bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure-based Design of Prefusion-stabilized SARS-CoV-2 Spikes
Authors: Hsieh Ching-Lin , Goldsmith Jory A. , Schaub Jeffrey M. , DiVenere Andrea M. , Kuo Hung-Che , Javanmardi Kamyab , Le Kevin C. , Wrapp Daniel , Lee Alison Gene-Wei , Liu Yutong , Chou Chia-Wei , Byrne Patrick O. , Hjorth Christy K. , Johnson Nicole V. , Ludes-Meyers John , Nguyen Annalee W. , Park Juyeon , Wang Nianshuang , Amengor Dzifa , Maynard Jennifer A. , Finkelstein Ilya J. , McLellan Jason S. 
Published: May 2020

ABSTRACTThe COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 has led to accelerated efforts to develop therapeutics, diagnostics, and vaccines to mitigate this public health emergency. A key target of these efforts is the spike (S) protein, a large trimeric class I fusion protein that is metastable and difficult to produce recombinantly in large quantities. Here, we designed and expressed over 100 structure-guided spike variants based upon a previously determined cryo-EM structure of the prefusion SARS-CoV-2 spike. Biochemical, biophysical and structural characterization of these variants identified numerous individual substitutions that increased protein yields and stability. The best variant, HexaPro, has six beneficial proline substitutions leading to ∼10-fold higher expression than its parental construct and is able to withstand heat stress, storage at room temperature, and multiple freeze-thaws. A 3.2 Å-resolution cryo-EM structure of HexaPro confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for SARS-CoV-2.
Threshold assessment, categorical perception, and the evolution of reliable signaling
Authors: Peniston James H. , Green Patrick A. , Zipple Matthew N. , Nowicki Stephen 
Published: May 2020

AbstractAnimals often use assessment signals to communicate information about their quality to a variety of receivers, including potential mates, competitors, and predators. But what maintains reliable signaling and prevents signalers from signaling a better quality than they actually have? Previous work has shown that reliable signaling can be maintained if signalers pay fitness costs for signaling at different intensities and these costs are greater for lower quality individuals than higher quality ones. Models supporting this idea typically assume that continuous variation in signal intensity is perceived as such by receivers. In many organisms, however, receivers have threshold responses to signals, in which they respond to a signal if it is above a threshold value and do not respond if the signal is below the threshold value. Here, we use both analytical and individual-based models to investigate how such threshold responses affect the reliability of assessment signals. We show that reliable signaling systems can break down when receivers have an invariant threshold response, but reliable signaling can be rescued if there is variation among receivers in the location of their threshold boundary. Our models provide an important step towards understanding signal evolution when receivers have threshold responses to continuous signal variation.
Improved analysis of CRISPR fitness screens and reduced off-target effects with the BAGEL2 gene essentiality classifier
Authors: Kim Eiru , Hart Traver 
Published: May 2020

AbstractIdentifying essential genes in genome-wide loss of function screens is a critical step in functional genomics and cancer target finding. We previously described the Bayesian Analysis of Gene Essentiality (BAGEL) algorithm for accurate classification of gene essentiality from short hairpin RNA and CRISPR/Cas9 genome wide genetic screens. Here, we introduce an updated version, BAGEL2, which employs an improved model that offers greater dynamic range of Bayes Factors, enabling detection of tumor suppressor genes, and a multi-target correction that reduces false positives from off-target CRISPR guide RNA. We also suggest a metric for screen quality at the replicate level and demonstrate how different algorithms handle lower-quality data in substantially different ways. BAGEL2 is written in Python 3 and source code, along with all supporting files, are available on github (https://github.com/hart-lab/bagel).
Structure-aided development of small molecule inhibitors of ENPP1, the extracellular phosphodiesterase of the immunotransmitter cGAMP
Authors: Carozza Jacqueline A , Brown Jenifer A. , Böhnert Volker , Fernandez Daniel , AlSaif Yasmeen , Mardjuki Rachel E. , Smith Mark , Li Lingyin 
Published: May 2020

