bluuebunny/crossref_metadata_2025_split huggingface dataset:
Papillary and Reticular Fibroblasts Generate Distinct Microenvironments that Differentially Impact Angiogenesis
Authors: Mauroux Adèle , Joncour Pauline , Gillet Benjamin , Hughes Sandrine , Ardidie-Robouant Corinne , Marchand Laëtitia , Liabotis Athanasia , Mailly Philippe , Monnot Catherine , Germain Stephane , Bordes Sylvie , Closs Brigitte , Ruggiero Florence , Muller Laurent 
Published: November 2020

ABSTRACTPapillary and reticular dermis show distinct extracellular matrix (ECM) and vascularization, and fibroblasts isolated from these compartments have different gene expression patterns and behaviourin vitro.However, due to lack of relevant models, the contribution of skin fibroblast sub-populations to vascularization remains unknown. We thus cultured human papillary and reticular fibroblasts as cell sheets. Differential transcriptomic analysis was performed by RNA sequencing to characterize their microenvironment. Bioinformatic analysis revealed that each fibroblast population expressed specific angiogenesis and matrisome gene expression signatures resulting in specific ECM that differed both in composition and structure. The impact of secreted and ECM-bound factors was then assessed using 3D angiogenesis assays. When co-cultivated with endothelial cells, the papillary and reticular microenvironments induced the formation of distinct capillary networks mimicking the characteristics of vasculature of native dermis subcompartments (vessel diameter and density, number of branch points). Whereas conditioned media of papillary fibroblasts displayed intrinsic high angiogenic potential, reticular ones only contributed to capillary formation induced by exogenous VEGF. These results show that skin fibroblast populations regulate angiogenesis via both secreted and ECM-bound factors. Our work emphasizes the importance of papillary and reticular fibroblasts, not only for modelling dermis microenvironment but also for its vascularization.
Crop-photoperiodism model 2.0 for the panicle-initiation date of sorghum and rice that includes daily changes in sunrise and sunset times
Authors: Clerget B. , Sidibe M. , Bueno C.S. , Grenier C. , Kawakata T. , Domingo A.J. , Layaoen H.L. , Palacios N.G. , Bernal J.H. , Trouche G. , Chantereau J. 
Published: November 2020

ABSTRACTBackground and AimsDaylength determines flowering dates. However, questions remain regarding flowering dates in the natural environment, such as the synchronous flowering of plants sown simultaneously at highly contrasting latitudes. The daily change in sunrise and sunset times is the cue for the flowering of trees and for the synchronisation moulting in birds at the equator. Sunrise and sunset also synchronise the cell circadian clock, which is involved in the regulation of flowering. The goal of this study was to update the photoperiodism model with knowledge acquired since its conception.MethodsA large dataset was gathered, including four 2-year series of monthly sowings of 28 sorghum varieties in Mali and two 1-year series of monthly sowings of eight rice varieties in the Philippines to compare with previously published monthly sowings in Japan and Malaysia, and data from sorghum breeders in France, Nicaragua, and Colombia. An additive linear model of the duration in days to panicle initiation (PI) using day length and daily changes in sunrise and sunset times was implemented.Key ResultsSimultaneous with the phyllochron, the duration to PI of field crops acclimated to the mean temperature at seedling emergence within the usual range of mean cropping temperatures. A unique additive linear model combining daylength and daily changes in sunrise and sunset hours was accurately fitted for any type of response in the duration to PI to the sowing date without any temperature input. Once calibrated on a complete and an incomplete monthly sowing series at two tropical latitudes, the model accurately predicted the duration to PI of the concerned varieties from the equatorial to the temperate zone.ConclusionsThe results of the updated photoperiodism model strongly supported the hypothesis that photoperiodism could be a combined response to day length and daily changes in sunrise and sunset times.
Design of proteins presenting discontinuous functional sites using deep learning
Authors: Tischer Doug , Lisanza Sidney , Wang Jue , Dong Runze , Anishchenko Ivan , Milles Lukas F. , Ovchinnikov Sergey , Baker David 
Published: November 2020

