bluuebunny/crossref_metadata_2025_split huggingface dataset:
FunSPU: a versatile and adaptive multiple functional annotation-based association test of whole-genome sequencing data
Authors: Ma Yiding , Wei Peng 
Published: June 2018

AbstractDespite ongoing large-scale population-based whole-genome sequencing (WGS) projects such as the NIH NHLBI TOPMed program and the NHGRI Genome Sequencing Program, WGS-based association analysis of complex traits remains a tremendous challenge due to the large number of rare variants, many of which are non-trait-associated neutral variants. External biological knowledge, such as functional annotations based on ENCODE, may be helpful in distinguishing causal rare variants from neutral ones; however, each functional annotation can only provide certain aspects of the biological functions. Our knowledge for selecting informative annotations a priori is limited, and incorporating non-informative annotations will introduce noise and lose power. We propose FunSPU, a versatile and adaptive test that incorporates multiple biological annotations and is adaptive at both the annotation and variant levels and thus maintains high power even in the presence of noninformative annotations. In addition to extensive simulations, we illustrate our proposed test using the TWINSUK cohort (n=1,752) of UK10K WGS data based on six functional annotations: CADD, RegulomeDB, FunSeq, Funseq2, GERP++, and GenoSkyline. We identified genome-wide significant genetic loci on chromosome 19 near gene TOMM40 and APOC4-APOC2 associated with low-density lipoprotein (LDL), which are replicated in the UK10K ALSPAC cohort (n=1,497). These replicated LDL-associated loci were missed by existing rare variant association tests that either ignore external biological information or rely on a single source of biological knowledge. We have implemented the proposed test in an R package “FunSPU”.
Ultra-Rapid Serial Visual Presentation Reveals Dynamics of Feedforward and Feedback Processes in the Ventral Visual Pathway
Authors: Mohsenzadeh Yalda , Qin Sheng , Cichy Radoslaw M , Pantazis Dimitrios 
Published: June 2018

ABSTRACTHuman visual recognition activates a dense network of overlapping feedforward and recurrent neuronal processes, making it hard to disentangle processing in the feedforward from the feedback direction. Here, we used ultra-rapid serial visual presentation to suppress sustained activity that blurs the boundaries of processing steps, enabling us to resolve two distinct stages of processing with MEG multivariate pattern classification. The first processing stage was the rapid activation cascade of the bottom-up sweep, which terminated early as visual stimuli were presented at progressively faster rates. The second stage was the emergence of categorical information with peak latency that shifted later in time with progressively faster stimulus presentations, indexing time-consuming recurrent processing. Using MEG-fMRI fusion with representational similarity, we localized recurrent signals in early visual cortex. Together, our findings segregated an initial bottom-up sweep from subsequent feedback processing, and revealed the neural signature of increased recurrent processing demands for challenging viewing conditions.
MGDrivE: A modular simulation framework for the spread of gene drives through spatially-explicit mosquito populations
Authors: Sánchez C. Héctor M. , Wu Sean L. , Bennett Jared B. , Marshall John M. 
Published: June 2018

AbstractMalaria, dengue, Zika, and other mosquito-borne diseases continue to pose a major global health burden through much of the world, despite the widespread distribution of insecticide-based tools and antimalarial drugs. The advent of CRISPR/Cas9-based gene editing and its demonstrated ability to streamline the development of gene drive systems has reignited interest in the application of this technology to the control of mosquitoes and the diseases they transmit. The versatility of this technology has also enabled a wide range of gene drive architectures to be realized, creating a need for their population-level and spatial dynamics to be explored. To this end, we present MGDrivE (Mosquito Gene Drive Explorer): a simulation framework designed to investigate the population dynamics of a variety of gene drive architectures and their spread through spatially-explicit mosquito populations. A key strength of the MGDrivE framework is its modularity: a) a genetic inheritance module accommodates the dynamics of gene drive systems displaying user-defined inheritance patterns, b) a population dynamic module accommodates the life history of a variety of mosquito disease vectors and insect agricultural pest species, and c) a landscape module accommodates the distribution of insect metapopulations connected by migration in space. Example MGDrivE simulations are presented to demonstrate the application of the framework to CRISPR/Cas9-based homing gene drive for: a) driving a disease-refractory gene into a population (i.e. population replacement), and b) disrupting a gene required for female fertility (i.e. population suppression), incorporating homing-resistant alleles in both cases. We compare MGDrivE with other genetic simulation packages, and conclude with a discussion of future directions in gene drive modeling.
Single cell RNAseq provides a molecular and cellular cartography of changes to the human endometrium through the menstrual cycle
Authors: Wang Wanxin , Vilella Felipe , Alama Pilar , Moreno Inmaculada , Mignardi Marco , Pan Wenying , Simon Carlos , Quake Stephen R. 
Published: June 2018

