bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seroprevalence and immunity of SARS-CoV-2 infection in children and adolescents in schools in Switzerland: design for a longitudinal, school-based prospective cohort study
Authors: Ulyte Agne , Radtke Thomas , Abela Irène , Haile Sarah R , Braun Julia , Jung Ruedi , Berger Christoph , Trkola Alexandra , Fehr Jan , Puhan Milo A. , Kriemler Susi 
Published: September 2020

AbstractIntroductionSeroprevalence and transmission routes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents, especially in school setting, are not clear. Resulting uncertainty is reflected in very different decisions on school closures and reopenings across countries. The aim of this longitudinal cohort study is to assess the extent and patterns of seroprevalence of SARS-CoV-2 antibodies in school-attending children repeatedly. It will examine risk factors for infection, relationship between seropositivity and symptoms, and temporal persistence of antibodies. Additionally, it will include testing of school personnel and parents.Methods and analysisThe study (Ciao Corona) will enroll a regionally representative, random sample of schools in the canton of Zurich, where 18% of the Swiss population live. Children aged 5 to 16 years, attending classes in primary and secondary schools are invited. Venous blood and saliva samples are collected for SARS-CoV-2 serological testing after the first wave of infections (June/July 2020), in fall (October/November 2020), and after winter (March/April 2021). Venous blood is also collected for serological testing of parents and school personnel. Bi-monthly questionnaires to children, parents and school personnel cover SARS-CoV-2 symptoms and tests, health, preventive behavior, lifestyle and quality of life information. Total seroprevalence and cumulative incidence will be calculated. Hierarchical Bayesian logistic regression models will account for sensitivity and specificity of the serological test in the analyses and for the complex sampling structure, i.e., clustering within classes and schools.Ethics and disseminationThe study was approved by the Ethics Committee of the Canton of Zurich, Switzerland (2020-01336). The results of this study will be published in peer-reviewed journals and will be made available to study participants and participating schools, the Federal Office of Public Health, and the Educational Department of the canton of Zurich. Trial registration numberNCT04448717.Ciao Corona is a large, prospective school-based cohort study and will provide robust data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence, transmission routes and immunity over time in a representative sample of school children.The longitudinal design will allow describing temporal trends of immunity to SARS-CoV-2 infection and to evaluate effects of school structure and preventive measures.This study will inform goal-oriented policy decisions in school management during subsequent outbreaks.Participation bias, missing questionnaires, desirability bias, and loss of follow up may occur. The validity of serological tests may also hamper results.
Fully automated detection and differentiation of pandemic and endemic coronaviruses (NL63, 229E, HKU1, OC43 and SARS-CoV-2) on the Hologic Panther Fusion
Authors: Cordes Anne Katrin , Rehrauer William M. , Accola Molly A. , Wölk Benno , Hilfrich Birgitta , Heim Albert 
Published: September 2020

AbstractThe Hologic Panther Fusion (PF) platform provides fully automated CE marked diagnostics for respiratory viruses, including recently SARS-coronavirus 2 by a transcription mediated amplification (TMA) assay, but not for the endemic human coronaviruses (hCoV). Therefore, a laboratory developed multiplexed RT-PCR protocol (LDT) that detects and differentiates the four hCoV NL63, 229E, HKU1 and OC43 was adapted on the PF.The novel CE marked Aptima SARS-CoV-2 TMA and the LDT for hCoV were validated with 321 diagnostic specimens from the upper and lower respiratory tract in comparison to two SARS-CoV-2 RT-PCRs (PF E-gene LDT and genesig RT-PCR, 157 specimens) or the R-GENE hCoV / hParaFlu RT-PCR (164 specimens), respectively.For the endemic hCoV, results were 96.3% concordant with two specimens discordantly positive in the PF and four specimens discordantly positive in the R-GENE assay. All discordantly positive samples had Ct values between 33 and 39. The PF hCoV LDT identified 23 hCoV positive specimens as NL63, 15 as 229E, 15 as HKU1 and 25 as OC43. The Aptima SARS-CoV-2 TMA gave 99.4 % concordant results compared to the consensus results with a single specimen discordantly positive. Moreover, 36 samples from proficiency testing panels were detected and typed correctly by both novel methods.In conclusion, the SARS-CoV-2 TMA and the LDT for hCoV enhanced the diagnostic spectrum of the PF for all coronaviruses circulating globally for a multitude of diagnostic materials from the upper and lower respiratory tract.
Governor partisanship explains the adoption of statewide mask mandates in response to COVID-19
Authors: Adolph Christopher , Amano Kenya , Bang-Jensen Bree , Fullman Nancy , Magistro Beatrice , Reinke Grace , Wilkerson John 
Published: September 2020

