STRESS AND STRAIN STATE OF THE KAZAKH SHIELD FROM THE EARTHQUAKE FOCAL MECHANISMS DATA

The paper presents the results obtained during the study of seismicity of the Kazakh shield based on the data from seismic stations of the Institute of Geophysical Researches of Kazakhstan which are a part of the international monitoring systems. Emphasis has been placed on seismic activation in 2016–2018 in the middle part of the Central Kazakhstan arch, previously considered aseismic. The earthquake focal mechanisms determined for 40 seismic events recorded in the investigated area are based on the displacement directions of the first arriving P waves.On the basis of the analysis of the earthquake focal mechanism data set, an assessment has been made of the present-day stress-strain state of the Earth’s crust of the low-seismicity Kazakh shield. It is shown that a system of stresses in the investigated area is characterized by conditions for near-horizontal compression whose direction is consistent with the direction of movement of the Alpine geomorphostructures. It has been found that the earthquake sources in the investigated area are dominated by reverse faults and reverse-slip faults which correspond structurally to the northeast-striking and submeridional tectonic faults, thus testifying to present-day seismic activation of the northeastern thrusts.This study allowed for concluding that the seismic events considered are human-induced, i.e. technogenic-tectonic, earthquakes. A long-term technogenic impact reducing the strength of rocks in fault zones can be a cause of critical stress drop in earthquake sources located in the Kazakh shield. The data on the character of motions and stresses in the earthquake sources influencing on shaking intensity will be used in combination with other methods for the assessment of natural and technogenic hazards related to geodynamic processes

НАПРЯЖЕННО-ДЕФОРМИРОВАННОЕ СОСТОЯНИЕ КАЗАХСКОГО ЩИТА ПО ДАННЫМ МЕХАНИЗМОВ ОЧАГОВ ЗЕМЛЕТРЯСЕНИЙ

The paper presents the results obtained during the study of seismicity of the Kazakh shield based on the data from seismic stations of the Institute of Geophysical Researches of Kazakhstan which are a part of the international monitoring systems. Emphasis has been placed on seismic activation in 2016–2018 in the middle part of the Central Kazakhstan arch, previously considered aseismic. The earthquake focal mechanisms determined for 40 seismic events recorded in the investigated area are based on the displacement directions of the first arriving P waves.On the basis of the analysis of the earthquake focal mechanism data set, an assessment has been made of the present-day stress-strain state of the Earth’s crust of the low-seismicity Kazakh shield. It is shown that a system of stresses in the investigated area is characterized by conditions for near-horizontal compression whose direction is consistent with the direction of movement of the Alpine geomorphostructures. It has been found that the earthquake sources in the investigated area are dominated by reverse faults and reverse-slip faults which correspond structurally to the northeast-striking and submeridional tectonic faults, thus testifying to present-day seismic activation of the northeastern thrusts.This study allowed for concluding that the seismic events considered are human-induced, i.e. technogenic-tectonic, earthquakes. A long-term technogenic impact reducing the strength of rocks in fault zones can be a cause of critical stress drop in earthquake sources located in the Kazakh shield. The data on the character of motions and stresses in the earthquake sources influencing on shaking intensity will be used in combination with other methods for the assessment of natural and technogenic hazards related to geodynamic processes.Приводятся результаты изучения сейсмичности Казахского щита по данным сейсмических станций Института геофизических исследований Республики Казахстан, входящих в международные системы мониторинга. Отмечена активизация сейсмичности в 2016–2018 гг. в центральной части Центрально-Казахстанского свода, считавшейся ранее асейсмичной. Для 40 сейсмических событий, зарегистрированных в рассматриваемом районе, построены механизмы очагов по направлениям смещений в первых вступлениях Р-волн.На основе анализа совокупности всех полученных данных о механизмах очагов землетрясений выполнена оценка современного напряженно-деформированного состояния земной коры слабосейсмичного Казахского щита. Показано, что система напряжений на рассматриваемой территории характеризуется условиями близгоризонтального сжатия в направлении, согласующемся с направлением движения альпийских геоморфоструктур. Установлено превалирование в очагах землетрясений исследуемого региона взбросо- и взбросо-сдвиговых подвижек по плоскостям разрывов, которые находят структурное соответствие с тектоническими разломами северо-восточного и субмеридионального простирания, свидетельствующее о сейсмической активизации северо-восточных надвигов в настоящее время.На основе проведенного исследования сделан вывод, что рассматриваемые сейсмические события являются землетрясениями, спровоцированными техногенной деятельностью человека, т.е. техногенно-тектоническими. В результате длительного техногенного воздействия, вызывающего снижение прочности пород разломных зон, в структурах Казахского щита происходит формирование очагов землетрясений с более низким уровнем критических напряжений. Сведения о характере подвижек и напряжений в очагах землетрясений, влияющих на интенсивность сотрясений, в комплексе с другими методами будут использоваться для оценки природных и техногенных опасностей, связанных с геодинамическими процессами

LMTK3 represses tumor suppressor-like genes through chromatin remodeling in breast cancer

LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is local-ized in different cellular compartments, but its nuclear function has not been investigated so far. We mapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are corre-lated with repressive chromatin markers. We further identified KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interac-tion is stabilized by PP1a, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In sum-mary, we propose a model where a scaffolding func-tion of nuclear LMTK3 promotes cancer progression through chromatin remodeling

Experience in managing patients with Churg-Strauss syndrome.

