E3 Ubiquitin Ligases: The Operators of the Ubiquitin Code That Regulates the RLR and cGAS-STING Pathways.

The outbreaks caused by RNA and DNA viruses, such as SARS-CoV-2 and monkeypox, pose serious threats to human health. The RLR and cGAS-STING pathways contain major cytoplasmic sensors and signaling transduction axes for host innate antiviral immunity. In physiological and virus-induced pathological states, the activation and inactivation of these signal axes are tightly controlled, especially post-translational modifications (PTMs). E3 ubiquitin ligases (E3s) are the direct manipulator of ubiquitin codons and determine the type and modification type of substrate proteins. Therefore, members of the E3s family are involved in balancing the host's innate antiviral immune responses, and their functions have been extensively studied over recent decades. In this study, we overviewed the mechanisms of different members of three E3s families that mediate the RLR and cGAS-STING axes and analyzed them as potential molecular targets for the prevention and treatment of virus-related diseases.

Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study.

BACKGROUND: Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF. METHOD: We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO2) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes. DISCUSSION: The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF. TRIAL REGISTRATION: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001.

Virome in the cloaca of wild and breeding birds revealed a diversity of significant viruses.

BACKGROUND: Wild birds may harbor and transmit viruses that are potentially pathogenic to humans, domestic animals, and other wildlife. RESULTS: Using the viral metagenomic approach, we investigated the virome of cloacal swab specimens collected from 3182 birds (the majority of them wild species) consisting of > 87 different species in 10 different orders within the Aves classes. The virus diversity in wild birds was higher than that in breeding birds. We acquired 707 viral genomes from 18 defined families and 4 unclassified virus groups, with 265 virus genomes sharing < 60% protein sequence identities with their best matches in GenBank comprising new virus families, genera, or species. RNA viruses containing the conserved RdRp domain with no phylogenetic affinity to currently defined virus families existed in different bird species. Genomes of the astrovirus, picornavirus, coronavirus, calicivirus, parvovirus, circovirus, retrovirus, and adenovirus families which include known avian pathogens were fully characterized. Putative cross-species transmissions were observed with viruses in wild birds showing > 95% amino acid sequence identity to previously reported viruses in domestic poultry. Genomic recombination was observed for some genomes showing discordant phylogenies based on structural and non-structural regions. Mapping the next-generation sequencing (NGS) data respectively against the 707 genomes revealed that these viruses showed distribution pattern differences among birds with different habitats (breeding or wild), orders, and sampling sites but no significant differences between birds with different behavioral features (migratory and resident). CONCLUSIONS: The existence of a highly diverse virome highlights the challenges in elucidating the evolution, etiology, and ecology of viruses in wild birds. Video Abstract.

Alzheimer's disease in elderly COVID-19 patients: potential mechanisms and preventive measures.

Advanced age correlates with higher morbidity and mortality among patients affected with the novel coronavirus disease 2019 (COVID-19). Because systemic inflammation and neurological symptoms are also common in severe COVID-19 cases, there is concern that COVID-19 may lead to neurodegenerative conditions such as Alzheimer's disease (AD). In this review, we summarize possible mechanisms by which infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, may cause AD in elderly COVID-19 patients and describe preventive measures to mitigate risk. Potential mechanisms include NLRP3 inflammasome activation and IL-1ß release, renin-angiotensin system hyperactivation, innate immune activation, oxidative stress, direct viral infection, and direct cytolytic ß-cell damage. Anti-inflammatory therapies, including TNF-α inhibitors and nonsteroidal anti-inflammatory drugs, antioxidants such as the vitamin E family, nutritional intervention, physical activity, blood glucose control, and vaccination are proposed as preventive measures to minimize AD risk in COVID-19 patients. Since several risk factors for AD may converge during severe SARS-CoV-2 infection, neurologists should be alert for potential symptoms of AD and actively implement preventive measures in patients presenting with neuropsychiatric symptoms and in high-risk patients such as the elderly.

Human menstrual blood-derived stem cells as immunoregulatory therapy in COVID-19: A case report and review of the literature.

BACKGROUND: The coronavirus disease 2019 (COVID-19) caused by novel coronavirus 2019 in December 2019 has spread all around the globe and has caused a pandemic. There is still no current effective guidance on the clinical management of COVID-19. Mesenchymal stem cell therapy has been shown to be one of the therapeutic approaches to alleviate pneumonia and symptoms through their immunomo-dulatory effect in COVID-19 patients. CASE SUMMARY: We describe the first confirmed case of COVID-19 in Hangzhou to explore the role of human menstrual blood-derived stem cells (MenSCs) in the treatment of COVID-19. Moreover, we review the immunomodulation effect including non-specific and specific immune functions of MenSCs for the therapy of COVID-19. CONCLUSION: MenSCs can be helpful to find a promising therapeutic approach for COVID-19.

Characteristics of pediatric multi-system inflammatory syndrome (PMIS) associated with COVID-19: a meta-analysis and insights into pathogenesis.

OBJECTIVES: There was an outbreak of pediatric multisystem inflammation syndrome (PMIS) was observed in multiple countries recently, and this syndrome was suspected to be associated with SARS-CoV-2 infection. At present, there is still no standardized diagnostic criteria and treatment regimen for PMIS, while the etiology and pathogenesis still remain unclear. METHODS: We performed a systematic review on PubMed and Embase from the time of inception to June 24th 2020 in order to find relevant cases. RESULTS: There are seven studies included, and 80% of patients suffered persistent fever and 90% appeared gastrointestinal symptoms. IgG antibody against SARS-CoV-2 was positive on 81% of patients, while 37% of the patients were nucleic acid positive. C-reactive protein, IL-6 and PCT were elevated and intravenous immunoglobulin was a routine treatment for PMIS. There were more than half of patients required inotropic supports and mechanical ventilation were applied to 33% of patients. The median length of hospital stay was 10.66 days and 74% had admitted to accept intensive care. CONCLUSIONS: Our study documented three common types of PMIS clinical presentation: persistent fever and gastrointestinal symptoms, shocked with heart dysfunction and Kawasaki disease-like syndrome. PMIS patients proved with a marked inflammatory state were possibly associated with SARS-CoV-2 infection.