Inflammasomes: a rising star on the horizon of COVID-19 pathophysiology.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a contagious respiratory virus that is the cause of the coronavirus disease 2019 (COVID-19) pandemic which has posed a serious threat to public health. COVID-19 is characterized by a wide spectrum of clinical manifestations, ranging from asymptomatic infection to mild cold-like symptoms, severe pneumonia or even death. Inflammasomes are supramolecular signaling platforms that assemble in response to danger or microbial signals. Upon activation, inflammasomes mediate innate immune defense by favoring the release of proinflammatory cytokines and triggering pyroptotic cell death. Nevertheless, abnormalities in inflammasome functioning can result in a variety of human diseases such as autoimmune disorders and cancer. A growing body of evidence has showed that SARS-CoV-2 infection can induce inflammasome assembly. Dysregulated inflammasome activation and consequent cytokine burst have been associated with COVID-19 severity, alluding to the implication of inflammasomes in COVID-19 pathophysiology. Accordingly, an improved understanding of inflammasome-mediated inflammatory cascades in COVID-19 is essential to uncover the immunological mechanisms of COVID-19 pathology and identify effective therapeutic approaches for this devastating disease. In this review, we summarize the most recent findings on the interplay between SARS-CoV-2 and inflammasomes and the contribution of activated inflammasomes to COVID-19 progression. We dissect the mechanisms involving the inflammasome machinery in COVID-19 immunopathogenesis. In addition, we provide an overview of inflammasome-targeted therapies or antagonists that have potential clinical utility in COVID-19 treatment.

Dynamic associations between the respiratory tract and gut antibiotic resistome of patients with COVID-19 and its prediction power for disease severity.

The antibiotic resistome is the collection of all antibiotic resistance genes (ARGs) present in an individual. Whether an individual's susceptibility to infection and the eventual severity of coronavirus disease 2019 (COVID-19) is influenced by their respiratory tract antibiotic resistome is unknown. Additionally, whether a relationship exists between the respiratory tract and gut ARGs composition has not been fully explored. We recruited 66 patients with COVID-19 at three disease stages (admission, progression, and recovery) and conducted a metagenome sequencing analysis of 143 sputum and 97 fecal samples obtained from them. Respiratory tract, gut metagenomes, and peripheral blood mononuclear cell (PBMC) transcriptomes are analyzed to compare the gut and respiratory tract ARGs of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between ARGs and immune response. Among the respiratory tract ARGs, we found that Aminoglycoside, Multidrug, and Vancomycin are increased in ICU patients compared with nICU patients. In the gut, we found that Multidrug, Vancomycin, and Fosmidomycin were increased in ICU patients. We discovered that the relative abundances of Multidrug were significantly correlated with clinical indices, and there was a significantly positive correlation between ARGs and microbiota in the respiratory tract and gut. We found that immune-related pathways in PBMC were enhanced, and they were correlated with Multidrug, Vancomycin, and Tetracycline ARGs. Based on the ARG types, we built a respiratory tract-gut ARG combined random-forest classifier to distinguish ICU COVID-19 patients from nICU patients with an AUC of 0.969. Cumulatively, our findings provide some of the first insights into the dynamic alterations of respiratory tract and gut antibiotic resistome in the progression of COVID-19 and disease severity. They also provide a better understanding of how this disease affects different cohorts of patients. As such, these findings should contribute to better diagnosis and treatment scenarios.

