bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility of white-tailed deer (Odocoileus virginianus) to SARS-CoV-2
Authors: Palmer Mitchell V. , Martins Mathias , Falkenberg Shollie , Buckley Alexandra , Caserta Leonardo C. , Mitchell Patrick K. , Cassmann Eric D. , Rollins Alicia , Zylich Nancy C. , Renshaw Rendall W. , Guarino Cassandra , Wagner Bettina , Lager Kelly , Diel Diego G. 
Published: January 2021

AbstractThe origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the global coronavirus disease 19 (COVID-19) pandemic, remains a mystery. Current evidence suggests a likely spillover into humans from an animal reservoir. Understanding the host range and identifying animal species that are susceptible to SARS-CoV-2 infection may help to elucidate the origin of the virus and the mechanisms underlying cross-species transmission to humans. Here we demonstrated that white-tailed deer (Odocoileus virginianus), an animal species in which the angiotensin converting enzyme 2 (ACE2) – the SARS-CoV-2 receptor – shares a high degree of similarity to humans, are highly susceptible to infection. Intranasal inoculation of deer fawns with SARS-CoV-2 resulted in established subclinical viral infection and shedding of infectious virus in nasal secretions. Notably, infected animals transmitted the virus to non-inoculated contact deer. Viral RNA was detected in multiple tissues 21 days post-inoculation (pi). All inoculated and indirect contact animals seroconverted and developed neutralizing antibodies as early as day 7 pi. The work provides important insights into the animal host range of SARS-CoV-2 and identifies white-tailed deer as a susceptible wild animal species to the virus.IMPORTANCEGiven the presumed zoonotic origin of SARS-CoV-2, the human-animal-environment interface of COVID-19 pandemic is an area of great scientific and public- and animal-health interest. Identification of animal species that are susceptible to infection by SARS-CoV-2 may help to elucidate the potential origin of the virus, identify potential reservoirs or intermediate hosts, and define the mechanisms underlying cross-species transmission to humans. Additionally, it may also provide information and help to prevent potential reverse zoonosis that could lead to the establishment of a new wildlife hosts. Our data show that upon intranasal inoculation, white-tailed deer became subclinically infected and shed infectious SARS-CoV-2 in nasal secretions and feces. Importantly, indirect contact animals were infected and shed infectious virus, indicating efficient SARS-CoV-2 transmission from inoculated animals. These findings support the inclusion of wild cervid species in investigations conducted to assess potential reservoirs or sources of SARS-CoV-2 of infection.
Real-Time Electronic Health Record Mortality Prediction During the COVID-19 Pandemic: A Prospective Cohort Study
Authors: Sottile Peter D. , Albers David , DeWitt Peter E. , Russell Seth , Stroh J.N. , Kao David P. , Adrian Bonnie , Levine Matthew E. , Mooney Ryan , Larchick Lenny , Kutner Jean S. , Wynia Matthew K. , Glasheen Jeffrey J. , Bennett Tellen D. 
Published: January 2021

