bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Gender on Covid-19 Infections and Mortality in Germany: Insights From Age- and Sex-Specific Modelling of Contact Rates, Infections, and Deaths
Authors: Dörre Achim , Doblhammer Gabriele 
Published: October 2020

BackgroundRecent research points towards age- and sex-specific transmission of COVID-19 infections and their outcomes. The effect of sex, however, has been overlooked in past modelling approaches of COVID-19 infections.AimThe aim of our study is to develop an age- and sex-specific model of COVID-19 transmission and to explore how contact changes effect COVID-19 infection and death rates.MethodWe consider a compartment model to establish forecasts of the COVID-19 epidemic, in which the compartments are subdivided into different age groups and genders. Estimated contact patterns, based on other studies, are incorporated to account for age- and sex-specific social behaviour. The model is fitted to real data and used for assessing hypothetical scenarios with regard to lockdown measures.ResultsUnder current mitigation measures as of mid-August, active COVID-19 cases will double by the end of October 2020. Infection rates will be highest among the young and working ages, but will also rise among the old. Sex ratios reveal higher infection risks among women than men at working ages; the opposite holds true at old age. Death rates in all age groups are twice as high among men as women. Small changes in contact rates at working and young ages may have a considerable effect on infections and mortality at old age, with elderly men being always at higher risk of infection and mortality.DiscussionOur results underline the high importance of the non-pharmaceutical mitigation measures in low-infection phases of the pandemic to prevent that an increase in contact rates leads to higher mortality among the elderly. Gender differences in contact rates, in addition to biological mechanisms related to the immune system, may contribute to sex-specific infection rates and their mortality outcome. To further explore possible pathways, more data on COVID-19 transmission is needed which includes socio-demographic information.
Misinterpretation of viral load in COVID-19
Authors: Miranda Renan Lyra , Guterres Alexandro , de Azeredo Lima Carlos Henrique , Filho Paulo Niemeyer , Gadelha Mônica R. 
Published: October 2020

AbstractKnowledge of viral load is essential for formulating strategies for antiviral treatment, vaccination, and epidemiological control of COVID-19. Moreover, patients identification with high viral load could also be useful to understand risk factors such as age, comorbidities, severity of symptoms and hypoxia to decide the need for hospitalization. Several studies are evaluating the importance of analyzing viral load in different types of samples, clinical outcomes and viral transmission pathways. However, in a great number of emerging studies cycle threshold (Ct) values by itself is often used as a viral load indicator, which may be a mistake. In this study, we compared tracheal aspirate with nasopharyngeal samples obtained from critically ill COVID-19 patients and demonstrate how the raw Ct could lead to misinterpretation of results. Further, we analyzed nasopharyngeal swabs positive samples and propose a method to reduce evaluation error that could occur from using raw Ct. Based on these findings, we show the impact that normalization of Ct values has on interpretation of viral load data from different biological samples from patients with COVID-19, transmission and lastly in relations with clinical outcomes.ImportanceIn a pandemic, prevention of disease transmission is key. Reliable data for profiles of viral load are needed and important to guide antiviral treatment, infection control and vaccination. The differential expression of SARS-CoV-2 viral RNA among patient groups is a current topic of interest and viral load has been associated with a diversity of outcomes. However, in a great number of emerging studies cycle threshold (Ct) values by itself is often used as a viral load indicator, which may be a mistake. In this study, we compared tracheal aspirate with nasopharyngeal samples obtained from critically ill COVID-19 patients and demonstrate how the raw Ct could lead to misinterpretation of results. Based on these findings, we show the impact that normalization of Ct values has on interpretation of viral load data from different biological samples from patients with COVID-19, transmission and lastly in relations with clinical outcomes.
FKBPL and SIRT-1, key angiogenesis proteins, are downregulated by diabetes in pregnancy
Authors: Alqudah Abdelrahim , Eastwood Kelly-Ann , Jerotic Djurdja , Todd Naomi , Hoch Denise , McNally Ross , Obradovic Danilo , Dugalic Stefan , Hunter Alyson J. , Holmes Valerie A. , McCance David R. , Young Ian S. , Watson Chris J , Robson Tracy , Desoye Gernot , Grieve David J , McClements Lana 
Published: October 2020