Advancements in organs-on-chips technology for viral disease and anti-viral research

Disease models that can accurately recapitulate human pathophysiology during infection and clinical response to antiviral therapeutics are still lacking, which represents a major barrier in drug development. The emergence of human Organs-on-a-Chip that integrated microfluidics with three-dimensional (3D) cell culture, may become the potential solution for this urgent need. Human Organs-on-a-Chip aims to recapitulate human pathophysiology by incorporating tissue-relevant cell types and their microenvironment, such as dynamic fluid flow, mechanical cues, tissue–tissue interfaces, and immune cells to increase the predictive validity of in vitro experimental models. Human Organs-on-a-Chip has a broad range of potential applications in basic biomedical research, preclinical drug development, and personalized medicine. This review focuses on its use in the fields of virology and infectious diseases. We reviewed various types of human Organs-on-a-Chip-based viral infection models and their application in studying viral life cycle, pathogenesis, virus-host interaction, and drug responses to virus- and host-targeted therapies. We conclude by proposing challenges and future research avenues for leveraging this promising technology to prepare for future pandemics.

Neurologic Complications of Patients With COVID-19 Requiring Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis.

In COVID-19 patients requiring extracorporeal membrane oxygenation (ECMO), our primary objective was to determine the frequency of intracranial hemorrhage (ICH). Secondary objectives were to estimate the frequency of ischemic stroke, to explore association between higher anticoagulation targets and ICH, and to estimate the association between neurologic complications and in-hospital mortality. DATA SOURCES: We searched MEDLINE, Embase, PsycINFO, Cochrane, and MedRxiv databases from inception to March 15, 2022. STUDY SELECTION: We identified studies that described acute neurological complications in adult patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requiring ECMO. DATA EXTRACTION: Two authors independently performed study selection and data extraction. Studies with 95% or more of its patients on venovenous or venoarterial ECMO were pooled for meta-analysis, which was calculated using a random-effects model. DATA SYNTHESIS: Fifty-four studies (n = 3,347) were included in the systematic review. Venovenous ECMO was used in 97% of patients. Meta-analysis of ICH and ischemic stroke on venovenous ECMO included 18 and 11 studies, respectively. The frequency of ICH was 11% (95% CI, 8-15%), with intraparenchymal hemorrhage being the most common subtype (73%), while the frequency of ischemic strokes was 2% (95% CI, 1-3%). Higher anticoagulation targets were not associated with increased frequency of ICH (p = 0.06). In-hospital mortality was 37% (95% CI, 34-40%) and neurologic causes ranked as the third most common cause of death. The risk ratio of mortality in COVID-19 patients with neurologic complications on venovenous ECMO compared with patients without neurologic complications was 2.24 (95% CI, 1.46-3.46). There were insufficient studies for meta-analysis of COVID-19 patients on venoarterial ECMO. CONCLUSIONS: COVID-19 patients requiring venovenous ECMO have a high frequency of ICH, and the development of neurologic complications more than doubled the risk of death. Healthcare providers should be aware of these increased risks and maintain a high index of suspicion for ICH.

Depressive symptoms, perceived social support, and anticipated HIV stigma among HIV-negative/unknown men who have sex with men in China during the COVID-19 pandemic: A multicenter online cross-sectional study.

OBJECTIVE: To investigate the prevalence of depressive symptoms among human immunodeficiency virus (HIV)-negative/unknown men who have sex with men (MSM) in China and explore the relationship between perceived social support, anticipated HIV stigma, and depressive symptoms. METHODS: Participants in this study were recruited from a gay social networking app (Blued) in China by convenience sampling from December 16, 2020 to March 1, 2021. Perceived Social Support Questionnaire, Anticipated HIV Stigma Questionnaire, and Center for Epidemiologic Studies Depression Scale were used to measure the social support, anticipated HIV stigma, and depressive symptoms of participants. Confirmatory factor analysis was performed to assess the reliability and validity of the measurement model. Structural equation modeling was employed to evaluate the association of perceived social support, anticipated HIV stigma, and depressive symptoms, as well as the mediation effects. RESULTS: Overall, 47.70% (665/1394) of the participants had depressive symptoms. Perceived social support could have both direct and indirect effects on depressive symptoms with the mediating role of anticipated HIV stigma among HIV-negative/unknown MSM. CONCLUSION: Tailored interventions regarding perceived social support and anticipated HIV stigma, such as group therapy, mutual support groups and mindfulness training, with the involvement of non-governmental or governmental organizations, should be taken into account to reduce depressive symptoms and stigma among HIV-negative/unknown MSM in China.