AbstractBackgroundThe SARS-CoV-2 virus has infected millions of people, overwhelming critical care resources in some regions. Many plans for rationing critical care resources during crises are based on the Sequential Organ Failure Assessment (SOFA) score. The COVID-19 pandemic created an emergent need to develop and validate a novel electronic health record (EHR)-computable tool to predict mortality.Research QuestionsTo rapidly develop, validate, and implement a novel real-time mortality score for the COVID-19 pandemic that improves upon SOFA.Study Design and MethodsWe conducted a prospective cohort study of a regional health system with 12 hospitals in Colorado between March 2020 and July 2020. All patients >14 years old hospitalized during the study period without a do not resuscitate order were included. Patients were stratified by the diagnosis of COVID-19. From this cohort, we developed and validated a model using stacked generalization to predict mortality using data widely available in the EHR by combining five previously validated scores and additional novel variables reported to be associated with COVID-19-specific mortality. We compared the area under the receiver operator curve (AUROC) for the new model to the SOFA score and the Charlson Comorbidity Index.ResultsWe prospectively analyzed 27,296 encounters, of which 1,358 (5.0%) were positive for SARS-CoV-2, 4,494 (16.5%) included intensive care unit (ICU)-level care, 1,480 (5.4%) included invasive mechanical ventilation, and 717 (2.6%) ended in death. The Charlson Comorbidity Index and SOFA scores predicted overall mortality with an AUROC of 0.72 and 0.90, respectively. Our novel score predicted overall mortality with AUROC 0.94. In the subset of patients with COVID-19, we predicted mortality with AUROC 0.90, whereas SOFA had AUROC of 0.85.InterpretationWe developed and validated an accurate, in-hospital mortality prediction score in a live EHR for automatic and continuous calculation using a novel model, that improved upon SOFA.Take Home PointsStudy QuestionCan we improve upon the SOFA score for real-time mortality prediction during the COVID-19 pandemic by leveraging electronic health record (EHR) data?ResultsWe rapidly developed and implemented a novel yet SOFA-anchored mortality model across 12 hospitals and conducted a prospective cohort study of 27,296 adult hospitalizations, 1,358 (5.0%) of which were positive for SARS-CoV-2. The Charlson Comorbidity Index and SOFA scores predicted all-cause mortality with AUROCs of 0.72 and 0.90, respectively. Our novel score predicted mortality with AUROC 0.94.InterpretationA novel EHR-based mortality score can be rapidly implemented to better predict patient outcomes during an evolving pandemic.
Factor V is an immune inhibitor that is expressed at increased levels in leukocytes of patients with severe Covid-19
Authors: Wang Jun , Kotagiri Prasanti , Lyons Paul A , Mescia Federica , Bergamaschi Laura , Turner Lorinda , Al-Lamki Rafia S , Morgan Michael D , Calero-Nieto Fernando J , Bach Karsten , Mende Nicole , Wilson Nicola K , Watts Emily R ,   Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID BioResource Collaboration, Chinnery Patrick F , Kingston Nathalie , Papadia Sofia , Stirrups Kathleen , Walker Neil , Gupta Ravindra K , Toshner Mark , Weekes Michael P , Nathan James A , Walmsley Sarah R , Ouwehand Willem H , Kasanicki Mary , Göttgens Berthold , Marioni John C , Smith Kenneth GC , Pober Jordan S , Bradley John R 
Published: January 2021

AbstractSevere Covid-19 is associated with elevated plasma Factor V (FV) and increased risk of thromboembolism. We report that neutrophils, T regulatory cells (Tregs), and monocytes from patients with severe Covid-19 express FV, and expression correlates with T cell lymphopenia.In vitrofull length FV, but not FV activated by thrombin cleavage, suppresses T cell proliferation. Increased and prolonged FV expression by cells of the innate and adaptive immune systems may contribute to lymphopenia in severe Covid-19. Activation by thrombin destroys the immunosuppressive properties of FV. Anticoagulation in Covid-19 patients may have the unintended consequence of suppressing the adaptive immune system.
Direct Simulation of the CoVid-19 epidemic
Authors: Cabrera-Becerril Augusto , Miramontes Pedro , Peralta Raúl 
Published: January 2021

AbstractWe introduce an agent-based model to simulate the epidemiological dynamics of COVID-19. Most computational models proposed to study this epidemic do no take into account human mobility. We present a direct simulation model where mobility plays a key role and propose as well four quarantine strategies. The results show that the no-quarantine strategy does lead to a high peak of contagions with no rebound. Quarantined strategies, for their part, show a re-emergence of the epidemic with smaller and softer peaks.
Near-atomic resolution Cryo-EM structure of Mayaro virus identifies key structural determinants of alphavirus particle formation
Authors: Chmielewski David , Kaelber Jason , Jin Jing , Weaver Scott C. , Auguste Albert J. , Chiu Wah 
Published: January 2021