AbstractContextDiabetes in pregnancy is associated with numerous complications, however the mechanisms are still poorly understood.ObjectiveTo investigate the role of new angiogenesis markers, FKBPL and SIRT-1, in pre-gestational (type 1 diabetes, T1D) and gestational diabetes (GDM).Design and interventionPlacental FKBPL, SIRT-1, PlGF and VEGF-R1 protein expression was determined from pregnant women with GDM or T1D, and in first trimester trophoblast cells exposed to high glucose and varying oxygen concentrations. Endothelial cell function was assessed in high glucose conditions and FKBPL overexpression.Settings and ParticipantsHuman placental samples from pregnant women with GDM (n=6) or T1D (n=8) were collected to assess FKBPL and SIRT-1 protein expression compared to non-diabetic controls.Main outcome measuresTo determine the role of placental FKBPL and/or SIRT-1 in diabetic pregnancies, in first trimester trophoblasts and endothelial cell function in high-glucose environment.ResultsPlacental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 (p<0.001) was significantly downregulated even when adjusted for gestational age (r=-0.92, p=0.001). FKBPL and SIRT-1 were also downregulated in ACH-3P cells in high glucose conditions and 6.5%/2.5% oxygen concentrations (p<0.05). FKBPL overexpression in HUVECs reduced tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05).ConclusionsFKBPL and/or SIRT-1 downregulation in response to diabetes may have a role in the development of vascular dysfunction in pregnancy, and associated complications such as preeclampsia.
Single-cell data and correlation analysis support the independent double adder model in bothEscherichia coliandBacillus subtilis
Authors: Le Treut Guillaume , Si Fangwei , Li Dongyang , Jun Suckjoon 
Published: October 2020

AbstractThe reference point for cell-size control in the cell cycle is a fundamental biological question. We previously reported that we were unable to reproduce the conclusions of Witzet al.’seLifepaper (Witz, van Nimwegen, and Julou 2019) entitled, “Initiation of chromosome replication controls both division and replication cycles inE. colithrough a double-adder mechanism”, despite extensive efforts. In this ‘replication double adder’ (RDA) model, both replication and division cycles are determined via replication initiation as the sole implementation point of size control. Witzet al.justified the RDA model using a type of correlation analysis (the “I-value analysis”) that they developed. By contrast, we previously showed that, in bothEscherichia coliandBacillus subtilis,replication initiation and cell division are determined by balanced biosynthesis of key cell cycle proteins (e.g., DnaA for initiation and FtsZ for cell division) and their accumulation to their respective threshold numbers, which Witzet al.coined the ‘independent double adder’ (IDA) model. The adder phenotype is a natural quantitative consequence of these mechanistic principles. In a recentbioRxivresponse to our report, Witz and colleagues explicitly confirmed two important limitations of theI-value analysis: (1) it is only applicable to non-overlapping cell cycles, whereinE. coliis known to deviate from the adder principle, and (2) it is only applicable to select biological models and, for example, cannot evaluate the IDA model. These limitations of theI-value analysis were not explained in the originaleLifepaper and were overlooked during the review process. In this report, we show using data analysis, mathematical modeling, and experiments why theI-value analysis - in its current implementation - cannot compare different biological models. Furthermore, the RDA model is incompatible with the adder principle and is not broadly supported by experimental data. For completeness, we also provide a detailed point-by-point response to Witzet al.’s response (Witz, Julou, and van Nimwegen 2020) in the Supplemental Information.
The macaque brain ONPRC18 template with combined gray and white matter labelmap for multimodal neuroimaging studies of nonhuman primates
Authors: Weiss Alison R , Liu Zheng , Wang Xiaojie , Liguore William A , Kroenke Christopher D. , McBride Jodi L. 
Published: October 2020

