bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economics of Implementing Preemptive School Closures to Mitigate Pandemic Influenza Outbreaks of Differing Severity in the United States
Authors: Dauelsberg Lori R , Maskery Brian , Joo Heesoo , Germann Timothy C , Del Valle Sara Y , Uzicanin Amra 
Published: November 2021

AbstractThe use of nonpharmaceutical interventions (NPIs) to slow disease spread, is a part of national pandemic preparedness as the first line of defense against influenza pandemics. Preemptive school closures (PSCs), an NPI reserved for use in severe pandemics, are highly effective in slowing influenza spread but have unintended consequences. We simulated PSC impacts during a 1957-like pandemic to estimate population impacts and quantify costs of closing schools at the national level. We also simulated 1957-like, 1968-like, and 2009-like pandemics at the Chicago regional level. We estimated economic impacts resulting from loss of income due to illness, providing childcare during closures, and other PSC costs while taking into consideration the number of cases averted with each mitigation strategy. The estimated net PSC costs ranged from $15 billion to $192 billion (2016 USD) (1957-like, national-level) where between 2.3 and 47 million US cases may be averted depending on strategy. We found that 2-week school-by-school PSCs (as opposed to county-wide or school district–wide ones) had the lowest cost per discounted life-year gained for both national and Chicago regional-level analyses of all pandemics. While feasibility of such spatiotemporally precise triggering is presently questionable for most locales, this is, theoretically, an attractive option early in an outbreak, while assessing transmissibility and severity of a novel influenza virus. In contrast, we found that county-wide PSCs of longer durations (8 to 12 weeks) would result in the most averted cases (31-47 million) and deaths (105,000-156,000), albeit at considerably more cost ($125-$150 billion net of averted illness costs) for the national-level, 1957-like analysis. The estimated net costs per death averted ($1.0 to $1.2 million) for these scenarios compare favorably to the range of values recommended for regulatory impact analyses ($4.6 to 15.0 million). Hence, economic benefits of such PSCs would exceed the population impacts and economic costs.
An immune correlate of SARS-CoV-2 infection and severity of reinfections
Authors: Maier Hannah E. , Balmaseda Angel , Ojeda Sergio , Cerpas Cristiam , Sanchez Nery , Plazaola Miguel , van Bakel Harm , Kubale John , Lopez Roger , Saborio Saira , Barilla Carlos ,   PSP Study Group, Harris Eva , Kuan Guillermina , Gordon Aubree 
Published: November 2021

AbstractBackgroundAn immune correlate of protection from SARS-CoV-2 infection is urgently needed.MethodsWe used an ongoing household cohort with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity. Sequencing was performed to determine circulating strains of SARS-CoV-2. We investigated the protection associated with seropositivity resulting from prior infection, the anti-spike antibody titers needed for protection, and we compared the severity of first and second infections.ResultsIn March 2021, 62.3% of the cohort was seropositive. After March 2021, gamma and delta variants predominated. Seropositivity was associated with 69.2% protection from any infection (95% CI: 60.7%-75.9%), with higher protection against moderate or severe infection (79.4%, 95% CI: 64.9%-87.9%). Anti-spike titers of 327 and 2,551 were associated with 50% and 80% protection from any infection; titers of 284 and 656 were sufficient for protection against moderate or severe disease. Second infections were less severe than first infections (Relative Risk (RR) of moderated or severe disease: 0.6, 95% CI: 0.38-0.98; RR of subclinical disease:1.9, 95% CI: 1.33-2.73).ConclusionsPrior infection-induced immunity is protective against infection when predominantly gamma and delta SARS-CoV-2 circulated. The protective antibody titers presented may be useful for vaccine policy and control measures. While second infections were somewhat less severe, they were not as mild as ideal. A strategy involving vaccination will be needed to ease the burden of the SARS-CoV-2 pandemic.
Antiviral activity of Molnupiravir precursor NHC against SARS-CoV-2 Variants of Concern (VOCs) and implications for the therapeutic window and resistance
Authors: Prince Tessa , Donovan-Banfield I’ah , Goldswain Hannah , Penrice-Randal Rebekah , Hartley Catherine , Khoo Saye , Fletcher Tom , Hiscox Julian A. 
Published: November 2021

