In Silico Transcriptomic Analysis of Wound-Healing-Associated Genes in Malignant Pleural Mesothelioma.

Background and objectives: Malignant pleural mesothelioma (MPM) is a devastating malignancy with poor prognosis. Reliable biomarkers for MPM diagnosis, monitoring, and prognosis are needed. The aim of this study was to identify genes associated with wound healing processes whose expression could serve as a prognostic factor in MPM patients. Materials and Methods: We used data mining techniques and transcriptomic analysis so as to assess the differential transcriptional expression of wound-healing-associated genes in MPM. Moreover, we investigated the potential prognostic value as well as the functional enrichments of gene ontologies relative to microRNAs (miRNAs) of the significantly differentially expressed wound-healing-related genes in MPM. Results: Out of the 82 wound-healing-associated genes analyzed, 30 were found significantly deregulated in MPM. Kaplan-Meier analysis revealed that low ITGAV gene expression could serve as a prognostic factor favoring survival of MPM patients. Finally, gene ontology annotation enrichment analysis pointed to the members of the hsa-miR-143, hsa-miR-223, and the hsa-miR-29 miRNA family members as important regulators of the deregulated wound healing genes. Conclusions: 30 wound-healing-related genes were significantly deregulated in MPM, which are potential targets of hsa-miR-143, hsa-miR-223, and the hsa-miR-29 miRNA family members. Out of those genes, ITGAV gene expression was a prognostic factor of overall survival in MPM. Our results highlight the role of impaired tissue repair in MPM development and should be further validated experimentally

Chronic neuropsychiatric sequelae of SARS‐CoV‐2: Protocol and methods from the Alzheimer's Association Global Consortium

Introduction Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. Methods This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection

Potentially irreversible olfactory and gustatory impairments in COVID-19: Indolent vs. fulminant SARS-CoV-2 neuroinfection

[No abstract available

SARS-CoV-2 dysregulation of PTBP1 and YWHAE/Z gene expression: A primer of neurodegeneration

SARS-CoV-2 neurotropism has been increasingly recognized by its imaging and syndromic manifestations in the literature. The purpose of this report is to explore the limited yet salient current evidence that SARS-CoV-2′s host genomic targets PTBP1 and the 14-3-3 protein isoform encoding genes YWHAE and YWHAZ may be hold the key to understanding how neurotropism triggers neurodegeneration and how it may contribute to the onset of neurodegenerative disease. Considering that PTBP1 silencing in particular has recently been shown to reverse clinical parkinsonism and induce neurogenesis, as well as the known interactions of PTBP1 and YWHAE/Z with coronaviruses – most notably 14-3-3 and SARS-CoV, recent studies reinvigorate the infectious etiology hypotheses on major neurodegenerative disease such as AD and iPD. Considering that human coronaviruses with definite neurotropism have been shown to achieve long-term latency within the mammalian CNS as a result of specific accommodating mutations, the corroboration of genomic-level evidence with neuroimaging has vast potential implications for neurodegenerative disease. © 2020 Elsevier Lt

Host proteases as determinants of coronaviral neurotropism and virulence

[No abstract available

Host – virus – drug interactions as determinants of COVID-19’s phenotypes: A data-driven hypothesis

There is a growing body of evidence on the significance of interactions between comorbidities, their treatments and COVID-19 clinical phenotypes. The hypothesis explored herein is that pharmaceutical compounds currently in use are affecting COVID-19 susceptibility and phenotypes by overlapping transcriptional networks. Using two distinct SARS-CoV-2 – host interactomes, gene set enrichment analysis is used to discover compounds and assorted gene signatures derived from SARS-CoV-2 interactomes. Micronutrients, antiplatelets, ACE2 inhibitors, NSAIDs, corticosteroids and tyrosine kinase inhibitors are among the compounds discovered. Considering the implication of their associated comorbidities such as diabetes and cardiovascular disease that are associated with severe COVID-19, this study outlines the need to consider specific compounds as modulators of the observed COVID-19 spectrum. Furthermore, given that micronutrient trafficking may be targeted by viral processes, and display synergism with other enriched compounds, such as statins, studies assessing their levels prior and during infection are more than warranted. © 202

Mycobacterial immunomodulation and viral manipulation of neuronal copper efflux in the setting of sporadic Parkinson's disease: A multi – hit, outside – in hypothesis of its pathogenesis

Following Braak's hypothesis on the infectious pathogenesis of sporadic Parkinson's disease (sPD), several bacteria and viruses have been investigated as likely culprits. Recent research has focused on neuroinvasive influenza A viruses (IAV), whereas a genetic link between sPD and tuberculosis has arisen in LRRK2 – dependent maturation of the phagosome. An integrative, outside – in, multi – hit hypothesis is presented here, where (a) mycobacterial immunomodulation creates a phagocyte niche along with cytokine mediated, site specific (i.e. the gut) alterations of both immunity and the microbiome, (b) copper modulating IAVs gain latency in and control over phagocytes and their phenotypes, (c) gain access to the central nervous system (CNS) via the olfactory and vagus nerves in subsequent infection cycles, (d) induce indolent neuroinflammation characterized by perturbed intraneuronal copper compartmentalization and (e) produce α – synuclein (aSyn) pathology at least in part via copper – induced aggregation and misfolding as well as potential synergy with other underlying, corroborating factors (either genetic or acquired) contributing to dopaminergic neurodegeneration. This hypothesis explores recently arisen evidence for each step of this process, as well as pre-existing, yet unexplored overlapping pathophysiological characteristics of sPD with mycobacterial and IAV infections. The implications of this proposed pathogenic model extend both in sPD research (i.e. determining non – tuberculous mycobacteria as the first hit organism, inactivating IAV – induced copper hijacking), as well as therapeutics. © 2019 Elsevier Lt

The continuum of SARS-CoV-2's neurotropism and the potential for immune-mediated neuronal injury

[No abstract available

Overlapping host pathways between SARS-CoV-2 and its potential copathogens: An in silico analysis

Background: SARS-CoV-2 coinfection with other viral and bacterial pathogens and their interactions are increasingly recognized in the literature as potential determinants of COVID-19 phenotypes. The aim of this study was to determine infection induced, host transcriptomic overlap between SARS-CoV-2 and other pathogens. Materials and methods: SARS-CoV-2 infection induced gene expression data were used for gene set enrichment analysis (GSEA) via the Enrichr platform. GSEA compared the extracted signature to VirusMINT, Virus and Microbe perturbations from Gene Expression Omnibus (GEO) in order to detect overlap with other pathogen induced host gene signatures. For all analyses, a false discovery rate (FDR) <0.05 was considered statistically significant. Results: GSEA via Enrichr revealed several significantly enriched sub-signatures associated with HSV1, EBV, HIV1, IAV, RSV, P.Aeruginosa, Staph. Aureus and Strep. Pneumoniae infections, among other pathogens (FDR < 0.05). These signatures were detected in at least 6 infection-induced transcriptomic studies from GEO and involved both bronchial epithelial and peripheral blood immune cells. Discussion: SARS-CoV-2 infection may function synergistically with other viral and bacterial pathogens at the transcriptomic level. Notably, several meta-analyses of COVID-19 cohorts have furthermore corroborated viral and bacterial pathogens reported herein as coinfections with SARS-CoV-2. The identification of common, perturbed gene networks outlines a common host targetome for these pathogens, and furthermore provides candidates for biomarker discovery and drug design. © 2020 Elsevier B.V

Letter to the editor: The role of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in developing a COVID-19 comorbidity-based host risk score

[No abstract available