bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-dependent changes in transcription factor FOXO targeting in Drosophila melanogaster
Authors: Birnbaum Allison , Wu Xiaofen , Tatar Marc , Liu Nan , Bai Hua 
Published: October 2018

SummaryFOXO transcription factors have long been associated with longevity control and tissue homeostasis. Although the transcriptional regulation of FOXO have been previously characterized (especially in long-lived insulin mutants and under stress conditions), how normal aging impacts the transcriptional activity of FOXO is poorly understood. Here, we conducted a chromatin immunoprecipitation sequencing (ChIP-Seq) analysis in both young and old wild-type fruit flies, Drosophila melanogaster, to evaluate the dynamics of FOXO gene targeting during aging. Intriguingly, the number of FOXO-bound genes dramatically decreases with age (from 2617 to 224). Consistent to the reduction of FOXO binding activity, many genes targeted by FOXO in young flies are transcriptionally altered with age, either up-regulated (FOXO-repressing genes) or down-regulated (FOXO-activating genes). In addition, we show that many FOXO-bound genes in wild-type flies are unique from those in insulin receptor substrate chico mutants. Distinct from chico mutants, FOXO targets specific cellular processes (e.g., actin cytoskeleton) and signaling pathways (e.g., Hippo, MAPK) in young wild-type flies. FOXO targeting on these pathways decreases with age. Interestingly, FOXO targets in old flies are enriched in cellular processes like chromatin organization and nucleosome assembly. Furthermore, FOXO binding to core histone genes is well maintained at aged flies. Together, our findings provide new insights into dynamic FOXO targeting under normal aging and highlight the diverse and understudied regulatory mechanisms for FOXO transcriptional activity.
Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies
Authors: Rajendran Pradeep S. , Challis Rosemary C. , Fowlkes Charless C. , Hanna Peter , Tompkins John D. , Jordan Maria C. , Hiyari Sarah , Gabris-Weber Beth A. , Greenbaum Alon , Chan Ken Y. , Deverman Benjamin E. , Münzberg Heike , Ardell Jeffrey L. , Salama Guy , Gradinaru Viviana , Shivkumar Kalyanam 
Published: October 2018

AbstractHeart rate is under the precise control of the autonomic nervous system. However, the wiring of peripheral neural circuits that regulate heart rate is poorly understood. Here, we developed a clearing-imaging-analysis pipeline to visualize innervation of intact hearts in 3D and employed a multi-technique approach to map parasympathetic and sympathetic neural circuits that control heart rate in mice. We anatomically and functionally identify cholinergic neurons and noradrenergic neurons in an intrinsic cardiac ganglion and the stellate ganglia, respectively, that project to the sinoatrial node. We also report that the heart rate response to optogenetic versus electrical stimulation of the vagus nerve displays different temporal characteristics and that vagal afferents enhance parasympathetic and reduce sympathetic tone to the heart via central mechanisms. Our findings provide new insights into neural regulation of heart rate, and our methodology to study cardiac circuits can be readily used to interrogate neural control of other visceral organs.
City-wide metagenomics uncover antibiotic resistance reservoirs in urban beach and sewage waters
Authors: Fresia Pablo , Antelo Verónica , Salazar Cecilia , Giménez Matías , D’Alessandro Bruno , Afshinnekoo Ebrahim , Mason Christopher , Gonnet Gastón H , Iraola Gregorio 
Published: October 2018

