Host adaptation of codon usage in SARS-CoV-2 from mammals indicates potential natural selection and viral fitness.

SARS-CoV-2 infection, which is the cause of the COVID-19 pandemic, has expanded across various animal hosts, and the virus can be transmitted particularly efficiently in minks. It is still not clear how SARS-CoV-2 is selected and evolves in its hosts, or how mutations affect viral fitness. In this report, sequences of SARS-CoV-2 isolated from human and animal hosts were analyzed, and the binding energy and capacity of the spike protein to bind human ACE2 and the mink receptor were compared. Codon adaptation index (CAI) analysis indicated the optimization of viral codons in some animals such as bats and minks, and a neutrality plot demonstrated that natural selection had a greater influence on some SARS-CoV-2 sequences than mutational pressure. Molecular dynamics simulation results showed that the mutations Y453F and N501T in mink SARS-CoV-2 could enhance the binding of the viral spike to the mink receptor, indicating the involvement of these mutations in natural selection and viral fitness. Receptor binding analysis revealed that the mink SARS-CoV-2 spike interacted more strongly with the mink receptor than the human receptor. Tracking the variations and codon bias of SARS-CoV-2 is helpful for understanding the fitness of the virus in virus transmission, pathogenesis, and immune evasion.

[PreS1 Antigen of HBV Down-Regulates MHC-â on the Surface of Hepatocytes and Promotes Hepatocarcinogenesis].

Objective: To explore the internal mechanism of hepatocellular carcinoma (HCC) induced by chronic hepatitis B virus (HBV) infection. Methods: L02, HepG2 and Huh7 cells stably overexpressing HBV preS1 antigen were analyzed by flow cytometry, qRT-PCR and tumorigenesis in nude mice to evaluate the effect of preS1 antigen in HBV-related hepatocarcinogenesis. Results: Our results showed that the expression of cancer stem cell (CSCs) related factors and cell surface markers in preS1 overexpressing cells were up-regulated, and the tumorigenicity of these cells was enhanced in nude mice. In addition, preS1 overexpression could down-regulate the expression of major histocompatibility complex Ⅰ (MHC-Ⅰ). The expression of MHC-Ⅰ on the cell surface could be restored by adding interferon gamma (IFN-γ) in the process of cell culturing and the tumorigenicity of cells in nude mice could thus be reduced. Conclusion: Based on the above results, we believe that preS1 is a carcinogen of HBV and that it promotes the formation of liver cancer through down regulating MHC-Ⅰ on the surface of hepatocytes.

Fecal microbiota transplantation ameliorates gut microbiota imbalance and intestinal barrier damage in rats with stress-induced depressive-like behavior.

The gut-microbiota-brain axis is the most important complex and bidirectional pathway between the gastrointestinal tract and the central nervous system. This study investigated the potential of microbe-induced gut-to-brain signaling to modulate the effect of stress on depressive-like behavior, intestinal barrier, and neuroinflammation. Result showed that fecal microbiota transplantation increased the consumption of sucrose solutions and decreased the immobility time in forced swimming test. This treatment also increased Firmicutes and decreased Bacteroidetes and Desulfobacterota at phylum levels; reduced the loss of villi and epithelial cells; suppressed the inflammatory cell infiltration in the ileum; increased the expression of ZO-1, occludin; protected the mucosal layer function; and suppressed the high levels of inflammasomes (NLRP3, ASC, caspase-1, and IL-1ß) in rat brain. In summary, fecal microbiota transplantation improves the depressive-like behavior, alters the gut microbiota imbalance, and alleviates the intestinal tract inflammation, intestinal mucosa disruption, and neuroinflammation in rats induced by chronic unpredictable mild stress.

Association of lymphoid tissue-resident commensal bacteria in mice with depressive-like behaviors induced by chronic social defeat stress.

