bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating insulin-like growth factor-I and risk of 25 common conditions: outcome-wide analyses in the UK Biobank Study
Authors: Papier Keren , Knuppel Anika , Perez-Cornago Aurora , Watts Eleanor L. , Tong Tammy YN , Schmidt Julie A , Allen Naomi , Key Timothy J , Travis Ruth C 
Published: May 2021

AbstractBackgroundWhile there is strong epidemiological evidence that circulating insulin-like growth factor-I (IGF-I) is associated with a higher risk of several cancers, little is known about its association with non-cancer outcomes. We investigated associations of circulating IGF-I with risk of 25 common conditions, other than cancer, in a large British cohort.MethodsStudy participants were 318 749 middle-aged adults enrolled in the UK Biobank Study. Serum IGF-I concentration was measured in samples collected at baseline (2006-2010), and re-measured in 12 334 participants after an average of 4.3 years. We followed-up participants over an average of 11.5 years by linking to hospital admissions and mortality registries. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between circulating IGF-I and 25 common conditions, using the repeated IGF-I measurements to correct for regression dilution bias.ResultsAfter correction for multiple testing (P<0.002), IGF-I was positively associated with carpal tunnel syndrome (HR per 5 nmol/l higher concentration=1.12, 95% CI, 1.08-1.16), and inversely associated with varicose veins (0.90, 0.85-0.95), cataracts (0.97, 0.95-0.99), diabetes (0.92, 0.90-0.95), and iron deficiency anaemia (0.90, 0.86-0.93). The associations for cataracts and diabetes attenuated when restricted to cases diagnosed after five or more years of follow-up, suggesting that these associations were likely affected by reverse causality.ConclusionsHigher IGF-I concentration might be associated with the risk for several conditions, but genetic studies are needed to clarify which associations may be causal.Key messagesEvidence on the association between circulating insulin-like growth factor-I (IGF-I) and risk of many common, non-cancer health outcomes in the general population is relatively limited.This study used an outcome-wide approach to prospectively examine associations of circulating IGF-I with risk of 25 common conditions in a large, prospective cohort of over 300,000 UK adults.Our study showed that circulating IGF-I is associated with risks of several common diseases and conditions; IGF-I was positively associated with carpal tunnel syndrome and inversely associated with varicose veins, cataracts, diabetes, and iron deficiency anaemia.Further research is needed to evaluate whether these differences in risk may reflect causal relationships.
A Prenylated dsRNA Sensor Protects Against Severe COVID-19 and is Absent in Horseshoe Bats
Authors: Wickenhagen Arthur , Sugrue Elena , Lytras Spyros , Kuchi Srikeerthana , Turnbull Matthew L , Loney Colin , Herder Vanessa , Allan Jay , Jarmson Innes , Cameron-Ruiz Natalia , Varjak Margus , Pinto Rute M , Stewart Douglas G , Swingler Simon , Noerenberg Marko , Greenwood Edward J D , Crozier Thomas W M , Gu Quan , Clohisey Sara , Wang Bo , Maranhão Costa Fabio Trindade , Santana Monique Freire , de Lima Ferreira Luiz Carlos ,   ISARIC4C investigators, Da Silva Filho Joao Luiz , Marti Matthias , Stanton Richard J , Wang Eddie C Y , Castello-Palomares Alfredo , Ho Antonia , Baillie Kenneth , Jarrett Ruth F , Robertson David L , Palmarini Massimo , Lehner Paul J , Rihn Suzannah J , Wilson Sam J 
Published: May 2021

AbstractCell autonomous antiviral defenses can inhibit the replication of viruses and reduce transmission and disease severity. To better understand the antiviral response to SARS-CoV-2, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that while some people can express a prenylated OAS1 variant, that is membrane-associated and blocks SARS-CoV-2 infection, other people express a cytosolic, nonprenylated OAS1 variant which does not detect SARS-CoV-2 (determined by the splice-acceptor SNP Rs10774671). Alleles encoding nonprenylated OAS1 predominate except in people of African descent. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response. Remarkably, approximately 55 million years ago, retrotransposition ablated the OAS1 prenylation signal in horseshoe bats (the presumed source of SARS-CoV-2). Thus, SARS-CoV-2 never had to adapt to evade this defense. As prenylated OAS1 is widespread in animals, the billions of people that lack a prenylated OAS1 could make humans particularly vulnerable to the spillover of coronaviruses from horseshoe bats.
Superiority of serum NFL in predicting Multiple Sclerosis severity
Authors: Kosa Peter , Masvekar Ruturaj , Komori Mika , Phillips Jonathan , Ramesh Vighnesh , Varosanec Mihael , Sandford Mary , Bielekova Bibiana 
Published: May 2021

