bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic landscape of the tumor microenvironment
Authors: Xiao Zhengtao , Dai Ziwei , Locasale Jason W. 
Published: January 2019

AbstractThe tumor milieu consists of numerous cell types with each cell existing in a different nutritional environment. However, a characterization of intratumoral metabolic heterogeneity at the single-cell level in human cancer is not established. Here, we develop a computational pipeline to analyze metabolic gene expression programs of single cells within human tumors. In two representative cancer types, melanoma and head and neck, we apply this algorithm to define the single-cell metabolic landscape of human tumors. We find that malignant cells in general have higher metabolic activity and higher metabolic variation than previously observed from studies of bulk tumor comparisons. Indeed, most of the observed metabolic variation of single tumor and normal cells were found to be inconsistent with comparisons with bulk tumor samples. Variation in the expression of mitochondrial programs is the major contributor to intratumoral metabolic heterogeneity. Surprisingly, the expression of both glycolytic and mitochondrial programs strongly correlates with hypoxia in almost all cell types. Immune and stromal cells could also be distinguished by their metabolic features. Taken together this analysis establishes a computational framework for characterizing metabolism using single cell expression data and defines principles of intratumoral metabolic heterogeneity.
Investigating Genetic Heterogeneity in Major Depression Through Item-level Genetic Analyses of the PHQ-9
Authors: Thorp Jackson G. , Marees Andries T. , Ong Jue-Sheng , An Jiyuan , MacGregor Stuart , Derks Eske M. 
Published: January 2019

AbstractBackgroundMajor Depressive Disorder (MDD) is a clinically heterogeneous disorder. Previous large-scale genetic studies of MDD have explored genetic risk factors of MDD case-control status or aggregated sums of depressive symptoms, ignoring possible clinical or genetic heterogeneity.AimIn this study, we present the results of symptom-level genetic analyses and compare SNP-based heritability (h2SNP) and genetic correlations across major depression symptoms. We further investigate genetic correlations with a range of psychiatric disorders and other associated traits. Methods: We have analysed data from the UK biobank and included 148,752 subjects of white British ancestry with genotype data who completed nine items of a self-rated measure of depression: the Patient Health Questionnaire (PHQ-9). Genome-Wide Association analyses were conducted for nine symptoms and two composite measures. LD score regression analysis was used to calculate SNP-based heritability (h2SNP) and genetic correlations (rg) across symptoms and to investigate genetic correlations with 25 external phenotypes. Confirmatory factor analyses were applied to test whether one, two, or three-factor models best fit the pattern of genetic correlations across the nine symptoms.ResultsWe identified 9 novel genome-wide significant genomic loci, with no overlap in loci across depression symptoms. h2SNP ranged from 3% (suicidal ideation) to 11% (fatigue). Genetic correlations range from 0.54 to 0.96 (all p < 1.39×10−3) with 30 of 36 correlations being significantly smaller than 1. A 3-factor model provided the best fit to the genetic correlation matrix, with factors representing “psychological”, “neurovegetative”, and “psychomotor / concentration” symptoms. The genetic correlations with external phenotypes showed large variation across the nine symptoms.DiscussionPatterns of h2SNP and genetic correlations differed across the nine symptoms of depression. Our findings suggest that the large phenotypic heterogeneity observed for MDD is recapitulated at a genetic level. Future studies should investigate how genetic heterogeneity in MDD influences the efficacy of clinical interventions.
Candida auris: multi-omics signature of an emerging and multidrug-resistant pathogen
Authors: Zamith-Miranda Daniel , Heyman Heino M. , Cleare Levi G. , Couvillion Sneha , Clair Geremy , Bredeweg Erin , Gacser Attila , Nimrichter Leonardo , Nakayasu Ernesto S. , Nosanchuk Joshua D. 
Published: January 2019

