bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post-hoc analyses of Surrogate Markers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Liver Fibrosis in Patients with Type 2 Diabetes in a Digitally-Supported Continuous Care Intervention: An Open Label, Non-Randomized, Controlled Study
Authors: Vilar-Gomez Eduardo , Athinarayanan Shaminie J. , AdamS Rebecca N. , Hallberg Sarah J. , Bhanpuri Nasir H. , McKenzie Amy L. , Campbell Wayne W. , McCarter James P. , Phinney Stephen D. , Volek Jeff S. , Chalasani Naga 
Published: April 2018

ABSTRACTObjectiveOne-year of comprehensive continuous care intervention (CCI) through nutritional ketosis improves HbA1c, body weight and liver enzymes among type 2 diabetes (T2D) patients. Here, we report the effect of the CCI on surrogate scores of non-alcoholic fatty liver disease (NAFLD) and liver fibrosis.MethodsThis was a non-randomized longitudinal study, including adults with T2D who were self-enrolled to the CCI (n=262) or to receive usual care (UC, n=87) during one year. A NAFLD liver fat score [N-LFS] > −0.640 defined the presence of fatty liver. A NAFLD fibrosis score [NFS] of > 0.675 identified subjects with advanced fibrosis. Changes in N-LFS and NFS at one year were the main endpoints.ResultsAt baseline, NAFLD was present in 95% of patients in the CCI and 90% of patients in the UC. At one year, weight loss of > 5% was achieved in 79% of patients in the CCI vs. 19% of patients in UC (P<0.001). N-LFS mean score was reduced in the CCI group (−1.95±0.22, P<0.001) whereas it was not changed in the UC (0.47±0.41, P=0.26) (CCI vs. UC, P<0.001). NFS was reduced in the CCI group (−0.65±0.06, P<0.001) compared with UC (0.26±0.11, P=0.02) (P<0.001 between two groups). In the CCI group, the percentage of individuals with a low probability of advanced fibrosis increased from 18% at baseline to 33% at 1 year (P<0.001).ConclusionsOne year of a digitally-supported CCI significantly improved surrogates of NAFLD and advanced fibrosis in patients with type 2 diabetes.DATA SHARINGData sets and statistical code used for the current study are available from the corresponding author on reasonable request.Article Summary Strengths and limitations of this studyThis study highlights the beneficial effect of the CCI on NAFLD in high risk patients with T2DThis study also identifies positive associations between glycemic improvements and improvements in ALT levelsThe assessment of resolution of steatosis and fibrosis is limited by the sensitivity and specificity of the non-invasive markers used in the studyThe patients were restricted in their carbohydrate intake and monitored for their nutritional ketosis state, but dietary energy, macronutrient and micronutrient intakes were not assessed.
Evolution of Portulacineae marked by gene tree conflict and gene family expansion associated with adaptation to harsh environments
Authors: Wang Ning , Yang Ya , Moore Michael J. , Brockington Samuel F. , Walker Joseph F. , Brown Joseph W , Liang Bin , Feng Tao , Edwards Caroline , Mikenas Jessica , Olivieri Julia , Hutchison Vera , Timoneda Alfonso , Stoughton Tommy , Puente Raúl , Majure Lucas C. , Eggli Urs , Smith Stephen A. 
Published: April 2018

