bluuebunny/crossref_metadata_2025 huggingface dataset:
Delayed Salicylate Toxicity in a 17-Year-Old Girl With Initially Undetectable Salicylate Concentration 3.9 Hours After Ingestion
Authors: Beauchamp Gillian A. , Hendrickson Robert G.
Published: October 2016

We report the case of a 17-year-old girl with a 126-mg/kg nonenteric coated aspirin ingestion with nontoxic salicylate concentrations at 1.5 and 3.9 hours postingestion, who developed tinnitus and vomiting an estimated 8 hours postingestion, and who was subsequently found to have a toxic salicylate concentration at 22.7 hours postingestion. This case, as well as previous cases of delayed aspirin therapy, may prompt providers to consider educating patients and their care providers regarding the need to return for further testing if symptoms, such as vomiting or tinnitus, develop after an aspirin ingestion.
Gastric Perforation After a Dog Attack
Authors: Uchino Hayaki , Kuriyama Akira , Bruce John , Laing Grant , Clarke Damian , Oosthuizen George
Published: October 2016

Dog bites are a major cause of injury, especially in the pediatric population. Common anatomic sites of dog bites on children are the peripheries and the head and neck. The torso is reportedly injured less frequently, and only 2 cases of intra-abdominal injury secondary to dog bites have been reported. We recently encountered a 3-year-old boy presenting with peritonitis who had sustained multiple dog bites to his trunk and upper limbs. Emergency laparotomy was performed. Surgical findings revealed penetration of the peritoneum and single perforation of the anterior gastric wall with multiple tooth marks; thus, the gastric perforation was debrided and repaired. After receiving rabies prophylaxis and amoxicillin-clavulanate, the patient had an uneventful postoperative course. The principles of management of dog bites include debridement of wounds and use of prophylactic antibiotics. Because rabies is always fatal, postexposure prophylaxis should be considered in appropriate cases. Dog bites can be life-threatening, and prevention is the best approach to solve this problem. Clinicians need to be aware that some dog bites can be devastating and should be familiar with the principles of managing these wounds.
Dimensions of Socioeconomic Status and Childhood Asthma Outcomes: Evidence for Distinct Behavioral and Biological Associations
Authors: Chen Edith , Shalowitz Madeleine U. , Story Rachel E. , Ehrlich Katherine B. , Levine Cynthia S. , Hayen Robin , Leigh Adam K.K. , Miller Gregory E.
Published: October 2016

Objectives

The objective of this study was to investigate 2 key dimensions of socioeconomic status (SES)—prestige and resources—and their associations with immune, behavioral, and clinical outcomes in childhood asthma.

Methods

Children ages 9 to 17 years with a physician's diagnosis of asthma (N = 150), and one of their parents participated in this study. Children and parents completed interviews and questionnaires about SES (prestige = parent education; resources = family assets), environmental exposures, and clinical asthma measures. Spirometry was conducted to assess children's pulmonary function, and blood was collected to measure cytokine production in response to nonspecific stimulation, allergen-specific stimulation, and microbial stimulation.

Results

Higher scores on both dimensions of childhood SES were associated with better clinical outcomes in children (β's from |.18 to .27|, p values < .05). Higher prestige, but not resources, was associated with better home environment control behaviors and less exposure to smoke (β's from |.21 to .22|, p values < .05). Higher resources, but not prestige, was associated with more favorable immune regulation, as manifest in smaller peripheral blood mononuclear cell (PBMC) TH1 and TH2 cytokine responses (β's from −.18 to −.19; p values < .05), and smaller proinflammatory cytokine responses (β = −.19; p < .05) after ex vivo stimulation. Higher resources also were associated with more sensitivity to glucocorticoid inhibition of TH1 and TH2 cytokine production (β's from −.18 to −.22; p values < .05).

Conclusions

These results suggest that prestige and resources in childhood family environments have different implications for behavioral and immunological processes relevant to childhood asthma. They also suggest that childhood SES relates to multiple aspects of immunologic regulation of relevance to the pathophysiology of asthma.
Associations Between Psychological Constructs and Cardiac Biomarkers After Acute Coronary Syndrome
Authors: Celano Christopher M. , Beale Eleanor E. , Beach Scott R. , Belcher Arianna M. , Suarez Laura , Motiwala Shweta R. , Gandhi Parul U. , Gaggin Hanna , Januzzi James L. , Healy Brian C. , Huffman Jeff C.
Published: October 2016

Objective

Psychological constructs are associated with cardiovascular health, but the biological mechanisms mediating these relationships are unknown. We examined relationships between psychological constructs and markers of inflammation, endothelial function, and myocardial strain in a cohort of post–acute coronary syndrome (ACS) patients.

Methods

Participants (N = 164) attended study visits 2 weeks and 6 months after ACS. During these visits, they completed self-report measures of depressive symptoms, anxiety, optimism, and gratitude; and blood samples were collected for measurement of biomarkers reflecting inflammation, endothelial function, and myocardial strain. Generalized estimating equations and linear regression analyses were performed to examine concurrent and prospective relationships between psychological constructs and biomarkers.

