SIGNIFICANCE ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.This article is highlighted in the In This Issue feature, p. 1775.
  During the coronavirus disease 2019 (COVID-19) crisis, Canada's provincial chief medical officers of health (CMOHs) have provided regular updates on the pandemic response. We sought to examine whether their messaging varied over time and whether it varied across jurisdictions.
 
  We conducted a qualitative study of news releases from Canadian provincial government websites during the initial phases of the COVID-19 outbreak between Jan. 21 and Mar. 31, 2020. We performed content analysis using a predefined data extraction framework to derive themes.
 
  We identified 290 news releases. Four broad thematic categories emerged describing the government's preparedness and capacity building, issuing recommendations and mandates, expressing reassurance and encouraging the public, and promoting public responsibility. Most of the news releases were prescriptive, conveying recommendations and mandates to slow transmission. Cross-jurisdictional variations in messaging reflected local realities, such as evidence of communtheir jurisdiction and the way the province has structured the CMOH role.Much evidence supports a fundamental role for the subthalamic nucleus (STN) in rapidly stopping behavior when a stop signal or surprising event occurs, but the extent to which the STN may be involved in stopping cognitive processes is less clear. Here, we used an optogenetic approach to control STN activity in a delayed-match-to-position (DMTP) task where mice had to recall a response location after a delay. We first demonstrated that a surprising event impaired performance by both slowing the latency to respond and increasing the rate of errors. We next showed that these effects could be mimicked by brief optogenetic activation of the STN. Further, inhibiting STN during surprise blocked surprise-induced slowing, although without changing surprise-induced errors. These data are consistent with the hypothesis that STN is recruited by surprise to slow responding and that this can also interrupt cognitive processes. Under normal conditions STN-mediated stopping of behavior may slow or stop ongoing cognition to facilitate cognitive reorienting and adaptive responses to unexpected sensory information, but when malfunctioning, it could produce pathologies related to over-rigidity or increased distractibility.Small ubiquitin-like modifier (SUMO) is a widespread regulatory mechanism of post-translational modification (PTM) that induces rapid and reversible changes in protein function and stability. Using SUMO conjugase Ubc9-overexpressing or knock-down cells in Parkinson's disease (PD) models, we demonstrate that SUMOylation protects dopaminergic cells against MPP+ or preformed fibrils (PFFs) of α-synuclein (α-syn)-induced toxicities in cell viability and cytotoxicity assays. In the mechanism of protection, Ubc9 overexpression significantly suppressed the MPP+ or PFF-induced reactive oxygen species (ROS) generation, while Ubc9-RNAi enhanced the toxicity-induced ROS production. Further, PFF-mediated protein aggregation was exacerbated by Ubc9-RNAi in thioflavin T staining, compared with NC1 controls. In cycloheximide (Chx)-based protein stability assays, higher protein level of α-syn was identified in Ubc9-enhanced green fluorescent protein (EGFP) than in EGFP cells. Since there was no difference in endogenous mRNA levels of α-syn between Ubc9 and EGFP cells in quantitative real-time PCR (qRT-PCR), we assessed the mechanisms of SUMO-mediated delayed α-syn degradation via MG132, proteasomal inhibitor, and PMA, lysosomal degradation inducer. Ubc9-mediated SUMOylated α-syn avoided PMA-induced lysosomal degradation because of its high solubility. Our results suggest that Ubc9 enhances the levels of SUMO1 and ubiquitin on α-syn and interrupts SUMO1 removal from α-syn. In immunohistochemistry, dopaminergic axon tips in the striatum and cell bodies in the substantia nigra from Ubc9-overexpressing transgenic mice were protected from MPTP toxicities compared with wild-type (WT) siblings. Our results support that SUMOylation can be a regulatory target to protect dopaminergic neurons from oxidative stress and protein aggregation, with the implication that high levels of SUMOylation in dopaminergic neurons can prevent the pathologic progression of PD.Transforming growth factor (TGF)β1 has repeatedly been associated with axonal regeneration and recovery after injury to the CNS. We found TGFβ1 upregulated in the stroke-denervated mouse spinal cord after ischemic injury to the motor cortex as early as 4 d postinjury (dpi) and persisting up to 28 dpi. Given the potential role of TGFβ1 in structural plasticity and functional recovery after stroke highlighted in several published studies, we investigated its downstream signaling in an in vitro model of neurite outgrowth. We found that in this model, TGFβ1 rescues neurite outgrowth under growth inhibitory conditions via the canonical TGFβR2/ALK5 signaling axis. Thereby, protein kinase A (PKA)-mediated phosphorylation of the E3 ubiquitin ligase SMURF1 induces a switch of its substrate preference from PAR6 to the Ras homolog A (RhoA), in this way enhancing outgrowth on the level of the cytoskeleton. This proposed mechanism of TGFβ1 signaling could underly the observed increase in structural plasticity after stroke in vivo as suggested by the temporal and spatial expression of TGFβ1. In accordance with previous publications, this study corroborates the potential of TGFβ1 and associated signaling cascades as a target for future therapeutic interventions to enhance structural plasticity and functional recovery for stroke patients.
  What is the role of drug interventions in the treatment and prevention of covid-19?
 
  The latest version of this WHO living guidance provides strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir in patients with covid-19 regardless of disease severity.  https://www.selleckchem.com/products/pt2399.html  These recommendations follow the publication of results from the WHO SOLIDARITY trial
 
  This guidance adds to recommendations for corticosteroids and remdesivir published in the previous versions, with no changes made in this update (a) a strong recommendation for systemic corticosteroids in patients with severe and critical covid-19, (b) a conditional recommendation against systemic corticosteroids in patients with non-severe covid-19, (c) a conditional recommendation against remdesivir in hospitalised patients with covid-19.
 
  WHO has partnered with the non-profit Magic Evidence Ecosystem Foundation (MAGIC) for methodologic support, to develop and disseminate living guidance for covid-19 drug treatments, based on a living systematic review and network analysis.