Wheeleresbensen3060

As cells enter mitosis, the genome is restructured to facilitate chromosome segregation, accompanied by dramatic changes in gene expression. However, the mechanisms that underlie mitotic transcriptional regulation are unclear. In contrast to transcribed genes, centromere regions retain transcriptionally active RNA polymerase II (Pol II) in mitosis. Here, we demonstrate that chromatin-bound cohesin is necessary to retain elongating Pol II at centromeres. We find that WAPL-mediated removal of cohesin from chromosome arms during prophase is required for the dissociation of Pol II and nascent transcripts, and failure of this process dramatically alters mitotic gene expression. Removal of cohesin/Pol II from chromosome arms in prophase is important for accurate chromosome segregation and normal activation of gene expression in G1. We propose that prophase cohesin removal is a key step in reprogramming gene expression as cells transition from G2 through mitosis to G1. The functional relevance and mechanistic basis of the effects of the neurotransmitter dopamine (DA) on inflammation remain unclear. Here we reveal that DA inhibited TLR2-induced NF-κB activation and inflammation via the DRD5 receptor in macrophages. We found that the DRD5 receptor, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2 to form a multi-protein complex also containing downstream signaling proteins, such as TAK1, IKKs, and PP2A, that impairs TRAF6-mediated activation of NF-κB and expression of pro-inflammatory genes. Furthermore, the DA-DRD5-ARRB2-PP2A signaling axis can prevent S. aureus-induced inflammation and protect mice against S. aureus-induced sepsis and meningitis after DA treatment. Collectively, these findings provide the first demonstration of DA-DRD5 signaling acting to control inflammation and a detailed delineation of the underlying mechanism and identify the DRD5-ARRB2-PP2A axis as a potential target for future therapy of inflammation-associated diseases such as meningitis and sepsis. Crown All rights reserved.BACKGROUND WHO recommends the use of psychological interventions as first-line treatment for depression in low-income and middle-income countries. However, evaluations of the effectiveness and cost-effectiveness of such interventions among people with HIV are scarce. Our aim was to establish the effectiveness of group support psychotherapy (GSP) delivered by lay health workers for depression treatment among people living with HIV in a rural area of Uganda on a large scale. METHODS In this cluster-randomised trial, we included 30 health centres offering HIV care. These were randomly assigned to deliver either GSP or group HIV education (GHE). Randomisation, in a ratio of 11, was achieved by health centre managers separately picking a paper containing the intervention allocation from a basket. Participants were people living with HIV, aged 19 years and older, with mild to moderate major depression assessed with the Mini International Neuropsychiatric Interview depression module, taking antiretroviral therapy, auals had 63 serious adverse events, which included 25 suicide attempts and 22 hospital admissions for medical complications. The outcomes of these serious adverse events included 16 deaths, 4 of which were completed suicides (GSP=2; GHE=2), and 12 of which were HIV-related medical complications (GSP=8; GHE=4). Cost-effectiveness estimates showed an incremental cost-effectiveness ratio of US$13·0 per disability-adjusted life-year averted, which can be considered very cost-effective in Uganda. INTERPRETATION Integration of cost-effective psychological treatments such as group support psychotherapy into existing HIV interventions might improve the mental health of people living with HIV. FUNDING MQ Transforming Mental Health and Grand Challenges Canada. BACKGROUND Four methods have previously been used to track aid for reproductive, maternal, newborn, and child health (RMNCH). At a meeting of donors and stakeholders in May, 2018, a single, agreed method was requested to produce accurate, predictable, transparent, and up-to-date estimates that could be used for analyses from both donor and recipient perspectives. Muskoka2 was developed to meet these needs. We describe Muskoka2 and present estimates of levels and trends in aid for RMNCH in 2002-17, with a focus on the latest estimates for 2017. METHODS Muskoka2 is an automated algorithm that generates disaggregated estimates of aid for reproductive health, maternal and newborn health, and child health at the global, donor, and recipient-country levels. find more We applied Muskoka2 to the Organisation for Economic Co-operation and Development's Creditor Reporting System (CRS) aid activities database to generate estimates of RMNCH disbursements in 2002-17. The percentage of disbursements that benefit RMNCH was determined & Child Health. BACKGROUND Schizophrenia has been associated with pregnancy and birth complications and fetal exposure to inflammation is thought to be a common underlying mechanism. However, whether the risk is specific to particular phases of pregnancy is unclear. The aim of this study was to characterise and compare longitudinal patterns of maternal serum concentrations of cytokines across pregnancy between