Results

In concurrent analyses, depressive symptoms were associated with elevated markers of inflammation (interleukin-17: β = .047; 95% confidence interval [CI] = .010–.083]), endothelial dysfunction (endothelin-1: β = .020; 95% [CI] = .004–.037]), and myocardial strain (N-terminal pro-B-type natriuretic peptide: β = .045; 95% [CI] = .008–.083]), independent of age, sex, medical variables, and anxiety, whereas anxiety was not associated with these markers in multivariable adjusted models. Optimism and gratitude were associated with lower levels of markers of endothelial dysfunction (endothelin-1: gratitude: β = −.009; 95% [CI] = −.017 to − .001]; optimism: β = −.009; 95% [CI] = −.016 to − .001]; soluble intercellular adhesion molecule-1: gratitude: β = −.007; 95% [CI] = −.014 to − .000]), independent of depressive and anxiety symptoms. Psychological constructs at 2 weeks were not prospectively associated with biomarkers at 6 months.

Conclusions

Depressive symptoms were associated with more inflammation, myocardial strain, and endothelial dysfunction in the 6 months after ACS, whereas positive psychological constructs were linked to better endothelial function. Larger prospective studies may clarify the directionality of these relationships.

Clinical Trial Registration

Clinicaltrials.gov identifier NCT01709669
Neolithic super-grandfather Y haplotypes, their related surnames, and autism spectrum disorder
Authors: He Pei , Chen Na , Hu Zhengmao , Zhu Zuobin , Xia Kun , Huang Shi
Published: October 2016

Recent studies found three Neolithic super-grandfather Y haplotypes among Han Chinese, consistent with the legend of Yan and Huang Emperors. Individuals of royal and noble ancestry or high social economic status (SES) are known to practice assortative mating and consanguineous marriages, which can produce offspring of both higher and lower than average fitness. However, the roles of the super-grandfather Y haplotypes and their descendant lines in history, fitness, and the male biased autism spectrum disorder (ASD) remain unknown. Here we show a link between the super-grandfathers and the legend ofYan-HuangEmperors and between their descendant haplotypes and ASD. We found that subjects carrying the O3a1c and O3a2c1a super-grandfather haplotypes were enriched withYanandHuangrelated surnames, respectively, in two independent datasets of 1564 and 772 male Han subjects. We identified high and low SES descendant haplotypes of the super-grandfathers using the Han dataset of the 1000 genomes project based on two criteria: more descendant branches and fewer mutations before star-like expansions. By genotyping 505 fathers of ASD affected male children from the Autism Clinical and Genetic Resources in China with surnames either closely related to Huang (Ying group) or less related (Ji group), we found the high SES haplotypes within the O3a2c1a clade at ∼2 fold lower (odds ratio 2.05, 95% CI 1.28-3.26, P=0.0026) while the low SES haplotypes at ∼2 fold higher frequency (odds ratio 1.92, 95% CI 1.01-3.64, P = 0.046) in the fathers relative to 505 normal subjects. The fraction of low SES haplotypes was greater than that of high SES in ASD fathers of the Ying group, in contrast to Ying controls or the Ji fathers and Ji controls. Consistently, analysis of 2366 ASD affected children showed higher male to female ratio for Ying versus Ji group (6.52 +/-1.11 v 4.59 +/-0.41, P = 0.028, one tailed). These results provide evidence for the Yan-Huang legend and suggest a role for Y in ASD.
Heterogeneity of single-cell mechanical responses to tumorigenic factors
Authors: Leal-Egaña Aldo , Letort Gaelle , Martiel Jean-Louis , Christ Andreas , Vignaud Timothée , Roelants Caroline , Filhol Odile , Théry Manuel
Published: October 2016

Tumor development progresses through a complex path of biomechanical changes leading first to cell growth and contraction followed by cell de-adhesion, scattering and invasion. Tumorigenic factors may act specifically on one of these steps or have wider spectrum of actions, leading to a variety of effects and thus sometimes to apparent contradictory outcomes. Here we used micropatterned lines of collagen type-I/fibronectin on deformable surfaces to standardize cell behavior and to measure simultaneously cell size, speed of motion and the magnitude of the associated contractile forces at the level of a single cell. We analyzed and compared normal human breast cell line MCF10A in control conditions and in response to various tumorigenic factors. In all conditions, distinct populations of cells with a wide range of biomechanical properties were identified. Despite this heterogeneity, normal and transformed motile cells followed a common trend whereby size and contractile forces were negatively correlated with cell speed. Some tumorigenic factors, such as activation of ErbB2 or the loss of the beta subunit of casein kinase 2 (CK2), shifted the whole population towards a faster speed and lower contractility state. Treatment with transforming growth factor beta (TGF-β), induced some cells to adopt opposing behaviors such as extreme high contractility versus extreme low contractility. Thus, tumor transformation amplified the pre-existing population heterogeneity and led some cells to exhibit biomechanical properties that were more extreme than that observed with normal cells.
MUMdex: MUM-based structural variation detection
Authors: Andrews Peter A. , Iossifov Ivan , Kendall Jude , Marks Steven , Muthuswamy Lakshmi , Wang Zihua , Levy Dan , Wigler Michael
Published: October 2016

Motivation

Standard genome sequence alignment tools primarily designed to find one alignment per read have difficulty detecting inversion, translocation and large insertion and deletion (indel) events. Moreover, dedicated split read alignment methods that depend only upon the reference genome may misidentify or find too many potential split read alignments because of reference genome anomalies.

