bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population-specific and transethnic genome-wide analyses reveal distinct and shared genetic risks of coronary artery disease
Authors: Koyama Satoshi , Ito Kaoru , Terao Chikashi , Akiyama Masato , Horikoshi Momoko , Momozawa Yukihide , Matsunaga Hiroshi , Ieki Hirotaka , Ozaki Kouichi , Onouchi Yoshihiro , Takahashi Atsushi , Nomura Seitaro , Morita Hiroyuki , Akazawa Hiroshi , Kim Changhoon , Seo Jeong-sun , Higasa Koichiro , Iwasaki Motoki , Yamaji Taiki , Sawada Norie , Tsugane Shoichiro , Koyama Teruhide , Ikezaki Hiroaki , Takashima Naoyuki , Tanaka Keitaro , Arisawa Kokichi , Kuriki Kiyonori , Naito Mariko , Wakai Kenji , Suna Shinichiro , Sakata Yasuhiko , Sato Hiroshi , Hori Masatsugu , Sakata Yasushi , Matsuda Koichi , Murakami Yoshinori , Aburatani Hiroyuki , Kubo Michiaki , Matsuda Fumihiko , Kamatani Yoichiro , Komuro Issei 
Published: November 2019

AbstractTo elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study (GWAS) of 168,228 Japanese (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,782 CAD cases and 3,148 controls. We detected 9 novel disease-susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a transethnic meta-analysis and discovered 37 additional novel loci. Using the result of the meta-analysis, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European GWAS. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improves clinical characterization of CAD genetics and suggests the utility of transethnic meta-analysis for PRS derivation in non-European populations.
Photoproximity Profiling of Protein-Protein Interactions in Cells
Authors: McCutcheon David C. , Lee Gihoon , Carlos Anthony , Montgomery Jeffrey E. , Moellering Raymond E. 
Published: November 2019

ABSTRACTWe report a novel photoproximity protein interaction (PhotoPPI) profiling method to map protein-protein interactions in vitro and in live cells. This approach utilizes a bioorthogonal, multifunctional chemical probe that can be targeted to a genetically encoded protein of interest (POI) through a modular SNAP-Tag/benzylguanine covalent interaction. A first generation photoproximity probe, PP1, responds to 365 nm light to simultaneously cleave a central nitroveratryl linker and a peripheral diazirine group, resulting in diffusion of a highly reactive carbene nucleophile away from the POI. We demonstrate facile probe loading, and subsequent interaction- and light-dependent proximal labeling of a model protein-protein interaction (PPI) in vitro. Integration of the PhotoPPI workflow with quantitative LC-MS/MS enabled un-biased interaction mapping for the redox regulated sensor protein, KEAP1, for the first time in live cells. We validated known and novel interactions between KEAP1 and the proteins PGAM5 and HK2, among others, under basal cellular conditions. By contrast, comparison of PhotoPPI profiles in cells experiencing metabolic or redox stress confirmed that KEAP1 sheds many basal interactions and becomes associated with known lysosomal trafficking and proteolytic proteins like SQSTM1, CTSD and LGMN. Together, these data establish PhotoPPI as a method capable of tracking the dynamic sub-cellular and protein interaction “social network” of a redox-sensitive protein in cells with high temporal resolution.SYNOPSIS TOC
Automated identification of maximal differential cell populations in flow cytometry data
Authors: Yue Alice , Chauve Cedric , Libbrecht Maxwell , Brinkman Ryan R. 
Published: November 2019

AbstractWe introduce a new cell population score called SpecEnr (specific enrichment) and describe a method that discovers robust and accurate candidate biomarkers from flow cytometry data. Our approach identifies a new class of candidate biomarkers we define as driver cell populations, whose abundance is associated with a sample class (e.g. disease), but not as a result of a change in a related population. We show that the driver cell populations we find are also easily interpretable using a lattice-based visualization tool. Our method is implemented in the R package flowGraph, freely available on GitHub (github.com/aya49/flowGraph) and on BioConductor.
An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans
Authors: Sayed Nazish , Gao Tianxiang , Tibshirani Robert , Hastie Trevor , Cui Lu , Kuznetsova Tatiana , Rosenberg-Hasson Yael , Ostan Rita , Monti Daniela , Lehallier Benoit , Shen-Orr Shai , Maecker Holden T. , Dekker Cornelia L. , Wyss-Coray Tony , Franceschi Claudio , Jojic Vladimir , Haddad François , Montoya José G. , Wu Joseph C. , Furman David 
Published: November 2019