SummaryIn a human menstrual cycle, the endometrium undergoes remodeling, shedding, and regeneration, all of which are driven by substantial gene expression changes in the underlying cellular hierarchy. Despite its importance in human fertility and regenerative biology, mechanistic understanding of this unique type of tissue homeostasis remains rudimentary. We characterized the transcriptomic transformation of human endometrium at single cell resolution, dissecting the multidimensional cellular heterogeneity of this tissue across the entire natural menstrual cycle. We profiled the behavior of 6 endometrial cell types, including a previously uncharacterized ciliated epithelial cell type, during four major phases of endometrial transformation, and found characteristic signatures for each cell type and phase. We discovered that human window of implantation opens with an abrupt and discontinuous transcriptomic activation in the epithelia, accompanied with widespread decidualized feature in the stromal fibroblasts. These data reveal signatures in the luminal and glandular epithelia during epithelial gland reconstruction, and suggest a mechanism for adult gland formation.
Identification of Klebsiella pneumoniae complex members using MALDI-TOF mass spectrometry
Authors: Rodrigues Carla , Passet Virginie , Brisse Sylvain 
Published: June 2018

ABSTRACTKlebsiella pneumoniae (phylogroup Kp1), one of the most problematic pathogens associated with antibiotic resistance worldwide, is phylogenetically closely related to K. quasipneumoniae [subsp. quasipneumoniae (Kp2) and subsp. similipneumoniae (Kp4)], K. variicola (Kp3) and two unnamed phylogroups (Kp5 and Kp6). Together, Kp1 to Kp6 make-up the K. pneumoniae complex. Currently, the phylogroups can be reliably identified only by gene sequencing. Misidentification using standard methods is common and the clinical significance of K. pneumoniae complex members is therefore imprecisely defined. Here, we evaluated the potential of MALDI-TOF mass spectrometry to discriminate K. pneumoniae complex members. We report for the first time the existence of mass spectrometry biomarkers associated with the phylogroups, with a sensitivity and specificity ranging between 80-100% and 97-100%, respectively. Strains within phylogroups Kp1, Kp2, Kp4 and Kp5 each shared two specific peaks not observed in other phylogroups. Kp3 strains shared a peak that was only observed otherwise in Kp5. Finally, Kp6 had a diagnostic peak shared only with Kp1. Kp3 and Kp6 could therefore be identified by exclusion criteria (lacking Kp5 and Kp1-specific peaks, respectively). Further, ranked Pearson correlation clustering of spectra grouped strains according to their phylogroup. These results call for incorporation of spectra of all K. pneumoniae complex members into reference MALDI-TOF spectra databases, in which they are currently lacking. This advance may allow for simple and precise identification of K. pneumoniae and closely related species, opening the way to a better understanding of their epidemiology, ecology and pathogenesis.
The Histone H3-H4 Tetramer is a Copper Reductase Enzyme
Authors: Attar Narsis , Campos Oscar A. , Vogelauer Maria , Cheng Chen , Xue Yong , Schmollinger Stefan , Mallipeddi Nathan V. , Boone Brandon A. , Yen Linda , Yang Sichen , Zikovich Shannon , Dardine Jade , Carey Michael F. , Merchant Sabeeha S. , Kurdistani Siavash K. 
Published: June 2018

AbstractAncestral histones were present in organisms with small genomes, no nucleus, and little evidence for epigenetic regulation, suggesting histones may have additional older functions. We report that the histone H3-H4 tetramer is an enzyme that catalyzes the reduction of Cu2+to Cu1+when assembledin vitrofrom recombinant histones. Mutations of residues in the putative active site at the interface of the apposing H3 proteins alter the enzymatic activity and cellular processes such as Sod1 function or mitochondrial respiration that depend on availability of reduced copper. These effects are not due to altered gene expression or copper abundance but are consistent with decreased levels of cuprous ions. We propose that the H3-H4 tetramer is an oxidoreductase that provides biousable copper for cellular and mitochondrial chemistry. As the emergence of eukaryotes coincided with the Great Oxidation Event and decreased biousability of metals, the histone enzymatic function may have facilitated eukaryogenesis.
Targeting integrin alpha5 receptor in pancreatic stellate cells to diminish tumor-promoting effects in pancreatic cancer
Authors: Kuninty Praneeth R. , Bansal Ruchi , De Geus Sanne W.L. , Schnittert Jonas , van Baarlen Joop , Storm Gert , Bijlsma Maarten F. , van Laarhoven Hanneke W. , Kuppen Peter J.K. , Vahrmeijer Alexander L. , Östman Arne , Sier Cornelis F.M. , Prakash Jai 
Published: June 2018