AbstractSeveral regulatory agencies have either licensed or given emergency use approval for treatment of patients at risk of developing severe COVID-19 with the anti-viral drug, Molnupiravir. Recent trials involving Molnupiravir suggested the drug was not as efficacious as earlier studies suggested. This study aimed to: (i) determine the effectiveness of the Molnupiravir active metabolite (NHC) against different SARS-CoV-2 Variants of Concern (VoCs), (ii) establish the therapeutic window of NHC in a human lung cell model, and (iii) and evaluate the genetic barrier to resistance. Dose response assays were performed in parallel to determine the IC50 (the concentration required to inhibit virus titre by 50%) of NHC against different variants. Human ACE-2 A549 cells were treated with NHC at different time points either before, during or after infection with SARS-CoV-2. Multiple passaging in the presence or absence of drug was used to evaluate whether resistance occurred. To obtain genomic information, virus was sequenced at regular intervals. After 20 passages in the presence of the drug, dose response assays and sequencing showed the virus did not appear to have developed resistance. The drug had equivalent activity against four VOCs ranging from 0.04 to 0.16μM IC50. The efficacy of the drug diminished when applied after 24 hours post-infection. Our results suggest that earlier administration in patients, perhaps pre- or post-exposure rather than symptom onset, would be a more effective treatment option.
Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk
Authors: de Biase Maria Stella , Massip Florian , Wei Tzu-Ting , Giorgi Federico M. , Stark Rory , Stone Amanda , Gladwell Amy , O’Reilly MarJn , Schütte Daniel , de Santiago Ines , Meyer Kerstin B. , Markowetz Florian , Ponder Bruce A J , Rintoul Robert C , Schwarz Roland F 
Published: November 2021

AbstractLung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear.To examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking status. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier.Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.
A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes
Authors: Carracedo Ángel ,   Spanish COalition to Unlock Research on host GEnetics on COVID-19 (SCOURGE)
Published: November 2021

AbstractWe describe the results of the Spanish Coalition to Unlock Research on Host Genetics on COVID-19 (SCOURGE). In sex-disaggregated genome-wide studies of COVID-19 hospitalization, we found two known loci associated among males (SLC6A20-LZTFL1 and IFNAR2), and a novel one among females (TLE1). Meta-analyses with independent studies revealed two novel associations (AQP3 and ARHGAP33) and replicated ELF5. A genetic risk score predicted COVID-19 severity, especially among younger males. We found less SNP-heritability and larger heritability differences by age (<60/≥60 years) among males than females. Inbreeding depression was associated with COVID-19 hospitalization and severity, and the effect was stronger among older males.
Severe COVID-19 induces molecular signatures of aging in the human brain
Authors: Mavrikaki Maria , Lee Jonathan D. , Solomon Isaac H. , Slack Frank J. 
Published: November 2021

AbstractCoronavirus disease 2019 (COVID-19) is predominantly an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and remains a significant threat to public health. COVID-19 is accompanied by neurological symptoms and cognitive decline, but the molecular mechanisms underlying this effect remain unclear. As aging induces distinct molecular signatures in the brain associated with cognitive decline in healthy populations, we hypothesized that COVID-19 may induce molecular signatures of aging. Here, we performed whole transcriptomic analysis of human frontal cortex, a critical area for cognitive function, in 12 COVID-19 cases and age- and sex-matched uninfected controls. COVID-19 induces profound changes in gene expression, despite the absence of detectable virus in brain tissue. Pathway analysis shows downregulation of genes involved in synaptic function and cognition and upregulation of genes involved in immune processes. Comparison with five independent transcriptomic datasets of aging human frontal cortex reveals striking similarities between aged individuals and severe COVID-19 patients. Critically, individuals below 65 years of age exhibit profound transcriptomic changes not observed among older individuals in our patient cohort. Our data indicate that severe COVID-19 induces molecular signatures of aging in the human brain and emphasize the value of neurological follow-up in recovered individuals.
Fast surveillance response and genome sequencing reveal the circulation of a new Yellow Fever Virus sublineage in 2021, in Minas Gerais, Brazil
Authors: Andrade Miguel S. , Campos Fabrício S. , de Oliveira Cirilo H. , Oliveira Ramon Silva , Campos Aline A. S. , Almeida Marco A. B. , Simonini-Teixeira Danilo , Sevá Anaiá da P. , Temponi Andrea Oliveira Dias , Magalhães Fernando Maria , Chaves Danielle Costa Capistrano , Pereira Maira Alves , Lamounier Ludmila Oliveira , de Menezes Givaldo Gomes , Teixeira Sandy Micaele Aquino , dos Santos Maria Eduarda Gonçalves , Bernal-Valle Sofía , Müller Nicolas F. D. , Cardoso Jader da C. , dos Santos Edmilson , Mares-Guia Maria A. , Albuquerque George R. , Romano Alessandro P. M. , Franco Ana C. , Ribeiro Bergmann M. , Roehe Paulo M. , Abreu Filipe V. S. 
Published: November 2021

AbstractYellow fever virus (YFV) exhibits a sylvatic cycle of transmission involving wild mosquitoes and non-human primates (NHP). In Brazil, YFV is endemic in the Amazon region, from where waves of epidemic expansion towards other Brazilian states eventually occur. During such waves, the virus usually follows the route from North to the Central-West and Southeast Brazilian regions. Amidst these journeys, outbreaks of Yellow Fever (YF) in NHPs, with spillovers to humans have been observed. In the present work, we describe a surveillance effort encompassing the technology of smartphone applications and the coordinated action of several research institutions and health services that succeeded in the first confirmation of YFV in NHPs in the state of Minas Gerais (MG), Southeast region, in 2021, followed by genome sequencing in an interval of only ten days. Samples from two NHPs (one of the species Alouatta caraya in the municipality of Icaraí de Minas and the other of the species Callithrix penicillata in the municipality of Ubaí) were collected and the presence of YFV was confirmed by RT-qPCR. We generated three near-complete by Nanopore sequencer MinION. Phylogenetic analysis revealed that all viral genomes recovered are equal and related to lineage South America 1, clustering with a genome detected in the Amazon region (Pará state) in 2017. These findings reveal the occurrence of a new wave of viral expansion in MG, six years after the beginning of the major outbreak in the state, between 2015-2018. No human cases were reported to date, showing the importance of coordinated work between local surveillance based on available technologies and support laboratories to ensure a quick response and implementation of contingency measures towards avoiding the occurrence of YF cases in humans.
Single-cell RNA sequencing ofPlasmodiumvivax sporozoites reveals stage- and species-specific transcriptomic signatures
Authors: Ruberto Anthony A. , Bourke Caitlin , Vantaux Amélie , Maher Steven P. , Jex Aaron , Witkowski Benoit , Snounou Georges , Mueller Ivo 
Published: November 2021

AbstractPlasmodium vivaxsporozoites reside in the salivary glands of a mosquito before infecting a human host. Previous transcriptome-wide studies in populations of these forms were limited in their ability to elucidate cell-to-cell variation, thereby masking cellular states potentially important in understanding transmission outcomes. In this study, we performed transcription profiling on 9,947P. vivaxsporozoites to assess the extent to which they differ at single-cell resolution. We show that sporozoites residing in the mosquito’s salivary glands exist in distinct developmental states, as defined by their transcriptomic signatures. Additionally, relative toP. falciparum, P. vivaxdisplays overlapping and unique gene usage patterns, highlighting conserved and species-specific gene programs. Notably, distinguishingP. vivaxfromP. falciparumwere a subset ofP. vivaxsporozoites expressing genes associated with translational regulation and repression. Finally, our comparison of single-cell transcriptomic data fromP. vivaxsporozoite and erythrocytic forms reveals gene usage patterns unique to sporozoites. In defining the transcriptomic signatures of individualP. vivaxsporozoites, our work provides new insights into the factors driving their developmental trajectory and lays the groundwork for a more comprehensiveP. vivaxcell atlas.
Neurotoxic Amyloidogenic Peptides Identified in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19
Authors: Islam Saba , Charnley Mirren , Bindra Guneet , Ratcliffe Julian , Zhou Jiangtao , Mezzenga Raffaele , Hulett Mark , Han Kyunghoon , Berryman Joshua T. , Reynolds Nicholas P. 
Published: November 2021