AbstractMayaro virus (MAYV) is an arthritis-inducing alphavirus circulating in the Americas, with potential to rapidly emerge in new geographical regions and populated environments. Intraparticle heterogeneity has typically limited atomic resolution structures of alphavirus virions, while imposing icosahedral symmetry in data processing prevents characterization of non-icosahedral features. Here, we report a near-atomic resolution cryo-EM structure of the MAYV E1-E2-E3-CP subunit by addressing deviations from icosahedral symmetry within each virus particle. We identified amino acid contacts at E1 protein interfaces forming the icosahedral lattice and investigated their effect on MAYV growth through site-directed mutagenesis. Further, mutation of a short stretch of conserved residues in E2 subdomain D, near an unidentified “pocket factor” including E2Y358, significantly reduced MAYV growth and provides strong evidence that this unknown factor influences assembly. Further, a symmetry-free reconstruction revealed the MAYV virion is not strictly icosahedral, suggesting defects in global symmetry may be a feature of the virus particle budding process. Our study provides insights into alphavirus assembly and suggests a common path in the formation of spherical, enveloped viruses, leading to particle imperfections.
Epidemiological and evolutionary consequences of CRISPR-Cas reactivity
Authors: Chabas Hélène , Müller Viktor , Bonhoeffer Sebastian , Regoes Roland R. 
Published: January 2021

AbstractAdaptive immune systems face a control challenge: they should react with enough strength to clear an infection while avoiding to harm their organism. CRISPR-Cas systems are adaptive immune systems of prokaryotes that defend against fast evolving viruses. Here, we explore the CRISPR-Cas control challenge and look how its reactivity, i.e. its probability to acquire a new resistance, impacts the epidemiological outcome of a phage outbreak and the prokaryote’s fitness. We show that in the absence of phage evolution, phage extinction is driven by the probability to acquire at least one resistance. However, when phage evolution is fast, phage extinction is characterised by an epidemiological critical threshold: any reactivity below this critical threshold leads to phage survival whereas any reactivity above it leads to phage extinction. We also show that in the absence of autoimmunity, high levels of reactivity evolve. However, when CRISPR-Cas systems are prone to autoimmune reactions, intermediate levels of reactivity are evolutionarily optimal. These results help explaining why natural CRISPR-Cas systems do not show high levels of reactivity.Author summaryCRISPR-Cas systems are adaptive immune systems that use a complex 3-step molecular mechanism to defend prokaryotes against phages. Viral infections of populations defending with CRISPR-Cas can result in rapid phage extinction or in medium-term phage maintenance. What controls phage fate? Using mathematical modeling, we show that two parameters control this outcome: the phage escape rate and CRISPR-Cas reactivity (i.e. its probability of resistance acquisition upon infection). Furthermore, CRISPR-Cas reactivity impacts host fitness. From this, we derive that 1) CRISPR-Cas reactivity is a key predictor of the efficiency and of the cost of a CRISPR-Cas system, 2) there is an optimal reactivity balancing the cost of autoimmunity and immune efficiency and 3) high phage escape rate selects for higher CRISPR-Cas reactivities.
Iron acquisition across outer membrane: The role of major outer membrane protein Slr1908 under iron supplemented conditions inSynechocystis6803
Authors: Agarwal Rachna , Choudhury Sharmistha Dutta , Narayana Rao Akipeddi V S S 
Published: January 2021

