bluuebunny/crossref_metadata_2025_split huggingface dataset:
A framework to assess the effects of changes in species composition on processes derived from trophic interactions
Authors: Landim Anna R. , Fernandez Fernando A. S. , Dias André T. C. 
Published: November 2020

AbstractFunctional diversity uses response and effect traits to understand how communities are affected by changes in the environment and their consequences on the structure and functioning of ecosystems. However, most studies focus on a single taxonomic or functional group, ignoring that many ecological processes result from trophic interactions. Here we established a multi-trophic trait-based framework to evaluate the consequences of community change for ecological processes resulting from trophic interactions. Specifically, we estimated the potential effect of each species considering the consumer and resource communities involved on the trophic interaction. The functional space of consumer and resource communities were incorporated into a single analysis by using resource traits to estimate consumers’ functional space. Our framework included a parameter that establishes different weights to unique interactions when estimating a species potential effect. We presented two modifications for application using abundance and species richness data and two modifications to allow incorporating absent species into the analysis. Our framework can be used to investigate consequences of community changes in different situations, such as species extinctions, invasions and refaunation. To demonstrate the insights derived from our framework we used an exemplary study case of refaunation of an impacted tropical forest. Our framework informs on a species contribution to an ecological process according to its originality, i.e., the uniqueness or redundancy of its interactions, and the magnitude of the effect, indicated by the frequency of the resource’s community trait values with which it interacts. Thus, it helps to increase the understanding of the effects of changes in community composition on ecological processes resulting from trophic interactions. It assists practitioners and researches with predictions and evaluations on potential loss and reestablishment of ecological functions resulted from changes in community functional composition.
IL-7-adjuvanted vaginal vaccine elicits strong mucosal immune responses in non-human primates
Authors: Logerot Sandrine , Figueiredo-Morgado Suzanne , Charmeteau-de-Muylder Bénédicte , Sandouk Abdelkader , Drillet-Dangeard Anne-Sophie , Bomsel Morgane , Bourgault-Villada Isabelle , Couëdel-Courteille Anne , Cheynier Rémi , Rancez Magali 
Published: November 2020

ABSTRACTMucosal immune responses are crucial in protecting against pathogens entering through mucosal surfaces. However, due to difficulties in disrupting the tolerogenic environment associated with mucosa, mucosal immunity remains difficult to stimulate through vaccines and requires appropriate adjuvants. We previously demonstrated that either administered systemically to healthy macaques or locally expressed in the intestinal mucosa of acutely SIV-infected macaques, interleukin-7 (IL-7) triggers chemokine expression and immune cell homing into mucosae, suggesting its important role in the development of mucosal immune responses.We therefore examined whether local delivery of recombinant glycosylated simian IL-7 (rs-IL-7gly) to the vaginal mucosa of rhesus macaques could prepare the lower female genital tract (FGT) for subsequent immunization and act as an efficient mucosal adjuvant.First, we showed that local administration of rs-IL-7gly triggers vaginal overexpression of chemokines and infiltration of mDCs, macrophages, NKs, B- and T-cells in the chorion while MamuLa-DR+APCs accumulated in the epithelium. Subsequent mucosal anti-DT immunization in macaques resulted in a faster, stronger, and more persistent mucosal antibody response compared to DT-immunization alone. Indeed, we detected robust productions of DT-specific IgAs and IgGs in their vaginal secretions and identified cells secreting DT-specific IgAs in their vaginal mucosa and IgGs in draining lymph nodes.Finally, the expression of chemokines involved in the organization of tertiary lymphoid structures (TLS) was only increased in the vaginal mucosa of IL-7-adjuvanted immunized macaques. Interestingly, TLSs developed around PNAd+high endothelial venules in their lower FGT sampled 2 weeks after the last immunization.Non-traumatic vaginal administration of rs-IL-7gly prepares the mucosa to respond to subsequent local immunization and allows the development of a strong mucosal immune response in macaques, through the chemokine-dependent recruitment of immune cells, the activation of mDCs and the formation of TLSs. The localization of DT-specific IgA plasma cells in the mucosa argues for their contribution to the production of specific immunoglobulins in the vaginal secretions. Our results highlight the potential of IL-7 as a potent mucosal adjuvant to stimulate the FGT immune system and elicit vaginal antibody responses to local immunization, which is the most promising way to confer protection against many sexually transmitted diseases.
censcyt: censored covariates in differential abundance analysis in cytometry
Authors: Gerber Reto , Robinson Mark D. 
Published: November 2020

