bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lichtenstein Versus Total Extraperitoneal Patch Plasty Versus Transabdominal Patch Plasty Technique for Primary Unilateral Inguinal Hernia Repair
Authors: Köckerling Ferdinand , Bittner Reinhard , Kofler Michael , Mayer Franz , Adolf Daniela , Kuthe Andreas , Weyhe Dirk 
Published: September 2017

Objective:
Outcome comparison of the Lichtenstein, total extraperitoneal patch plasty (TEP), and transabdominal patch plasty (TAPP) techniques for primary unilateral inguinal hernia repair.

Background:
For comparison of these techniques the number of cases included in meta-analyses of randomized controlled trials is limited. There is therefore an urgent need for more comparative data.

Methods:
In total, 57,906 patients with a primary unilateral inguinal hernia and 1-year follow up from the Herniamed Registry were selected between September 1, 2009 and February 1, 2015. Using propensity score matching, 12,564 matched pairs were formed for comparison of Lichtenstein versus TEP, 16,375 for Lichtenstein versus TAPP, and 14,426 for TEP versus TAPP.

Results:
Comparison of Lichtenstein versus TEP revealed disadvantages for the Lichtenstein operation with regard to the postoperative complications (3.4% vs 1.7%; P < 0.001), complication-related reoperations (1.1% vs 0.8%; P = 0.008), pain at rest (5.2% vs 4.3%; P = 0.003), and pain on exertion (10.6% vs 7.7%; P < 0.001). TEP had disadvantages in terms of the intraoperative complications (0.9% vs 1.2%; P = 0.035). Likewise, comparison of Lichtenstein versus TAPP showed disadvantages for the Lichtenstein operation with regard to the postoperative complications (3.8% vs 3.3%; P = 0.029), complication-related reoperations (1.2% vs 0.9%; P = 0.019), pain at rest (5% vs 4.5%; P = 0.029), and on exertion (10.2% vs 7.8%; P < 0.001).

Conclusions:
TEP and TAPP were found to have advantages over the Lichtenstein operation.
Internal Protein Motions in Molecular Dynamics Simulations of Bragg and Diffuse X-ray Scattering
Authors: Wall Michael E. 
Published: September 2017

SynopsisA molecular dynamics simulation of diffuse X-ray scattering from staphylococcal nuclease crystals is greatly improved when the unit cell model is expanded to a 2×2×2 layout of eight unit cells. The dynamics are dominated by internal protein motions rather than rigid packing interactions.AbstractMolecular dynamics (MD) simulations of Bragg and diffuse X-ray scattering provide a means of obtaining experimentally validated models of protein conformational ensembles. This paper shows that, compared to a single periodic unit cell model, the accuracy in simulating diffuse scattering is increased when the crystal is modeled as a periodic supercell, consisting of a 2×2×2 layout of eight unit cells. The MD simulations capture the general dependence of correlations on the separation of atoms. There is substantial agreement between the simulated Bragg reflections and the crystal structure; there are local deviations, however, indicating both the limitation of using a single structure to model disordered regions of the protein and local deviations of the average structure away from the crystal structure. Although it was anticipated that a longer duration simulation might be required to achieve convergence of the diffuse scattering calculation using the supercell model, only a microsecond is required, the same as for the unit cell. Rigid protein motions only account for a small fraction of the variation in atom positions from the simulation. The results indicate that protein crystal dynamics can be dominated by internal motions rather than packing interactions, and that MD simulations can be combined with Bragg and diffuse X-ray scattering to model the protein conformational ensemble.
Improved Prokaryotic Gene Prediction Yields Insights into Transcription and Translation Mechanisms on Whole Genome Scale
Authors: Lomsadze Alexandre , Gemayel Karl , Tang Shiyuyun , Borodovsky Mark 
Published: September 2017

