bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA methylation-based immune cell deconvolution in solid tumors
Authors: Liang Cong , Yu Xiaoqing , Li Bo , Chen Y. Ann , Conejo-Garcia Jose R. , Wang Xuefeng 
Published: April 2019

AbstractUnderstanding of the tumor microenvironment (TME) structure is likely to have a profound and immediate impact on therapeutic interventions as well as the development of signatures for diagnostic and prognostic evaluations. DNA methylation arrays represent one of the most reproducible molecular assays across replicates and studies, but its value of profiling tumor-infiltrating immune lymphocytes (TILs) hasn’t been intensively investigated. Here we report a model-based evaluation of tumor TIL levels using DNA methylation profiles. By employing a hybrid method of stability selection and elastic net, we show that methylation array data in ten TCGA cancer types provide a strikingly accurate prediction of immune cell abundance, in particular the levels of T cells, B cells and cytotoxic cells in skin cutaneous melanoma (SKCM). The immune-informative CpG sites showed significant prognostic values, representing important candidates for further functional validation. Further, we present regression models each using only ten CpG sites to estimate the levels of infiltrated immune cell types in melanoma. To validate these models, we performed matched methylation EPIC array and RNA-seq on 30 new melanoma samples. We observed high concordance on methylation and gene expression predicted tumor immune infiltration levels in our new dataset. Our study demonstrated that DNA methylation data is a valuable resource in reliably evaluating tumor immune responses. The selected methylation panels provide candidate targets for future clinical researches. Our prediction models are easy to implement and will provide reference for future clinical practices.
Factors affecting the survival of tree seedlings following shifting cultivation in the Eastern Himalaya
Authors: Teegalapalli Karthik , Arthur Rohan , Quader Suhel , Datta Aparajita 
Published: April 2019

AbstractThe seedling stage is considered an important bottleneck determining forest community composition during succession. Seedling growth and survival are known to be affected by factors such as light availability, herbivory and competition with existing vegetation. A shifting cultivation landscape with a cycle of clearing and regeneration provides an experimental setup to understand secondary succession.We introduced tree seedlings of three species with differing life history strategies in an uncut forest and in sites formed 2, 6, 12, 25, 50 and 100 years following shifting cultivation in a subtropical landscape in the Eastern Himalaya. Seedlings of a pioneer species Saurauia nepalensis, a mid-successional species Terminalia myriocarpa and a mature forest species Castanopsis indica were introduced in plots with a control and three treatments: shading (light manipulated), clearing of vegetation (reduced competition), and exclosures (mammal herbivory excluded) and monitored for 18, 22 and 23 months, respectively.Saurauia survived relatively well in all sites, Terminalia seedlings survived relatively well in the 12 and 25 year sites, and Castanopsis seedlings survived well in the 100 year site and the uncut forest. In the early successional site, survival of Saurauia was higher within exclosures indicating negative effects of herbivory. In the same site, clearing vegetation improved the survival of Terminalia, implying competition with existing vegetation. Castanopsis had the highest survival in uncut forest and survival was almost nil in the early successional site.Synthesis: Seedling survival in a successional landscape depended on species-as well as site-specific factors. The existing vegetation in an early successional site had a negative effect on the survival of the mid-successional species, while herbivory had a negative effect on the pioneer species. Survival of the mature forest species in the early successional site was negligible but was high in old successional and uncut forest sites, indicating that mature forest species can colonize sites and survive only after certain physical and biotic aspects of the environment have been met. Our experiments were useful to examine factors that affect survival of tree species with differing life history strategies in a shifting cultivation landscape.
DeepPoseKit, a software toolkit for fast and robust animal pose estimation using deep learning
Authors: Graving Jacob M. , Chae Daniel , Naik Hemal , Li Liang , Koger Benjamin , Costelloe Blair R. , Couzin Iain D. 
Published: April 2019