AbstractPancreatic stellate cells (PSCs) are the main precursors of cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC), known to induce cancer aggressiveness. Integrin alpha5 (ITGA5), a fibronectin receptor, was found to be overexpressed by CAFs in stroma and linked to poor overall survival (log-rank p=0.022, n=137) of patients with PDAC. In vitro, knockdown of ITGA5 in human PSCs (hPSCs) inhibited their adhesion, migration, and proliferation and also inhibited TGF-β-mediated differentiation. In vivo, co-injection of PANC-1 tumor cells and hPSCs (sh-ITGA5) developed tumors with reduced fibrosis and slower growth rate compared to those composed of PANC-1 and hPSC (sh-Ctrl). Furthermore, we developed a ITGA5-antagonizing peptidomimetic (AV3) which inhibited TGFβ-mediated hPSC differentiation by blocking ITGA5/FAK pathway. In vivo, treatment with AV3 intraperitoneally attenuated tumor fibrosis and thereby enhanced the efficacy of gemcitabine in patient-derived xenografts in mice. Altogether, this study reports the therapeutic importance of ITGA5 in PDAC and provides novel therapeutic peptidomimetic to enhance the effect of chemotherapy.
17-(Allylamino)-17demethoxygeldanamycin reduces Endoplasmic Reticulum (ER) stress-induced mitochondrial dysfunction in C2C12 myotubes
Authors: Lightfoot Adam P. , Morgan Rhiannon S. , Parkes Joanna E. , Thoma Anastasia , Iwanejko Lesley A. , Cooper Robert G. 
Published: June 2018

AbstractIn patients with myositis, persistent skeletal muscle weakness in the absence of significant inflammatory cell infiltrates is a well-recognised, but poorly understood, cause of morbidity. This has led researchers to investigate cellular mechanisms independent of immune cells, which may contribute to this underlying muscle weakness. Chronic ER stress pathway activation is evident in the muscle of myositis patients, and is now a potential mediator of muscle weakness in the absence of inflammation. Abnormal ER stress pathway activation is associated with mitochondrial dysfunction, resulting in bioenergetic deficits and reactive oxygen species (ROS) generation, which in this context may potentially damage muscle proteins and thus impair contractile performance. This study examined whether treatment with the HSP90 inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17AAG) could mitigate these ER stress-induced changes. C2C12 myotubes were treated with the ER stress-inducing compound Tunicamycin, in the presence or absence of 17AAG. Myotubes were examined for changes relating to ER stress pathway activation, mitochondrial function, markers of oxidative damage and in myotubular dimensions. ER stress pathway activation caused mitochondrial dysfunction, as evidenced by reduced oxygen consumption and ATP generation and by increased gene expression levels of the bio-energetic regulator, uncoupling protein 3 (UCP-3), the latter indicative of electron transport chain uncoupling. ER stress pathway activation also caused increased gene expression of superoxide dismutase (SOD) 2 and peroxiredoxin (PRDX) 3, elevated H2O2 levels, and reduced total thiol pool levels and a significant diminution of myotubular dimensions. Exposure to 17AAG ameliorated these ER stress-induced changes. These findings, which suggest that 17AAG can reduce ER stress-induced mitochondrial dysfunction, oxidative damage and myotubular atrophy, have potential implications in the context of human myositis.
A new cancer-testis long noncoding RNA, the OTP-AS1 RNA
Authors: Karnaukhova Iuliia K. , Polev Dmitrii E. , Krukovskaya Larisa L. , Masharsky Alexey E. , Nazarenko Olga V. , Makashov Andrei A. , Kozlov Andrei P. 
Published: June 2018