AbstractPublic mask use has emerged as a key tool in response to COVID-19. We develop and document a classification of statewide mask mandates that reveals variation in their scope and timing. Some U.S. states quickly mandated the wearing of face coverings in most public spaces, whereas others issued narrow mandates or no man-date at all. We consider how differences in COVID-19 epidemiological indicators and partisan politics affect when states adopted broad mask mandates, starting with the earliest broad public mask mandates in April 2020 and continuing though the end of 2020. The most important predictor is whether a state is led by a Republican governor. These states adopt statewide indoor mask mandates an estimated 98.0 days slower (95% CI: 88.8 to 107.3), if they did so at all (hazard ratio=7.54, 95% CI: 2.87 to 16.19). COVID-19 indicators such as confirmed cases or deaths per million are much less important predictors of statewide mask mandates. This finding highlights a key challenge to public efforts to increase mask-wearing, one of the most effective tools for preventing the spread of SARS-CoV-2 while restoring economic activity.
Branched chain amino acids and risk of breast cancer
Authors: Zeleznik Oana A. , Balasubramanian Raji , Ren Yumeng , Tobias Deirdre K. , Rosner Bernard , Peng Cheng , Bever Alaina M. , Frueh Lisa , Clish Clary B. , Mora Samia , Hu Frank , Eliassen A. Heather 
Published: September 2020

AbstractCirculating branched chain amino acid (BCAA) levels reflect metabolic health as well as dietary intake and have been linked to some cancers. Associations with breast cancer are unclear.We evaluated the association between circulating BCAA levels and risk of breast cancer in a prospective nested case-control study (1,997 cases, 1,997 controls) within the Nurses’ Health Study (NHS) and NHSII. Two-thirds of women in NHS (592 cases) donated two blood samples collected 10 years apart. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk in multivariable models which included BMI at age 18 and adulthood weight gain, in addition to other risk factors. We conducted an external validation with secondary analyses in the Women’s Health Study (WHS) (1,297 cases).Among NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with suggestively lower breast cancer risk (e.g., isoleucine highest vs. lowest quartile, multivariable OR (95% CI)= 0.86 (0.65-1.13), p-trend=0.20), with significant linear trends among fasting samples (e.g., isoleucine OR (95% CI)=0.74 (0.53-1.05), p-trend=0.05). In contrast, among postmenopausal women, proximate measures (within 10y from blood draw) were associated with increased breast cancer risk (e.g., isoleucine highest vs. lowest quartile multivariable OR (95% CI)=1.63 (1.12-2.39), p-trend=0.01), with slightly stronger associations among fasting samples (OR (95% CI)=1.73 (1.15-2.61), p-trend=0.01). Distant measures (10-20y since blood draw) were not statistically significantly associated with risk (OR (95% CI)=1.15 (0.87-1.52), p-trend=0.35). We did not observe significant heterogeneity by ER status or BMI. In the WHS, a suggestive positive association was observed for distant measures of leucine among postmenopausal women: OR (95% CI)=1.31 (0.97-1.75), p-trend=0.05.Although elevated circulating BCAA levels were associated with lower breast cancer risk among premenopausal NHSII women and higher risk of postmenopausal breast cancer in NHS when assessed within 10 years of diagnosis, independent of established risk factors, including adiposity, results were not validated in WHS. Additional independent studies are needed to reassess and understand the complex relationship between BCAAs, menopausal status and timing, and risk of breast cancer.Statement of significanceElevated circulating BCAA levels were associated with lower breast cancer risk among premenopausal NHSII women and higher risk of postmenopausal breast cancer in NHS when assessed within 10 years of diagnosis, independent of established risk factors, including adiposity.
Extreme stiffness of neuronal synapses and implications for synaptic adhesion and plasticity
Authors: Yang Ju , Mandriota Nicola , Harrellson Steven Glenn , Jones-Molina John Anthony , Yuste Rafael , Lefort Roger , Sahin Ozgur 
Published: September 2020