AbstractAn outstanding challenge in protein design is the design of binders against therapeutically relevant target proteins via scaffolding the discontinuous binding interfaces present in their often large and complex binding partners. There is currently no method for sampling through the almost unlimited number of possible protein structures for those capable of scaffolding a specified discontinuous functional site; instead, current approaches make the sampling problem tractable by restricting search to structures composed of pre-defined secondary structural elements. Such restriction of search has the disadvantage that considerable trial and error can be required to identify architectures capable of scaffolding an arbitrary discontinuous functional site, and only a tiny fraction of possible architectures can be explored. Here we build on recent advances in de novo protein design by deep network hallucination to develop a solution to this problem which eliminates the need to pre-specify the structure of the scaffolding in any way. We use the trRosetta residual neural network, which maps input sequences to predicted inter-residue distances and orientations, to compute a loss function which simultaneously rewards recapitulation of a desired structural motif and the ideality of the surrounding scaffold, and generate diverse structures harboring the desired binding interface by optimizing this loss function by gradient descent. We illustrate the power and versatility of the method by scaffolding binding sites from proteins involved in key signaling pathways with a wide range of secondary structure compositions and geometries. The method should be broadly useful for designing small stable proteins containing complex functional sites.
Investigating the effects of healthy cognitive aging on brain functional connectivity using 4.7 T resting-state functional Magnetic Resonance Imaging
Authors: Hrybouski Stanislau , Cribben Ivor , McGonigle John , Olsen Fraser , Carter Rawle , Seres Peter , Madan Christopher R. , Malykhin Nikolai V. 
Published: November 2020

ABSTRACTIntroductionFunctional changes in the aging human brain have been previously reported using functional magnetic resonance imaging (fMRI). Earlier resting-state fMRI studies revealed an age-associated weakening of intra-system functional connectivity (FC) and age-associated strengthening of inter-system FC. However, the majority of such FC studies did not investigate the relationship between age and network amplitude, without which correlation-based measures of FC can be challenging to interpret. Consequently, the main aim of this study was to investigate how three primary measures of resting-state fMRI signal – network amplitude, network topography, and inter-network FC – are affected by healthy cognitive aging.MethodsWe acquired resting-state fMRI data on a 4.7 T scanner for 105 healthy participants representing the entire adult lifespan (18-85 years of age). To study age differences in network structure, we combined ICA-based network decomposition with sparse graphical models.ResultsOlder adults displayed lower blood-oxygen-level-dependent (BOLD) signal amplitude in all functional systems with sensorimotor networks showing the largest age differences. Our age comparisons of network topography and inter-network FC demonstrated a substantial amount of age-invariance in the brain’s functional architecture. Despite architecture similarities, old adults displayed a loss of communication efficiency in our inter-network FC comparisons, driven primarily by FC reduction in frontal and parietal association cortices. Together, our results provide a comprehensive overview of age effects on fMRI-based FC.
Variant Curation Expert Panel Recommendations for RYR1 Pathogenicity Assertions in Malignant Hyperthermia Susceptibility
Authors: Johnston Jennifer J. , Dirksen Robert T. , Girard Thierry , Gonsalves Stephen G. , Hopkins Phil M. , Riazi Sheila , Saddic Louis A. , Sambuughin Nyamkhishig , Saxena Richa , Stowell Kathryn , Weber James , Rosenberg Henry , Biesecker Leslie G. 
Published: November 2020

ABSTRACTPurposePrevention of malignant hyperthermia (MH) requires an understanding ofRYR1variant pathogenicity to assess the risk of exposure to triggering agents. Personalized medicine, especially secondary findings and eventually genomic screening, will contribute toward this goal.MethodsWe specified ACMG/AMP criteria for variant interpretation forRYR1and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework.ResultsSeven ACMG/AMP criteria were adopted without changes, ten were adopted withRYR1-specific modifications, and nine were dropped. Thein silico(PP3 and BP4) and hot spot criteria (PM1) were evaluated quantitatively. REVEL gave an OR of 23:1 for PP3 and 16:1 for BP4 using trichotomized cut-offs of >0.85 (pathogenic) and <0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG criteria to 44 recognized MH variants, 30 were assessed as pathogenic, 12 as likely pathogenic, and two as VUS.ConclusionCuration of these variants will facilitate interpretation ofRYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria are generalizable to other variant curation expert panels.
VGLL1 drives therapy resistance in estrogen receptor positive breast cancer
Authors: Gemma Carolina , Lai Chun-Fui , Singh Anup K , Belfiore Antonino , Portman Neil , Milioli Heloisa Z , Periyasamy Manikandan , Abuelmaaty Sara , Nicholls Alyssa J. , Davies Claire M , Patel Naina R. , Simmons Georgia M. , Fan Hailing , Nguyen Van T M , Magnani Luca , Rakha Emad , Martin Lesley-Ann , Lim Elgene , Coombes R. Charles , Pruneri Giancarlo , Buluwela Lakjaya , Ali Simak 
Published: November 2020

SummaryResistance to endocrine therapies (ET) is common in estrogen receptor (ER) positive breast cancer and most relapsed patients die with ET-resistant disease. While genetic mutations provide explanations for some relapsed patients1, mechanisms of resistance remain undefined in many cases. Drug-induced epigenetic reprogramming provides possible routes to resistance2. By analysing histone H3 lysine 27 acetylation (H3K27ac) profiles in models of ET resistance, we discovered that selective ER down-regulators (SERDs) such as fulvestrant promote epigenetic activation ofVGLL1, a co-activator for TEAD transcription factors. We show thatVGLL1, acting via TEADs, promotes expression of genes that drive growth of fulvestrant-resistant breast cancer cells. Pharmacological disruption of VGLL1/TEAD4 interaction inhibits VGLL1/TEAD transcriptional programmes to block growth of the resistant cells and prevents growth. Among the VGLL1/TEAD-regulated genes, we identifyEGFR, whereby VGLL1-directed EGFR upregulation sensitises fulvestrant-resistant breast cancer cells to EGFR inhibitors. Taken together, our findings identify VGLL1 as a transcriptional driver in ET resistance and advance new therapeutic possibilities for relapsed ER+ breast cancer patients.
Pan-primate DNA methylation clocks
Authors: Horvath Steve , Haghani Amin , Zoller Joseph A. , Lu Ake T. , Ernst Jason , Pellegrini Matteo , Jasinska Anna J. , Mattison Julie A. , Salmon Adam B. , Raj Ken , Horvath Markus , Paul Kimberly C. , Ritz Beate R. , Robeck Todd R. , Spriggs Maria , Ehmke Erin E. , Jenkins Susan , Li Cun , Nathanielsz Peter W. 
Published: November 2020

ABSTRACTDNA methylation data have been successfully used to develop highly accurate estimators of age (“epigenetic clocks”) in many mammalian species. With a view of extending such epigenetic clocks to all primate species, we analyzed DNA methylation profiles of 2400 tissues derived from 37 primate species including 11 haplorhine species (baboons, marmosets, vervets, rhesus macaque, chimpanzees, gorillas, orangutan, humans) and 26 strepsirrhine species (suborders Lemuriformes and Lorisiformes). From these we present here, pan-primate epigenetic clocks which are highly accurate for all primates including humans (age correlation R=0.98). We also carried out in-depth analysis of baboon DNA methylation profiles and generated five epigenetic clocks for baboons (Olive-yellow baboon hybrid), one of which, the pan-tissue epigenetic clock, was trained on seven tissue types (fetal cerebral cortex, adult cerebral cortex, cerebellum, adipose, heart, liver, and skeletal muscle) with ages ranging from late fetal life to 22.8 years of age. To facilitate translation of findings in baboons to humans, we further constructed two dual-species, human-baboon clocks. We also identified and present here, epigenetic predictors of sex that apply to all primate species. Low overlap can be observed between age- and sex-related CpGs. Overall, this study advances our understanding of conserved age- and sex-related epigenetic changes in primates, and provides biomarkers to study the aging of all primate species with the facility to readily translate any findings between primate species.
Temperature but not ocean acidification affects energy metabolism and enzyme activities in the blue mussel,Mytilus edulis
Authors: Matoo Omera B. , Lannig Gisela , Bock Christian , Sokolova Inna M. 
Published: November 2020

SUMMARYIn mosaic marine habitats such as intertidal zones ocean acidification (OA) is exacerbated by high variability of pH, temperature, and biological CO2production. The non-linear interactions among these drivers can be context-specific and their effect on organisms in these habitats remains largely unknown, warranting further investigation.We were particularly interested inMytilus edulis(the blue mussel) from intertidal zones of Gulf of Maine (GOM), USA for this study. GOM is a hot spot of global climate change (average SST increasing by > 0.2 °C y-1) with > 60% decline in mussel population over the past 40 years.Here, we utilize bioenergetic underpinnings to identify limits of stress tolerance inM. edulisfrom GOM exposed to warming and OA. We have measured whole-organism oxygen consumption rates and metabolic biomarkers in mussels exposed to control and elevated temperatures (10 vs. 15 °C) and moderate PCO2levels (~ 400 vs. 800 μatm).Our study demonstrates that adultM. edulisfrom GOM are metabolically resilient to the moderate OA scenario but responsive to warming as seen in changes in metabolic rate, energy reserves, metabolite profiles and enzyme activities.Our results are in agreement with recent literature that OA scenarios for the next 100-300 years do not affect this species, possibly as a consequence of maintaining itsin vivoacid-base balance.
Description of the updated nutrition calculation of the Oxford WebQ questionnaire and comparison with the previous version among 207,144 participants in UK Biobank
Authors: Perez-Cornago Aurora , Pollard Zoe , Young Heather , van Uden Marloes , Andrews Colm , Piernas Carmen , Key Tim J , Mulligan Angela , Lentjes Marleen 
Published: November 2020

AbstractPurposeThe Oxford WebQ is a web-based 24-hour dietary assessment method which has been used in UK Biobank and other large prospective studies. The food composition table used to calculate nutrient intakes has recently been replaced with the UK Nutrient Databank, which has food composition data closer in time to when participants completed the questionnaire, and new dietary variables were incorporated. Here we describe the updated version of the Oxford WebQ questionnaire nutrient calculation, and compare nutrient intakes with the previous version used.Methods207,144 UK Biobank participants completed ≥1 Oxford WebQs, and means and standard deviations of nutrient intakes were averaged for all completed 24-h dietary assessments. Spearman correlations and weighted kappa statistics were used to compare the re-classification and agreement of nutrient intakes between the two versions.Results35 new nutrients were incorporated in the updated version. Compared to the previous version, most nutrients were very similar in the updated version except for a few nutrients which showed a difference of >10%: lower with the new version for trans-fat (−20%), and vitamin C (−15%), but higher for retinol (+42%), vitamin D (+26%) and vitamin E (+20%). Most participants were in the same (>60%) or adjacent (>90%) quintile of intake for the two versions. Except for trans-fat (r=0.58, κ=0.42), very high correlations were found between the nutrients calculated using the two versions (r>0.79 and κ>0.60).ConclusionSmall absolute differences in nutrient intakes were observed between the two versions, and the ranking of individuals was minimally affected, except for trans-fat.
Remote working in mental health services: a rapid umbrella review of pre-COVID-19 literature
Authors: Barnett Phoebe , Goulding Lucy , Casetta Cecilia , Jordan Harriet , Sheridan-Rains Luke , Steare Thomas , Williams Julie , Wood Lisa , Gaughran Fiona , Johnson Sonia 
Published: November 2020

AbstractBackgroundTele-mental health care has been rapidly adopted to maintain services during the pandemic, and there is now substantial interest in its future role. Service planning and policy making for recovery from the pandemic and beyond should draw not only on COVID-19 experiences, but also on the substantial research evidence accumulated prior to this.Aimsto conduct an umbrella review of systematic reviews of research literature and evidence-based guidance on remote working in mental health, including both qualitative and quantitative literature.MethodThree databases were searched between January 2010 and August 2020 for systematic reviews meeting pre-defined criteria. Reviews retrieved were independently screened and those meeting inclusion criteria were synthesised and assessed for risk of bias. Narrative synthesis was used to report findingsResultsNineteen systematic reviews met inclusion criteria. Fifteen examined clinical effectiveness, eight reported on aspects of tele-mental health implementation, ten reported on acceptability to service users and clinicians, two on cost-effectiveness and one on guidance. Most reviews were assessed as low quality. Findings suggested that video-based communication could be as effective and acceptable as face-face formats, at least in the short-term. Evidence was lacking on extent of digital exclusion and how it can be overcome, or on significant context such as children and young people and inpatient settings.ConclusionsThis umbrella review suggests that tele-mental health has potential to be an effective and acceptable form of service delivery. However, we found limited evidence on impacts of large-scale implementation across catchment areas. Combining previous evidence and COVID-19 experiences may allow realistic planning for future tele-mental health implementation.
Comparative analysis of variation in the quality and completeness of local outbreak control plans for SARS-CoV-2 in English local authorities
Authors: Yu Xinming , Li Mengye , Lawson-Portuphy Laurie , Chowdhury Avirup , Badrinath Padmanabhan 
Published: November 2020

AbstractBackgroundLocal outbreak control plans (LOCPs) are statutory documents produced by local authorities (LAs) across England. LOCPs outlines LAs’ response to COVID-19 outbreaks and the coordination of local resources, data, and communication to support outbreak response. LOCPs are therefore crucial in the nation’s response to COVID-19. However, there has been no previous systematic assessment of these documents. We performed this study to systematically assess the quality of LOCPs and offer recommendations of good practice.MethodsAll published LOCPs were assessed for basic characteristics. A framework based on Department of Health and Social Care guidelines was used to assess a random sample of LOCPs. Qualitative analysis was undertaken for LOCPs with highest completeness.Results137 of 150 LAs publicly published a full LOCP; nine were drafts. Statistical analysis demonstrated significant difference between reporting of mainstream schools, care homes, and the homeless population and other educational settings, high-risk settings, and other vulnerable groups. LOCPs varied in approach when structuring outbreak response information and focussed on different areas of outbreak management.ConclusionsThe majority of LAs are publicly accessible. There is significant variation between the reporting of high-risk settings and groups. Suggested recommendations may help to improve future LOCP updates.
Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci
Authors: Sobczyk Maria K , Richardson Tom G , Zuber Verena , Min Josine L ,   eQTLGen Consortium,   BIOS Consortium,   GoDMC, Gaunt Tom R , Paternoster Lavinia 
Published: November 2020

AbstractBackgroundGenome-wide association studies for atopic dermatitis (AD, eczema) have identified 25 reproducible loci associated in populations of European descent. We attempt to prioritise candidate causal genes at these loci using a multifaceted bioinformatic approach and extensive molecular resources compiled into a novel pipeline: ADGAPP (Atopic Dermatitis GWAS Annotation & Prioritisation Pipeline).MethodsWe identified a comprehensive list of 103 accessible molecular resources for AD aetiology, including expression, protein and DNA methylation QTL datasets in skin or immune-relevant tissues. These were used to test for overlap with GWAS signals (including colocalisation testing where possible). This was combined with functional annotation based on regulatory variant prediction, and independent genomic features such as chromatin accessibility, promoter-enhancer interactions, splicing sites, non-coding RNA regions, differential expression studies involving eczema patients and fine-mapping of causal variants. For each gene at each locus, we condensed the evidence into a prioritisation score.ResultsAcross the 25 AD loci investigated, we detected significant enrichment of genes with adaptive immune regulatory function and epidermal barrier formation among the top prioritised genes. At 8 loci, we were able to prioritise a single candidate gene (IL6R, ADO, PRR5L, IL7R, ETS1, INPP5D, MDM1, TRAF3). At a further 2 loci, 2 candidate genes emerge (IL18R1/IL18RAP, LRRC32/EMSY). For the majority of these, the prioritised gene has been previously proposed as a plausible candidate, but the evidence we combine here, strengthens the case for many of these. In addition, at 6 of the 25 loci, our ADGAPP analysis prioritises novel alternative candidates (SLC22A5, IL2RA, MDM1, DEXI, ADO, STMN3), highlighting the importance of this comprehensive approach.ConclusionsOur ADGAPP analysis provides additional support for previously implicated genes at several AD GWAS loci, as well as evidence for plausible novel candidates at others. We highlight several genes with good/converging evidence of involvement in AD that represent potential new targets for drug discovery.