ВЛИЯНИЕ СЕВОФЛЮРАНА И АЦЕТИЛЦИСТЕИНА НА ИШЕМИЧЕСКИ-РЕПЕРФУЗИОННОЕ ПОВРЕЖДЕНИЕ ПЕЧЕНИ ДОНОРА СО СМЕРТЬЮ МОЗГА

Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury. Целью нашей работы явилась оценка влияния прекондиционирования ацетилцистеином и севофлюра- ном на степень ишемически-реперфузионного повреждения печени умерших доноров с признаками мар- гинальности. Методы и результаты. Дизайн исследования – проспективное, контролируемое, рандо- мизированное исследование. Исследование было проведено на 21 доноре с умершим головным мозгом и бьющимся сердцем. В основную группу исследования вошли 11 доноров, в контрольную группу 10. В основной группе определялись морфологические признаки ишемически-реперфузионного поврежде- ния после прекондиционирования ацетилцистеином и севофлюраном, в группе сравнения – без прекон- диционирования. Заключение. Применение фармакологического прекондиционирования севофлюраном и ацетилцистеином достоверно привело к уменьшению степени некроза и апоптоза гепатоцитов по срав- нению с группой сравнения, т. е. обладает протективным эффектом от ишемически-реперфузионного повреждения.

The population history of northeastern Siberia since the Pleistocene.

Northeastern Siberia has been inhabited by humans for more than 40,000 years but its deep population history remains poorly understood. Here we investigate the late Pleistocene population history of northeastern Siberia through analyses of 34 newly recovered ancient genomes that date to between 31,000 and 600 years ago. We document complex population dynamics during this period, including at least three major migration events: an initial peopling by a previously unknown Palaeolithic population of 'Ancient North Siberians' who are distantly related to early West Eurasian hunter-gatherers; the arrival of East Asian-related peoples, which gave rise to 'Ancient Palaeo-Siberians' who are closely related to contemporary communities from far-northeastern Siberia (such as the Koryaks), as well as Native Americans; and a Holocene migration of other East Asian-related peoples, who we name 'Neo-Siberians', and from whom many contemporary Siberians are descended. Each of these population expansions largely replaced the earlier inhabitants, and ultimately generated the mosaic genetic make-up of contemporary peoples who inhabit a vast area across northern Eurasia and the Americas

The Lsm1-7/Pat1 complex binds to stress-activated mRNAs and modulates the response to hyperosmotic shock

RNA-binding proteins (RBPs) establish the cellular fate of a transcript, but an understanding of these processes has been limited by a lack of identified specific interactions between RNA and protein molecules. Using MS2 RNA tagging, we have purified proteins associated with individual mRNA species induced by osmotic stress, STL1 and GPD1. We found members of the Lsm1-7/Pat1 RBP complex to preferentially bind these mRNAs, relative to the non-stress induced mRNAs, HYP2 and ASH1. To assess the functional importance, we mutated components of the Lsm1-7/Pat1 RBP complex and analyzed the impact on expression of osmostress gene products. We observed a defect in global translation inhibition under osmotic stress in pat1 and lsm1 mutants, which correlated with an abnormally high association of both non-stress and stress-induced mRNAs to translationally active polysomes. Additionally, for stress-induced proteins normally triggered only by moderate or high osmostress, in the mutants the protein levels rose high already at weak hyperosmosis. Analysis of ribosome passage on mRNAs through co-translational decay from the 5' end (5P-Seq) showed increased ribosome accumulation in lsm1 and pat1 mutants upstream of the start codon. This effect was particularly strong for mRNAs induced under osmostress. Thus, our results indicate that, in addition to its role in degradation, the Lsm1-7/Pat1 complex acts as a selective translational repressor, having stronger effect over the translation initiation of heavily expressed mRNAs. Binding of the Lsm1-7/Pat1p complex to osmostress-induced mRNAs mitigates their translation, suppressing it in conditions of weak or no stress, and avoiding a hyperresponse when triggered

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. / Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. / Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. / Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis

IMPACT OF SEVOFLURANE AND ACETYLCYSTEINE ON ISCHEMIA-REPERFUSION INJURY OF THE LIVER FROM BRAIN-DEAD DONOR

Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury

CENTRAL PONTINE MYELINOLYSIS AFTER ORTHOTOPIC LIVER TRANSPLANTATION (TWO CASE REPORTS)

Central pontine myelinolysis (CPM) is the rare, but extremely severe complication after orthotopic liver trans- plantation. The reason for CPM is currently not precisely defined. However, the rapid correction of hyponatremia is considered as the main etiological factor. In this paper we present two clinical cases of CPM in patients under- went orthotopic liver transplantation. We also discuss the pathophysiology, epidemiology, clinical presentation, treatment options and preventive measures of CPM