AbstractSynapses play a critical role in neural circuits, and they are potential sites for learning and memory. Maintenance of synaptic adhesion is critical for neural circuit function, however, biophysical mechanisms that help maintain synaptic adhesion are not clear. Studies with various cell types demonstrated the important role of stiffness in cellular adhesions. Although synaptic stiffness could also play a role in synaptic adhesion, stiffnesses of synapses are difficult to characterize due to their small size and challenges in verifying synapse identity and function. To address these challenges, we have developed an experimental platform that combines atomic force microscopy, fluorescence microscopy, and transmission electron microscopy. Here, using this platform, we report that functional, mature, excitatory synapses had an average elastic modulus of approximately 200 kPa, two orders of magnitude larger than that of the brain tissue, suggesting stiffness might have a role in synapse function. Similar to various functional and anatomical features of neural circuits, synaptic stiffness had a lognormal-like distribution, hinting a possible regulation of stiffness by processes involved in neural circuit function. In further support of this possibility, we observed that synaptic stiffness was correlated with spine size, a quantity known to correlate with synaptic strength. Using established stages of the long-term potentiation timeline and theoretical models of adhesion cluster dynamics, we developed a biophysical model of the synapse that not only explains extreme stiffness of synapses, their statistical distribution, and correlation with spine size, but also offers an explanation to how early biomolecular and structural changes during functional potentiation could lead to strengthening of synaptic adhesion. According to this model, synaptic stiffness serves as an indispensable physical messenger, feeding information back to synaptic adhesion molecules to facilitate maintenance of synaptic adhesion.
Widespread decline in plant diversity across six decades
Authors: David Eichenberg , Bowler Diana E. , Aletta Bonn , Helge Bruelheide , Volker Grescho , David Harter , Ute Jandt , Rudolf May , Marten Winter , Florian Jansen 
Published: September 2020

AbstractBased on plant occurrence data covering all parts of Germany, we investigated changes in the distribution of 2146 plant species between 1960 and 2017. We analyzed 29 million occurrence records over an area of ∼350.000 km2on a 5 × 5 km grid using temporal and spatio-temporal models and accounting for sampling bias. Since the 1960s, more than 70% of investigated plant species showed significant declines in nation-wide occurrence. Archaeophytes (species introduced before 1492) most strongly declined but also native plant species experienced severe declines. In contrast, neophytes (species introduced after 1492) increased in their nation-wide occurrence but not homogeneously throughout the country. Our analysis suggests that the strongest declines in native species already happened in the 1960s-80s, a time frame in which usually few data exist. Increases in neophytic species were strongest in the 1990s and 2010s. Overall, the increase in neophytes did not compensate for the loss of other species, resulting in a decrease in mean grid-cell species-richness of -1.9% per decade. The decline in plant biodiversity is a widespread phenomenon occurring in different habitats and geographic regions. It is likely that this decline has major repercussions on ecosystem functioning and overall biodiversity, potentially with cascading effects across trophic levels. The approach used in this study is transferable to large-scale trend analyses using heterogeneous occurrence data.
Attenuation of homeostatic signaling from apoptotic thymocytes triggers a global regenerative response in the thymus
Authors: Kinsella Sinéad , Evandy Cindy A. , Cooper Kirsten , Iovino Lorenzo , deRoos Paul C. , Hopwo Kayla S. , Granadier David W. , Smith Colton W. , Rafii Shahin , Dudakov Jarrod A. 
Published: September 2020

