Факторы риска, определяющие развитие эпидемического процесса ВИЧ-инфекции в пенитенциарной системе региона с высоким уровнем пораженности ВИЧ

The Tyumen Region, being the largest one in the Ural Federal District in terms of territory, has a high level of HIV prevalence, particularly among those taken into custody. This group of people involves the maximum number of injecting drug users, men having sexual encounters with other men and sex workers. All acquired diseases including the diseases aggravated during the service of sentence become the problem of the expirees as well as the entire civil society. From an epidemiological perspective it is important to search for the risk factors which are active among the prisoner population serving their sentence in the region and which cause HIV progression with fatal outcome, taking into account their unequal significance among the prisoner population and the civilians.Object of research. 365 HIV-infected, deaths were identified, including: the study group — 222 prisoners, HlV-infected and died at the regional hospital of the Federal penitentiary service of Tyumen for the period 2008-2018; the control group - 143 civil (law-abiding) patients, HIV-infected and died at the Regional infectious diseases hospital for the period 2011-2018.Purpose of research. Identification and assessment of priority risk factors for the expansion of the epidemic process of HIV infection with a fatal outcome in the zone of high concentration of the risk group.Methods of research. The following methods have been used in this work: methods of epidemiological research, methods of mathematical modeling and forecasting, as well as the method, of logistic regression, of step-by-step inclusion with ROC analysis.Results. To assess the epidemiological situation in terms of the HIV infection prevalence in the prison area a long-term and intra-annual dynamics of the epidemic process expansion in the region have been studied along with assessment of the priority risk factors, trends, forecasting of the HIV infection expansion in the penitentiary system specifying the social significance and risks to the civilian population over a long period.Тюменская область — территориально самая большая в Уральском федеральном округе, имеет высокий уровень пораженности ВИЧ, особенно среди заключенных под стражу лиц. В обозначенной группе максимально сосредоточены потребители инъекционных наркотиков, мужчины, имеющие половые контакты с мужчинами, работники коммерческого секса. Все приобретенные заболевания или заболевания, усугубившиеся в условиях отбывания наказания, становятся проблемой не только освободившихся заключенных, но и всего гражданского общества. Важным, с эпидемиологической точки зрения, является поиск факторов риска, действующих в среде заключенных, отбывающих срок наказания на территории области, способствующих прогрессированию ВИЧ до летального исхода с учетом их неравноценного значения среди заключенных и гражданского населения.Объект исследования. Определены 365 умерших ВИЧ-инфицированных, из них: исследуемая группа — 222 заключенных, умерших ВИЧ-инфицированных на базе Областной больницы ФСИН города Тюмени за период 2008—2018 гг.; контрольная группа — 143 гражданских (законопослушных) умерших ВИЧ-инфицированных пациентов на базе Областной инфекционной больницы за период 2011—2018 гг.Цель: выявление и оценка факторов риска, определяющих развитие эпидемического процесса ВИЧ-инфекции в зоне высокой концентрации группы риска.Методы исследования. В работе использованы методы эпидемиологического исследования, методы математического моделирования и прогнозирования, метод логистической регрессии пошагового включения с проведением. ROC-анализа.Результаты. Для оценки эпидемиологической ситуации в отношении пораженности ВИЧ-инфекцией в местах лишения свободы изучена многолетняя и внутригодовая динамика развития эпидемического процесса с оценкой приоритетных факторов риска, тенденций, прогнозирования развития эпидемического процесса ВИЧ-инфекции в пенитенциарной системе с установлением социальной значимости и риска для гражданского населения за многолетний период

Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption

Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression

Major mood disorders have been linked to abnormalities in circadian rhythms, leading to disturbances in sleep, mood, temperature, and hormonal levels. We provide evidence that ketamine, a drug with rapid antidepressant effects, influences the function of the circadian molecular machinery. Ketamine modulates CLOCK:BMAL1-mediated transcriptional activation when these regulators are ectopically expressed in NG108-15 neuronal cells. Inhibition occurs in a dose-dependent manner and is attenuated after treatment with the GSK3β antagonist SB21673. We analyzed the effect of ketamine on circadian gene expression and observed a dose-dependent reduction in the amplitude of circadian transcription of the Bmal1, Per2, and Cry1 genes. Finally, chromatin-immunoprecipitation analyses revealed that ketamine altered the recruitment of the CLOCK:BMAL1 complex on circadian promoters in a time-dependent manner. Our results reveal a yet unsuspected molecular mode of action of ketamine and thereby may suggest possible pharmacological antidepressant strategies

