bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations between vascular risk factors and brain MRI indices in UK Biobank
Authors: Cox SR , Lyall DM , Ritchie SJ , Bastin ME , Harris MA , Buchanan CR , Fawns-Ritchie C , Barbu MC , de Nooij L , Reus LM , Alloza C , Shen X , Neilson E , Alderson HL , Hunter S , Liewald DC , Whalley HC , McIntosh AM , Lawrie SJ , Pell JP , Tucker-Drob EM , Wardlaw JM , Gale CR , Deary IJ 
Published: January 2019

AbstractAimsSeveral factors are known to increase risk for cerebrovascular disease and dementia, but there is limited evidence on associations between multiple vascular risk factors (VRFs) and detailed aspects of brain macro- and microstructure in large community-dwelling populations across middle- and older age.Methods and ResultsAssociations between VRFs (smoking, hypertension, pulse pressure, diabetes, hypercholersterolaemia, BMI, and waist-hip ratio) and both global and regional brain structural and diffusion MRI markers were examined in UK Biobank (N = 9722, age range 44-77 years). A larger number of VRFs was associated with greater brain atrophy, lower grey matter volume, and poorer white matter health. Effect sizes were small (brain structural R2 ≤ 1.8%). Higher aggregate vascular risk was related to multiple regional MRI hallmarks associated with dementia risk: lower frontal and temporal cortical volumes, lower subcortical volumes, higher white matter hyperintensity volumes, and poorer white matter microstructure in association and thalamic pathways. Smoking pack years, hypertension and diabetes showed the most consistent associations across all brain measures. Hypercholesterolaemia was not uniquely associated with any MRI marker.ConclusionHigher levels of VRFs were associated with poorer brain health across grey and white matter macro- and microstructure. Effects are mainly additive, converging upon frontal and temporal cortex, subcortical structures, and specific classes of white matter fibres. Though effect sizes were small, these results emphasise the vulnerability of brain health to vascular factors even in relatively healthy middle and older age, and the potential to partly ameliorate cognitive decline by addressing these malleable risk factors.
Combining 3D-MOT with motor and perceptual decision-making tasks: conception of a life-sized virtual perceptual-cognitive training paradigm
Authors: Romeas Thomas , Chaumillon Romain , Labbé David , Faubert Jocelyn 
Published: January 2019

AbstractThe present study introduces a virtual life-sized perceptual-cognitive paradigm combining three dimensional multiple object tracking (3D-MOT) with motor (Experiment 1) or perceptual (Experiment 2) decision-making tasks. The objectives were to assess the impact of training on task performance and to determine the best training conditions for improvement and learning.Seventy-one participants were randomly trained under one of four training conditions (isolated 3D-MOT task, 3D-MOT simultaneously combined with a decision-making task, consolidated 3D-MOT and decision-making task, isolated decision-making task). Task performance was evaluated using speed thresholds, decision accuracy (%) and reaction time (s).Findings showed that the dual-task paradigm allowed satisfactory degrees of performance on both tasks despite an important dual-task cost. Interestingly, the results seemed to favor consolidated over simultaneous training for dual-task performance when 3D-MOT was combined with a motor task. The amount of attentional shared resources in regards to the nature of the additional task was discussed.
Structure and function of a 9.6 megadalton bacterial iron storage compartment
Authors: Giessen T. W. , Orlando B. J. , Verdegaal A. A. , Chambers M. G. , Gardener J. , Bell D. C. , Birrane G. , Liao M. , Silver P. A. 
Published: January 2019

AbstractIron storage proteins are essential for maintaining intracellular iron homeostasis and redox balance. Iron is generally stored in a soluble and bioavailable form inside ferritin protein compartments. However, some organisms do not encode ferritins and thus rely on alternative storage strategies. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment fromQuasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo. We show that the cargo-loaded compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. These results form the basis for understanding alternate microbial strategies for dealing with the essential element iron.
Selection and characterization of a reovirus mutant with improved thermostability
Authors: Snyder Anthony J. , Danthi Pranav 
Published: January 2019