AbstractBackgroundMicrobial communities present in environmental waters constitute a reservoir for antibiotic-resistant pathogens that impact human health. For this reason a diverse variety of water environments are being analyzed using metagenomics to uncover public health threats. However, the composition of these communities along the coastal environment of a whole city where sewage and beach waters are mixed, is poorly understood.ResultsWe shotgun-sequenced 20 coastal areas from the city of Montevideo (capital of Uruguay) including beach and sewage water samples to characterize bacterial communities and their virulence and antibiotic resistance repertories. We found that sewage and beach environments presented significantly different bacterial communities. Sewage waters harbored a higher prevalence and a more diverse repertory of virulence and antibiotic resistant genes mainly from well-known enterobacteria, including carbapenemases and extended-spectrum betalactamases reported in hospital infections in Montevideo. Additionally, we were able to genotype the presence of both globally-disseminated pathogenic clones as well as emerging antibiotic-resistant bacteria in sewage waters.ConclusionsOur study represents the first in using metagenomics to jointly analyze beaches and the sewage system from an entire city, allowing us to characterize antibiotic-resistant pathogens circulating in urban waters. The data generated in this initial study represent a baseline metagenomic exploration to guide future longitudinal (time-wise) studies, whose systematic implementation will provide useful epidemiological information to improve public health surveillance.
Inference of tumor cell-specific transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection of cancer
Authors: Ulz Peter , Perakis Samantha , Zhou Qing , Moser Tina , Belic Jelena , Lazzeri Isaac , Wölfler Albert , Zebisch Armin , Gerger Armin , Pristauz Gunda , Petru Edgar , White Brandon , Roberts Charles E.S. , St. John John , Schimek Michael G. , Geigl Jochen B. , Bauernhofer Thomas , Sill Heinz , Bock Christoph , Heitzer Ellen , Speicher Michael R. 
Published: October 2018

AbstractDeregulation of transcription factors (TFs) is an important driver of tumorigenesis. We developed and validated a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyzed whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a newly developed bioinformatics pipeline that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observed patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of early detection of colorectal carcinomas. Our approach for mapping tumor-specific transcription factor bindingin vivobased on blood samples makes a key part of the noncoding genome amenable to clinical analysis.
The Molecular Basis of Monopolin Recruitment to the Kinetochore
Authors: Plowman Rebecca , Singh Namit , Payan Angel , Duro Eris , Corbett Kevin D. , Marston Adele L. 
Published: October 2018

AbstractIn budding yeast meiosis I, the kinetochores of each sister chromatid pair are fused by the monopolin complex to mediate their monoorientation on the meiosis I spindle, enabling the biorientation and segregation of homologs. Monopolin forms a V-shaped complex with binding sites for the kinetochore protein Dsn1 at the apices of the V, suggesting that monopolin forms a physical bridge between the two sister kinetochores. Here, we reveal the molecular basis of the monopolin-kinetochore interaction and identify the key interfaces required for monopolin function at the kinetochore. The disordered N-terminus of budding-yeast Dsn1 unexpectedly possesses two binding motifs for the monopolin subunit Csm1, encompassing the previously-identified “Box 1” and “Box 2-3” regions of Dsn1. Strikingly, Dsn1 Box 1 and Box 2-3 bind the same conserved hydrophobic cavity on the monopolin complex subunit Csm1, suggesting that they are mutually exclusive for Csm1 binding, yet both regions are critical for monopolin function in Saccharomyces cerevisiae meiosis I. We find that Dsn1 Box 1 is an ancestral monopolin-binding motif that is conserved throughout fungi, including in the fission yeast Schizosaccharomyces pombe. In contrast, Box 2-3 is found only in species with sequence-defined point centromeres (S. cerevisiae and its close relatives), suggesting that this region contributes specifically to sister kinetochore crosslinking in meiosis I. Finally, we propose that phosphorylation of two conserved serine residues in Box 3 may stabilize monopolin at the kinetochore, providing a potential mechanism for enforcing specific sister kinetochore crosslinking in meiosis I.
Nanopore sequencing enables high-resolution analysis of resistance determinants and mobile elements in the human gut microbiome
Authors: Bertrand Denis , Shaw Jim , Kalathiappan Manesh , Hui Qi Ng Amanda , Muthiah Senthil , Li Chenhao , Dvornicic Mirta , Soldo Janja Paliska , Koh Jia Yu , Tek Ng Oon , Barkham Timothy , Young Barnaby , Marimuthu Kalisvar , Rei Chng Kern , Sikic Mile , Nagarajan Niranjan 
Published: October 2018