ABSTRACTIn a conventional view of the prokaryotic genome organization promoters precede operons and RBS sites with Shine-Dalgarno consensus precede genes. However, recent experimental research suggesting a more diverse view motivated us to develop an algorithm with improved gene-finding accuracy. We describe GeneMarkS-2, anab initioalgorithm that uses a model derived by self-training for finding species-specific (native) genes, along with an array of pre-computedheuristicmodels designed to identify harder-to-detect genes (likely horizontally transferred). Importantly, we designed GeneMarkS-2 to identify several types of distinct sequence patterns (signals) involved in gene expression control, among them the patterns characteristic for leaderless transcription as well as non-canonical RBS patterns. To assess the accuracy of GeneMarkS-2 we used genes validated by COG annotation, proteomics experiments, and N-terminal protein sequencing. We observed that GeneMarkS-2 performed better on average in all accuracy measures when compared with the current state-of-the-art gene prediction tools. Furthermore, the screening of ∼5,000 representative prokaryotic genomes made by GeneMarkS-2 predicted frequent leaderless transcription in both archaea and bacteria. We also observed that the RBS sites in some species with leadered transcription did not necessarily exhibit the Shine-Dalgarno consensus. The modeling of different types of sequence motifs regulating gene expression prompted a division of prokaryotic genomes into five categories with distinct sequence patterns around the gene starts.[Supplemental material is available for this article].
The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology
Authors: Brikell Isabell , Larsson Henrik , Lu Yi , Pettersson Erik , Chen Qi , Kuja-Halkola Ralf , Karlsson Robert , Lahey Benjamin B , Lichtenstein Paul , Martin Joanna 
Published: September 2017

AbstractAttention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder, with common genetic risk variants implicated in the clinical diagnosis and symptoms of ADHD. However, given evidence of comorbidity and genetic overlap across neurodevelopmental and externalizing conditions, it remains unclear whether these genetic risk variants are ADHD-specific. The aim of this study was to evaluate the associations between ADHD genetic risks and related neurodevelopmental and externalizing conditions, and to quantify the extent to which any such associations can be attributed to a general genetic liability towards psychopathology. We derived ADHD polygenic risk scores (PRS) for 13,460 children aged 9 and 12 years from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. Associations between ADHD PRS, a latent general psychopathology factor, and six latent neurodevelopmental and externalizing factors were estimated using structural equation modelling. ADHD PRS were statistically significantly associated with elevated levels of inattention, hyperactivity/impulsivity, autistic traits, learning difficulties, oppositional-defiant, and conduct problems (standardized regression coefficients=0.07-0.12). Only the association with specific hyperactivity/impulsivity remained significant after accounting for a general psychopathology factor, on which all symptoms loaded positively (standardized mean loading=0.61, range=0.32-0.91). ADHD PRS simultaneously explained 1% (p-value<0.001) of the variance in the general psychopathology factor and 0.50% (p-value<0.001) in the specific hyperactivity/impulsivity factor. Our results suggest that common genetic risk variants associated with ADHD have largely general pleiotropic effects on neurodevelopmental and externalizing traits in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.
Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer
Authors: Patten Darren K. , Corleone Giacomo , Győrffy Balázs , Erdős Edina , Saiakhova Alina , Goddard Kate , Vingiani Andrea , Shousha Sami , Pongor Lőrinc Sándor , Hadjiminas Dimitri J. , Schiavon Gaia , Barry Peter , Palmieri Carlo , Coombes Raul C. , Scacheri Peter , Pruneri Giancarlo , Magnani Luca 
Published: September 2017

AbstractThe degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ERα)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1.In vitrowork shows that YY1 is essential for ERα transcriptional activity and defines the critical subset of functional ERα binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.
Non-canonical aberrant DNA hypermethylation in glioma
Authors: Fernandez Agustin F. , Bayón Gustavo F. , Sierra Marta I. , Urdinguio Rocio G. , Toraño Estela G. , García Maria , Carella Antonella , Lopez Virginia , Santamarina Pablo , Belmonte Thalia , Tejedor Juan Ramon , Cobo Isabel , Menendez Pablo , Mangas Cristina , Ferrero Cecilia , Rodrigo Luís , Astudillo Aurora , Ortea Ignacio , Cueto Díaz Sergio , Rodríguez-Gonzalez Pablo , García Alonso J. Ignacio , Mollejo Manuela , Meléndez Bárbara , Dominguez Gemma , Bonilla Felix , Fraga Mario F. 
Published: September 2017

AbstractAberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC in primary samples from 54 gliomas and 72 colorectal cancer patients. Levels of 5hmC in colorectal cancer were very low and no consistent changes were detected between control tissues and tumors. As expected, levels of 5hmC in non-tumoral brain samples were high and significantly reduced at the 49,601 CpG sites in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) of these CpG sites was associated with aberrant DNA hypermethylation. The DNA regions containing these CpG sites were enriched in H3K4me2, and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. We conclude that this data identifies a novel 5hmC-dependent non-canonical class of aberrant DNA hypermethylation in glioma.
A literature review at genome scale: improving clinical variant assessment
Authors: Cassa Christopher A. , Jordan Daniel M. , Adzhubei Ivan , Sunyaev Shamil 
Published: September 2017

AbstractIntroduction: Over 150,000 variants have been reported to cause Mendelian disease in the medical literature. It is still difficult to leverage this knowledge base in clinical practice as many reports lack strong statistical evidence or may include false associations. Clinical laboratories assess whether these variants (along with newly observed variants that are adjacent to these published ones) underlie clinical disorders.Materials and Methods: We measured whether citation data—including journal impact factor and the number of cited variants (NCV) in each gene with published disease associations—can be used to improve variant assessment.Results: Surprisingly, we find that impact factor is not predictive of pathogenicity, but the NCV score for each gene can provide statistical support of pathogenicity. When combining this gene-level citation metric with variant-level evolutionary conservation and structural features, classification accuracy reaches 89.5%. Further, variants identified in clinical exome sequencing cases have higher NCV scores than simulated rare variants from ExAC in matched genes and consequences (p<2.22x10-16).Discussion: Aggregate citation data can complement existing variant-based predictive algorithms, and can boost their performance without accessing and reviewing large numbers of manuscripts. The NCV is a slow-growing metric of scientific knowledge about each gene’s association with disease.Funding: This research was supported by NIH NHGRI grant HG007229 (C.C.) and NIGMS grant GM078598 (I.A., D.J., and S.S.).
DAFi: A Directed Recursive Filtering and Clustering Approach to Data-Driven Identification of Cell Populations from Polychromatic Flow Cytometry Data
Authors: Lee Alexandra J. , Chang Ivan , Burel Julie G. , Lindestam Arlehamn Cecilia S. , Weiskopf Daniela , Peters Bjoern , Sette Alessandro , Scheuermann Richard H. , Qian Yu 
Published: September 2017

AbstractComputational methods for identification of cell populations from high-dimensional flow cytometry data are changing the paradigm of cytometry bioinformatics. Data clustering is the most common computational approach to unsupervised identification of cell populations from multidimensional cytometry data. We found that combining recursive filtering and clustering with constraints converted from the user manual gating strategy can effectively identify overlapping and rare cell populations from smeared data that would have been difficult to resolve by either a single run of data clustering or manual segregation. We named this new method DAFi: Directed Automated Filtering and Identification of cell populations. Design of DAFi preserves the data-driven characteristics of unsupervised clustering for identifying novel cell-based biomarkers, but also makes the results interpretable to experimental scientists as in supervised classification through mapping and merging the high-dimensional data clusters into the user-defined 2D gating hierarchy. By recursive data filtering before clustering, DAFi can uncover small local clusters which are otherwise difficult to identify due to the statistical interference of the irrelevant major clusters. Quantitative assessment of cell type specific characteristics demonstrates that the population proportions calculated by DAFi, while being highly consistent with those by expert centralized manual gating, have smaller technical variance than those from individual manual gating analysis. Visual examination of the dot plots showed that the boundaries of the DAFi-identified cell populations followed the natural shapes of the data distributions. To further exemplify the utility of DAFi, we show that DAFi can incorporate the FLOCK clustering method to identify novel cell-based biomarkers. Implementation of DAFi supports options including clustering, bisecting, slope-based gating, and reversed filtering to meet various auto-gating needs from different scientific use cases.
Leveraging lung tissue transcriptome to uncover candidate causal genes in COPD genetic associations
Authors: Obeidat Ma’en , Lamontagne Maxime , Bérubé Jean-Christophe , Cho Michael H , Hobbs Brian D. , de Jong Kim , Boezen H. Marike ,   the International COPD Genetics Consortium, Nickle David , Hao Ke , Timens Wim , van den Berge Maarten , Joubert Philippe , Laviolette Michel , Sin Don D , Paré Peter D , Bossé Yohan 
Published: September 2017