Methods

We introduce MUMdex, a Maximal Unique Match (MUM)-based genomic analysis software package consisting of a sequence aligner to the reference genome, a storage-indexing format and analysis software. Discordant reference alignments of MUMs are especially suitable for identifying inversion, translocation and large indel differences in unique regions. Extracted population databases are used as filters for flaws in the reference genome. We describe the concepts underlying MUM-based analysis, the software implementation and its usage.

Results

We demonstrate via simulation that the MUMdex aligner and alignment format are able to correctly detect and record genomic events. We characterize alignment performance and output file sizes for human whole genome data and compare to Bowtie 2 and the BAM format. Preliminary results demonstrate the practicality of the analysis approach by detectingde novomutation candidates in human whole genome DNA sequence data from 510 families. We provide a population database of events from these families for use by others.

Availability

http://mumdex.com/

Contact

andrewsp@cshl.edu(orpaa@drpa.us)

Supplementary information

Supplementary data are available online.
Self-oligomerization regulates stability of Survival Motor Neuron (SMN) protein isoforms by sequestering an SCFSlmbdegron
Authors: Gray Kelsey M. , Kaifer Kevin A. , Baillat David , Wen Ying , Bonacci Thomas R. , Ebert Allison D. , Raimer Amanda C. , Spring Ashlyn M. , Have Sara ten , Glascock Jacqueline J. , Gupta Kushol , Van Duyne Gregory D. , Emanuele Michael J. , Lamond Angus I. , Wagner Eric J. , Lorson Christian L. , Matera A. Gregory
Published: October 2016

Spinal muscular atrophy (SMA) is caused by homozygous mutations in humanSMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. AlthoughSMN2exon skipping is the principal contributor to SMA severity, mechanisms governing stability of SMN isoforms are poorly understood. We used aDrosophilamodel system and label-free proteomics to identify the SCFSlmbubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmbinteracts with a phospho-degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmbbinding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric, and sequestered when SMN forms higher-order multimers.
Familial migration of the Neolithic contrasts massive male migration during Bronze Age in Europe inferred from ancient X chromosomes
Authors: Goldberg Amy , Günther Torsten , Rosenberg Noah A. , Jakobsson Mattias
Published: October 2016

Dramatic events in human prehistory, such as the spread of agriculture to Europe from Anatolia and the Late Neolithic/Bronze Age (LNBA) migration from the Pontic-Caspian steppe, can be investigated using patterns of genetic variation among the people that lived in those times. In particular, studies of differing female and male demographic histories on the basis of ancient genomes can provide information about complexities of social structures and cultural interactions in prehistoric populations. We use a mechanistic admixture model to compare the sex-specifically-inherited X chromosome to the autosomes in 20 early Neolithic and 16 LNBA human remains. Contrary to previous hypotheses suggested by the patrilocality of many agricultural populations, we find no evidence of sex-biased admixture during the migration that spread farming across Europe during the early Neolithic. For later migrations from the Pontic steppe during the LNBA, however, we estimate a dramatic male bias, with ~5-14 migrating males for every migrating female. We find evidence of ongoing, primarily male, migration from the steppe to central Europe over a period of multiple generations, with a level of sex bias that excludes a pulse migration during a single generation. The contrasting patterns of sex-specific migration during these two migrations suggest a view of differing cultural histories in which the Neolithic transition was driven by mass migration of both males and females in roughly equal numbers, perhaps whole families, whereas the later Bronze Age migration and cultural shift were instead driven by male migration, potentially connected to new technology and conquest.
Estimating the timing of multiple admixture events using 3-locus Linkage Disequilibrium
Authors: Liang Mason , Shishkin Mikhail , Mikhailova Anastasia , Shchur Vladimir , Nielsen Rasmus
Published: October 2016

Estimating admixture histories is crucial for understanding the genetic diversity we see in present-day populations. Allele frequency or phylogeny-based methods are excellent for inferring the existence of admixture or its proportions. However, to estimate admixture times, spatial information from admixed chromosomes of local ancestry or the decay of admixture linkage disequilibrium (ALD) is used. One popular method, implemented in the programs ALDER and ROLLOFF, uses two-locus ALD to infer the time of a single admixture event, but is only able to estimate the time of the most recent admixture event based on this summary statistic. To address this limitation, we derive analytical expressions for the expected ALD in a three-locus system and provide a new statistical method based on these results that is able to resolve more complicated admixture histories. Using simulations, we evaluate the performance of this method on a range of different admixture histories. As an example, we apply the method to the Colombian and Mexican samples from the 1000 Genomes project. The implementation of our method is available athttps://github.com/Genomics-HSE/LaNeta.