Supercoiling Structure-Based Design of a Trimeric Coiled-Coil Peptide with High Potency against HIV-1 and Human ß-Coronavirus Infection.

Hexameric structure formation through packing of three C-terminal helices and an N-terminal trimeric coiled-coil core has been proposed as a general mechanism of class I enveloped virus entry. In this process, the C-terminal helical repeat (HR2) region of viral membrane fusion proteins becomes transiently exposed and accessible to N-terminal helical repeat (HR1) trimer-based fusion inhibitors. Herein, we describe a mimetic of the HIV-1 gp41 HR1 trimer, N3G, as a promising therapeutic against HIV-1 infection. Surprisingly, we found that in addition to protection against HIV-1 infection, N3G was also highly effective in inhibiting infection of human ß-coronaviruses, including MERS-CoV, HCoV-OC43, and SARS-CoV-2, possibly by binding the HR2 region in the spike protein of ß-coronaviruses to block their hexameric structure formation. These studies demonstrate the potential utility of anti-HIV-1 HR1 peptides in inhibiting human ß-coronavirus infection. Moreover, this strategy could be extended to the design of broad-spectrum antivirals based on the supercoiling structure of peptides.

Viral Entry Inhibitors Targeting Six-Helical Bundle Core against Highly Pathogenic Enveloped Viruses with Class I Fusion Proteins.

Type Ⅰ enveloped viruses bind to cell receptors through surface glycoproteins to initiate infection or undergo receptor-mediated endocytosis and initiate membrane fusion in the acidic environment of endocytic compartments, releasing genetic material into the cell. In the process of membrane fusion, envelope protein exposes fusion peptide, followed by an insertion into the cell membrane or endosomal membrane. Further conformational changes ensue in which the type 1 envelope protein forms a typical six-helix bundle structure, shortening the distance between viral and cell membranes so that fusion can occur. Entry inhibitors targeting viral envelope proteins, or host factors, are effective antiviral agents and have been widely studied. Some have been used clinically, such as T20 and Maraviroc for human immunodeficiency virus 1 (HIV-1) or Myrcludex B for hepatitis D virus (HDV). This review focuses on entry inhibitors that target the six-helical bundle core against highly pathogenic enveloped viruses with class I fusion proteins, including retroviruses, coronaviruses, influenza A viruses, paramyxoviruses, and filoviruses.

A Computer Simulation of SARS-CoV-2 Mutation Spectra for Empirical Data Characterization and Analysis.

It is very important to compute the mutation spectra, and simulate the intra-host mutation processes by sequencing data, which is not only for the understanding of SARS-CoV-2 genetic mechanism, but also for epidemic prediction, vaccine, and drug design. However, the current intra-host mutation analysis algorithms are not only inaccurate, but also the simulation methods are unable to quickly and precisely predict new SARS-CoV-2 variants generated from the accumulation of mutations. Therefore, this study proposes a novel accurate strand-specific SARS-CoV-2 intra-host mutation spectra computation method, develops an efficient and fast SARS-CoV-2 intra-host mutation simulation method based on mutation spectra, and establishes an online analysis and visualization platform. Our main results include: (1) There is a significant variability in the SARS-CoV-2 intra-host mutation spectra across different lineages, with the major mutations from G- > A, G- > C, G- > U on the positive-sense strand and C- > U, C- > G, C- > A on the negative-sense strand; (2) our mutation simulation reveals the simulation sequence starts to deviate from the base content percentage of Alpha-CoV/Delta-CoV after approximately 620 mutation steps; (3) 2019-NCSS provides an easy-to-use and visualized online platform for SARS-Cov-2 online analysis and mutation simulation.