AbstractThe analysis of information rich whole-metagenome datasets acquired from complex microbial communities is often restricted by the fragmented nature of assembly from short-read sequencing. The availability of long-reads from third-generation sequencing technologies (e.g. PacBio or Oxford Nanopore) can help improve assembly quality in principle, but high error rates and low throughput have limited their application in metagenomics. In this work, we describe the first hybrid metagenomic assembler which combines the advantages of short and long-read technologies, providing an order of magnitude improvement in contiguity compared to short read assemblies, and high base-pair level accuracy. The proposed approach (OPERA-MS) integrates a novel assembly-based metagenome clustering technique with an exact scaffolding algorithm that can efficiently assemble repeat rich sequences. Based on evaluations with defined in vitro communities and virtual gut microbiomes, we show that it is possible to assemble near complete genomes from metagenomes with as little as 9× long read coverage, thus enabling high quality assembly of lowly abundant species (<1%). Furthermore, OPERA-MS’s fine-grained clustering is able to deconvolute and assemble multiple genomes of the same species in a single sample, allowing us to study the complex dynamics of the human microbiome at the sub-species level. Applying nanopore sequencing to gut metagenomes of patients undergoing antibiotic treatment, we show that long reads can be obtained from stool samples in clinical studies to produce more meaningful metagenomic assemblies (up to 200× improvement over short-read assemblies), including the closed assembly of >80 putative plasmid/phage sequences and a 263kbp jumbo phage. Our results highlight that high-quality hybrid assemblies provide an unprecedented view of the gut resistome in these patients, including strain dynamics and identification of novel plasmid sequences.
Autistic traits, resting-state connectivity and absolute pitch in professional musicians: shared and distinct neural features
Authors: Wenhart T. , Bethlehem R.A.I. , Baron-Cohen S. , Altenmüller E. 
Published: October 2018

AbstractBackgroundRecent studies indicate increased autistic traits in musicians with absolute pitch and a higher incidence of absolute pitch in people with autism. Theoretical accounts connect both of these with shared neural principles of local hyper- and global hypoconnectivity, enhanced perceptual functioning and a detail-focused cognitive style. This is the first study to investigate absolute pitch proficiency, autistic traits and brain correlates in the same study.Sample and MethodsGraph theoretical analysis was conducted on resting state (eyes closed and eyes open) EEG connectivity (wPLI, weighted Phase Lag Index) matrices obtained from 31 absolute pitch (AP) and 33 relative pitch (RP) professional musicians. Small Worldness, Global Clustering Coefficient and Average Path length were related to autistic traits, passive (tone identification) and active (pitch adjustment) absolute pitch proficiency and onset of musical training using Welch-two-sample-tests, correlations and general linear models.ResultsAnalyses revealed increased Path length (delta 2-4 Hz), reduced Clustering (beta 13-18 Hz), reduced Small-Worldness (gamma 30-60 Hz) and increased autistic traits for AP compared to RP. Only Clustering values (beta 13-18 Hz) were predicted by both AP proficiency and autistic traits. Post-hoc single connection permutation tests among raw wPLI matrices in the beta band (13-18 Hz) revealed widely reduced interhemispheric connectivity between bilateral auditory related electrode positions along with higher connectivity between F7-F8 and F8-P9 for AP. Pitch naming ability and Pitch adjustment ability were predicted by Path length, Clustering, autistic traits and onset of musical training (for pitch adjustment) explaining 44% respectively 38% of variance.ConclusionsResults show both shared and distinct neural features between AP and autistic traits. Differences in the beta range were associated with higher autistic traits in the same population. In general, AP musicians exhibit a widely underconnected brain with reduced functional integration and reduced small-world-property during resting state. This might be partly related to autism-specific brain connectivity, while differences in Path length and Small-Worldness reflect other ability-specific influences. This is further evidence for different pathways in the acquisition and development of absolute pitch, likely influenced by both genetic and environmental factors and their interaction.
Eliminating effects of particle adsorption to the air/water interface in single-particle cryo-electron microscopy: Bacterial RNA polymerase and CHAPSO
Authors: Chen James , Noble Alex J. , Kang Jin Young , Darst Seth A. 
Published: October 2018

