bluuebunny/crossref_metadata_2025_split huggingface dataset:
Topographic Heterogeneity of Lung Microbiota in End-Stage Idiopathic Pulmonary Fibrosis: The Microbiome in Lung Explants-2 (MiLEs-2) Study
Authors: Valenzi Eleanor B , Yang Haopu , Sembrat John C , Yang Libing , Winters Spencer , Nettles Rachel , Kass Daniel J , Qin Shulin , Wang Xiaohong , Myerburg Michael M , Methé Barbara , Fitch Adam , Alder Jonathan K , Benos Panayiotis V , McVerry Bryan J , Rojas Mauricio , Morris Alison , Kitsios Georgios D 
Published: March 2020

AbstractBackgroundLung microbiota profiles in patients with early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression; however, the topographic heterogeneity of lung microbiota and their roles in advanced IPF are unknown.MethodsWe sampled subpleural tissue from up to three lobes as well as airway-based specimens (bronchial washings and airway tissue) in patients with IPF, connective tissue disease-associated interstitial lung disease (CTD-ILD), cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD) and donor lungs deemed unsuitable for transplant (controls). We quantified bacterial load and profiled communities by polymerase chain reaction (PCR) amplification and sequencing of the 16S rRNA gene.FindingsExplants from 62 IPF, 15 CTD-ILD, 20 CF, 20 COPD and 20 control patients were included. Airway-based samples had higher bacterial load compared to distal parenchymal tissue across all patient groups. IPF basilar tissue had much lower bacterial load compared to CF and control lungs (p<0.001). Among patients with IPF, no differences in microbial community profiles were found between parenchymal tissue samples from different lobes. With Dirichlet multinomial models, a cluster of IPF patients (29%) with distinct composition, high bacterial load and low alpha diversity was identified, exhibiting higher odds for acute exacerbation of IPF or death.InterpretationIPF explants exhibited low biomass in the distal parenchyma of all three lobes with higher bacterial load in the airways. The discovery of a distinct subgroup of IPF patients with higher bacterial load and worse clinical outcomes supports investigation of personalized medicine approaches for microbiome-targeted interventions.Key MessagesWhat is the key question?Bronchoalveolar lavage microbiome profiles in early idiopathic pulmonary fibrosis (IPF) have been associated with disease progression, but the regional heterogeneity of resident microbiota in end-stage IPF has not been defined.What is the bottom line?IPF explants demonstrate higher bacterial load in airway compared to parenchymal samples, but no differences in between apical or basilar parenchymal samples. A subgroup of patients with higher bacterial load and respiratory pathogen abundance was associated with worse clinical outcomes.Why read on?Patient-specific heterogeneity in the lung microbiome of IPF supports the need for personalized microbiome-targeted interventions in IPF.
Prediction of Venous Thromboembolism Based on Clinical and Genetic Factors
Authors: Kolin David A. , Kulm Scott , Elemento Olivier 
Published: March 2020