AbstractInnovations in single cell technologies have lead to a flurry of datasets and computational tools to process and interpret them, including analyses of cell composition changes and transition in cell states. Thediffcytworkflow for differential discovery in cytometry data consist of several steps, including preprocessing, cell population identification and differential testing for an association with a binary or continuous covariate. However, the commonly measured quantity of survival time in clinical studies often results in a censored covariate where classical differential testing is inapplicable. To overcome this limitation, multiple methods to directly include censored covariates in differential abundance analysis were examined with the use of simulation studies and a case study. Results show high error control and decent sensitivity for a subset of the methods. The tested methods are implemented in the R packagecenscytas an extension ofdiffcytand are available athttps://github.com/retogerber/censcyt. Methods for the direct inclusion of a censored variable as a predictor in GLMMs are a valid alternative to classical survival analysis methods, such as the Cox proportional hazard model, while allowing for more flexibility in the differential analysis.
Inferring functionally relevant molecular tissue substructures by agglomerative clustering of digitized spatial transcriptomes
Authors: Moehlin Julien , Mollet Bastien , Colombo Bruno Maria , Mendoza-Parra Marco Antonio 
Published: November 2020

SummaryDevelopments on spatial transcriptomics (ST) are providing means to interrogate organ/tissue architecture from the angle of the gene programs defining their molecular complexity. However, computational methods to analyze ST data under-exploits the spatial signature retrieved within the maps. Inspired by contextual pixel classification strategies applied to image analysis, we have developed MULTILAYER, allowing to stratify ST maps into functionally-relevant molecular substructures. For it, MULTILAYER applies agglomerative clustering strategies within contiguous locally-defined transcriptomes (herein defined as gene expression elements or Gexels), combined with community detection methods for graph partitioning.MULTILAYER has been evaluated over multiple public ST data, including developmental tissues but also tumor biopsies. Its performance has been challenged for the processing of high-resolution ST maps and it has been used for an enhanced comparison of multiple public tissue biopsies issued from a cancerous prostate.MULTILAYER provides a digital perspective for the analysis of spatially-resolved transcriptomes and anticipates the application of contextual gexel classification strategies for developing self-supervised molecular diagnostics solutions.Overall, the development of MULTILAYER anticipates the application of contextual gexel classification strategies for developing self-supervised molecular diagnostics solutions.
Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution
Authors: Williams Nicholas , Lee Joe , Moore Luiza , Baxter E Joanna , Hewinson James , Dawson Kevin J , Menzies Andrew , Godfrey Anna L , Green Anthony R , Campbell Peter J , Nangalia Jyoti 
Published: November 2020

ABSTRACTMutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 448,553 somatic mutations from whole-genome sequencing of 843 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 10 patients with myeloproliferative neoplasms which are blood cancers more common in older age.JAK2V617F, the pathognomonic mutation in these cancers, was acquiredin uteroor childhood, with upper estimates of age of acquisition ranging between 4.1 months and 11.4 years across 5 patients.DNMT3Amutations, which are associated with age-related clonal haematopoiesis, were also acquiredin uteroor childhood, by 7.9 weeks of gestation to 7.8 years across 4 patients. Subsequent driver mutation acquisition was separated by decades. The mean latency betweenJAK2V617Facquisition and clinical presentation was 31 years (range 12-54 years). Rates of clonal expansion varied substantially (<10% to >200% expansion/year), were affected by additional driver mutations, and predicted latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition very early in life with life-long growth and evolution drive adult blood cancer, providing opportunities for early detection and intervention, and a new paradigm for cancer development.
Using open data to rapidly benchmark biomolecular simulations: Phospholipid conformational dynamics
Authors: Antila Hanne S. , Ferreira Tiago M. , Ollila O. H. Samuli , Miettinen Markus S. 
Published: November 2020