Author summary

We establish a theoretical framework to model 3-locus admixture linkage disequilibrium of an admixed population taking into account the effects of genetic drift, migration and recombination. The theory is used to develop a method for estimating the times of multiple admixtures events. We demonstrate the accuracy of the method on simulated data and we apply it to previously published data from Mexican and Columbian populations to explore the complex history of American populations in the post-Columbian period.
PyVar: An Extensible Framework for Variant Annotator Comparison
Authors: Wertz Julie , Liao Qianli , Bair Thomas B , Chimenti Michael S
Published: October 2016

Modern genomics projects are generating millions of variant calls that must be annotated for predicted functional consequences at the level of gene expression and protein function. Many of these variants are of interest owing to their potential clinical significance. Unfortunately, state-of-the-art methods do not always agree on downstream effects for any given variant. Here we present a readily extensible python framework (PyVar) for comparing the output of variant annotator methods in order to aid the research community in quickly assessing differences between methods and benchmarking new methods as they are developed. We also apply our framework to assess the annotation performance of ANNOVAR, VEP, and SnpEff when annotating 81 million variants from the ‘1000 Genomes Project’ against both RefSeq and Ensembl human transcript sets.
AGO4 is specifically required for heterochromatic siRNA accumulation at Pol V-dependent loci inArabidopsis thaliana
Authors: Wang Feng , Axtell Michael J.
Published: October 2016

Significance statement

Genome-wide characterization ofAGO4-dependent siRNAs revealed thatAGO4is required for the accumulation of a small subset of heterochromatic siRNAs inArabidopsis thaliana. TheseAGO4-depdenent siRNAs are likely secondary het-siRNAs produced by a self-reinforcing loop of RdDM. Slicing-defectiveAGO4is unable to fully complement het-siRNA accumulation from anago4mutant, demonstrating the critical role of AGO4 catalytic ability in het-siRNA accumulation.

Summary: 152; Introduction: 618; Results: 1291; Discussion: 1013; Experimental procedures: 881; Acknowledgements: 24; Figure legends: 568; Author contribution: 25; Conflict of interest: 13; Funding: 34; References: 1289

In plants, 24 nucleotide long heterochromatic siRNAs (het-siRNAs) transcriptionally regulate gene expression by RNA-directed DNA methylation (RdDM). The biogenesis of most het-siRNAs depends on the plant-specific RNA polymerase IV (Pol IV), and ARGONAUTE4 (AGO4) is a major het-siRNA effector protein. Through genome-wide analysis of sRNA-seq data sets, we found thatAGO4is required for the accumulation of a small subset of het-siRNAs. The accumulation ofAGO4-dependent het-siRNAs also requires several factors known to participate in the effector portion of the RdDM pathway, including RNA POLYMERASE V (POL V), DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1). Like many AGO proteins, AGO4 is an endonuclease that can ‘slice’ RNAs. We found that a slicing-defective AGO4 was unable to fully recoverAGO4-dependent het-siRNA accumulation fromago4mutant plants. Collectively, our data suggest thatAGO4-dependent siRNAs are secondary siRNAs dependent on the prior activity of the RdDM pathway at certain loci.
A Forward Model at Purkinje Cell Synapses Facilitates Cerebellar Anticipatory Control
Authors: Herreros-Alonso Ivan , Arsiwalla Xerxes D. , Verschure Paul F.M.J.
Published: October 2016

How does our motor system solve the problem of anticipatory control in spite of a wide spectrum of response dynamics from different musculo-skeletal systems, transport delays as well as response latencies throughout the central nervous system? To a great extent, our highly-skilled motor responses are a result of a reactive feedback system, originating in the brain-stem and spinal cord, combined with a feed-forward anticipatory system, that is adaptively fine-tuned by sensory experience and originates in the cerebellum. Based on that interaction we design the counterfactual predictive control (CFPC) architecture, an anticipatory adaptive motor control scheme, in which a feed-forward module, based on the cerebellum, steers an error feedback controller withcounterfactualerror signals. Those are signals that trigger reactions as actual errors would, but that do not code for any current of forthcoming errors. In order to determine the optimal learning strategy, we derive a novel learning rule for the feed-forward module that involves an eligibility trace and operates at the synaptic level. In particular, our eligibility trace provides a mechanism beyond co-incidence detection in that it convolves a history of prior synaptic inputs with error signals. In the context of cerebellar physiology, this solution implies that Purkinje cell synapses should generate eligibility traces using a forward model of the system being controlled. From an engineering perspective, CFPC provides a general-purpose anticipatory control architecture equipped with a learning rule that exploits the full dynamics of the closed-loop system.
Adaptive potential of a drug-targeted viral protein as a function of environmental stress
Authors: Dai Lei , Du Yushen , Qi Hangfei , Huber Christian D. , Wu Nicholas C. , Wang Ergang , Lloyd-Smith James O. , Sun Ren
Published: October 2016