AbstractThe Ton-B dependent outer membrane (OM) transporters are responsible for active iron (Fe) import inSynechocystissp. strain PCC 6803 (S. 6803 or WT) under Fe depletion. However, the mechanism of Fe acquisition under Fe supplemented conditions remains uncharacterised. In the present study, functional role of OMP Slr1908 inS. 6803 was addressed by insertional mutagenesis. TheΔslr1908cells exhibited slower growth in the first week in comparison to the WT and displayed an absorption and 77K fluorescence spectrum typical of Fe deficiency. Indeed, the mutant had ∼ 80% less Fe as confirmed by atomic absorption spectroscopy and55Fe-radiotracer uptake. The iron deficiency was paralleled with low Mn content. The mutant had low SOD content as well as activity, less cytochromes, less chlorophyll content, less Fv/ Fm, lower ETRII and high oxidative stress in comparison to the WT at the end of first week. Interestingly, the mutant showed transcriptional upregulation of iron stress induced proteinisiAandisiBsignifying intracellular Fe deficiency. Upregulation of OMP Slr0042 was also observed at RNA and protein level. The results indicate that Slr1908 is a major Fe uptake OMP inS. 6803 the deletion of which leads to initial slow growth that gets partially offset by induction of other Fe importing OMPs.
The impact of age and education on phonemic and semantic verbal fluency: Behavioral and fMRI correlates
Authors: Fonseca Rochele Paz , Marcotte Karine , Hubner Lilian C. , Zimmermann Nicolle , Netto Tânia Maria , Bizzo Bernardo , Döring Thomas , Landeira-Fernandez J. , Gasparetto Emerson L. , Joanette Yves , Ansaldo Ana Inés 
Published: January 2021

AbstractThe purpose of this study was to examine the impact of age and education on the neural and behavioral correlates of verbal fluency. Forty-eight healthy adult participants were included: high-educated young and elderly, low-educated young and elderly. Participants performed semantic and phonemic and a control task during fMRI scanning. The phonemic fluency data showed an education effect across age groups. As for the semantic fluency data, there was an education effect only in young participants. The second-level fMRI results showed, in phonemic fluency, a main effect of age in the left posterior cingulate, superior temporal gyrus (STG) and right caudate, whereas the main effect of education involved activation in the right semantic fluency, there were a main effect of age in the left paracentral lobule and posterior cingulate, a main effect of education in the left claustrum and an interaction in the right claustrum and STG and the hippocampus bilaterally.
ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats
Authors: Har-Paz Ilona , Arieli Elor , Moran Anan 
Published: January 2021

AbstractThe E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learningviachanges in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.
Clinically Relevant Gene Editing in Hematopoietic Stem Cells for the Treatment of Pyruvate Kinase Deficiency Hemolytic Anemia
Authors: Fañanas-Baquero Sara , Quintana-Bustamante Oscar , Dever Daniel P. , Alberquilla Omaira , Sanchez Rebeca , Camarena Joab , Ojeda-Perez Isabel , Dessy-Rodriguez Mercedes , Turk Rolf , Schubert Mollie S. , Lopez-Lorenzo Jose L. , Bianchi Paola , Bueren Juan A. , Behlke Mark A. , Porteus Matthew , Segovia Jose-Carlos 
Published: January 2021

ABSTRACTPyruvate Kinase Deficiency (PKD) is an autosomal recessive disorder caused by mutations in the PKLR gene, which constitutes the main cause of chronic non-spherocytic hemolytic anemia. PKD incidence is estimated in 1 in 20,000 people worldwide. The PKLR gene encodes for the erythroid pyruvate kinase protein (RPK) implicated in the last step of the anaerobic glycolysis in red blood cells. The defective enzyme fails to maintain normal erythrocyte ATP levels, producing severe hemolytic anemia, and can be fatal in severe patients. The only curative treatment for PKD is allogeneic hematopoietic stem and progenitor cells (HSPC) transplantation, so far. However, HSPC transplant is associated with a significant morbidity and mortality, especially in PKD patients. Here, we address the correction of PKD through precise gene editing at the PKLR endogenous locus to keep the tight regulation of RPK enzyme during erythropoiesis. We combined CRISPR/Cas9 system and rAAVs for donor matrix delivery to build an efficient and safe system to knock-in a therapeutic donor at the translation start site of the RPK isoform in human hematopoietic progenitors. Edited human hematopoietic progenitors efficiently reconstituted human hematopoiesis in primary and secondary immunodeficient recipient mice. Moreover, erythroid cells derived from edited PKD-HSPCs restored normal levels of ATP, demonstrating the restoration of RPK function in PKD erythropoiesis after gene editing. Our gene editing strategy may represent a lifelong therapy to restore RPK functionality in RBCs of patients and correct PKD.Single Sentence SummaryClinically relevant gene editing in hematopoietic stem cells for the treatment of Pyruvate Kinase Deficiency.
Mice in a labyrinth: Rapid learning, sudden insight, and efficient exploration
Authors: Rosenberg Matthew , Zhang Tony , Perona Pietro , Meister Markus 
Published: January 2021