BACKGROUNDBoth clinical and genetic factors drive the risk of venous thromboembolism. However, whether clinically recorded risk factors and genetic variants can be combined into a clinically applicable predictive score remains unknown.METHODSUsing Cox proportional-hazard models, we analyzed the association of risk factors with the likelihood of venous thromboembolism in U.K. Biobank, a large prospective cohort. We created a novel ten point clinical score using seven established clinical risk factors for venous thromboembolism. We also generated a polygenic risk score of 21 single nucleotide polymorphisms to quantify genetic risk. The genetic score was categorized into high risk (top two deciles of scores), intermediate risk (deciles three to eight), and low risk (lowest two deciles). The discrete clinical score led to the following approximate decile categorizations: high risk (5 to 10 points), intermediate risk (3 to 4 points), and low risk (0 to 2 points).RESULTSAmongst the 502,536 participants in the U.K. Biobank, there were 4,843 events of venous thromboembolism. Analyses of established clinical risk factors and the most commonly used medications revealed that participants were at decreased risk of venous thromboembolism if they had ever used oral contraceptive pills (hazard ratio, 0.88; 95% confidence interval [CI], 0.79 to 0.99) or if they currently used bendroflumethiazide (hazard ratio, 0.84; 95% CI, 0.74 to 0.95), cod liver oil capsules (hazard ratio, 0.87; 95% CI, 0.77 to 0.99), or atenolol (hazard ratio, 0.79; 95% CI, 0.68 to 0.91). Participants were at significantly increased risk of venous thromboembolism if they were at high clinical risk (hazard ratio, 5.98; 95% CI, 5.43 to 6.59) or high genetic risk (hazard ratio, 2.28; 95% CI, 2.07 to 2.51) relative to participants at low clinical or genetic risk, respectively. Combining clinical risk factors with genetic risk factors produced a model that better predicted risk of venous thromboembolism than either model alone (P<0.001). Participants at high clinical and genetic risk in the combined score had over an eightfold increased risk of venous thromboembolism relative to participants at low risk (hazard ratio, 8.27; 95% CI 7.59 to 9.00).CONCLUSIONSBy assessing venous thromboembolic events in over 500,000 participants, we identified several known and novel associations between risk factors and venous thromboembolism. Participants in the high risk group of a combined score, consisting of clinical and genetic factors, were over eight times more likely to experience venous thromboembolism than participants in the low risk group.
Extensive single-cell genomics reveals bacterial diversity and diverse phage host ranges in the area in and around the Red Sea
Authors: Nishikawa Yohei , Kogawa Masato , Hosokawa Masahito , Wagatsuma Ryota , Mineta Katsuhiko , Takahashi Kai , Ide Keigo , Yura Kei , Behzad Hayedeh , Gojobori Takashi , Takeyama Haruko 
Published: March 2020

AbstractTo improve our understanding of the environmental microbiome, we developed a single-cell genome sequencing platform, named SAG-gel, which utilizes gel beads for single-cell isolation, cell lysis, and whole genome amplification (WGA) for sequencing. SAG-gel enables serial, parallel and independent reactions of > 100,000 single cells in a single tube, delivering high-quality genome recovery with storable randomized single-cell genome libraries. From soil and marine environmental sources, we acquired 734 partial genomes that are recapitulated in 231 species, 35% of which were assigned as high-to-medium qualities. We found that each genome to be almost unique and 98.7% of them were newly identified, implying the complex genetic diversities across 44 phyla. The various metabolic capabilities including virulence factors and biosynthetic gene clusters were found across the lineages at single-cell resolution. This technology will accelerate the accumulation of reference genomes of uncharacterized environmental microbes and provide us new insights for their roles.
Arhgap25deficiency leads to decreased numbers of peripheral blood B cells and defective germinal center reactions
Authors: Lindner Silke E. , Egelston Colt A. , Huard Stephanie M. , Lee Peter P. , Wang Leo D. 
Published: March 2020

ABSTRACTRho family GTPases are critical for normal B cell development and function and their activity is regulated by a large and complex network of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). However, the role of GAPs in B cell development is poorly understood. Here we show that the novel Rac-GAP ARHGAP25 is important for B cell development in mice in a CXCR4-dependent manner. We show thatArhgap25deficiency leads to a significant decrease in peripheral blood B cell numbers, as well as defects in mature B cell differentiation.Arhgap25-/-B cells respond to antigen stimulationin vitroandin vivobut have impaired germinal center formation and decreased IgG1 class switching. Additionally,Arhgap25-/-B cells exhibit increased chemotaxis to CXCL12. Taken together, these studies demonstrate an important role forArhgap25 in peripheral B cell development and antigen response.
Intraepithelial T cells diverge by intestinal location as pigs age
Authors: Wiarda Jayne E. , Trachsel Julian M. , Bond Zahra F. , Byrne Kristen A. , Gabler Nicholas K. , Loving Crystal L. 
Published: March 2020

