bluuebunny/crossref_metadata_2025_split huggingface dataset:
The circulating lipidome is largely defined by sex descriptors in the GOLDN, GeneBank and the ADNI studies
Authors: Barupal Dinesh Kumar , Zhang Ying , Fan Sili , Hazen Stanley L. , Tang W. H. Wilson , Cajka Tomas , Irvin Marguerite R. , Arnett Donna K. , Kind Tobias , Kaddurah-Daouk Rima , Fiehn Oliver 
Published: August 2019

AbstractBiological sex is one of the major anthropometric factors which influences physiology, metabolism and health status. We have investigated the effect of sexual dimorphism on the blood lipidome profile in three large population level studies - the Alzheimer’s disease neuroimaging initiative - ADNI (n =806), the GeneBank Functional Cardio-Metabolomics cohort (n= 1015) and the Genetics of Lipid lowering Drugs and Diet Network - GOLDN (n=422). In total, 355 unique lipids from 15 lipid classes were detected across all three studies using LC-MS. Sixty percent of these lipids differed between men and women in all three cohorts, and up to 87% of all lipids demonstrated sex differences in at least one cohort. ChemRICH enrichment statistics on lipid classes showed that phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, ceramides, sphingomyelins and cholesterol esters were found at higher levels in female subjects while triacylglycerols and lysophosphatidylcholines were found at higher levels in male participants across the three cohorts. This strong sex effect on the blood lipidome suggests that specific regulatory mechanisms may exist that regulate lipid metabolism in a different manner between men and women. Cohort studies involving blood lipidomics should consider separate analyses for male and female participants instead of combined analyses treating sex as a confounding factor.
Myristate can be used as a carbon and energy source for the asymbiotic growth of arbuscular mycorrhizal fungi
Authors: Sugiura Yuta , Akiyama Rei , Tanaka Sachiko , Yano Koji , Kameoka Hiromu , Marui Shiori , Saito Masanori , Kawaguchi Masayoshi , Akiyama Kohki , Saito Katsuharu 
Published: August 2019

AbstractArbuscular mycorrhizal (AM) fungi, forming symbiotic associations with land plants, are obligate symbionts that cannot complete their natural life cycle without a host. Recently, fatty acid auxotrophy of AM fungi is supported by studies showing that lipids synthesized by the host plants are transferred to the fungi and that the latter lack genes encoding cytosolic fatty acid synthases (1-7). Therefore, to establish an asymbiotic cultivation system for AM fungi, we tried to identify the fatty acids that could promote biomass production. To determine whether AM fungi can grow on medium supplied with fatty acids or lipids under asymbiotic conditions, we tested eight saturated or unsaturated fatty acids (C12–C18) and two β-monoacylglycerols. Only myristate (C14:0) led to an increase in biomass ofRhizophagus irregularis, inducing extensive hyphal growth and formation of infection-competent secondary spores. However, such spores were smaller than those generated symbiotically. Furthermore, we demonstrated thatR. irregulariscan take up fatty acids in its branched hyphae and use myristate as a carbon and energy source. Myristate also promoted the growth ofRhizophagus clarusandGigaspora margarita. Finally, mixtures of myristate and palmitate accelerated fungal growth and induced a substantial change in fatty acid composition of triacylglycerol compared with single myristate application, although palmitate was not used as a carbon source for cell wall biosynthesis in this culture system. In conclusion, here we demonstrate that myristate boosts asymbiotic growth of AM fungi and can also serve as a carbon and energy source.Significance statementThe origins of arbuscular mycorrhizal (AM) fungi, which form symbiotic associations with land plants, date back over 460 million years ago. During evolution, these fungi acquired an obligate symbiotic lifestyle, and thus depend on their host for essential nutrients. In particular, fatty acids are regarded as crucial nutrients for the survival of AM fungi owing to the absence of genes involved inde novofatty acid biosynthesis in the AM fungal genomes that have been sequenced so far. Here, we show that myristate initiates AM fungal growth under asymbiotic conditions. These findings will advance pure culture of AM fungi.
Laccase-mediated catalyzed fluorescent reporter deposition for live cell imaging
Authors: Cisneros Brandon , Devaraj Neal K. 
Published: August 2019