AbstractWhile many diseases of aging have been linked to the immunological system, immune metrics with which to identify the most at-risk individuals are lacking. Here, we studied the blood immunome of 1001 individuals age 8-96 and derived an inflammatory clock of aging (iAge), which tracked with multi-morbidity and immunosenescence. In centenarians, iAge was on average, 40 years lower than their corresponding chronological age. The strongest contributor to this metric was the chemokine CXCL9, which was involved in cardiac aging, affected vascular function, and down-regulated Sirtuin-3, a longevity-associated molecule. Thus, our results identify an important link between inflammatory molecules and pathways known to govern lifespan.
Citizen science and aquatic macroinvertebrates: public engagement for catchment-scale pollution vigilance
Authors: Moolna Adam , Duddy Mike , Fitch Ben , White Keith 
Published: November 2019

ABSTRACTCitizen science aims to engage the wider population beyond scientists and statutory agencies, providing a catalyst for positive change and influencing policymakers and institutions. The Riverfly Partnership has been supporting a growing network of citizen science volunteers monitoring aquatic macroinvertebrates in rivers and streams across the United Kingdom since 2004. In Manchester, Salford and surrounding areas, Riverfly Partnership monitoring began in 2011 with volunteers from a catchment-wide fishing club. This provided a catalyst for broader public engagement, wider environmental projects, and the establishment of a new grassroots environmental charity. The vigilance of the network demonstrated its value by flagging a major pollution event wiping out all macroinvertebrates along 19 km of the River Irwell in April 2017. By evaluating monitoring data and the citizen science program’s impacts, we identify key lessons for taking forward public engagement in river catchment management both in Greater Manchester and elsewhere.
Diffusion Histology Imaging Combining Diffusion Basis Spectrum Imaging (DBSI) and Machine Learning Improves Detection and Classification of Glioblastoma Pathology
Authors: Ye Zezhong , Price Richard L. , Liu Xiran , Lin Joshua , Yang Qingsong , Sun Peng , Wu Anthony T. , Wang Liang , Han Rowland , Song Chunyu , Yang Ruimeng , Gary Sam E. , Mao Diane D. , Wallendorf Michael , Campian Jian L. , Li Jr-Shin , Dahiya Sonika , Kim Albert H. , Song Sheng-Kwei 
Published: November 2019

AbstractPurposeGlioblastoma (GBM) is one of the deadliest cancers with no cure. While conventional MRI has been widely adopted for examining GBM clinically, accurate neuroimaging assessment of tumor histopathology for improved diagnosis, surgical planning, and treatment evaluation, remains an unmet need in the clinical management of GBMs.Experimental DesignWe employ a novel Diffusion Histology Imaging (DHI) approach, combining diffusion basis spectrum imaging (DBSI) and machine learning, to detect, differentiate, and quantify areas of high cellularity, tumor necrosis, and tumor infiltration in GBM.ResultsGd-enhanced T1W or hyper-intense FLAIR failed to reflect the morphological complexity underlying tumor in GBM patients. Contrary to the conventional wisdom that apparent diffusion coefficient (ADC) negatively correlates with increased tumor cellularity, we demonstrate disagreement between ADC and histologically confirmed tumor cellularity in glioblastoma specimens, whereas DBSI-derived restricted isotropic diffusion fraction positively correlated with tumor cellularity in the same specimens. By incorporating DBSI metrics as classifiers for a supervised machine learning algorithm, we accurately predicted high tumor cellularity, tumor necrosis, and tumor infiltration with 87.5%, 89.0% and 93.4% accuracy, respectively.ConclusionOur results suggest that DHI could serve as a favorable alternative to current neuroimaging techniques for guiding biopsy or surgery as well as monitoring therapeutic response in the treatment of glioblastoma.Translational RelevanceCurrent clinical diagnosis, surgical planning, and assessment of treatment response for GBM patients relies heavily on gadolinium-enhanced T1-weighted MRI, which is non-specific for tumor growth and merely reflects a disrupted blood-brain barrier. The complex tumor microenvironment and spatial heterogeneity make GBM difficult to characterize using current clinical imaging modalities. In this study, we developed a novel imaging technique to characterize and accurately predict key histological features of GBM - high tumor cellularity, tumor necrosis, and tumor infiltration. While further validation in a larger cohort of patients is needed, the current proof-of-concept approach could provide a solution to resolve important clinical questions such as the identification of true tumor progression vs. pseudoprogression or radiation necrosis.
How past exposure to predation affects personality and behavioural plasticity?
Authors: Tariel Juliette , Plénet Sandrine , Luquet Émilien 
Published: November 2019

