bluuebunny/crossref_metadata_2025_split huggingface dataset:
The TIM-3 pathway ameliorates Theiler’s murine encephalomyelitis virus-induced demyelinating disease
Authors: Kaneyama Tomoki , Tomiki Hiroki , Tsugane Sayaka , Inaba Yuji , Ichikawa Motoki , Akiba Hisaya , Yagita Hideo , Kim Byung S. , Koh Chang-Sung 
Published: February 2014

AbstractInfection by Theiler’s murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-γ and IL-10 by CD4+ T cells and IFN-γ by CD8+ T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4+ T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb-treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD.
Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation
Authors: Aik WeiShen , Scotti John S. , Choi Hwanho , Gong Lingzhi , Demetriades Marina , Schofield Christopher J. , McDonough Michael A. 
Published: February 2014

Abstract
ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N6-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66–292) to 2.0 Å resolution. ALKBH566–292 has a double-stranded β-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD…H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (βIV–V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX–nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit.
Coordinated repressive chromatin-remodeling of Oct4 and Nanog genes in RA-induced differentiation of embryonic stem cells involves RIP140
Authors: Wu Cheng-Ying , Feng Xudong , Wei Li-Na 
Published: February 2014

Abstract
Maintaining pluripotency and indefinite self-renewal of embryonic stem cells requires a tight control of the expression of several key stemness factors, particularly Nanog and Oct4 transcription factors. The mammalian SWItch/Sucrose NonFermentable (SWI/SNF) complex contains Brg1 or Brm as its core subunit, along with Brg1-associated factors. Our previous studies have addressed chromatin-remodeling of the Oct4 gene locus in retinoic acid (RA)-treated embryonal carcinoma cell line P19, which involves receptor-interacting protein 140 (RIP140) for heterochromatinization on the proximal promoter region of this gene locus. However, the mechanism of RIP140 action in RA-triggered repressive chromatin-remodeling is unclear. The current study examines RA repression of the Nanog gene and compares the results with RA repression of the Oct4 gene on the chromatin level. The results show a loose nucleosome array on the Nanog gene promoter in undifferentiated embryonic stem cells. On RA treatment, the Nanog gene locus remodels specifically in the CR1 region of its proximal promoter, with the insertion of a nucleosome and compaction of this region. Further, RA induces coordinated chromatin-remodeling of both Nanog and Oct4 gene loci, which requires RA receptor-α, RIP140 and Brm. Finally, in these RA-triggered repressive chromatin-remodeling processes, lysine acetylation of RIP140 is critical for its recruiting Brm.
FALDO: A semantic standard for describing the location of nucleotide and protein feature annotation
Authors: Bolleman Jerven , Mungall Christopher J. , Strozzi Francesco , Baran Joachim , Dumontier Michel , Bonnal Raoul J. P. , Buels Robert , Hoehndorf Robert , Fujisawa Takatomo , Katayama Toshi-aki , Cock Peter J. A. 
Published: February 2014

AbstractBackgroundNucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples.DescriptionWe have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned “omics” areas. Using the same data format to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations.ConclusionsOur ontology allows users to uniformly describe – and potentially merge – sequence annotations from multiple sources. Data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores.
Predicting growth conditions from internal metabolic fluxes in anin-Silicomodel ofE. Coli
Authors: Sridhara Viswanadham , Meyer Austin G. , Rai Piyush , Barrick Jeffrey E. , Ravikumar Pradeep , Segrè Daniel , Wilke Claus O. 
Published: February 2014

AbstractA widely studied problem in systems biology is to predict bacterial phenotype from growth conditions, using mechanistic models such as flux balance analysis (FBA). However, the inverse prediction of growth conditions from phenotype is rarely considered. Here we develop a computational framework to carry out this inverse prediction on a computational model of bacterial metabolism. We use FBA to calculate bacterial phenotypes from growth conditions inE. coli, and then we assess how accurately we can predict the original growth conditions from the phenotypes. Prediction is carried out via regularized multinomial regression. Our analysis provides several important physiological and statistical insights. First, we show that by analyzing metabolic end products we can consistently predict growth conditions. Second, prediction is reliable even in the presence of small amounts of impurities. Third, flux through a relatively small number of reactions per growth source (~10) is sufficient for accurate prediction. Fourth, combining the predictions from two separate models, one trained only on carbon sources and one only on nitrogen sources, performs better than models trained to perform joint prediction. Finally, that separate predictions perform better than a more sophisticated joint prediction scheme suggests that carbon and nitrogen utilization pathways, despite jointly affecting cellular growth, may be fairly decoupled in terms of their dependence on specific assortments of molecular precursors.
Stress, heritability, tissue type and human methylome variation in mother-newborn dyads
Authors: Hughes David A. , Rodney Nicole C. , Mulligan Connie J. 
Published: February 2014

