SARS-CoV-2 envelope protein causes acute respiratory distress syndrome (ARDS)-like pathological damages and constitutes an antiviral target

Cytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of excessive damages caused by SARS-CoV-2 remains largely unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is able to cause acute respiratory distress syndrome (ARDS)-like damages in vitro and in vivo. 2-E proteins were found to form a type of pH-sensitive cation channels in bilayer lipid membranes. As observed in SARS-CoV-2-infected cells, heterologous expression of 2-E channels induced rapid cell death in various susceptible cell types and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damages in lung and spleen. A dominant negative mutation lowering 2-E channel activity attenuated cell death and SARS-CoV-2 production. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent cell protective activity in vitro and these activities were positively correlated with inhibition of 2-E channel. Importantly, prophylactic and therapeutic administration of the channel inhibitor effectively reduced both the viral load and secretion of inflammation cytokines in lungs of SARS-CoV-2-infected transgenic mice expressing human angiotensin-converting enzyme 2 (hACE-2). Our study supports that 2-E is a promising drug target against SARS-CoV-2.Subject terms: Cell death, Molecular biology     

Insolubility of Cr2O3 in Bioaccessibility Tests Points to Requirement for a New Human Oral Reference Dose for Trivalent Chromium

Bioaccessibility measurements have the potential to improve the accuracy of risk assessments and reduce the potential costs of remediation when they reveal that the solubility of chemicals in a matrix (e.g., soil) differs markedly from that in the critical toxicity study (i.e., the key study from which a toxicological or toxicity reference value is derived). We aimed to apply this approach to a brownfield site contaminated with chromium, and found that the speciation was Cr^III, using a combination of alkaline digestion/diphenylcarbazide complexation and X-ray absorption near edge structure analysis. The bioaccessibility of Cr₂O₃, the compound on which a reference dose for Cr^III is based, was substantially lower (<0.1%) than that of the Cr^III in the soils, which was a maximum of 9%, giving relative bioaccessibility values of 13,000% in soil. This shows that the reference dose is based on essentially an insoluble compound, and thus we suggest that other compounds be considered for toxicity testing and derivation of reference dose. Two possibilities are CrCl₃·6H₂O and KCr(SO₄)₂·12H₂O, which have been used for derivation of ecological toxicity reference values and are soluble at a range of dosing levels in our bioaccessibility tests.     

Effects of exogenous abscisic acid on leaf carbohydrate metabolism during cucumber seedling dehydration

Cucumber (Cucumis sativus L.) seeds were pretreated with exogenous abscisic acid (ABA) prior to germination. After germination, seedlings with three leaves were exposed to gradual dehydration. The effects of ABA on photosynthetic rate (Pn), daily water loss (WL) and water utilization efficiency (WUE) during dehydration were investigated, in addition to the variation of carbohydrates in leaves. ABA improved the Pn, WL and WUE of cucumber seedlings during dehydration. After rehydration, the seedlings pretreated with ABA showed a higher recovery in Pn, WL and WUE, as compared to those without an ABA pretreatment. Subsequent to dehydration, concentration of stachyose, raffinose, sucrose, glucose, and fructose increased in seedlings pretreated with ABA. Dehydration altered the proportions of the sugars in the total carbohydrates, and accelerated the accumulation of stachyose, raffinose and sucrose. After rehydration, carbohydrate concentrations of seedlings pretreated with ABA recovered to levels observed prior to dehydration. These results demonstrated that pretreatment of seeds with exogenous ABA enhanced carbohydrate tolerance to dehydration of cucumber seedlings.     

Unraveling the Novel Structure and Biosynthetic Pathway of O-Linked Glycans in the Golgi Apparatus of the Human Pathogenic Yeast Cryptococcus neoformans

Cryptococcus neoformans is an encapsulated basidiomycete causing cryptococcosis in immunocompromised humans. The cell surface mannoproteins of C. neoformans were reported to stimulate the host T-cell response and to be involved in fungal pathogenicity; however, their O-glycan structure is uncharacterized. In this study, we performed a detailed structural analysis of the O-glycans attached to cryptococcal mannoproteins using HPLC combined with exoglycosidase treatment and showed that the major C. neoformans O-glycans were short manno-oligosaccharides that were connected mostly by α1,2-linkages but connected by an α1,6-linkage at the third mannose residue. Comparison of the O-glycan profiles from wild-type and uxs1Δ mutant strains strongly supports the presence of minor O-glycans carrying a xylose residue. Further analyses of C. neoformans mutant strains identified three mannosyltransferase genes involved in O-glycan extensions in the Golgi. C. neoformans KTR3, the only homolog of the Saccharomyces cerevisiae KRE2/MNT1 family genes, was shown to encode an α1,2-mannosyltransferase responsible for the addition of the second mannose residue via an α1,2-linkage to the major O-glycans. C. neoformans HOC1 and HOC3, homologs of the Saccharomyces cerevisiae OCH1 family genes, were shown to encode α1,6-mannosyltransferases that can transfer the third mannose residue, via an α1,6-linkage, to minor O-glycans containing xylose and to major O-glycans without xylose, respectively. Moreover, the C. neoformans ktr3Δ mutant strain, which displayed increased sensitivity to SDS, high salt, and high temperature, showed attenuated virulence in a mouse model of cryptococcosis, suggesting that the extended structure of O-glycans is required for cell integrity and full pathogenicity of C. neoformans.     

The Neural Basis of Responsibility Attribution in Decision-Making

Social responsibility links personal behavior with societal expectations and plays a key role in affecting an agent’s emotional state following a decision. However, the neural basis of responsibility attribution remains unclear. In two previous event-related brain potential (ERP) studies we found that personal responsibility modulated outcome evaluation in gambling tasks. Here we conducted a functional magnetic resonance imaging (fMRI) study to identify particular brain regions that mediate responsibility attribution. In a context involving team cooperation, participants completed a task with their teammates and on each trial received feedback about team success and individual success sequentially. We found that brain activity differed between conditions involving team success vs. team failure. Further, different brain regions were associated with reinforcement of behavior by social praise vs. monetary reward. Specifically, right temporoparietal junction (RTPJ) was associated with social pride whereas dorsal striatum and dorsal anterior cingulate cortex (ACC) were related to reinforcement of behaviors leading to personal gain. The present study provides evidence that the RTPJ is an important region for determining whether self-generated behaviors are deserving of praise in a social context.