Weathering and degradation of polylactic acid masks in a simulated environment in the context of the COVID-19 pandemic and their effects on the growth of winter grazing ryegrass.

The COVID-19 pandemic has led to explosive growth in the production and consumption of disposable medical masks, which has caused new global environmental problems due to the improper disposal of these masks and lack of effective mask recycling methods. To reduce the environmental load caused by the inability of synthetic plastics to degrade, polylactic acid (PLA) masks, as a biodegradable environmentally friendly plastic, may become a solution. This study simulated the actual degradation process of new PLA masks in different environments by soaking them in various solutions for 4 weeks and explored the influence of the treated PLA fabric fibers on the growth of winter ryegrass. The results show that the weathering degradation of PLA fibers in water mainly occurs through the hydrolysis of ester bonds, and weathering leads to cheese-like and gully-like erosion on the surface of the PLA fiber fabric layer and finally to fiber fracture and the release of microplastics (MPs). The average number of MPs released within 4 weeks is 149.5 items/piece, the particle size is 20-500 µm (44%), and 63.57% of the MPs are transparent fibers. The outer, middle, and inner layers of weathered PLA masks tend to be hydrophilic and have lower mechanical strength. PLA fibers after different treatment methods affect the growth of winter ryegrass. PLA masks are undoubtedly a greener choice than ordinary commercial masks, but in order to confirm this, the entire degradation process, the final products, and the impact on the environment need to be further studied. In the future, masks may be developed to be made from more environmentally friendly biodegradable materials that can have good protecting effects and also solve the problem of end-of-life recycling. A SYNOPSIS: Simulation of the actual degradation process of PLA masks and exploration of the influence of mask degradation on the growth of winter ryegrass.

Comparative study on the clinical characteristics of local cases of COVID-19 and imported cases from abroad: A retrospective cohort study.

ABSTRACT: It is presently unknown whether imported cases of the 2019 coronavirus disease (COVID-19) have different characteristics when compared with local cases. To compare the clinical characteristics of local cases of COVID-19 in China compared with those imported from abroad.This was a retrospective study of confirmed cases of COVID-19 admitted at the Beijing Ditan Fever Emergency Department between February 29th, 2020, and March 27th, 2020. The clinical characteristics of the patients were compared between local and imported cases.Compared with local cases, the imported cases were younger (27.3 ±â€Š11.7 vs. 43.6 ±â€Š22.2 years, P < .001), had a shorter interval from disease onset to admission (1.0 (0.0-2.0) vs 4.0 (2.0-7.0) days, P < .001), lower frequencies of case contact (17.4% vs 94.1%, P < .001), fever (39.1% vs 82.4%, P < .001), cough (33.3% vs 51.0%, P = .03), dyspnea (1.9% vs 11.8%, P = .01), fatigue (7.5% vs. 27.5%, P = 0.001), muscle ache (4.7% vs. 25.5%, P < 0.001), and comorbidities (P < .05). The imported cases were less severe than the local cases, with 40.4% versus 5.9% mild cases, 2.8% versus 15.7% severe cases, and no critical cases (P < .001). The length of hospital stay was longer in imported cases than in local cases (32.3 ±â€Š14.5 vs 21.7 ±â€Š11.2 days, P < .001). The imported cases showed smaller biochemical perturbations than the local cases. More imported cases had no sign of pneumonia at computed tomography (45.0% vs 14.9%, P = .001), and none had pleural effusion (0% vs 14.9%, P < .001).Compared with local cases, the imported cases of COVID-19 presented with milder disease and less extensive symptoms and signs.