AbstractSeveral plant lineages have evolved adaptations that allow survival in extreme and harsh environments including many within the plant clade Portulacineae (Caryophyllales) such as the Cactaceae, Didiereaceae of Madagascar, and high altitude Montiaceae. Here, using newly generated transcriptomic data, we reconstructed the phylogeny of Portulacineae and examine potential correlates between molecular evolution within this clade and adaptation to harsh environments. Our phylogenetic results were largely congruent with previous analyses, but we identified several early diverging nodes characterized by extensive gene tree conflict. For particularly contentious nodes, we presented detailed information about the phylogenetic signal for alternative relationships. We also analyzed the frequency of gene duplications, confirmed previously identified whole genome duplications (WGD), and identified a previously unidentified WGD event within the Didiereaceae. We found that the WGD events were typically associated with shifts in climatic niche and did not find a direct association with WGDs and diversification rate shifts. Diversification shifts occurred within the Portulacaceae, Cactaceae, and Anacampserotaceae, and while these did not experience WGDs, the Cactaceae experienced extensive gene duplications. We examined gene family expansion and molecular evolutionary patterns with a focus on genes associated with environmental stress responses and found evidence for significant gene family expansion in genes with stress adaptation and clades found in extreme environments. These results provide important directions for further and deeper examination of the potential links between molecular evolutionary patterns and adaptation to harsh environments.
Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils
Authors: Grassi Luigi , Pourfarzad Farzin , Ullrich Sebastian , Merkel Angelika , Were Felipe , Pau Enrique Carrillo de Santa , Yi Guoqiang , Hiemstra Ida H , Tool Anton TJ , Mul Erik , Perner Juliane , Janssen-Megens Eva , Berentsen Kim , Kerstens Hinri , Habibi Ehsan , Gut Marta , Yaspo Marie Laure , Linser Matthias , Lowy Ernesto , Datta Avik , Clarke Laura , Flicek Paul , Vingron Martin , Roos Dirk , Berg Timo K van den , Heath Simon , Rico Daniel , Frontini Mattia , Kostadima Myrto , Gut Ivo , Valencia Alfonso , Ouwehand Willem H , Stunnenberg Hendrik G , Martens Joost HA , Kuijpers Taco W 
Published: April 2018

SummaryNeutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic and functional overview of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of epigenetic and transcriptome dynamics reveals an enforced regulation of differentiation, through cellular functions such as: release of proteases, respiratory burst, cell cycle regulation and apoptosis. We observe an early establishment of the cytotoxic capability, whilst the signaling components that activate antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the epigenetic landscape orchestrate the daily production of large number of neutrophils required for innate host defense and provide a comprehensive overview of the epigenomes of differentiating human neutrophils.Key pointsDynamic acetylation enforces human neutrophil progenitor differentiation.Neutrophils cytotoxic capability is established early at the (pro)myelocyte stage.Coordinated signaling component expression prevents unwanted toxic effects to the bone marrow niche.
Evolutionary dynamics of sex chromosomes of paleognathous birds
Authors: Xu Luohao , Sin Simon Yung Wa , Grayson Phil , Edwards Scott V. , Sackton Timothy B. 
Published: April 2018

AbstractStandard models of sex chromosome evolution propose that recombination suppression leads to the degeneration of the heterogametic chromosome, as is seen for the Y chromosome in mammals and the W chromosome in most birds. Unlike other birds, paleognaths (ratites and tinamous) possess large non-degenerate regions on their sex chromosomes (PARs or pseudoautosomal regions). It remains unclear why these large PARs are retained over more than 100 MY, and how this retention impacts the evolution of sex chromosomes within this system. To address this puzzle, we analysed Z chromosome evolution and gene expression across 12 paleognaths, several of whose genomes have recently been sequenced. We confirm at the genomic level that most paleognaths retain large PARs. As in other birds, we find that all paleognaths have incomplete dosage compensation on the regions of the Z chromosome homologous to degenerated portions of the W (differentiated regions or DRs), but we find no evidence for enrichments of male-biased genes in PARs. We find limited evidence for increased evolutionary rates (faster-Z) either across the chromosome or in DRs for most paleognaths with large PARs, but do recover signals of faster-Z evolution in tinamou species with mostly degenerated W chromosomes, similar to the pattern seen in neognaths. Unexpectedly, in some species PAR-linked genes evolve faster on average than genes on autosomes, suggested by diverse genomic features to be due to reduced efficacy of selection in paleognath PARs. Our analysis shows that paleognath Z chromosomes are atypical at the genomic level, but the evolutionary forces maintaining largely homomorphic sex chromosomes in these species remain elusive.
Auxiliary subunits keep AMPA receptors compact during activation and desensitization
Authors: Baranovic Jelena , Plested Andrew J.R. 
Published: April 2018

