bluuebunny/crossref_metadata_2025_split huggingface dataset:
Underdetection of COVID-19 cases in France in the exit phase following lockdown
Authors: Pullano Giulia , Domenico Laura Di , Sabbatini Chiara E , Valdano Eugenio , Turbelin Clément , Debin Marion , Guerrisi Caroline , Kengne-Kuetche Charly , Souty Cécile , Hanslik Thomas , Blanchon Thierry , Boëlle Pierre-Yves , Figoni Julie , Vaux Sophie , Campèse Christine , Bernard-Stoecklin Sibylle , Colizza Vittoria 
Published: August 2020

ABSTRACTA novel testing policy was implemented in May in France to systematically screen potential COVID-19 infections and suppress local outbreaks while lifting lockdown restrictions. 20,736 virologically-confirmed cases were reported in mainland France from May 13, 2020 (week 20, end of lockdown) to June 28 (week 26). Accounting for missing data and the delay from symptom onset to confirmation test, this corresponds to 7,258 [95% CI 7,160-7,336] cases with symptom onset during this period, a likely underestimation of the real number. Using age-stratified transmission models parameterized to behavioral data and calibrated to regional hospital admissions, we estimated that 69,115 [58,072-77,449] COVID-19 symptomatic cases occurred, suggesting that 9 out of 10 cases with symptoms were not ascertained. Median detection rate increased from 7% [6-9]% to 31% [28-35]% over time, with regional estimates varying from 11% (Grand Est) to 78% (Normandy) by the end of June. Healthcare-seeking behavior in COVID-19 suspect cases remained low (31%) throughout the period. Model projections for the incidence of symptomatic cases (4.5 [3.9-5.0] per 100,000) were compatible with estimates integrating participatory and virological surveillance data, assuming all suspect cases consulted. Encouraging healthcare-seeking behavior and awareness in suspect cases is critical to improve detection. Substantially more aggressive and efficient testing with easier access is required to act as a pandemic-fighting tool. These elements should be considered in light of the currently observed resurgence of cases in France and other European countries.
At-level allodynia after mid-thoracic contusion in the rat
Authors: Blumenthal G. H. , Nandakumar B. , Schnider A. K. , Detloff M. R. , Ricard J. , Bethea J. R. , Moxon K. A. 
Published: August 2020

AbstractThe rat mid-thoracic contusion model has been used to study at-level tactile allodynia after spinal cord injury (SCI), one of the more common types of allodynia. An important advantage of this model is that not all animals develop allodynia and, therefore, it could be used to more clearly examine mechanisms that are strictly related to pain development separately from mechanisms related to the injury itself. However, how to separate those that develop allodynia from those that do not is unclear. The aims of the current study were to identify where allodynia and spasticity develop and use this information to identify metrics that separate animals that develop allodynia from those that do not in order study difference in their behavior. To accomplish these aims, a standardized grid was used to localize pain on the dorsal trunk and map it to thoracic dermatomes, providing for the development of a pain score that relied on supraspinal responses and separated subgroups of animals. Similar to human studies, the development of allodynia often occurred with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of pain phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans who have sustained an SCI. However, the amount of spared spinal matter in the injured cord did not explain the development of allodynia, as was previously reported. This approach can be used to study the mechanism underlying the development of allodynia separately from mechanisms related to the injury alone.
The conserved Arabidopsis PM19L1 protein functions as an osmosensor and regulator of dormancy and germination
Authors: Alexander Ross D. , Castillejo-Pons Pablo , Melzer Nina , Alsaif Omar , Strotmann Vivien I. , Stahl Yvonne , Seale Madeleine , Morris Peter C. 
Published: August 2020

AbstractHow plants perceive water, especially during the critical stages of seed formation and germination, is key to their survival. During development and germination, seeds undergo large changes in water content, down to around 10% during maturation and up to 90% again within 24 hours of germination. We find the evolutionary conserved Arabidopsis plasma membrane protein PM19L1 to be an osmosensor, regulating dormancy and germination under osmotic stress. The PM19L1 protein structurally resembles the yeast osmosensor Sho1, with four transmembrane domains, andPM19L1complements the osmosensitivesho1mutant. Arabidopsispm19l1mutants have enhanced dormancy and reduced germination under salt and osmotic stress, and enhanced ABA levels. In a striking parallel to osmosensing in yeast, signalling downstream of PM19L1 involves a MAP kinase signal transduction pathway.PM19L1is a positive regulator ofABI3, which promotes the late maturation of the seed, and negatively regulates theABI4andABI5dormancy- regulating transcription factors. These results have implications for the study of dormancy, drought, and salinity tolerance in crops, and may provide an insight into evolutionary adaptation of plants to a terrestrial environment.
The selection of reference genome and the search for the origin of SARS-CoV-2
Authors: Liu Yuan , Yan Changhui 
Published: August 2020