AbstractCatalyzed reporter deposition (CARD) is a widely established method for labeling biological samples analyzed using microscopy. Horseradish peroxidase, commonly used in CARD to amplify reporter signals, requires the addition of hydrogen peroxide which may perturb samples used in live-cell microscopy. Herein we describe an alternative method of performing CARD using a laccase enzyme, which does not require exogenous hydrogen peroxide. Laccase is an oxidative enzyme which can carry out single-electron oxidations of phenols and related compounds by reducing molecular oxygen. We demonstrate proof-of-concept for this technique through the non-targeted covalent labeling of bovine serum albumin using a fluorescently-labeled ferulic acid derivative as the laccase reporter substrate. We further demonstrate the viability of this approach by performing live-cell CARD with an antibody-conjugated laccase against a surface bound target. CARD using laccase produces an amplified fluorescence signal by labeling cells without the need for exogenous hydrogen peroxide.
Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Biallelic Loss of ENG or ACVRL1
Authors: Snellings Daniel , Gallione Carol , Clark Dewi , Vozoris Nicholas , Faughnan Marie , Marchuk Douglas 
Published: August 2019

AbstractHereditary Hemorrhagic Telangiectasia (HHT) is a Mendelian disease characterized by vascular malformations including visceral arteriovenous malformations and mucosal telangiectasia. HHT is caused by loss-of-function mutations in one of 3 genes; ENG, ACVRL1 or SMAD4 and is inherited as an autosomal dominant condition. Intriguingly, the constitutional mutation causing HHT is present throughout the body, yet the multiple vascular malformations in HHT patients occur focally, rather than manifesting as a systemic vascular defect. This disconnect between genotype and phenotype suggests that a local event is necessary for the development of vascular malformations. We investigated the hypothesis that local somatic mutations seed the formation HHT-related telangiectasia in a genetic two-hit mechanism. We identified low-frequency somatic mutations in 9/19 telangiectasia using high depth next-generation sequencing. We established phase for 7 of 9 samples using long-read sequencing, which confirm that the germline and somatic mutations in all 7 samples exist in trans configuration; consistent with a genetic two-hit mechanism. These combined data suggest that biallelic loss of ENG or ACVRL1 may be a required event in the development of telangiectasia, and that rather than haploinsufficiency, vascular malformations in HHT are caused by a Knudsonian two-hit mechanism.
CrowdGO: machine learning and semantic similarity guided consensus Gene Ontology annotation
Authors: Reijnders Maarten J.M.F. , Waterhouse Robert M. 
Published: August 2019

AbstractBackgroundCharacterising gene function for the ever-increasing number and diversity of species with annotated genomes relies almost entirely on computational prediction methods. These software are also numerous and diverse, each with different strengths and weaknesses as revealed through community benchmarking efforts. Meta-predictors that assess consensus and conflict from individual algorithms should deliver enhanced functional annotations.ResultsTo exploit the benefits of meta-approaches, we developed CrowdGO, an open-source consensus-based Gene Ontology (GO) term meta-predictor that employs machine learning models with GO term semantic similarities and information contents. By re-evaluating each gene-term annotation, a consensus dataset is produced with high-scoring confident annotations and low-scoring rejected annotations. Applying CrowdGO to results from a deep learning-based, a sequence similarity-based, and two protein domain-based methods, delivers consensus annotations with improved precision and recall. Furthermore, using standard evaluation measures CrowdGO performance matches that of the community’s best performing individual methods.ConclusionCrowdGO offers a model-informed approach to leverage strengths of individual predictors and produce comprehensive and accurate gene functional annotations.Availability and ImplementationCrowdGO is implemented in Python3, and is freely available from https://gitlab.com/mreijnders/CrowdGO, with a Snakemake workflow and pre-trained models.
A Combinatorial MAP Code Dictates Polarized Microtubule Transport
Authors: Monroy Brigette Y. , Tan Tracy C. , Oclaman Janah May , Han Jisoo S. , Simo Sergi , Nowakowski Dan W. , McKenney Richard J. , Ori-McKenney Kassandra M. 
Published: August 2019

