bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteopontin and iCD8α cells promote intestinal intraepithelial lymphocyte homeostasis
Authors: Nazmi Ali , Greer Michael J. , Hoek Kristen L. , Piazuelo M. Blanca , Weitkamp Joern-Hendrik , Olivares-Villagómez Danyvid 
Published: June 2019

AbstractIntestinal intraepithelial lymphocytes (IEL) comprise a diverse population of cells residing in the epithelium at the interface between the intestinal lumen and the sterile environment of the lamina propria. Because of this anatomical location, IEL are considered critical components of intestinal immune responses. Indeed, IEL are involved in many different immunological processes ranging from pathogen control to tissue stability. However, despite their critical importance in mucosal immune responses, very little is known about the homeostasis of different IEL subpopulations. The phosphoprotein osteopontin is important for critical physiological processes, including cellular immune responses such as survival of Th17 cells and homeostasis of NK cells, among others. Because of its impact in the immune system, we investigated the role of osteopontin in the homeostasis of IEL. Here, we report that mice deficient in the expression of osteopontin exhibit reduced numbers of the IEL subpopulations TCRγδ+, TCRβ+CD4+, TCRβ+CD4+CD8α+and TCRβ+CD8αα+cells in comparison to wild-type mice. For some IEL subpopulations the decrease in cells numbers could be attributed to apoptosis and reduced cell division. Moreover, we showin vitrothat exogenous osteopontin stimulates the survival of murine IEL subpopulations and unfractionated IEL derived from human intestines, an effect mediated by CD44, a known osteopontin receptor. We also show that iCD8α IEL, but not TCRγδ+IEL, TCRβ+IEL or intestinal epithelial cells, can promote survival of different IEL populations via osteopontin, indicating an important role for iCD8α cells in the homeostasis of IEL.Key PointsOsteopontin promotes homeostasis of mouse and human IEL, mediated by its ligand CD44iCD8α cells produce osteopontin which impacts the survival of other IELLack of osteopontin renders mice susceptible to intestinal inflammation
Clinicopathological characteristics and survival of lymphoepithelial carcinoma of the oral cavity and pharynx: a population-based study
Authors: Bai Jinbo , Zhao Fen , Pan Shuang 
Published: June 2019

AbstractLymphoepithelial carcinoma (LEC) of the oral cavity and pharynx is uncommon, and the characteristics and survival remains unclear. The present study aims to describe the clinicopathological characteristics and determine the factors associated with survival of this uncommon cancer. A population-based study was carried out to investigate clinical characteristics and prognosis of LEC of the oral cavity and pharynx using the data from Surveillance, Epidemiology and End Results (SEER) database between 1988 and 2013. The propensity-matched analysis was conducted for prognostic analysis, and a prognostic nomogram was also constructed. Totally, 1025 patients with LEC of the oral cavity and pharynx were identified, including 769 nasopharyngeal LEC patients and 256 non-nasopharyngeal LEC patients. The median OS of all LEC patients was 232.0m (95% CI 169.0-258.0). The 1-, 5-, 10- and 20-year survival rates were 92.9%, 72.9%, 59.3%, and 46.8%, respectively. Surgery could significantly prolong the survival time of LEC patients (P<0.01, mOS: 190m vs. 255m). Radiotherapy, as well as radiotherapy after surgery, could prolong the mOS (P<0.01 for both). The survival analysis demonstrated that old age (>60 years), lymph node (N3) and distant metastases were independent factors for poor survival, whereas radiotherapy and surgery were independent factors for favorable survival. No significant differences in survival time between nasopharyngeal LEC and non-nasopharyngeal LEC patients were observed. The prognostic nomogram was established base on five independent prognostic factors (C-index=0.70; 95% CI 0.66-0.74). In conclusion, LEC of the oral cavity and pharynx is a rare disease, and old age, lymph node and distant metastases, surgery and radiotherapy were significantly associated with prognosis. The prognostic nomogram could be used to make individual predictions of OS.
Genomic structure ofHstx2modifier ofPrdm9-dependent hybrid male sterility in mice
Authors: Lustyk Diana , Kinský Slavomír , Ullrich Kristian Karsten , Yancoskie Michelle , Kašíková Lenka , Gergelits Václav , Sedláček Radislav , Chan Yingguang Frank , Odenthal-Hesse Linda , Forejt Jiří , Jansa Petr 
Published: June 2019