Emerging evidence suggests that the microbiota-gut-brain axis affects a variety of complex behaviors, including social, emotional, and depressive-like behaviors. Peyer's patches (PPs), a well-characterized gut-associated lymphoid tissue, are the entry site for luminal antigens and the initiation site for antigen-specific immune responses. However, few studies have explored the composition of lymphoid tissue-resident commensal bacteria (LRCs) in stress-associated disorders. Male C57BL/6 mice exposed to chronic social stress were analyzed for microbiome on the interior of PPs and changes in inflammation. Susceptible mice (SUS) exhibited a composition of bacteria inside PPs that was distinct from that of control (CON) and resilient (RES) mice, including an increase in Candidatus Arthromitus (SFB) and a decrease in Lactobacillus. The CD4+ CD25+ Foxp3+ T cells were significantly reduced in SUS mice. Relative mRNA levels of IL-2 were significantly reduced in SUS mice, and the mRNA levels of Bcl-6, IFN-γ, IL-6, and the IgA protein levels in the ileum were significantly increased. Moreover, in the prefrontal cortex of SUS mice, IL-6 and TNF-α were increased, whereas IL-10 was decreased. The correlational analyses revealed that social interaction ratio was negatively correlated with SFB and positively associated with Lactobacillus and four other candidate protective organisms. These results pointed the possibility that the changes in the LRCs induced by chronic social defeat stress were ultimately associated with the inflammation of the brain and exacerbation of depressive-like behaviors.

15-Lipoxygenase promotes chronic hypoxia-induced pulmonary artery inflammation via positive interaction with nuclear factor-κB.

OBJECTIVE: Our laboratory has previously demonstrated that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) is involved in hypoxic pulmonary arterial hypertension. Chronic hypoxia-induced vascular inflammation has been considered as an important stage in the development of pulmonary arterial hypertension. Here, we determined the contribution of 15-HETE in the hypoxia-induced pulmonary vascular inflammation. APPROACH AND RESULTS: Chronic hypoxia-induced monocyte/macrophage infiltration and the expressions of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed in hypoxic rat model and cultured pulmonary arterial endothelium cells using immunochemistry methods. We found that monocyte/macrophage infiltration and the expressions of intercellular adhesion molecules under hypoxia were markedly inhibited by 15-HETE inhibitors or 15-LO1/2 small interfering RNA. In addition, exogenous 15-HETE enhanced the expression of both adhesion molecules in pulmonary arterial endothelium cells in a time-dependent manner. Hypoxia-induced 15-LO1/2 expression in rat pulmonary arterial endothelium cells was significantly abolished by nuclear factor-κB inhibitors. Meanwhile, nuclear factor-κB activity was enhanced prominently by the 15-LO1/2 product, 15-HETE, suggesting a positive feedback mechanism. CONCLUSIONS: Taken together, our results suggest that chronic hypoxia promotes monocyte infiltration into the vasculature and adhesion molecules upregulation in pulmonary arterial endothelium cells via a positive interaction between 15-LO/15-HETE and nuclear factor-κB. Our study revealed a novel mechanism underlying hypoxia-induced pulmonary arterial inflammation and suggested new therapeutic strategies targeting 15-LO/15-HETE and nuclear factor-κB in the treatment of pulmonary arterial hypertension.

Investigating the Distribution and Antibiotic Resistance of Bacterial Pathogens in Clinical Specimens from a Chinese Maternal and Child Hospital: The Role of Environmental Factors.

Objective: To analyze bacterial distribution and antibiotic resistance in clinical specimens from a Chinese hospital for evaluating environmental factors' impact on pathogen prevalence. Methods: From January 2017 to December 2021, we collected 42,854 clinical specimens from hospitalized children and women. The specimens were cultured on various agar plates and incubated at 35°C for 18-48 h. Their identification was performed using standard biochemical methods and Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF), whereas antibiotic susceptibilities were determined using the VITEK 2 system. Concurrent environmental data from Wuhan were analyzed for correlations with pathogen prevalence using multiple linear stepwise regression. Results: Of the 24,555 bacterial strains isolated, the majority were gram-positive, and sputum was the most common specimen type. Haemophilus influenzae and Escherichia coli were the most prevalent pathogens in sputum and urine samples, respectively. Notably, H. influenzae and Streptococcus pneumoniae affected children under 6 years of age the most. Furthermore, H. influenzae showed high ampicillin resistance but low cefotaxime resistance; S. pneumoniae was sensitive to penicillin G, and E. coli was resistant to ampicillin but sensitive to cefotetan. The prevalence of multidrug-resistant organisms was below national averages. In terms of seasonality, H. influenzae peaked during late winter and early spring, and environmental analysis indicated positive correlations between PM2.5 and PM10, and H. influenzae and S. pneumoniae prevalence. In addition, NO2 levels were positively correlated with increased S. aureus and M. catarrhalis prevalence; E coli prevalence was negatively correlated with ozone levels. Conclusion: This study provides valuable insights into the distribution and antibiotic resistance patterns of bacterial pathogens in maternal and child healthcare facilities in Wuhan, China. Environmental factors significantly influence the epidemiology of certain bacterial pathogens. Implementing integrated health strategies that combine microbial surveillance with environmental monitoring is needed to effectively manage and prevent bacterial infections.