AbstractCancer cells initiate an innate immune response by synthesizing and exporting the small molecule immunotransmitter cGAMP, which activates the anti-cancer Stimulator of Interferon Genes (STING) pathway in the host. An extracellular enzyme, ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), hydrolyzes cGAMP and negatively regulates this anti-cancer immune response. Small molecule ENPP1 inhibitors are much needed as tools to study basic biology of extracellular cGAMP and as investigational cancer immunotherapy drugs. Here, we surveyed structure-activity relationships around a series of cell-impermeable and thus extracellular-targeting phosphonate inhibitors of ENPP1. Additionally, we solved the crystal structure of an exemplary phosphonate inhibitor to elucidate the interactions that drive potency. This study yielded several best-in-class compounds withKi< 2 nM and excellent physicochemical and pharmacokinetic properties. Finally, we demonstrate that an ENPP1 inhibitor delays tumor growth in a breast cancer mouse model. Together, we have developed ENPP1 inhibitors that are excellent tool compounds and potential therapeutics.
Patterns of speciation are similar across mountainous and lowland regions for a Neotropical plant radiation (Costaceae:Costus)
Authors: Vargas Oscar M. , Goldston Brittany , Grossenbacher Dena L. , Kay Kathleen M. 
Published: May 2020

AbstractHigh species richness and endemism in tropical mountains are recognized as major contributors to the latitudinal diversity gradient. The processes underlying mountain speciation, however, are largely untested. The prevalence of steep ecogeographic gradients and the geographic isolation of populations by topographic features are predicted to promote speciation in mountains. We evaluate these processes in a species-rich Neotropical genus of understory herbs that range from the lowlands to montane forests and have higher species richness in topographically complex regions. We ask whether climatic niche divergence, geographic isolation, and pollination shifts differ between mountain-influenced and lowland Amazonian sister pairs inferred from a 756-gene phylogeny. NeotropicalCostusancestors diverged in Central America during a period of mountain formation in the last 3 My with later colonization of Amazonia. Although climatic divergence, geographic isolation, and pollination shifts are prevalent in general, these factors don’t differ between mountain-influenced and Amazonian sister pairs. Despite higher climatic niche and species diversity in the mountains, speciation modes inCostusappear similar across regions. Thus, greater species richness in tropical mountains may reflect differences in colonization history, diversification rates, or the prevalence of rapidly evolving plant life forms, rather than differences in speciation mode.
Deforestation and bird habitat loss in Colombia
Authors: Negret Pablo Jose , Maron Martine , Fuller Richard A. , Possingham Hugh P. , Watson James E.M. , Simmonds Jeremy S. 
Published: May 2020

AbstractTropical forests harbor most of the planet’s terrestrial biodiversity, and their loss means destruction of habitat for many species. Tropical deforestation continues at high rates in many regions, but it is often reported only in terms of area lost or its impacts on high-profile threatened species. We estimated the impact of both past and projected future deforestation on habitat extent for the entire assemblage of forest-dependent birds across Colombia, the country with more bird species than any other. Of the 550 forest-dependent species analysed, Almost all (n=536; 96.5%) had lost habitat, and 18% had lost at least half of their habitat by 2015. We used the recently developed Loss Index (LI) to capture the severity of habitat loss for the forest bird assemblage, discovering that the current LI for Colombia is 35, which means 35% of bird species have lost at least 35% of their habitat. The national LI for Colombia is projected to rise to 43 by 2040 if recent forest loss trends continue. There were large regional differences; Caribe had an LI of 82 while for the Pacific it was 14. A threat assessment for the regionally endemic species in the country showed that 12 (30%) of the species that are projected to lose 50% or more of their historical habitat by 2040 are not currently classified as threatened by the IUCN, suggesting that there are many species that are not listed but that face an imminent extinction threat from habitat loss. This extensive habitat depletion affecting entire species assemblages has significant implications for tropical forest ecosystems, and risks eroding ecosystem function and ecosystem service provision.
EasyCOV : LAMP based rapid detection of SARS-CoV-2 in saliva
Authors: L’Helgouach Nicolas , Champigneux Pierre , Schneider Francisco Santos , Molina Laurence , Espeut Julien , Alali Mellis , Baptiste Julie , Cardeur Lise , Dubuc Benjamin , Foulongne Vincent , Galtier Florence , Makinson Alain , Marin Grégory , Picot Marie-Christine , Prieux-Lejeune Alexandra , Quenot Marine , Robles Francisco Checa , Salvetat Nicolas , Vetter Diana , Reynes Jacques , Molina Franck 
Published: May 2020

AbstractCovid-19 crisis showed us that rapid massive virus detection campaign is a key element in SARS-CoV-2 pandemic response. The classical RT-PCR laboratory platforms must be complemented with rapid and simplified technologies to enhance efficiency of large testing strategies.To this aim, we developed EasyCOV, a direct saliva RT-LAMP based SARS-CoV-2 virus detection assay that do not requires any RNA extraction step. It allows robust and rapid response under safe and easy conditions for healthcare workers and patients.EasyCOV test was assessed under double blind clinical conditions (93 asymptomatic healthcare worker volonteers, 10 actively infected patients, 20 former infected patients tested during late control visit). EasyCOV results were compared with classical laboratory RT-PCR performed on nasopharyngeal samples.Our results show that compared with nasopharyngeal laboratory RT-PCR, EasyCOV SARS-CoV-2 detection test has a sensitivity of 72.7%. Measured on healthcare worker population the specificity was 95.7%. LAMP technology on saliva is clearly able to identify subjects with infectivity profile. Among healthcare worker population EasyCOV test detected one presymptomatic subject.Because it is simple, rapid and painless for patients, EasyCOV saliva SARS-Cov-2 detection test may be useful for large screening of general population.
SIGLEC5: An immune checkpoint ligand in sepsis
Authors: Lozano-Rodríguez Roberto , Avendaño-Ortíz José , Montalbán-Hernández Karla , Ruiz-Rodríguez Juan Carlos , Ferrer Ricardo , Martín-Quirós Alejandro , Maroun-Eid Charbel , González-López Juan José , Fàbrega Anna , Terrón Verónica , Fresno Carlos del , Toledano Víctor , Marín Elvira , Guitiérrez-Fernández María , Alonso-López Elisa , Cubillos-Zapata Carolina , Stringa Pablo , Pérez de Diego Rebeca , Pelegrin Pablo , García-Palenciano Carlos , Valentín Jaime , Gómez-Campelo Paloma , Aguirre Luis A. , López-Collazo Eduardo 
Published: May 2020

ABSTRACTSepsis is a global health priority. Despite thorough studies in mice models, its molecular and cellular basis remain unclear and there is no pharmacological effective treatment other than antimicrobial and supportive therapy. During sepsis, T cells exhaustion compromises patients’ outcome, and immune checkpoints (ICs) become crucial players in disease management. Here, a total of 425 patients with systemic inflammatory response criteria and 127 controls were studied. Soluble SIGLEC5 (sSIGLEC5) levels in plasma were higher in patients with sepsis compared to the other groups and even higher in those patients with septic-shock. sSIGLEC5 plasma levels were higher in non-survivors than in survivors and ROC curves analysis revealed sSIGLEC5 as a survival marker (cut-off ≤ 523.6 ng/mL). In vitro experiments illustrated how SIGLEC5 impaired CD8+ proliferation through binding to PSGL1. Blocking the SIGLEC5/PSGL1 axis reverted the latter effect. Mechanistically, SIGLEC5 overexpression was driven by HIF1α. Exogenous sSIGLEC5 accelerated death and magnified acute lung injury in mice models. Our data demonstrates how plasma sSIGLEC5 level on admission predicts death and stratifies patients with sepsis. This molecule exhibits the hallmarks of an IC ligand.
Remarkable variability in SARS-CoV-2 antibodies across Brazilian regions: nationwide serological household survey in 27 states
Authors: Hallal Pedro C , Hartwig Fernando P , Horta Bernardo L , Victora Gabriel D , Silveira Mariângela F , Struchiner Claudio J , Vidaleti Luís Paulo , Neumann Nelson Arns , Pellanda Lúcia C , Dellagostin Odir A , Burattini Marcelo N , Menezes Ana M B , Barros Fernando C , Barros Aluísio J D , Victora Cesar G 
Published: May 2020