AbstractsThe pandemic caused by SARS-CoV-2 has a great impact on the whole world. In a theory of the origin of SARS-CoV-2, pangolins were considered a potential intermediate host. To assemble the coronavirus found in pangolins, SARS-CoV-2 were used a reference genome in most of studies, assuming that pangolins CoV and SARS-CoV-2 are the closest neighbors in the evolution. However, this assumption may not be true. We investigated how the selection of reference genome affect the resulting CoV genome assembly. We explored various representative CoV as reference genome, and found significant differences in the resulting assemblies. The assembly obtained using RaTG13 as reference showed better statistics in total length and N50 than the assembly guided by SARS-CoV-2, indicating that RaTG13 maybe a better reference for assembling CoV in pangolin or other potential intermediate hosts.
The Ebola virus interferon antagonist VP24 undergoes active nucleocytoplasmic trafficking
Authors: Harrison Angela R. , Moseley Gregory W. 
Published: August 2020

AbstractViral interferon (IFN) antagonist proteins mediate evasion of IFN-mediated innate immunity and are often multifunctional, having distinct roles in viral replication processes. Functions of the Ebola virus (EBOV) IFN antagonist VP24 include nucleocapsid assembly during cytoplasmic replication and inhibition of IFN-activated signalling by STAT1. For the latter, VP24 prevents STAT1 nuclear importviacompetitive binding to nuclear import receptors (karyopherins). Many viral proteins, including proteins from viruses with cytoplasmic replication cycles, interact with the trafficking machinery to undergo nucleocytoplasmic transport, with key roles in pathogenesis. Despite established karyopherin interaction, the nuclear trafficking profile of VP24 has not been investigated. We find that VP24 becomes strongly nuclear following overexpression of karyopherin or inhibition of nuclear export pathways. Molecular mapping indicates that cytoplasmic localisation of VP24 depends on a CRM1-dependent nuclear export sequence at the VP24 C-terminus. Nuclear export is not required for STAT1 antagonism, consistent with competitive karyopherin binding being the principal antagonistic mechanism while export mediates return of nuclear VP24 to the cytoplasm for replication functions. Thus, nuclear export of VP24 might provide novel targets for antiviral approaches.ImportanceEbola virus (EBOV) is the causative agent of ongoing outbreaks of severe haemorrhagic fever with case-fatality rates between 40 and 60%. Proteins of many viruses with cytoplasmic replication cycles similar to EBOV interact with the nuclear trafficking machinery, resulting in active nucleocytoplasmic shuttling important to immune evasion and other intranuclear functions. However, exploitation of host trafficking machinery for nucleocytoplasmic transport by EBOV has not been directly examined. We find that the EBOV protein VP24 is actively trafficked between the nucleus and cytoplasm, and identify the specific pathways and sequences involved. The data indicate that nucleocytoplasmic trafficking is important for the multifunctional nature of VP24, which has critical roles in immune evasion and viral replication, identifying a new mechanism in infection by this highly lethal pathogen, and potential target for antivirals.
Using serum metabolomics analysis to predict sub-clinical atherosclerosis in patients with SLE
Authors: Coelewij Leda , Waddington Kirsty E , Robinson George A , Chocano Elvira , McDonnell Thomas , Farinha Filipa , Peng Junjie , Dönnes Pierre , Smith Edward , Croca Sara , Griffin Maura , Nicolaides Andrew , Rahman Anisur , Jury Elizabeth C , Pineda-Torra Ines 
Published: August 2020

