Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern ...globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans.
We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed.
Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor.
A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.
ObjectiveType 2 diabetes mellitus is increasing in young adults, and greater adiposity is considered a major risk factor. However, whether there is an association between obesity and diabetes and how ...this might be impacted by age is not clear. Therefore, we investigated the association between body mass index (BMI) and diabetes across a wide range of age groups (20–30, 30–40, 40–50, 50–60, 60–70 and ≥70 years old).DesignWe performed a retrospective cohort study using healthy screening programme data.SettingA total of 211 833 adult Chinese persons >20 years old across 32 sites and 11 cities in China (Shanghai, Beijing, Nanjing, Suzhou, Shenzhen, Changzhou, Chengdu, Guangzhou, Hefei, Wuhan, Nantong) were selected for the study; these persons were free of diabetes at baseline.Primary and secondary outcome measuresFasting plasma glucose levels were measured and information regarding the history of diabetes was collected at each visit. Diabetes was diagnosed as fasting plasma glucose ≥7.00 mmol/L and/or self-reported diabetes. Patients were censored at the date of diagnosis or the final visit, whichever came first.ResultsWith a median follow-up of 3.1 years, 4174 of the 211 833 participants developed diabetes, with an age-adjusted incidence rate of 7.35 per 1000 persons. The risk of incident diabetes increased proportionally with increasing baseline BMI values, with a 23% increased risk of incident diabetes with each kg/m2 increase in BMI (95% CI 1.22 to 1.24). Across all age groups, there was a linear association between BMI and the risk of incident diabetes, although there was a stronger association between BMI and incident diabetes in the younger age groups (age×BMI interaction, p<0.0001).ConclusionsAn increased BMI is also independently associated with a higher risk of developing diabetes in young adults and the effects of BMI on incident diabetes were accentuated in younger adults.
Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism ...of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.
Physical environment, man-made pollution, nutrition and their mutual interactions can be major causes of human diseases. These disease determinants have distinct spatial distributions across ...geographical units, so that their adequate study involves the investigation of the associated geographical strata. We propose four geographical detectors based on spatial variation analysis of the geographical strata to assess the environmental risks of health: the risk detector indicates where the risk areas are; the factor detector identifies factors that are responsible for the risk; the ecological detector discloses relative importance between the factors; and the interaction detector reveals whether the risk factors interact or lead to disease independently. In a real-world study, the primary physical environment (watershed, lithozone and soil) was found to strongly control the neural tube defects (NTD) occurrences in the Heshun region (China). Basic nutrition (food) was found to be more important than man-made pollution (chemical fertilizer) in the control of the spatial NTD pattern. Ancient materials released from geological faults and subsequently spread along slopes dramatically increase the NTD risk. These findings constitute valuable input to disease intervention strategies in the region of interest.
Suppressor of cytokine signaling 3 (SOCS3) plays a significant role in the process of myocardial adaptation to chronic hypoxia. SOCS3 finely regulates cell signaling cross-talk that occurs between ...NF-κB and STAT3 during the compensatory protective response. However, the role and mechanism of SOCS3 in hypoxic cardiomyocytes are not fully understood. In the study, we investigated the effect of SOCS3 on the p65 and STAT3 signaling pathways and further examined the potential molecular mechanism involved in regulating apoptosis. Our data showed that SOCS3 silencing could upregulate Ac-p65, p-p65, and p-STAT3 expression in nuclear extracts of H9c2 cells that received hypoxic treatment for 24, 48, and 72 h. SOCS3 silencing also remarkably increased the DNA-binding activity of the p65 motif in hypoxic cultivated H9c2 cells. We also found that SOCS3 knockdown increased cleaved-caspase-3, Bax, and PUMA expression and decreased cleaved PARP and Bcl-2 in expression in hypoxic H9c2 cells. Silencing of SOCS3 caused an increase in LDH leakage from injured cardiomyocytes and reduced cell viability under conditions of hypoxic stress. Furthermore, SOCS3 silencing enhanced the apoptosis of H9c2 cells at 72 h of hypoxia. These findings suggest that knockdown of SOCS3 leads to excessive activation of the NF-κB pathway, which, in turn, might promote apoptosis under conditions of chronic hypoxia.
Graphical Abstract
Diagram showing the mechanism of SOCS3 in hypoxic cardiomyocytes. Silencing SOCS3 could induce the apoptosis of H9c2 cells by regulating the apoptosis-associated gene expression, which may be accomplished by activation of the p-STAT3/NF-κB signaling pathway and rely on hypoxia condition.
Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy ...status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.
Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis.
Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy.
Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients.
TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system ...diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer's disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer's disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aβ25-35) to stimulate human microglia to construct microglia models of Alzheimer's disease. The levels of TMEM16F, inducible nitric oxide synthase (iNOS), proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ25-35 treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors interleukin-1, interleukin-6 and tumor necrosis factor-α, and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1β and interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin. Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer's disease through participating in polarization of microglia and activation of the NLRP3 inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer's disease treatment.
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•A pseudo-supercapacitor based on core-sheathed ternary electrodes was prepared.•The growth of capacitance with increasing temperature stops beyond 40 ℃.•The mismatched thermal ...expansion of PANI and porous CNTs affects the capacitance.•Low temperature will lead to high internal resistance and poor capacitance.•The cyclic stability of the supercapacitor decreases with elevating temperature.
The work temperatures have a crucial influence on the performance of supercapacitors. However, temperature effects on pseudocapacitive behaviors are rarely studied for flexible high-performance fiber supercapacitors. Herein, we systematically investigated the electrochemical responses of all-solid-state fiber-based supercapacitors composed of carbon nanotube fiber (CNF) electrodes decorated with porous carbon nanotubes (CNTs)/polyaniline (PANI) and gel electrolyte at various ambient temperatures between −5 °C and 55 °C. The results show that the capacitance of the supercapacitor first enhances with the rising temperature under 40 °C and declines at 55 °C. The internal resistance presents a gradual downward trend and the self-discharge behavior accelerates at high operating temperatures. CNTs/PANI-modified flexible fiber supercapacitors are also far from unsatisfactory for cycling stability tests in a high-temperature environment. After experiencing 5000 charge–discharge cycles at 55 °C, the capacitance retains only 43.86 %, far below the counterpart at low temperatures. This study provides a fundamental comprehension of the temperature dependence of pseudocapacitive behaviors of PANI-based fiber supercapacitors.
Xanthoceras sorbifolia Bunge seed oils are suitable for broad nutritional and bio-functional purposes. In this study, the oil yield, physicochemical properties, fatty acid profile, Fourier transform ...infrared spectra, tocopherol content, antioxidant activity, oxidative and thermal stability, and rheological properties of seed oils, obtained by subcritical n-butane, supercritical carbon dioxide (CO2), and Soxhlet method, were investigated and compared. The results indicated that subcritical n-butane had higher yield (58.79%) than supercritical CO2 (56.47%), corresponding to 97.29% efficiency of the Soxhlet method. All the extracted oils were rich in linoleic acid (379.61–385.86 mg/g oil), and oleic acid (276.58–285.77 mg/g oil), with high thermal stabilities and Newtonian flow behavior. The subcritical n-butane-extracted oil showed the highest tocopherol content, antioxidant activity, and oxidative stability. Thus, subcritical n-butane extraction was the best method to extract yellow horn seed oil and potentially other edible oils.
•Profiles of yellow horn seed oils obtained by three methods were studied.•Subcritical n-butane-extracted oil showed higher tocopherol content, antioxidant activity, and oxidative stability than the other oils.•The extraction method affected the rheological behavior of the obtained plant oil.•The extracted oils showed high thermal stability and Newtonian flow behavior.
Gastric cancer is one of the common malignant tumors worldwide. Increasing studies have indicated that circular RNAs (circRNAs) play critical roles in the cancer progression and have shown great ...potential as useful markers and therapeutic targets. However, the precise mechanism and functions of most circRNAs are still unknown in gastric cancer. In the present study, we performed a microarray analysis to detect circRNA expression changes between tumor samples and adjacent nontumor samples. The miRNA expression profiles were obtained from the National Center of Biotechnology Information Gene Expression Omnibus (GEO). The differentially expressed circRNAs and miRNAs were identified through fold change filtering. The interactions between circRNAs and miRNAs were predicted by Arraystar’s home-made miRNA target prediction software. After circRNA-related miRNAs and dysregulated miRNAs were intersected, 23 miRNAs were selected. The target mRNAs of miRNAs were predicted by TarBase v7.0. Gene ontology (GO) enrichment analysis and pathway analysis were performed using standard enrichment computational methods for the target mRNAs. The results of pathway analysis showed that p53 signaling pathway and hippo signal pathway were significantly enriched and CCND2 was a cross-talk gene associated with them. Finally, a circRNA-miRNA-mRNA regulation network was constructed based on the gene expression profiles and bioinformatics analysis results to identify hub genes and hsa_circRNA_101504 played a central role in the network.
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