AbstractCandida aurisis a recently described pathogenic fungus that is causing invasive outbreaks on all continents. The fungus is of high concern given the numbers of multidrug-resistant strains that have been isolated in distinct sites across the globe. The fact that its diagnosis is still problematic suggests that the spreading of the pathogen remains underestimated. Notably, the molecular mechanisms of virulence and antifungal resistance employed by this new species are largely unknown. In the present work, we compared two clinical isolates ofC. auriswith distinct drug susceptibility profiles and aCandida albicansreference strain using a multi-omics approach. Our results show that, despite the distinct drug-resistance profile, bothC. aurisstrains appear to be very similar, albeit with a few notable differences. However, when compared toC. albicansbothC. aurisstrains have major differences regarding their carbon utilization and downstream lipid and protein content, suggesting a multi-factorial mechanism of drug resistance. The molecular profile displayed byC. aurishelps to explain the antifungal resistance and virulence phenotypes of this new emerging pathogen.ImportanceCandida auriswas firstly described in Japan in 2009 and has now been the cause of significant outbreaks across the globe. The high number of isolates that are resistant to one or more antifungals, as well as the high mortality rates from patients with bloodstream infections, has caught the attention of the medical mycology, infectious disease and public health communities to this pathogenic fungus. In the current work, we performed a broad multi-omics approach on two clinical isolates isolated in New York, the most affected area in the USA and found that the omic profile ofC. aurisdiffers significantly fromC. albicans. Besides our insights intoC. auriscarbon utilization and lipid and protein content, we believe that the availability of these data will enhance our ability to combat this rapidly emerging pathogenic yeast.
RBL1 (p107) functions as tumor suppressor in glioblastoma and small-cell pancreatic neuroendocrine carcinoma
Authors: Naert Thomas , Dimitrakopoulou Dionysia , Tulkens Dieter , Demuynck Suzan , Noelanders Rivka , Eeckhout Liza , Isterdael Gert van , Deforce Dieter , Vanhove Christian , Dorpe Jo Van , Creytens David , Vleminckx Kris 
Published: January 2019

AbstractAlterations of the retinoblastoma and/or the p53 signaling network are associated with specific cancers such as high-grade astrocytoma/glioblastoma, small cell lung cancer (SCLC), choroid plexus tumors and small-cell pancreatic neuroendocrine carcinoma (SC-PaNEC). However, the intricate functional compensation between RB1 and the related pocket proteins RBL1/p107 and RBL2/p130 in suppressing tumorigenesis remains poorly understood. Here we performed lineage-restricted parallel inactivation ofrb1andrbl1by multiplex CRISPR/Cas9 genome editing in the true diploidXenopus tropicalisto gain insight into thesein vivocompensatory mechanisms. We show that whilerb1inactivation is sufficient to induce choroid plexus papilloma, combinedrb1andrbl1inactivation is required and sufficient to drive SC-PaNEC, retinoblastoma and astrocytoma. Further, using a novel Li-Fraumeni syndrome-mimickingtp53mutantX. tropicalisline, we demonstrate increased malignancy of retinoblastoma-mutant neural malignancies upon concomitant inactivation oftp53. Interestingly, although clinical SC-PaNEC samples are characterized by abnormal p53 expression or localization, in the current experimental models, thetp53status had little effect on the establishment and growth of SC-PaNEC, but may rather be essential for maintaining chromosomal stability. SCLC was only rarely observed in our experimental set-up, indicating requirement of additional or alternative oncogenic insults. In conclusion, we used CRISPR/Cas9 to delineate the tumor suppressor properties of Rbl1 and generate new insights in functional compensation within the retinoblastoma protein family in suppressing pancreatic and specific neural cancers.
Habitat loss does not always entail negative genetic consequences
Authors: Carvalho Carolina S. , Lanes Éder C. M. , Silva Amanda R. , Caldeira Cecilio F. , Carvalho-Filho Nelson , Gastauer Markus , Imperatriz-Fonseca Vera L. , Júnior Wilson Nascimento , Oliveira Guilherme , Siqueira José O. , Viana Pedro L. , Jaffé Rodolfo 
Published: January 2019

