Flyglow: Single-fly observations of simultaneous molecular and behavioural circadian oscillations in controls and an Alzheimer's model.

Circadian rhythms are essential for health and are frequently disturbed in disease. A full understanding of the causal relationships between behavioural and molecular circadian rhythms requires simultaneous longitudinal observations over time in individual organisms. Current experimental paradigms require the measurement of each rhythm separately across distinct populations of experimental organisms, rendering the comparability of the resulting datasets uncertain. We therefore developed FLYGLOW, an assay using clock gene controlled luciferase expression detected by exquisitely sensitive EM-CCD imaging, to enable simultaneous quantification of parameters including locomotor, sleep consolidation and molecular rhythms in single flies over days/weeks. FLYGLOW combines all the strengths of existing techniques, and also allows powerful multiparametric paired statistics. We found the age-related transition from rhythmicity to arrhythmicity for each parameter occurs unpredictably, with some flies showing loss of one or more rhythms during middle-age. Using single-fly correlation analysis of rhythm robustness and period we demonstrated the independence of the peripheral clock from circadian behaviours in wild type flies as well as in an Alzheimer's model. FLYGLOW is a useful tool for investigating the deterioration of behavioural and molecular rhythms in ageing and neurodegeneration. This approach may be applied more broadly within behavioural neurogenetics research

Secretory immune status of oral cavity in the patients with <i>Сandida</i>-associated denture stomatitis

Age-related changes in the oral mucosa immunity, including decreased contents of secretory immunoglobulins and antimicrobial peptides in saliva, along with changed balance of pro- and antiinflammatory cytokines, care risks for development of purulent-inflammatory or allergic diseases of the oral cavity. For example, denture stomatitis (DS) caused by Candida albicans occurs in about 30—70% of denture users. The purpose of this study was to assess the secretory immune state of oral mucous membranes in the patients with Candida-associated denture stomatitis. We examined 42 elderly patients (61-72 years old) with one-piece acrylic dentures for at least, 6 months (15 men and 27 women). Based on clinical and microbiological studies, the patients were divided into a group with DS (n = 24) and a group without DS (n = 18). The contents of secretory immunoglobulin A (sIgA) and proinflammatory cytokines was determined, i.e., interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNFα), and anti-inflammatory cytokines, e.g., receptor antagonist of interleukin-1 (RAIL), interleukin-4 (IL-4), interleukin-10 (IL-10), as well as antimicrobial peptides (cathelicidin LL-37, lactoferrin and alphadefensins 1-3 (HNP1-3). The sIgA levels in the salivary fluid of patients with DS (0.92 (0.80-1.26) g/l) were significantly lower (p &lt; 0.05) than in patients without stomatitis (1.71 (1.23-2,13) g/l). In the group with advanced DS, a significant increase of IL-1β levels in saliva was observed, along with simultaneous decrease of IL-8 concentrations, compared to the other group, without differences in TNFα and IL-6 concentrations. Increased contents of IL-10 in saliva was also noted. It was shown that the concentrations of cathelicidin LL-37 in saliva of the DS patients was increased two-fold, whereas the contents of neutrophil-derived alpha-defensins (HNP 1-3) was decreased. Conclusions: The development of inflammation in denture stomatitis caused by usage of removable acrylic dentures associated with Candida albicans infection is characterized by functional insufficiency of the secretory immunity of the oral mucosa associated with decreased amounts of secretory immunoglobulin A and antimicrobial peptides of neutrophilic origin. Low levels of alpha-defensins may suggest a decrease in the functional activity of neutrophils in the elderly, thus leading to higher susceptibility to fungal infection of oral cavity

Resources for developing the research publication competencies of Russian researchers

