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.

Spermatogenesis is precisely controlled by complex gene expression programs and involves epigenetic reprogramming, including histone modification and DNA methylation. SET domain-containing 2 (SETD2) is the predominant histone methyltransferase catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3) and plays key roles in embryonic stem cell differentiation and somatic cell development. However, its role in male germ cell development remains elusive. Here, we demonstrate an essential role of for spermiogenesis, the final stage of spermatogenesis. Using RNA-seq, we found that, in postnatal mouse testes, mRNA levels dramatically increase in 14-day-old mice. Using a germ cell-specific knockout mouse model, we also found that targeted knockout in germ cells causes aberrant spermiogenesis with acrosomal malformation before step 8 of the round-spermatid stage, resulting in complete infertility. Furthermore, we noted that the deficiency results in complete loss of H3K36me3 and significantly decreases expression of thousands of genes, including those encoding acrosin-binding protein 1 () and protamines, required for spermatogenesis. Our findings thus reveal a previously unappreciated role of the SETD2-dependent H3K36me3 modification in spermiogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.

SummaryCytokine storm and multi-organ failure are the main causes of SARS-CoV-2-related death. However, the origin of the virus’ excessively damaging abilities remains unknown. Here we show that the SARS-CoV-2 envelope (2-E) protein alone is sufficient to cause acute respiratory distress syndrome (ARDS)-like damage in vitro and in vivo. Overexpression of 2-E protein induced rapid pyroptosis-like cell death in various susceptible cells and robust secretion of cytokines and chemokines in macrophages. Intravenous administration of purified 2-E protein into mice caused ARDS-like pathological damage in lung and spleen. Overexpressed 2-E protein formed cation channels in host cell membranes, eventually leading to membrane rupture. Newly identified channel inhibitors exhibited potent anti-SARS-CoV-2 activity and excellent protective effects against the 2-E-induced damage both in vitro and in vivo. Importantly, their channel inhibition, cell protection and antiviral activities were positively correlated with each other, supporting 2-E is a promising drug target against SARS-CoV-2.

Coral bleaching, caused by elevated sea surface temperature (SST), is occurring more frequently and seriously worldwide. Due to the lack of field observations, we understand little about the large-scale variability of thermal stress in the South China Sea (SCS) and its effect on Chinas coral reefs. This paper used 4-km high resolution gap-filled SST (FilledSST) data and thermal stress data related to coral bleaching derived from Coral Reef Temperature Anomaly Database (CoRTAD) to quantify the spatial and temporal characteristics of chronic thermal stress and acute thermal stress to China's coral reefs in SCS from 1982 to 2009. We analyzed the trend of SST in summer and the thermal stress frequency, intensity and duration during this period. The results indicate that, as a chronic thermal stress, summer mean SST in SCS shows an average upward trend of 0.2 /decade and the spatial pattern is heterogeneous.℃ Waters of Xisha Islands and Dongsha Islands of the northern SCS are warming faster through time compared to Zhongsha Islands and Nansha Islands sea areas of the southern SCS. High frequency bleaching related thermal stress events for these reefs are seen in the area to the northwest of Luzon Island. Severe anomaly thermal stress events are more likely to occur during the subsequent year of the El Niño year for these coral reefs. Besides, the duration of thermal stress varies considerably by anomaly year and by region.

