bluuebunny/crossref_metadata_2025_split huggingface dataset:
Levels and factors of social and physical distancing based on the Theory of Planned Behavior during the COVID-19 pandemic among Chinese adults
Authors: Yu Yanqiu , Lau Joseph Tak Fai , Lau Mason M C 
Published: February 2021

Abstract
Social and physical distancing is important in controlling the COVID-19 pandemic and it impacts people’s financial/social well-being tremendously. This study tested the application of the Theory of Planned Behaviors (TPB) to three types of social/physical distancing indicators (i.e., the number of close physical contacts on a single day in public venues, the frequencies of avoiding social gathering, and the levels of physical distancing in public venues). A population-based random telephone survey interviewed 300 Hong Kong Chinese adults in April 2020 when gatherings involving &gt;4 people were banned. The participants on average made 15.3 close physical contacts (&lt;1.5 m and for &gt;3 min) in a day (5.0 in public transportation). About 80% practiced social distancing (avoided/reduced social gatherings) and physical distancing in public spaces (e.g., avoidance of going out, visiting crowded places, and gatherings of &gt;4 people) but only 35.4% avoided using public transportations. Positive but not negative attitudes (inconvenience and lack of necessity), perceived behavioral control, and subjective norm were significantly associated with the three social/physical distancing outcomes. The data suggest that the levels of social/physical distancing were relatively high in the Hong Kong general population, and it, in general, supports the application of TPB to understand factors of social distancing for preventing COVID-19. Health promotion should take the findings into account. Furthermore, cross-cultural and time-series studies are warranted to compare the levels of social/physical distancing across countries and further explore their effectiveness in controlling the COVID-19 pandemic.
Probing the SAM Binding Site of SARS-CoV-2 nsp14 in vitro Using SAM Competitive Inhibitors Guides Developing Selective bi-substrate Inhibitors
Authors: Devkota Kanchan , Schapira Matthieu , Perveen Sumera , Yazdi Aliakbar Khalili , Li Fengling , Chau Irene , Ghiabi Pegah , Hajian Taraneh , Loppnau Peter , Bolotokova Albina , Satchell Karla J.F. , Wang Ke , Li Deyao , Liu Jing , Smil David , Luo Minkui , Jin Jian , Fish Paul V. , Brown Peter J. , Vedadi Masoud 
Published: February 2021

AbstractThe COVID-19 pandemic has clearly brought the healthcare systems world-wide to a breaking point along with devastating socioeconomic consequences. The SARS-CoV-2 virus which causes the disease uses RNA capping to evade the human immune system. Non-structural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small molecule inhibitors of nsp14 methyltransferase (MT) activity, we developed and employed a radiometric MT assay to screen a library of 161 in house synthesized S-adenosylmethionine (SAM) competitive methyltransferase inhibitors and SAM analogs. Among seven identified screening hits, SS148 inhibited nsp14 MT activity with an IC50value of 70 ± 6 nM and was selective against 20 human protein lysine methyltransferases indicating significant differences in SAM binding sites. Interestingly, DS0464 with IC50value of 1.1 ± 0.2 μM showed a bi-substrate competitive inhibitor mechanism of action. Modeling the binding of this compound to nsp14 suggests that the terminal phenyl group extends into the RNA binding site. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein methyltransferases. The structure-activity relationship provided by these compounds should guide the optimization of selective bi-substrate nsp14 inhibitors and may provide a path towards a novel class of antivirals against COVID-19, and possibly other coronaviruses.
Droplet and fibril formation of the functional amyloid Orb2
Authors: Ashami Kidist , Falk Alexander S. , Hurd Connor , Garg Samridhi , Cervantes Silvia A. , Rawat Anoop , Siemer Ansgar B 
Published: February 2021

