Clinical case: glycine encephalopathy

The aim of the study – description of a clinical case of a child diagnosed with glycine encephalopathy.Цель исследования – описать клинический случай ребенка с диагнозом глициновая энцефалопатия

A Loss of Function Screen of Identified Genome-Wide Association Study Loci Reveals New Genes Controlling Hematopoiesis

The formation of mature cells by blood stem cells is very well understood at the cellular level and we know many of the key transcription factors that control fate decisions. However, many upstream signalling and downstream effector processes are only partially understood. Genome wide association studies (GWAS) have been particularly useful in providing new directions to dissect these pathways. A GWAS meta-analysis identified 68 genetic loci controlling platelet size and number. Only a quarter of those genes, however, are known regulators of hematopoiesis. To determine function of the remaining genes we performed a medium-throughput genetic screen in zebrafish using antisense morpholino oligonucleotides (MOs) to knock down protein expression, followed by histological analysis of selected genes using a wide panel of different hematopoietic markers. The information generated by the initial knockdown was used to profile phenotypes and to position candidate genes hierarchically in hematopoiesis. Further analysis of brd3a revealed its essential role in differentiation but not maintenance and survival of thrombocytes. Using the from-GWAS-to-function strategy we have not only identified a series of genes that represent novel regulators of thrombopoiesis and hematopoiesis, but this work also represents, to our knowledge, the first example of a functional genetic screening strategy that is a critical step toward obtaining biologically relevant functional data from GWA study for blood cell traits

Клинико-эпидемиологическая характеристика гепатита А у детей в период подъема заболеваемости

Objective. Study of clinical and epidemiological characteristicsof hepatitis A in children.Materials and methods. The paper presents the epidemiological situation of this issue in the Krasnoyarsk Territory, as well as the results of clinical observations of 104 children with hepatitis A in age from 1 to 14 years.Results. It was found that at the present time is marked deterioration of the epidemiological situation of hepatitis A with involvement in the epidemiological process of young children. In this severe hepatitis A, often occurring with the phenomena of cholestasis, significantly more frequent among children aged 7–14 years. Despite the apparent beneficial for the infection at discharge on the part of school-age children has been a recovery with residual effects that require continued monitoring and corrective therapy appointment.Цель. Изучение клинико-эпидемиологической характеристики гепатита А (ГА) у детей.Материалы и методы. Представлена эпидемиологическая ситуация по данной проблеме в Красноярском крае, а также результаты клинического наблюдения за 104 детьми с ГА в возрасте от 1 до 14 лет.Результаты. Установлено, что в настоящее время отмечено ухудшение эпидемиологической ситуации по ГА с вовлечением в эпидемиологический процесс детей раннего возраста. При этом тяжелые формы ГА, зачастую протекающие с явлениями холестаза, достоверно чаще встречаются у детей 7–14 лет. Несмотря на кажущееся благоприятное течение данной инфекции, при выписке у части детей школьного возраста имело место выздоровление с остаточными явлениями, что требовало продолжения наблюдения и назначения корригирующей терапии

Dynamic relocalization of NHERF1 mediates chemotactic migration of ovarian cancer cells toward lysophosphatidic acid stimulation

NHERF1/EBP50 (Na+/H+ exchanger regulating factor 1; Ezrin-binding phosphoprotein of 50 kDa) organizes stable protein complexes beneath the apical membrane of polar epithelial cells. By contrast, in cancer cells without any fixed polarity, NHERF1 often localizes in the cytoplasm. The regulation of cytoplasmic NHERF1 and its role in cancer progression remain unclear. In this study, we found that, upon lysophosphatidic acid (LPA) stimulation, cytoplasmic NHERF1 rapidly translocated to the plasma membrane, and subsequently to cortical protrusion structures, of ovarian cancer cells. This movement depended on direct binding of NHERF1 to C-terminally phosphorylated ERM proteins (cpERMs). Moreover, NHERF1 depletion downregulated cpERMs and further impaired cpERM-dependent remodeling of the cell cortex, suggesting reciprocal regulation between these proteins. The LPA-induced protein complex was highly enriched in migratory pseudopodia, whose formation was impaired by overexpression of NHERF1 truncation mutants. Consistent with this, NHERF1 depletion in various types of cancer cells abolished chemotactic cell migration toward a LPA gradient. Taken together, our findings suggest that the high dynamics of cytosolic NHERF1 provide cancer cells with a means of controlling chemotactic migration. This capacity is likely to be essential for ovarian cancer progression in tumor microenvironments containing LPA

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

NEW METHOD OF PHARMACOLOGICAL CORRECTION OF POST-HYPOXIC CARDIOPATHY IN NEWBORNS

Early diagnosis and timely correction of pathological changes in the newborns’ heart can be a major factor in reducing the frequency and severity of cardiovascular pathology in older children and adults. Given the important role of secondary carnitine deficiency in developing disadaptant cardiopathies in newborns (especially premature and immature), the study of the efficacy of exogenous levocarnitine (L-carnitine) in neonatal cardiology offers the greatest promise. The study was aimed at evaluating the efficacy of L-carnitine solution in the post-hypoxic syndrome of cardiovascular deconditioning in newborns, including premature infants. After the treatment course, the newborns showed the effective reduction of signs of electrical instability and myocardial ischemia, restoration of heart rate and resetting of systolic and diastolic function of the heart, the size of the heart cavities, a decrease in the diameter and hemodynamic significance of functioning fetal communications, the restoration of the circadian heart rhythm profile, as well as a reduction in the duration of pauses in rhythm and arrhythmias. The study results showed the efficacy and safety of the L-carnitine solution in correcting cardiac disorders in newborns with hypoxic myocardial damage

Clinical and epidemiological characteristics of hepatitis A in children during rise of morbidity

Objective. Study of clinical and epidemiological characteristicsof hepatitis A in children.Materials and methods. The paper presents the epidemiological situation of this issue in the Krasnoyarsk Territory, as well as the results of clinical observations of 104 children with hepatitis A in age from 1 to 14 years.Results. It was found that at the present time is marked deterioration of the epidemiological situation of hepatitis A with involvement in the epidemiological process of young children. In this severe hepatitis A, often occurring with the phenomena of cholestasis, significantly more frequent among children aged 7–14 years. Despite the apparent beneficial for the infection at discharge on the part of school-age children has been a recovery with residual effects that require continued monitoring and corrective therapy appointment

Antigen presentation by lung epithelial cells directs CD4(+) T-RM cell function and regulates barrier immunity

The maintenance of T resident memory (T-RM) cells within pulmonary tissues is incompletely understood. Here the authors show that antigen presentation by lung epithelial cells maintains function and phenotype of pulmonary T-RM cells within specific locational niches. Barrier tissues are populated by functionally plastic CD4(+) resident memory T (T-RM) cells. Whether the barrier epithelium regulates CD4(+) T-RM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)(MHChigh)-M-low epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4(+) T-RM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4(+) T-RM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4(+) T-RM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4(+) T-RM cell function and identify epithelial-CD4(+) T-RM cell immune interactions as core elements of barrier immunity