AbstractWhen behaviour is observed multiple times on animals from the same population, between-individual difference in mean behaviour (personality) and in behavioural plasticity are often reported. While the developmental environment might explain such an individual difference, the effect of parental environment is still unexplored -a surprising observation as parental carry-over effect are now well-known to influence the average phenotype and plastic responses of offspring-.We tested whether parental and developmental exposure to predator cues impacted the immediate behavioural predator-induced response in the snailPhysa acutaat both mean level (average response) and individual level (between-individual variation). Two generations of snails were reared in laboratory without or with exposure to predator cues. Then, escape behaviour was repeatedly assessed on adult snails in the presence or absence of predator cues.Both parental and developmental exposure to predator cues acted additively towards a lower average behavioural plasticity. At the individual level, developmental exposure induced higher differentiation in personality trait but not in behavioural plasticity while parental environment did not influence the between-individual differences.These results highlight that past environments can strongly influence behaviour at the population level and that they should be taken into consideration when investigating why individuals differ in behaviour.
Fungal effector Jsi1 hijacks plant JA/ET signaling through Topless
Authors: Darino Martin , Marques Joana , Chia Khong-Sam , Aleksza David , Soto Luz Mayela , Uhse Simon , Borg Michael , Betz Ruben , Bindics Janos , Zienkiewicz Krzysztof , Feussner Ivo , Petit-Houdenot Yohann , Djamei Armin 
Published: November 2019

AbstractUstilago maydis (U. maydis) is the causal agent of maize smut disease. During the colonization process, the fungus secretes effector proteins which suppress immune responses and redirect the host-metabolism in favor of the pathogen. Here we describe a novel strategy by which U. maydis induces plant jasmonate/ethylene (JA/ET) hormone signaling and thereby biotrophic susceptibility. The U. maydis effector Jasmonate/Ethylene signaling inducer 1 (Jsi1) possesses an ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif, DLNxxP, which interacts with the second WD40 domain of the conserved plant co-repressor family Topless/Topless related (TPL/TPR). Jsi1 interaction with TPL/TPRs leads to derepression of the ethylene response factor (ERF) branch of the JA/ET signaling pathway, supporting biotrophic susceptibility. Jsi1 likely activates the ERF branch by interfering with the binding of endogenous DLNxxP motif-containing ERF transcription factors to TPL/TPR proteins. The identification of effector proteins possessing a DLNxxP motif in different fungal species with biotrophic and hemibiotrophic lifestyles together with the validation of the interaction between such effectors from Magnaporthe oryzae (M. oryzae), Sporisorium scitamineum (S. scitamineum), and S. reilianum with TPL proteins indicates the convergent evolution of effectors for modulating the TPL/TPR co-repressor hub.
Expression, Purification, and Functional Reconstitution of19F-labeled Cytochrome b5 in Peptide Nanodiscs for NMR Studies
Authors: Bai Jia , Wang Jian , Ravula Thirupathi , Im Sang-Choul , Anantharamaiah G. M. , Waskell Lucy , Ramamoorthy Ayyalusamy 
Published: November 2019

ABSTRACTMicrosomal cytochrome b5 (cytb5) is a membrane-bound protein capable of donating the second electron to cytochrome P450s (CYP P450s) in the CYP P450s monooxygenase reactions. Recent studies have demonstrated the importance of the transmembrane domain of cytb5 in the interaction with cytP450 by stabilizing its monomeric structure. While recent NMR studies have provided high-resolution insights into the structural interactions between the soluble domains of ~16-kDa cytb5 and ~57-kDa cytP450 in a membrane environment, there is need for studies to probe the residues in the transmembrane region as well as to obtain intermolecular distance constraints to better understand the very large size cytb5-cytP450 complex structure in a near native membrane environment. In this study, we report the expression, purification, functional reconstitution of19F-labeled full-length rabbit cytb5 in peptide based nanodiscs for structural studies using NMR spectroscopy. Size exclusion chromatography, dynamic light scattering, transmission electron microscopy, and NMR experiments show a stable reconstitution of cytb5 in 4F peptide-based lipid-nanodiscs. Our results demonstrate that the use of peptide-nanodiscs containing cytb519F-labeled with 5-fluorotryptophan (5FW) enables, for the first time, the detection of residues from the transmembrane domain in different lipid compositions by solution19F NMR experiments.19F NMR results revealing the interaction of the transmembrane domain of cytb5 with the full-length rabbit Cytochrome P450 2B4 (CYP2B4) are also presented. We expect the results presented in this study to be useful to devise approaches to probe the structure, dynamics and functional roles of transmembrane domains of a membrane protein, and also to measure intermolecular19F-19F distance constraints to determine the structural interactions between the transmembrane domains.
Evolutionary repair: changes in multiple functional modules allow meiotic cohesin to support mitosis
Authors: Hsieh Yu-Ying Phoebe , Makrantoni Vasso , Robertson Daniel , Marston Adèle L , Murray Andrew W 
Published: November 2019

AbstractDifferent members of the same protein family often perform distinct cellular functions. How much are these differing functions due to changes in a protein’s biochemical activity versus changes in other proteins? We asked how the budding yeast,Saccharomyces cerevisiae,evolves when forced to use the meiosis-specific kleisin, Rec8, instead of the mitotic kleisin, Scc1, during the mitotic cell cycle. This perturbation impairs sister chromosome linkage and reduces reproductive fitness by 45%. We evolved 15 populations for 1750 generations, substantially increasing their fitness, and analyzed their genotypes and phenotypes. We found no mutations in Rec8, but many populations had mutations in the transcriptional mediator complex, cohesin-related genes, and cell cycle regulators that induce S phase. These mutations improve sister chromosome cohesion and slow genome replication in Rec8-expressing cells. We conclude that changes in known and novel partners allow proteins to improve their ability to perform new functions.
Gene Expression of Functionally-Related Genes Coevolves Across Fungal Species: Detecting Coevolution of Gene Expression Using Phylogenetic Comparative Methods
Authors: Cope Alexander L. , O’Meara Brian , Gilchrist Michael A. 
Published: November 2019

AbstractBackgroundResearchers often measure changes in gene expression across conditions to better understand the shared functional roles and regulatory mechanisms of different genes. Analogous to this is comparing gene expression across species, which can improve our understanding of the evolutionary processes shaping the evolution of both individual genes and functional pathways. One area of interest is determining genes showing signals of coevolution, which can also indicate potential functional similarity, analogous to co-expression analysis often performed across conditions for a single species. However, as with any trait, comparing gene expression across species can be confounded by the non-independence of species due to shared ancestry, making standard hypothesis testing inappropriate.ResultsWe compared RNA-Seq data across 18 fungal species using a multivariate Brownian Motion phylogenetic comparative method (PCM), which allowed us to quantify coevolution between protein pairs while directly accounting for the shared ancestry of the species. Our work indicates proteins which physically-interact show stronger signals of coevolution than randomly-generated pairs. Interactions with stronger empirical and computational evidence also showing stronger signals of coevolution. We examined the effects of number of protein interactions and gene expression levels on coevolution, finding both factors are overall poor predictors of the strength of coevolution between a protein pair. Simulations further demonstrate the potential issues of analyzing gene expression coevolution without accounting for shared ancestry in a standard hypothesis testing framework. Furthermore, our simulations indicate the use of a randomly-generated null distribution as a means of determining statistical significance for detecting coevolving genes with phylogenetically-uncorrected correlations, as has previously been done, is less accurate than PCMs, although is a significant improvement over standard hypothesis testing. These methods are further improved by using a phylogenetically-corrected correlation metric.ConclusionsOur work highlights potential benefits of using PCMs to detect gene expression coevolution from high-throughput omics scale data. This framework can be built upon to investigate other evolutionary hypotheses, such as changes in transcription regulatory mechanisms across species.
Elucidating the regulation of glucose tolerance through the interaction between the reaction product and active site pocket residues of a β-glucosidase from Halothermothrix orenii
Authors: Sinha Sushant K , Das Shibashis , Konar Sukanya , Ghorai Pradip Kr. , Das Rahul , Datta Supratim 
Published: November 2019