Computed Tomography-Derived Fractional Flow Reserve: Developing A Gold Standard for Coronary Artery Disease Diagnostics.

In recent years, a new technique called computed tomography-derived fractional flow reserve (CT-FFR) has been developed. CT-FFR overcomes many limitations in the current gold-standard fractional flow reserve (FFR) techniques while maintaining a better concordance with FFR. This technique integrates static coronary CT angiography data with hydrodynamic models, employing algorithms rather than guidewire interventions to compute the FFR. In addition to diagnosing coronary heart disease, CT-FFR has been applied in the preoperative risk assessment of major adverse cardiovascular events (MACEs) in organ transplantation and transcatheter aortic valve replacement (TAVR). Continuous advancements in CT-FFR techniques and algorithms are expanding their applicability to other methodologies. Subsequently, with robust clinical trial validation, CT-FFR can potentially supersede FFR as the primary "gatekeeper" for interventions.

Flexible and Energy-Efficient Synaptic Transistor with Quasi-Linear Weight Update Protocol by Inkjet Printing of Orientated Polar-Electret/High-k Oxide Composite Dielectric.

Inkjet printing artificial synapse is cost-effective but challenging in emulating synaptic dynamics with a sufficient number of effective weight states under ultralow voltage spiking operation. A synaptic transistor gated by inkjet-printed composite dielectric of polar-electret polyvinylpyrrolidone (PVP) and high-k zirconia oxide (ZrOx) is proposed and thus synthesized to solve this issue. Quasi-linear weight update with a large variation margin is obtained through the coupling effect and the facilitation of dipole orientation, which can be attributed to the orderly arranged molecule chains induced by the carefully designed microfluidic flows. Crucial features of biological synapses including long-term plasticity, spike-timing-dependence-plasticity (STDP), "Learning-Experience" behavior, and ultralow energy consumption (<10 fJ/pulse) are successfully implemented on the device. Simulation results exhibit an excellent image recognition accuracy (97.1%) after 15 training epochs, which is the highest for printed synaptic transistors. Moreover, the device sustained excellent endurance against bending tests with radius down to 8 mm. This work presents a very viable solution for constructing the futuristic flexible and low-cost neural systems.

Giant primary liposarcoma of the mediastinum: A case report and review of the literature.

Liposarcoma is a carcinomatous mesenchymal tumor with various histologic features and is the most common soft tissue sarcoma originating in adipose tissue. Liposarcoma commonly occurs in the lower extremities and retroperitoneum but rarely in the mediastinum, specially extending into the thoracic cavity. We report a giant primary liposarcoma of the posterior mediastinum in a 63-year-old female who complained of cough, sputum, and pain in the right chest wall. A computed tomography scan of the chest showed a giant mass of 24 × 15 × 24 cm in the posterior mediastinum of the right thoracic cavity. After a thorough examination, no suspected lipomatous lesions were found elsewhere in the patient's body. The patient underwent a thoracotomy to remove the mediastinal mass through a right thoracic approach. Subsequently, hematoxylin-eosin staining revealed dedifferentiated liposarcoma (DDL), immunohistochemistry showed positive expression of cyclin-dependent kinase 4, and murine double minute 2 (MDM2), in addition, fluorescence in situ hybridization for the MDM2 gene was also positive, which suggested DDL. The patient was discharged without any complications, and no metastasis or recurrence was observed after 19 months of follow-up. To provide a reference for clinical diagnosis and treatment, we reviewed and discussed the literature on primary liposarcoma of the mediastinum.

The key role of PGC-1α in mitochondrial biogenesis and the proliferation of pulmonary artery vascular smooth muscle cells at an early stage of hypoxic exposure.

Peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α) induced by hypoxia regulates mitochondrial biogenesis and oxidative stress. However, the potential role of PGC-1α in hypoxia-promoted proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is completely unknown. In this study, we found that hypoxia significantly induced the expression of PGC-1α in cultured PASMCs and activated mitochondrial biogenesis through upregulation of nuclear respiratory factor-1 and mitochondria transcription factor A in a time-dependent manner. Knockdown of PGC-1α by siRNA abrogated hypoxia-induced PASMCs proliferation via the downregulation of PCNA, cyclinA, and cyclinE. Furthermore, we observed that PI3K/Akt signaling pathway was involved in hypoxia induced PGC-1α expression and PASMCs proliferation. Taken together, these datas reveal PGC-1α as the key regulator to mediate mitochondrial biogenesis and the proliferation of PASMCs at an early stage of hypoxic exposure. This process might bring to light a potential adaptive mechanism for PASMCs to minimize hypoxic damage and our novel findings provide new insight into the development of hypoxic pulmonary hypertension.

A soluble epoxide hydrolase inhibitor--8-HUDE increases pulmonary vasoconstriction through inhibition of K(ATP) channels.

Epoxyeicosatrienoic acids (EETs), cytochrome P450-derived metabolites of arachidonic acid, are endogenously produced epoxides that act as substrates for the soluble epoxide hydrolase (sEH). Recent studies indicate that EETs increase the tension of rat pulmonary arteries (PAs), and inhibition of sEH augments hypoxic pulmonary vasoconstriction. However, the mechanisms underlying the proconstrictive effects of sEH inhibitors in pulmonary artery smooth muscle cells (PASMCs) are unclear. In the present study, we used a sEH inhibitor, 12-(3-hexylureido) dodec-8-enoic acid (8-HUDE), to examine the ionic mechanisms underlying the constriction of PAs. 8-HUDE increased the tension of rat PAs to 145% baseline in a manner which was effectively eliminated by 10 µmol/L glibenclamide, an inhibitor of ATP-sensitive K(+) (K(ATP)) channels. Whole cell currents of HEK cells transfected with Kir6.1 or SUR2B were activated by K(ATP) channel opener pinacidil, inhibited by K(ATP) channel inhibitor glibenclamide or inhibited by 8-HUDE in a concentration-dependent manner with an IC50 value of 40 uM. In addition, 8-HUDE inhibited the expression of Kir6.1 and SUR2B at both mRNA and protein level in rat PASMCs. These observations suggest that 8-HUDE exerts acute effects on K(ATP) channel activity as well as subacute effects through decreased channel expression, and these effects are, at least in part, via the Kir6.1/SUR2B channel.

[Analysis of non-bacterial respiratory pathogen infection in children with asthmatic diseases].

OBJECTIVE: To investigate the association of non-bacterial respiratory pathogens with asthmatic diseases in children, and the clinical significance of total serum IgE levels and peripheral eosinophil count in infection with non-bacterial respiratory pathogens. METHODS: Indirect immunofluorescence assay was used to detect IgM antibodies against nine types of non-bacterial respiratory pathogens in the sera of 490 children with asthmatic diseases between September 2010 and September 2011. Pathogens were analyzed and total serum IgE levels and peripheral eosinophil count were measured in IgM-positive cases. RESULTS: Of the 490 children with asthmatic diseases, 47.6% (233 cases) were positive with IgM antibodies against non-bacterial respiratory pathogens, the most common being Mycoplasma pneumoniae (MP) (25.3%), followed by adenovirus (ADV) (8.9%) and influenza B virus (Flu B) (8.8%). Thirty-six cases suffered from co-infection of two or more non-bacterial pathogens, mainly comprising MP and other pathogens (94%). There were significant differences in the total detection rate of IgM antibodies among all age groups (0-30 days: 50.0%; 1-6 months: 67.3%; 0.5-1 year: 33.1%; 1-3 years: 57.3%; 3-8.9 years: 61.7%). The positive rate of IgM antibodies against respiratory pathogens was highest in children with bronchial asthma, followed by children with asthmatic bronchitis, and it was lowest in children with bronchiolitis. IgM-positive children had significantly decreased blood eosinophils and significantly increased total serum IgE levels. CONCLUSIONS: The main non-bacterial respiratory pathogens include MP, ADV and Flu B in children with asthmatic diseases, and co-infection of MP and other non-bacterial pathogens is common. Infants aged 1 to 6 months have a higher infection rate than other age groups. Monitoring the changes in total serum IgE levels and peripheral eosinophil count has great significance for the clinical diagnosis and treatment of asthmatic diseases in children.