AbstractThe functional amyloid Orb2 belongs to the cytoplasmic polyadenylation element binding (CPEB) protein family and plays an important role in long-term memory formation inDrosophila. The Orb2 domain structure combines RNA recognition motifs with low complexity sequences similar to many RNA binding proteins shown to form protein droplets via liquid-liquid phase separation (LLPS) in vivo and in vitro. This similarity suggests that Orb2 might also undergo LLPS. However, cellular Orb2 puncta have very little internal protein mobility and Orb2 forms fibrils inDrosophilabrains that are functionally active indicating that LLPS might not play a role for Orb2. In the present work, we reconcile these two views on Orb2 droplet formation. We show that soluble Orb2 can indeed phase separate into protein droplets. However, these droplets have either no or only an extremely short-lived liquid phase and appear maturated right after formation. For Orb2 fragments that lack the C-terminal RNA binding domain (RBD), droplet formation is a prerequisite for fibril formation of an otherwise stable monomeric Orb2 solution. Solid-state NMR shows that these fibrils have additional well ordered static domains beside the Gln/His-rich fibril core. Further, we find that full-length Orb2B, which is by far the major component of Orb2 fibrils in vivo, does not transition into cross-β fibrils but remains in the droplet phase. Together, our data suggest that phase separation might play a role in initiating the formation of functional Orb2 fibrils.
Individual variation in brain structural-cognition relationships in aging
Authors: Patel Raihaan , Mackay Clare E. , Jansen Michelle G. , Devenyi Gabriel A. , O’Donoghue M. Clare , Kivimäki Mika , Singh-Manoux Archana , Zsoldos Enikő , Ebmeier Klaus P. , Chakravarty M. Mallar , Suri Sana 
Published: February 2021

AbstractThe sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ±4.9 years) and late-life (mean age = 67.7 ±4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ±4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive declineandmaintenance across diverse cognitive functions that are both positively and negatively associated with cortical structure.
Defining the transcriptional signature of esophageal-to-skin lineage conversion
Authors: Bejar Maria T. , Jimenez-Gomez Paula , Moutsopoulos Ilias , Colom Bartomeu , Han Seungmin , Calero-Nieto Fernando J , Göttgens Berthold , Mohorianu Irina , Simons Benjamin D. , Alcolea Maria P. 
Published: February 2021

AbstractThe ability of epithelial cells to rewire their cell fate program beyond their physiological repertoire has become a new paradigm in stem cell biology. This plasticity leaves behind the concept of strict stem cell hierarchies, opening up new exciting questions about its limits and underlying regulation. Here we developed a heterotypic 3D culture system to study the mechanisms modulating changes in the identity of adult esophageal epithelial cells. We demonstrate that, when exposed to the foreign stroma of adult skin, esophageal cells transition towards hair follicle identity and architecture. Heterotypic transplantation experiments recapitulated this cell fate conversion processin vivo. Single-cell RNA sequencing and histological analysis, capturing the temporality of this process, reveal that most esophageal cells switching towards skin identity remain in an intermediate state marked by a transient regenerative profile and a particularly strong hypoxic signature. Inhibition of HIF1a establishes the central role of this pathway in regulating epithelial cell plasticity, driving cells away from their transition state in favor of cell fate conversion.
Genetic diversification of persistentMycobacterium abscessuswithin Cystic Fibrosis patients
Authors: Lewin Astrid , Kamal Elisabeth , Semmler Torsten , Winter Katja , Kaiser Sandra , Schäfer Hubert , Mao Lei , Eschenhagen Patience , Grehn Claudia , Schwarz Carsten 
Published: February 2021

AbstractMycobacterium (M.) abscessusinfections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight onM. abscessusgenomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate phylogeny and genomic diversification of in-patientM. abscessus. Eleven of the 42 CF patients were infected withM. abscessus. Global human-transmissibleM. abscessuscluster strains were isolated from five of these 11 patients. Phylogenetic analysis of 88 genomes from isolates of the 11 patients excluded occurrence ofM. abscessustransmission among members of the study group. Genome sequencing and variant analysis of 30 isolates from 11 serial respiratory samples collected over four years from a chronically infected patient demonstrated accumulation of gene mutations. In total, 53 genes exhibiting non-synonymous variations were identified. Enrichment analysis emphasized genes involved in synthesis of glycopeptidolipids, genes from theembABC(arabinosyltransferase) operon,betA(glucose-methanol-choline oxidoreductase) andchoD(cholesterol oxidase). Genetic diversity evolved in a variety of virulence- and resistance-associated genes. The strategy ofM. abscessuspopulations in chronic lung infection is not clonal expansion of dominant variants, but to sustain simultaneously a wide range of genetic variants facilitating adaptation of the population to changing living conditions in the lung. Genomic diversification during chronic infection requires increased attention when new control strategies againstM. abscessusinfections are explored.
An Interpretable Deep Learning Approach for Biomarker Detection in LC-MS Proteomics Data
Authors: Iravani Sahar , Conrad Tim O.F. 
Published: February 2021