AbstractQuantitative behavioral measurements are important for answering questions across scientific disciplines—from neuroscience to ecology. State-of-the-art deep-learning methods offer major advances in data quality and detail by allowing researchers to automatically estimate locations of an animal’s body parts directly from images or videos. However, currently-available animal pose estimation methods have limitations in speed and robustness. Here we introduce a new easy-to-use software toolkit,DeepPoseKit, that addresses these problems using an eZcient multi-scale deep-learning model, calledStacked DenseNet, and a fast GPU-based peak-detection algorithm for estimating keypoint locations with subpixel precision. These advances improve processing speed >2× with no loss in accuracy compared to currently-available methods. We demonstrate the versatility of our methods with multiple challenging animal pose estimation tasks in laboratory and field settings—including groups of interacting individuals. Our work reduces barriers to using advanced tools for measuring behavior and has broad applicability across the behavioral sciences.
DrosophilaSnazarus regulates a lipid droplet population at plasma membrane-droplet contacts in adipocytes
Authors: Ugrankar Rupali , Bowerman Jade , Hariri Hanaa , Chandra Mintu , Chen Kevin , Bossanyi Marie-France , Datta Sanchari , Rogers Sean , Eckert Kaitlyn M. , Vale Gonçalo , Victoria Alexia , Fresquez Joseph , McDonald Jeffrey G. , Jean Steve , Collins Brett M. , Henne W. Mike 
Published: April 2019

SummaryAdipocytes store nutrients as lipid droplets (LDs), but how they organize their LD stores to balance lipid uptake, storage, and mobilization remains poorly understood. Here, usingDrosophilafat body (FB) adipocytes we characterize spatially distinct LD populations that are maintained by different lipid pools. We identify peripheral LDs (pLDs) that make close contact with the plasma membrane (PM) and are maintained by lipophorin-dependent lipid trafficking. pLDs are distinct from larger cytoplasmic medial LDs (mLDs) which are maintained by FASN1-dependentde novolipogenesis. We find that sorting nexin CG1514/Snazarus (Snz) associates with pLDs and regulates LD homeostasis at ER-PM contact sites. Loss ofSNZperturbs pLD organization whereas Snz over-expression drives LD expansion, triacylglyceride production, starvation resistance, and lifespan extension through a DESAT1-dependent pathway. We propose thatDrosophilaadipocytes maintain spatially distinct LD populations and identify Snz as a novel regulator of LD organization and inter-organelle crosstalk.
Human neutrophils produce antifungal extracellular vesicles againstAspergillus fumigatus
Authors: Shopova Iordana A. , Belyaev Ivan , Dasari Prasad , Jahreis Susanne , Stroe Maria C. , Cseresnyés Zoltán , Zimmermann Ann-Kathrin , Medyukhina Anna , Svensson Carl-Magnus , Krüger Thomas , Szeifert Viktòria , Nietzsche Sandor , Conrad Theresia , Blango Matthew G. , Kniemeyer Olaf , von Lilienfeld-Toal Marie , Zipfel Peter F. , Ligeti Erzsébet , Figge Marc Thilo , Brakhage Axel A. 
Published: April 2019

AbstractPolymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human pathogenic fungusAspergillus fumigatustriggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. Two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae, which led to reduced fungal growth relative to a control retinol binding protein 7 producing strain. In conclusion, the production of afEVs by PMNs offers an intriguing, previously overlooked mechanism of antifungal defense againstA. fumigatus.ImportanceInvasive fungal infections caused by the moldAspergillus fumigatusare a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high mortality as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination ofA. fumigatusfrom the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils againstA. fumigatusnot previously described. We find that extracellular vesicles produced by neutrophils in response toA. fumigatusinfection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding ofA. fumigatushost pathogenesis and opens up novel diagnostic and therapeutic possibilities.
Impaired EAT-4 Vesicular Glutamate Transporter Leads to Defective Nocifensive Response of Caenorhabditis elegans to Noxious Heat
Authors: Leonelli Sophie , Nkambeu Bruno , Beaudry Francis 
Published: April 2019