AbstractAlthough habitat loss has large, consistently negative effects on biodiversity, its genetic consequences are not yet fully understood. In this paper, we assess the genetic consequences of extreme habitat loss driven by mining in two endemic plants from Amazonian Savannas. Our analyses are the first to overcome major methodological limitations like the confounding effect of habitat fragmentation, historical processes underpinning genetic differentiation, time-lags between the onset of disturbances and genetic outcomes, and the need for large numbers of samples, genetic markers and replicated landscapes to ensure sufficient statistical power. We found that both species are remarkably resilient, as genetic diversity and gene flow patterns were unaffected by habitat loss. Our study unambiguously demonstrates that it is not possible to generalize about the genetic consequences of habitat loss, and imply that future conservation efforts need to consider species-specific genetic information.
Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice
Authors: Huysmans Hanne , Zhong Zifu , De Temmerman Joyca , Mui Barbara L. , Tam Ying K. , Mc Cafferty Séan , Gitsels Arlieke , Vanrompay Daisy , Sanders Niek N. 
Published: January 2019

AbstractIn this work we studied the expression kinetics and innate immune response of a self-amplifying mRNA (sa-RNA) after electroporation and lipid nanoparticle (LNP) mediated delivery in the skin of mice. Intradermal electroporation of the sa-RNA resulted in a plateau-shaped expression with the plateau between day 3 and 10. The overall protein expression of sa-RNA was significant higher than that obtained after electroporation of pDNA or non-replication mRNAs. Moreover, intradermal electroporation of sa-RNA induced a short-lived innate immune response that did not affect the expression of the sa-RNA. A complete different expression profile and innate immune response was observed when LNPs were used. The expression peaked 24h after intradermal injection of sa-RNA-LNPs and subsequently showed a sharp drop. This drop can be explained by the strong innate immune response elicited by the sa-RNA-LNPs 4h after injection. Interestingly, sa-RNA-LNPs were able to transfection the draining lymph nodes after intradermal injection.
Verticillium dahliae strains that infect the same host plant display highly divergent effector catalogs
Authors: Gibriel Hesham A.Y. , Li Jinling , Zhu Longfu , Seidl Michael F. , Thomma Bart P.H.J. 
Published: January 2019

Originality and significance statementDuring host colonization, plant pathogens secrete molecules that enable host colonization, also known as effector proteins. Here, we show that strains of the fungal plant pathogen Verticillium dahliae that are able to infect the same host plant harbour highly divergent LS effector repertoires. Our study outlines the variability within LS effector gene repertoires of V. dahliae strains, which may allow the various strains to be competitive in the co-evolution with their hosts.SummaryEffectors are proteins secreted by pathogens to support colonization of host plants, often by deregulating host immunity. Effector genes are often localized within dynamic lineage-specific (LS) genomic regions, allowing rapid evolution of effector catalogues. Such localization permits pathogens to be competitive in the co-evolutionary arms races with their hosts. For a broad host-range pathogen such as Verticillium dahliae it is unclear to what extent single members of their total effector repertoires contribute to disease development on multiple hosts. Here, we determined the core and LS effector repertoires of a collection of V. dahliae strains, as well as the ability of these strains to infect a range of plant species comprising tomato, cotton, Nicotiana benthamiana, Arabidopsis, and sunflower to assess whether the presence of particular LS effectors correlates with the ability to infect particular plant species. Surprisingly, we found that V. dahliae strains that are able to infect the same host plant harbor highly divergent LS effector repertoires. Furthermore, we observed differential V. dahliae core effector gene expression between host plants. Our data suggest that different V. dahliae lineages utilise divergent effector catalogs to colonize the same host plant, suggesting considerable redundancy among the activities of effector catalogs between lineages.
Scale dependent patterns in interaction diversity maintain resiliency in a frequently disturbed ecosystem
Authors: Dell Jane E. , Salcido Danielle M. , Lumpkin Will , Richards Lora A. , Pokswinski Scott M. , Loudermilk E. Louise , O’Brien Joseph J. , Dyer Lee A. 
Published: January 2019