ABSTRACTF1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, namely thePrdm9hybrid sterility gene, intersubspecific homeology ofMus musculus musculusandMus musculus domesticusautosomes, and the X-linkedHstx2locus.Hstx2modulates the extent ofPrdm9-dependent meiotic arrest and harbors two additional genetic factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and reduced global meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb genomicDob interval encompassing theHstx2locus we designedHstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within theHstx2locus. The resulting recombinant reduced theHstx2locus to 2.70 Mb (Chr X:66.51-69.21 Mb). The newly definedHstx2still operates as the major X-linked factor of the F1 hybrid sterility, controls meiotic chromosome synapsis, and modifies meiotic recombination rate. Despite extensive further crosses, the 2.70 MbHstx2interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4 hotspots and absence of DMC1-defined DNA DSB hotspots. To search for structural anomalies as a possible cause of recombination suppression we used optical mapping of theHstx2interval and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNAMir465cluster. Finally, we analyzed the role of one of theHstx2candidate genes, the Fmr1 neighbor (Fmr1nb) gene in male fertility.Article summaryEarly meiotic arrest of mouse intersubspecific hybrids depends on the interaction between thePrdm9gene and Hybrid sterility X2 (Hstx2) locus on chromosome X. Lustyk et al. conducted high-resolution genetic and physical mapping of theHstx2locus, reduced it to 2.7 Mb interval within a constitutive recombination cold spot and found that the newly definedHstx2still operates as the X-linked hybrid sterility factor, controls meiotic chromosome synapsis, and modifies recombination rate. Optical mapping of theHstx2genomic region excluded inversion as a cause of recombination suppression and revealed a striking copy number polymorphism of the microRNAMir465cluster.
A Comprehensive Genome-wide and Phenome-wide Examination of BMI and Obesity in a Northern Nevadan Cohort
Authors: Schlauch Karen A. , Read Robert W. , Lombardi Vincent C. , Elhanan Gai , Metcalf William J , Slonim Anthony D. ,   the 23andMe Research Team, Grzymski Joseph J. 
Published: June 2019

AbstractThe aggregation of Election Health Records (EHR) and personalized genetics leads to powerful discoveries relevant to population health. Here we perform genome-wide association studies (GWAS) and accompanying phenome-wide association studies (PheWAS) to validate phenotype-genotype associations of BMI, and to a greater extent, severe Class 2 obesity, using comprehensive diagnostic and clinical data from the EHR database of our cohort. Three GWASs of 500,000 variants on the Illumina platform of 6,645 Healthy Nevada participants identified several published and novel variants that affect BMI and obesity. Each GWAS was followed with two independent PheWASs to examine associations between extensive phenotypes (incidence of diagnoses, condition, or disease), significant SNPs, BMI, and incidence of extreme obesity. The first GWAS excludes DM2-diagnosed individuals and focuses on associations with BMI exclusively. The second GWAS examines the interplay between Type 2 Diabetes (DM2) and BMI. The intersection of significant variants of these two studies is surprising. The third complementary case-control GWAS, with cases defined as extremely obese (Class 2 or 3 obesity), identifies strong associations with extreme obesity, including established variants in theFTOandNEGR1genes, as well as loci not yet linked to obesity. The PheWASs validate published associations between BMI and extreme obesity and incidence of specific diagnoses and conditions, yet also highlight novel links. This study emphasizes the importance of our extensive longitudinal EHR database to validate known associations and identify putative novel links with BMI and obesity.
Extensive Evaluation of Weighted Ensemble Strategies for Calculating Rate Constants and Binding Affinities of Molecular Association/Dissociation Processes
Authors: Pratt A. J. , Suárez Ernesto , Zuckerman Daniel M. , Chong Lillian T. 
Published: June 2019

ABSTRACTThe weighted ensemble (WE) path sampling strategy is highly efficient in generating pathways and rate constants for rare events using atomistic molecular dynamics simulations. Here we extensively evaluated the impact of several advances to the WE strategy on the efficiency of computing association and dissociation rate constants (kon, koff) as well as binding affinities (KD) for a set of benchmark systems, listed in order of increasing timescales of molecular association/dissociation processes: methane/methane, Na+/Cl-, and K+/18-crown-6 ether. In particular, we assessed the advantages of carrying out (i) a large set of “light-weight” WE simulations that each consist of a small number of trajectories vs. a single “heavy-weight” WE simulation that consists of a relatively large number of trajectories, (ii) equilibrium vs. steady-state WE simulations, (iii) history augmented Markov State Model (haMSM) post-simulation analysis of equilibrium sets of trajectories, and (iv) tracking of trajectory history (the state last visited) during the dynamics propagation of equilibrium WE simulations. Provided that state definitions are known in advance, our results reveal that heavy-weight, steady-state WE simulations are the most efficient protocol for calculating kon, koff, and KD values. If states are not strictly defined in advance, heavy-weight, equilibrium WE simulations are the most efficient protocol. This efficiency can be further improved with the inclusion of trajectory history during dynamics propagation. In addition, applying the haMSM post-simulation analysis enhances the efficiency of both steady-state and equilibrium WE simulations. Recommendations of appropriate WE protocols are made according to the goals of the simulations (e.g. to efficiently calculate rate constants and/or generate a diverse set of pathways).
Occurrence of cross-resistance and beta-lactam seesaw effect in glycopeptide, lipopeptide, and lipoglycopeptide-resistant MRSA correlates with membrane phosphatidylglycerol levels
Authors: Hines Kelly M. , Shen Tianwei , Ashford Nate K. , Waalkes Adam , Penewit Kelsi , Holmes Elizabeth A. , McLean Kathryn , Salipante Stephen J. , Werth Brian J. , Xu Libin 
Published: June 2019