RNA viruses are notorious for their ability to evolve rapidly under selection in novel environments. It is known that the high mutation rate of RNA viruses can generate huge genetic diversity to facilitate viral adaptation. However, less attention has been paid to the underlying fitness landscape that represents the selection forces on viral genomes. Here we systematically quantified the distribution of fitness effects (DFE) of about 1,600 single amino acid substitutions in the drug-targeted region of NS5A protein of Hepatitis C Virus (HCV). We found that the majority of non-synonymous substitutions incur large fitness costs, suggesting that NS5A protein is highly optimized in natural conditions. We characterized the adaptive potential of HCV by subjecting the mutant viruses to selection by the antiviral drug Daclatasvir. Both the selection coefficient and the number of beneficial mutations are found to increase with the level of environmental stress, which is modulated by the concentration of Daclatasvir. The changes in the spectrum of beneficial mutations in NS5A protein can be explained by a pharmacodynamics model describing viral fitness as a function of drug concentration. We test theoretical predictions regarding the distribution of beneficial fitness effects of mutations. We also interpret the data in the context of Fisher’s Geometric Model and find an increased distance to optimum as a function of environmental stress. Finally, we show that replication fitness of viruses is correlated with the pattern of sequence conservation in nature and viral evolution is constrained by the need to maintain protein stability.
Quantitative Seq-LGS – Genome-Wide Identification of Genetic Drivers of Multiple Phenotypes in Malaria Parasites
Authors: Abkallo Hussein M. , Martinelli Axel , Inoue Megumi , Ramaprasad Abhinay , Xangsayarath Phonepadith , Gitaka Jesse , Tang Jianxia , Yahata Kazuhide , Zoungrana Augustin , Mitaka Hayato , Hunt Paul , Carter Richard , Kaneko Osamu , Mustonen Ville , Illingworth Christopher J. R. , Pain Arnab , Culleton Richard
Published: October 2016

Identifying the genetic determinants of phenotypes that impact on disease severity is of fundamental importance for the design of new interventions against malaria. Traditionally, such discovery has relied on labor-intensive approaches that require significant investments of time and resources. By combining Linkage Group Selection (LGS), quantitative whole genome population sequencing and a novel mathematical modeling approach (qSeq-LGS), we simultaneously identified multiple genes underlying two distinct phenotypes, identifying novel alleles for growth rate and strain specific immunity (SSI), while removing the need for traditionally required steps such as cloning, individual progeny phenotyping and marker generation. The detection of novel variants, verified by experimental phenotyping methods, demonstrates the remarkable potential of this approach for the identification of genes controlling selectable phenotypes in malaria and other apicomplexan parasites for which experimental genetic crosses are amenable.

Significance Statement

This paper describes a powerful and rapid approach to the discovery of genes underlying medically important phenotypes in malaria parasites. This is crucial for the design of new drug and vaccine interventions. The approach bypasses the most time-consuming steps required by traditional genetic linkage studies and combines Mendelian genetics, quantitative deep sequencing technologies, genome analysis and mathematical modeling. We demonstrate that the approach can simultaneously identify multigenic drivers of multiple phenotypes, thus allowing complex genotyping studies to be conducted concomitantly. This methodology will be particularly useful for discovering the genetic basis of medically important phenotypes such as drug resistance and virulence in malaria and other apicomplexan parasites, as well as potentially in any organism undergoing sexual recombination.
Real-time tagging of biomedical entities
Authors: Pafilis Evangelos , Jensen Lars Juhl
Published: October 2016

Automatic annotation of text is an important complement to manual annotation, because the latter is highly labor intensive. We have developed a fast dictionary-based named entity recognition system, which is used for both real-time and bulk processing of text in a variety of biomedical web resources. We propose to adapt the system to make it interoperable with the PubAnnotation and Open Annotation standards.
Human enhancers harboring specific sequence composition, activity, and genome organization are linked to the immune response
Authors: Lecellier Charles-Henri , Wasserman Wyeth W. , Mathelier Anthony
Published: October 2016

The FANTOM5 consortium recently characterized 65,423 human enhancers from 1,829 cell and tissue samples using the Cap Analysis of Gene Expression technology. We showed that the guanine and cytosine content at enhancer regions distinguishes two classes of enhancers harboring distinct DNA structural properties at flanking regions. A functional analysis of their predicted gene targets highlighted one class of enhancers as significantly enriched for associations with immune response genes. Moreover, these enhancers were specifically enriched for regulatory motifs recognized by TFs involved in immune response. We observed that enhancers enriched for links to immune response genes were more cell type specific, preferentially activated upon bacterial infection, and with specific response activity. Looking at chromatin capture data, we found that the two classes of enhancers were lying in distinct topologically-associated domains and chromatin loops. Our results suggest that specific nucleotide compositions encode for classes of enhancers that are functionally distinct and specifically organized in the human genome.
Accuracy of demographic inferences from site frequency spectrum: the case of the yoruba population
Authors: Lapierre Marguerite , Lambert Amaury , Achaz Guillaume
Published: October 2016

