тувы и сконцентрировано на проблемных аспектах её развития на современном этапе. Работа является результатом осмысления личного опыта участия в культурной политике Республики Тыва, материалов доклада и последующего его обсуждения (в рамках Форума «Тува будущего: стратегия перемен», 28-30 июня 2017 г., г. Кызыл) на основе применения сравнительно-исторического, структурно-типологического и метода включенного наблюдения. Основная проблема развития отрасли культуры Тувы видится автору в изначальном несоответствии избранной в советский период институциональной модели культурного строительства с недостаточным объемом людских ресурсов региона. Для этнической культуры постсоветского этапа истории Тувы характерна замкнутость в ценностном отношении на себе самой. Решению проблемных аспектов культурной политики могут способствовать реализация институциональных моделей кластерного типа и эффективное использование культурного бренда Тувы, который представляет собой эко-экзо-этнокультурный синтез. Результаты исследования могут найти применение при разработке концепций и республиканских целевых программ культурного развития Тувы. Перспективы развития отрасли видятся в оптимальном балансе охранительных и инновационных тенденций. Дисбаланс соотношения этнической и национальной культуры в современной культурной жизни республики следует скорректировать нацеленностью в сторону осмысления национальной (общероссийской) идентичност

Music in Maxim Munzuk’s life

Article presents the musical heritage of Tuvan artist M.M. Munzuk. It reviews his song repertoire, his fieldwork on collecting the people’s songs, about the musical heritage of Munzuk which still awaits it’s time to be published

О тенденциях современной художественной культуры Сибири (на материале музыкально-зрелищных проектов Тувы)

The article is devoted to the trends in the modern art culture of Siberia. The throat singing art of the Tuvans, one of the indigenous ethnic groups of Siberia, has been acknowledged at the international level. The latest events in the musical and cultural life of the Republic of Tuva have not become a research object for musicology yet, so the article addresses the phenomena of the last decade’s musical culture of the Republic of Tuva. It considers the genre problem of modern Tuvan art. The research methodology is based on the systematic approach, combined methods of musical and cultural analysis. The purpose of the article is to determine the genre specificity of musical and spectacular projects. The material was musical stagings или musical dramatizations, choreographic performances and concert programs of orchestral groups (Tuvan National Orchestra, the Brass Band and the Symphonic Orchestra). The author notes the interest for the underlying fundament of ethnic culture and puts forward the concept of “syncresis of the second order” in the analysis of ethnoballets, programs of “Sayany” National Ensemble of Song and Dance and Tuvan National Orchestra. Creative projects of the Brass Band are characterized by the manifestation of the so-called “crossover” phenomenon. A special genre mix (musical-visual art-poetry) was demonstrated by the “The Wind’s Song of the Age of Change…” project of the symphonic orchestra. As a result, the article presents the evaluation of different genre modifications in Tuvan musical art from the position of interaction between different types of cultures, searching for new meanings of addressing the ethno-archaic culture. In this context, modern creativity is a sort of a channel for transmitting axiological meanings of Siberian ethnic cultures into the global cultural spaceСтатья посвящена тенденциям в современной художественной культуре Сибири. Mировое признание получило музыкальное искусство горлового пения тувинцев, одного из коренных сибирских этносов. Новейшие события музыкально-культурной жизни в Туве еще не становились объектом музыкознания, поэтому статья обращена к явлениям музыкальной культуры Республики Тува последнего десятилетия. Рассматривается проблема жанровой природы в современном искусстве Тувы. Методология исследования опирается на системный подход в сочетании музыковедческих и культурологических методов анализа. Целью статьи стало определение жанровой специфики музыкально-зрелищных проектов. Материалом послужили музыкально-театральные и хореографические постановки, а также концертные программы оркестровых коллективов (тувинского национального, духового и симфонического оркестров). В процессе анализа этнобалетов, программ национального ансамбля песни и танца «Саяны» и тувинского национального оркестра отмечается тяготение к глубинным основам этнокультуры и выдвигается понятие «синкрезис второго порядка». Для творческих проектов духового оркестра характерно проявление феномена «кроссовера». Особый жанровый микст (музыкально-визуально-поэтический) воплотился в проекте симфонического оркестра «Песнь ветра века переменЪ…». В результате, различные варианты жанровых модификаций в музыкальном искусстве Тувы оцениваются с позиции сложного взаимодействия различных типов культур и поиска новых смыслов в обращении к этноархаике. Современное творчество в данном русле – своего рода канал трансляции ценностных смыслов сибирских этнокультур в мировое культурное пространство