Abstractβ-glucosidase catalyzes the hydrolysis of β-1,4 linkage between two glucose molecules in cello-oligosaccharides and is prone to inhibition by the reaction product glucose. Relieving the glucose inhibition of β-glucosidase is a significant challenge. Towards the goal of understanding how glucose interacts with β-glucosidase, we expressed in Escherichia coli, the Hore_15280 gene encoding a β-glucosidase in Halothermothrix orenii. Our results show that the enzyme is glucose tolerant, and its activity stimulated in the presence of up to 0.5 M glucose. NMR analyses show the unexpected interactions between glucose and the β-glucosidase at lower concentrations of glucose that however does not lead to enzyme inhibition. We identified non-conserved residues at the aglycone-binding and the gatekeeper site and show that increased hydrophobicity at the pocket entrance and a reduction in steric hindrances are critical towards enhanced substrate accessibility and significant improvement in activity. Analysis of structures and in combination with molecular dynamics simulations show that glucose increases the accessibility of the substrate by enhancing the structural flexibility of the active site pocket and may explain the stimulation in specific activity up to 0.5 M glucose. Such novel regulation of β-glucosidase activity by its reaction product may offer novel ways of engineering glucose tolerance.
Exhaustive reconstruction of the CRISPR locus inMycobacterium tuberculosiscomplex using short reads
Authors: Guyeux Christophe , Sola Christophe , Refrégier Guislaine 
Published: November 2019

AbstractSpoligotyping, a graphical partial display of the CRISPR locus that can be producedin vitroorin silico, is an important tool for analyzing the diversity of givenMycobacterium tuberculosiscomplex (MTC) isolates. As other CRISPR loci, this locus is made up of an alternation between direct repeats and spacers, and flanked bycasgenes. Unveiling the genetic mechanisms of its evolution requires to have a fairly large amount of fully reconstructed loci among all MTC lineages.In this article, we point out and resolve the problem of CRISPR reconstruction based on short read sequences. We first show that more than 1/3 of the currently assembled genomes available for this complex contain a CRISPR locus erroneously reconstructed, and errors can be very significant. Second, we present a new computational method allowing this locus to be reconstructed extensively and reliablyin silicousing short read sequencing runs. Third, using this method, we describe new structural characteristics of CRISPR locus by lineages. We show how both the classical experimentalin vitroapproach and the basicin silicospoligotyping provided by existing analytic tools miss a whole diversity of this locus in MTC, by not capturing duplications, spacer and direct repeats variants, and IS6110insertion locations. This description is extended in a second article that presents general rules for the evolution of the CRISPR locus in MTC.This work opens new perspectives for a larger exploration of CRISPR loci diversity and of mechanisms involved in its evolution and its functionality.
Effects of surfaces and macromolecular crowding on bimolecular reaction rates
Authors: Andrews Steven S. 
Published: November 2019

AbstractBiological cells are complex environments that are densely packed with macromolecules and subdivided by membranes, both of which affect the rates of chemical reactions. It is well known that crowding reduces the volume available to reactants, which increases reaction rates, and also inhibits reactant diffusion, which decreases reaction rates. This work investigates these effects quantitatively using analytical theory and particle-based simulations. A reaction rate equation based on only these two processes turned out to be inconsistent with simulation results. However, accounting for diffusion inhibition by the surfaces of nearby obstacles, which affects access to reactants, led to perfect agreement for reactions near impermeable planar membranes and improved agreement for reactions in crowded spaces. A separate model that quantified reactant occlusion by crowders, and extensions to a thermodynamic “cavity” model proposed by Berezhkovskii and Szabo (J. Phys. Chem. B 120:5998, 2016), were comparably successful. These results help elucidate reaction dynamics in confined spaces and improve prediction of in vivo reaction rates from in vitro ones.