AbstractFrequently disturbed ecosystems are characterized by resilience to ecological disturbances. For example, longleaf pine ecosystems are exposed to frequent fire disturbance, and this feature sustains biodiversity. We examined how fire frequency maintains beta diversity of multi-trophic interactions, as this community parameter provides a measure of functional redundancy of an ecosystem. We found that turnover in interaction diversity at small local scales is highest in the most frequently burned stands, conferring immediate resiliency to disturbance by fire. Interactions become more specialized and less resilient as fire frequency decreases. Local scale patterns of interaction diversity contribute to broader scale patterns and confer long-term ecosystem resiliency. Such natural disturbances are likely to be important for maintaining regional diversity of interactions for a broad range of ecosystems.
Environmental Consistency Modulation of Error Sensitivity During Motor Adaptation is Explicitly Controlled
Authors: Avraham Guy , Keizman Matan , Shmuelof Lior 
Published: January 2019

AbstractMotor adaptation, the adjustment of sensorimotor representations in face of changes in the environment, may operate at different rates. When human participants encounter repeated or consistent perturbations, their corrections for the experienced errors are larger compared to when the perturbations are new or inconsistent. Such modulations of error sensitivity were traditionally considered to be an implicit process that does not require attentional resources. In recent years, the implicit view of motor adaptation is challenged by evidence showing a contribution of explicit strategies to learning. These findings raise a fundamental question regarding the nature of the error sensitivity modulation processes. We tested the effect of explicit control on error sensitivity in a series of experiments, in which participants controlled a screen cursor to virtual targets. We manipulated environmental consistency by presenting rotations in random (low consistency) or random walk (high consistency) sequences, and illustrated that perturbation consistency affects the rate of adaptation, corroborating previous studies. When participants were instructed to ignore the cursor and move directly to the target, thus, eliminating the contribution of explicit strategies, consistency-driven error sensitivity modulation was abolished. In addition, delaying the visual feedback, a manipulation that affects implicit learning, did not influence error sensitivity under consistent perturbations. These results suggest that increases of learning rate in consistent environments are attributable to an explicit rather than implicit process in sensorimotor adaptation.Significant StatementWhen experiencing an error in a motor task (e.g., missing a basketball shot in a windy day), the motor system modifies its next action based on environmental consistency (how frequent the changes in wind’s direction and strength are). It is unknown whether this process is driven by an implicit and automatic process, or by an explicit process that employs cognitive strategies. We examined these possibilities in a simple visuomotor task by perturbing the feedback in each trial with different consistency levels, and manipulating the use of implicit and explicit processes. We found that participants increase their sensitivity to errors in consistent environments when employing explicit strategies, and do not change their behavior when the implicit process is operating alone.
Cranial Bone Growth in Isolated Sagittal Craniosynostosis Compared to Normal Growth in the First Six Months of Age
Authors: Mercan Ezgi , Hopper Richard A. , Maga A. Murat 
Published: January 2019

