Notes

Forties ribosomal health proteins S18 can be a fresh mother's peptidoglycan-binding health proteins in which shields embryos associated with zebrafish from bacterial infections.
ccination, is necessary to effectively decrease household transmission.Universities have turned to SARS-CoV-2 models to examine campus reopening strategies 1-9 . While these studies have explored a variety of modeling techniques, all have relied on simulated data. Here, we use an empirical proximity network of college freshmen 10 , ascertained using smartphone Bluetooth, to simulate the spread of the virus. We investigate the role of testing, isolation, mask wearing, and social distancing in the presence of implementation challenges and imperfect compliance. Here we show that while frequent testing can drastically reduce spread if mask wearing and social distancing are not widely adopted, testing has limited impact if they are ubiquitous. Furthermore, even moderate levels of immunity can significantly reduce new infections, especially when combined with other interventions. Our findings suggest that while testing and isolation are powerful tools, they have limited benefit if other interventions are widely adopted. If universities can attain high levels of masking and social distancing, they may be able to relax testing frequency to once every two to four weeks.Close contact between people is the primary route for transmission of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19). We sought to quantify interpersonal contact at the population-level by using anonymized mobile device geolocation data. We computed the frequency of contact (within six feet) between people in Connecticut during February 2020 - January 2021. Then we aggregated counts of contact events by area of residence to obtain an estimate of the total intensity of interpersonal contact experienced by residents of each town for each day. When incorporated into a susceptible-exposed-infective-removed (SEIR) model of COVID-19 transmission, the contact rate accurately predicted COVID-19 cases in Connecticut towns during the timespan. The pattern of contact rate in Connecticut explains the large initial wave of infections during March-April, the subsequent drop in cases during June-August, local outbreaks during August-September, broad statewide resurgence during September-December, and decline in January 2021. Contact rate data can help guide public health messaging campaigns to encourage social distancing and in the allocation of testing resources to detect or prevent emerging local outbreaks more quickly than traditional case investigation.
Close interpersonal contact measured using mobile device location data explains dynamics of COVID-19 transmission in Connecticut during the first year of the pandemic.
Close interpersonal contact measured using mobile device location data explains dynamics of COVID-19 transmission in Connecticut during the first year of the pandemic.
Correctional institutions nationwide are seeking to mitigate Covid-19-related risks.

To quantify changes to California's prison population since the pandemic began and identify risk factors for Covid-19 infection.

We described residents' demographic characteristics, health status, Covid-19 risk scores, room occupancy, and labor participation. We used Cox proportional hazard models to estimate the association between rates of Covid-19 infection and room occupancy and out-of-room labor, respectively.

California state prisons (March 1-October 10, 2020).

Residents of California state prisons.

Changes in the incarcerated population's size, composition, housing, and activities. For the risk factor analysis, the exposure variables were room type (cells vs dormitories) and labor participation (any room occupant participating in the prior 2 weeks) and the outcome variable was incident Covid-19 case rates.