Some methods for demographic inference based on the observed genetic diversity of current populations rely on the use of summary statistics such as the Site Frequency Spectrum (SFS). Demographic models can be either model-constrained with numerous parameters such as growth rates, timing of demographic events and migration rates, or model-flexible, with an unbounded collection of piecewise constant sizes. It is still debated whether demographic histories can be accurately inferred based on the SFS. Here we illustrate this theoretical issue on an example of demographic inference for an African population. The SFS of the Yoruba population (data from the 1000 Genomes Project) is fit to a simple model of population growth described with a single parameter (e.g., founding time). We infer a time to the most recent common ancestor of 1.7 million years for this population. However, we show that the Yoruba SFS is not informative enough to discriminate between several different models of growth. We also show that for such simple demographies, the fit of one-parameter models outperforms the model-flexible method recently developed by Liu and Fu. The use of this method on simulated data suggests that it is biased by the noise intrinsically present in the data.
A Machine Learning-based Framework to Identify Type 2 Diabetes through Electronic Health Records
Authors: Zheng Tao , Xie Wei , Xu Liling , He Xiaoying , Zhang Ya , You Mingrong , Yang Gong , Chen You
Published: October 2016

Objective

To discover diverse genotype-phenotype associations affiliated with Type 2 Diabetes Mellitus (T2DM) via genome-wide association study (GWAS) and phenome-wide association study (PheWAS), more cases (T2DM subjects) and controls (subjects without T2DM) are required to be identified (e.g., via Electronic Health Records (EHR)). However, existing expert based identification algorithms often suffer in a low recall rate and could miss a large number of valuable samples under conservative filtering standards. The goal of this work is to develop a semi-automated framework based on machine learning as a pilot study to liberalize filtering criteria to improve recall rate with a keeping of low false positive rate.

Materials and Methods

We propose a data informed framework for identifying subjects with and without T2DM from EHR via feature engineering and machine learning. We evaluate and contrast the identification performance of widely-used machine learning models within our framework, including k-Nearest-Neighbors, Naïve Bayes, Decision Tree, Random Forest, Support Vector Machine and Logistic Regression. Our framework was conducted on 300 patient samples (161 cases, 60 controls and 79 unconfirmed subjects), randomly selected from 23,281 diabetes related cohort retrieved from a regional distributed EHR repository ranging from 2012 to 2014.

Results

We apply top-performing machine learning algorithms on the engineered features. We benchmark and contrast the accuracy, precision, AUC, sensitivity and specificity of classification models against the state-of-the-art expert algorithm for identification of T2DM subjects. Our results indicate that the framework achieved high identification performances (~0.98 in average AUC), which are much higher than the state-of-the-art algorithm (0.71 in AUC).

Discussion

Expert algorithm-based identification of T2DM subjects from EHR is often hampered by the high missing rates due to their conservative selection criteria. Our framework leverages machine learning and feature engineering to loosen such selection criteria to achieve a high identification rate of cases and controls.

Conclusions

Our proposed framework demonstrates a more accurate and efficient approach for identifying subjects with and without T2DM from EHR.
Comparing multi- and single-sample variant calls to improve variant call sets from deep coverage whole-genome sequencing data
Authors: Shringarpure Suyash S. , Mathias Rasika A. , Hernandez Ryan D. , O’Connor Timothy D. , Szpiech Zachary A. , Torres Raul , De La Vega Francisco M. , Bustamante Carlos D. , Barnes Kathleen C. , Taub Margaret A. ,   Behalf of the CAAPA consortium
Published: October 2016

Motivation

Variant calling from next-generation sequencing (NGS) data is susceptible to false positive calls due to sequencing, mapping and other errors. To better distinguish true from false positive calls, we present a method that uses genotype array data from the sequenced samples, rather than public data such as HapMap or dbSNP, to train an accurate classifier using Random Forests. We demonstrate our method on a set of variant calls obtained from 642 African-ancestry genomes from the The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA), sequenced to high depth (30X).

Results

We have applied our classifier to compare call sets generated with different calling methods, including both single-sample and multi-sample callers. At a False Positive Rate of 5%, our method determines true positive rates of 97.5%, 95% and 99% on variant calls obtained using Illumina’s single-sample caller CASAVA, Real Time Genomics’ multisample variant caller, and the GATK Unified Genotyper, respectively. Since most NGS sequencing data is accompanied by genotype data for the same samples, our method can be trained on each dataset to provide a more accurate computational validation of site calls compared to generic methods. Moreover, our method allows for adjustment based on allele frequency (e.g., a different set of criteria to determine quality for rare vs. common variants) and thereby provides insight into sequencing characteristics that indicate data quality for variants of different frequencies.