ABSTRACTMany eukaryotic cells distribute their intracellular components through asymmetrically regulated active transport driven by molecular motors along microtubule tracks. While intrinsic and extrinsic regulation of motor activity exists, what governs the overall distribution of activated motor-cargo complexes within cells remains unclear. Here, we utilize in vitro reconstitution of purified motor proteins and non-enzymatic microtubule-associated proteins (MAPs) to demonstrate that these MAPs exhibit distinct influences on the motility of the three main classes of transport motors: kinesin-1, kinesin-3, and cytoplasmic dynein. Further, we dissect how combinations of MAPs affect motors, and reveal how transient interactions between MAPs and motors may promote these effects. From these data, we propose a general “MAP code” that has the capacity to strongly bias directed movement along microtubules and helps elucidate the intricate intracellular sorting observed in highly polarized cells such as neurons.
Estimates of locus coeruleus function with functional magnetic resonance imaging are influenced by localization approaches and the use of multi-echo data
Authors: Turker Hamid B. , Riley Elizabeth , Luh Wen-Ming , Colcombe Stan J. , Swallow Khena M. 
Published: August 2019

AbstractThe locus coeruleus (LC) plays a central role in regulating human cognition, arousal, and autonomic states. Efforts to characterize the LC’s function in humans using functional magnetic resonance imaging have been hampered by its small size and location near a large source of noise, the fourth ventricle. We tested whether the ability to characterize LC function is improved by employing neuromelanin-T1 weighted images (nmT1) for LC localization and multi-echo functional magnetic resonance imaging (ME-fMRI) for estimating intrinsic functional connectivity (iFC). Analyses indicated that, relative to a probabilistic atlas, utilizing nmT1 images to individually localize the LC increases the specificity of seed time series and clusters in the iFC maps. When combined with independent components analysis (ME-ICA), ME-fMRI data provided significant gains in the temporal signal to noise ratio relative to denoised single-echo (1E) data. The effects of acquiring nmT1 images and ME-fMRI data did not appear to only reflect increases in power: iFC maps for each approach only moderately overlapped. This is consistent with findings that ME-fMRI offers substantial advantages over 1E data acquisition and denoising. It also suggests that individually identifying LC with nmT1 scans is likely to reduce the influence of other nearby brainstem regions on estimates of LC function.HighlightsManual tracing of locus coeruleus increased specificity of seed time seriesManual tracing of locus coeruleus increased specificity of intrinsic connectivityMulti-echo fMRI increased temporal signal-to-noise ratio compared to single-echo fMRIConnectivity maps across methodologies overlapped only moderatelyMeasurement of LC function benefits from multi-echo fMRI and tracing ROIs
scDoc: Correcting Drop-out Events in Single-cell RNA-seq Data
Authors: Ran Di , Zhang Shanshan , Lytal Nicholas , An Lingling 
Published: August 2019

AbstractSingle-cell RNA sequencing (scRNA-seq) has become an important tool to unravel cellular heterogeneity, discover new cell types, and understand cell development at single-cell resolution. However, one major challenge to scRNA-seq research is the presence of “drop-out” events, which usually is due to extremely low mRNA input or the stochastic nature of gene expression. In this paper, we present a novel Single-Cell RNA-seq Drop-Out Correction (scDoc) method, imputing drop-out events by borrowing information for the same gene from highly similar cells. scDoc is the first method that involves drop-out information to account for cell-to-cell similarity estimation, which is crucial in scRNA-seq drop-out imputation but has not been appropriately examined. We evaluated the performance of scDoc using both simulated data and real scRNA-seq studies. Results show that scDoc can impute the drop-out events more accurately and robustly; specifically, it outperforms all available imputation methods in reference to data visualization, cell subpopulation identification, and differential expression detection in scRNA-seq data.
DLDG1, the Arabidopsis Homolog of the Cyanobacterial H+-Extrusion Protein, Regulates Non-Photochemical Quenching in Chloroplasts
Authors: Harada Kyohei , Arizono Takatoshi , Sato Ryoichi , Trinh Mai Duy Luu , Hashimoto Akira , Kono Masaru , Tsujii Masaru , Uozumi Nobuyuki , Takaichi Shinichi , Masuda Shinji 
Published: August 2019