The incarcerated population decreased 19.1% (119,401 to 96,623) during the study period.On October 1ch Fellowship; Open Society Foundations.
Horowitz Family Foundation; National Institute on Drug Abuse; National Science Foundation Graduate Research Fellowship; Open Society Foundations.Backtracking, the reverse motion of the transcriptase enzyme on the nucleic acid template, is a universal regulatory feature of transcription in cellular organisms but its role in viruses is not established. Here we present evidence that backtracking extends into the viral realm, where backtracking by the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) may aid viral transcription and replication. Structures of SARS-CoV-2 RdRp bound to the essential nsp13 helicase and RNA suggested the helicase facilitates backtracking. We use cryo-electron microscopy, RNA-protein crosslinking, and unbiased molecular dynamics simulations to characterize SARS-CoV-2 RdRp backtracking. The results establish that the single-stranded 3'-segment of the product-RNA generated by backtracking extrudes through the RdRp NTP-entry tunnel, that a mismatched nucleotide at the product-RNA 3'-end frays and enters the NTP-entry tunnel to initiate backtracking, and that nsp13 stimulates RdRp backtracking. Backtracking may aid proofreading, a crutracking may play a critical role in proofreading, a crucial process for SARS-CoV-2 resistance against many antivirals.The papain-like protease (PL pro ) of SARS-CoV-2 is a validated antiviral drug target. PL pro is involved in the cleavage of viral polyproteins and antagonizing host innate immune response through its deubiquitinating and deISG15ylating activities, rendering it a high profile antiviral drug target. Through a FRET-based high-throughput screening, several hits were identified as PL pro inhibitors with IC 50 values at the single-digit micromolar range. Subsequent lead optimization led to potent inhibitors with IC 50 values ranging from 0.56 to 0.90 µM. To help prioritize lead compounds for the cellular antiviral assay against SARS-CoV-2, we developed the cell-based FlipGFP assay that is suitable for quantifying the intracellular enzymatic inhibition potency of PL pro inhibitors in the BSL-2 setting. Two compounds selected from the FlipGFP-PL pro assay, Jun9-53-2 and Jun9-72-2, inhibited SARS-CoV-2 replication in Caco-2 hACE2 cells with EC 50 values of 8.89 and 8.32 µM, respectively, which were 3-fold more potent than GRL0617 (EC 50 = 25.1 µM). The X-ray crystal structures of PL pro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to the more closed conformation. Overall, the PL pro inhibitors identified in this study represent promising starting points for further development as SARS-CoV-2 antivirals, and FlipGFP-PL pro assay might be a suitable surrogate for screening PL pro inhibitors in the BSL-2 setting.Development of effective vaccines against Coronavirus Disease 2019 (COVID-19) is a global imperative. Rapid immunization of the world human population against a widespread, continually evolving, and highly pathogenic virus is an unprecedented challenge, and many different vaccine approaches are being pursued to meet this task. Engineered filamentous bacteriophage (phage) have unique potential in vaccine development due to their inherent immunogenicity, genetic plasticity, stability, cost-effectiveness for large-scale production, and proven safety profile in humans. Herein we report the design, development, and initial evaluation of targeted phage-based vaccination approaches against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) by using dual ligand peptide-targeted phage and adeno-associated virus/phage (AAVP) particles. Towards a unique phage- and AAVP-based dual-display candidate approach, we first performed structure-guided antigen design to select six solvent-exposed epitopes of the SARS-Co and reinforce the research for additional strategic alternatives. Phage are viruses that only infect bacteria and have been safely administered to humans as antibiotics for decades. As experimental proof-of-concept, we demonstrated that aerosol pulmonary vaccination with lung-targeted phage particles that display short epitopes of the S protein on the capsid as well as preclinical vaccination with targeted AAVP particles carrying the S protein gene elicit a systemic and specific immune response against SARS-CoV-2 in immunocompetent mice. Given that targeted phage- and AAVP-based viral particles are sturdy yet simple to genetically engineer, cost-effective for rapid large-scale production in clinical grade, and relatively stable at room temperature, such unique attributes might perhaps become additional tools towards COVID-19 vaccine design and development for immediate and future unmet needs.Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. read more For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.Memory B cell reserves can generate protective antibodies against repeated SARS-CoV-2 infections, but with an unknown reach from original infection to antigenically drifted variants. We charted memory B cell receptor-encoded monoclonal antibodies (mAbs) from 19 COVID-19 convalescent subjects against SARS-CoV-2 spike (S) and found 7 major mAb competition groups against epitopes recurrently targeted across individuals. Inclusion of published and newly determined structures of mAb-S complexes identified corresponding epitopic regions. Group assignment correlated with cross-CoV-reactivity breadth, neutralization potency, and convergent antibody signatures. mAbs that competed for binding the original S isolate bound differentially to S variants, suggesting the protective importance of otherwise-redundant recognition. The results furnish a global atlas of the S-specific memory B cell repertoire and illustrate properties conferring robustness against emerging SARS-CoV-2 variants.The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via binding human angiotensin-converting enzyme (ACE2) 1,2 , and infection can result in pneumonia and acute respiratory dist ress syndrome. Circadian rhythms coordinate an organisms response to its environment and recent studies report a role for the circadian clock to regulate host susceptibility to virus infection 3 . Influenza A infection of arhythmic mice, lacking the circadian component BMAL1, results in higher viral replication 4 and elevated inflammatory responses leading to more severe bronchitis 5,6 , highlighting the impact of circadian pathways in respiratory function. We demonstrate circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with the synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry and RNA replication. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system.
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