AbstractDNA methylation variation has been implicated as a factor that influences inter-individual and inter-tissue phenotypic variation in numerous organisms and under various conditions. Here, using a unique collection of three tissues, derived from 24 mother-newborn dyads from war-torn Democratic Republic of Congo, we estimate how stress, heritability, tissue type and genomic/regulatory context influence genome-wide DNA methylation. We also evaluate if stress-associated variation may mediate an observed phenotype - newborn birthweight. On average, a minimal influence of stress and heritability are observed, while in contrast extensive among tissues and context dependency is evident. However, a notable overlap in heritable and stress-associated variation is observed and that variation is commonly correlated with birthweight variation. Finally, we observe that variation outside of promoter regions, particularly in enhancers, is far more dynamic across tissues and across conditions than in promoters, suggesting that variation outside of promoters may play a larger role in expression variation than variation found within promoter regions.
Separating Active and Passive Influences on Stomatal Control of Transpiration
Authors: McAdam Scott A.M. , Brodribb Timothy J. 
Published: February 2014

Abstract
Motivated by studies suggesting that the stomata of ferns and lycophytes do not conform to the standard active abscisic acid (ABA) -mediated stomatal control model, we examined stomatal behavior in a conifer species (Metasequoia glyptostroboides) that is phylogenetically midway between the fern and angiosperm clades. Similar to ferns, daytime stomatal closure in response to moderate water stress seemed to be a passive hydraulic process in M. glyptostroboides immediately alleviated by rehydrating excised shoots. Only after prolonged exposure to more extreme water stress did active ABA-mediated stomatal closure become important, because foliar ABA production was triggered after leaf turgor loss. The influence of foliar ABA on stomatal conductance and stomatal aperture was highly predictable and additive with the passive hydraulic influence. M. glyptostroboides thus occupies a stomatal behavior type intermediate between the passively controlled ferns and the characteristic ABA-dependent stomatal closure described in angiosperm herbs. These results highlight the importance of considering phylogeny as a major determinant of stomatal behavior.
The Rice TAL Effector–Dependent Resistance Protein XA10 Triggers Cell Death and Calcium Depletion in the Endoplasmic Reticulum
Authors: Tian Dongsheng , Wang Junxia , Zeng Xuan , Gu Keyu , Qiu Chengxiang , Yang Xiaobei , Zhou Zhiyun , Goh Meiling , Luo Yanchang , Murata-Hori Maki , White Frank F. , Yin Zhongchao 
Published: February 2014

Abstract
The recognition between disease resistance (R) genes in plants and their cognate avirulence (Avr) genes in pathogens can produce a hypersensitive response of localized programmed cell death. However, our knowledge of the early signaling events of the R gene–mediated hypersensitive response in plants remains limited. Here, we report the cloning and characterization of Xa10, a transcription activator–like (TAL) effector-dependent R gene for resistance to bacterial blight in rice (Oryza sativa). Xa10 contains a binding element for the TAL effector AvrXa10 (EBE AvrXa10) in its promoter, and AvrXa10 specifically induces Xa10 expression. Expression of Xa10 induces programmed cell death in rice, Nicotiana benthamiana, and mammalian HeLa cells. The Xa10 gene product XA10 localizes as hexamers in the endoplasmic reticulum (ER) and is associated with ER Ca2+ depletion in plant and HeLa cells. XA10 variants that abolish programmed cell death and ER Ca2+ depletion in N. benthamiana and HeLa cells also abolish disease resistance in rice. We propose that XA10 is an inducible, intrinsic terminator protein that triggers programmed cell death by a conserved mechanism involving disruption of the ER and cellular Ca2+ homeostasis.
Cumulative Prospect Theory and Managerial Incentives for Fraudulent Financial Reporting
Authors: Fung Michael K. 
Published: February 2014