AbstractIn mammals, glutamate is an important excitatory neurotransmitter. Glutamate and glutamate receptors are found in areas specifically involved in pain sensation, transmission and transduction such as peripheral nervous system, spinal cord and brain. In C. elegans, several studies have suggested glutamate pathways are associated with withdrawal responses to mechanical stimuli and to chemical repellents. However, few evidences demonstrate that glutamate pathways are important to mediate nocifensive response to noxious heat. The thermal avoidance behavior of C. elegans was studied and results illustrated that mutants of glutamate receptors (glr-1, glr-2, nmr-1, nmr-2) behaviors was not affected. However, results revealed that all strains of eat-4 mutants, C. elegans vesicular glutamate transporters, displayed defective thermal avoidance behaviors. Due to the interplay between the glutamate and the FLP-18/FLP-21/NPR-1 pathways, we analyzed the effectors FLP-18 and FLP-21 at the protein level, we did not observebiologically significant differences compared to N2 (WT) strain (fold-change < 2) except for the IK602 strain. The data presented in this manuscript reveals that glutamate signaling pathways are essential to elicit a nocifensive response to noxious heat in C. elegans.
Population-specific effect ofWolbachiaon the cost of fungal infection in spider mites
Authors: Zélé Flore , Altintaş Mustafa , Santos Inês , Cakmak Ibrahim , Magalhães Sara 
Published: April 2019

ABSTRACTMany studies have revealed the ability of the endosymbiotic bacteriaWolbachiato protect its arthropod hosts against diverse pathogens. However, asWolbachiamay also increase the susceptibility of its host to infection, predicting the outcome of a particularWolbachia-host-pathogen interaction remains elusive. Yet, understanding such interactions is crucial for disease and pest control strategies.Tetranychus urticaespider mites are herbivorous crop pests, causing severe damage on numerous economically important crops. Due to the rapid evolution of pesticide resistance, biological control strategies using generalist entomopathogenic are being developed. However, although spider mites are infected with variousWolbachiastrains worldwide, whether this endosymbiont protects them from fungi is as yet unknown. Here, we compared the survival of two populations, treated with antibiotics or harbouring differentWolbachiastrains, after exposure to the fungal biocontrol agentsMetarhizium brunneumandBeauveria bassiana. In one population,Wolbachiaaffected survival in absence of fungi but not in their presence, whereas in the other populationWolbachiaincreased the mortality induced byB. bassiana. To control for potential effects of the bacterial community of spider mites, we also compared the susceptibility of two populations naturally uninfected byWolbachia, treated with antibiotics or not. The antibiotic treatment increased the susceptibility of spider mites toM. brunneumin one naturallyWolbachia-uninfected population, but it had no effect in the other treatments. These results highlight the complexity of within-host pathogens interactions, and the importance of considering the whole bacterial community of arthropods when assessing the effect ofWolbachiain a particular system.
Association and impact of hypertension defined using the 2017 AHA/ACC guidelines on the risk of atrial fibrillation in the Atherosclerosis Risk in Communities Study
Authors: Rattani Anas , Claxton J’Neka S. , Ali Mohammed K. , Chen Lin Y. , Soliman Elsayed Z. , Alvaro Alonso 
Published: April 2019