SummarySignal transduction at vertebrate excitatory synapses involves the activity of ionotropic glutamate receptors, including the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor. Technical advances in cryo-electron microscopy have brought a slew of full-length structures of AMPA receptors, on their own and in combination with auxiliary subunits. These structures illustrate a wide range of conformations, indicating that individual domains might undergo substantial lateral motions during gating, resulting in an open, “relaxed” extracellular layer. Here, we used bifunctional methanethiosulfonate cross-linkers to calibrate the conformations found in functional AMPA receptors both in the presence and absence of the auxiliary subunit Stargazin. Our data indicate that AMPA receptors have considerable conformational freedom and can get trapped in stable, relaxed conformations, especially upon long exposures to glutamate. In contrast, Stargazin limits this conformational flexibility. Thus, under synaptic conditions, where brief glutamate exposures and the presence of Stargazin dominate, AMPA receptors are unlikely to adopt very relaxed conformations during gating.
Lysosome enlargement during inhibition of the lipid kinase PIKfyve proceeds through lysosome coalescence
Authors: Choy Christopher H. , Saffi Golam , Gray Matthew A. , Wallace Callen , Dayam Roya M. , Ou Zhen-Yi A. , Lenk Guy , Puertollano Rosa , Watkins Simon C. , Botelho Roberto J. 
Published: April 2018

AbstractLysosomes receive and degrade cargo from endocytosis, phagocytosis and autophagy. They also play an important role in sensing and instructing cells on their metabolic state. The lipid kinase PIKfyve generates phosphatidylinositol-3,5-bisphosphate to modulate lysosome function. PIKfyve inhibition leads to impaired degradative capacity, ion dysregulation, abated autophagic flux, and a massive enlargement of lysosomes. Collectively, this leads to various physiological defects including embryonic lethality, neurodegeneration and overt inflammation. While being the most dramatic phenotype, the reasons for lysosome enlargement remain unclear. Here, we examined whether biosynthesis and/or fusion-fission dynamics contribute to swelling. First, we show that PIKfyve inhibition activates TFEB, TFE3 and MITF enhancing lysosome gene expression. However, this did not augment lysosomal protein levels during acute PIKfyve inhibition and deletion of TFEB and/or related proteins did not impair lysosome swelling. Instead, PIKfyve inhibition led to fewer but enlarged lysosomes, suggesting that an imbalance favouring lysosome fusion over fission causes lysosome enlargement. Indeed, conditions that abated fusion curtailed lysosome swelling in PIKfyve-inhibited cells.Summary statementPIKfyve inhibition causes lysosomes to coalesce, resulting in fewer, enlarged lysosomes. We also show that TFEB-mediated lysosome biosynthesis does not contribute to swelling.
In Silico Benchmarking of Metagenomic Tools for Coding Sequence Detection Reveals the Limits of Sensitivity and Precision
Authors: Golob Jonathan Louis , Minot Samuel Schwartz 
Published: April 2018

AbstractHigh-throughput sequencing can establish the functional capacity of a microbial community by cataloging the protein-coding sequences (CDS) present in the metagenome of the community. The relative performance of different computational methods for identifying CDS from whole-genome shotgun sequencing (WGS) is not fully established.Here we present an automated benchmarking workflow, using synthetic shotgun sequencing reads for which we know the true CDS content of the underlying communities, to determine the relative performance (sensitivity, positive predictive value or PPV, and computational efficiency) of different metagenome analysis tools for extracting the CDS content of a microbial community.Assembly-based methods are limited by coverage depth, with poor sensitivity for CDS at < 5X depth of sequencing, but have excellent PPV. Mapping-based techniques are more sensitive at low coverage depths, but can struggle with PPV. We additionally describe an expectation maximization based iterative algorithmic approach which we show to successfully improve the PPV of a mapping based technique while retaining improved sensitivity and computational efficiency.
Lipoprotein Signatures of Cholesteryl Ester Transfer Protein and HMG-CoA Reductase Inhibition
Authors: Kettunen Johannes , Holmes Michael V. , Allara Elias , Anufrieva Olga , Ohukainen Pauli , Oliver-Williams Clare , Tillin Therese , Hughes Alun D. , Kähönen Mika , Lehtimäki Terho , Viikari Jorma , Raitakari Olli T. , Salomaa Veikko , Järvelin Marjo-Riitta , Perola Markus , Smith George Davey , Chaturvedi Nish , Danesh John , Angelantonio Emanuele Di , Butterworth Adam S. , AlaKorpela Mika 
Published: April 2018