Systematic assessment of long-read RNA-seq methods for transcript identification and quantification

The Long-read RNA-Seq Genome Annotation Assessment Project (LRGASP) Consortium was formed to evaluate the effectiveness of long-read approaches for transcriptome analysis. The consortium generated over 427 million long-read sequences from cDNA and direct RNA datasets, encompassing human, mouse, and manatee species, using different protocols and sequencing platforms. These data were utilized by developers to address challenges in transcript isoform detection and quantification, as well as de novo transcript isoform identification. The study revealed that libraries with longer, more accurate sequences produce more accurate transcripts than those with increased read depth, whereas greater read depth improved quantification accuracy. In well-annotated genomes, tools based on reference sequences demonstrated the best performance. When aiming to detect rare and novel transcripts or when using reference-free approaches, incorporating additional orthogonal data and replicate samples are advised. This collaborative study offers a benchmark for current practices and provides direction for future method development in transcriptome analysis

Effects of circadian disruption on physiology and pathology: from bench to clinic (and back)

Nested within the hypothalamus, the suprachiasmatic nuclei (SCN) represent a central biological clock that regulates daily and circadian (i.e., close to 24 h) rhythms in mammals. Besides the SCN, a number of peripheral oscillators throughout the body control local rhythms and are usually kept in pace by the central clock. In order to represent an adaptive value, circadian rhythms must be entrained by environmental signals or zeitgebers, the main one being the daily light?dark (LD) cycle. The SCN adopt a stable phase relationship with the LD cycle that, when challenged, results in abrupt or chronic changes in overt rhythms and, in turn, in physiological, behavioral, and metabolic variables. Changes in entrainment, both acute and chronic, may have severe consequences in human performance and pathological outcome. Indeed, animal models of desynchronization have become a useful tool to understand such changes and to evaluate potential treatments in human subjects. Here we review a number of alterations in circadian entrainment, including jet lag, social jet lag (i.e., desynchronization between body rhythms and normal time schedules), shift work, and exposure to nocturnal light, both in human subjects and in laboratory animals. Finally, we focus on the health consequences related to circadian/entrainment disorders and propose a number of approaches for the management of circadian desynchronization.Fil: Chiesa, Juan José. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Casiraghi, Leandro Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Идентификация нового сайта метилирования в промоторном районе гена Sept9 для диагностики гепатоцеллюлярной карциномы