Uncovering the Effects of Ammonium Sulfate on Neomycin B Biosynthesis in Streptomyces fradiae SF-2

The aminoglycoside antibiotic neomycin has broad antibacterial properties and is widely used in medicine and agriculture. With the discovery of neomycin's potential applications in treating tumors and SARS-CoV-2, it is necessary to accelerate the biosynthesis of neomycin. In the present study, we investigated the effects of various inorganic salts on neomycin B (the main active neomycin) biosynthesis in Streptomyces fradiae SF-2. We found that 60 mM (NH4)2SO4 could promote neomycin B biosynthesis and cell growth most effectively. Further comparative transcriptomic analyses revealed that 60 mM (NH4)2SO4 inhibited the EMP and TCA cycles and enhanced the expression of neo genes involved in the neomycin B biosynthesis pathway. Finally, a neomycin B potency of 17,399 U/mL in shaking flasks was achieved by overexpressing neoE and adding 60 mM (NH4)2SO4, corresponding to a 51.2% increase compared with the control S. fradiae SF-2. In the present study, the mechanism by which (NH4)2SO4 affects neomycin biosynthesis was revealed through transcriptomics, providing a reference for the further metabolic engineering of S. fradiae SF-2 for neomycin B production.

HIV Testing Among Gay, Bisexual, and Other Men Who Have Sex with Men During the COVID-19 Pandemic in China: Implications for Promoting HIV Self-Testing Among Key Populations.

The COVID-19 pandemic has created additional barriers to accessing sexual health services among gay, bisexual, and other men who have sex with men (GBMSM) in China. Yet, little is known about the frequency of HIV testing and how GBMSM get tested during the pandemic. We surveyed an online sample of GBMSM recruited on a gay networking app in China. Among 956 sexually active, 70.1% had received an HIV test in the past 6 months. Among these, 61.0% reported having undergone HIV self-testing (HIVST). Young GBMSM aged 18-24 years old were more likely to receive a recent HIV test, and the number of sexual partners was associated with recent HIV testing [adjusted odds ratio (AOR) = 1.14, 95% confidence interval (CI): 1.03-1.20]. Among those who had a recent HIV test, young GBMSM and those who had anal sex with both main partner and casual partners were more likely to utilize HIVST (AOR = 1.83, 95% CI: 1.16-2.84), as well as GBMSM who did not use a condom the last time engaged in anal sex (AOR = 1.57, 95% CI: 1.06-2.34). Among GBMSM never tested for HIV, a majority perceived low risk of HIV, while some suggested that they did not know where to get tested or they were scared of finding out they had HIV. HIVST has the potential to fill the gap in HIV testing among Chinese GBMSM, and future HIV testing programs should emphasize HIV education, accurate information dissertation, and timely point-to-care services.

The COVID-19 Restrictions and Biological Invasion: A Global Terrestrial Ecosystem Perspective on Propagule Pressure and Invasion Trajectory

Biological invasions driven by climate change, transportation, and intercontinental trade, as well as land-use change and tourism, pose severe threats to biodiversity and ecosystem services worldwide. However, the COVID-19-induced shutdowns and cross-border restrictions could have significantly impacted some of these drivers. Thus, COVID-19-induced restrictions may potentially alter the invasion trajectories and propagule pressure of invasive alien species, yet very few studies have examined this possibility. Here, we provide a unique conceptual framework to examine how COVID-19-induced restrictions may influence the rate, magnitude, and trajectories of biological invasions. We also discuss the similarities between the high-hit regions of COVID-19 and the global hotspot of biological invasions. Additionally, we assessed whether previous predictions of biological invasions still hold despite the strong impact of COVID-19 on the drivers of invasions. Finally, we emphasize the possibility of harnessing such restrictive measures to manage invasive species, nature reserves, and national parks. The present study is a significant addition to the current understanding of the interplay between pandemic outbreaks and biological invasions in the context of both direct and indirect effects of global ecosystem change.

A highly powerful nonspecific strategy to reduce COVID-19 deaths.