ABSTRACTMacaques are the most common nonhuman primate (NHP) species used in neuroscience research. With the advancement of many neuroimaging techniques, new studies are beginning to apply multiple types of in vivo magnetic resonance imaging (MRI), such as structural imaging (sMRI) with T1 and T2 weighted contrasts alongside diffusion weighed (DW) imaging. In studies involving rhesus macaques, this approach can be used to better understand micro-structural changes that occur during development, in various disease states or with normative aging. However, many of the available rhesus brain atlases have been designed for only one imaging modality, making it difficult to consistently define the same brain regions across multiple imaging modalities in the same subject. To address this, we created a brain atlas from 18 adult rhesus macaques that includes co-registered templates constructed from images frequently used to characterize macroscopic brain structure (T2/SPACE and T1/MP-RAGE), and a diffusion tensor imaging (DTI) template. The DTI template was up-sampled from 1 mm isotropic resolution to resolution match to the T1 and T2-weighted images (0.5 mm isotropic), and the parameter map was derived for fractional anisotropy (FA). The labelmap volumes delineate 57 gray matter regions of interest (ROIs; 36 cortical regions and 21 subcortical structures), as well as 74 white matter tracts. Importantly, the labelmap overlays both the structural and diffusion templates, enabling the same regions to be consistently identified across imaging modalities. A specialized condensed version of the labelmap ROIs are also included to further extend the usefulness of this tool for imaging data with lower spatial resolution, such as functional MRI (fMRI) or positron emission tomography (PET).Graphical Abstract
Ablation of Proliferating Osteoblast Lineage Cells After Fracture Leads to Atrophic Nonunion in a Mouse Model
Authors: Hixon Katherine R. , McKenzie Jennifer A. , Sykes David A.W. , Yoneda Susumu , Hensley Austin , Buettmann Evan G. , Zheng Hongjun , Skouteris Dimitrios , McAlinden Audrey , Miller Anna N. , Silva Matthew J. 
Published: October 2020

ABSTRACTNonunion is defined as the permanent failure of a fractured bone to heal, often necessitating surgical intervention. Atrophic nonunions are a subtype that are particularly difficult to treat. Animal models of atrophic nonunion are available; however, these require surgical or radiation-induced trauma to disrupt periosteal healing. These methods are invasive and not representative of many clinical nonunions where osseous regeneration has been arrested by a “failure of biology”. We hypothesized that arresting osteoblast cell proliferation after fracture would lead to atrophic nonunion in mice. Using mice that express a thymidine kinase (tk) “suicide gene” driven by the 3.6Col1a1 promoter (Col1-tk), proliferating osteoblast lineage cells can be ablated upon exposure to the nucleoside analog ganciclovir (GCV). Wild-type (WT; control) and Col1-tk littermates were subjected to a full femur fracture and intramedullary fixation at 12 weeks age. We confirmed abundant tk+ cells in fracture callus of Col-tk mice dosed with water or GCV, specifically many osteoblasts, osteocytes, and chondrocytes at the cartilage-bone interface. Histologically, we observed altered callus composition in Col1-tk mice at 2 and 3 weeks post fracture, with significantly less bone and more fibrous tissue. Col1-tk mice, monitored for 12 weeks within vivoradiographs and microCT scans, had delayed bone bridging and reduced callus size. Following sacrifice,ex vivomicroCT and histology demonstrated failed union with residual bone fragments and fibrous tissue in Col1-tk mice. Biomechanical testing demonstrated a failure to recover torsional strength in Col1-tk mice, in contrast to WT. Our data indicates that suppression of proliferating osteoblast-lineage cells for at least 2 weeks after fracture blunts the formation and remodeling of a mineralized callus leading to a functional nonunion. We propose this as a new murine model of atrophic nonunion.
Gene regulatory network (GRN) embedded agents connect cellular decision making to human pluripotent stem cell derived germ layer-like pattern formation
Authors: Kaul Himanshu , Werschler Nicolas , Tewary Mukul , Hagner Andrew , Ostblom Joel , Aguilar-Hidalgo Daniel , Zandstra Peter W. 
Published: October 2020