AbstractT cells resident within the intestinal epithelium play a central role in barrier integrity and provide a first line of immune defense. Intraepithelial T cells (IETs) are among the earliest immune cells to populate and protect intestinal tissues, thereby giving them an important role in shaping gut health early in life. In pigs, IETs are poorly defined, and their maturation in young pigs has not been well studied. Given the importance of IETs in contributing to early life and long-term intestinal health through interactions with epithelial cells, the microbiota, and additional environmental factors, a deeper characterization of IETs in pigs is warranted. The objective of this study was to analyze age- and intestinal location-dependent changes in IETs across multiple sites of the small and large intestine in pigs between 4 and 8 weeks of age. IETs increased in abundance over time and belonged to both γδ and αβ T cell lineages. Similar compositions of IETs were identified across intestinal sites in 4-week-old pigs, but compositions diverged between intestinal sites as pigs aged. CD2+CD8α+γδ T cells and CD4−CD8α+αβ T cells comprised >78% of total IETs at all intestinal locations and ages examined. Greater percentages of γδ IETs were present in large intestine compared to small intestine in older pigs. Small intestinal tissues had greater percentages of CD2+CD8α−γδ IETs, while CD2+CD8α+γδ IET percentages were greater in the large intestine. Percentages of CD4−CD8α+αβ IETs increased over time across all intestinal sites. Moreover, percentages of CD27+cells decreased in ileum and large intestine over time, indicating increased IET activation as pigs aged. Percentages of CD27+cells were also higher in small intestine compared to large intestine at later timepoints. Results herein emphasize 4 to 8 weeks of age as a critical window of IET maturation and suggest strong associations between intestinal location and age with IET heterogeneity in pigs.
An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits
Authors: Shi Chenfu , Ray-Jones Helen , Ding James , Duffus Kate , Fu Yao , Gaddi Vasanthi Priyadarshini , Gough Oliver , Hankinson Jenny , Martin Paul , McGovern Amanda , Yarwood Annie , Gaffney Patrick , Eyre Steve , Rattray Magnus , Warren Richard B , Orozco Gisela 
Published: March 2020

AbstractChromatin looping between regulatory elements and gene promoters presents a potential mechanism whereby disease risk variants affect their target genes. Here we use H3K27ac HiChIP, a method for assaying the active chromatin interactome in two cell lines: keratinocytes and skin derived CD8+ T cells. We integrate public datasets for a lymphoblastoid cell line and primary CD4+ T cells and identify gene targets at risk loci for skin-related disorders. Interacting genes enrich for pathways of known importance in each trait, such as cytokine response (psoriatic arthritis, psoriasis) and replicative senescence (melanoma). We show examples of how our analysis can inform changes in the current understanding of multiple psoriasis associated risk loci. For example, the variant rs10794648, which is generally assigned toIFNLR1, was linked toGRHL3in our dataset, a gene essential in skin repair and development. Our findings, therefore, indicate a renewed importance of skin related factors in the risk of disease.Abstract FigureGraphical AbstractIn this article we take disease associated variants from 5 dermatological conditions and use cell type specific datasets to map genes that could be affected by these variants, providing insight into disease mechanisms.
Resident and elicited macrophages differ in expression of their glycomes and lectins
Authors: Park Diane D. , Chen Jiaxuan , Kudelka Matthew R. , Jia Nan , Haller Carolyn A. , Kosaraju Revanth , Premji Alykhan M. , Galizzi Melina , Nairn Alison V. , Moreman Kelley W. , Cummings Richard D. , Chaikof Elliot L. 
Published: March 2020

AbstractThe pleiotropic functions of macrophages in immune defense, tissue repair, and maintenance of tissue homeostasis are supported by the heterogeneity in macrophage sub-populations that differ both in ontogeny and polarization. Although glycans and lectins are integral to macrophage function, little is known about the factors governing their expression. Here we show that the cellular glycome of murine peritoneal macrophages primarily reflects developmental origin and to a lesser degree, cellular polarization. Resident macrophages were characterized by a simple glycome, predominantly consisting of core 1 O-glycans, while elicited macrophages also expressed core 2 O-glycans, along with highly branched and extended complex-type N-glycans, that exhibited a higherN-acetylneuraminic acid:N-glycolylneuraminic acid ratio. Strikingly, our analysis revealed that resident and elicited macrophages express 139 lectin genes, with differential expression of 49 lectin genes, including galectins, Siglecs, and C-type lectins. These results suggest that regulation of self-glycan-protein complexes may be central to macrophage residence and recruitment.
Active Vision in Immersive, 360° Real-World Environments
Authors: Haskins Amanda J. , Mentch Jeff , Botch Thomas L. , Robertson Caroline E. 
Published: March 2020

AbstractVision is an active process. Humans actively sample their sensory environment via saccades, head turns, and body movements. Yet, little is known about active visual processing in real-world environments. Here, we exploited recent advances in immersive virtual reality (VR) and in-headset eye-tracking to show that active viewing conditions impact how humans process complex, real-world scenes. Specifically, we used quantitative, model-based analyses to compare which visual features participants prioritize over others while encoding a novel environment in two experimental conditions: active and passive. In the active condition, participants used head-mounted VR displays to explore 360º scenes from a first-person perspective via self-directed motion (saccades and head turns). In the passive condition, 360º scenes were passively displayed to participants within the VR headset while they were head-restricted. Our results show that signatures of top-down attentional guidance increase in active viewing conditions: active viewers disproportionately allocate their attention to semantically relevant scene features, as compared with passive viewers. We also observed increased signatures of exploratory behavior in eye movements, such as quicker, more entropic fixations during active as compared with passive viewing conditions. These results have broad implications for studies of visual cognition, suggesting that active viewing influences every aspect of gaze behavior – from the way we move our eyes to what we choose to attend to – as we construct a sense of place in a real-world environment.Significance StatementEye-tracking in immersive virtual reality offers an unprecedented opportunity to study human gaze behavior under naturalistic viewing conditions without sacrificing experimental control. Here, we advanced this new technique to show how humans deploy attention as they encode a diverse set of 360º, real-world scenes, actively explored from a first-person perspective using head turns and saccades. Our results build on classic studies in psychology, showing that active, as compared with passive, viewing conditions fundamentally alter perceptual processing. Specifically, active viewing conditions increase information-seeking behavior in humans, producing faster, more entropic fixations, which are disproportionately deployed to scene areas that are rich in semantic meaning. In addition, our results offer key benchmark measurements of gaze behavior in 360°, naturalistic environments.
Discriminating the Influence of Correlated Factors from Multivariate Observations: the Back-to-Back Regression
Authors: King Jean-Rémi , Charton François , Lopez-Paz David , Oquab Maxime 
Published: March 2020

AbstractIdentifying causes solely from observations can be particularly challenging when i) potential factors are difficult to manipulate independently and ii) observations are multi-dimensional. To address this issue, we introduce “Back-to-Back” regression (B2B), a linear method designed to efficiently measure, from a set of correlated factors, those that most plausibly account for multidimensional observations. First, we prove the consistency of B2B, its links to other linear approaches, and show how it provides a robust, unbiased and interpretable scalar estimate for each factor. Second, we use a variety of simulated data to show that B2B outperforms least-squares regression and cross-decomposition techniques (e.g. canonical correlation analysis and partial least squares) on causal identification when the factors and the observations are partially collinear. Finally, we apply B2B to magneto-encephalography of 102 subjects recorded during a reading task to test whether our method appropriately disentangles the respective contribution of word length and word frequency - two correlated factors known to cause early and late brain responses respectively. The results show that these two factors are better disentangled with B2B than with other standard techniques.
Parallelism in gene expression between foothill and alpine ecotypes inArabidopsis arenosa
Authors: Wos Guillaume , Bohutínská Magdalena , Nosková Jana , Mandáková Terezie , Kolář Filip 
Published: March 2020