Availability

Code will be made available prior to publication on Github.
No evidence for adaptation to local rhizobial mutualists in the legumeMedicago lupulina
Authors: Harrison Tia L. , Wood Corlett W. , Borges Isabela L. , Stinchcombe John R.
Published: October 2016

Local adaptation is a common but not ubiquitous feature of species interactions, and understanding the circumstances under which it evolves illuminates the factors that influence adaptive population divergence. Antagonistic species interactions dominate the local adaptation literature relative to mutualistic ones, preventing an overall assessment of adaptation within interspecific interactions. Here, we tested whether the legumeMedicago lupulinais adapted to the locally abundant species of mutualistic nitrogen-fixing bacteria (“rhizobia”), which vary in frequency across its eastern North American range. We reciprocally inoculated northern and southernM. lupulinagenotypes with the northern(Ensifer medicae)or southern bacterium(E. meliloti)in a greenhouse experiment. Neither northern nor southern plants produced more seed flowered earlier, or were more likely to flower when inoculated with their local rhizobium species, although plants produced more root nodules (the structures that house the bacteria) wit their local rhizobia. We used a pre-existing dataset to perform a genome scan for loci that showed elevated differentiation between field-collected plants that hosted different bacteria. None of the loci we identified belonged to the well-characterized suite of legume-rhizobia symbiosis genes, suggesting that the rhizobia do not drive genetic divergence betweenM. lupulinapopulations. Our results demonstrate that symbiont local adaptation is weak in this mutualism despite large-scale geographic variation in the identity of the interacting species.
Identifying cis-mediators for trans-eQTLs across many human tissues using genomic mediation analysis
Authors: Yang Fan , Wang Jiebiao ,   the GTEx consortium, Pierce Brandon L. , Chen Lin S.
Published: October 2016

The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is “mediation” by a local (cis) transcript. Thus, mediation analysis can be applied to genome-wide SNP and expression data in order to identify transcripts that are “cis-mediators” of trans-eQTLs, including those “cis-hubs” involved in regulation of many trans-genes. Identifying such mediators helps us understand regulatory networks and suggests biological mechanisms underlying trans-eQTLs, both of which are relevant for understanding susceptibility to complex diseases. The multi-tissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. However, the presence of complex hidden confounding effects in biological systems can make mediation analyses challenging and prone to confounding bias, particularly when conducted among diverse samples. To address this problem, we propose a new method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It enables the search of a very large pool of variables, and adaptively selects potential confounding variables for each mediation test. Analyses of simulated data and GTEx data demonstrate that the adaptive selection of confounders by GMAC improves the power and precision of mediation analysis. Application of GMAC to GTEx data provides new insights into the observed patterns of cis-hubs and trans-eQTL regulation across tissue types.
Automated refinement of macromolecular structures at low resolution using prior information
Authors: Kovalevskiy Oleg , Nicholls Robert A. , Murshudov Garib N.
Published: October 2016

Since the ratio of the number of observations to adjustable parameters is small at low resolution, it is necessary to use complementary information for the analysis of such data. ProSMART is a program that can generate restraints for macromolecules using homologous structures, as well as generic restraints for the stabilization of secondary structures. These restraints are used by REFMAC5 to stabilize the refinement of an atomic model. However, the optimal refinement protocol varies from case to case, and it is not always obvious how to select appropriate homologous structure(s), or other sources of prior information, for restraint generation. After running extensive tests on a large data set of low-resolution models, the best-performing refinement protocols and strategies for the selection of homologous structures have been identified. These strategies and protocols have been implemented in the Low-Resolution Structure Refinement (LORESTR) pipeline. The pipeline performs auto-detection of twinning and selects the optimal scaling method and solvent parameters. LORESTR can either use user-supplied homologous structures, or run an automated BLAST search and download homologues from the PDB. The pipeline executes multiple model-refinement instances using different parameters in order to find the best protocol. Tests show that the automated pipeline improves R factors, geometry and Ramachandran statistics for 94% of the low-resolution cases from the PDB included in the test set.
Naringin in Ganshuang Granule suppresses activation of hepatic stellate cells for anti‐fibrosis effect by inhibition of mammalian target of rapamycin
Authors: Shi Hongbo , Shi Honglin , Ren Feng , Chen Dexi , Chen Yu , Duan Zhongping
Published: October 2016