AbstractAnalyzing mass spectrometry-based proteomics data with deep learning (DL) approaches poses several challenges due to the high dimensionality, low sample size, and high level of noise. Additionally, DL-based workflows are often hindered to be integrated into medical settings due to the lack of interpretable explanation. We present DLearnMS, a DL biomarker detection framework, to address these challenges on proteomics instances of liquid chromatography-mass spectrometry (LC-MS) - a well-established tool for quantifying complex protein mixtures. Our DLearnMS framework learns the clinical state of LC-MS data instances using convolutional neural networks. Based on the trained neural networks, we show how biomarkers can be identified using layer-wise relevance propagation. This enables detecting discriminating regions of the data and the design of more robust networks. One of the main advantages over other established methods is that no explicit preprocessing step is needed in our DLearnMS framework.Our evaluation shows that DLearnMS outperforms conventional LC-MS biomarker detection approaches in identifying fewer false positive peaks while maintaining a comparable amount of true positives peaks.Code availabilityThe code is available from the following GIT repository:https://github.com/SaharIravani/DlearnMS
Time series models for prediction of Leptospirosis in different climate zones in Sri Lanka
Authors: Warnasekara Janith , Agampodi SB , Abeynayake R 
Published: February 2021

AbstractIn tropical countries such as Sri Lanka, where leptospirosis—a deadly disease with a high mortality rate—is endemic, prediction is required for public health planning and resource allocation. Routinely collected meteorological data may offer an effective means of making such predictions. This study included monthly leptospirosis and meteorological data from January 2007 to April 2019 from Sri Lanka. Factor analysis was used first with rainfall data to classify districts into meteorological zones. We used a seasonal autoregressive integrated moving average (SARIMA) model for univariate predictions and autoregressive distributed lag (ARDL) model for multivariable analysis of leptospirosis with monthly average rainfall, temperature, relative humidity (RH), solar radiation (SR) and the number of rainy days/month (RD). Districts were classified into wet (WZ) and dry (DZ) zones and highlands (HL) based on the factor analysis of rainfall data. The WZ had the highest leptospirosis incidence; there was no difference in the incidence between the DZ and HL. Leptospirosis was fluctuated positively with rainfall, RH and RD, whereas temperature and SR were fluctuated negatively. ARIMA(1,0,0)(0,1,1)12, ARIMA(1,0,0)(1,1,1)12, and ARIMA(0,1,1)(0,1,1)12were the best univariate models for DZ, WZ, and HL, respectively. Despite its known association, rainfall was positively significant in the WZ only at lag 5 (P= 0.03) but was negatively associated at lag 2 and 3 (P= 0.04). RD was positively associated for all three zones. Temperature was positively associated at lag 0 for the WZ and HL (P< 0.009) and was negatively associated at lag 1 for the WZ (P= 0.01). There was no association with RH in contrast to previous studies. Based on altitude and rainfall data, meteorological variables could effectively predict the incidence of leptospirosis with different models for different climatic zones. These predictive models could be effectively used in public health planning purposes.
Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo
Authors: Saenz Steven A. , Local Andrea , Carr Tiffany , Shakya Arvind , Koul Shivsmriti , Hu Haiqing , Chourb Lisa , Stedman Justin , Malley Jenna , D’Agostino Laura Akullian , Shanmugasundaram Veerabahu , Malona John , Schwartz Eric , Beebe Lisa , Clements Meghan , Rajaraman Ganesh , Cho John , Jiang Lan , Dubrovskiy Alex , Kreilein Matt , Shimanovich Roman , Hamann Lawrence G. , Escoubet Laure , Ellis J. Michael 
Published: February 2021

AbstractRetinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production. However, excessive IL-17A production has been linked to numerous autoimmune diseases. Moreover, Th17 cells have been shown to elicit both pro- and anti-tumor effects. Thus, modulation of the RORγt/IL-17A axis may represent an attractive therapeutic target for the treatment of autoimmune disorders and some cancers. Herein we report the design, synthesis and characterization of three selective allosteric RORγt inhibitors in preclinical models of inflammation and tumor growth. We demonstrate that these compounds can inhibit Th17 differentiation and maintenancein vitroand Th17-dependent inflammation and associated gene expressionin vivo, in a dose-dependent manner. Finally, RORγt inhibitors were shown to inhibit tumor formation in pancreatic ductal adenocarcinoma (PDAC) organoids.
Juvenile Huntington’s Disease and Other PolyQ diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic Data
Authors: Świtońska-Kurkowska Karolina , Krist Bart , Delimata Joanna Maria , Figiel Maciej 
Published: February 2021

AbstractPolyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.
Genetic manipulation using hepatocyte-targeting adeno-associated viral vectors has minimal off-target effects
Authors: Kiourtis Christos , Wilczynska Ania , Nixon Colin , Clark William , May Stephanie , Bird Thomas G 
Published: February 2021

AbstractMice are a widely used pre-clinical model system in large part due to their potential for genetic manipulation. The ability to manipulate gene expression in specific cells under temporal control is a powerful experimental tool. The liver is central to metabolic homeostasis and a site of many diseases, making the targeting of hepatocytes attractive. Adeno-Associated Virus 8 (AAV8) vectors are valuable instruments for the manipulation of hepatocellular gene expression. However, their off-target effects in mice have not been thoroughly explored. Here, we sought to identify the short-term off-target effects of AAV8 administration in mice. To do this, we injected C57BL/6J Wild-Type mice with either recombinant AAV8 vectors expressing Cre recombinase or empty AAV8 vectors and characterised the changes in general health and in liver physiology, histology and transcriptomics compared to uninjected controls over 1 week. We observed an acute and transient reduction in homeostatic liver proliferation together with induction of the DNA damage marker γH2AX following AAV8 administration. The latter was enhanced upon Cre recombinase expression by the vector. Furthermore, we observed transcriptional changes in genes involved in circadian rhythm and response to infection. Notably, there were no additional transcriptomic changes upon expression of Cre recombinase by the AAV8 vector. Overall, there was no evidence of liver injury, dysfunction or leukocyte infiltration following AAV8 infection. These data support the use of AAV8-based Cre recombinase delivery as a specific tool for hepatocellular gene manipulation with minimal effects on murine physiology but highlight the off target effects of these systems.Summary statementThis paper provides a comprehensive characterisation of the short-term effects of administration of Adeno-Associated Virus 8 on murine physiology, liver histology and liver transcriptome.
The molecular infrastructure of glutamatergic synapses in the mammalian forebrain
Authors: Peukes J. , Lovatt C. , Leistner C. , Boulanger J. , Morado D. R. , Fuller M. J. G. , Kukulski W. , Zhu F. , Komiyama N. H. , Briggs J. A. G. , Grant S. G. N. , Frank R. 
Published: February 2021

AbstractGlutamatergic synapses form the vast majority of connections within neuronal circuits, but how these subcellular structures are molecularly organized within the mammalian brain is poorly understood. Conventional electron microscopy using chemically fixed, metal-stained tissue has identified a proteinaceous, membrane-associated thickening called the ‘postsynaptic density’ (PSD). Here, we combined mouse genetics and cryo-electron tomography to determine the 3D molecular architecture of fresh isolated and anatomically intact synapses in the adult forebrain. The native glutamatergic synapse did not consistently show a high density of proteins at the postsynaptic membrane thought to be characteristic of the PSD. Instead, a ‘synaptoplasm’ consisting of cytoskeletal elements, macromolecular complexes and membrane-bound organelles extended throughout the pre- and post-synaptic compartments. Snapshots of active processes gave insights into membrane remodeling processes. Clusters of 4-60 ionotropic glutamate receptors were positioned inside and outside the synaptic cleft. Together, these information-rich tomographic maps present a detailed molecular framework for the coordinated activity of synapses in the adult mammalian brain.
A photoswitchable GPCR-based opsin for presynaptic silencing
Authors: Copits Bryan A. , O’Neill Patrick R. , Gowrishankar Raaj , Yoo Judy J. , Meshik Xenia , Parker Kyle E. , Spangler Skylar M. , Vasquez Alexis M. , Elerding Abigail J. , Stander M. Christine , Kalyanaraman Vani , Vogt Sherri K. , Samineni Vijay K. , Gautam N. , Sunahara Roger K. , Gereau Robert W. , Bruchas Michael R. 
Published: February 2021

SUMMARYOptical manipulations of genetically defined cell types have generated significant insights into the dynamics of neural circuits. While optogenetic activation has been relatively straightforward, rapid and reversible synaptic inhibition has been far more difficult to achieve. Instead of relying on unpredictable ion manipulations or slow photoactivatable toxins at axon terminals, we took a different approach to leverage the natural ability of inhibitory presynaptic GPCRs to silence synaptic transmission. Here we characterize parapinopsin (PPO), a photoswitchable non-visual opsin from lamprey pineal gland that couples to Gi/o-signaling cascades. PPO can be rapidly activated by pulsed blue light, switched off with amber light, and is effective for repeated or prolonged inhibition. We developed viral vectors for cell-specific expression of PPO, which traffics very effectively in numerous neuron types. At presynaptic terminals, PPO can silence glutamate release and suppress dopamine-dependent reward and cocaine place preference behaviorsin vivo. PPO immediately fills a significant gap in the neuroscience toolkit for rapid and reversible synaptic inhibition, and has broader utility for achieving spatiotemporal control of inhibitory GPCR signaling cascades in other biological and pharmacological applications.