AbstractHypertension is an established risk factor for the development of atrial fibrillation (AF). We evaluated the association and population impact of hypertension, defined using the new 2017 guidelines, on risk of AF. In this analysis, we included 9,207 participants in the Atherosclerosis Risk in Communities study without history of cardiovascular disease or diabetes. Participants underwent blood pressure measurements at baseline and their antihypertensive medication use was assessed. AF was ascertained from study electrocardiograms, hospital records and death certificates. Cox proportional models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of AF among individuals with hypertension based on the JNC7 and 2017 ACC/AHA guidelines. Poisson models were used to obtain risk ratios and calculate population-attributable fractions (PAFs). We identified 1,573 cases of incident AF during 22.1 years of mean follow-up. Prevalence of hypertension was 29% and 43% under the JNC7 and 2017 ACC/AHA definitions, respectively. HRs (95%CI) of AF in hypertensives versus non-hypertensives were 1.54 (1.39, 1.72) and 1.45 (1.31, 1.61) after multivariable adjustment under the old and new guidelines, respectively. The corresponding PAF (95%CI) using the old and new guidelines were 12% (9%, 14%) and 14% (10%, 18%), respectively. Overall, our analysis shows that even though the prevalence of hypertension using the new criteria is 50% higher than with the old criteria, this does not translate into meaningful increases in AF attributable to hypertension. These results suggest that prevention or treatment of hypertension based on the new (versus old) guidelines may have limited impact on AF incidence.
Contributions of white matter connectivity and BOLD modulation to cognitive aging: A lifespan structure-function association study
Authors: Webb Christina E. , Rodrigue Karen M. , Hoagey David A. , Foster Chris M. , Kennedy Kristen M. 
Published: April 2019

AbstractThe ability to flexibly modulate brain activation to increasing cognitive challenge decreases with aging. This age-related decrease in dynamic range of function of regional gray matter may be, in part, due to age-related degradation of regional white matter tracts. Here, a lifespan sample of 171 healthy adults (aged 20-94) underwent MRI scanning including diffusion-weighted imaging (for tractography) and functional imaging (a digit n-back task). We utilized structural equation modeling to test the hypothesis that age-related decrements in white matter microstructure are associated with altered BOLD modulation, and both in turn, are associated with scanner-task accuracy and executive function performance. Specified structural equation model evidenced good fit, demonstrating that increased age negatively affects n-back task accuracy and executive function performance in part due to both degraded white matter tract microstructure and reduced task-difficulty related BOLD modulation. We further demonstrated that poorer white matter microstructure integrity was associated with weakened BOLD modulation, particularly in regions showing positive modulation effects, as opposed to negative modulation effects. This structure-function association study provides further evidence that structural connectivity influences functional activation, and the two mechanisms in tandem are predictive of cognitive performance, both during the task, and for cognition measured outside the scanner environment.
Personalized deep learning of individual immunopeptidomes to identify neoantigens for cancer vaccines
Authors: Tran Ngoc Hieu , Qiao Rui , Xin Lei , Chen Xin , Shan Baozhen , Li Ming 
Published: April 2019

AbstractTumor-specific neoantigens play the main role for developing personal vaccines in cancer immunotherapy. We propose, for the first time, a personalized de novo sequencing workflow to identify HLA-I and HLA-II neoantigens directly and solely from mass spectrometry data. Our workflow trains a personal deep learning model on the immunopeptidome of an individual patient and then uses it to predict mutated neoantigens of that patient. This personalized learning and mass spectrometry-based approach enables comprehensive and accurate identification of neoantigens. We applied the workflow to datasets of five melanoma patients and substantially improved the accuracy and identification rate of de novo HLA peptides by 14.3% and 38.9%, respectively. This subsequently led to the identification of 10,440 HLA-I and 1,585 HLA-II new peptides that were not presented in existing databases. Most importantly, our workflow successfully discovered 17 neoantigens of both HLA-I and HLA-II, including those with validated T cell responses and those novel neoantigens that had not been reported in previous studies.
Tendon response to matrix unloading is determined by the patho-physiological niche
Authors: Wunderli Stefania L. , Blache Ulrich , Piccoli Agnese Beretta , Niederöst Barbara , Holenstein Claude N. , Passini Fabian , Silván Unai , Bundgaard Louise , auf dem Keller Ulrich , Snedeker Jess G. 
Published: April 2019