AbstractBackgroundPatients with systemic lupus erythematosus (SLE) have an increased risk of developing cardiovascular disease (CVD) and 30-40% have sub-clinical atherosclerosis on vascular ultrasound scanning. Standard measurements of serum lipids in clinical practice do not predict CVD risk in patients with SLE. We hypothesise that more detailed analysis of lipoprotein taxonomy could identify better predictors of CVD risk in SLE.MethodsEighty patients with SLE and no history of CVD underwent carotid and femoral ultrasound scans; 30 had atherosclerosis plaques (SLE-P) and 50 had no plaques (SLE-NP). Serum samples obtained at the time of the scan were analysed using a lipoprotein-focused metabolomics platform assessing 228 metabolites by nuclear magnetic resonance spectroscopy. Data was analysed using logistic regression and five binary classification models with 10-fold cross validation; decision tree, random forest, support vector machine and lasso (Least Absolute Shrinkage and Selection Operator) logistic regression with and without interactions.ResultsUnivariate logistic regression identified four metabolites associated with the presence of sub-clinical plaque; three subclasses of very low density lipoprotein (VLDL) (percentage of free cholesterol in medium and large VLDL particles and percentage of phospholipids in chylomicrons and extremely large VLDL particles) and Leucine. Together with age, these metabolites were also within the top features identified by the lasso logistic regression (with and without interactions) and random forest machine learning models. Logistic regression with interactions differentiated between SLE-P and SLE-NP with greatest accuracy (0.800). Notably, percentage of free cholesterol in large VLDL particles and age were identified by all models as being important to differentiate between SLE-P and SLE-NP patients.ConclusionSerum metabolites are a promising biomarker for prediction of sub-clinical atherosclerosis development in SLE patients and could provide novel insight into mechanisms of early atherosclerosis development.
A Comprehensive Classification of Coronaviruses and Inferred Cross-Host Transmissions
Authors: Fu Yiran , Pistolozzi Marco , Yang Xiaofeng , Lin Zhanglin 
Published: August 2020

AbstractIn this work, we present a unified and robust classification scheme for coronaviruses based on concatenated protein clusters. This subsequently allowed us to infer the apparent “horizontal gene transfer” events via reconciliation with the corresponding gene trees, which we argue can serve as a marker for cross-host transmissions. The cases of SARS-CoV, MERS-CoV, and SARS-CoV-2 are discussed. Our study provides a possible technical route to understand how coronaviruses evolve and are transmitted to humans.
AT-527 is a potentin vitroreplication inhibitor of SARS-CoV-2, the virus responsible for the COVID-19 pandemic
Authors: Good Steven S. , Westover Jonna , Jung Kie Hoon , La Colla Paolo , Collu Gabriella , Moussa Adel , Canard Bruno , Sommadossi Jean-Pierre 
Published: August 2020

ABSTRACTAT-527, an orally administered double prodrug of a guanosine nucleotide analog, has been shown previously to be highly efficacious and well tolerated in HCV-infected subjects. Herein we report the potentin vitroactivity of AT-511, the free base form of AT-527, against several coronaviruses, including SARS-CoV-2, the causative agent of COVID-19. In normal human airway epithelial (HAE) cell preparations, the average concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.5 µM, very similar to the EC90for AT-511 against HCoV-229E, HCoV-OC43 and SARS-CoV in Huh-7 cells. No cytotoxicity was observed for AT-511 in any of the antiviral assays up to the highest concentration tested (100 µM). Surprisingly, AT-511 was 30-fold less active against MERS-CoV. This differential activity may provide a clue to the apparent unique mechanism of action of the guanosine triphosphate analog formed from AT-527.
Ana1 recruits PLK1 to mother centrioles to promote mitotic PCM assembly and centriole elongation
Authors: Alvarez-Rodrigo Ines , Wainman Alan , Raff Jordan W. 
Published: August 2020

AbstractPolo kinase (PLK1) is a master cell cycle regulator that is recruited to various subcellular structures by its Polo-Box domain (PBD), which binds to phosphorylated S-pS/pT motifs. Polo has multiple functions at centrioles and centrosomes, and we previously showed that phosphorylated Sas-4 initiates Polo recruitment to newly formed centrioles, while phosphorylated Spd-2 recruits Polo to the mitotic Pericentriolar Material (PCM) that assembles around mother centrioles. Here, we investigate whether additional proteins recruit Polo to centrioles and/or centrosomes, and find that Ana1 (Cep295 in mammals) helps recruit Polo to mother centrioles. If this function is impaired, mother centrioles can still duplicate and disengage from their daughters, but they can no longer efficiently assemble a mitotic PCM or elongate their centrioles in G2. Thus, Ana1 is part of a sequential phosphorylation cascade that recruits Polo to centrioles to drive mitotic centrosome assembly and centriole elongation in G2, but not centriole duplication or disengagement.
Model-based prediction of bacterial population dynamics in gastrointestinal infection
Authors: Geißert Janina K. , Bohn Erwin , Mostolizadeh Reihaneh , Dräger Andreas , Autenrieth Ingo B. , Beier Sina , Deusch Oliver , Eichner Martin , Schütz Monika S. 
Published: August 2020