Hepatitis B virus promotes hepatocellular carcinoma development by activating GP73 to repress the innate immune response.

BACKGROUND: Hepatitis B virus (HBV) causes acute and chronic infection in the clinic. Hepatocellular carcinoma (HCC) is closely linked to HBV infection. Serum Golgi protein 73 (GP73) increases during HBV infection. However, the role of GP73 during HBV infection and the occurrence of HBV-related HCC is still poorly understood. METHODS: The underlying role of HBV-induced GP73 in regulating HCC development was investigated in this study. GP73 expression in HBV-related clinical HCC tissues and in HBV-infected hepatoma cells and primary human hepatocytes was evaluated by immunohistochemistry, ELISAs, Western blotting and quantitative real-time PCR (qRT-PCR) analysis. Tumorigenicity of GP73 overexpressed cells was detected by flow cytometry, qRT-PCR, xenograft nude mouse analyses and sphere formation assays. The effects of GP73 and HBV infection on host innate immune responses in hepatocytes were further investigated by Western blotting and qRT-PCR analysis. RESULTS: Initially, we confirmed that HBV-positive HCC tissues had significantly higher expression of GP73. Ectopic expression of the HBV gene could induce GP73 expression in primary human hepatocytes and hepatoma cells in vitro. In addition, we discovered that GP73 promotes HCC in both normal liver cells and hepatoma cells. We also found that ectopic expression of HBV genes increases GP73 expression, suppressing the host's innate immune responses in hepatocytes. CONCLUSIONS: Our results demonstrate that HBV facilitates HCC development by activating GP73 to repress the host's innate immune response. This study adds to our understanding of the pathogenesis of HBV infection-induced HCC. The findings also provide preclinical support for GP73 as a potential HCC prevention or treatment target.

Ubiquitination of SARS-CoV-2 ORF7a Prevents Cell Death Induced by Recruiting BclXL To Activate ER Stress.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has emerged in the last 2 years. The accessory protein ORF7a has been proposed as an immunomodulating factor that can cause dramatic inflammatory responses, but it is unknown how ORF7a interacts with host cells. We show that ORF7a induces cell apoptosis by recruiting the prosurvival factor BclXL to the endoplasmic reticulum (ER) via the exposed C-terminal residues Lys117 and Lys119. Simultaneously, ORF7a activates ER stress via the PERK-elF2α-CHOP pathway and inhibits the expression of endogenous BclXL, resulting in enhanced cell apoptosis. Ubiquitination of ORF7a interrupts the interaction with BclXL in the ER and weakens the activation of ER stress, which to some extent rescues the cells. Our work demonstrates that SARS-CoV-2 ORF7a hires antiapoptosis protein and aggregates on the ER, resulting in ER stress and apoptosis initiation. On the other hand, ORF7a utilizes the ubiquitin system to impede and escape host elimination, providing a promising potential target for developing strategies for minimizing the COVID-19 pandemic. IMPORTANCE Viruses struggle to reproduce after infecting cells, and the host eliminates infected cells through apoptosis to prevent virus spread. Cells adopt a special ubiquitination code to protect against viral infection, while ORF7a manipulates and exploits the ubiquitin system to eliminate host cells' effect on apoptosis and redirect cellular pathways in favor of virus survival. Our results revealed that SARS-CoV-2-encoded accessory protein ORF7a recruits prosurvival factor BclXL to the ER and activates the cellular ER stress response resulting in the initiation of programmed death to remove virus-infected cells. Ubiquitination of ORF7a blocked the recruitment of BclXL and suppressed the ER stress response, which helps to counteract cell apoptosis and rescue cell fate. These findings help us understand the mechanism of SARS-CoV-2 invasion and contribute to a theoretical foundation for the clinical prevention of COVID-19.

Design of Bacillus fastidious Uricase Mutants Bearing Long Lagging Phases Before Exponential Decreases of Activities Under Physiological Conditions.