ABSTRACTTreatment of methicillin-resistantStaphylococcus aureus(MRSA) infections is challenging and is associated with high rates of therapeutic failure. The glycopeptide (GP) vancomycin and the lipopeptide (LP) daptomycin are still relied upon to manage invasive MRSA infections; however, resistance to these antibiotics has emerged and there is evidence of cross-resistance between them. It has been observed that the susceptibility of MRSA to beta-lactams increases as susceptibility to GPs and LPs decreases, a phenomenon termed the seesaw effect. Recent efforts to understand the mechanism underlying the seesaw effect have focused on the penicillin binding proteins (PBPs). However, while daptomycin resistance is largely mediated by remodeling of membrane lipid composition, the role of membrane lipids in producing cross-resistance and the seesaw effect has not yet been investigated. Here, we evaluate the lipid profiles, cross susceptibilities, and beta-lactam susceptibilities of a collection of isogenic MRSA strains selected against daptomycin, vancomycin or dalbavancin (a lipoglycopeptide; LGP) to assess the relationship between membrane composition, cross-resistance, and the seesaw effect. We found that modification of membrane composition occurs not only in daptomycin-selected strains, but also vancomycin- and dalbavancin-selected strains. Significantly, we observed that typically the levels of short-chain phosphatidylglycerols (PGs) negatively correlate with MICs of GP/LP/LGP and positively correlate with MIC of certain beta-lactams, the latter being dependent on the primary PBP target of the particular beta-lactam. Furthermore, changes to certain PGs with long-chain fatty acids correlate well with presence of the seesaw effect. These studies demonstrate a major association between membrane remodeling and the seesaw effect.
Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
Authors: Heyne Henrike O. , Baez-Nieto David , Iqbal Sumaiya , Palmer Duncan , Brunklaus Andreas ,   the Epi25 Collaborative, Johannesen Katrine M. , Lauxmann Stephan , Lemke Johannes R. , Møller Rikke S. , Pérez-Palma Eduardo , Scholl Ute , Syrbe Steffen , Lerche Holger , May Patrick , Lal Dennis , Campbell Arthur J. , Pan Jen , Wang Hao-Ran , Daly Mark J. 
Published: June 2019

SummaryMalfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) have been associated with severe neurologic, psychiatric, cardiac and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) which is not only corresponding to clinical disease manifestations, but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants inSCN1/2/8AandCACNA1I(ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice.
Estimating abundance with interruptions in data collection using open population spatial capture-recapture models
Authors: Milleret Cyril , Dupont Pierre , Chipperfield Joseph , Turek Daniel , Brøseth Henrik , Gimenez Olivier , de Valpine Perry , Bischof Richard 
Published: June 2019

AbstractThe estimation of population size remains one of the primary goals and challenges in ecology and provides a basis for debate and policy in wildlife management. Despite the development of efficient non-invasive sampling methods and robust statistical tools to estimate abundance, maintenance of field sampling is still subject to economic and logistic constraints. These can result in intentional or unintentional interruptions in sampling and cause gaps in data time series, posing a challenge to abundance estimation, and ultimately conservation and management decisions.We applied an open population spatial capture-recapture (OPSCR) model to simulations and a real case study to test the reliability of abundance inferences models to interruption in data collection. Using individual detections occurring over consecutive sampling occasions, OPSCR models allow the estimation of abundance from individual detection data while accounting for lack of demographic and geographic closure between occasions. First, we simulated sampling data with interruptions in field sampling of different lengths and timing. We checked the performance of an OPSCR model in deriving abundance for species with slow and intermediate life history strategies. Finally, we introduced artificial sampling interruptions of various magnitudes and timing to a five-year non-invasive monitoring data set of wolverines (Gulo gulo) in Norway and quantified the consequences for OPSCR model predictions.Inferences from OPSCR models were reliable even with temporal interruptions in monitoring. Interruption did not cause any systematic bias, but increased uncertainty. Interruptions occurring at occasions towards the beginning and the end of the sampling caused higher uncertainty. The loss in precision was more severe for species with a faster life history strategy.We provide a reliable framework to estimate abundance even in the presence of sampling interruptions. OPSCR allows monitoring studies to provide contiguous abundance estimates to managers, stakeholders, and policy makers even when data are non-contiguous. OPSCR models do not only help cope with unintentional interruptions during sampling but also offer opportunities for using intentional sampling interruptions during the design of cost-effective population surveys.
Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons
Authors: Koppers Max , Cagnetta Roberta , Shigeoka Toshiaki , Wunderlich Lucia C.S. , Zhao Sixian , Minett Michael S. , Bellon Anaïs , Kaminski Clemens F. , Flanagan John. G. , Holt Christine E. 
Published: June 2019