AbstractPopulation based data on COVID-19 are essential for guiding public policies. We report on the first of a series of planned seroprevalence surveys relying upon on household probabilistic samples of 133 large sentinel cities in Brazil, including 25,025 participants from all 26 states and the Federal District. Seroprevalence of antibodies to SARS-CoV-2, assessed using a lateral flow rapid test, varied markedly across the country’s cities and regions, from below 1% in most cities in the South and Center-West regions to up to 25% in the city of Breves in the Amazon (North) region. Eleven of the 15 cities with the highest seroprevalence were located in the North, including the six cities with highest prevalence which were located along a 2,000 km stretch of the Amazon river. Overall seroprevalence for the 90 cities with sample size of 200 or greater was 1.4% (95% CI 1.3–1.6). Extrapolating this figure to the population of these cities, which represent 25% of the country’s population, led to an estimate of 760,000 cases, as compared to the 104,782 cases reported in official statistics. Seroprevalence did not vary significantly between infancy and age 79 years, but fell by approximately two-thirds after age 80 years. Prevalence was highest among indigenous people (3.7%) and lowest among whites (0.6%), a difference which was maintained when analyses were restricted to the North region, where most indigenous people live. Our results suggest that pandemic is highly heterogenous, with rapid escalation in Brazil’s North and Northeast, and slow progression in the South and Center-West regions.
Assessing visible aerosol generation during vitrectomy in the era of Covid-19
Authors: Liyanage Sidath , Ramasamy Pathma , Elhaddad Omar , Darcy Kieren , Hudson Andrew , Keller Johannes 
Published: May 2020

AbstractObjectiveTo assess visible aerosol generation during simulated vitrectomy surgery. Methods: A model comprising a human cadaveric corneoscleral rim mounted on an artificial anterior chamber was used. Three-port 25 gauge vitrectomy simulated surgery was performed with any visible aerosol production recorded using high speed 4K camera. The following were assessed: (1) vitrector at maximum cut rate in static and dynamic conditions inside the model, (2) vitrector at air-fluid interface in physical model, (3) passive fluid-air exchange with a backflush hand piece, (4) valved cannulas under air, and (5) defective valved cannula under air.ResultsNo visible aerosol or droplets were identified when the vitrector was used within the model. In the physical model, no visible aerosol or droplets were seen when the vitrector was engaged at the air-fluid interface. Droplets were produced from the opening of backflush hand piece during passive fluid-air exchange. No visible aerosol was produced from the intact valved cannulas under air pressure, but droplets were seen at the beginning of fluid-air exchange when the valved cannula was defective.ConclusionsWe found no evidence of visible aerosol generation during simulated vitrectomy surgery with competent valved cannulas. In the physical model, no visible aerosol was generated by the high-speed vitrector despite cutting at the air-fluid interface.
Assessing the quality, readability and reliability of online information on COVID-19: an infoveillance observational study
Authors: Lins-Filho Paulo Cardoso , Macêdo Thuanny Silva de , Ferreira Andressa Kelly Alves , Melo Maria Cecília Freire de , Araújo Millena Mirella Silva de , de Melo Freitas Jaciel Leandro , Caldas Thaise Urbano , de França Caldas Arnaldo 
Published: May 2020

AbstractObjectiveThis study aimed to assess the quality, reliability and readability of internet-based information on COVID-19 available on Brazil’ most used search engines.MethodsA total of 68 websites were selected through Google, Bing, and Yahoo. The websites content quality and reliability were evaluated using the DISCERN questionnaire, the Journal of American Medical Association (JAMA) benchmark criteria, and the presence of the Health on Net (HON) certification. Readability was assessed by the Flesch Reading Ease adapted to Brazilian Portuguese (FRE-BP).ResultsThe web contents were considered moderate to low quality according to DISCERN and JAMA mean scores. Most of the sample presented very difficult reading levels and only 7.4% displayed HON certification. Websites of Governmental and health-related authorship nature showed lower JAMA mean scores and quality and readability measures did not correlate to the webpages content type.ConclusionCOVID-19 related contents available online were considered of low to moderate quality and not accessible.
An inverse stage-shift model to estimate the excess mortality and health economic impact of delayed access to cancer services due to the COVID-19 pandemic
Authors: Degeling Koen , Baxter Nancy N. , Emery Jon , Franchini Fanny , Gibbs Peter , Mann G. Bruce , McArthur Grant , Solomon Benjamin J. , IJzerman Maarten J. 
Published: May 2020