ABSTRACTThe environment represents a significant barrier to infection. Physical stressors (heat) or chemical agents (ethanol and sodium dodecyl sulfate) can render virions noninfectious. As such, discrete proteins are necessary to stabilize the dual layered structure of mammalian orthoreovirus (reovirus). The outer capsid participates in cell entry: (i) σ3 is degraded to generate the infectious subviral particle and (ii) μ1 facilitates membrane penetration and subsequent core delivery. μ1-σ3 interactions also prevent inactivation; however, this activity is not fully characterized. Using forward and reverse genetic approaches, we identified two mutations (μ1 M258I and σ3 S344P) within heat resistant strains. σ3 S344P was sufficient to enhance capsid integrity and to reduce protease sensitivity. Moreover, these changes impaired replicative fitness in a reassortant background. This work reveals new details regarding the determinants of reovirus stability.SIGNIFICANCENonenveloped viruses rely on protein-protein interactions to shield their genomes from the environment. The capsid, or protective shell, must also disassemble during cell entry. In this work, we identified a determinant within mammalian orthoreovirus that regulates heat resistance, disassembly kinetics, and replicative fitness. Together, capsid function is balanced for optimal replication and for spread to a new host.
WDR76 promotes MLL-rearranged leukemia via selective recognition of 5-hydroxymethylcytosine in DNA
Authors: Malecek Kathryn E. , Weng Hengyou , Sullivan Matthew A. , Kokontis Claire Y. , Werner Michael S. , Chen Jianjun , Ruthenburg Alexander J. 
Published: January 2019

SUMMARYAlthough rare, the distribution of the 5-hydroxymethylcytosine (hmC) modification in mammalian DNA is tissue- and gene-specific, yet distinct from its transcriptionally-repressive methylcytosine (mC) precursor, suggesting unique signaling potential. To examine this possibility, we fractionated mammalian brain extracts to discover binding partners specific for oxidized states of mC. We demonstrate that one such factor, WDR76, is a highly hmC-specific binding protein that modulates gene expression within chromosomal regions enriched in hmC where it binds. We demonstrate direct transcriptional activation of several target genes in mouse embryonic stem cells as a function of hmC levels and contingent upon WDR76. In human cell lines and mouse models, WDR76 recruitment by hmC is critical for the initiation and maintenance of MLL-rearranged leukemias. Beyond its canonical role as an intermediate in mC remediation, we show that hmC can be an epigenetic mark whose recognition drives leukemogenesis, portending analogous signaling pathways for other rare DNA modifications.
Cytoplasmic volume and limiting nucleoplasmin scale nuclear size duringXenopus laevisdevelopment
Authors: Chen Pan , Tomschik Miroslav , Nelson Katherine , Oakey John , Gatlin J. C. , Levy Daniel L. 
Published: January 2019

SUMMARYHow nuclear size is regulated relative to cell size is a fundamental cell biological question. Reductions in both cell and nuclear sizes duringXenopus laevisembryogenesis provide a robust scaling system to study mechanisms of nuclear size regulation. To test if the volume of embryonic cytoplasm is limiting for nuclear growth, we encapsulated gastrula stage embryonic cytoplasm and nuclei in droplets of defined volume using microfluidics. Nuclei grew and reached new steady-state sizes as a function of cytoplasmic volume, supporting a limiting component mechanism of nuclear size control. Through biochemical fractionation, we identified the histone chaperone nucleoplasmin (Npm2) as a putative nuclear size-scaling factor. Cellular amounts of Npm2 decrease over development, and nuclear size was sensitive to Npm2 levels both in vitro and in vivo, affecting nuclear histone levels and chromatin organization. Thus, reductions in cell volume with concomitant decreases in Npm2 amounts represent a developmental mechanism of nuclear size-scaling that may also be relevant to cancers with increased nuclear size.
ABC transporters confer multidrug resistance to Drosophila intestinal stem cells
Authors: Dayton Hannah , DiRusso Jonathan , Kolbert Kristopher , Williamson Olivia , Balciunaite Aiste , D’Souza Edridge , Becker Kelly , Hosage Elizaveta , Issa Muneera , Liu Victoria , Viswanatha Raghuvir , Kondo Shu , Markstein Michele 
Published: January 2019