AbstractPreferred particle orientation presents a major challenge for many single particle cryoelectron microscopy (cryo-EM) samples. Orientation bias limits the angular information used to generate three-dimensional maps and thus affects the reliability and interpretability of the structural models. The primary cause of preferred orientation is presumed to be due to adsorption of the particles at the air/water interface during cryo-EM grid preparation. To ameliorate this problem, detergents are often added to cryo-EM samples to alter the properties of the air/water interface. We have found that many bacterial transcription complexes suffer severe orientation bias when examined by cryo-EM. The addition of non-ionic detergents, such as NP-40, does not remove the orientation bias but the Zwitter-ionic detergent CHAPSO significantly broadens the particle orientation distributions, yielding isotropically uniform maps. We used cryoelectron tomography to examine the particle distribution within the ice layer of cryo-EM grid preparations of Escherichia coli 6S RNA/RNA polymerase holoenzyme particles. In the absence of CHAPSO, essentially all of the particles are located at the ice surfaces. CHAPSO at the critical micelle concentration eliminates particle absorption at the air/water interface and allows particles to randomly orient in the vitreous ice layer. We find that CHAPSO eliminates orientation bias for a wide range of bacterial transcription complexes containing E. coli or Mycobacterium tuberculosis RNA polymerases. Findings of this study confirm the presumed basis for how detergents can help remove orientation bias in cryo-EM samples and establishes CHAPSO as a useful tool to facilitate cryo-EM studies of baterial transcription complexes.
Bifunctional Substrate Activation via an Arginine Residue Drives Catalysis in Chalcone Isomerases
Authors: Burke Jason R. , La Clair James J. , Philippe Ryan N. , Pabis Anna , Jez Joseph M. , Cortina George A. , Kaltenbach Miriam , Bowman Marianne E. , Louie Gordon V. , Woods Katherine B. , Nelson Andrew T. , Tawfik Dan S. , Kamerlin Shina C.L. , Noel Joseph P. 
Published: October 2018

AbstractChalcone isomerases are plant enzymes that perform enantioselective oxa-Michael cyclizations of 2′-hydroxy-chalcones into flavanones. An X-ray crystal structure of an enzyme-product complex and molecular dynamics simulations reveal an enzyme mechanism wherein the guanidinium ion of a conserved arginine positions the nucleophilic phenoxide and activates the electrophilic enone for cyclization through Brønsted and Lewis acid interactions. The reaction terminates by asymmetric protonation of the carbanion intermediate syn to the guanidinium. Interestingly, bifunctional guanidine- and urea-based chemical reagents, increasingly used for asymmetric organocatalytic applications, are synthetic counterparts to this natural system. Comparative protein crystal structures and molecular dynamics simulations further demonstrate how two active site water molecules coordinate a hydrogen bond network that enables expanded substrate reactivity for 6′-deox-ychalcones in more recently evolved type-2 chalcone isomerases.
Genetic Consequences of Social Stratification in Great Britain
Authors: Abdellaoui Abdel , Hugh-Jones David , Kemper Kathryn E. , Holtz Yan , Nivard Michel G. , Veul Laura , Yengo Loic , Zietsch Brendan P. , Frayling Timothy M. , Wray Naomi , Yang Jian , Verweij Karin J.H. , Visscher Peter M. 
Published: October 2018

AbstractHuman DNA varies across geographic regions, with most variation observed so far reflecting distant ancestry differences. Here, we investigate the geographic clustering of genetic variants that influence complex traits and disease risk in a sample of ~450,000 individuals from Great Britain. Out of 30 traits analyzed, 16 show significant geographic clustering at the genetic level after controlling for ancestry, likely reflecting recent migration driven by socio-economic status (SES). Alleles associated with educational attainment (EA) show most clustering, with EA-decreasing alleles clustering in lower SES areas such as coal mining areas. Individuals that leave coal mining areas carry more EA-increasing alleles on average than the rest of Great Britain. In addition, we leveraged the geographic clustering of complex trait variation to further disentangle regional differences in socio-economic and cultural outcomes through genome-wide association studies on publicly available regional measures, namely coal mining, religiousness, 1970/2015 general election outcomes, and Brexit referendum results.
An empirical investigation of consumer perceptions of online shopping in an emerging economy
Authors: Dang Van Thac , Pham Thuy Linh 
Published: October 2018