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The aim of the present study was to investigate the protein expression profiling of pregnane X receptor (PXR) and ATP-binding cassette sub-family B member 1 (ABCB1; also known as MDR1 or P-gp), present in the peripheral blood mononuclear cells (PBMCs) and cancerous tissues of cases of non-small cell lung cancer (NSCLC). Furthermore, the study aimed to assess the feasibility of predicting drug resistance through the medium of PBMCs. Of the subjects included in the study, 37 were histopathologically diagnosed with NSCLC and 17 were control patients without cancer. ThinPrep liquid-based smears with cytosine were applied in the examination of the PBMCs and proved quite effective in preserving the morphology and surface antigens of the lymphocytes. Measurements of expression levels in the PBMCs and cancerous tissues were obtained by immunohistochemical means. The results showed that, with the exception of the selective PXR expression in the normal lung tissues, the two types of proteins existed extensively throughout the PBMCs, normal tissues and tumors. Among the cancer patients, prior to chemotherapy, a significant rise in ABCB1 expression could be observed in the PBMCs, together with a similar rise in ABCB1 and PXR expression in the tumor specimens. Marked upregulation of the two proteins was detected in the PBMCs following 1 cycle of first-line chemotherapy. ABCB1 expression, correlated with PXR, persisted mostly in the PBMCs and tissue samples. When bound to and activated by ligands, PXR translocates from the cytoplasm to the nucleus of the cells. PXR subsequently binds to its DNA response elements as a heterodimer with the retinoid X receptor. A PXR translocation of moderate or low differentiation was identified in 3 cases of adenocarcinoma, which were co-expressing the two genes in the PBMCs prior to chemotherapy. During follow-up visits, tumor recurrence was observed within 3 months in 5 cases, which were characterized by PXR translocation. These findings indicate that the combined expression of PXR and ABCB1 in PBMCs may be used as a prospective indicator in diagnosis prior to histopathological diagnosis, and therefore may function as a novel biomarker for the prediction of drug resistance.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Antibody resistance dampens neutralizing antibody therapy and threatens current global Coronavirus (COVID-19) vaccine campaigns. In addition to the emergence of resistant SARS-CoV-2 variants, little is known about how SARS-CoV-2 evades antibodies. Here, we report a novel mechanism of extracellular vesicle (EV)-mediated cell-to-cell transmission of SARS-CoV-2, which facilitates SARS-CoV-2 to escape from neutralizing antibodies. These EVs, initially observed in SARS-CoV-2 envelope protein-expressing cells, are secreted by various SARS-CoV-2-infected cells, including Vero E6, Calu-3, and HPAEpiC cells, undergoing infection-induced pyroptosis. Various SARS-CoV-2-infected cells produce similar EVs characterized by extra-large sizes (1.6–9.5 μm in diameter, average diameter > 4.2 μm) much larger than previously reported virus-generated vesicles. Transmission electron microscopy analysis and plaque assay reveal that these SARS-CoV-2-induced EVs contain large amounts of live virus particles. In particular, the vesicle-cloaked SARS-CoV-2 virus is resistant to neutralizing antibodies and able to reinfect naïve cells independent of the reported receptors and cofactors. Consistently, the constructed 3D images show that intact EVs could be taken up by recipient cells directly, supporting vesicle-mediated cell-to-cell transmission of SARS-CoV-2. Our findings reveal a novel mechanism of receptor-independent SARS-CoV-2 infection via cell-to-cell transmission, provide new insights into antibody resistance of SARS-CoV-2 and suggest potential targets for future antiviral therapeutics.

The technique of incremental updating, which can better guarantee the real-time situation of navigational map, is the developing orientation of navigational road network updating. The data center of vehicle navigation system is in charge of storing incremental data, and the spatio-temporal data model for storing incremental data does affect the efficiency of the response of the data center to the requirements of incremental data from the vehicle terminal. According to the analysis on the shortcomings of several typical spatio-temporal data models used in the data center and based on the base map with overlay model, the reverse map with overlay model (RMOM) was put forward for the data center to make rapid response to incremental data request. RMOM supports the data center to store not only the current complete road network data, but also the overlays of incremental data from the time when each road network changed to the current moment. Moreover, the storage mechanism and index structure of the incremental data were designed, and the implementation algorithm of RMOM was developed. Taking navigational road network in Guangzhou City as an example, the simulation test was conducted to validate the efficiency of RMOM. Results show that the navigation database in the data center can response to the requirements of incremental data by only one query with RMOM, and costs less time. Compared with the base map with overlay model, the data center does not need to temporarily overlay incremental data with RMOM, so time-consuming of response is significantly reduced. RMOM greatly improves the efficiency of response and provides strong support for the real-time situation of navigational road network.