ABSTRACTWe collated 129 non-overlapping risk loci for chronic obstructive pulmonary disease (COPD) from the GWAS literature. Using recent and complementary integrative genomics approaches, combining GWAS and lung eQTL results, we identified 12 novel COPD loci and corresponding causal genes. In addition, we mapped candidate causal genes for 60 out of the 129 GWAS-nominated loci as well as for four sub-genome-wide significant COPD risk loci derived from the largest GWAS on COPD. Mapping causal genes in lung tissue represents an important contribution on the genetics of COPD, enriches our biological interpretation of GWAS findings, and brings us closer to clinical translation of genetic associations.
Impaired competence in flagellar mutants ofBacillus subtilisis connected to the regulatory network governed by DegU
Authors: Hölscher Theresa , Schiklang Tina , Dragoš Anna , Dietel Anne-Kathrin , Kost Christian , Kovács Ákos T. 
Published: September 2017

SummaryThe competent state is a developmentally distinct phase, in which bacteria are able to take up and integrate exogenous DNA into their genome.Bacillus subtilisis one of the naturally competent bacterial species and the domesticated laboratory strain 168 is easily transformable. In this study, we report a reduced transformation frequency ofB. subtilismutants lacking functional and structural flagellar components. This includeshag, the gene encoding the flagellin protein forming the filament of the flagellum. We confirm that the observed decrease of the transformation frequency is due to reduced expression of competence genes, particularly of the main competence regulatorcomK. The impaired competence is due to an increase in the phosphorylated form of the response regulator DegU, which is involved in regulation of both flagellar motility and competence. Altogether, our study identified a close link between motility and natural competence inB. subtilissuggesting that hindrance in motility has great impact on differentiation of this bacterium not restricted only to the transition towards sessile growth stage.Originality-Significance statementUnderstanding how versatile bacterial phenotypes influence each other is important for our basic understanding of microbial ecology. Our research highlights the novel intertwinement of bacterial differentiation and reveal how lack of single cell motility adjusts DNA exchange among bacterial strains.
Gauss-power mixing distributions comprehensively describe stochastic variations in RNA-seq data
Authors: Awazu Akinori , Tanabe Takahiro , Kamitani Mari , Tezuka Ayumi , Nagano Atsushi J. 
Published: September 2017

AbstractMotivationGene expression levels exhibit stochastic variations among genetically identical organisms under the same environmental conditions. In many recent transcriptome analyses based on RNA sequencing (RNA-seq), variations in gene expression levels among replicates were assumed to follow a negative binomial distribution although the physiological basis of this assumption remain unclear.ResultsIn this study, RNA-seq data were obtained fromArabidopsis thalianaunder eight conditions (21–27 replicates), and the characteristics of gene-dependent distribution profiles of gene expression levels were analyzed. ForA. thaliana and Saccharomyces cerevisiae,the distribution profiles could be described by a Gauss-power mixing distribution derived from a simple model of a stochastic transcriptional network containing a feedback loop. The distribution profiles of gene expression levels were roughly classified as Gaussian, power law-like containing a long tail, and mixed. The fitting function predicted that gene expression levels with long-tailed distributions would be strongly influenced by feedback regulation. Thus, the features of gene expression levels are correlated with their functions, with the levels of essential genes tending to follow a Gaussian distribution and those of genes encoding nucleic acid-binding proteins and transcription factors exhibiting long-tailed distributions.AvailabilityFastq files of RNA-seq experiments were deposited into the DNA Data Bank of Japan Sequence Read Archive as accession no. DRA005887. Quantified expression data are available in supplementary information.Contactawa@hiroshima-u.ac.jpSupplementary informationSupplementary data are available atBioinformaticsonline.
Name Conditioning in Event-Related Brain Potentials
Authors: Kotchoubey Boris , Pavlov Yuri G. 
Published: September 2017