ABSTRACTThe emergence of germ layers in embryos during gastrulation is a key developmental milestone. How morphogenetic signals engage the regulatory networks responsible for early embryonic tissue patterning is incompletely understood. To understand this, we developed a gene regulatory network (GRN) model of human pluripotent stem cell (hPSC) lineage commitment and embedded it into ‘cellular’ agents that respond to a dynamic signalling microenvironment. We found that cellular pattern order, composition, and dynamics were predictably manipulable based on the GRN wiring. We showed that feedback between OCT4, and BMP and WNT pathways created a dynamic OCT4 front that mediates the spatiotemporal evolution of developmental patterns. Translocation of this radial front can be predictively disrupted in vitro to control germ-layer pattern composition. This work links the emergence of multicellular patterns to regulatory network activity in individual hPSCs. We anticipate our approach will help to understand how GRN structure regulates organogenesis in different contexts.
Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer’s disease
Authors: Haytural Hazal , Jordá-Siquer Tomás , Winblad Bengt , Mulle Christophe , Tjernberg Lars O. , Granholm Ann-Charlotte , Frykman Susanne , Barthet Gaël 
Published: October 2020

AbstractSynaptic degeneration has been reported as one of the best pathological correlate of cognitive deficit in Alzheimer’s Disease (AD). However, the location of these synaptic alterations within hippocampal sub-regions, the vulnerability of the presynaptic versus postsynaptic compartments, and the biological mechanisms for these impairments remain unknown. Here, we performed immunofluorescence labeling of different synaptic proteins in fixed and paraffin embedded human hippocampal sections and report reduced levels of several presynaptic proteins of the neurotransmitter release machinery (complexin-1, syntaxin-1A, synaptotagmin-1 and synaptogyrin-1) in AD cases. The deficit was restricted to the outer molecular layer (OML) of the dentate gyrus whereas other hippocampal sub-fields were preserved. Interestingly, standard markers of postsynaptic densities (SHANK2) and dendrites (MAP2) were unaltered, as well as the relative number of granule cells in the dentate gyrus, indicating that the deficit is preferentially presynaptic. Notably, staining for the axonal components, myelin basic protein, SMI-312 and Tau, was unaffected, suggesting that the local presynaptic impairment does not result from axonal loss or alterations of structural proteins of axons. There was no correlation between the reduction in presynaptic proteins in OML and the extent of the amyloid load or of the dystrophic neurites expressing phosphorylated forms of Tau. Altogether, this study highlights the distinctive vulnerability of the OML of dentate gyrus and supports the notion of presynaptic failure in AD.
Miro1-dependent Mitochondrial Dynamics in Parvalbumin Interneurons
Authors: Kontou Georgina , Antonoudiou Pantelis , Podpolny Marina , Arancibia-Carcamo I. Lorena , Higgs Nathalie F. , Szulc Blanka R. , Lopez-Domenech Guillermo , Salinas Patricia C. , Mann Edward O. , Kittler Josef T. 
Published: October 2020

SUMMARYThe spatiotemporal distribution of mitochondria is crucial for precise ATP provision and calcium buffering required to support neuronal signaling. Fast-spiking GABAergic interneurons expressing parvalbumin (PV) have a high mitochondrial content reflecting their large energy utilization. The importance for correct trafficking and precise mitochondrial positioning remains poorly elucidated in inhibitory neurons. Miro1 is a Ca2+-sensing adaptor protein that links mitochondria to the trafficking apparatus, for their microtubule-dependent transport along axons and dendrites, in order to meet the metabolic and Ca2+-buffering requirements of the cell. Here, we explore the role of Miro1 in parvalbumin interneurons and how changes in mitochondrial trafficking could alter brain network activity. By employing live and fixed imaging, we found that the impairments in Miro1-directed trafficking in PV+ interneurons altered their mitochondrial distribution and axonal arborization. These changes were accompanied by an increase in theex vivohippocampal γ-oscillation (30 – 80 Hz) frequency and promoted anxiolysis. Our findings show that precise regulation of mitochondrial dynamics in PV+ interneurons is crucial for proper neuronal signaling and network synchronization.
Estimating genetic nurture with summary statistics of multi-generational genome-wide association studies
Authors: Wu Yuchang , Zhong Xiaoyuan , Lin Yunong , Zhao Zijie , Chen Jiawen , Zheng Boyan , Li James J. , Fletcher Jason M. , Lu Qiongshi 
Published: October 2020