AbstractPlants convert solar energy into chemical energy through photosynthesis, which supports almost all life activities on earth. Because the intensity and quality of sunlight can change dramatically throughout the day, various regulatory mechanisms help plants adjust their photosynthetic output accordingly, including the regulation of light energy accumulation to prevent the generation of damaging reactive oxygen species. Non-photochemical quenching (NPQ) is a regulatory mechanism that dissipates excess light energy, but how it is regulated is not fully elucidated. Herein, we report a new NPQ-regulatory protein named Day-Length-dependent Delayed-Greening1 (DLDG1). The Arabidopsis DLDG1 associates with the chloroplast envelope membrane, and thedldg1mutant had a large NPQ value compared with wild type. The mutant also had a pale-green phenotype in developing leaves but only under continuous light; this phenotype was not observed whendldg1was cultured in the dark for ≥8 h per day. DLDG1 is a homolog of the plasma-membrane-localizing cyanobacterial proton-extrusion-protein A that is required for light-induced H+extrusion, and also shows similarity in its amino-acid sequence to that of Ycf10 encoded in the plastid genome. Arabidopsis DLDG1 enhances the growth-retardation phenotype of theEscherichia coliK+/H+antiporter mutant, and the everted membrane vesicles of theE. coliexpressing DLDG1 show the K+/H+antiport activity. Our findings suggest that DLDG1 functionally interacts with Ycf10 to control H+homeostasis in chloroplasts, which is important for the light-acclimation response, by optimizing the extent of NPQ.
Structural insights into the mechanism of the human soluble guanylate cyclase
Authors: Kang Yunlu , Liu Rui , Wu Jing-Xiang , Chen Lei 
Published: August 2019

SummarySoluble guanylate cyclase (sGC) is the primary nitric oxide (NO) sensor. It plays a central role in NO signaling and is implicated in many essential physiological processes and disease conditions. The binding of NO leads to a significant boost in sGC enzymatic activity. However, the mechanism of NO activation remains incompletely understood. Here, we report the cryo-electron microscopy structures of the human sGC α1β1 heterodimer in different functional states. These structures revealed that the transducer module bridges the NO sensor module and the catalytic module. NO binding to the β1 H-NOX domain triggers the structural rearrangement of the sensor module and the bending-straightening conformational switch of the transducer module. The resulting movement of the N-termini of the catalytic domains drives the structural changes within the catalytic module, which in turn boost sGC enzymatic activity. These observations indicate the structural framework for the mechanism of sGC activation induced by NO binding.
PIWI-piRNA pathway-mediated transposable element repression inHydrasomatic stem cells
Authors: Teefy Bryan B. , Siebert Stefan , Cazet Jack F. , Lin Haifan , Juliano Celina E. 
Published: August 2019

AbstractTransposable elements (TEs) can damage genomes, thus organisms employ a variety of mechanisms to repress TE expression. However, these mechanisms often fail over time leading to de-repression of TEs in aging tissues. The PIWI-piRNA pathway is a small RNA pathway that represses TE expression in the germline of animals. Here we explore the function of the pathway in the epithelial stem cells ofHydra, a long-lived freshwater cnidarian.Hydrahave three stem cell populations; endodermal and ectodermal epithelial stem cells are strictly somatic, whereas the interstitial stem cells retain germline competence. In our previous study, we found that the PIWI proteins are expressed in all threeHydrastem cell types. In this study, we focus on the ectodermal and endodermal epithelial stem cells to understand the somatic function of the pathway. We isolated piRNAs fromHydrathat lack the interstitial lineage and found that these somatic piRNAs map predominantly to TE transcripts and display the conserved sequence signatures typical of germline piRNAs. Three lines of evidence suggest that the PIWI-piRNA pathway represses TEs inHydraepithelial stem cells. First, epithelial knockdown of theHydraPIWI proteinhywiresulted in upregulation of TE expression. Second, degradome sequencing revealed evidence of PIWI-mediated cleavage of TE RNAs in epithelial cells using the ping-pong mechanism. Finally, we demonstrated a direct association between Hywi protein and TE transcripts in epithelial cells using RNA immunoprecipitation. Interestingly, we found that RNAi knockdown ofhywileads to an upregulation of genes involved in innate immunity, which may be in response to TE upregulation; this is consistent with recent studies on TE expression in mammalian cells. Altogether, this study suggests a function for the PIWI-piRNA pathway in maintaining the long-lived somatic cell lineages ofHydraand may point to a broader role for this pathway in protecting somatic tissue from TE-induced damage.
An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis
Authors: Xiang Guanjue , Keller Cheryl A. , Heuston Elisabeth , Giardine Belinda M. , An Lin , Wixom Alexander Q. , Miller Amber , Cockburn April , Sauria Michael E.G. , Weaver Kathryn , Lichtenberg Jens , Göttgens Berthold , Li Qunhua , Bodine David , Mahony Shaun , Taylor James , Blobel Gerd A. , Weiss Mitchell J. , Cheng Yong , Yue Feng , Hughes Jim , Higgs Douglas R. , Zhang Yu , Hardison Ross C. 
Published: August 2019