AbstractDuring neuronal wiring, extrinsic cues trigger the local translation of specific mRNAs in axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors bind to distinct sets of mRNAs and RNA-binding proteins. Cue stimulation induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs in retinal axon growth cones. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by simultaneous exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and provide a general model for the rapid, localized and selective control of cue-induced translation.
Larval mannitol diets increase mortality, prolong development, and decrease adult body sizes in fruit flies (Drosophila melanogaster)
Authors: Barrett Meghan , Fiocca Katherine , Waddell Edward A. , McNair Cheyenne , O’Donnell Sean , Marenda Daniel R. 
Published: June 2019

AbstractIngestion of the polyol mannitol caused sex-biased mortality in adultDrosophila melanogaster, but larval mortality was not sex-biased. High-sugar diets prolong development and generate smaller adult body sizes inD. melanogaster. We hypothesized that mannitol ingestion would generate similar developmental phenotypes as other high-carbohydrate diets. We predicted concentration-dependent effects on development similar to high-sugar diets whenD. melanogasterlarvae are fed mannitol, as well as a concentration-dependent amelioration of developmental effects if introduction to mannitol media is delayed past the third instar. Both male and female larvae had prolonged development and smaller adult body sizes when fed increasing concentrations of mannitol. Mannitol-induced increases in mortality were concentration dependent in 0 M to 0.8 M treatments beginning as early as 48 hours post-hatching. Larval survival, and pupation and eclosion times, were normal in 0.4 M mannitol treatments when larvae were first introduced to mannitol 72 hours post-hatching (the beginning of the third-instar); the adverse mannitol effects occurred in 0.8 M mannitol treatments, but at a lower magnitude. FemaleD. melanogasteradults prefer laying eggs on diets with high sugar concentrations, despite the negative effects on offspring performance. However, when given a choice, femaleD. melanogasteravoided laying eggs on mannitol-containing media that was otherwise identical to the control media, suggesting females perceived and avoided mannitol. In conclusion, the developmental effects of a larval mannitol diet closely resemble those of high-sugar diets, but adult female oviposition responses to mannitol in laying substrates are distinct from responses to other carbohydrates.
Reliable data-driven modeling of high-frequency structures by means of nested kriging with enhanced design of experiments
Authors: Koziel Slawomir , Pietrenko-Dabrowska Anna 
Published: June 2019

Purpose
A framework for reliable modeling of high-frequency structures by nested kriging with an improved sampling procedure is developed and extensively validated. A comprehensive benchmarking including conventional kriging and previously reported design of experiments technique is provided. The proposed technique is also demonstrated in solving parameter optimization task.

Design/methodology/approach
The keystone of the proposed approach is to focus the modeling process on a small region of the parameter space (constrained domain containing high-quality designs with respect to the selected performance figures) instead of adopting traditional, hyper-cube-like domain defined by the lower and upper parameter bounds. A specific geometry of the domain is explored to improve a uniformity of the training data set. In consequence, the predictive power of the model is improved.

Findings
Building the model in a constrained domain allows for a considerable reduction of a training data set size without a necessity to either narrow down the parameter ranges or to reduce the parameter space dimensionality. Improving uniformity of training data set allocation permits further reduction of the computational cost of setting up the model. The proposed technique can be used to expedite the parameter optimization and enables locating good initial designs in a straightforward manner.

Research limitations/implications
The developed framework opens new possibilities inaccurate surrogate modeling of high-frequency structures described by a large number of geometry and/or material parameters. Further extensions can be investigated such as the inclusion of the sensitivity data into the model or exploration of the particular geometry of the model domain to further reduce the computational overhead of training data acquisition.

Originality/value
The efficiency of the proposed method has been demonstrated for modeling and parameter optimization of high-frequency structures. It has also been shown to outperform conventional kriging and previous constrained modeling approaches. To the authors’ knowledge, this approach to formulate and handle the modeling process is novel and permits the establishment of accurate surrogates in highly dimensional spaces and covering wide ranges of parameters.