Under physiological conditions, Bacillus fastidious uricase (BFU) activity shows negligible lagging phase before the exponential decrease; mutants are thus designed for long lagging phases before exponential activity decreases. On homodimer surface of BFU (4R8X.pdb), the last fragment ANSEYVAL at the C-terminus forms a loop whose Y319 is H-bonded by the buried D257 in the same monomer. Within 1.5 nm from the α-carboxyl group of the last leucine (L322), E30, K26, D257, R258, E311, K312 and E318 from the same monomer plus D126 and K127 from a monomer of the other homodimer generate an electrostatic interaction network. Within 1.5 nm from Y319, D307 and R310 in the same monomer interact with ionized residues around the inter-chain ß-sheet in the same homodimer. Mutagenesis of Y319R is designed to strengthen the original interactions and concomitantly generate new electrostatic attractions between homodimers. Under physiological conditions, the mutant V144A/Y319R showed an approximately 4 week lagging phase before the exponential activity decrease, an apparent half-life of activity nearly three folds of mutant V144A, but comparable activity. The introduction of ionizable residues into the C-terminus contacting the other homodimer for additional and/or stronger electrostatic attractions between homodimers may be a universal approach to thermostable mutants of uricases.

Fecal microbiota transplantation ameliorates stress-induced depression-like behaviors associated with the inhibition of glial and NLRP3 inflammasome in rat brain.

BACKGROUND: Evidence from previous studies has demonstrated that the gut-microbiota-brain axis is vital in regulating of behavior and neuroinflammation in the central nervous system. Considering the putative connection among gut microbiota, neural function, and behavior, the present study investigated the potential signaling of gut microbiota to modulate depression-like behaviors and neuroinflammation. METHODS: Rats showing depression-like behaviors induced by chronic unpredictable mild stress received fecal microbiota treatment or vehicle for 14 days, and alterations in behavior and neuroinflammation were assessed. ELISA, immunofluorescence staining and Western blot were used to analysis the activation of glial cells and NLRP3 inflammasome. RESULTS: Treatment with fecal microbiota transplantation ameliorated depression-like behaviors. 5-Hydroxytryptamine decreased in the chronic unpredictable mild stress rat model but significantly increased after fecal microbiota transplantation. The treatment with fecal microbiota transplantation decreased the production of IL-1ß and TNF-α. Moreover, fecal microbiota transplantation administration suppressed the activation of Iba1 positive microglia cells and GFAP positive astrocytes cells and reduced the expression of NLRP3, ASC, Caspase-1, and IL-1ß pathway in the prefrontal cortex and hippocampus. CONCLUSIONS: Fecal microbiota transplantation can improve depression-like behaviors induced by chronic unpredictable mild stress. The anti-depression effects of fecal microbiota transplantation were associated with the suppressed activation of glial cells and NLRP3 inflammasome in the brain.

Comparison of Clinical Features and Outcomes of Medically Attended COVID-19 and Influenza Patients in a Defined Population in the 2020 Respiratory Virus Season.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which is causing the coronavirus disease-2019 (COVID-19) pandemic, poses a global health threat. However, it is easy to confuse COVID-19 with seasonal influenza in preliminary clinical diagnosis. In this study, the differences between influenza and COVID-19 in epidemiological features, clinical manifestations, comorbidities and pathogen biology were comprehensively compared and analyzed. SARS-CoV-2 causes a higher proportion of pneumonia (90.67 vs. 17.07%) and acute respiratory distress syndrome (12.00 vs. 0%) than influenza A virus. The proportion of leukopenia for influenza patients was 31.71% compared with 12.00% for COVID-19 patients (P = 0.0096). The creatinine and creatine kinase were significantly elevated when there were COVID-19 patients. The basic reproductive number (R0) for SARS-CoV-2 is 2.38 compared with 1.28 for seasonal influenza A virus. The mutation rate of SARS-CoV-2 ranges from 1.12 × 10-3 to 6.25 × 10-3, while seasonal influenza virus has a lower evolutionary rate (0.60-2.00 × 10-6). Overall, this study compared the clinical features and outcomes of medically attended COVID-19 and influenza patients. In addition, the S477N and N439K mutations on spike may affect the affinity with receptor ACE2. This study will contribute to COVID-19 control and epidemic surveillance in the future.

SARS-CoV-2 Accessory Protein ORF7b Mediates Tumor Necrosis Factor-α-Induced Apoptosis in Cells.

The accessory proteins of coronaviruses are essential for virus-host interactions and the modulation of host immune responses. It has been reported that accessory protein ORF3a encoded by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can induce apoptosis, and accessory protein ORF6 and ORF8 could be inhibitors of the type-I interferon (IFN) signaling pathway. However, the function of accessory protein ORF7b is largely unknown. We investigated the apoptosis-inducing activity of ORF7b in cells. Cytokine levels and host innate immune responses, including expression of interferon regulatory transcription factor (IRF)-3, signal transducer and activator of transcription (STAT)-1, interferon (IFN)-ß, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, were also investigated. We found that ORF7b promoted expression of IFN-ß, TNF-α, and IL-6, activated type-I IFN signaling through IRF3 phosphorylation, and activated TNFα-induced apoptosis in HEK293T cells and Vero E6 cells. These results could provide deeper understanding about the pathogenicity of SARS-CoV-2 as well as the interaction between the accessory protein ORF7b with host immune responses.

Oral treatment with Lactobacillus reuteri attenuates depressive-like behaviors and serotonin metabolism alterations induced by chronic social defeat stress.

BACKGROUND: Alterations in bidirectional gut-brain interactions are believed to be involved in the pathogenesis of neuropsychiatric diseases. Considering the putative connections among gut microbiota, neural function, and behavior, this study investigated the potential of microbe-induced gut-to-brain signaling to modulate the impact of stress on depressive-like behaviors and serotonin metabolism. METHODS: Depression-susceptible mice induced by chronic social defeat stress received oral treatment of either Lactobacillus reuteri 3 (L. reuteri 3) or vehicle for 28 days, and alterations in behavior and serotonin metabolism were assessed. 16S rRNA sequencing and gas chromatograph were employed to analyze the gut microbiota community and short-chain fatty acids (SCFAs). RESULTS: Treatment with L. reuteri 3 ameliorated depressive-like behaviors, suppressed the increase in the relative abundances of Clostridiales and Adlercreutzia, improved the decrease in abundances of Lactobacillus, Allobaculum, and Sutterella induced by stress, and significantly increased the proportion of Bifidobacterium. L. reuteri 3 reduced the acetate and total SCFAs levels in the depression group. Blood and colon 5-HT were decreased in depressive-like mice but were significantly ameliorated after L. reuteri 3 treatment. Moreover, L. reuteri 3 administration increased the expression of enzymes involved in serotonin biosynthesis but suppressed that of the enzymes involved in tryptophan metabolism along the kynurenine pathway in colon and prefrontal cortex. CONCLUSIONS: Despite the complexity of the gut microbiota, exposure to a single microbial strain L. reuteri 3 can protect against depressive-like behaviors induced by chronic social defeat stress. The anti-depressive effects of L. reuteri 3 were associated with improved gut microbiota and serotonin metabolism.

Highly Controllable and Silicon-Compatible Ferroelectric Photovoltaic Synapses for Neuromorphic Computing.

Ferroelectric synapses using polarization switching (a purely electronic switching process) to induce analog conductance change have attracted considerable interest. Here, we propose ferroelectric photovoltaic (FePV) synapses that use polarization-controlled photocurrent as the readout and thus have no limitations on the forms and thicknesses of the constituent ferroelectric and electrode materials. This not only makes FePV synapses easy to fabricate but also reduces the depolarization effect and hence enhances the polarization controllability. As a proof-of-concept implementation, a Pt/Pb(Zr0.2Ti0.8)O3/LaNiO3 FePV synapse is facilely grown on a silicon substrate, which demonstrates continuous photovoltaic response modulation with good controllability (small nonlinearity and write noise) enabled by gradual polarization switching. Using photovoltaic response as synaptic weight, this device exhibits versatile synaptic functions including long-term potentiation/depression and spike-timing-dependent plasticity. A simulated FePV synapse-based neural network achieves high accuracies (>93%) for image recognition. This study paves a new way toward highly controllable and silicon-compatible synapses for neuromorphic computing.