Thermo-oxidative Stability and Flammability of Three-dimensional Polymers Based on Olygocarbonate-methacrylates

By the irreversible condensation reaction of the mono-methacrylic ester of ethylene glycol and chlorocarbonic esters of 2,2-dimethylpropandiol- 1,3 and 2,2-dimethylene chloride-propandiol-1,3, two olygocarbonate methacrylate (OCM-I and -II, respectively) containing unsaturated ends were synthesised. The polymerization of OCM-I and OCM-II in the presence of cumene hydro.peroxide and an accelerator gave two cross-liinked polymers Ln a yield of 70-750/o. The thermal and thermo-oxidative decompositions of the prepared polymers were studied by the thermogravimetric method and by characterization of the volatile pyrolysis products and the nonvolatile polymer residue. The influence of the polymer structure on the mechanism of the decomposition reactions in vacuo as well as iin the presence of oxygen was discussed. The temperature dependence of thermostabiLity was compared with some polymer flammability parameters

Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR

Background Understanding the influence of genetic variants on DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL), but also for discriminating general from cell type-specific effects. Results Here, we present a two-step computational framework MAGAR (https://bioconductor.org/packages/MAGAR), which fully supports the identification of methQTLs from matched genotyping and DNA methylation data, and additionally allows for illuminating cell type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T cells, B cells) from healthy individuals and demonstrate the discrimination of common from cell type-specific methQTLs. We experimentally validate both types of methQTLs in an independent data set comprising additional cell types and tissues. Finally, we validate selected methQTLs located in the PON1, ZNF155, and NRG2 genes by ultra-deep local sequencing. In line with previous reports, we find cell type-specific methQTLs to be preferentially located in enhancer elements. Conclusions Our analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell type-specific epigenomic variation

Identification of tissue-specific and common methylation quantitative trait loci in healthy individuals using MAGAR.

BackgroundUnderstanding the influence of genetic variants on DNA methylation is fundamental for the interpretation of epigenomic data in the context of disease. There is a need for systematic approaches not only for determining methylation quantitative trait loci (methQTL), but also for discriminating general from cell type-specific effects.ResultsHere, we present a two-step computational framework MAGAR ( https://bioconductor.org/packages/MAGAR ), which fully supports the identification of methQTLs from matched genotyping and DNA methylation data, and additionally allows for illuminating cell type-specific methQTL effects. In a pilot analysis, we apply MAGAR on data in four tissues (ileum, rectum, T cells, B cells) from healthy individuals and demonstrate the discrimination of common from cell type-specific methQTLs. We experimentally validate both types of methQTLs in an independent data set comprising additional cell types and tissues. Finally, we validate selected methQTLs located in the PON1, ZNF155, and NRG2 genes by ultra-deep local sequencing. In line with previous reports, we find cell type-specific methQTLs to be preferentially located in enhancer elements.ConclusionsOur analysis demonstrates that a systematic analysis of methQTLs provides important new insights on the influences of genetic variants to cell type-specific epigenomic variation

The GWAS-MAP platform for aggregation of results of genome-wide association studies and the GWAS-MAP|homo database of 70 billion genetic associations of human traits

Hundreds of genome-wide association studies (GWAS) of human traits are performed each year. The results of GWAS are often published in the form of summary statistics. Information from summary statistics can be used for multiple purposes – from fundamental research in biology and genetics to the search for potential biomarkers and therapeutic targets. While the amount of GWAS summary statistics collected by the scientific community is rapidly increasing, the use of this data is limited by the lack of generally accepted standards. In particular, the researchers who would like to use GWAS summary statistics in their studies have to become aware that the data are scattered across multiple websites, are presented in a variety of formats, and, often, were not quality controlled. Moreover, each available summary statistics analysis tools will ask for data to be presented in their own internal format. To address these issues, we developed GWAS-MAP, a high-throughput platform for aggregating, storing, analyzing, visualizing and providing access to a database of big data that result from region- and genome-wide association studies. The database currently contains information on more than 70 billion associations between genetic variants and human diseases, quantitative traits, and “omics” traits. The GWAS-MAP platform and database can be used for studying the etiology of human diseases, building predictive risk models and finding potential biomarkers and therapeutic interventions. In order to demonstrate a typical application of the platform as an approach for extracting new biological knowledge and establishing mechanistic hypotheses, we analyzed varicose veins, a disease affecting on average every third adult in Russia. The results of analysis confirmed known epidemiologic associations for this disease and led us to propose a hypothesis that increased levels of MICB and CD209 proteins in human plasma may increase susceptibility to varicose veins

The GWAS-MAP|ovis platform for aggregation and analysis of genome-wide association study results in sheep.