AbstractUsing samples of restating and nonrestating U.S. firms, the study empirically investigates the relationship between the incidence of fraudulent financial reporting and accounting‐based performance outcomes. The outcomes are framed as gains and losses relative to a reference point, defined as the mean performance of industry peers. Consistent with cumulative prospect theory (CPT), the findings show that fraud incidence is positively (negatively) related to the probability of a loss (gain); more (less) sensitive to the probability of a loss (gain) (i.e., loss‐aversion); and more (less) sensitive to an extra unit of the probability at a high‐ or low‐ (medium‐) probability level (i.e., nonlinear probability weighting function). The study extends the fraudulent financial reporting literature by formulating fraud incidence as a function of performance outcomes using peer performance as a reference point. By testing CPT's individual‐level behavioral implications on firm‐level archival data, the study reconceptualizes the investigation of fraudulent financial reporting in terms of risk attitude and extends prior investigations of CPT from laboratory experiments to a real‐world setting of fraudulent financial reporting.
Hedge Fund Intervention and Accounting Conservatism
Authors: Cheng C.S. Agnes , Huang Henry He , Li Yinghua 
Published: February 2014

AbstractHedge fund intervention has been associated with many positive corporate changes and is an important vehicle for informed shareholder monitoring. Effective monitoring has also been positively associated with accounting conservatism. Building upon these prior results, we predict an increase in accounting conservatism after hedge fund intervention. We use a large sample of hedge fund activist events and identify control firms with similar likelihoods of being targeted using the propensity score matching method to apply difference‐in‐difference tests. We find that when hedge fund activists have relatively large ownership and sufficient time to exert their monitoring power, target firms experience significant increases in conditional conservatism. CFO turnovers, upward/lateral auditor switches, and improvements in audit committee independence after intervention are accompanied by greater increases in conditional conservatism. Finally, we find greater increases in conditional conservatism when there is a lack of monitoring by dedicated institutional investors before the intervention. Our study suggests that hedge fund activists improve accounting monitoring tools and thus adds important new evidence on the effectiveness of shareholder monitoring on accounting practices.
Improving effect of Sivelestat on lipopolysaccharide‐induced lung injury in rats
Authors: Yuan Qing , Jiang Yan‐Wen , Fang Qiu‐Hong 
Published: February 2014

Sepsis causes neutrophil sequestration in the lung, which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play an important role in the pathogenesis of ALI. This study investigated whether Sivelestat, a specific NE inhibitor, can attenuate ALI induced by lipopolysaccharide (LPS). In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Sivelestat treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet‐weight to dry‐weight (W/D) ratio, immunohistochemical analysis of intercellular adhesion molecule‐1 (ICAM‐1), the number of myeloperoxidase (MPO)‐positive cells, and gene expression of ICAM‐1. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Sivelestat; nuclear factor‐κB (NF‐κB) p65 was measured by immunocytochemistry staining and Western blotting. Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, the number of MPO‐positive cells and enhanced expression of ICAM‐1 and ICAM‐1 gene. In vitro, the significant increased release of NF‐κB p65 and its subsequent translocation into the nucleus in PMVECs. In contrast, Sivelestat treatment significantly ameliorated the LPS‐induced lung injury, as judged by the marked improvement in all these indices. These results indicated that inhibition of NE attenuated LPS‐induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on NE.
Time until first dental caries for young children first seen in Federally Qualified Health Centers: a retrospective cohort study
Authors: Kuthy Raymond A. , Jones Michael , Kavand Golnaz , Momany Elizabeth , Askelson Natoshia , Chi Donald , Wehby George , Damiano Peter 
Published: February 2014