ABSTRACTCOVID-19 is primarily known as a respiratory disease caused by the virus SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called ‘long COVID’). These neurological symptoms are thought to be caused by brain inflammation, triggered by the virus infecting the central nervous system of COVID-19 patients, however we still don’t fully understand the mechanisms for these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides and discovered that they do rapidly self-assemble into amyloid. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID, especially those symptoms which are novel to long COVID in contrast to other post-viral syndromes.
Age-specific survival in an English Twite population
Authors: Gkourtsouli-Antoniadou Ismini , Ewing Steven R. , Hudson George , Pearson Michael A. , Schroeder Julia , Welch Peter E. , Wilkinson Nicholas , Dunning Jamie 
Published: November 2021

AbstractLike many bird species associated with agricultural habitats in the UK, the Twite Linaria flavirostris has undergone severe declines over recent decades due to habitat degradation, with populations in England, Wales and Ireland now restricted to a few small pockets. However, the demographic drivers of these declines are still largely unresolved. We estimated the survival of Twite from a small population at the southernmost edge of the English range in Derbyshire using capture-mark-recapture data from 2016–2019. Annual apparent survival for juveniles (0.14-0.34) was lower than for adults (0.29-0.56) and less than that of other Cardueline finches. Our results suggest that low juvenile survival may be one demographic driver underpinning the recent decline of the Derbyshire Twite population, although we also cannot rule out the possibility that differences in emigration of juveniles and adults from the population also contribute to the observed age-specific apparent survival rates.
Recombination of standing variation in a multi-hybrid swarm drove adaptive radiation in a fungal pathogen and gave rise to two pandemic plant diseases
Authors: Rahnama Mostafa , Condon Bradford , Ascari Joao P. , Dupuis Julian R. , Del Ponte Emerson , Pedley Kerry F. , Martinez Sebastián , Valent Barbara , Farman Mark L. 
Published: November 2021

ABSTRACTAdaptive radiations fuel speciation and are characterized by rapid genetic diversification and expansion into new ecological niches. Historically, these processes were believed to be driven by selection on novel mutations but genomic analyses now indicate that standing variation and gene flow often have prominent roles. How “old” variation is combined, however, and its resulting genetic architecture within newly-adapted populations is not well understood. We reconstructed a recent radiation in the fungus, Pyricularia oryzae, that spawned a population pathogenic to eleven grass genera, and caused two new plant diseases: wheat blast - already a serious threat to global agriculture - and gray leaf spot of ryegrasses. We show that the new population evolved in a multi-hybrid swarm using only the standing variation that was present in seven individuals from five distinct, host-specialized lineages. Sexual and parasexual recombination within the swarm reassorted key host-specificity factors and generated more diversity in possibly just a few weeks than existing lineages had accumulated over hundreds to thousands of years. We suggest that the process was initiated by sexual opportunity arising when a fertile fungal strain was imported into Brazil on Urochloa introduced as forage for beef production; and we further contend that the host range expansion was largely fortuitous, with host selection playing little, if any, role in driving the process. Finally, we believe that our findings point to an overlooked role for happenstance in creating situations that allow organisms to skirt rules that would normally hold evolution in check.Commercial Endorsement DisclaimerMention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture.Equal Opportunity/Non-Discrimination StatementUSDA is an equal opportunity provider and employer.
Atazanavir is a competitive inhibitor of SARS-CoV-2 Mpro, impairing variants replication in vitro and in vivo
Authors: Chaves Otávio Augusto , Sacramento Carolina Q. , C. Ferreira André , Mattos Mayara , Fintelman-Rodrigues Natalia , Temerozo Jairo R. , Pinto Douglas Pereira , da Silveira Gabriel P. E. , da Fonseca Laís Bastos , Pereira Heliana Martins , Carlos Aluana Santana , Pinto d’Ávila Joana da Costa , Viola João P.B. , Monteiro Robson Q. , Vazquez Leonardo , Bozza Patrícia T. , Castro-Faria-Neto Hugo Caire , Souza Thiago Moreno L. 
Published: November 2021

AbstractAtazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19), however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based, and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki) 1.5-fold higher than boceprevir (GC376, a positive control). ATV was a competitive inhibition, increasing the Mpro’s Michaelis-Menten (Km) more than 6-fold. Cell-based assays indicated that SARS-CoV-2 gamma is more susceptible to ATV than its predecessor strain B.1. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.