PurposeEmerging markets are showing rapid growth and retaining high potential for the adoption of e-commerce and online shopping. Among the many high potential markets in Asia–Pacific, Vietnam has had a rapid economic development with an average GDP growth rate of 6.19 percent for the last two decades. To tap the growing online market of Vietnam, the purpose of this paper is to draw on adoption theory and the technology acceptance model to investigate the interrelationships among consumer perceptions of web design, reliability, privacy and customer service and their effects on purchase intention.Design/methodology/approachSurvey data were collected from 221 consumers in Vietnam. Structural equation modeling was used to analyze the data.FindingsEmpirical findings show that consumer perception of web design is positively related to perceptions of reliability, privacy, customer service and purchase intention. Consumer perception of reliability is positively related to perception of customer service but not to purchase intention. Consumer perception of privacy is also positively related to perception of customer service but not to purchase intention. Finally, consumer perception of customer service is positively related to purchase intention.Originality/valueThis study provides empirical evidence to understand the consumer perceptions of online shopping in the specific context of Vietnam. Findings of this study will benefit future researchers who will study consumer behavior in the e-commerce B2C industry, particularly those who are interested in the expanding e-commerce market in Vietnam. Furthermore, this study provides empirical evidence to assist business managers of domestic and foreign firms to further understand Vietnamese consumers. Knowledge of consumer behavior from the specific culture of a developing country may assist business managers advance their decision-making quality in developing markets.
Finding greener grass on the other side of hill
Authors: Kashif Muhammad , Fernando P.M.P. , Samad Sarminah , Thurasamy Ramayah 
Published: October 2018

PurposeThe research concerning brand credibility of charity brands is scantly examined. The purpose of this paper is to examine the moderating role of brand credibility within the customer-based brand equity model to investigate donor perceived brand equity of charity brands.Design/methodology/approachIn a cross-sectional research design, a survey-based research strategy is followed to collect data from 448 active Muslim donors in Pakistan. The collected data are analysed by employing confirmatory factor analysis based on Smart PLS 2.0.FindingsThe results indicate that donor perceived brand association, brand awareness and brand loyalty strongly relate to perceived brand equity of charity brands. The brand credibility moderates the relationship between perceived quality, equity and brand loyalty, and equity paths.Practical implicationsThe charity brands need to focus on building a strong brand image and reputation to uplift brand credibility which can be achieved by offering training programmes addressing various social causes such as HIV and Cancer prevention.Originality/valueThe proposed moderating effects of brand credibility and its application to charity brands operating in an Asian Muslim country context are unique products of this study.
A model-based approach for inspection of aeronautical multi-layered structures by eddy currents
Authors: Cung Long Thanh , Nguyen Nam Hoang , Joubert Pierre Yves , Vourch Eric , Larzabal Pascal 
Published: October 2018

Purpose
The purpose of this paper is to propose an approach, which is easy to implement, for estimating the thickness of the air layer that may separate metallic parts in some aeronautical assemblies, by using the eddy current method.

Design/methodology/approach
Based on an experimental study of the coupling of a magnetic cup core coil sensor with a metallic layered structure (consisting of first metal layer/air layer/second metal layer), which is confirmed by finite element modelling simulations, an inversion technique relying on a polynomial forward model of the coupling is proposed to estimate the air layer thickness. The least squares and the nonnegative least squares algorithms are applied and analysed to obtain the estimation results.

Findings
The choice of an appropriate inversion technique to optimize the estimation results is dependent on the signal-to-noise ratio of measured data. The obtained estimation error is smaller than a few percent, for both simulated and experimental data. The proposed approach can be used to estimate both the air layer thickness and the second metal layer thickness simultaneously/separately.

Originality/value
This model-based approach is easy to implement and available to all types of eddy current sensors.