AbstractBackgroundSagittal craniosynostosis (SCS), the most common type of premature perinatal cranial suture fusion, results in abnormal head shape that requires extensive surgery to correct. It is important to find objective and repeatable measures of severity and surgical outcome to examine the effect of timing and technique on different SCS surgeries. The purpose of this study was to develop statistical models of infant (0-6 months old) skull growth in both normative and SCS subjects (prior to surgery). Our goal was to apply these models to the assessment of differences between these two groups in overall post-natal growth patterns and sutural growth rates as a first step to develop methods for predictive models of surgical outcome.Methods and Findings:We identified 81 patients with isolated, non-syndromic SCS from Seattle Children’s Craniofacial Center patient database who had a pre-operative CT exam before the age of six months. As a control group, we identified 117 CT exams without any craniofacial abnormalities or bone fractures in the same age group. We first created population-level templates from the CT images of the SCS and normal groups. All CT images from both groups, as well as the canonical templates of both cohorts were annotated with anatomical landmarks, which were used in a growth model that predicted the locations of these landmarks at a given age based on each population. Using the template images and the landmark positions predicted by the growth models, we created 3D meshes for each week of age up to six months for both populations. To analyze the growth patterns at the suture sites, we annotated both templates with additional semi-landmarks equally spaced along the metopic, coronal, sagittal and lambdoidal cranial sutures. By transferring these semi-landmarks to meshes produced from the growth model, we measured the displacement of the bone borders and suture closure rates. We found that the growth at the metopic and coronal sutures were more rapid in the SCS cohort compared to the normal cohort. The antero-posterior displacement of the semi-landmarks indicated a more rapid growth in the sagittal plane in the SCS model compared to the normal model as well.Conclusions:Statistical templates and geometric morphometrics are promising tools for understanding the growth patterns in normal and synostotic populations and to produce objective and reproducible measurements of severity and outcome. Our study is the first of its kind to quantify the bone growth for the first six months of life in both normal and sagittal synostosis patients.
Mechanically activated Piezo channels control outflow tract valve development through Yap1 and Klf2-Notch signaling axis
Authors: Duchemin Anne Laure , Vignes Hélène , Vermot Julien 
Published: January 2019

AbstractMechanical forces are well known for modulating heart valve developmental programs. Yet, it is still unclear how genetic programs and mechanosensation interact during heart valve development. Here, we assessed the mechanosensitive pathways involved during zebrafish outflow tract (OFT) valve development in vivo. Our results show that the hippo effector Yap1, Klf2, and the Notch signaling pathway are all essential for OFT valve morphogenesis in response to mechanical forces, albeit active in different cell layers. Furthermore, we show that Piezo and TRP mechanosensitive channels are essential for regulating these pathways. In addition, live reporters reveal that piezo controls Klf2 and Notch activity in the endothelium and Yap1 expression in the smooth muscle progenitors to coordinate OFT valve morphogenesis. Together, this work identifies a unique morphogenetic program during OFT valve formation and places Piezo as a central modulator of the cell response to forces in this process.
Incomplete influenza A virus genomes are abundant but readily complemented during spatially structured viral spread
Authors: Jacobs Nathan T. , Onuoha Nina O. , Antia Alice , Antia Rustom , Steel John , Lowen Anice C. 
Published: January 2019

AbstractViral genomes comprising multiple distinct RNA segments can undergo genetic exchange through reassortment, a process that facilitates viral evolution and can have major epidemiological consequences. Segmentation also allows the replication of incomplete viral genomes (IVGs), however, and evidence suggests that IVGs occur frequently for influenza A viruses. Here we quantified the frequency of IVGs using a novel single cell assay and then examined their implications for viral fitness. We found that each segment of influenza A/Panama/2007/99 (H3N2) virus has only a 58% probability of being present in a cell infected with a single virion. These observed frequencies accurately account for the abundant reassortment seen in co-infection, and suggest that an average of 3.7 particles are required for replication of a full viral genome in a cell. This dependence on multiple infection is predicted to decrease infectivity and to slow viral propagation in a well-mixed system. Importantly, however, modeling of spatially structured viral growth predicted that the need for complementation is met more readily when secondary spread occurs locally. This expectation was supported by experimental infections in which the level spatial structure was manipulated. Furthermore, a virus engineered to be entirely dependent on co-infection to replicatein vivowas found to grow robustly in guinea pigs, suggesting that coinfection is sufficiently commonin vivoto support propagation of IVGs. The infectivity of this mutant virus was, however, reduced 815-fold relative wild-type and the mutant virus did not transmit to contacts. Thus, while incomplete genomes augment reassortment and contribute to within-host spread, the existence of rare complete IAV genomes may be critical for transmission to new hosts.