AbstractMolecular dynamics (MD) simulations are widely used to monitor time-resolved motions of biomacromolecules, although it often remains unknown how closely the conformational dynamics correspond to those occurring in real life. Here, we used a large set of open-access MD trajectories of phosphatidylcholine (PC) lipid bilayers to benchmark the conformational dynamics in several contemporary MD models (force fields) against nuclear magnetic resonance (NMR) data available in the literature: effective correlation times and spin-lattice relaxation rates.We found none of the tested MD models to fully reproduce the conformational dynamics. That said, the dynamics in CHARMM36 and Slipids are more realistic than in the Amber Lipid14, OPLS-based MacRog, and GROMOS-based Berger force fields, whose sampling of the glycerol backbone conformations is too slow. The performance of CHARMM36 persists when cholesterol is added to the bilayer, and when the hydration level is reduced. However, for conformational dynamics of the PC headgroup, both with and without cholesterol, Slipids provides the most realistic description, because CHARMM36 overestimates the relative weight of ~1-ns processes in the headgroup dynamics.We stress that not a single new simulation was run for the present work. This demonstrates the worth of open-access MD trajectory databanks for the indispensable step of any serious MD study: Benchmarking the available force fields. We believe this proof of principle will inspire other novel applications of MD trajectory databanks, and thus aid in developing biomolecular MD simulations into a true computational microscope—not only for lipid membranes, but for all biomacromolecular systems.
Turing’s diffusive threshold in random reaction-diffusion systems
Authors: Haas Pierre A. , Goldstein Raymond E. 
Published: November 2020

AbstractTuring instabilities of reaction-diffusion systems can only arise if the diffusivities of the chemical species are sufficiently different. This threshold is unphysical in most systems withN= 2 diffusing species, forcing experimental realizations of the instability to rely on fluctuations or additional nondiffusing species. Here we ask whether this diffusive threshold lowers forN> 2 to allow “true” Turing instabilities. Inspired by May’s analysis of the stability of random ecological communities, we analyze the probability distribution of the diffusive threshold in reaction-diffusion systems defined by random matrices describing linearized dynamics near a homogeneous fixed point. In the numerically tractable casesN≤ 6, we find that the diffusive threshold becomes more likely to be smaller and physical asNincreases and that most of these many-species instabilities cannot be described by reduced models with fewer species.
Heterozygous Cell Models of STAT1 Gain-of-Function Reveal a Broad Spectrum of Interferon-Signature Gene Transcriptional Responses
Authors: Scott Ori , Lindsay Kyle , Erwood Steven , Roifman Chaim M. , Cohn Ronald D. , Ivakine Evgueni A. 
Published: November 2020

AbstractSignal Transducer and Activator of Transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype-phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenousSTAT1gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNαor IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modelling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with variousSTAT1mutations, adding to global efforts in establishing STAT1 GOF genotype-phenotype correlation and enhancing our understanding of disease pathogenesis.
Combined assessment of MHC binding and antigen expression improves T cell epitope predictions
Authors: Koşaloğlu-Yalçın Zeynep , Lee Jenny , Nielsen Morten , Greenbaum Jason , Schoenberger Stephen P , Miller Aaron , Kim Young J , Sette Alessandro , Peters Bjoern 
Published: November 2020

