bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiometabolic risk factors associated with brain age and accelerate brain ageing
Authors: Beck Dani , de Lange Ann-Marie G. , Pedersen Mads L. , Alnæs Dag , Maximov Ivan I. , Voldsbekk Irene , Richard Geneviève , Sanders Anne-Marthe , Ulrichsen Kristine M. , Dørum Erlend S. , Kolskår Knut K. , Høgestøl Einar A. , Steen Nils Eiel , Djurovic Srdjan , Andreassen Ole A. , Nordvik Jan E. , Kaufmann Tobias , Westlye Lars T. 
Published: March 2021

AbstractThe structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean and standard deviation = 19.7 ± 0.5 months), including 1062 datasets from 790 healthy individuals (mean (range) age = 46.7 (18-94) years, 54% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modelling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomised controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.
Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke
Authors: Zuber Verena , Cameron Alan , Myserlis Evangelos P. , Bottolo Leonardo , Fernandez-Cadenas Israel , Burgess Stephen , Anderson Christopher D. , Dawson Jesse , Gill Dipender 
Published: March 2021

AbstractBackgroundThe relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly defined. We aimed to leverage genetic data to investigate reported associations.MethodsGenetic association estimates for liability to Covid-19 and cardiovascular traits were obtained from large-scale consortia. Analyses primarily focused on critical Covid-19, defined as hospitalization with Covid-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical Covid-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both Covid-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical Covid-19 was associated with increased risk of any of the cardiovascular outcomes for which genetic correlation was identified.ResultsThere was evidence of genetic correlation between critical Covid-19 and ischemic stroke (rg=0.29, FDRp-value=4.65×10−3), body mass index (rg=0.21, FDR-p-value=6.26×10−6) and C-reactive protein (rg=0.20, FDR-p-value=1.35×10−4), but none of the other considered traits. In Mendelian randomization analysis, liability to critical Covid-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical Covid-19 liability 1.03, 95% confidence interval 1.00-1.06,p-value=0.03). Similar estimates were obtained when considering ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical Covid-19.ConclusionsThese data support that liability to critical Covid-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe Covid-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.
Burden of Post-COVID-19 Syndrome and Implications for Healthcare Service Planning: A Population-based Cohort Study
Authors: Menges Dominik , Ballouz Tala , Anagnostopoulos Alexia , Aschmann Hélène E , Domenghino Anja , Fehr Jan S , Puhan Milo A 
Published: March 2021

AbstractBackgroundLonger-term consequences after SARS-CoV-2 infection are becoming an important burden to societies and healthcare systems. Data on post-COVID-19 syndrome in the general population are required for the timely planning of healthcare services and resources. The objective of this study was to assess the prevalence of impaired health status and physical and mental health symptoms among individuals at least six months after SARS-CoV-2 infection, and to characterize their healthcare utilization.MethodsThis population-based prospective cohort study (Zurich SARS-CoV-2 Cohort) enrolled 431 adults from the general population with polymerase chain reaction-confirmed SARS-CoV-2 infection reported to health authorities between 27 February 2020 and 05 August 2020 in the Canton of Zurich, Switzerland. We evaluated the proportion of individuals reporting not to have fully recovered since SARS-CoV-2 infection, and the proportion reporting fatigue (Fatigue Assessment Scale), dyspnea (mMRC dyspnea scale) or depression (DASS-21) at six to eight months after diagnosis. Furthermore, the proportion of individuals with at least one healthcare contact after their acute illness was evaluated. Multivariable logistic regression models were used to assess factors associated with these main outcomes.ResultsSymptoms were present in 385 (89%) participants at diagnosis and 81 (19%) were initially hospitalized. At six to eight months, 111 (26%) reported not having fully recovered. 233 (55%) participants reported symptoms of fatigue, 96 (25%) had at least grade 1 dyspnea, and 111 (26%) had DASS-21 scores indicating symptoms of depression. 170 (40%) participants reported at least one general practitioner visit related to COVID-19 after acute illness, and 10% (8/81) of initially hospitalized individuals were rehospitalized. Individuals that have not fully recovered or suffer from fatigue, dyspnea or depression were more likely to have further healthcare contacts. However, a third of individuals (37/111) that have not fully recovered did not seek further care.ConclusionsIn this population-based study, a relevant proportion of participants suffered from longer-term consequences after SARS-CoV-2 infection. With millions infected across the world, our findings emphasize the need for the timely planning of resources and patient-centered services for post-COVID-19 care.RegistrationISRCTN14990068
Towards 3D-Bioprinting of an Endocrine Pancreas: A Building-Block Concept for Bioartificial Insulin-Secreting Tissue
Authors: Salg Gabriel Alexander , Poisel Eric , Munoz Matthias Neulinger , Cebulla Daniel , Vieira Vitor , Bludszuweit-Philipp Catrin , Nickel Felix , Herr Ingrid , Giese Nathalia A. , Hackert Thilo , Goetz Kenngott Hannes 
Published: March 2021

AbstractBackground & Aims3D-Bioprinting of an endocrine pancreas is a promising future curative treatment for selected patients with insulin secretion deficiency. In this study we present an end-to-end integrative, scalable concept extending from the molecular to the macroscopic level.MethodsA hybrid scaffold device was manufactured by 3D-(bio)printing. INS-1 cells with/without endothelial cells were bioprinted in gelatin methacrylate blend hydrogel. Polycaprolactone was 3D-printed and heparin-functionalized as structural scaffold component. In vitro evaluation was performed by viability and growth assays, total mRNA sequencing, and glucose-stimulated insulin secretion. In vivo, xenotransplantation to fertilized chicken eggs was used to investigate vascularization and function, and finite element analysis modeling served to detect boundary conditions and applicability for human islets of Langerhans.ResultsInsulin-secreting pseudoislets were formed and resulted in a viable and proliferative experimental model. Transcriptomics revealed upregulation of proliferative and β-cell-specific signaling cascades, downregulation of apoptotic pathways, and overexpression of extracellular matrix proteins and VEGF induced by pseudoislet formation and 3D culture. Co-culture with human endothelial cells created a natural cellular niche resulting in enhanced insulin response after glucose stimulation. Survival and function of the pseudoislets after explantation and extensive scaffold vascularization of both the hydrogel and heparinized polycaprolactone components were demonstratedin ovo.Computer simulations of oxygen, glucose, and insulin flows were used to evaluate scaffold architectures and Langerhans islets at a future transplantation site along neurovascular structures.ConclusionA defined end-to-end process for multidisciplinary bioconvergence research on a bioartificial endocrine pancreas was developed. A modular, patient-specific device architecture is proposed for future research studies.
Small Directional Treadmill Perturbations Induce Differential Gait Stability Adaptation
Authors: Li Jinfeng , Huang Helen J. 
Published: March 2021

AbstractIntroducing unexpected perturbations to challenge gait stability is an effective approach to investigate balance control strategies. Little is known about the extent to which people can respond to small perturbations during walking. This study aimed to determine how subjects adapted gait stability to multidirectional perturbations with small magnitudes applied on a stride-by-stride basis. Ten healthy young subjects walked on a treadmill that either briefly decelerated belt speed (“stick”), accelerated belt speed (“slip”), or shifted the platform medial-laterally at right leg mid-stance. We quantified gait stability adaptation in both anterior-posterior and medial-lateral directions using margin of stability and its components, base of support and extrapolated center of mass. Gait stability was disrupted upon initially experiencing the small perturbations as margin of stability decreased in the stick, slip, and medial shift perturbations and increased in the lateral shift perturbation. Gait stability metrics were generally disrupted more for perturbations in the coincident direction. Subjects employed both feedback and feedforward strategies in response to the small perturbations, but mostly use feedback strategies during adaptation. Subjects primarily used base of support (foot placement) control in the lateral shift perturbation and extrapolated center of mass control in the slip and medial shift perturbations. These findings provide new knowledge about the extent of gait stability adaptation to small magnitude perturbations applied on a stride-by-stride basis and reveal potential new approaches for balance training interventions to target foot placement and center of mass control.NEW & NOTEWORTHYLittle is known about if and how humans can adapt to small magnitude perturbations experienced on a stride-by-stride basis during walking. Here, we show that even small perturbations disrupted gait stability and that subjects could still adapt their reactive balance control. Depending on the perturbation direction, subjects might prefer adjusting their foot placement over their center of mass and vice versa. These findings could help potentially tune balance training to target specific aspects of balance.
Identification of Kinases Activated by Multiple Pro-Angiogenic Growth Factors
Authors: Gruver Scott , Rata Scott , Peshkin Leonid , Kirschner Marc W 
Published: March 2021

ABSTRACTAntiangiogenic therapy began as an effort to inhibit VEGF signaling, which was thought to be the sole factor driving tumor angiogenesis. It has become clear that there are more pro-angiogenic growth factors that can substitute for VEGF during tumor vascularization. This has led to the development of multi-kinase inhibitors which simultaneously target multiple growth factor receptors. These inhibitors perform better than monotherapies yet to date no multi-kinase inhibitor targets all receptors known to be involved in pro-angiogenic signaling and resistance inevitably occurs. Given the large number of pro-angiogenic growth factors identified, it may be impossible to simultaneously target all pro-angiogenic growth factor receptors. Here we search for kinase targets, some which may be intracellularly localized, that are critical in endothelial cell proliferation irrespective of the growth factor used. We develop a quantitative endothelial cell proliferation assay and combine it with “kinome regression” or KIR, a recently developed method capable of identifying kinases that influence a quantitative phenotype. We report the kinases implicated by KIR and provide orthogonal evidence of their importance in endothelial cell proliferation. Our approach may point to a new strategy to develop a more complete anti-angiogenic blockade.
The global carrier frequency and genetic prevalence of Upshaw-Schulman syndrome
Authors: Zhao Ting , Fan Shanghua , Sun Liu 
Published: March 2021

AbstractPurposeUpshaw–Schulman syndrome (USS) is an autosomal recessive disease of thrombotic microangiopathy, caused by pathogenic variants in ADAMTS13. We aimed to (1) perform data mining pathogenicity of ADAMTS13 variants, (2) estimate carrier frequency and genetic prevalence of USS from gnomAD data, and (3) curated ADAMTS13 gene pathogenic variants dataset.MethodsPubMed and Scopus were comprehensive retrieved. All previously reported pathogenic ADAMTS13 variants were compiled and annotated with gnomAD allele frequencies. Pooled global and population-specific carrier frequency and genetic prevalence for USS were calculated using Hardy-Weinberg equation.Resultswe mined reported disease-causing variants, of these were present in gnomAD exomes v2.1.1, filtering by allele frequency, pathogenicity of variants were classified by American College of Medical Genetics and Genomics criteria. The genetic prevalence and carrier frequency of USS was 0.43 per 1 million (95% CI: [0.36, 0.55]) and 1.31 per thousand, respectively. Combining known with novel pathogenic/likely pathogenic variants, the genetic prevalence and carrier frequency are 1.1 per 1 million (95% CI: [0.89, 1.37]) and 2.1 per thousand, respectively.Conclusionthe genetic prevalence and carrier frequency of Upshaw-Schulman syndrome are within range of previously rough estimated.
Social information used to elicit cache protection differs between pinyon jays and Clark’s nutcrackers
Authors: Vernouillet Alizée , Clary Dawson , Kelly Debbie M. 
Published: March 2021

AbstractBehavioral plasticity can be described as the ability to adjust behavior depending on environmental information. We used a food-storing (caching) paradigm, during which individuals either ate or cached food under different conditions, to investigate whether they could adjust their caching behavior when observed by conspecifics and heterospecifics, and which cues they used to elicit these behavioral changes. We examined the location and number of caches made by two corvid species differing in sociality, highly social pinyon jays (Gymnorhinus cyanocephalus) and less social Clark’s nutcrackers (Nucifraga columbiana). Although pinyon jays cached a similar amount of food across conditions, they allocated more caches to areas less accessible to the observer. Nutcrackers, however, reduced the number of seeds cached when another nutcracker was present in comparison to when they cached alone. Both species relied on different social cues to elicit re-caching: pinyon jays responded to the amount of time the observer spent close to the caching locations, whereas nutcrackers responded to the amount of time the observer spent pilfering their caches. The differences in cache protection behaviors and the social cues eliciting them may be explained by the species’ social organization. Pinyon jays may only adjust their caching behavior when necessary, as they are often surrounded by other individuals. Clark’s nutcrackers reduce their caching when observed, as they have more opportunities to cache alone, and may resort to additional cache protection when experiencing pilferage. Overall, our results provide insight into understanding how pressures associated with the social environment may influence foraging behaviors.
Delivering on Biden’s 2030 conservation commitment
Authors: Simmons B. Alexander , Nolte Christoph , McGowan Jennifer 
Published: March 2021

AbstractOn January 27, 2021, President Biden signed an executive order,Tackling the Climate Crisis at Home and Abroad, committing the United States to various goals within his campaign’s major climate policy, theBiden Plan for a Clean Energy Revolution and Environmental Justice. Included in this executive order is a commitment to “conserving at least 30 percent of [the United States’] lands and oceans by 2030.” This ambitious conservation target signals a promising direction for biodiversity in the United States. However, while the executive order outlines several goals for climate mitigation, the ‘30×30’ target remains vague in its objectives, actions, and implementation strategies for protecting biodiversity. Biodiversity urgently needs effective conservation action, but it remains unclearwhereandwhatthis 30% target will be applied to. Achieving different climate and biodiversity objectives will require different strategies and, in combination with the associated costs of implementation, will lead to different priority areas for conservation actions. Here, we illustrate what the 30% target could look like across four objectives reflective of the ambitious goals outlined in the executive order. We compile several variations of terrestrial protected area networks guided by these different objectives and examine the trade-offs in costs, ecosystem representation, and climate mitigation potential between each. We find little congruence in priority areas across objectives, emphasizing just how crucial it will be for the Biden administration to develop clear objectives and establish appropriate performance metrics from the outset to maximize both conservation and climate outcomes in support of the 30×30 target. We discuss important considerations that must guide the administration’s conservation strategies in order to ensure meaningful conservation outcomes can be achieved over the next decade.
Transcriptomic analysis of loss of Gli1 in neural stem cells responding to demyelination in the mouse brain
Authors: Samanta Jayshree , Silva Hernandez Moura , Lafaille Juan J. , Salzer James L. 
Published: March 2021

ABSTRACTIn the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they generate new oligodendrocytes, the myelin forming cells. Remarkably, genetic loss or pharmacologic inhibition of Gli1 enhances the efficacy of remyelination by these neural stem cells. To understand the molecular mechanisms involved, we performed a transcriptomic analysis of this Gli1-pool of neural stem cells. We compared murine NSCs with either intact or deficient Gli1 expression from adult mice on a control diet or on a cuprizone diet which induces widespread demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.
Assessing heterogeneity in spatial data using the HTA index with applications to spatial transcriptomics and imaging
Authors: Levy-Jurgenson Alona , Tekpli Xavier , Yakhini Zohar 
Published: March 2021

AbstractMotivationTumour heterogeneity is being increasingly recognised as an important characteristic of cancer and as a determinant of prognosis and treatment outcome. Emerging spatial transcriptomics data hold the potential to further our understanding of tumour heterogeneity and its implications. However, existing statistical tools are not sufficiently powerful to capture heterogeneity in the complex setting of spatial molecular biology.ResultsWe provide a statistical solution, the HeTerogeneity Average index (HTA), specifically designed to handle the multivariate nature of spatial transcriptomics. We prove that HTA has an approximately normal distribution, therefore lending itself to efficient statistical assessment and inference. We first demonstrate that HTA accurately reflects the level of heterogeneity in simulated data. We then use HTA to analyse heterogeneity in two cancer spatial transcriptomics datasets: spatial RNA sequencing by 10x Genomics and spatial transcriptomics inferred from H&E. Finally, we demonstrate that HTA also applies to 3D spatial data using brain MRI. In spatial RNA sequencing we use a known combination of molecular traits to assert that HTA aligns with the expected outcome for this combination. We also show that HTA captures immune-cell infiltration at multiple resolutions. In digital pathology we show how HTA can be used in survival analysis and demonstrate that high levels of heterogeneity may be linked to poor survival. In brain MRI we show that HTA differentiates between normal ageing, Alzheimer’s disease and two tumours. HTA also extends beyond molecular biology and medical imaging, and can be applied to many domains, including GIS.Availability<attached; publicly available upon acceptance>.Contactlevyalona@gmail.comzohar.yakhini@gmail.comSupplementary informationSupplementary data are available atBioinformaticsonline.
Poly(rC)-binding protein 1 limits hepatitis C virus virion assembly and secretion
Authors: Cousineau Sophie E. , Rheault Marylin , Sagan Selena M. 
Published: March 2021

ABSTRACTThe hepatitis C virus (HCV) co-opts numerous cellular elements – including proteins, lipids, and microRNAs – to complete its viral life cycle. The cellular RNA-binding protein, poly(rC)-binding protein 1 (PCBP1), was previously reported to bind to the 5’ untranslated region (UTR) of the HCV genome; however, its importance in the viral life cycle has remained unclear. Herein, we sought to clarify the role of PCBP1 in the HCV life cycle. Using the HCV cell culture (HCVcc) system, we found that knockdown of endogenous PCBP1 resulted in an overall decrease in viral RNA accumulation, yet resulted in an increase in extracellular viral titers. To dissect PCBP1’s specific role in the HCV life cycle, we carried out assays for viral entry, translation, genome stability, RNA replication, as well as virion assembly and secretion. We found that PCBP1 knockdown did not directly affect viral entry, translation, RNA stability, or RNA replication, but resulted in an overall increase in infectious particle secretion. This increase in virion secretion was evident even when viral RNA synthesis was inhibited, and blocking virus secretion could partially restore the viral RNA accumulation decreased by PCBP1 knockdown. We therefore propose a model where endogenous PCBP1 normally limits virion assembly and secretion, which increases viral RNA accumulation in infected cells by preventing the departure of viral genomes packaged into virions. Overall, our findings improve our understanding of how cellular RNA-binding proteins influence viral genomic RNA utilization during the HCV life cycle.