Our goal was to analyze the possibilities of impro­ving the diagnostics of CSS and to improve the effectiveness of treatment according to the existing literature and our own experience of long-term care for patients with eosinophilic granulomatosis with polyangiitis or Churg-Strauss syndrome (CSS). The medical histories of three female patients aged 26 to 46-years and a 20-year-old male patient were considered. The duration of the disease before the established diagnosis was 5-17 years. Anamnesis and medical documents analysis showed a typical CSS debut in the form of allergic rhinitis, nasal polyps, which were recurrent after polypectomy, and respiratory disorders, which were regarded as bronchitis or bronchial asthma – corresponding to the first phase, also called the prodromal or allergic stage of CSS. The prodromal period lasts up to 10 years or more and is characterized by various allergic manifestations, more often –  pollinosis or bronchial asthma, that is difficult to control. But CSS can be suspected because of low effectiveness of the therapy with inhaled steroids, lack of effect of antibiotics and eosinophilia more than 10% that occurs periodically. Even in the third stage of CSS in systemic manifestations of vasculitis and severe secondary lesions of organs and tissues with functional impairment, constant intake of maintenance doses of corticosteroids and cytostatics allows to achieve stabilization of the process in patients with CSS

The chromatin assembly factor complex 1 (CAF1) and 5-Azacytidine (5-AzaC) affect cell motility in Src-transformed human epithelial cells

Tumor invasion into surrounding stromal tissue is a hallmark of high grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness, and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor 5-azacytidine (5-AzaC) potently blocks the increased cell motility and invasiveness induced by Src activation. A proteomic screen for chromatin regulators acting downstream of activated Src identified the replication-dependent histone chaperone CAF1 as an important factor for Src-mediated increased cell motility and invasion. We show that Src causes a 5-AzaC-sensitive decrease in both mRNA and protein levels of the p150 (CHAF1A) and p60 (CHAF1B), subunits of CAF1. Depletion of CAF1 in untransformed epithelial cells using siRNA was sufficient to recapitulate the increased motility and invasive phenotypes characteristic of transformed cells without activation of Src. Maintaining high levels of CAF1 by exogenous expression suppressed the increased cell motility and invasiveness phenotypes when Src was activated. These data identify a critical role of CAF1 in the dysregulation of cell invasion and motility phenotypes seen in transformed cells and also highlight an important role for epigenetic remodeling through DNA methylation for Src-mediated induction of cancer phenotypes

KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state

Heterochromatin plays an essential role in the preservation of epigenetic information, the transcriptional repression of repeti- tive DNA elements and inactive genes, and the proper segregation of chromosomes during mitosis. Here we identify KDM2A, a JmjC-domain containing histone demethylase, as a heterochro- matin-associated and HP1-interacting protein that promotes HP1 localization to chromatin. We show that KDM2A is required to maintain the heterochromatic state, as determined using a candidate-based approach coupled to an in vivo epigenetic reporter system. Remarkably, a parallel and independent siRNA screen also detected a role for KDM2A in epigenetic silencing. Moreover, we demonstrate that KDM2A associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Dissecting the relationship between heterochromatin and centromeric RNA transcription is the basis of ongoing studies. We demonstrate that forced expression of these satellite RNA transcripts compromise the heterochromatic state and HP1 localization to chromatin. Finally, we show that KDM2A is required to sustain centromeric integ- rity and genomic stability, particularly during mitosis. Since the disruption of epigenetic control mechanisms contributes to cellular transformation, these results, together with the low levels of KDM2A found in prostate carcinomas, suggest a role for KDM2A in cancer development

Transcriptional provirus silencing as a crosstalk of de novo DNA methylation and epigenomic features at the integration site

The autonomous transcription of integrated retroviruses strongly depends on genetic and epigenetic effects of the chromatin at the site of integration. These effects are mostly suppressive and proviral activity can be finally silenced by mechanisms, such as DNA methylation and histone modifications. To address the role of the integration site at the whole-genome-scale, we performed clonal analysis of provirus silencing with an avian leucosis/sarcoma virus-based reporter vector and correlated the transcriptional silencing with the epigenomic landscape of respective integrations. We demonstrate efficient provirus silencing in human HCT116 cell line, which is strongly but not absolutely dependent on the de novo DNA methyltransferase activity, particularly of Dnmt3b. Proviruses integrated close to the transcription start sites of active genes into the regions enriched in H3K4 trimethylation display long-term stability of expression and are resistant to the transcriptional silencing after over-expression of Dnmt3a or Dnmt3b. In contrast, proviruses in the intergenic regions tend to spontaneous transcriptional silencing even in Dnmt3a−/− Dnmt3b−/− cells. The silencing of proviruses within genes is accompanied with DNA methylation of long terminal repeats, whereas silencing in intergenic regions is DNA methylation-independent. These findings indicate that the epigenomic features of integration sites are crucial for their permissivity to the proviral expression