AbstractBackgroundCETP inhibition reduces vascular event rates but confusion surrounds its low-density lipoprotein (LDL)-cholesterol effects. We sought to clarify associations of genetic inhibition of CETP on detailed lipoproteins.Methods and ResultsWe used variants associated withCETP(rs247617) andHMGCR(rs12916) expression in 62,400 Europeans with detailed lipoprotein profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% lower risk of coronary heart disease (CHD). Associations of lipoprotein measures with risk of incident CHD in three population-based cohorts (770 cases) were examined.CETPandHMGCRhad near-identical associations with LDL-cholesterol concentration estimated by Friedewald-equation.HMGCRhad a relatively consistent effect on cholesterol concentrations across all apolipoprotein B-containing lipoproteins.CETPhad stronger effects on remnant and very-low-density lipoprotein cholesterol but no effect on cholesterol concentrations in LDL defined by particle size (diameter 18–26 nm) (-0.02SD 95%CI: -0.10, 0.05 forCETPversus -0.24SD, 95%CI -0.30, -0.18 forHMGCR).CETPhad profound effects on lipid compositions of lipoproteins, with strong reductions in the triglyceride content of all highdensity lipoprotein (HDL) particles. These alterations in triglyceride composition within HDL subclasses were observationally associated with risk of CHD, independently of total cholesterol and triglycerides (strongest HR per 1-SD higher triglyceride composition in very-large HDL 1.35; 95%CI: 1.18, 1.54).ConclusionCETP inhibition does not affect size-specific LDL cholesterol but may lower CHD risk by lowering cholesterol in other apolipoprotein-B containing lipoproteins and lowering triglyceride content of HDL particles. Conventional composite lipid assays may mask heterogeneous effects of lipid-altering therapies.
Inversion frequencies and phenotypic effects are modulated by the environment
Authors: Berdan Emma , Rosenquist Hanna , Larson Keith , Wellenreuther Maren 
Published: April 2018

AbstractUnderstanding how environmental variation drives phenotypic diversification within species is a major objective in evolutionary biology. The seaweed flyCoelopa frigidaprovides an excellent model for the study of genetically driven phenotypes because it carries an α/β inversion polymorphism that affects body size.Coelopa frigidainhabits highly variable beds of decomposing seaweed on the coast in Scandinavia thus providing a suitable test ground to investigate the genetic effects of substrate on both the frequency of the inversion (directional selection) and on the phenotype (genotype x environment effects). Here we use a reciprocal transplant experiment to test the effect of the α/β inversion on body size traits and development time across four suitable natural breeding substrates from the clinal distribution. We show that while development time is unaffected by GxE effects, both the frequency of the inversion and the relative phenotypic effects of the inversion on body size differ between population x substrate combinations. This indicates that the environment modulates the fitness as well as the phenotypic effects of the inversion karyotypes. It further suggests that the inversion may have accumulated qualitatively different mutations in different populations that interact with the environment. Together our results are consistent with the idea that the inversion inC. frigidalikely evolves via a combination of local mutation, GxE effects, and differential fitness of inversion karyotypes in heterogeneous environments.
Secondary neurulation-fated cells in the tail bud undergo self-renewal and tubulogenesis regulated by a Sox2 gradient
Authors: Kawachi Teruaki , Shimokita Eisuke , Tadokoro Ryosuke , Takahashi Yoshiko 
Published: April 2018

AbstractDuring amniote development, anterior and posterior components of the neural tube form by primary neurulation (PN) and secondary neurulation (SN), respectively. Unlike PN, SN proceeds by the mesenchymal-to-epithelial transition of SN precursors in the tail bud, a critical structure for the axial elongation. Our direct cell labeling delineates non-overlapping territories of SN- and mesodermal precursors in the chicken tail bud. SN-fated precursors are further divided into self-renewing and differentiating cells, a decision regulated by graded expression levels of Sox2. Whereas Sox2 is confined to SN precursors, Brachyury (T) is widely and uniformly distributed in the tail bud, indicating that Sox2+/Brachyury+ cells are neural-fated and not mesodermal. These results uncover multiple steps during the neural posterior elongation, including precocious segregation of SN precursors, their self-renewal, and regulation by graded Sox 2.
Target variant detection in leukemia using unaligned RNA-Seq reads
Authors: Audemard Eric Olivier , Gendron Patrick , Lavallée Vincent-Philippe , Hébert Josée , Sauvageau Guy , Lemieux Sébastien 
Published: April 2018