AbstractMarginal effect estimates in genome-wide association studies (GWAS) are mixtures of direct and indirect genetic effects. Existing methods to dissect these effects require family-based, individual-level genetic and phenotypic data with large samples, which is difficult to obtain in practice. Here, we propose a novel statistical framework to estimate direct and indirect genetic effects using summary statistics from GWAS conducted on own and offspring phenotypes. Applied to birth weight, our method showed nearly identical results with those obtained using individual-level data. We also decomposed direct and indirect genetic effects of educational attainment (EA), which showed distinct patterns of genetic correlations with 45 complex traits. The known genetic correlations between EA and higher height, lower BMI, less active smoking behavior, and better health outcomes were mostly explained by the indirect genetic component of EA. In contrast, the consistently identified genetic correlation of autism spectrum disorder (ASD) with higher EA resides in the direct genetic component. Polygenic transmission disequilibrium test showed a significant over-transmission of the direct component of EA from healthy parents to ASD probands. Taken together, we demonstrate that traditional GWAS approaches, in conjunction with offspring phenotypic data collection in existing cohorts, could greatly benefit studies on genetic nurture and shed important light on the interpretation of genetic associations for human complex traits.
Making the invisible enemy visible
Authors: Croll Tristan , Diederichs Kay , Fischer Florens , Fyfe Cameron , Gao Yunyun , Horrell Sam , Joseph Agnel Praveen , Kandler Luise , Kippes Oliver , Kirsten Ferdinand , Müller Konstantin , Nolte Kristoper , Payne Alex , Reeves Matt , Richardson Jane , Santoni Gianluca , Stäb Sabrina , Tronrud Dale , von Soosten Lea , Williams Christopher , Thorn Andrea 
Published: October 2020

AbstractDuring the COVID-19 pandemic, structural biologists rushed to solve the structures of the 28 proteins encoded by the SARS-CoV-2 genome in order to understand the viral life cycle and enable structure-based drug design. In addition to the 204 previously solved structures from SARS-CoV-1, 548 structures covering 16 of the SARS-CoV-2 viral proteins have been released in a span of only 6 months. These structural models serve as the basis for research to understand how the virus hijacks human cells, for structure-based drug design, and to aid in the development of vaccines. However, errors often occur in even the most careful structure determination - and may be even more common among these structures, which were solved quickly and under immense pressure.The Coronavirus Structural Task Force has responded to this challenge by rapidly categorizing, evaluating and reviewing all of these experimental protein structures in order to help downstream users and original authors. In addition, the Task Force provided improved models for key structures online, which have been used by Folding@Home, OpenPandemics, the EU JEDI COVID-19 challenge and others.
Deploying andin vitrogut model to assay the impact of a mannan-oligosaccharide prebiotic, Bio-MOS® on the Atlantic salmon (Salmo salar) gut microbiome
Authors: Kazlauskaite R. , Cheaib B. , Humble J. , Heys C. , Ijaz U. , Connelly S. , Sloan W.T. , Russell J. , Martinez-Rubio L. , Sweetman J. , Kitts A. , McGinnity P. , Lyons P. , Llewellyn M. 
Published: October 2020

AbstractMannose-oligosaccharide (MOS) pre-biotics are widely deployed in animal agriculture as immunomodulators as well as to enhance growth and gut health. Their mode of action is thought to be mediated through their impact on host microbial communities and associated metabolism. Bio-MOS is a commercially available pre-biotic currently used in the agri-feed industry. To assay Bio-MOS for potential use as a pre-biotic growth promotor in salmonid aquaculture, we modified an established Atlantic salmonin vitrogut model, SalmoSim, to evaluate its impact on host microbial communities. In biological triplicate, microbial communities were stabilised in SalmoSim followed by twenty-day exposure to the pre-biotic and then an eight day ‘wash out’ period. Exposure the MOS resulted in a significant increase in formate (p=0.001), propionate (p=0.037) and isovalerate (p=0.024) levels, correlated with increased abundances of several principally anaerobic microbial genera (Fusobacteria, Agarivorans, Pseudoalteromonas, Myroides). 16S rDNA sequencing confirmed a significant shift in microbial community composition in response to supplementation. In conjunction with previousin vivostudies linking enhanced VFA production alongside MOS supplementation to host growth and performance, our data suggest that Bio-MOS may be of value in salmonid production. Furthermore, our data highlight the potential role ofin vitrogut models to augmentin vivotrials of microbiome modulators.