AbstractThe complex interplay of a pathogen with the host immune response and the endogenous microbiome determines the course and outcome of gastrointestinal infection (GI). Expansion of a pathogen within the gastrointestinal tract implies an increased risk to develop systemic infection. Through computational modeling, we aimed to calculate bacterial population dynamics in GI in order to predict infection course and outcome. For the implementation and parameterization of the model, oral mouse infection experiments withYersinia enterocoliticawere used. Our model takes into account pathogen specific characteristics, such as virulence, as well as host properties, such as microbial colonization resistance or immune responses. We were able to confirm the model calculations in these scenarios by experimental mouse infections and show that it is possible to computationally predict the infection course. Far future clinical application of computational modeling of infections may pave the way for personalized treatment and prevention strategies of GI.
Lactoferrin as potential supplementary nutraceutical agent in COVID-19 patients:in vitroandin vivopreliminary evidences
Authors: Campione Elena , Lanna Caterina , Cosio Terenzio , Rosa Luigi , Conte Maria Pia , Iacovelli Federico , Romeo Alice , Falconi Mattia , Del Vecchio Claudia , Franchin Elisa , Lia Maria Stella , Minieri Marilena , Chiaramonte Carlo , Ciotti Marco , Nuccetelli Marzia , Terrinoni Alessandro , Magrini Andrea , Bernardini Sergio , Andreoni Massimo , Sarmati Loredana , Miani Alessandro , Piscitelli Prisco , Valenti Piera , Bianchi Luca 
Published: August 2020

ABSTRACTLactoferrin, a multifunctional cationic glycoprotein, secreted by exocrine glands and neutrophils, possesses an antiviral activity extendable to SARS-CoV-2.We performedin vitroassays proving lactoferrin antiviral activity through direct attachment to both virus and cell surface components. This activity varied according to concentration (100/500μg/ml), multiplicity of infection (0.1/0.01) and cell type (Vero E6/Caco-2 cells).Interestingly, thein silicoresults strongly supported the hypothesis of a direct recognition between the lactoferrin and the Spike S glycoprotein, thus hindering the viral entry into the cells.Hence, we conducted a clinical trial to investigate effect and tolerability of a liposomal lactoferrin formulation as a supplementary nutraceutical agent in mild-to-moderate and asymptomatic COVID-19 patients.A total of 92 mild-to-moderate (67/92) and asymptomatic (25/92) COVID-19 patients were recruited and divided in 3 groups according to the administered regimen. Thirty-two patients, 14 hospitalised and 18 in home-based insolation received oral and intranasal liposomal bovine lactoferrin (bLf), 32 hospitalised patients were treated with standard of care treatment (hydroxychloroquine, azitromicin and lopinavir/darunavir), and 28, in home-based isolation, did not take any medication. Furthermore, 32 COVID-19 negative, not-treated, healthy subjects were added as a control group for ancillary analysis.bLf-supplemented COVID-19 patients obtained an earlier and significant (p < 0,0001.) median rRT-PCR SARS-COV-2 RNA negative conversion than standard of care-treated and non-treated COVID-19 patients (14.25 vs 27.13 vs 32.61 days, respectively).In addition, bLf-supplemented COVID-19 patients showed significant fast clinical symptoms recovery than standard of care-treated and non-treated COVID-19 patients. Moreover, in bLf-supplemented patients, a significant decrease of either serum ferritin or IL-6 levels or host iron overload, all parameters characterizing inflammatory processes, were observed. Serum D-dimers was also found significantly decreased following bLf supplement. No adverse events were reported.Thesein vitroandin vivoobservations led us to speculate a potential and safe supplementary role of Blf in the management of mild-to-moderate and asymptomatic COVID-19 patients.
Structural and molecular basis for Cardiovirus 2A protein as a viral gene expression switch
Authors: Hill Chris H. , Napthine Sawsan , Pekarek Lukas , Kibe Anuja , Firth Andrew E. , Graham Stephen C. , Caliskan Neva , Brierley Ian 
Published: August 2020