ABSTRACTThe molecular triggers of organotypic tissue repair are unknown. The thymus, which is the primary site of T cell development, is a model of tissue damage and regeneration as it is particularly sensitive to insult, but also has a remarkable capacity for repair. However, acute and profound damage, such as that caused by common cytoreductive therapies or age-related decline, lead to involution of the thymus and prolonged T cell deficiency, precipitating life-threatening infections and malignant relapse. Consequently, there is an unmet need to boost thymic function and enhance T cell immunity. Here, we demonstrate an innate trigger of the reparative response in the thymus, centered on the attenuation of signaling directly downstream of apoptotic cell detection as thymocytes are depleted after acute damage. We found that the intracellular pattern recognition receptor NOD2, via induction of microRNA-29c, suppressed the induction of the regenerative factors IL-23 and BMP4, from thymic dendritic cells (DCs) and endothelial cells (ECs), respectively. During steady-state, when a high proportion of thymocytes are undergoing apoptosis (as a consequence of selection events during T cell development), this suppressive pathway is constitutively activated by the detection of exposed phosphatidylserine on apoptotic thymocytes by cell surface TAM receptors on DCs and ECs, with subsequent downstream activation of the Rho GTPase Rac1. However, after damage, when profound cell depletion occurs across the thymus, the TAM-Rac1-NOD2-miR29c pathway is abrogated, therefore triggering the increase in IL-23 and BMP4 levels. Importantly, this pathway could be modulated pharmacologically by inhibiting Rac1 GTPase activation with the small molecule inhibitor EHT1864, leading to increased thymic function and T cell recovery after acute damage. In conclusion, our work not only represents a novel regenerative strategy for restoring immune competence in patients whose thymic function has been compromised due to cytoreductive conditioning, infection, or age; but also, identifies a mechanism by which tissue regenerative responses are triggered.
Selective effects of arousal on population coding of natural sounds in auditory cortex
Authors: Heller Charles R. , Schwartz Zachary P. , Saderi Daniela , David Stephen V. 
Published: September 2020

AbstractThe ability to discriminate between complex natural sounds is critical for survival. Changes in arousal and other aspects of behavioral state can impact the accuracy of sensory coding, affecting both the reliability of single neuron responses and the degree of correlated noise between neurons. However, it is unclear how these effects interact to influence coding of diverse natural stimuli. We recorded the spiking activity of neural populations in primary auditory cortex (A1) evoked by a large library of natural sounds while monitoring changes in pupil size as an index of arousal. Heightened arousal increased response magnitude and reduced noise correlations between neurons, improving coding accuracy on average. Rather than suppressing shared noise along all dimensions of neural activity, the change in noise correlations occurred via coherent, low-dimensional modulation of response variability in A1. The modulation targeted a different group of neurons from those undergoing changes in response magnitude. Thus, changes in response magnitude and correlation are mediated by distinct mechanisms. The degree to which these low-dimensional changes were aligned with the high-dimensional natural sound-evoked activity was variable, resulting in stimulus-dependent improvements in coding accuracy.
Multi-modal pooled Perturb-CITE-Seq screens in patient models define novel mechanisms of cancer immune evasion
Authors: Frangieh Chris J. , Melms Johannes C. , Thakore Pratiksha I. , Geiger-Schuller Kathryn R. , Ho Patricia , Luoma Adrienne M. , Cleary Brian , Malu Shruti , Cuoco Michael S. , Zhao Maryann , Rogava Meri , Hovey Lila , Rotem Asaf , Bernatchez Chantale , Wucherpfennig Kai W. , Johnson Bruce E. , Rozenblatt-Rosen Orit , Schadendorf Dirk , Regev Aviv , Izar Benjamin 
Published: September 2020

