Publisher: American Society for Microbiology Journals
ABSTRACT Small noncoding RNAs regulate a variety of cellular processes, including genomic imprinting, chromatin remodeling, replication, transcription, and translation. Here, we report small replication-regulating RNAs (srRNAs) that specifically inhibit DNA replication of the human BK polyomavirus (BKV) in vitro and in vivo . srRNAs from FM3A murine mammary tumor cells were enriched by DNA replication assay-guided fractionation and hybridization to the BKV noncoding control region (NCCR) and synthesized as cDNAs. Selective mutagenesis of the cDNA sequences and their putative targets suggests that the inhibition of BKV DNA replication is mediated by srRNAs binding to the viral NCCR, hindering early steps in the initiation of DNA replication. Ectopic expression of srRNAs in human cells inhibited BKV DNA replication in vivo . Additional srRNAs were designed and synthesized that specifically inhibit simian virus 40 (SV40) DNA replication in vitro . These observations point to novel mechanisms for regulating DNA replication and suggest the design of synthetic agents for inhibiting replication of polyomaviruses and possibly other viruses.
Publisher: The Authors. Published by Elsevier Inc.
The extensive sequence data generated from SARS-CoV-2 during the 2020 pandemic has facilitated the study of viral genome evolution over a brief period of time. This has highlighted instances of directional mutation pressures exerted on the SARS-CoV-2 genome from host antiviral defense systems. In this brief review we describe three such human defense mechanisms, the apolipoprotein B mRNA editing catalytic polypeptide-like proteins (APOBEC), adenosine deaminase acting on RNA proteins (ADAR), and reactive oxygen species (ROS), and discuss their potential implications on SARS-CoV-2 evolution.
Bacillus Calmette–Guérin (BCG) vaccination has been reported to decrease susceptibility to respiratory tract infections, an effect proposed to be mediated by the general long-term boosting of innate immune mechanisms, also termed trained immunity. Here, we discuss the non-specific beneficial effects of BCG against viral infections and whether this vaccine may afford protection to COVID-19. Could the BCG vaccine be used to bridge the gap until a specific COVID-19 vaccine is developed? Luke O’Neill and Mihai Netea discuss the science behind this approach.
The entry of falsified and substandard medicines into the legitimate pharmaceutical supply chain has negative impacts on healthcare systems, patient safety, and patient access to medicine. The COVID-19 pandemic has highlighted the importance of access to safe medicine through legitimate pharmaceutical supply chains and the willingness of criminals to target medical products such as PPE (personal protective equipment) and COVID-19 treatments. In this article, we analyse data from the United Kingdom (UK) national medicine alert and recall database to identify and understand recent cases of substandard and falsified medicine in the UK’s healthcare systems. Using the UK as a case study, we describe that national drug alert and recall data are useful in their current form to record and understand cases of substandard and falsified medicines in the supply chain. However, if regulatory agencies published further data, these drug recall databases may be useful to support longitudinal and international comparative medicine quality studies. We suggest that regulatory agencies publish the number of affected medicine packs in each recalled batch, as part of the recall process. This will help policy makers, practitioners, and researchers to better understand, monitor and compare the quality of medicines within legitimate supply chains.
This research report looks at leadership and wellbeing in Primary Schools two months after the COVID-19 school closures, in total 939 leaders completed the survey. It follows a previous report on practice in Primary Schools two weeks after school closures (Burke and Dempsey, 2020). It reports on the changes in communication, concerns and wellbeing from week two to month two after the COVID-19 school closure; the wellbeing of school leaders in the middle of the COVID-19 school closure; and, investigates the intricacies in wellbeing between teaching and administrative principals, given that their daily duties differ significantly. Quantitative data was analysed using SPSS, and qualitative data was analysed using MAXQDA. It found that principals are adapting to the impact of the pandemic, both professionally and personally, however there have been significant challenges noted. It was noted that social wellbeing is the biggest challenge for principals, however seven out of 10 principals have taken specific actions to address this challenge during the lockdown. Lack of time was an issue for those principals who have not taken positive action regarding their wellbeing, with some fulfilling multiple professional and personal roles. While there have been challenges associated with the adaptation and implementation of new online practices, and some schools lack technology, there has been a positive move to online learning.
Abstract Background Coronavirus disease 2019 (COVID-19) has evolved as a pandemic of unimaginable magnitude. The health care system is facing a tremendous challenge to provide ethical and quality care. The transformation of the patient-based care to population-based care during the COVID-19 pandemic has raised ethical dilemma among urologists. Our objective is to explore the consensus in modified standard urology care, that can be adopted and applied during COVID-19 and similar pandemic. Methods We adopted an exploratory study design using secondary data. The data were extracted from a web-based medical library using keywords “COVID-19,” “severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),” and “urology.” We identify and extrapolate (screening, eligibility, and inclusion) the data using PRISMA protocol, and summarize pandemic standard urology care under four main themes: (1) general urology care, (2) choice of surgical modality, (3) triage, and (4) urology training. Result We identified 63 academic papers related to our research question. The majority are expert opinions and perspectives on urology care. The common consensus is triage-based urology care and surgeries. Life or organ threatening conditions need immediate attention. Universal protective measures (personal protective equipment, safe operative environment) and protocol-based patient care are necessary to prevent and control SARS-CoV-2 infection. Conservation of the resources and its rational distribution provide an ethical basis for population-based health care during a pandemic. Informed decision making serves best to patients, families, and society during the public health crisis. Conclusion COVID-19 pandemic tends to transform standard urology practice into crisis standard population-based care. The consensus in crisis is drawn from evolving pieces of medical evidence and public health ethics. The provision of urology care during a pandemic is based on the availability of resources; severity of the disease, consequences of deferment of service, and dynamics of the pandemic.