ABSTRACTAdult stem cells can survive a wide variety of insults from ionizing radiation to toxic chemicals1–3. To date, the multidrug resistant features of stem cells have been characterized only in vertebrates, where there is a critical need to understand how cancer stem cells thwart chemotherapy drugs4–6. These studies reveal that the ability of both normal and cancer stem cells to survive toxins hinges on their high levels of expression of ABC transporters, transmembrane pumps that efflux lipophilic compounds out of cells7,8. This has been observed across a wide spectrum of vertebrate stem cells including breast, blood, intestine, liver, and skin, suggesting that high efflux ability and multidrug resistance may be general features of stem cells that distinguish them from their differentiated daughter cells. Here we show that these previously described vertebrate stem cell features are conserved in Drosophila intestinal stem cells. Using a novel in vivo efflux assay and multiple drug challenges, we show that stem cells in the fly intestine depend on two ABC transporters—one constitutively expressed and the other induced—for efflux and multidrug resistance. These results suggest that stem cell multidrug resistance by ABC transporters is a general stem cell feature conserved over 500 million years of evolution.
Divergence in gut microbial communities mirrors a social group fission event in a black-and-white colobus monkey (Colobus vellerosus)
Authors: Goodfellow Claire K. , Whitney Tabor , Christie Diana M. , Sicotte Pascale , Wikberg Eva C. , Ting Nelson 
Published: January 2019

ABSTRACTHost behavior and social factors have increasingly been implicated in structuring the composition of gut microbial communities. In social animals, distinct microbial communities characterize different social groups across a variety of taxa, although little longitudinal research has been conducted that demonstrates how this divergence occurs. Our study addresses this question by characterizing the gut microbial composition of an African Old World monkey, the black-and-white colobus (Colobus vellerosus), prior to and after a social group fission event. Gut microbial taxonomic composition of these monkeys was profiled using the V-4 hypervariable region of the bacterial 16s rRNA gene, and pairwise-relatedness values were calculated for all individuals using 17 STR loci and partial pedigree information. The two social groups in this study were found to harbor distinct microbial signatures after the fission event from which they emerged, while these communities were not divergent in the same individuals prior to this event. Three genera were found to differ in abundance between the two new social groups: Parabacteroides, Coprococcus, and Porphyromonadaceae. Additionally, although this fission happened partially along lines of relatedness, relatedness did not structure the differences that we found. Taken together, this study suggests that distinct gut microbial profiles can emerge in social groups in less than one year and recommends further work into more finely mapping the timescales, causes, and potentially adaptive effects of this recurring trend toward distinct group microbial signatures.Research highlightsDistinct gut microbial profiles emerge in two social groups of C. vellerosus less than nine months after a fission event.Three genera differ in abundance between the two new social groups.Relatedness does not structure differences in microbial composition between the groups.
A Hybrid Deep Clustering Approach for Robust Cell Type Profiling Using Single-cell RNA-seq Data
Authors: Srinivasan Suhas , Johnson Nathan T. , Korkin Dmitry 
Published: January 2019

AbstractSingle-cell RNA sequencing (scRNA-seq) is a recent technology that enables fine-grained discovery of cellular subtypes and specific cell states. It routinely uses machine learning methods, such as feature learning, clustering, and classification, to assist in uncovering novel information from scRNA-seq data. However, current methods are not well suited to deal with the substantial amounts of noise that is created by the experiments or the variation that occurs due to differences in the cells of the same type. Here, we develop a new hybrid approach, Deep Unsupervised Single-cell Clustering (DUSC), that integrates feature generation based on a deep learning architecture with a model-based clustering algorithm, to find a compact and informative representation of the single-cell transcriptomic data generating robust clusters. We also include a technique to estimate an efficient number of latent features in the deep learning model. Our method outperforms both classical and state-of-the-art feature learning and clustering methods, approaching the accuracy of supervised learning. The method is freely available to the community and will hopefully facilitate our understanding of the cellular atlas of living organisms as well as provide the means to improve patient diagnostics and treatment.
Setting off the Alarms:Candida albicansElicits Pro-Inflammatory Differential Gene Expression in Intestinal Peyer’s Patches
Authors: Singh Navjot , Kim Heather C. , Song Renjie , Dhinsa Jaskiran K. , Torres Steven R. , Jesus Magdia De 
Published: January 2019

AbstractCandida albicanshas been associated with a number of human diseases that pertain to the gastrointestinal (GI) tract. However, the details of how gut-associated lymphoid tissues (GALT) such as Peyer’s patches (PPs) in the small intestine play a role in immune surveillance and microbial differentiation, and what mechanisms PP use to protect the mucosal barrier in response to fungal organisms such asC. albicans, are still unclear. We particularly focus on PPs as they are the immune sensors and inductive sites of the gut that influence inflammation and tolerance. We have previously demonstrated that CD11c+phagocytes located in the sub-epithelial dome (SED) within PPs sampleC. albicans. To gain insight on how specific cells within PPs sense and respond to the sampling of fungi, we gavaged mice withC. albicansstrains ATCC 18804 and SC5314 as well asSaccharomyces cerevisiae. We measured the differential gene expression of sorted CD45+B220+B-cells, CD3+T-cells, and CD11c+DCs within the first 24 hrs post-gavage using nanostring nCounter® technology. The results reveal that at 24 hrs, PP phagocytes were the cell type that displayed differential gene expression. These phagocytes were both able to sampleC. albicansand able to discriminate between strains. In particular, strain ATCC 18804 upregulated fungal specific pro-inflammatory genes in CD11c+phagocytes pertaining to innate and adaptive immune responses. Interestingly, PP CD11c+phagocytes differentially expressed genes in response toC. albicansthat were important in the protection of the mucosal barrier. These results highlight that the mucosal barrier not only responds toC. albicans, but also aids in the protection of the host.ImportanceThe specific gene expression changes within PPs that send the warning signals when encountering fungi, and how PPs can discriminate between innocuousS. cerevisiaeor different strains ofC. albicansduring early stages of sampling, have not been elucidated. Here we show that within the first 24 hours of sampling, CD11c+phagocytes were not only important in sampling, but they were the cell type that exhibited clear differential gene expression. These differentially expressed genes play important dual roles in inflammation, chemotaxis, and fungal specific recognition, as well as maintaining homeostasis and protection of the mucosal barrier. Using nanostring technology, we were also able to demonstrate that PPs can distinguish between different strains ofC. albicansand can “set off the alarms” when necessary.
Identifying small proteins by ribosome profiling with stalled initiation complexes
Authors: Weaver Jeremy , Mohammad Fuad , Buskirk Allen R. , Storz Gisela 
Published: January 2019

ABSTRACTSmall proteins consisting of 50 or fewer amino acids have been identified as regulators of larger proteins in bacteria and eukaryotes. Despite the importance of these molecules, the true prevalence of small proteins remains unknown because conventional annotation pipelines usually exclude small open reading frames (smORFs). We previously identified several dozen small proteins in the model organismEscherichia coliusing theoretical bioinformatic approaches based on sequence conservation and matches to canonical ribosome binding sites. Here, we present an empirical approach for discovering new proteins, taking advantage of recent advances in ribosome profiling in which antibiotics are used to trap newly-initiated 70S ribosomes at start codons. This approach led to the identification of many novel initiation sites in intergenic regions inE. coli. We tagged 41 smORFs on the chromosome and detected protein synthesis for all but three. The corresponding genes are not only intergenic, but are also found antisense to other genes, in operons, and overlapping other open reading frames (ORFs), some impacting the translation of larger downstream genes. These results demonstrate the utility of this method for identifying new genes, regardless of their genomic context.IMPORTANCEProteins comprised of 50 or fewer amino acids have been shown to interact with and modulate the function of larger proteins in a range of organisms. Despite the possible importance of small proteins, the true prevalence and capabilities of these regulators remain unknown as the small size of the proteins places serious limitations on their identification, purification and characterization. Here, we present a ribosome profiling approach with stalled initiation complexes that led to the identification of 38 new small proteins.
Effects of phenotypic robustness on adaptive evolutionary dynamics
Authors: Rigato Emanuele , Fusco Giuseppe 
Published: January 2019

AbstractTheoretical and experimental studies have provided evidence for a positive role of phenotype resistance to genetic mutation in enhancing long-term adaptation to novel environments. With the aim of contributing to an understanding of the origin and evolution of phenotypic robustness to genetic mutations in organismal systems, we adopted a theoretical approach, elaborating on a classical mathematical formalizations of evolutionary dynamics, the quasispecies model. We show that a certain level of phenotypic robustness is not only a favourable condition for adaptation to occur, but that it is also a necessary condition for short-term adaptation in most real organismal systems. This appears as a threshold effect, i.e. as a minimum level of phenotypic robustness (critical robustness) below which evolutionary adaptation cannot consistently occur or be maintained, even in the case of sizably selection coefficients and in the absence of any drift effect. These results, are in agreement with the observed pervasiveness of robustness at different levels of biological organization, from molecules to whole organisms.
Coupling water fluxes with cell wall mechanics in a multicellular model of plant development
Authors: Cheddadi Ibrahim , Génard Michel , Bertin Nadia , Godin Christophe 
Published: January 2019

The growth of plant organs is a complex process powered by osmosis that attracts water inside the cells; this influx induces simultaneously an elastic extension of the walls and pressure in the cells, called turgor pressure; above a threshold, the walls yield and the cells grow. Based on Lockhart’s seminal work, various models of plant morphogenesis have been proposed, either for single cells, or focusing on the wall mechanical properties. However, the synergistic coupling of fluxes and wall mechanics has not yet been fully addressed in a multicellular model. This work lays the foundations of such a model, by simplifying as much as possible each process and putting emphasis on the coupling itself. Its emergent properties are rich and can help to understand plant morphogenesis. In particular, we show that the model can display a new type of lateral inhibitory mechanism that could contribute to the amplification of growth heterogeneities, essential for shape differentiation.Significance StatementPlant cells are surrounded by a rigid wall that prevents cell displacements and rearrangements as in animal tissues. Therefore, plant morphogenesis relies only on cell divisions, shape changes, and local modulation of growth rate. It has long been recognized that cell growth relies on the competition between osmosis that tends to attract water into the cells and wall mechanics that resists to it, but this interplay has never been fully explored in a multicellular model. The goal of this work is to analyze the theoretical consequences of this coupling. We show that the emergent behavior is rich and complex: among other findings, pressure and growth rate heterogeneities are predicted without any ad-hoc assumption; furthermore the model can display a new type of lateral inhibition based on fluxes that could complement and strengthen the efficiency of already known mechanisms.
Interaction of HelQ helicase with RPA modulates RPA-DNA binding and stimulates HelQ to unwind DNA through a protein roadblock
Authors: Northall Sarah J. , Jenkins Tabitha , Ptchelkine Denis , Taresco Vincenzo , Cooper Christopher D. O. , Soultanas Panos , Bolt Edward L. 
Published: January 2019

ABSTRACTCells reactivate compromised DNA replication forks using enzymes that include DNA helicases for separating DNA strands and remodelling protein-DNA complexes. HelQ helicase promotes replication-coupled DNA repair in mammals in a network of interactions with other proteins. We report newly identified HelQ helicase activities, when acting alone and when interacting with RPA. HelQ helicase was strongly inhibited by a DNA-protein barrier (BamHIE111A), and by an abasic site in the translocating DNA strand. Interaction of HelQ with RPA activated DNA unwinding through the protein barrier, but not through the abasic site. Activation was lost when RPA was replaced with bacterial SSB or DNA binding-defective RPA, RPAARO1. We observed stable HelQ-RPA-DNA ternary complex formation, and present evidence that an intrinsically disordered N-terminal region of HelQ (N-HelQ) interacts with RPA, destabilising RPA-DNA binding. Additionally, SEC-MALS showed that HelQ multimers are converted into catalytically active dimers when ATP-Mg2+is bound. HelQ and RPA are proposed to jointly promote replication fork recovery by helicase-catalysed displacement of DNA-bound proteins, after HelQ gains access to ssDNA through its N-terminal domain interaction with RPA.