ABSTRACTMHC class I antigen processing consists of multiple steps that result in the presentation of MHC bound peptides that can be recognized as T cell epitopes. Many of the pathway steps can be predicted using computational methods, but one is often neglected: mRNA expression of the epitope source proteins. In this study, we improve epitope prediction by taking into account both peptide-MHC binding affinities and expression levels of the peptide’s source protein. Specifically, we utilized biophysical principles and existing MHC binding prediction tools in concert with RNA expression to derive a function that estimates the likelihood of a peptide being presented on a given MHC class I molecule. Our combined model of Antigen eXpression based Epitope Likelihood-Function (AXEL-F) outperformed predictions based only on binding or based only on antigen expression for discriminating eluted ligands from random background peptides as well as in predicting neoantigens that are recognized by T cells. We also showed that in cases where cancer patient-specific RNA-Seq data is not available, cancer-type matched expression data from TCGA can be used to accurately estimate patient-specific gene expression. Using AXEL-F together with TGCA expression data we were able to more accurately predict neoantigens that are recognized by T cells. The method is available in the IEDB Analysis Resource and free to use for the academic community.Significance statementEpitope prediction tools have been used to call epitopes in viruses and other pathogens for almost 30 years, and more recently, to call cancer neoantigens. Several such tools have been developed, however most of them ignore the mRNA expression of the epitope source proteins. In the present study, we have, to our knowledge for the first time, developed a biophysically motivated model to combine peptide-MHC binding and abundance of the peptide’s source protein to improve epitope predictions. Our novel tool AXEL-F is freely available on the IEDB and presents a clear opportunity for predicting and selecting epitopes more efficiently.
Bacteria have numerous phage-plasmid families with conserved phage and variable plasmid gene repertoires
Authors: Pfeifer Eugen , de Sousa Jorge A. Moura , Touchon Marie , Rocha Eduardo P.C. 
Published: November 2020

ABSTRACTPlasmids and temperate phages are mobile genetic elements driving bacterial evolution. They are usually regarded as very distinct. However, some elements, termed phage-plasmids, are known to be both plasmids and phages,e.g. P1, N15 or SSU5. The number, distribution, relatedness and characteristics of these phage-plasmids are poorly known. Here, we screened for these elements among ca. 14000 phages and plasmids and identified 780 phage-plasmids across very diverse bacterial phyla. We grouped 92% of them by similarity of gene repertoires to define 8 families and 18 other broader communities of elements. The existence of these large groups suggests that phage-plasmids are ancient. Their gene repertoires are large, the average element is larger than an average phage or plasmid, and they include slightly more homologs to phages than to plasmids. We analyzed the pangenomes and the genetic organization of each group of phage-plasmids and found the key phage genes to be conserved and co-localized within families, whereas genes with homologs in plasmids are much more variable and include most accessory genes. Phage-plasmids are a sizeable fraction of all phages and plasmids and could have key roles in bridging the genetic divide between phages and other mobile genetic elements.
Evolution of mouse circadian enhancers from transposable elements
Authors: Judd Julius , Sanderson Hayley , Feschotte Cédric 
Published: November 2020

AbstractBackgroundTransposable elements are increasingly recognized as a source of cis-regulatory variation. Previous studies have revealed that transposons are often bound by transcription factors and some have been co-opted into functional enhancers regulating host gene expression. However, the process by which transposons mature into complex regulatory elements, like enhancers, remains poorly understood. To investigate this process, we examined the contribution of transposons to the cis-regulatory network controlling circadian gene expression in the mouse liver, a well-characterized network serving an important physiological function.ResultsChIP-seq analyses revealed that transposons and other repeats contribute ~14% of the binding sites for core circadian regulators (CRs) including BMAL1, CLOCK, PER1/2, and CRY1/2, in the mouse liver. RSINE1, an abundant murine-specific SINE, was the only transposon family enriched for CR binding sites across all datasets. Sequence analyses and reporter assays revealed that the circadian regulatory activity of RSINE1 stems from the presence of imperfect CR binding motifs in the ancestral RSINE1 sequence. These motifs matured into canonical motifs through point mutations after transposition. Furthermore, maturation occurred preferentially within elements inserted in proximity of ancestral CR binding sites. RSINE1 also acquired motifs that recruit nuclear receptors known to cooperate with CR to regulate circadian gene expression specifically in the liver.ConclusionsOur results suggest that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site. This model illuminates how transposition fuels the emergence and turnover of enhancers during mammalian evolution.
Anin vivoreporter for tracking lipid droplet dynamics in transparent zebrafish
Authors: Lumaquin Dianne , Johns Eleanor , Weiss Joshua , Montal Emily , Ooladipupo Olayinka , Abuhashem Abderhman , White Richard M. 
Published: November 2020

AbstractLipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets require fixation or static imaging which limits investigation of their rapidin vivodynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparentcasperzebrafish enabledin vivoimaging of adipose depots responsive to nutrient deprivation and high-fat diet. Using this system, we tested novel regulators of lipolysis, revealing an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts.