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Regarding the latter, prominence is laid upon inherited susceptibility genes and the genetic and epigenetic abnormalities that lead to the developmental and progression of the disease. Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.Many exposures considered in Mendelian randomization (MR) studies are polygenic in that they are influenced by thousands of genetic variants. By using many single-nucleotide polymorphisms (SNPs) as instrumental variables, more variation in the exposure is explained, increasing the precision of MR. Furthermore, methods can be designed that relax the assumptions of MR, especially concerning direct pleiotropic effects on the outcome. This article reviews the concepts and assumptions underlying the commonly used polygenic MR methods. Using a polygenic score as an instrument is equivalent to a weighted mean of individual SNP results, and the other fundamental averages, median and mode, may also be used to estimate causal effects. Outlier detection is useful for identifying pleiotropic SNPs to be excluded from analysis. Bayesian approaches are available to incorporate prior beliefs about pleiotropy. These methods each entail different assumptions, and together provide a set of sensitivity analyses to help triangulate evidence about causality. Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.The incidence of neonatal opioid withdrawal syndrome (NOWS) has increased substantially in the setting of the opioid epidemic, a major public health problem in the United States. At present, NOWS has commonly used assessment and treatment protocols, but new protocols have questioned old practices. However, because of limited access to opioid use disorder (OUD) treatment and socioeconomic factors, many pregnant (and postpartum) women with OUD do not receive treatment. The pathophysiology of NOWS is not completely understood, although limited research studies have been conducted in humans and animals to better understand its etiology. Moreover, there is evidence that epigenetic and genetic factors play a role in the development of NOWS, but further study is needed. Animal models have suggested that there are deleterious effects of in utero opioid exposure later in life. Clinical research has revealed the harmful long-term sequelae of NOWS, with respect to cognitive function and childhood development. Many psychiatric disorders begin during adolescence, so as infants born with NOWS approach adolescence, additional clinical and molecular studies are warranted to identify biologic and psychosocial risk factors and long-term effects of NOWS. Additionally, access to specialized OUD treatment for pregnant women must be more readily available in the United States, especially in rural areas. Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.The circadian clock is a complex transcriptional network that regulates gene expression in anticipation of the day-night cycle and controls agronomic traits in plants. However, in crops, how the internal clock and day-night cues affect the transcriptome remains poorly understood. We analyzed the diel and circadian leaf transcriptomes in the barley (Hordeum vulgare) cultivar Bowman and derived introgression lines harboring mutations in EARLY FLOWERING 3 (ELF3), LUX ARRHYTHMO 1 (LUX1), and EARLY MATURITY 7 (EAM7). The elf3 and lux1 mutants exhibited abolished circadian transcriptome oscillations under constant conditions, whereas eam7 maintained oscillations of ≈30% of the circadian transcriptome. However, day-night cues fully restored transcript oscillations in all three mutants and thus compensated for a disrupted oscillator in the arrhythmic barley clock mutants elf3 and lux1. Nevertheless, elf3, but not lux1, affected the phase of the diel oscillating transcriptome and thus the integration of external cues into the clock. Using dynamical modeling, we predicted a structure of the barley circadian oscillator and interactions of its individual components with day-night cues. Our findings provide a valuable resource for exploring the function and output targets of the circadian clock and for further investigations into the diel and circadian control of the barley transcriptome. copyright, serif 2020 American Society of Plant Biologists. All rights reserved.The Antarctic green alga Chlamydomonas sp. UWO 241 (UWO 241) is adapted to permanent low temperatures, hypersalinity, and extreme shade. one of the most striking phenotypes of UWO 241 is an altered photosystem I (PSI) organization and constitutive PSI cyclic electron flow (CEF). To date, little attention has been paid to CEF during long-term stress acclimation, and the consequences of sustained CEF in UWO 241 are not known. In this study, we combined photobiology, proteomics, and metabolomics to understand the underlying role of sustained CEF in high salinity stress acclimation. High salt-grown UWO 241 exhibited increased thylakoid proton motive flux and an increased capacity for non-photochemical quenching. Under high salt, a significant proportion of the upregulated enzymes were associated with the Calvin Benson Bassham Cycle, carbon storage metabolism, and protein translation. Two key enzymes of the Shikimate pathway, DAHP synthase and chorismate synthase, were also upregulated, as well as indole-3-glycerol phosphate synthase, an enzyme involved in the biosynthesis of L-tryptophan and indole acetic acid. In addition, several compatible solutes (glycerol, proline, and sucrose) accumulated to high levels in high salt-grown UWO 241 cultures. We suggest that UWO 241 maintains constitutively high CEF through the associated PSI-cytochrome b6f supercomplex to support robust growth and strong photosynthetic capacity under a constant growth regime of low temperatures and high salinity. copyright, serif 2020 American Society of Plant Biologists. All rights reserved.The programmed cell death 1 (PD-1) pathway represents a major immune checkpoint, which may be engaged by cells in the tumor microenvironment to overcome active T-cell immune surveillance. Pembrolizumab (Keytruda®, MK-3475) is a potent and highly selective humanized monoclonal antibody of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. https://www.selleckchem.com/products/adenosine-cyclophosphate.html This blockade enhances the functional activity of T-cells to facilitate tumor regression and ultimately immune rejection. Pembrolizumab binds to human and cynomolgus monkey PD-1 with picomolar affinity and blocks the binding of human and cynomolgus monkey PD-1 to PD-L1 and PD-L2 with comparable potency. Pembrolizumab binds both the C'D and FG loops of PD-1. Pembrolizumab overcomes human and cynomolgus monkey PD-L1 mediated immune suppression in T-cell cultures by enhancing IL-2 production following Staphylococcal enterotoxin B (SEB) stimulation of healthy donor and cancer patient cells, and IFNγ production in human primary tumor histoculture.