Background. Over 600,000 people die from hepatocellular carcinoma (HCC) each year worldwide. The disease is often detected at advanced stages and in many cases is not curable. Early diagnostic and monitoring of HCC recurrences remains a substantial problem in clinical oncology. That determines the need for a search for highly sensitive and specific biomarkers for the non-invasive of HCC diagnostics. The objective of the study. Identification of the hypermethylated locus in the promoter region of the septin 9 (Sept9) gene based on the annotated methylomes from the public databases. Experimental validation of methylation on a pilot panel of paired clinical samples of patients with HCC, as well as tissue samples from patients with benign liver tumors and lymphocytes from healthy donors. Materials and methods. To analyze the methyl data, samples of HCC from TCGA, hepatocellular adenoma from GEO (Gene Expression Omnibus) depository, peripheral blood cells and tissues of healthy donors from Methbank were used. Experimental validation of methylation levels of the identified site was carried out on a pilot panel of clinical samples by bisulphite pyrosequencing using PyroMark Q24.Results. Based on the analysis of methylome data, we selected cg20275528 site, which is characterized by high level of methylation in HCC tissues and minimal levels of methylation in non-tumor liver tissue, hepatocellular adenoma and peripheral blood of healthy donors. Experimental testing on a pilot panel of clinical specimens showed that the level of marker site methylation in HCC (42 % median) is significantly higher than in non-tumor liver tissues (3 % median) and benign neoplasms (1.5 % median) and exceeds the threshold value in HCC compared to paired samples of adjacent non-tumor liver tissue in 20 out of 30 studied cases (66.6 %). The general possibility for cg20275528 methylation detection in circulating DNA of plasma in HCC patients was shown.Conclusion. The obtained results indicate that the approach to the detection and experimental verification of diagnostically significant markers developed and tested in this study can be used to identify new differentially methylated sites and to establish new approaches for non-invasive HCC diagnosis.Введение. Ежегодно во всем мире от гепатоцеллюлярной карциномы (ГЦК) умирают более 600 тыс. человек. Заболевание часто выявляется на поздних стадиях и во многих случаях является некурабельным. Ранняя диагностика и мониторинг развития рецидивов ГЦК продолжают оставаться существенной проблемой клинической онкологии. Это определяет актуальность поиска высокочувствительных и специфичных биомаркеров для неинвазивной диагностики ГЦК. Цель исследования – идентификация гиперметилированного при ГЦК локуса в промоторном районе гена септин 9 (Sept9) на основании анализа общедоступных данных метиломных исследований; экспериментальная валидация метилирования на пилотной панели парных клинических образцов пациентов с ГЦК, а также образцов ткани пациентов с доброкачественными опухолями печени и лимфоцитов здоровых доноров.Материалы и методы. Для анализа метиломных данных были использованы выборки ГЦК TCGA, гепатоцеллюлярной аденомы из депозитария GEO (Gene Expression Omnibus), а также клеток периферической крови и тканей здоровых доноров Methbank. Экспериментальную валидацию уровней метилирования идентифицированного сайта проводили на пилотной выборке клинических образцов с использованием метода бисульфитного пиросеквенирования на приборе PyroMark Q24.Результаты. На основании анализа метиломных данных нами был выбран сайт cg20275528, который характеризуется высоким уровнем метилирования в тканях ГЦК и минимальными уровнями метилирования в клетках неопухолевой ткани печени, гепатоцеллюлярной аденомы и периферической крови здоровых доноров. Экспериментальная проверка на пилотной выборке клинических образцов показала, что уровень метилирования маркерного сайта в ГЦК (медиана 42 %) значительно выше, чем в неопухолевых тканях печени (медиана 3 %) и доброкачественных новообразованиях (медиана 1,5 %) и превышает пороговое значение в ГЦК по сравнению с парными образцами прилежащей неопухолевой ткани печени в 20 (66,6 %) из 30 исследованных случаев. Показана принципиальная возможность детекции метилирования cg20275528 в циркулирующей ДНК плазмы больных ГЦК.Заключение. Полученные результаты позволяют предположить, что разработанный и апробированный в этой работе подход к поиску и экспериментальной верификации диагностически значимых маркеров может быть использован для выявления новых дифференциально метилированных сайтов и разработки новых подходов к неинвазивной диагностике ГЦК

Litter decomposition in the post-fire larch forests of the Tukuringra Range (Upper Priamurie)

Boreal forests are one of the main carbon (С) pools on the planet. Decomposition of the litter is a main mechanism of C accumulation in soil. This process is often influenced by fires. Thus, we need to enhance our understanding about decomposition of the litter in post-fire forests to better understand the mechanism of C accumulation in boreal forests. Here, we studied initial stages of decomposition of litter in the post-fire forest (12 years after fires) and in the background larch forest located in the Tukuringra mountain range in the northern part of the Amur oblast. We present the results of a field experiment on the decomposition of the main typical fractions of larch forest. We used the litter bags method for studying rate of decomposition litter (leaves, grass, branches and needles). After 150 days mass loss of litter was 36.7 % of initial mass in the post-fire forest and 39.9 % in the background forest. Mass loss was most rapid in the first 75 days of the experiment in the both cases. In both plots the rate of decomposition of litter was decreased in order: grass – leaves – needles – branches. In both the post-fire and background forests, rate of litter decomposition is a function of moisture. Soil acidity was higher in post-fire forest than background forest (5.3 and 4.8, respectively, p < 0.01). However, this soil property does not influence early stages of litter decomposition in either case