AbstractAnimals learn certain complex tasks remarkably fast, sometimes after a single experience. What behavioral algorithms support this efficiency? Many contemporary studies based on two-alternative-forced-choice (2AFC) tasks observe only slow or incomplete learning. As an alternative, we study the unconstrained behavior of mice in a complex labyrinth and measure the dynamics of learning and the behaviors that enable it. A mouse in the labyrinth makes ~2000 navigation decisions per hour. The animal quickly discovers the location of a reward in the maze and executes correct 10-bit choices after only 10 reward experiences – a learning rate 1000-fold higher than in 2AFC experiments. Many mice improve discontinuously from one minute to the next, suggesting moments of sudden insight about the structure of the labyrinth. The underlying search algorithm does not require a global memory of places visited and is largely explained by purely local turning rules.
Estimating and forecasting the burden and spread of SARS-CoV2 first wave in Colombia
Authors: Vega Jaime E. Cascante , Cordovez Juan M. , Santos-Vega Mauricio 
Published: January 2021

AbstractFollowing the rapid dissemination of COVID-19 cases in Colombia in 2020, large-scale non-pharmaceutical interventions (NPIs) were implemented as national emergencies in most of the municipalities of the country starting by a lockdown on March 20th of 2020. Using combinations of meta-population models SEAIIRD (Susceptible-Exposed-Asymptomatic-Infected-Recovered-Diseased) which describes the disease dynamics in the different localities, with movement data that accounts for the number of commuters between units and statistical inference algorithms could be an effective approach to both nowcast and forecast the number of cases and deaths in the country. Here we used an iterated filtering (IF) framework to fit the parameters of our model to the reported data across municipalities from march to late October in locations with more than 50 reported deaths and cases historically. Since the model is high dimensional (6 state variable by municipality) inference on those parameters is highly non-trivial, so we used an Ensemble-Adjustment-Kalman-Filter (EAKF) to estimate time variable system states and parameters. Our results show that the model is capable of capturing the evolution of the outbreak in the country and providing estimates of the epidemiological parameters in time. These estimates could become the base for planning future interventions as well as evaluate the impact of NPIs on the effective reproductive number (ℛeff) and the key epidemiological parameters, such as the contact rate or the reporting rate. Our approach demonstrates that real-time, publicly available ensemble forecasts can provide robust short-term predictions of reported COVID-19 deaths in Colombia. This model has the potential to be used as a forecasting and prediction tool to evaluate disease dynamics and to develop a real time surveillance system for management and control.
Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury
Authors: Kokkinopoulos Ioannis , Banos Aggelos , Grigoriou Maria , Filia Anastasia , Manolakou Theodora , Alissafi Themis , Malissovas Nikolaos , Mitroulis Ioannis , Verginis Panayotis , Boumpas Dimitrios T. 
Published: January 2021

ABSTRACTSystemic Lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). By employing next-generation sequencing, we compared the gene transcription signatures of CD34+HSPCs deriving from either the bone marrow or HSPCs patrolling the bloodstream of healthy and individuals with SLE, seeking common transcriptional pathways that may have been modified between steady and disease states. Our findings indicate that circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Non-mobilised, SLE-derived circulating HSPCs demonstrated enhanced engrafting and altered differentiation capacities. Importantly, xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. SLE CD34+HSPCs homing and engraftment at extramedullary sites such as the spleen and kidneys may participate in peripheral tissue injury.