AbstractParallel adaptation results from independent evolution of similar traits between closely related lineages and allows testing to which extent evolution is repeatable. Parallel adaptation often involves similar gene expression changes but the identity of genes shaped by parallel selection and the causes of expression parallelism remains largely unknown. By comparing genomes and transcriptomes of four independent foothill–alpine population pairs across four treatments, we addressed genetic basis, plasticity and functional consequences of gene expression parallelism in alpine adaptation. Seeds of four population pairs ofArabidopsis arenosafrom distinct mountain regions were raised under four treatments that differed in temperature and irradiance, factors varying strongly with elevation. Parallelism in gene expression was quantified by RNA-seq in leaves of young plants. By manipulating temperature and irradiance, we also tested for parallelism in plasticity (gene-by-environment interaction [GEI]). We found significant parallelism in differential gene expression across four independently recruited alpine ecotypes with an overrepresentation of genes involved in biotic stress response. In addition, we demonstrated significant parallelism in GEI indicating shared response to environmental variation in our foothill and alpine populations. Fraction of genes showing expression parallelism also encompassed genomic variants showing outlying differentiation, with greater enrichment of such variants in cis-regulatory elements. In summary, our results suggest frequent evolutionary repeatability in shaping expression difference associated with colonization of an alpine environment and support the hypothesis of an important role of genetic variation in cis-regulatory elements in gene expression parallelism.
Root-derivedtrans-zeatin cytokinin protectsArabidopsisplants against photoperiod stress
Authors: Frank Manuel , Cortleven Anne , Novak Ondrej , Schmülling Thomas 
Published: March 2020

ABSTRACTRecently, a novel type of abiotic stress caused by a prolongation of the light period - coined photoperiod stress - has been described inArabidopsis. During the night after the prolongation of the light period, stress and cell death marker genes are induced. The next day, strongly stressed plants display a reduced photosynthetic efficiency and leaf cells eventually enter programmed cell death. The phytohormone cytokinin (CK) acts as a negative regulator of this photoperiod stress syndrome. In this study, we show thatArabidopsiswild-type plants increase the CK concentration in response to photoperiod stress. Analysis of cytokinin synthesis and transport mutants revealed that root-derivedtrans-zeatin (tZ)-type CKs protect against photoperiod stress. The CK signaling proteins ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN 2 (AHP2), AHP3 and AHP5 and transcription factors ARABIDOPSIS RESPONSE REGULATOR 2 (ARR2), ARR10 and ARR12 are required for the protective activity of CK. Analysis of higher order B-typearrmutants suggested that a complex regulatory circuit exists in which the loss ofARR10orARR12can rescue thearr2phenotype. Together the results revealed the role of root-derived CK acting in the shoot through the two-component signaling system to protect from the negative consequences of strong photoperiod stress.
Dentate gyrus population activity during immobility supports formation of precise memories
Authors: Pofahl Martin , Nikbakht Negar , Haubrich André N. , Nguyen Theresa , Masala Nicola , Braganza Oliver , Macke Jakob H. , Ewell Laura A. , Golcuk Kurtulus , Beck Heinz 
Published: March 2020

AbstractThe hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in-vivo two-photon Ca2+imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they recapitulate population patterns evoked during self-motion. Using optogenetic inhibition during immobility, we show that granule cell activity during immobility is required to form dentate gyrus-dependent spatial memories. These data suggest that memory formation is supported by dentate gyrus replay of population codes of the current environment.
Mycobacterium tuberculosisFasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine
Authors: Lara Julia , Diacovich Lautaro , Trajtenberg Felipe , Larrieux Nicole , Malchiodi Emilio L. , Fernandez Marisa M. , Gago Gabriela , Gramajo Hugo , Buschiazzo Alejandro 
Published: March 2020

ABSTRACTMycobacterium tuberculosisis a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a two-domain transcriptional activator that belongs to the TetR family of regulators, and plays a central role in mycobacterial long-chain fatty acyl-CoA sensing and lipid biosynthesis regulation. We now disclose crystal structures ofM. tuberculosisFasR in complex with acyl effector ligands and with DNA, uncovering its sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration, with its DNA-binding domains in an open state that leads to DNA dissociation. Structure-guided point-mutations further support this effector-dependent mechanism. The protein-folding hydrophobic core, connecting the two domains, is completed by the effector ligand into a continuous spine, explaining the allosteric flexible-to-ordered transition. The transmission spine is conserved in all TetR-like transcription factors, offering new opportunities for anti-tuberculosis drug discovery.