AbstractThousands of epigenomic datasets have been generated in the past decade, but it is difficult for researchers to effectively utilize all the data relevant to their projects. Systematic integrative analysis can help meet this need, and the VISION project was established forValIdatedSystematicIntegratiONof epigenomic data in hematopoiesis. Here, we systematically integrated extensive data recording epigenetic features and transcriptomes from many sources, including individual laboratories and consortia, to produce a comprehensive view of the regulatory landscape of differentiating hematopoietic cell types in mouse. By employing IDEAS as ourIntegrative andDiscriminativeEpigenomeAnnotationSystem, we identified and assigned epigenetic states simultaneously along chromosomes and across cell types, precisely and comprehensively. Combining nuclease accessibility and epigenetic states produced a set of over 200,000 candidatecis-regulatory elements (cCREs) that efficiently capture enhancers and promoters. The transitions in epigenetic states of these cCREs across cell types provided insights into mechanisms of regulation, including decreases in numbers of active cCREs during differentiation of most lineages, transitions from poised to active or inactive states, and shifts in nuclease accessibility of CTCF-bound elements. Regression modeling of epigenetic states at cCREs and gene expression produced a versatile resource to improve selection of cCREs potentially regulating target genes. These resources are available from our VISION website (usevision.org) to aid research in genomics and hematopoiesis.
Structure-activity relationship studies of three novel 4-aminopyridine K+ channel blockers
Authors: Rodríguez-Rangel Sofia , Bravin Alyssa D. , Ramos-Torres Karla M. , Brugarolas Pedro , Sánchez-Rodríguez Jorge E. 
Published: August 2019

Abstract4-Aminopyridine (4AP) is a specific blocker of voltage-gated potassium channels (KV1 family) clinically approved for the symptomatic treatment of patients with multiple sclerosis (MS). It has recently been shown that [18F]3F4AP, a radiofluorinated analog of 4AP, also binds to KV1 channels and can be used as a PET tracer for the detection of demyelinated lesions in rodent models of MS. Here, we investigate three novel 4AP derivatives containing methyl (-CH3), methoxy (-OCH3) and trifluoromethyl (-CF3) in the 3 position as potential candidates for PET imaging and/or therapy. We characterized the physicochemical properties of these compounds (pKa and logD) and analyzed their ability to block Shaker K+ channel under different voltage and pH conditions. Our results demonstrate that all three derivatives are able to block voltage-gated potassium channels. Specifically, 3-methyl-4-aminopyridine (3Me4AP) was found to be approximately 7-fold more potent than 4AP, whereas the methoxy (3MeO4AP) and trifluoromethyl (3CF34AP) containing compounds were about 3- to 4-fold less potent than 4AP, respectively. These results suggest that these novel derivatives are potential candidates for therapy and imaging.
GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling
Authors: Lex Rachel K. , Ji Zhicheng , Falkenstein Kristin N. , Zhou Weiqiang , Henry Joanna L. , Ji Hongkai , Vokes Steven A. 
Published: August 2019

ABSTRACTTranscriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of these regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific limb activity. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. The Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target gene expression by altering the acetylation status at enhancers.