Біофармацевтичні дослідження препарату Валавір 0,5 г, таблетки, вкриті оболонкою

The biopharmaceutical studies of Valavir film-coated tablets, 0.5 g, with valaciclovir hydrochloride have been substantiated in the article. The biopharmaceutical studies have been conducted in vitro; the dissolution profiles of Valavir film-coated tablets, 0.5 g, and the reference drug Valtrex (film-coated tablets, 500 mg, manufactured by GlaxoSmithKline Pharmaceuticals S.A., Poland) have been compared by the method for Dissolution Kinetics. The results of the experimental study in vivo, namely the value of Cmax, AUC0-t and other values confirm that Valavir film-coated tablets, 0.5 g, manufactured by Farmak JSC is bioequivalent to the reference drug Valtrex film-coated tablets, 500 mg, (GlaxoSmithKline Pharmaceuticals S.A., Poland).В статье обоснованы и отражены биофармацевтические исследования препарата Валавир с Валацикловира гидрохлоридом 0,5 г, таблетки, покрытые оболочкой. Проведены биофармацевтические исследования in vitro – сравнение профилей растворения таблеток Валавир 0,5, покрытых оболочкой, и референтного препарата Вальтрекс (таблетки 500 мг, покрытые оболочкой, «ГлаксоСмітКляйн Ф. С.А», Польша) по методике «Кинетика растворения». Результаты экспериментального исследования in vivo, а именно значение Сmax, AUC0-t и др., подтверждают, что препарат Валавир 0,5 г, таблетки, покрытые оболочкой, производства ПАО «Фармак» является биоэквивалентным референтному препарату Вальтрекс 500 мг, таблетки, покрытые оболочкой («ГлаксоСмітКляйн Ф. С.А», Польша).Обосновані та відображені біофармацевтичні дослідження препарату Валавір з Валацикловіру гідрохлоридом 0,5 г, таблетки, вкриті оболонкою. Проведені біофармацевтичні дослідження in vitro – порівняння профілів розчинення таблеток Валавіру 0,5, вкритих оболонкою, та референтного препарату Вальтрекс (таблетки 500 мг, вкриті оболонкою, «ГлаксоСмітКляйн Ф. С.А.», Польща) методикою «Кінетика розчинення». Результати експериментального дослідження in vivo, а саме значення Сmax, AUC0-t та ін. підтверджують, що препарат Валавір 0,5 г, таблетки, вкриті оболонкою, виробництва ПАТ «Фармак» є біоеквівалентним референтному препарату Вальтрекс 500 мг, таблетки, вкриті оболонкою («ГлаксоСмітКляйн Ф. С.А.», Польща)

HIV in the Penitentiary System of the Region with High Level of Prevalence of HIV-infection over a Period of Years (on the Example of Tyumen Region)

Relevance.  HIV infection has a negative impact on the demographic and economic situation. Despite the slowdown in prevalence, incidence and prevalence rates remain. Aim. Analysis of the development of the HIV epidemic process in the risk group of prisoners ofthe Tyumen region over a period of many years. Materials and methods.  The work used statistical data from the Center for the Fight against AIDS of the Tyumen Oblast State Budgetary Health Institution, the Office of the Federal Service for Supervision of Human Welfare in the Tyumen Region. The work uses analytical, epidemiological methods, research methods, statistical evaluation methods, average errors, average errors, estimated significance, differences between comparison factors. Results. In the region, HIV-infection affects more than 1% of the population. The group of prisoners occupies a leading position Prisoners in prisons are at increased risk of infection  in the structure of HIV-infected  region with an average multiyear share of 16.3%. The maximum rate of increase in HIV among prisoners was + 44.0%, the minimum – -27.0%. The average long-term  share of nonresident prisoners was 40.6 ± 0.65%, and among those registered in the region – 59.4 ± 0.65%. Places of deprivation of liberty must be considered as one of the main places with a high degree of probability of contracting HIV due to the contact of a healthy population with HIV infected, like in no other location. Conclusions. In 2001, the share of prisoners of all identified HIV – positive in the region amounted to 30.3%. The nature of the generalized course of HIV infection has acquired in prisons since 2005. The intensity of the HIV epidemic process in the region is supported, among other things, by the continuity of the formed connection between the special contingent and the law-abiding population, which requires targeted attention from the sanitary and preventive services