Robinsontychsen4378

Our results reveal that acetylation-dependent formation of GluR1/2-β-arrestin1/2-STAT3 signalosome is critical for glutamate-induced cell proliferation.Magnetic islands (MIs), resulting from a magnetic field reconnection, are ubiquitous structures in magnetized plasmas. In tokamak plasmas, recent researches suggested that the interaction between an MI and ambient turbulence can be important for the nonlinear MI evolution, but a lack of detailed experimental observations and analyses has prevented further understanding. Here, we provide comprehensive observations such as turbulence spreading into an MI and turbulence enhancement at the reconnection site, elucidating intricate effects of plasma turbulence on the nonlinear MI evolution.Many tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet.The Atlantic Niño is the leading mode of interannual sea-surface temperature (SST) variability in the equatorial Atlantic and assumed to be largely governed by coupled ocean-atmosphere dynamics described by the Bjerknes-feedback loop. However, the role of the atmospheric diabatic heating, which can be either an indicator of the atmosphere's response to, or its influence on the SST, is poorly understood. Here, using satellite-era observations from 1982-2015, we show that diabatic heating variability associated with the seasonal migration of the Inter-Tropical Convergence Zone controls the seasonality of the Atlantic Niño. The variability in precipitation, a measure of vertically integrated diabatic heating, leads that in SST, whereas the atmospheric response to SST variability is relatively weak. Our findings imply that the oceanic impact on the atmosphere is smaller than previously thought, questioning the relevance of the classical Bjerknes-feedback loop for the Atlantic Niño and limiting climate predictability over the equatorial Atlantic sector.The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd protection and control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) from the full-length spike (S) protein that is stable in the prefusion conformation. NVX-CoV2373 S form 27.2-nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicit high titer anti-S IgG that blocks hACE2 receptor binding, neutralize virus, and protects against SARS-CoV-2 challenge with no evidence of vaccine-associated enhanced respiratory disease. NVX-CoV2373 also elicits multifunctional CD4+ and CD8+ T cells, CD4+ follicular helper T cells (Tfh), and antigen-specific germinal center (GC) B cells in the spleen. In baboons, low-dose levels of NVX-CoV2373 with Matrix-M was also highly immunogenic and elicited high titer anti-S antibodies and functional antibodies that block S-protein binding to hACE2 and neutralize virus infection and antigen-specific T cells. check details These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2373 with Matrix-M (NCT04368988).Both high-fidelity and mismatch-tolerant recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for genomic integrity. Here, we use cryo-EM, MD simulation and functional analysis to elucidate the structural basis for the mismatch tolerance of DMC1. Structural analysis of DMC1 presynaptic and postsynaptic complexes suggested that the lineage-specific Loop 1 Gln244 (Met243 in RAD51) may help stabilize DNA backbone, whereas Loop 2 Pro274 and Gly275 (Val273/Asp274 in RAD51) may provide an open "triplet gate" for mismatch tolerance. In support, DMC1-Q244M displayed marked increase in DNA dynamics, leading to unobservable DNA map. MD simulation showed highly dispersive mismatched DNA ensemble in RAD51 but well-converged DNA in DMC1 and RAD51-V273P/D274G. Replacing Loop 1 or Loop 2 residues in DMC1 with RAD51 counterparts enhanced DMC1 fidelity, while reciprocal mutations in RAD51 attenuated its fidelity. Our results show that three Loop 1/Loop 2 residues jointly enact contrasting fidelities of DNA recombinases.Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) displayed promising potential for the treatment of esophageal squamous cell carcinoma (ESCC) with frequent activation in PI3K signaling. However, acquired resistance is likely to develop and limit the efficacy of PI3Kαi like other targeted therapies. To identify genomic adaptation to PI3Kαi, we applied whole-genome sequencing and detected gene mutation and amplification in four lines of ESCC cells established with adapted resistance to a novel PI3Kαi CYH33. Particularly, HRASG12S mutation was found in KYSE180C cells. Overexpression of HRASG12S in ESCC parental cells rendered resistance to CYH33. By contrast, down-regulation of HRASG12S restored the sensitivity of KYSE180C1 cells to CYH33, and combination of CYH33 and MEK162 displayed synergistic effect against KYSE180C1 cells and xenografts. Furthermore, elevated mTORC1, mitogen-activated protein kinase (MAPK), and c-Myc signaling pathways were found in resistant cells by RNA sequencing and combination of CYH33 and RAD001, MEK162, or OTX015 overcame the resistance to CYH33, which was accompanied with enhanced inhibition on S6, extracellular signal-regulated kinase 1 (ERK), or c-Myc, respectively. Overall, we