AbstractOrthopedia homeobox (OTP) gene encodes a homeodomain-containing transcription factor involved in brain development.OTPis mapped to human chromosome 5q14.1. Earlier we described transcription in the second intron of this gene in wide variety of tumors, but among normal tissues only in testis. In GeneBank these transcripts are presented by several 300-400 nucleotides long AI267901-like ESTs.We assumed that AI267901-like ESTs belong to longer transcript(s). We used the Rapid Amplification of cDNA Ends (RACE) approach and other methods to find the full-length transcript. The found transcript was 2436 nucleotides long polyadenylated sequence in antisense toOTPgene. The corresponding gene consisted of two exons separated by an intron of 2961 bp long. The first exon was found to be 91 bp long and located in the third exon ofOTPgene. The second exon was 2345bp long and located in the second intron ofOTPgene.The search of possible open reading frames (ORFs) showed the lack of significant ORFs. We have shown the expression of new gene in many human tumors and only in one sampled normal testis. The data suggest that we discovered a new antisense cancer-testis sequenceOTP-AS1(OTP- antisense RNA 1), which belongs to long noncoding RNAs (lncRNAs). According to our findings we assume thatOTP-AS1andOTPgenes may be the CT-coding gene/CT-ncRNA pair involved in regulatory interactions.Author summaryPreviously, long non-coding RNAs (lncRNAs) were considered as genetic “noise”. However, it was later shown that only 2% of genomic transcripts have a protein-coding ability. Non-coding RNA is divided into short non-coding RNAs (20-200 nucleotides) and long noncoding RNAs (200-100,000 nucleotides). Genes encoding lncRNA often overlap or are adjacent to protein-coding genes, and localization of this kind is beneficial in order to regulate the transcription of neighboring genes. Studies have shown that of lncRNAs play many roles in the regulation of gene expression. New evidence indicates that dysfunctions of lncRNAs are associated with human diseases and cancer.In our study we found a new cancer-testis long noncoding RNA (OTP-AS1), which is an antisense of protein-coding cancer-testis gene (OTP). Thus,OTP-AS1andOTPgenes may be the CT-coding gene/CT-ncRNA pair involved in regulatory interactions. This is supported by the similar profile of their expression.OTP-AS1may be of interest as a potential diagnostic marker of cancer or a potential target for cancer therapy.Part ofOTP-AS1gene (5’-end of the second exon) is evolutionary younger than the rest of gene sequence and is less conservative. This linksOTP-AS1gene with so-called TSEEN (tumor-specifically expressed, evolutionary novel) genes described by the authors in previous papers.
SpoT and GppA hydrolases prevent the gratuitous activation of RelA by pppGpp inEscherichia coli
Authors: Sanyal Rajeshree , Harinarayanan Rajendran 
Published: June 2018

SummaryStringent response, a conserved regulation seen in bacteria, is effected through the modified nucleotides (p)ppGpp. The metabolic cycle of these molecules is driven by the synthase activity of RelA and SpoT and the hydrolase activity of SpoT and GppA which together sets the basal (p)ppGpp pool. Growth arrest due to (p)ppGpp accumulation from basal RelA activity apparently explained the essentiality of SpoT hydrolase function. We found, pppGpp degradation was enhanced when the SpoT hydrolase activity was lowered or eliminated and when this was alleviated by inactivation of the GppA hydrolase, gratuitous synthesis of (p)ppGpp by RelA was activated, leading to growth arrest. The RelA-ribosome interaction was not mandatory for these phenotypes. Our results show, for the first time, elevated pppGpp promoted the amplification of RelA-mediated stringent response in the absence of established RelA activating signals in the cell and the SpoT and GppA hydrolases prevented this. The accumulation of pppGpp inhibited the SpoT hydrolase activity. We propose this autocatalytic activation of RelA by pppGpp is likely to be an allosteric regulation and can result in a bistable switch.
Single-cell ID-seq identifies BMP signaling as a driver of a late stage epidermal differentiation program
Authors: van Eijl Roderick E. , van Buggenum Jessie A.G. , Tanis Sabine E.J. , Hendriks Joost , Mulder Klaas W. 
Published: June 2018

AbstractEpidermal homeostasis requires balanced and coordinated adult stem cell renewal and differentiation. These processes are controlled by both extracellular signaling and by cell intrinsic transcription regulatory networks, yet how these control mechanisms are integrated to achieve this unclear. Here, we developed single-cell ID-seq and measured 69 antibody-DNA conjugates (including 34 phospho-specific epitopes) to study the activation state of signaling pathways during epidermal differentiation at the single-cell level. Computational pseudo-timing inference revealed activation of the JAK-STAT, WNT and BMP pathways along the epidermal differentiation trajectory. During differentiation, cells start producing BMP2 ligands and activate the canonical intracellular effectors SMAD1/5/9. Mechanistically, the BMP pathway is responsible for directly activating a specific transcription program that includes the key differentiation transcription factors MAF and MAFB to allow terminal differentiation. We propose that incorporating autocrine signaling pathway activation into a transcription regulatory network enables regional coordination of transcription programs during epidermal differentiation.
Biophysical insights into a highly selective L-arginine-binding lipoprotein of a pathogenic treponeme
Authors: Deka Ranjit K. , Liu Wei Z. , Tso Shih-Chia , Norgard Michael V. , Brautigam Chad A. 
Published: June 2018