AbstractResistance to immune checkpoint inhibitors (ICI) that activate T cell mediated anti-tumor immunity is a key challenge in cancer therapy, yet the underlying mechanisms remain poorly understood. To further elucidate those, we developed a new approach, Perturb-CITE-seq, for pooled CRISPR perturbation screens with multi-modal RNA and protein single-cell profiling readout and applied it to screen patient-derived autologous melanoma and tumor infiltrating lymphocyte (TIL) co-cultures. We profiled RNA and 20 surface proteins in over 218,000 cells under ~750 perturbations, chosen by their membership in an immune evasion program that is associated with immunotherapy resistance in patients. Our screen recovered clinically-relevant resistance mechanisms concordantly reflected in RNA, protein and perturbation effects on susceptibility to T cell mediated killing. These were organized in eight co-functional modules whose perturbation distinctly affect four co-regulated programs associated with immune evasion. Among these were defects in the IFNγ-JAK/STAT pathway and in antigen presentation, and several novel mechanisms, including loss or downregulation ofCD58, a surface protein without known mouse homolog. Leveraging the rich profiles in our screen, we found that loss ofCD58did not compromise MHC protein expression and thatCD58was not transcriptionally induced by the IFNγ pathway, allowing us to distinguish it as a novel mechanism of immune resistance. We further show that loss ofCD58on cancer cells conferred immune evasion across multiple T cell and Natural Killer cell patient co-culture models. Notably, CD58 is downregulated in tumors with resistance to immunotherapy in melanoma patients. Our work identifies novel mechanisms at the nexus of immune evasion and drug resistance and provides a general framework for deciphering complex mechanisms by large-scale perturbation screens with multi-modal singlecell profiles, including in systems consisting of multiple cell types.
Spatially-targeted proteomics of the host-pathogen interface during staphylococcal abscess formation
Authors: Guiberson Emma R. , Weiss Andy , Ryan Daniel J. , Monteith Andrew J. , Sharman Kavya , Gutierrez Danielle B. , Perry William J. , Caprioli Richard M. , Skaar Eric P. , Spraggins Jeffrey M. 
Published: September 2020

AbstractStaphylococcus aureusis a common cause of invasive and life-threatening infections that are often multi-drug resistant. To develop novel treatment approaches, a detailed understanding of the complex host-pathogen interactions during infection is essential. This is particularly true for the molecular processes that govern the formation of tissue abscesses, as these heterogeneous structures are important contributors to staphylococcal pathogenicity. To fully characterize the developmental process leading to mature abscesses, temporal and spatial analytical approaches are required. Spatially targeted proteomic technologies, such as micro liquid extraction surface analysis, offer insight into complex biological systems including detection of bacterial proteins, and their abundance in the host environment. By analyzing the proteomic constituents of different abscess regions across the course of infection, we defined the immune response and bacterial contribution to abscess development through spatial and temporal proteomic assessment. The information gathered was mapped to biochemical pathways to characterize the metabolic processes and immune strategies employed by the host. These data provide insights into the physiological state of bacteria within abscesses and elucidate pathogenic processes at the host-pathogen interface.
Branching microtubule nucleation is controlled by importin-mediated inhibition of TPX2 phase separation
Authors: Safari Mohammad S. , King Matthew R. , Brangwynne Clifford P. , Petry Sabine 
Published: September 2020

AbstractThe microtubule-based mitotic spindle is responsible for equally partitioning the genome during each cell division, and its assembly is executed by several microtubule nucleation pathways. In the spindle center, Targeting Protein for XKlp2 (TPX2) promotes branching microtubule nucleation, where new microtubules are nucleated from pre-existing ones. Until the onset of spindle assembly, TPX2 is sequestered by importins-α/β, yet the molecular nature of this regulation remains unclear, particularly since TPX2 was recently found to undergo a liquid-liquid phase separation to execute its function. Here we demonstrate that TPX2 interacts with importins-α/β with nanomolar affinity as a 1:1:1 mono-dispersed trimer. We identify a new nuclear localization sequence (NLS) on TPX2, which contributes to its high-affinity interaction with importin-α. Interestingly, importin-β alone can also associate with TPX2, and does so via dispersed, weak interactions. Interactions of both importin-α and importin-β with TPX2 each inhibit its propensity for phase separation, and consequently its ability to orchestrate branching microtubule nucleation. In sum, our study explains how TPX2 is regulated in order to facilitate spindle assembly, and provides novel insight into how a protein phase separation can be inhibited via weak biomolecular interactions.Significance StatementThe discovery that proteins can undergo phase separation is revolutionizing biology. Characterization of dozens of phase separating proteins in vitro over the past several years has mainly focused on how macromolecules undergo liquid-liquid phase separation (LLPS). The next, and possibly bigger challenge is to investigate how LLPS is regulated in the cell, namely how it is inhibited to spatiotemporally control a certain cellular function. Here, we addressed this challenge by identifying how the spindle assembly factor TPX2 is inhibited by importins from undergoing LLPS and thereby turning on spindle assembly.