peer reviewedIn recent years, the number of genome-wide association studies (GWAS) carried out for various economically important animal traits has been increasing. GWAS discoveries provide summary statistics that can be used both for targeted marker-oriented selection and for studying the genetic control of economically important traits of farm animals. In contrast to research in human genetics, GWAS on farm animals often does not meet generally accepted standards (availability of information about effect and reference alleles, the size and direction of the effect, etc.). This greatly complicates the use of GWAS results for breeding needs. Within the framework of human genetics, there are several technological solutions for researching the harmonized results of GWAS, including one of the largest, the GWAS-MAP platform. For other types of living organisms, including economically important agricultural animals, there are no similar solutions. To our knowledge, no similar solution has been proposed to date for any of the species of economically important animals. As part of this work, we focused on creating a platform similar to GWAS-MAP for working with the results of GWAS of sheep, since sheep breeding is one of the most important branches of agriculture. By analogy with the GWAS-MAP platform for storing, unifying and analyzing human GWAS, we have created the GWAS-MAP|ovis platform. The platform currently contains information on more than 34 million associations between genomic sequence variants and traits of meat production in sheep. The platform can also be used to conduct colocalization analysis, a method that allows one to determine whether the association of a particular locus with two different traits is the result of pleiotropy or whether these traits are associated with different variants that are in linkage disequilibrium. This platform will be useful for breeders to select promising markers for breeding, as well as to obtain information for the introduction of genomic breeding and for scientists to replicate the results obtained.В последние годы увеличивается количество полногеномных исследований ассоциаций (ПГИА, GWAS), проведенных для различных экономически важных признаков животных. Результаты этих исследований представлены в виде суммарных статистик, которые можно использовать для изучения генетического контроля экономически важных признаков сельскохозяйственных животных, в том числе и при разработке методик маркер-ориентированной селекции. В большинстве случаев ПГИА сельскохозяйственных животных не соответствуют общепринятым в области исследований генетики человека стандартам формата публикаций результатов ПГИА в виде суммарных статистик (наличие информации об эффекторном и референсном аллелях, значение и направление эффекта и др.). Это существенно затрудняет использование суммарных статистик для нужд селекции. В области исследований генетики человека имеется несколько технологических решений для анализа результатов ПГИА, в том числе одно из самых крупных – платформа GWAS-MAP. Для других видов живых организмов, включающих и экономически важных сельскохозяйственных животных, подобных решений нет. В настоящей работе мы сфокусировались на создании схожей платформы для работы с суммарными статистиками ПГИА различных признаков овец, так как овцеводство в последнее время становится все более актуальной областью сельского хозяйства. По аналогии с платформой GWAS-MAP для хранения, унификации и анализа GWAS человека мы создали платформу GWAS-MAP|ovis. На сегодняшний день платформа содержит информацию о более чем 34 млн ассоциаций между вариантами геномной последовательности и признаками мясной продуктивности. Платформа может быть использована и для проведения анализа колокализации – метода, который позволяет установить, является ли ассоциация определенного локуса с двумя разными признаками результатом плейотропии или же данные признаки ассоциированы с разными вариантами, которые находятся в неравновесии по сцеплению. Эта платформа будет полезна как селекционерам для выбора перспективных маркеров для селекции (эффекты и аллели различных маркеров, влияющих на изучаемые признаки), так и для ученых, ведущих исследования в области генетики овец

The GWAS-MAP|ovis platform for aggregation and analysis of genome-wide association study results in sheep

In recent years, the number of genome-wide association studies (GWAS) carried out for various economically important animal traits has been increasing. GWAS discoveries provide summary statistics that can be used both for targeted marker-oriented selection and for studying the genetic control of economically important traits of farm animals. In contrast to research in human genetics, GWAS on farm animals often does not meet generally accepted standards (availability of information about effect and reference alleles, the size and direction of the effect, etc.). This greatly complicates the use of GWAS results for breeding needs. Within the framework of human genetics, there are several technological solutions for researching the harmonized results of GWAS, including one of the largest, the GWAS-MAP platform. For other types of living organisms, including economically important agricultural animals, there are no similar solutions. To our knowledge, no similar solution has been proposed to date for any of the species of economically important animals. As part of this work, we focused on creating a platform similar to GWAS-MAP for working with the results of GWAS of sheep, since sheep breeding is one of the most important branches of agriculture. By analogy with the GWAS-MAP platform for storing, unifying and analyzing human GWAS, we have created the GWAS-MAP|ovis platform. The platform currently contains information on more than 34 million associations between genomic sequence variants and traits of meat production in sheep. The platform can also be used to conduct colocalization analysis, a method that allows one to determine whether the association of a particular locus with two different traits is the result of pleiotropy or whether these traits are associated with different variants that are in linkage disequilibrium. This platform will be useful for breeders to select promising markers for breeding, as well as to obtain information for the introduction of genomic breeding and for scientists to replicate the results obtained