AbstractObjectivesThe study assessed the time until first dental caries for young children seen at five Federally Qualified Health Centers (FQHC) in Iowa and the relationship with the frequency and gaps (in months) of dental episodes, the number of topical fluoride treatments, and the number of dentists caring for the subject.MethodsForty children were randomly selected at each FQHC (n = 200). All children were continuously enrolled in the Medicaid program and had their first dental visit prior to age 6. Dental chart findings, claims data for the child and family, and birth certificate information were merged into one dataset. Dental visits were followed for a minimum of 36 months, including dental visits external to the FQHCs. Using time until first caries as the dependent variable, the data were subject to left, interval, and right censoring and were analyzed via Weibull regression.ResultsSlightly more than half of the 200 children experienced caries. Regression analysis indicated that the hazard of first dental caries increased by approximately 2% with each additional month that transpired between preventive recall examinations. In addition, children with older siblings who had a dental visit at the same center during the previous year prior to the subject's first visit were more likely to have a longer time until first dental caries.ConclusionsTiming of dental care episodes was associated with caries experience in young children from low income families. Dental professionals should focus on regularity of dental care to prevent or delay caries experience in young children.
AJAP1 is Dysregulated at an Early Stage of Gliomagenesis and Suppresses Invasion Through Cytoskeleton Reorganization
Authors: Han Lei , Zhang Kai‐Liang , Zhang Jun‐Xia , Zeng Liang , Di Chun‐Hui , Fee Brian E. , Rivas Miriam , Bao Zhao‐Shi , Jiang Tao , Bigner Darrell , Kang Chun‐Sheng , Adamson David Cory 
Published: February 2014

SummaryAimsDown‐regulation of AJAP1 in glioblastoma multiforme (GBM) has been reported. However, the expression profiles of AJAP1 in gliomas and the underlying mechanisms of AJAP1 function on invasion are still poorly understood.MethodsThe gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 overexpression in GBM cell lines, cellular polarity, cytoskeleton distribution, and antitumor effect were investigated in vitro and in vivo.ResultsAJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low‐grade gliomas and AJAP1‐overexpressing GBM cells, but difficult to assess in high‐grade gliomas due to its absence. AJAP1 overexpression altered the cytoskeleton and cellular polarity in vitro and inhibited the tumor growth in vivo.ConclusionsAJAP1 is dysregulated at an early stage of gliomagenesis and may suppress glioma cell invasion and proliferation, which suggests that AJAP1 may be a potential diagnostic and prognostic marker for gliomas.
Critically endangered island endemic or peripheral population of a widespread species? Conservation genetics ofKikuchi's gecko and the global challenge of protecting peripheral oceanic island endemic vertebrates
Authors: Siler Cameron D. , Oaks Jamie R. , Cobb Kerry , Ota Hidetoshi , Brown Rafe M. 
Published: February 2014

AbstractAimTo highlight the significant conservation challenge of evaluating peripheral endemic vertebrates in island archipelago systems and to assess empirically the complexities of approaches to conservation genetic studies across political and biogeographic boundaries. To demonstrate the poignant need for international collaboration and coordination when species delimitation problems with high conservation concern involve island endemics with biogeographically peripheral ranges.LocationSoutheastAsia,LanyuIsland,Taiwan, and thePhilippines.MethodsGenetic samples were collected and sequenced for one mitochondrial gene and five nuclear loci for species of theGekko mindorensis‐G. kikuchiispecies complex in Southeast Asia. We used maximum likelihood andBayesian phylogenetic methods and coalescent‐based species delimitation analyses to estimate phylogeographic relationships, construct multilocus haplotype networks and test putative species boundaries.ResultsPhylogenetic and population genetic analyses suggest thatKikuchi'sGecko may represent a peripheral population of a widespread species distributed from the northern Philippines to Taiwan. However, we identify a discrepancy between inferences of species boundaries resulting from methods based on allele frequencies versus coalescent‐based methods that incorporate evolutionary history. Coalescent‐based analyses suggest thatG. kikuchiimay be a distinct evolutionary lineage. Our study underscores the need for coalescent‐based methods in conjunction with population genetic approaches for conservation genetic assessments of widespread species.Main conclusionsThis study joins a few recent works suggesting thatPhilippine‐derived anomalies in the fauna ofLanyu (and possibly greaterTaiwan) are worthy of careful reconsideration. Determining whether each is the result of recent human‐mediated introduction or (possibly more ancient) natural dispersal should be the goal of future studies on this seldom‐conceived biogeographic relationship. Isolated species endemic to islands on the outer periphery of biogeographic and political regions represent particular conservation challenges. This is especially true if a species occurs on an isolated island that is allied biogeographically with one nation, but politically administered by another.