AbstractProgrammed −1 ribosomal frameshifting (PRF) in cardioviruses is activated by the 2A protein: a multi-functional virulence factor that also inhibits cap-dependent translational initiation. Here we present the X-ray crystal structure of 2A and show that it selectively binds to and stabilises the PRF stimulatory RNA element in the viral genome. Using optical tweezers, we define the conformational repertoire of this element and measure changes in unfolding pathways arising from mutation and 2A binding. Next, we demonstrate a strong interaction between 2A and the small ribosomal subunit and present a cryo-EM structure of 2A bound to initiated 70S ribosomes. Multiple copies of 2A bind to the 16S rRNA where they may compete for binding with initiation and elongation factors. Together, these results define the structural basis for RNA recognition by 2A, expand our understanding of the 2A-dependent gene expression switch and reveal how 2A accumulation may shut down translation during virus infection.
Ambroxol and Ciprofloxacin Show Activity Against SARS-CoV2 in Vero E6 Cells at Clinically-Relevant Concentrations
Authors: Bradfute Steven B , Ye Chunyan , Clarke Elizabeth C , Kumar Suresh , Timmins Graham S , Deretic Vojo 
Published: August 2020

AbstractWe studied the activity of a range of weakly basic and moderately lipophilic drugs against SARS CoV2 in Vero E6 cells, using Vero E6 survival, qPCR of viral genome and plaque forming assays. No clear relationship between their weakly basic and hydrophobic nature upon their activity was observed. However, the approved drugs ambroxol and ciprofloxacin showed potent activity at concentrations that are clinically relevant and within their known safety profiles, and so may provide potentially useful agents for preclinical and clinical studies in COVID-19.
A 3.4-Å cryo-EM structure of the human coronavirus spike trimer computationally derived from vitrified NL63 virus particles
Authors: Zhang Kaiming , Li Shanshan , Pintilie Grigore , Chmielewski David , Schmid Michael F. , Simmons Graham , Jin Jing , Chiu Wah 
Published: August 2020

AbstractHuman coronavirus NL63 (HCoV-NL63) is an enveloped pathogen of the family Coronaviridae that spreads worldwide and causes up to 10% of all annual respiratory diseases. HCoV-NL63 is typically associated with mild upper respiratory symptoms in children, elderly and immunocompromised individuals. It has also been shown to cause severe lower respiratory illness. NL63 shares ACE2 as a receptor for viral entry with SARS-CoV and SARS-CoV-2. Here we present the in situ structure of HCoV-NL63 spike (S) trimer at 3.4-Å resolution by single-particle cryo-EM imaging of vitrified virions without chemical fixative. It is structurally homologous to that obtained previously from the biochemically purified ectodomain of HCoV-NL63 S trimer, which displays a 3-fold symmetric trimer in a single conformation. In addition to previously proposed and observed glycosylation sites, our map shows density at other amino acid positions as well as differences in glycan structures. The domain arrangement within a protomer is strikingly different from that of the SARS-CoV-2 S and may explain their different requirements for activating binding to the receptor. This structure provides the basis for future studies of spike proteins with receptors, antibodies, or drugs, in the native state of the coronavirus particles.
Jasmonic Acid coordinates with Light, Glucose and Auxin signalling in Regulating Branching Angle ofArabidopsisLateral Roots
Authors: Sharma Manvi , Sharma Mohan , Muhammed Jamsheer K , Laxmi Ashverya 
Published: August 2020

AbstractThe role of jasmonates (JAs) in primary root growth and development and in plant response to external stimuli is already known. However, its role in lateral root (LR) development remains to be explored. Our work identified methyl jasmonate (MeJA) as a key phytohormone in determining the branching angle ofArabidopsisLRs. MeJA inclines the LRs to a more vertical orientation, which was dependent on the canonicalJAR1-COI1-MYC2, 3, 4signalling. Our work also highlights the dual roles of light in governing LR angle. Light signalling enhances JA biosynthesis, leading to erect root architecture; whereas, glucose (Glc) induces wider branching angles. Combining physiological and molecular assays, we revealed that Glc antagonizes the MeJA response via TARGET OF RAPAMYCIN (TOR) signalling. Moreover, physiological assays using auxin mutants, MYC2-mediated transcriptional activation ofLAZY2, LAZY4and auxin biosynthetic geneCYP79B2, and asymmetric distribution ofDR5::GFPandPIN2::GFPpinpointed the role of an intact auxin mechanism required by MeJA for vertical growth of LRs. We also demonstrated that light perception and signalling are indispensable for inducing vertical angles by MeJA. Thus, our investigation highlights antagonism between light and Glc signalling and how they interact with JA-auxin signals to optimize the branching angle of LRs.