Скрининг бронхообструкции, вызванной физической нагрузкой, у лыжников и биатлонистов в различные периоды годового тренировочного цикла

Summary. The purpose of the study was to investigate prevalence of exercise-induced bronchoconstriction (EIB) in winter sports athletes at different periods of an annual training cycle and to evaluate a role of NO production in the respiratory tract for EIB occurrence. 92 athletes were examined during a precompetitive period and 78 were examined during a competitive period of an annual training cycle (mean age was 17.5 ± 2.3 years). EIB was detected using an indirect exercise field-test in cold air. Before and after the challenge test the fractional exhaled NO (FeNO) was measured. Postexercise FEV1 decreased ≥ 10 % in 6.4 % and 6.5 % of athletes during the competitive and the precompetitive periods, respectively. A correlation was found between ΔFEV1 and ΔFEF25–75. In EIB-positive athletes, there was a significantly lower baseline FeNO during the precompetitive period (p = 0.03). Relationships were determined between post-exercise FEV1, FVC, PEF, FEF25–75 and post-exercise FeNO. The EIB prevalence among skiers and biathletes was as low as 6.5 %. The NO level correlated with pulmonary function in elite athletes.Резюме. Целью исследования было изучение распространенности бронхоспазма, вызванного физической нагрузкой (БФН), среди спортсменов лыжников и биатлонистов в различные периоды годового тренировочного цикла; исследование роли продукции NO в респираторном тракте в реализации данного феномена. В подготовительный период были обследованы 92 спортсмена, в соревновательный – 78 (средний возраст – 17,5 ± 2,3 года). Для выявления БФН использован непрямой провокационный тест с физической нагрузкой на открытом воздухе при низких температурах окружающей среды с динамической оценкой функции внешнего дыхания (ФВД). Исходно и после нагрузки определялся уровень оксида азота в выдыхаемом воздухе (NOвыд.). Снижение объема форсированного выдоха за 1-ю секунду (ОФВ1) на ≥10 % после нагрузки зарегистрировано у 6,4 % и 6,5 % спортсменов в соревновательном и подготовительном периодах соответственно. Установлена положительная взаимосвязь между показателями ΔОФВ1 и ΔМОС25–75. Определен достоверно меньший исходный уровень NOвыд. у спортсменов с БФН в подготовительный период (p = 0,03). Выявлена положительная взаимосвязь постнагрузочных значений ОФВ1, ФЖЕЛ, ПСВ, МОС25–75 с уровнем NOвыд. после нагрузки.Распространенность БФН среди лыжников и биатлонистов невысока и составляет ≤ 6,5 %. Описана взаимосвязь уровня NOвыд. с показателями ФВД у атлетов, занимающихся зимними видами спорта

Requirements for Receptor Engagement during Infection by Adenovirus Complexed with Blood Coagulation Factor X

Human adenoviruses from multiple species bind to coagulation factor X (FX), yet the importance of this interaction in adenovirus dissemination is unknown. Upon contact with blood, vectors based on adenovirus serotype 5 (Ad5) binds to FX via the hexon protein with nanomolar affinity, leading to selective uptake of the complex into the liver and spleen. The Ad5:FX complex putatively targets heparan sulfate proteoglycans (HSPGs). The aim of this study was to elucidate the specific requirements for Ad5:FX-mediated cellular uptake in this high-affinity pathway, specifically the HSPG receptor requirements as well as the role of penton base-mediated integrin engagement in subsequent internalisation. Removal of HS sidechains by enzymatic digestion or competition with highly-sulfated heparins/heparan sulfates significantly decreased FX-mediated Ad5 cell binding in vitro and ex vivo. Removal of N-linked and, in particular, O-linked sulfate groups significantly attenuated the inhibitory capabilities of heparin, while the chemical inhibition of endogenous HSPG sulfation dose-dependently reduced FX-mediated Ad5 cellular uptake. Unlike native heparin, modified heparins lacking O- or N-linked sulfate groups were unable to inhibit Ad5 accumulation in the liver 1h after intravascular administration of adenovirus. Similar results were observed in vitro using Ad5 vectors possessing mutations ablating CAR- and/or αv integrin binding, demonstrating that attachment of the Ad5:FX complex to the cell surface involves HSPG sulfation. Interestingly, Ad5 vectors ablated for αv integrin binding showed markedly delayed cell entry, highlighting the need for an efficient post-attachment internalisation signal for optimal Ad5 uptake and transport following surface binding mediated through FX. This study therefore integrates the established model of αv integrin-dependent adenoviral infection with the high-affinity FX-mediated pathway. This has important implications for mechanisms that define organ targeting following contact of human adenoviruses with blood