Introduction. In the last decades, due to the increased number of international research collaborations, the role of auxiliary institutions which contribute to the development of research publication competencies has increased. Competencies are required for writing, preparing, publishing, and promoting scientific articles. The formation of such competencies is carried out at different levels of higher education as part of the current Federal State Educational Standard (FSES), including prorammes of additional professional education, as well as initiatives of auxiliary university departments and non-university organisations. Aim. This article aims to analyse the resources available for the development of research publication competencies in Russia in terms of the opportunities offered by different participants of the educational process. Methodology and research methods. The study compared and analysed open access regulatory documentation, reviewed and systematised data from the websites of auxiliary university departments and non-university organisations, and used data from in-depth interviews. Results. The article describes the prerequisites for the formation of research publication competencies in higher education in Russia. An overview of effective practices to develop such competencies is given, taking into account the national context and available higher education programmes. The article provides an overview of the functionality of auxiliary university departments and non-university organisations, whose activities support publication activity. The role of academic writing teachers, consultants, translators, editors, and reviewers in the development of the competencies of the authors of scientific publications is determined. The importance of the closer interaction of all participants in the publication process is substantiated: authors, translators, and editors of texts; and teachers of scientific writing courses with editors and reviewers of scientific journals. Scientific novelty. The scientific novelty of this article refers to a detailed description of the resources for the development of research publication competencies and their compliance with the requirements of the Federal State Educational Standard, which have not been investigated in such correlation before. Practical significance. The results can be used to develop a set of measures to systematise approaches to developing research publication competencies.Введение. В последние десятилетия в связи с увеличением объема международных научных коллабораций возрастает роль вспомогательных учреждений, которые способствуют развитию научно-публикационных компетенций исследователей. Научно-публикационные компетенции представляют собой совокупность компетенций, необходимых для написания, подготовки, публикации и продвижения научной статьи. Формирование компетенций, связанных с научно-исследовательской и публикационной деятельностью российских исследователей, осуществляется на разных ступенях высшего образования в рамках действующего Федерального государственного образовательного стандарта (ФГОС). Этот процесс продолжается в рамках программ дополнительного профессионального образования, а также отдельных инициатив вспомогательных университетских подразделений и внеуниверситетских организаций. Цель данной статьи – проанализировать имеющиеся ресурсы по развитию научно-публикационных компетенций в России с точки зрения возможностей, предлагаемых разными акторами процесса образовательной деятельности. Методология, методы и методики. В исследовании использовались сравнительно-сопоставительный анализ нормативной документации открытого доступа, а также обзор и систематизация данных с официальных сайтов вспомогательных университетских подразделений и внеуниверситетских организаций, метод глубинных интервью. Результаты. В статье описаны предпосылки формирования научно-публикационных компетенций в системе высшего образования в России. Приводится обзор эффективных отечественных практик, направленных на развитие научно-публикационных компетенций, с учетом национального контекста и программ высшего образования. В статье представлен обзор функционала вспомогательных подразделений вузов и внеуниверситетских организаций, деятельность которых направлена на поддержку публикационной активности. Определена роль преподавателей академического письма, консультантов, переводчиков, редакторов и рецензентов в развитии компетенций авторов научных публикаций. Обоснована значимость более тесного взаимодействия всех участников публикационного процесса: авторов, переводчиков и редакторов научного текста, преподавателей курсов научного письма с редакторами и рецензентами научных журналов. Научная новизна данной статьи состоит в детальном описании ресурсов развития научно-публикационных компетенций и их соответствия требованиям Федерального государственного образовательного стандарта, которые в таком соотношении прежде не исследовались. Практическая значимость. Полученные результаты могут быть использованы для разработки комплекса мероприятий по систематизации подходов к формированию научно-публикационных компетенций.Авторы выражают благодарность за консультации и предоставление статистических данных Т. А. Лоскутовой (АНРИ), И. В. Самойленко (СтГАУ), И. Шрайбер и Н. Емельяновой (Западно-Сибирский межрегиональный НОЦ), Е. Л. Богуславской (ИФиП УрО РАН), И. В. Отрадновой (Президиум УрО РАН), С. В. Мыльникову (Эко-Вектор). Авторы выражают признательность анонимным рецензентам, которые высказали ценные рекомендации по доработке статьи.The authors express their gratitude to T. A. Loskutova (RASSEP), I. V. Samoilenko (StSAU), I. Schreiber and N. Emelianova (West Siberian Interregional Scientific Centre), E. L. Boguslavskaya (Institute for Philosophy and Law UB RAS), I. V. Otradnova (Presidium UB RAS), S. V. Mylnikov (Eco-Vector) for their consultations and providing statistical data. The authors are grateful to the anonymous reviewers, who provided valuable suggestions for improving the article

Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues

Single cell derived mRNA signals across human kidney tumors.

Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer