bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing the human methylome across the life course: findings from eight UK-based studies
Authors: Walton Esther , Marioni Riccardo , Elliott Hannah R , Cox Simon R , Deary Ian J , Hughes Alun D , Tillin Therese , Kumari Meena , Woofenden Tom , Castillo-Fernandez Juan E , Bell Jordana T , Goodman Alissa , Ploubidis George , Tilling Kate , Suderman Matthew , Gaunt Tom R , Dunn Erin C , Smith Andrew , Relton Caroline L 
Published: September 2021

AbstractVariation in DNA methylation (DNAm) is associated with multiple biological processes that track growth and development, ageing and age-related diseases. However, there is little understanding of what constitutes typical patterns of DNAm variation and how these patterns change across the life course. In this study, we synthesised a map of the human methylome across the life course, focussing on changes in variability and mean DNAm.Harmonizing DNAm datasets across eight longitudinal and cross-sectional UK-based studies, we meta-analysed n=13,215 blood samples from n=7,037 unique individuals from birth to 98 years of age. Changes in CpG-specific variability and means were described across the life course using a meta-regression framework. CpG-specific associations of variability or mean DNAm in relation to the likelihood of association with 100 traits linked to environmental exposures, health and disease were tested within and across ten developmental age bins across the life course.Age was linked to DNAm variability at 29,212 CpG sites. On average, we observed a 1.26 fold increase in DNAm variability per year across the life course. 33,730 CpGs displayed changes in mean DNAm, with 64% of these loci showing decreases in DNAm over time. CpG sites linked to traits were in general more variable across the life course.Our study provides, for the first time, a map of the human methylome across the life course, which is publicly accessible through a searchable online database. This resource allows researchers to query CpG-specific trajectories from birth to old age and link these to health and disease.
A Genotype-to-Phenotype Modeling Framework to Predict Human Pathogenicity of Novel Coronaviruses
Authors: Davis Phillip , Russell Joseph A. 
Published: September 2021

AbstractLeveraging prior viral genome sequencing data to make predictions on whether an unknown, emergent virus harbors a ‘phenotype-of-concern’ has been a long-sought goal of genomic epidemiology. A predictive phenotype model built from nucleotide-level information alone has previously been considered un-tenable with respect to RNA viruses due to the ultra-high intra-sequence variance of their genomes, even within closely related clades. Building from our prior work developing a degenerate k-mer method to accommodate this high intra-sequence variation of RNA virus genomes for modeling frameworks, and leveraging a taxonomic ‘group-shuffle-split’ paradigm on complete coronavirus assemblies from prior to October 2018, we trained multiple regularized logistic regression classifiers at the nucleotide k-mer level capable of accurately predicting withheld SARS-CoV-2 genome sequences as human pathogens and accurately predicting withheld Swine Acute Diarrhea Syndrome coronavirus (SADS-CoV) genome sequences as non-human pathogens. LASSO feature selection identified several degenerate nucleotide predictor motifs with high model coefficients for the human pathogen class that were present across widely disparate classes of coronaviruses. However, these motifs differed in which genes they were present in, what specific codons were used to encode them, and what the translated amino acid motif was. This emphasizes the importance of a phenetic view of emerging pathogenic RNA viruses, as opposed to the canonical phylogenetic interpretations most-commonly used to track and manage viral zoonoses. Applying our model to more recent Orthocoronavirinae genomes deposited since October 2018 yields a novel contextual view of pathogen-potential across bat-related, canine-related, porcine-related, and rodent-related coronaviruses and critical adaptations which may have contributed to the emergence of the pandemic SARS-CoV-2 virus. Finally, we discuss the utility of these predictive models (and their associated predictor motifs) to novel biosurveillance protocols that substantially increase the ‘pound-for-pound’ information content of field-collected sequencing data and make a strong argument for the necessity of routine collection and sequencing of zoonotic viruses.
Age-related differences in performance and fatigability during an isometric quadriceps intermittent fatigue test
Authors: Varesco Giorgio , Luneau Eric , Féasson Léonard , Lapole Thomas , Rozand Vianney 
Published: September 2021

AbstractThe aim of the present study was to investigate age-related differences in fatigability induced by an isometric quadriceps intermittent fatiguing test in young (<35 years old), old (>60 years old) and very old (>80 years old) men and women. Maximal force loss, contractile function and voluntary activation of the knee extensors were evaluated throughout an isometric fatiguing test using femoral nerve magnetic stimulations. Older adults performed more contractions (index of relative performance) than young (P = 0.046) and very old adults (P = 0.007), without differences between young and very old adults. Total work (absolute performance) was greater for young and old adults compared to very old adults (P < 0.001), without differences between young and old adults. At exhaustion, force loss was greater for young (−28 ± 9%) compared to old adults (−19 ± 8%), but not very old adults (−23 ± 8%). The response to femoral nerve stimulation decreased similarly at exhaustion for the three age groups, indicating similar alteration in contractile function with age. No impairment in voluntary activation was observed. Impairments in neuromuscular parameters were similar for men and women. This study showed that older adults were less fatigable than young adults during an isometric intermittent fatiguing task of the knee extensors. This greater fatigue resistance was not maintained in very old adults independent of sex. Fatigability at exhaustion was likely due to impairments in contractile function for the three age groups.
Quantification of new and archived Diaphorina citri transcriptome data using a chromosomal length D. citri genome assembly reveals the vector’s tissue-specific transcriptional response to citrus greening disease
Authors: Mann Marina , Saha Surya , Cicero Joseph M. , Pitino Marco , Moulton Kathy , Cano Lilianna , Hunter Wayne B. , Mueller Lukas A. , Heck Michelle 
Published: September 2021

AbstractBackgroundHuanglongbing (HLB) is the most serious disease of citrus. HLB is caused by the obligate, intracellular bacterium “Candidatus Liberibacter asiaticus” (CLas). CLas is transmitted by Diaphorina citri, the Asian citrus psyllid. Development of transmission blocking strategies to manage HLB relies on knowledge of CLas-D. citri interactions at the molecular level. Prior transcriptome analyses of CLas-infected and un-infected D. citri point to changes in psyllid biology due to CLas-infection. These studies relied on incomplete versions of the D. citri genome, lacked proper host plant controls, and/or were analyzed using different statistical approaches. Therefore, we used standardized experimental and computational approaches to identify differentially expressed genes in both CLas (+) and CLas (-) D. citri. The comparative analysis utilized the newest chromosomal length D. citri genome assembly Diaci_v3. In this work, we present a quantitative transcriptome analysis of excised heads, salivary glands, midguts and bacteriomes from CLas (+) and CLas (-) insects.ResultsEach organ had unique transcriptome profiles and responses to CLas infection. Though most psyllids were infected with CLas, CLas-derived transcripts were not detected in all organs. By analyzing the midgut dataset using both the Diaci_v1.1 and v3.0 D. citri genomes, we showed that improved genome assembly led to significant and quantifiable differences in RNAseq data interpretation.ConclusionsOur results support the hypothesis that future transcriptome studies on circulative, vector-borne pathogens should be conducted at the tissue specific level using complete, chromosomal-length genome assemblies for the most accurate understanding of pathogen-induced changes in vector gene expression.
The Siberian wild apple, Malus baccata (L.) Borkh., is an additional contributor to the genomes of cultivated European and Chinese apples
Authors: Chen Xilong , Cornille Amandine , An Na , Xing Libo , Ma Juanjuan , Zhao Caiping , Wang Yibin , Han Mingyu , Zhang Dong 
Published: September 2021

AbstractIt is crucial to understand domestication to unravel the evolutionary processes that shape the divergence of populations. Differences in life-history traits have probably led to marked differences in the mode and speed of evolution between trees and annuals, particularly the extent of crop-wild gene flow during domestication. Apple is an iconic tree and major fruit crop grown worldwide. The contribution of wild apple species to the genetic makeup of the cultivated apple genome remains a topic of intense investigations. We used population genomics in combination with SNPs to investigate the contributions of the two known wild apple relatives, Malus sylvestris and Malus sieversii, and a supposed contributor, Malus baccata, to European and Chinese rootstock and dessert genomes, with a focus on the extent of wild-crop gene flow during apple domestication. We showed that the European dessert and rootstock apples form a specific gene pool, whereas the Chinese dessert and rootstock apples were a mixture of three wild gene pools. Coalescent-based inferences and gene flow estimates indicated that M. baccata is an additional contributor to the genome of both European and Chinese cultivated apples through wild-to-crop introgressions. We also confirmed previous results on the contribution of M. sylvestris to the cultivated apple genome, and provided insights into the origin of the apple rootstock. This study further demonstrates the role of gene flow during apple domestication, as seen in other woody perennials, and show that domestication of the apple tree involved several wild apple species.
Connectome Spatial Smoothing (CSS): concepts, methods, and evaluation
Authors: Mansour L. Sina , Seguin Caio , Smith Robert E. , Zalesky Andrew 
Published: September 2021

AbstractStructural connectomes are increasingly mapped at high spatial resolutions comprising many hundreds—if not thousands—of network nodes. However, high-resolution connectomes are particularly susceptible to image registration misalignment, tractography artifacts, and noise, all of which can lead to reductions in connectome accuracy and test-retest reliability. We investigate a network analogue of image smoothing to address these key challenges. Connectome Spatial Smoothing (CSS) involves jointly applying a carefully chosen smoothing kernel to the two endpoints of each tractography streamline, yielding a spatially smoothed connectivity matrix. We develop computationally efficient methods to perform CSS using a matrix congruence transformation and evaluate a range of different smoothing kernel choices on CSS performance. We find that smoothing substantially improves the identifiability, sensitivity, and test-retest reliability of high-resolution connectivity maps, though at a cost of increasing storage burden. For atlas-based connectomes (i.e. low-resolution connectivity maps), we show that CSS marginally improves the statistical power to detect associations between connectivity and cognitive performance, particularly for connectomes mapped using probabilistic tractography. CSS was also found to enable more reliable statistical inference compared to connectomes without any smoothing. We provide recommendations on optimal smoothing kernel parameters for connectomes mapped using both deterministic and probabilistic tractography. We conclude that spatial smoothing is particularly important for the reliability of high-resolution connectomes, but can also provide benefits at lower parcellation resolutions. We hope that our work enables computationally efficient integration of spatial smoothing into established structural connectome mapping pipelines.HighlightsWe establish a network equivalent of image smoothing for structural connectomes.Connectome Spatial Smoothing (CSS) improves connectome test-retest reliability, identifiability and sensitivity.CSS also facilitates reliable inference and improves power to detect statistical associations.Both high-resolution and atlas-based connectomes can benefit from CSS.
A single-cell reference atlas delineates CD4+T cell subtype-specific adaptation during acute and chronic viral infections
Authors: Andreatta Massimo , Sherman Zachary , Tjitropranoto Ariel , Kelly Michael C. , Ciucci Thomas , Carmona Santiago J. 
Published: September 2021

AbstractCD4+T cells are critical orchestrators of immune responses against a large variety of pathogens, including viruses. The multifaceted roles of CD4+T cells, including their help to innate cells, CD8+T and B cells and their support for long-lived immunity rely on a profound functional heterogeneity. While multiple CD4+T cell subtypes and their key transcriptional regulators have been identified, there is a lack of consistent definition for CD4+T cell transcriptional states. In addition, the progressive changes affecting CD4+T cell subtypes during and after immune responses remain poorly defined. Taking advantage of single-cell transcriptomics, efficient computational methods, and robust animal models, we characterize the transcriptional landscape of CD4+T cells responding to self-resolving and chronic viral infections. We build a comprehensive atlas of virus-specific CD4+T cells and their evolution over time, and identify six major distinct cell states that are consistently observed in acute and chronic infections. During the course of acute infection, T cell composition progressively changes from effector to memory states, with subtype-specific gene modules and kinetics. Conversely, T cells in persistent infections fail to transition from effector to memory states, and acquire distinct, chronicity-associated transcriptional programs. By single-cell T cell receptor (TCR) sequencing analysis, we characterize the clonal structure of virus-specific CD4+T cells across individuals and T cell subtypes. We find that virus-specific CD4+T cell responses are mainly private across individuals and that most T cells differentiate into all subtypes independently of their TCR, in both acute and chronic infections. Finally, we show that our CD4+T cell atlas can be used as a reference to accurately interpret cell states in external single-cell datasets. Overall, this study describes a previously unappreciated level of adaptation of the transcriptional states of CD4+T cells responding to viruses and provides a new computational resource for CD4+T cell analysis, available online athttps://spica.unil.ch.
Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk
Authors: Kwon Jaedeok , Suessmilch Maria , McColl Alison , Cavanagh Jonathan , Morris Brian J. 
Published: September 2021

AbstractExposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) RNA viral or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure specifically with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with the current SARS-CoV-2 pandemic. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNFα, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNFα mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnfα) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.
A conformational switch controlling the toxicity of the prion protein
Authors: Frontzek Karl , Bardelli Marco , Senatore Assunta , Henzi Anna , Reimann Regina R. , Bedir Seden , Marino Marika , Hussain Rohanah , Jurt Simon , Meisl Georg , Pedotti Mattia , Mazzola Federica , Siligardi Giuliano , Zerbe Oliver , Losa Marco , Knowles Tuomas , Lakkaraju Asvin , Zhu Caihong , Schwarz Petra , Hornemann Simone , Holt Matthew G. , Simonelli Luca , Varani Luca , Aguzzi Adriano 
Published: September 2021

SummaryPrion infections cause conformational changes of PrPC and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (“H-latch”) altering the flexibility of the α2-α3 and β2-α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation, prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is causally linked to prion neurotoxicity.
Endogenous virus sRNA regulates gene expression following genome shock in tomato hybrids
Authors: Lopez-Gomollon Sara , Müller Sebastian Y. , Baulcombe David C. 
Published: September 2021

AbstractHybridization and environmental stress trigger genome shock that perturbs patterns of gene expression leading to phenotypic changes. In extreme examples it is associated to transposon mobilization and genome rearrangement. Here we discover a novel alternative mechanism in interspecific Solanum hybrids in which changes to gene expression were associated with DCL2-mediated small (s)RNAs derived from endogenous (para)retroviruses (EPRVs). Correspondingly, the altered patterns of gene expression overlapped with the effects of dcl2 mutation and the changes to sRNA profiles involved 22nt species produced in the DCL2 biogenesis pathway. These findings implicate hybridization-induced genome shock leading to EPRV activation and sRNA silencing as causing changes in gene expression. Such hybridization-induced variation in gene expression could increase the range of traits available for selection in natural evolution or in breeding for agriculture.
Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26
Authors: Salerno-Kochan Anna , Horn Andreas , Ghosh Pritha , Nithin Chandran , Kościelniak Anna , Strauss Daniela , Rossbach Oliver , Bujnicki Janusz M. , Gaik Monika , Medenbach Jan , Glatt Sebastian 
Published: September 2021

AbstractThe TRIM-NHL protein Meiotic P26 (Mei-P26) acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes and spermatogenesis. Mei-P26 functions as a post-transcriptional regulator of gene expression, however, the molecular details of how its NHL domain selectively recognizes and regulates its mRNA targets have remained elusive. Here, we present the crystal structure of the Mei-P26 NHL domain at 1.6 Å resolution and identify key amino acids that confer substrate specificity and distinguish Mei-P26 from closely related TRIM-NHL proteins. Furthermore, we identify mRNA targets of Mei-P26 in cultured Drosophila cells and show that Mei-P26 can act as either a repressor or activator of gene expression on different RNA targets. Our work reveals the molecular basis of RNA recognition by Mei-P26 and the fundamental functional differences between otherwise very similar TRIM-NHL proteins.
STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus
Authors: Zhang Yanfeng , Day Kenneth , Absher Devin M. 
Published: September 2021

AbstractMapping of allelic imbalance (AI) at heterozygous loci has the potential to establish links between genetic risk for disease and biological function. Leveraging multi-omics data for AI analysis and functional annotation, we discovered a novel functional risk variant rs1047643 at 8p23 in association with SLE. This variant displays dynamic AI of chromatin accessibility and allelic expression on FDFT1 gene in B cells with SLE. We further found a B-cell restricted super-enhancer (SE) that physically contacts with this SNP-residing locus, an interaction that also appears specifically in B cells. Quantitative analysis of open chromatin and DNA methylation profiles further demonstrated that the SE exhibits aberrant activity in B cell development with SLE. Functional studies identified that STAT3, a master factor associated with autoimmune diseases, directly regulates both the AI of risk variant and the activity of SE in cultured B cells. Our study reveals that STAT3-mediated SE activity and cis-regulatory effects of SNP rs1047643 at 8p23 locus are associated with B cell deregulation in SLE.