AbstractBackgroundDecreased cancer incidence and reported changes to clinical management indicate that the COVID-19 pandemic will result in diagnostic and treatment delays for cancer patients. We aimed to develop a flexible model to estimate the impact of delayed diagnosis and treatment initiation on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation.MethodsThe stage-shift model estimates population-level health economic outcomes by weighting disease stage-specific outcomes by the distribution of stages at treatment initiation, assuming delays lead to stage-progression. It allows for extrapolation of population-level survival data using parametric distributions to calculate the expected survival in life years. The model was demonstrated based on an analysis of the impact of 3 and 6-month delays for stage I breast cancer, colorectal cancer and lung cancer patients, and for T1 melanoma, based on Australian data. In the absence of patient-level data about time to stage progression, two approaches were explored to estimate the proportion of patients that would experience a stage shift following the delay: 1) based on the relation between time to treatment initiation and overall survival (breast, colorectal and lung cancer), and 2) based on the tumour growth rate (melanoma). The model is available on http://stage-shift.personex.nl/.ResultsA shift from stage I to stage II due to a 6-month delay is least likely for colorectal cancer patients, with an estimated proportion of 3% of the stage I patients diagnosed in 2020 progressing to stage II, resulting in 11 excess deaths after 5 years and a total of 96 life years lost over a 10-year time horizon. For breast and lung cancer, progression from stage I to stage II due to a 6-month delay were slightly higher at 5% (breast cancer) and 8% (lung cancer), resulting in 25 and 43 excess deaths after 5 years, and 239 and 373 life years lost over a 10-year time horizon, respectively. For melanoma, with 32% of T1 patients progressing to T2 disease following a 6-month delay, the model estimated 270 excess death after 5 years and 2584 life years lost over a 10-year time horizon.ConclusionsUsing a conservative 3-month delay in diagnosis and treatment initiation due to the COVID-19 pandemic, this study predicts nearly 90 excess deaths and $12 million excess healthcare costs in Australia over 5 years for the in 2020 diagnosed patients for 4 cancers. If the delays increase to 6 months, excess mortality and cost approach nearly 350 deaths and $46 million in Australia. More accurate data on stage of disease during and after the COVID-19 pandemic are critical to obtain more reliable estimates.
Fusion protein EWS-FLI1 is incorporated into a protein granule in cells
Authors: Ahmed Nasiha S. , Harrell Lucas M. , Wieland Daniel R. , Lay Michelle A. , Thompson Valery F. , Schwartz Jacob C. 
Published: May 2020

ABSTRACTEwing sarcoma is driven by fusion proteins containing a low complexity (LC) domain that is intrinsically disordered and a powerful transcriptional regulator. The most common fusion protein found in Ewing sarcoma, EWS-FLI1, takes its LC domain from the RNA-binding protein EWSR1 (Ewing Sarcoma RNA-binding protein 1) and a DNA-binding domain from the transcription factor FLI1 (Friend Leukemia Virus Integration 1). EWS-FLI1 can bind RNA polymerase II (RNA Pol II) and self-assemble through its low-complexity (LC) domain. The ability of RNA-binding proteins like EWSR1 to self-assemble or phase separate in cells has raised questions about the contribution of this process to EWS-FLI1 activity. We examined EWSR1 and EWS-FLI1 activity in Ewing sarcoma cells by siRNA-mediated knockdown and RNA-seq analysis. More transcripts were affected by the EWSR1 knockdown than expected and these included many EWS-FLI1 regulated genes. We reevaluated physical interactions between EWS-FLI1, EWSR1, and RNA Pol II, and employed a cross-linking based strategy to investigate protein assemblies associated with the proteins. The LC domain of EWS-FLI1 was required for the assemblies observed to form in cells. These results offer new insights into a protein assembly that may enable EWS-FLI1 to bind its wide network of protein partners and contribute to regulation of gene expression in Ewing sarcoma.