AbstractMutations identified in each Acute Myeloid Leukemia (AML) patients are useful for prognosis and to select targeted therapies. Detection of such mutations by the analysis of Next-Generation Sequencing (NGS) data requires a computationally intensive read mapping step and application of several variant calling methods. Targeted mutation identification drastically shifts the usual tradeoff between accuracy and performance by concentrating all computations over a small portion of sequence space. Here, we present km, an efficient approach leveraging k-mer decomposition of reads to identify targeted mutations. Our approach is versatile, as it can detect single-base mutations, several types of insertions and deletions, as well as fusions. We used two independent AML cohorts (The Cancer Genome Atlas and Leucegene), to show that mutation detection bykmis fast, accurate and mainly limited by sequencing depth. Therefore,kmallows to establish fast diagnostics from NGS data, and could be suitable for clinical applications.
Comparative Genome Analysis Reveals Important Genetic Factors Associated with Probiotic Property inEnterococcus faeciumstrains
Authors: Ghattargi Vikas C. , Gaikwad Meghana A. , Meti Bharati S. , Nimonkar Yogesh S. , Dixit Kunal , Prakash Om , Shouche Yogesh S. , Pawar Shrikant S. , Dhotre Dhiraj 
Published: April 2018

ABSTRACTEnterococcus faeciumthough commensals in human gut, few strains provide beneficial effect to humans as probiotics, few are responsible for nosocomial infection and few as non-pathogens. Comparative genomics ofE. faeciumwill help to reveal the genomic differences responsible for the said properties. In this study, we comparedE. faeciumstrain 17OM39 with a marketed probiotic, non-pathogenic non-probiotic (NPNP) and pathogenic strains. The core genome analysis revealed, 17OM39 was closely related with marketed probiotic strain T110. Strain 17OM39 was found to be devoid of known vancomycin, tetracycline resistance genes and functional virulence genes. Moreover, 17OM39 is „less open‟ due to absence of frequently found transposable elements. Genes imparting beneficial functional properties were observed to be present in marketed probiotic T110 and 17OM39 strains. Additional, genes associated with colonization within gastrointestinal tract were detected across all the strains. Beyond shared genetic features; this study particularly identified genes that are responsible to impart probiotic, non-pathogenic and pathogenic features to the strains ofE. faecium.The study also provides insights into the acquired and intrinsic drug resistance genes, which will be helpful for better understanding of the physiology of antibiotic resistance inE. faeciumstrains. In addition, we could identify genes contributing to the intrinsic ability of 17OM39E. faeciumisolate to be a potential probiotic.The study has comprehensively characterized genome sequence of each strain to find the genetic variation and understand effects of these on functionality, phenotypic complexity. Further the evolutionary relationship of species along with adaptation strategies have been including in this study.
When more is less: Dual phosphorylation protects signaling off-state against overexpression
Authors: Witzel Franziska , Blüthgen Nils 
Published: April 2018

ABSTRACTKinases in signaling pathways are commonly activated by multisite phosphorylation. For example, the mitogen-activated protein kinase Erk is activated by its kinase Mek by two consecutive phosphorylations within its activation loop. In this article, we use kinetic models to study how the activation of Erk is coupled to its abundance. Intuitively, Erk activity should rise with increasing amounts of Erk protein. However, a mathematical model shows that the signaling off-state is robust to increasing amounts of Erk, and Erk activity may even decline with increasing amounts of Erk. This counter-intuitive, bell-shaped response of Erk activity to increasing amounts of Erk arises from the competition of the unmodified and single phosphorylated form of Erk for access to its kinase Mek. This shows that phosphorylation cycles can contain an intrinsic robustness mechanism that protects signaling from aberrant activation e.g. by gene expression noise or kinase overexpression following gene duplication events in diseases like cancer.