AbstractObjectiveSerum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. While sNFL correlates with cerebrospinal fluid NFL (cNFL), 40-60% of variance remains unexplained. Assuming that for diseases of the central nervous system (CNS), such as multiple sclerosis (MS), the cNFL better reflects CNS injury, our goal was to develop and validate adjustment of sNFL for relevant confounders, to strengthen cNFL-sNFL correlations.MethodsWe used 1,378 matched cNFL-sNFL pairs divided into training and validation cohort with matching data on 11 confounders, neuroexam, and magnetic resonance imaging (MRI). The effect of confounders on cNFL-sNFL relationship was tested using multiple linear regression (MLR) model. Propensity score matching was used to identify effect of spinal cord damage on sNFL levels.ResultsIn the training cohort (n=898) we correlated 11 confounders with the residuals from cNFL-sNFL linear regression. Four non-overlapping confounders explaining highest proportion of variance (12%: age, 8.7%: blood urea nitrogen, 3%: alkaline phosphatase, and 3.9%: weight) were used in MLR model. The model strengthened the cNFL-sNFL correlation from R2 = 0.52 to 0.64 in the independent validation cohort and strengthened correlation of adjusted sNFL with number of contrast-enhancing lesions (from R2 0.11 to 0.18). However, only sNFL, but not cNFL correlated with MS severity outcomes. Using propensity score matching, we demonstrated that subjects with proportionally higher sNFL to cNFL levels have significantly higher clinical and radiological evidence of spinal cord injury.InterpretationSuperiority of sNFL likely resides in the release of NFL from axons of lower motor or dorsal ganglia neurons directly to blood.
Community-level face mask usage in Boston, MA
Authors: McLane Meera , Casey Sharon M. , Gallagher Allison , Ohemeng-Tinyase Maame Akosua , Yosif Sabina , Chaparala Sree Ramya , Lincoln Sarah , Murray Eleanor J. 
Published: May 2021

SummaryWhat is already known about this topic?Community-level face mask use is encouraged as an important preventive measure against COVID-19 transmission, and evidence suggests that jurisdictions which implement face mask mandates see a subsequent decline in COVID incidence.What is added by this report?In the Greater Boston area when a face mask mandate is in effect, 95% of people observed were wearing some type of face covering. Most of which were wearing fabric/cloth coverings (51%) or single use surgical masks (40%). Of those wearing a face covering, 85% were appropriately fitted. Indoor locations have higher adherence of appropriately worn face masks, compared to outdoor locations.What are the implications for public health practice?Adherence with face mask mandates was very high, but many individuals wore fabric face masks with unknown filtration efficacy. In addition, it was common for individuals to mis-wear, adjust, or remove their masks. Public health policies requiring mask use should include messaging about appropriate type and best practices for use.
Perigenual and Subgenual Anterior Cingulate Afferents Converge on Common Pyramidal Cells in Amygdala Subregions of the Macaque
Authors: Kelly EA , Thomas VK , Indraghanty A , Fudge JL 
Published: May 2021

AbstractThe subgenual (sgACC) and pregenual (pgACC) anterior cingulate are important afferents of the amygdala, with different cytoarchitecture, connectivity, and function. The sgACC is associated with arousal mechanisms linked to salient cues, while the pgACC is engaged in conflict decision-making, including in social contexts. After placing same-size, small volume tracer injections into sgACC and pgACC of the same hemisphere in male Macaques, we examined anterogradely labeled fiber distribution to understand how these different functional systems communicate in the main amygdala nuclei at both mesocopic and cellular levels. The sgACC has broad-based termination patterns. In contrast, the pgACC has a more restricted pattern which was always nested in sgACC terminals. Terminal overlap occurred in subregions of the accessory basal and basal nuclei, which we termed ‘hotspots’. In triple-labeling confocal studies, the majority of randomly selected CAMKIIα (+) cells (putative amygdala glutamatergic neurons) in ‘hotspots’ received dual contacts from the sgACC and pgACC. The ratio of dual contacts occurred over a surprisingly narrow range, suggesting a consistent, tight balance of afferent contacts on postsynaptic neurons. Large boutons, which are associated with greater synaptic strength, were approximately 3 times more frequent on sgACC versus pgACC axon terminals in ‘hotspots’, consistent with a fast ‘driver’ function. Together, the results reveal a nested interaction in which pgACC (’conflict/social monitoring’) terminals converge with the broader sgACC (’salience’) terminals at both the mesoscopic and cellular level. The pre-synaptic organization in ‘hotspots’ suggest that shifts in arousal states can rapidly, and flexibly influence decision-making functions in the amygdala.Significance statementThe subgenual (sgACC) and perigenual cingulate (pgACC) have distinct structural and functional characteristics and are important afferent modulators of the amygdala. The sgACC is critical for arousal, while the pgACC mediates conflict-monitoring, including in social contexts. Using dual tracer injections in the same monkey, we found that sgACC inputs broadly project in the main amygdala nuclei, whereas pgACC inputs were more restricted and nested in zones containing sgACC terminals (‘hotspots’). The majority of CAMKIIα + (excitatory) amygdala neurons in ‘hotspots’ received converging contacts, which were tightly balanced. pgACC and sgACC afferent streams are therefore highly interdependent in these specific amygdala subregions, permitting ‘internal arousal’ states to rapidly shape responses of amygdala neurons involved in conflict and social monitoring networks.
Comparing host module activation patterns and temporal dynamics in infection by influenza H1N1 viruses
Authors: Nudelman Irina , Kudrin Daniil , Nudelman German , Deshpande Raamesh , Hartmann Boris M. , Kleinstein Steven H. , Myers Chad L. , Sealfon Stuart C. , Zaslavsky Elena 
Published: May 2021

ABSTRACTInfluenza is a serious global health threat that shows varying pathogenicity among different virus strains. Understanding similarities and differences among activated functional pathways in the host responses can help elucidate therapeutic targets responsible for pathogenesis. To compare the types and timing of functional modules activated in host cells by four influenza viruses of varying pathogenicity, we developed a new DYNAmic MOdule (DYNAMO) method that addresses the need to compare functional module utilization over time. This integrative approach overlays whole genome time series expression data onto an immune-specific functional network, and extracts conserved modules exhibiting either different temporal patterns or overall transcriptional activity. We identified a common core response to influenza virus infection that is temporally shifted for different viruses. We also identified differentially regulated functional modules that reveal unique elements of responses to different virus strains. Our work highlights the usefulness of combining time series gene expression data with a functional interaction map to capture temporal dynamics of the same cellular pathways under different conditions. Our results help elucidate conservation of the immune response both globally and at a granular level, and provide mechanistic insight into the differences in the host response to infection by influenza strains of varying pathogenicity.
Assessing chromatin relocalization in 3D using the patient rule induction method
Authors: Segal Mark R. 
Published: May 2021

AbstractThree dimensional (3D) genome architecture is critical for numerous cellular processes, including transcription, while certain conformation-driven structural alterations are frequently oncogenic. Inferring 3D chromatin configurations has been advanced by the emergence of chromatin conformation capture assays, notably Hi-C, and attendant 3Dreconstructionalgorithms. These have enhanced understanding of chromatin spatial organization and afforded numerous downstream biological insights. Until recently,comparisonsof 3D reconstructions between conditions and/or cell types were limited to prescribed structural features. However,multiMDS, a pioneering approach developed by Rieber and Mahony (2019) that performs joint reconstruction and alignment, enables quantification of all locus-specific differences between paired Hi-C data sets. By subsequently mapping these differences to the linear (1D) genome the identification ofrelocalizationregions is facilitated through use of peak calling in conjunction with continuous wavelet transformation. Here, we seek to refine this approach by performing the search for significant relocalization regions in terms of the 3D structures themselves, thereby retaining the benefits of 3D reconstruction and avoiding limitations associated with the 1D perspective. The search for (extreme) relocalization regions is conducted using thepatient rule induction method(PRIM). Considerations surrounding orienting structures with respect to compartmental and principal component axes are discussed, as are approaches to inference and reconstruction accuracy assessment. Illustration makes recourse to comparisons between four different cell types.
SARS-CoV-2 B.1.617.2 Delta variant replication, sensitivity to neutralising antibodies and vaccine breakthrough
Authors: Mlcochova Petra , Kemp Steven , Dhar Mahesh Shanker , Papa Guido , Meng Bo , Mishra Swapnil , Whittaker Charlie , Mellan Thomas , Ferreira Isabella , Datir Rawlings , Collier Dami A. , Albecka Anna , Singh Sujeet , Pandey Rajesh , Brown Jonathan , Zhou Jie , Goonawardne Niluka , Marwal Robin , Datta Meena , Sengupta Shantanu , Ponnusamy Kalaiarasan , Radhakrishnan Venkatraman Srinivasan , Abdullahi Adam , Charles Oscar , Chattopadhyay Partha , Devi Priti , Caputo Daniela , Peacock Tom , Wattal Chand , Goel Neeraj , Satwik Ambrish , Vaishya Raju , Agarwal Meenakshi ,   The Indian SARS-CoV-2 Genomics Consortium (INSACOG),   The CITIID-NIHR BioResource COVID-19 Collaboration,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Mavousian Antranik , Lee Joo Hyeon , Bassi Jessica , Silacci-Fegni Chiara , Saliba Christian , Pinto Dora , Irie Takashi , Yoshida Isao , Hamilton William L. , Sato Kei , James Leo , Corti Davide , Piccoli Luca , Bhatt Samir , Flaxman Seth , Barclay Wendy S. , Rakshit Partha , Agrawal Anurag , Gupta Ravindra K. 
Published: May 2021

AbstractThe SARS-CoV-2 B.1.617.2 (Delta) variant was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha).In vitro, B.1.617.2 is 6-fold less sensitive to serum neutralising antibodies from recovered individuals, and 8-fold less sensitive to vaccine-elicited antibodies as compared to wild type Wuhan-1 bearing D614G. Serum neutralising titres against B.1.617.2 were lower in ChAdOx-1 versus BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies against the receptor binding domain (RBD) and N-terminal domain (NTD), in particular to the clinically approved bamlavinimab and imdevimab monoclonal antibodies. B.1.617.2 demonstrated higher replication efficiency in both airway organoid and human airway epithelial systems as compared to B.1.1.7, associated with B.1.617.2 spike being in a predominantly cleaved state compared to B.1.1.7. Additionally we observed that B.1.617.2 had higher replication and spike mediated entry as compared to B.1.617.1, potentially explaining B.1.617.2 dominance. In an analysis of over 130 SARS-CoV-2 infected healthcare workers across three centres in India during a period of mixed lineage circulation, we observed substantially reduced ChAdOx-1 vaccine efficacy against B.1.617.2 relative to non-B.1.617.2. Compromised vaccine efficacy against the highly fit and immune evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.
Elastic energy savings and active energy cost in a simple model of running
Authors: Schroeder Ryan T. , Kuo Arthur D. 
Published: May 2021

AbstractThe energetic economy of running benefits from tendon and other tissues that store and return elastic energy, thus saving muscles from costly mechanical work. The classic “Spring-mass” computational model successfully explains the forces, displacements and mechanical power of running, as the outcome of dynamical interactions between the body center of mass and a purely elastic spring for the leg. Conversely, the Spring-mass model does not include active muscles and cannot explain the metabolic energy cost of running. Here we add explicit actuation and dissipation to the Spring-mass model, resulting in substantial active (and thus costly) work for running on level ground and up or down slopes. Dissipation is modeled as modest energy losses (5% of total mechanical energy for running at 3 m · s-1) from hysteresis and foot-ground collisions, that must be restored by active work each step. Even with substantial elastic energy return (59% of positive work, comparable to empirical observations), the active work could account for most of the metabolic cost of human running (about 68%, assuming human-like muscle efficiency). We also introduce a previously unappreciated energetic cost for rapid production of force, that helps explain the relatively smooth ground reaction forces of running, and why muscles might also actively perform negative work. Although elastic return is key to energy savings, there are still losses that require restorative muscle work, which can cost substantial energy during running.Author SummaryRunning is an energetically economical gait whereby the legs bounce like pogo sticks. Leg tendons act elastically to store and return energy to the body, thus saving the muscles from costly work with each running step. Although elasticity is known to save energy, it does not explain why running still requires considerable effort, and why the muscles still do any work at all. We use a simple computational model to demonstrate two possible reasons why. One is that small amounts of energy are lost when the leg collides with the ground and when the tendons are stretched, and muscles must restore that energy during steady running. A second reason is that muscles may perform work to avoid turning on and off rapidly, which may be even more energetically costly. The resulting muscle work, while small, may actually explain most of the energetic cost of running. Economy may be gained from elasticity, but running nonetheless requires muscles to do active work.
Astrocyte plasticity ensures continued endfoot coverage of cerebral blood vessels and integrity of the blood brain barrier, with plasticity declining with normal aging
Authors: Mills William A. , Jiang Shan , Martin Joelle , Woo AnnaLin M. , Bergstresser Matthew , Kimbrough Ian F. , Sontheimer Harald 
Published: May 2021

AbstractAstrocytes extend endfeet that enwrap the vasculature. Disruptions to this association in disease coincide with breaches in blood-brain barrier (BBB) integrity, so we asked if the focal ablation of an astrocyte is sufficient to disrupt the BBB. 2Phatal ablation of astrocytes induced a plasticity response whereby surrounding astrocytes extended processes to cover vascular vacancies. This occurred prior to endfoot retraction in young mice yet occurred with significant delay in aged animals. Laser-stimulating replacement astrocytes showed them to induce constrictions in pre-capillary arterioles indicating that replacement astrocytes are functional. Inhibition of EGFR and pSTAT3 significantly reduced astrocyte replacement post-ablation yet without perturbations to BBB integrity. Identical endfoot replacement following astrocyte cell death due to reperfusion post-stroke supports the conclusion that astrocyte plasticity ensures continual vascular coverage so as to retain the BBB. Together, these studies uncover the ability of astrocytes to maintain cerebrovascular coverage via substitution from nearby cells and may represent a novel therapeutic target for vessel recovery post-stroke.
An intranasal vaccine durably protects against SARS-CoV-2 variants in mice
Authors: Hassan Ahmed O. , Shrihari Swathi , Gorman Matthew J. , Ying Baoling , Yuan Dansu , Raju Saravanan , Chen Rita E. , Dmitriev Igor P. , Kashentseva Elena , Adams Lucas J. , Shi Pei-Yong , Fremont Daved H. , Curiel David T. , Alter Galit , Diamond Michael S. 
Published: May 2021

ABSTRACTSARS-CoV-2 variants that attenuate antibody neutralization could jeopardize vaccine efficacy and the end of the COVID-19 pandemic. We recently reported the protective activity of a single-dose intranasally-administered spike protein-based chimpanzee adenovirus-vectored vaccine (ChAd-SARS-CoV-2-S) in animals, which has advanced to human trials. Here, we assessed its durability, dose-response, and cross-protective activity in mice. A single intranasal dose of ChAd-SARS-CoV-2-S induced durably high neutralizing and Fc effector antibody responses in serum and S-specific IgG and IgA secreting long-lived plasma cells in the bone marrow. Protection against a historical SARS-CoV-2 strain was observed across a 100-fold vaccine dose range and over a 200-day period. At 6 weeks or 9 months after vaccination, serum antibodies neutralized SARS-CoV-2 strains with B.1.351 and B.1.1.28 spike proteins and conferred almost complete protection in the upper and lower respiratory tracts after challenge. Thus, in mice, intranasal immunization with ChAd-SARS-CoV-2-S provides durable protection against historical and emerging SARS-CoV-2 strains.