AbstractFour experiments are reported in which two harmonic tones (CS+ and CS-) were paired with a participant’s own name (SON) and different names (DN), respectively. A third tone was not paired with any other stimulus and served as a standard (frequent stimulus) in a three-stimuli oddball paradigm. The larger posterior positivity (P3) to SON than DN, found in previous studies, was replicated in all experiments. Conditioning of the P3 response was albeit observed in two similar experiments (1 and 3), but the obtained effects were weak and not identical in the two experiments. Only Experiment 4, where the number of CS/UCS pairings and the Stimulus-Onset Asynchrony between CS and UCS were increased, showed clear CS+/CS- differences both in time and time-frequency domains. Surprisingly, differential responses to CS+ and CS- were also obtained in Experiment 2, although SON and DN in that experiment were masked and never consciously recognized as meaning words (recognition rate 0/63 participants). The results are discussed in the context of other ERP conditioning experiments and, particularly, the studies of non-conscious effect on ERP. Several further experiments are suggested to replicate and extend the present findings and to remove the remaining methodological limitations.
The mechano-chemistry of a monomeric reverse transcriptase
Authors: Malik Omri , Khamis Hadeel , Rudnizky Sergei , Kaplan Ariel 
Published: September 2017

ABSTRACTRetroviral reverse transcriptase catalyses the synthesis of an integration-competent dsDNA molecule, using as a substrate the viral RNA. Using optical tweezers, we follow the Murine Leukemia Virus reverse transcriptase as it performs strand-displacement polymerization on a template under mechanical force. Our results indicate that reverse transcriptase functions as a Brownian ratchet, with dNTP binding as the rectifying reaction of the ratchet. We also found that reverse transcriptase is a relatively passive enzyme, able to polymerize on structured templates by exploiting their thermal breathing. Finally, our results indicate that the enzyme enters the recently characterized backtracking state from the pre-translocation complex.
Cell-type heterogeneity in the zebrafish olfactory placode is generated from progenitors within preplacodal ectoderm
Authors: Aguillon Raphaël , Batut Julie , Subramanian Arul , Madelaine Romain , Dufourcq Pascale , Schilling Thomas F. , Blader Patrick 
Published: September 2017

AbstractVertebrate olfactory placodes consists of a variety of neuronal populations, which are thought to have distinct embryonic origins. In the zebrafish, while ciliated sensory neurons arise from preplacodal ectoderm (PPE), previous lineage tracing studies suggest that both Gonadotropin releasing hormone 3 (Gnrh3) and microvillous sensory neurons derive from cranial neural crest (CNC). We find that the expression of Islet1/2 is restricted to Gnrh3 neurons associated with the olfactory placode. Unexpectedly, however, we find no change in Islet1/2+ cell numbers insox10mutant embryos, calling into question their CNC origin. Lineage reconstruction based on backtracking in time-lapse confocal datasets, and confirmed by photoconversion experiments, reveals that Gnrh3 neurons derive from the anterior/medial PPE. Similarly, all of the microvillous sensory neurons we have traced arise from preplacodal progenitors. Our results suggest that rather than originating from separate ectodermal populations, cell-type heterogeneity is generated from overlapping pools of progenitors within the preplacodal ectoderm.