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3-H4 histones and lamin-B receptor

Diverting a protein from its intracellular location is a unique property of intrabodies. To interfere with the intracellular traffic of heterochromatin protein 1β (HP1β) in living cells, we have generated a cytoplasmic targeted anti-HP1β intrabody, specifically directed against the C-terminal portion of the molecule. HP1β is a conserved component of mouse and human constitutive heterochromatin involved in diverse nuclear functions including gene silencing, DNA repair and nuclear membrane assembly. We found that the anti-HP1β intrabody sequesters HP1β into cytoplasmic aggregates, inhibiting its traffic to the nucleus. Lamin B receptor (LBR) and a subset of core histones (H3/H4) are also specifically co-sequestered in the cytoplasm of anti-HP1β intrabody-expressing cells. Methylated histone H3 at K9 (Me9H3), a marker of constitutive heterochromatin, is not affected by the anti-HP1β intrabody expression. Hyper-acetylating conditions completely dislodge H3 from HP1β:LBR containing aggregates. The expression of anti-HP1β scFv fragments induces apoptosis, associated with an alteration of nuclear morphology. Both these phenotypes are specifically rescued either by overexpression of recombinant full length HP1β or by HP1β mutant containing the chromoshadow domain, but not by recombinant LBR protein. The HP1β-chromodomain mutant, on the other hand, does not rescue the phenotypes, but does compete with LBR for binding to HP1β. These findings provide new insights into the mode of action of cytoplasmic-targeted intrabodies and the interaction between HP1β and its binding partners involved in peripheral heterochromatin organisation

Удаление минеральных и органических веществ из поверхностных вод с использованием нанофильтрационных мембран

Screening investigations of organic and mineral substances’ removal from the different surface water sources by nanofiltration membranes have been carried out. It has been found that degree of water purification from organic substances was high, regardless to their concentration and filtrate conversion. On the contrary, removal degree for dissolved mineral substances depended highly on nanofiltration operating conditions and the water source origin.Проведены скрининговые исследования по удалению минеральных и органических веществ из поверхностных источников при помощи нанофильтрационных (НФ) мембран. В качестве объектов исследования были выбраны образцы поверхностных вод: р. Западная Двина (г. Витебск), р. Полота (г. Полоцк) и р. Свислочь (г. п. Свислочь, ТЭЦ-5). Исследования показали, что использование НФ мембран позволяет достигнуть высокой степени очистки воды от органических загрязнений независимо от степени отбора фильтрата и концентрации органических веществ в исходной воде. Степень удаления растворенных минеральных веществ зависит от рабочих параметров процесса нанофильтрации и источника происхождения воды

Global histone modification fingerprinting in human cells using epigenetic reverse phase protein array

The balance between acetylation and deacetylation of histone proteins plays a critical role in the regulation of genomic functions. Aberrations in global levels of histone modifications are linked to carcinogenesis and are currently the focus of intense scrutiny and translational research investments to develop new therapies, which can modify complex disease pathophysiology through epigenetic control. However, despite significant progress in our understanding of the molecular mechanisms of epigenetic machinery in various genomic contexts and cell types, the links between epigenetic modifications and cellular phenotypes are far from being clear. For example, enzymes controlling histone modifications utilize key cellular metabolites associated with intra- and extracellular feedback loops, adding a further layer of complexity to this process. Meanwhile, it has become increasingly evident that new assay technologies which provide robust and precise measurement of global histone modifications are required, for at least two pressing reasons: firstly, many approved drugs are known to influence histone modifications and new cancer therapies are increasingly being developed towards targeting histone deacetylases (HDACs) and other epigenetic readers and writers. Therefore, robust assays for fingerprinting the global effects of such drugs on preclinical cell, organoid and in vivo models is required; and secondly, robust histone-fingerprinting assays applicable to patient samples may afford the development of next-generation diagnostic and prognostic tools. In our study, we have used a panel of monoclonal antibodies to determine the relative changes in the global abundance of post-translational modifications on histones purified from cancer cell lines treated with HDAC inhibitors using a novel technique, called epigenetic reverse phase protein array. We observed a robust increase in acetylation levels within 2–24 h after inhibition of HDACs in different cancer cell lines. Moreover, when these cells were treated with N-acetylated amino acids in addition to HDACs, we detected a further increase in histone acetylation, demonstrating that these molecules could be utilized as donors of the acetyl moiety for protein acetylation. Consequently, this study not only offers a novel assay for diagnostics and drug screening but also warrants further research of the novel class of inexpensive, non-toxic natural compounds that could potentiate the effects of HDAC inhibitors and is therefore of interest for cancer therapeutics