The coronavirus disease 2019 (COVID-19) pandemic caused by the coronavirus severe acute respiratory syndrome coronavirus 2 remains risky worldwide. We elucidate here that good IDM (isolation, disinfection, and maintenance of health) is powerful to reduce COVID-19 deaths based on the striking differences in COVID-19 case fatality rates among various scenarios. IDM means keeping COVID-19 cases away from each other and from other people, disinfecting their living environments, and maintaining their health through good nutrition, rest, and treatment of symptoms and pre-existing diseases (not through specific antiviral therapy). Good IDM could reduce COVID-19 deaths by more than 85% in 2020 and more than 99% in 2022. This is consistent with the fact that good IDM can minimize co-infections and maintain body functions and the fact that COVID-19 has become less pathogenic (this fact was supported with three novel data in this report). Although IDM has been frequently implemented worldwide to some degree, IDM has not been highlighted sufficiently. Good IDM is relative, nonspecific, flexible, and feasible in many countries, and can reduce deaths of some other relatively mild infectious diseases. IDM, vaccines, and antivirals aid each other to reduce COVID-19 deaths. The IDM concept and strategy can aid people to improve their health behavior and fight against COVID-19 and future pandemics worldwide.

The impact of COVID-19 pandemic on mental health in gay, bisexual, and other men who have sex with men in China: Difference by HIV status.

Population-based measures and public health response to stem the spread of the coronavirus may have caused unintended isolation and increased the risk of psychiatric illnesses. The objective of this study is to assess psychological distress among gay, bisexual, and other men who have sex with men (MSM) in China during the COVID-19 pandemic and examine whether these mental health outcomes differ by HIV status. Data were derived from a cross-sectional survey on the impact of COVID-19 on users of Blued, the largest gay social networking app in July 2020. All active users on Blued were invited to complete a survey regarding sexual behaviors, HIV prevention and treatment service utilization, and various health and mental health outcomes. Among all participants (n = 1205), over half (53.2%) of the participants screened mild to severe psychological distress: 34.9% screened mild, 11.6% screened moderate, and 6.6% screened severe psychological distress. Of all participants, 20.9% met the criteria for anxiety and 19.6% for depression. Psychological distress was associated with younger age having a degree below college, being unemployed, and having lower income. MSM with HIV were more likely to report depression or anxiety compared to HIV negative/unknown status MSM after adjusting for study covariates (AOR = 1.80, 95%CI 1.01-3.26; AOR = 2.04, 95%CI 1.11-3.67, respectively). MSM in China experience a high burden of psychological distress during the COVID-19 pandemic. Integrated HIV treatment and mental health services are needed to provide adequate and timely mental health support to MSM living with HIV.

Dynamic Alterations in the Respiratory Tract Microbiota of Patients with COVID-19 and its Association with Microbiota in the Gut.

The role of respiratory tract microbes and the relationship between respiratory tract and gut microbiomes in coronavirus disease 2019 (COVID-19) remain uncertain. Here, the metagenomes of sputum and fecal samples from 66 patients with COVID-19 at three stages of disease progression are sequenced. Respiratory tract, gut microbiome, and peripheral blood mononuclear cell (PBMC) samples are analyzed to compare the gut and respiratory tract microbiota of intensive care unit (ICU) and non-ICU (nICU) patients and determine relationships between respiratory tract microbiome and immune response. In the respiratory tract, significantly fewer Streptococcus, Actinomyces, Atopobium, and Bacteroides are found in ICU than in nICU patients, while Enterococcus and Candida increase. In the gut, significantly fewer Bacteroides are found in ICU patients, while Enterococcus increases. Significant positive correlations exist between relative microbiota abundances in the respiratory tract and gut. Defensin-related pathways in PBMCs are enhanced, and respiratory tract Streptococcus is reduced in patients with COVID-19. A respiratory tract-gut microbiota model identifies respiratory tract Streptococcus and Atopobium as the most prominent biomarkers distinguishing between ICU and nICU patients. The findings provide insight into the respiratory tract and gut microbial dynamics during COVID-19 progression, considering disease severity, potentially contributing to diagnosis, and treatment strategies.