Rachel P. Rosovsky; Kristen M. Sanfilippo; Tzu-Fei Wang; Sandeep K. Rajan; Surbhi Shah; Karlyn Martin; Fionnuala Ní Áinle; Menno V. Huisman; Beverley J. Hunt; Susan R. Kahn; +4 more
Rachel P. Rosovsky; Kristen M. Sanfilippo; Tzu-Fei Wang; Sandeep K. Rajan; Surbhi Shah; Karlyn Martin; Fionnuala Ní Áinle; Menno V. Huisman; Beverley J. Hunt; Susan R. Kahn; Barry Kevane; Agnes Y.Y. Lee; Claire McLintock; Lisa Baumann Kreuziger;
Abstract Background Best practice for prevention, diagnosis, and management of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID‐19) is unknown due to limited published data in this population. Objectives We aimed to assess current global practice and experience in management of COVID‐19–associated coagulopathy to identify information to guide prospective and randomized studies. Methods Physicians were queried about their current approach to prophylaxis, diagnosis, and treatment of VTE in patients with COVID‐19 using an online survey tool distributed through multiple international organizations between April 10 and 14, 2020. Results Five hundred fifteen physicians from 41 countries responded. The majority of respondents (78%) recommended prophylactic anticoagulation for all hospitalized patients with COVID‐19, with most recommending use of low‐molecular‐weight heparin or unfractionated heparin. Significant practice variation was found regarding the need for dose escalation of anticoagulation outside the setting of confirmed or suspected VTE. Respondents reported the use of bedside testing when unable to perform standard diagnostic imaging for diagnosis of VTE. Two hundred ninety‐one respondents reported observing thrombotic complications in their patients, with 64% noting that the complication was pulmonary embolism. Of the 44% of respondents who estimated incidence of thrombosis in patients with COVID‐19 in their hospital, estimates ranged widely from 1% to 50%. One hundred seventy‐four respondents noted bleeding complications (34% minor bleeding, 14% clinically relevant nonmajor bleeding, and 12% major bleeding). Conclusion Well‐designed epidemiologic studies are urgently needed to understand the incidence and risk factors of VTE and bleeding complications in patients with COVID‐19. Randomized clinical trials addressing use of anticoagulation are also needed.
Wastewater surveillance for pathogens using reverse transcription-polymerase chain reaction (RT-PCR) is an effective and resource-efficient tool for gathering community-level public health information, including the incidence of coronavirus disease-19 (COVID-19). Surveillance of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in wastewater can potentially provide an early warning signal of COVID-19 infections in a community. The capacity of the world's environmental microbiology and virology laboratories for SARS-CoV-2 RNA characterization in wastewater is increasing rapidly. However, there are no standardized protocols or harmonized quality assurance and quality control (QA/QC) procedures for SARS-CoV-2 wastewater surveillance. This paper is a technical review of factors that can cause false-positive and false-negative errors in the surveillance of SARS-CoV-2 RNA in wastewater, culminating in recommended strategies that can be implemented to identify and mitigate some of these errors. Recommendations include stringent QA/QC measures, representative sampling approaches, effective virus concentration and efficient RNA extraction, PCR inhibition assessment, inclusion of sample processing controls, and considerations for RT-PCR assay selection and data interpretation. Clear data interpretation guidelines (e.g., determination of positive and negative samples) are critical, particularly when the incidence of SARS-CoV-2 in wastewater is low. Corrective and confirmatory actions must be in place for inconclusive results or results diverging from current trends (e.g., initial onset or reemergence of COVID-19 in a community). It is also prudent to perform interlaboratory comparisons to ensure results' reliability and interpretability for prospective and retrospective analyses. The strategies that are recommended in this review aim to improve SARS-CoV-2 characterization and detection for wastewater surveillance applications. A silver lining of the COVID-19 pandemic is that the efficacy of wastewater surveillance continues to be demonstrated during this global crisis. In the future, wastewater should also play an important role in the surveillance of a range of other communicable diseases.
Project: EC | MODELIST (233348), FWF | Type I interferons in inn... (P 20522)
International audience; Synthesis of interferon-beta (IFN-beta) is an innate response to cytoplasmic infection with bacterial pathogens. Our recent studies showed that Listeria monocytogenes limits immune detection and IFN-beta synthesis via deacetylation of its peptidoglycan, which renders the bacterium resistant to lysozyme degradation. Here, we examined signaling requirements for the massive IFN-beta production resulting from the infection of murine macrophages with a mutant strain of L. monocytogenes, Delta pgdA, which is unable to modify its peptidoglycan. We report the identification of unconventional signaling pathways to the IFN-beta gene, requiring TLR2 and bacterial internalization. Induction of IFN-beta was independent of the Mal/TIRAP adaptor protein but required TRIF and the transcription factors IRF3 and IRF7. These pathways were stimulated to a lesser degree by wild-type L. monocytogenes. They operated in both resident and inflammatory macrophages derived from the peritoneal cavity, but not in bone marrow-derived macrophages. The novelty of our findings thus lies in the first description of TLR2 and TRIF as two critical components leading to the induction of the IFN-beta gene and in uncovering that individual macrophage populations adopt different strategies to link pathogen recognition signals to IFN-beta gene expression.