offspring who were later ascertained to have a psychotic disorder, non-psychotic siblings of these cases, and unrelated, non-psychotic individuals who served as controls. METHODS The National Collaborative Perinatal Project was a large-scale prospective longitudinal study that assessed the effects of perinatal factors on infant and child development. At sites across the USA, over 50 000 pregnant women were enrolled during prenatal clinical visits between 1959 and 1965. The present study draws from the Philadelphia cohort, which includes 9236 surviving offspring of 6753 pregnant women. Psychotic disorder diagnoses in adn much earlier in prenatal development than previously documented in humans and provide insight into a potential developmental pathway to the disorder. FUNDING National Institute of Mental Health (P50) Silvio O Conte Center at Johns Hopkins, Stanley Foundation, March of Dimes, Yale University, National Science Foundation, and National Institute of Child Health and Human Development/Division of Intramural Population Health Research. An in-depth annotation of the newly discovered coronavirus (2019-nCoV) genome has revealed differences between 2019-nCoV and severe acute respiratory syndrome (SARS) or SARS-like coronaviruses. A systematic comparison identified 380 amino acid substitutions between these coronaviruses, which may have caused functional and pathogenic divergence of 2019-nCoV. Intra-arterial administration of an adenovirus serotype 5 (Ad5) vector in a gene therapy trial caused lethal, systemic inflammation in subject 019 with ornithine transcarbamylase deficiency. This unanticipated inflammatory response was absent in another subject receiving the same vector dose and in 16 subjects receiving lower vector doses. We hypothesized that an immune memory to a previous natural adenovirus infection enhanced the immune response to high-dose systemic Ad5 vector, causing the exaggerated immune response in subject 019. To investigate this, we found that rabbit polyclonal sera to Ad5 and pooled human immunoglobulin (Ig) inhibited Ad5 vector transduction of non-immune cells in vitro, but enhanced transduction and activation of human dendritic cells (DCs). Sera from approximately 7% of normal human subjects and 50% of patients treated topically with Ad5 vectors enhanced Ad5 transduction and activation of DCs, apparently from formation of Ig-Ad5 immune complexes and binding to DCs through FcγR. Subject 019's blood substantially increased Ad5-vector activation of human DC primary cultures at levels exceeding those from normal subjects. Although this study is based on one event in a single subject, the results implicate a pre-existing humoral immune response to Ad5 in the lethal systemic inflammatory response that occurred in subject 019. BACKGROUND Capivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer. METHODS In this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (11) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycl assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related. INTERPRETATION Progression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials. FUNDING AstraZeneca and Cancer Research UK. Central nervous system (CNS) maintains a high level of metabolism, which leads to the generation of large amounts of free radicals, and it is also one of the most vulnerable organs to oxidative stress. Emerging evidences have shown that, as the key homeostatic cells in CNS, astrocytes are deeply involved in multiple aspects of CNS function including oxidative stress regulation. Besides, the redox level in CNS can in turn affect astrocytes in morphology and function. The complex and multiple roles of astrocytes indicate that their correct performance is crucial for the normal functioning of the CNS, and its dysfunction may result in the occurrence and progression of various neurological disorders. To date, the influence of astrocytes in CNS oxidative stress is rarely reviewed. Therefore, in this review we sum up the roles of astrocytes in redox regulation and the corresponding mechanisms under both normal and different pathological conditions. © 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.Surviving changing climate conditions is particularly difficult for organisms such as insects that depend on environmental temperature to regulate their physiological functions. Insects are extremely threatened by global warming, since many do not have enough physiological tolerance even to survive continuous exposure to the current maximum temperatures experienced in their habitats. Here, we review literature on the physiological mechanisms that regulate responses to heat and provide heat tolerance in insects (i) neuronal mechanisms to detect and respond to heat; (ii) metabolic responses to heat; (iii) thermoregulation; (iv) stress responses to tolerate heat; and (v) hormones that coordinate developmental and behavioural responses at warm temperatures. Our review shows that, apart from the stress response mediated by heat shock proteins, the physiological mechanisms of heat tolerance in insects remain poorly studied. Based on life-history theory, we discuss the costs of heat tolerance and the potential evolutionary mechanisms driving insect adaptations to high temperatures.