characterized the adaptations to PI3Kαi in ESCC cells and identified combinatorial regimens that may circumvent resistance.Sleep deprivation is a form of stress that provokes both inflammatory responses and neuropsychiatric disorders. Because persistent inflammation is implicated as a physiological process in anxiety disorders, we investigated the contributions of NLRP3 inflammasome signaling to anxiety and anxiolytic properties of flavanol diets in a model of chronic sleep deprivation. The results show a flavanol-rich dietary preparation (FDP) exhibits anxiolytic properties by attenuating markers of neuroimmune activation, which included IL-1β upregulation, NLRP3 signaling, and microglia activation in the cortex and hippocampus of sleep-deprived mice. Production of IL-1β and NLRP3 were critical for both anxiety phenotypes and microglia activation. Individual FDP metabolites potently inhibited IL-1β production from microglia following stimulation with NLRP3-specific agonists, supporting anxiolytic properties of FDP observed in models of sleep deprivation involve inhibition of the NLRP3 inflammasome. The study further showed sleep deprivation alters the expression of the circadian gene Bmal1, which critically regulated NLRP3 expression and IL-1β production.A20 haploinsufficiency (HA20), a disease caused by loss-of-function TNFAIP3 mutations, manifests various autoinflammatory and/or autoimmune symptoms. Some cases of HA20 were initially diagnosed as very early onset inflammatory bowel disease (VEO-IBD). We performed whole-exome sequencing (WES) for a Japanese girl with infantile-onset IBD and a severe perianal lesion and detected a novel de novo 119 kb microdeletion containing only TNFAIP3 (arr[GRCh37] 6q23.3(138125829_138244816) × 1).Xylanolytic enzymes from glycoside hydrolase family 43 (GH43) are involved in the breakdown of hemicellulose, the second most abundant carbohydrate in plants. Here, we kinetically and mechanistically describe the non-reducing-end xylose-releasing exo-oligoxylanase activity and report the crystal structure of a native GH43 Michaelis complex with its substrate prior to hydrolysis. Two distinct calcium-stabilized conformations of the active site xylosyl unit are found, suggesting two alternative catalytic routes. These results are confirmed by QM/MM simulations that unveil the complete hydrolysis mechanism and identify two possible reaction pathways, involving different transition state conformations for the cleavage of xylooligosaccharides. Such catalytic conformational promiscuity in glycosidases is related to the open architecture of the active site and thus might be extended to other exo-acting enzymes. These findings expand the current general model of catalytic mechanism of glycosidases, a main reaction in nature, and impact on our understanding about their interaction with substrates and inhibitors.Significant advances during the past decades in the design and studies of Ru complexes with polypyridine ligands have led to the great development of molecular water oxidation catalysts and understanding on the O-O bond formation mechanisms. Here we report a Ru-based molecular water oxidation catalyst [Ru(bds)(pic)2] (Ru-bds; bds2- = 2,2'-bipyridine-6,6'-disulfonate) containing a tetradentate, dianionic sulfonate ligand at the equatorial position and two 4-picoline ligands at the axial positions. This Ru-bds catalyst electrochemically catalyzes water oxidation with turnover frequencies (TOF) of 160 and 12,900 s-1 under acidic and neutral conditions respectively, showing much better performance than the state-of-art Ru-bda catalyst. Density functional theory calculations reveal that (i) under acidic conditions, the high valent Ru intermediate RuV=O featuring the 7-coordination configuration is involved in the O-O bond formation step; (ii) under neutral conditions, the seven-coordinate RuIV=O triggers the O-O bond formation; (iii) in both cases, the I2M (interaction of two M-O units) pathway is dominant over the WNA (water nucleophilic attack) pathway.All-day passive radiative cooling has recently attracted tremendous interest by reflecting sunlight and radiating heat to the ultracold outer space. While some progress has been made, it still remains big challenge in fabricating highly efficient and low-cost radiative coolers for all-day and all-climates. Herein, we report a hierarchically structured polymethyl methacrylate (PMMA) film with a micropore array combined with random nanopores for highly efficient day- and nighttime passive radiative cooling. This hierarchically porous array PMMA film exhibits sufficiently high solar reflectance (0.95) and superior longwave infrared thermal emittance (0.98) and realizes subambient cooling of ~8.2 °C during the night and ~6.0 °C to ~8.9 °C during midday with an average cooling power of ~85 W/m2 under solar intensity of ~900 W/m2, and promisingly ~5.5 °C even under solar intensity of ~930 W/m2 and relative humidity of ~64% in hot and moist climate. The micropores and nanopores in the polymer film play crucial roles in enhancing the solar reflectance and thermal emittance.