AbstractAberrant matrix turnover with elevated matrix proteolysis is a hallmark of tendon pathology. While tendon disease mechanisms remain obscure, mechanical cues are central regulators. Unloading of tendon explants in standard culture conditions provokes rapid cell-mediated tissue breakdown. Here we show that biological response to tissue unloading depends on the mimicked physiological context. Our experiments reveal that explanted tendon tissues remain functionally stable in a simulated avascular niche of low temperature and oxygen, regardless of the presence of serum. This hyperthermic and hyperoxic niche-dependent catabolic switch was shown by whole transcriptome analysis (RNA-seq) to be a strong pathological driver of an immune-modulatory phenotype, with a stress response to reactive oxygen species (ROS) and associated activation of catabolic extracellular matrix proteolysis that involved lysosomal activation and transcription of a range of proteolytic enzymes. Secretomic and degradomic analysis through terminal amine isotopic labeling of substrates (TAILS) confirmed that proteolytic activity in unloaded tissues was strongly niche dependent. Through targeted pharmacological inhibition we isolated ROS mediated oxidative stress as a major checkpoint for matrix proteolysis. We conclude from these data that the tendon stromal compartment responds to traumatic mechanical unloading in a manner that is highly dependent on the extrinsic niche, with oxidative stress response gating the proteolytic breakdown of the functional collagen backbone.
Zebrafish use visual cues and geometric relationships to form a spatial memory
Authors: Yashina Ksenia , Tejero-Cantero Álvaro , Herz Andreas , Baier Herwig 
Published: April 2019

AbstractAnimals use salient cues to navigate in their environment, but their specific cognitive strategies are largely unknown. We developed a conditioned place avoidance paradigm to discover whether and how zebrafish form spatial memories in a Y-shaped maze. Juvenile zebrafish, older than three weeks, learned to avoid the arm of the maze that was cued with a mild electric shock. We found that the fish required distinct visual patterns to develop a conditioned response. Interestingly, individual fish solve this task in different ways: by staying in the safe center of the maze, by preference for one, or both, of the safe patterns, or by mixed strategies. In experiments in which the learned patterns were swapped, rotated or replaced, the animals could transfer the association of safety to a different arm or to a different pattern using either visual cues or location as the conditioned stimulus. These findings show that juvenile zebrafish exhibit several complementary spatial learning modes and pave the way for neurobiological studies of navigational mechanisms in this model species.
Museum epigenomics: characterizing cytosine methylation in historic museum specimens
Authors: Rubi Tricia L. , Knowles L. Lacey , Dantzer Ben 
Published: April 2019

AbstractMuseum genomics has transformed the field of collections-based research, opening up a range of new research directions for paleontological specimens as well as natural history specimens collected over the past few centuries. Recent work demonstrates that it is possible to characterize epigenetic markers such as DNA methylation in well-preserved ancient tissues. This approach has not yet been tested in traditionally-prepared natural history specimens such as dried bones and skins, the most common specimen types in vertebrate collections. In this study, we develop and test methods to characterize cytosine methylation in dried skulls up to 76 years old. Using a combination of ddRAD and bisulfite treatment, we characterized patterns of cytosine methylation in two species of deer mouse (Peromyscus spp.) collected in the same region in Michigan in 1940, 2003, and 2013-2016. We successfully estimated methylation in specimens of all age groups, though older specimens yielded less data and showed greater interindividual variation in data yield than newer specimens. Global methylation estimates were reduced in the oldest specimens (76 years old) relative to the newest specimens (1-3 years old), which may reflectpost mortemhydrolytic deamination. Methylation was reduced in promoter regions relative to gene bodies and showed greater bimodality in autosomes relative to female X chromosomes, consistent with expectations for methylation in mammalian somatic cells. Our work demonstrates the utility of historic specimens for methylation analyses, as with genomic analyses; however, such studies will need to accommodate the large variance in the quantity of data produced by older specimens.