ABSTRACTBiophysical and biochemical studies on the lipoproteins and other periplasmic proteins from the spirochetal speciesTreponema pallidumhave yielded numerous insights into the functioning of the organism’s peculiar membrane organization, its nutritional requirements, and intermediary metabolism. However, not allT. pallidumproteins have proven to be amenable to biophysical studies. One such recalcitrant protein is Tp0309, a putative polar-amino-acid-binding protein of an ABC transporter system. To gain further information on its possible function, a homolog of the protein from the related speciesT. vincentiiwas used as a surrogate. This protein, Tv2483, was crystallized, resulting in the determination of its crystal structure at a resolution of 1.75 Å. The protein has a typical fold for a ligand-binding protein, and a single molecule of L-arginine was bound between its two lobes. Differential scanning fluorimetry and isothermal titration calorimetry experiments confirmed that L-arginine bound to the protein with unusually high selectivity. However, further comparison to Tp0309 showed differences in key amino-acid-binding residues may impart an alternate specificity for theT. pallidumprotein.
M4Au12Ag32(p-MBA)30(M= Na, Cs) bimetallic monolayer-protected clusters: synthesis and structure
Authors: Conn Brian E. , Bhattarai Badri , Atnagulov Aydar , Yoon Bokwon , Landman Uzi , Bigioni Terry P. 
Published: June 2018

Crystals ofM4Au12Ag32(p-MBA)30bimetallic monolayer-protected clusters (MPCs), wherep-MBA isp-mercaptobenzoic acid andM+is a counter-cation (M = Na, Cs) have been grown and their structure determined. The molecular structure of triacontakis[(4-carboxylatophenyl)sulfanido]dodecagolddotriacontasilver, Au12Ag32(C7H5O2S)30or C210H150Ag32Au12O60S30, exhibits point group symmetry 3 at 100 K. The overall diameter of the MPC is approximately 28 Å, while the diameter of the Au12Ag20metallic core is 9 Å. The structure displays ligand bundling and intermolecular hydrogen bonding, which gives rise to a framework structure with 52% solvent-filled void space. The positions of theM+cations and the DMF solvent molecules within the void space of the crystal could not be determined. Three out of the five crystallographically independent ligands in the asymmetric unit cell are disordered over two sets of sites. Comparisons are made to the all-silverM4Ag44(p-MBA)30MPCs and to expectations based on density functional theory.
Thirty years of Accounting, Auditing and Accountability Journal
Authors: Dumay John , de Villiers Charl , Guthrie James , Hsiao Pei-Chi 
Published: June 2018

Purpose
The purpose of this paper is to analyse the highly cited articles published in Accounting, Auditing and Accountability Journal (AAAJ), since its inception, to answer three research questions: first, how have scholarly articles published in AAAJ developed? second, what are the focus areas and characteristics of articles in AAAJ, and who are the influential authors? third, who are the emerging next generation scholars and what are the emerging research themes in AAAJ?

Design/methodology/approach
A structured literature review (SLR) was used to analyse 126 most cited classic AAAJ articles and 21 additional emerging articles published between 1988 and 2016. Traditional literature reviews can have varied results because of a lack of rigour. The SLR method allows for an examination in detail of the articles, authors, focus areas and pattern of AAAJ publishing over three decades.

Findings
The findings show increased diversity in more recent years in theories, methods, origins, focus areas, and where AAAJ articles are cited, which highlights that the interdisciplinary accounting research project is maturing and remaining true to the ideal of being inclusive.

Research limitations/implications
Within this diversity, the analyses show that AAAJ remains focussed on and presents opportunities for impactful accounting research related to social issues, including non-financial corporate reporting/disclosure, public sector accounting, corporate governance and alternative forms of accounting, audit and accountability. Additionally, there is a need for more practice-based research to address the “wicked” problems at the intersection between accounting and society.

Originality/value
This paper presents accounting researchers with an opportunity to develop insightful and publishable studies. Also, it serves as a basis for developing future research agendas in the interdisciplinary accounting field.