A previous study has demonstrated that Ganshuang granule (GSG) plays an anti‐fibrotic role partially by deactivation of hepatic stellate cells (HSCs). In HSCs activation, mammalian target of rapamycin (mTOR)‐autophagy plays an important role. We attempted to investigate the role of mTOR‐autophagy in anti‐fibrotic effect of GSG. The cirrhotic mouse model was prepared to demonstrate the anti‐fibrosis effect of GSG. High performance liquid chromatography (HPLC) analyses were used to identify the active component of GSG. The primary mouse HSCs were isolated and naringin was added into activated HSCs to observe its anti‐fibrotic effect. 3‐methyladenine (3‐MA) and Insulin‐like growth factor‐1 (IGF‐1) was added, respectively, into fully activated HSCs to explore the role of autophagy and mTOR. GSG played an anti‐fibrotic role through deactivation of HSCs in cirrhotic mouse model. The concentration of naringin was highest in GSG by HPLC analyses and naringin markedly suppressed HSCs activation in vitro, which suggested that naringin was the main active component of GSG. The deactivation of HSCs caused by naringin was not because of the autophagic activation but mTOR inhibition, which was supported by the following evidence: first, naringin induced autophagic activation, but when autophagy was blocked by 3‐MA, deactivation of HSCs was not attenuated or reversed. Second, naringin inhibited mTOR pathway, meanwhile when mTOR was activated by IGF‐1, deactivation of HSCs was reversed. In conclusion, we have demonstrated naringin in GSG suppressed activation of HSCs for anti‐fibrosis effect by inhibition of mTOR, indicating a potential therapeutic application for liver cirrhosis.
Structure of myosin filaments from relaxed
Lethocerus
flight muscle by cryo-EM at 6 Å resolution
Authors: Hu Zhongjun , Taylor Dianne W. , Reedy Michael K. , Edwards Robert J. , Taylor Kenneth A.
Published: October 2016

Cryo-EM of relaxed myosin filament reveals unique molecular motor conformation and unprecedented details of the filament backbone.
Giant facet-dependent spin-orbit torque and spin Hall conductivity in the triangular antiferromagnet IrMn
3
Authors: Zhang Weifeng , Han Wei , Yang See-Hun , Sun Yan , Zhang Yang , Yan Binghai , Parkin Stuart S. P.
Published: October 2016

A giant facet-dependent spin Hall conductivity is found in IrMn
3
due to its chiral triangular antiferromagnetic structure.
Satellite tidal magnetic signals constrain oceanic lithosphere-asthenosphere boundary
Authors: Grayver Alexander V. , Schnepf Neesha R. , Kuvshinov Alexey V. , Sabaka Terence J. , Manoj Chandrasekharan , Olsen Nils
Published: October 2016

Researchers present results on the oceanic upper mantle electrical structure revealed by satellite-detected tidal magnetic signals.
Listeria monocytogenes in Stone Fruits Linked to a Multistate Outbreak: Enumeration of Cells and Whole-Genome Sequencing
Authors: Chen Yi , Burall Laurel S. , Luo Yan , Timme Ruth , Melka David , Muruvanda Tim , Payne Justin , Wang Charles , Kastanis George , Maounounen-Laasri Anna , De Jesus Antonio J. , Curry Phillip E. , Stones Robert , K'Aluoch Okumu , Liu Eileen , Salter Monique , Hammack Thomas S. , Evans Peter S. , Parish Mickey , Allard Marc W. , Datta Atin , Strain Errol A. , Brown Eric W.
Published: October 2016

In 2014, the identification of stone fruits contaminated with
Listeria monocytogenes
led to the subsequent identification of a multistate outbreak. Simultaneous detection and enumeration of
L. monocytogenes
were performed on 105 fruits, each weighing 127 to 145 g, collected from 7 contaminated lots. The results showed that 53.3% of the fruits yielded
L. monocytogenes
(lower limit of detection, 5 CFU/fruit), and the levels ranged from 5 to 2,850 CFU/fruit, with a geometric mean of 11.3 CFU/fruit (0.1 CFU/g of fruit). Two serotypes, IVb-v1 and 1/2b, were identified by a combination of PCR- and antiserum-based serotyping among isolates from fruits and their packing environment; certain fruits contained a mixture of both serotypes. Single nucleotide polymorphism (SNP)-based whole-genome sequencing (WGS) analysis clustered isolates from two case-patients with the serotype IVb-v1 isolates and distinguished outbreak-associated isolates from pulsed-field gel electrophoresis (PFGE)-matched, but epidemiologically unrelated, clinical isolates. The outbreak-associated isolates differed by up to 42 SNPs. All but one serotype 1/2b isolate formed another WGS cluster and differed by up to 17 SNPs. Fully closed genomes of isolates from the stone fruits were used as references to maximize the resolution and to increase our confidence in prophage analysis. Putative prophages were conserved among isolates of each WGS cluster. All serotype IVb-v1 isolates belonged to singleton sequence type 382 (ST382); all but one serotype 1/2b isolate belonged to clonal complex 5.

IMPORTANCE
WGS proved to be an excellent tool to assist in the epidemiologic investigation of listeriosis outbreaks. The comparison at the genome level contributed to our understanding of the genetic diversity and variations among isolates involved in an outbreak or isolates associated with food and environmental samples from one facility. Fully closed genomes increased our confidence in the identification and comparison of accessory genomes. The diversity among the outbreak-associated isolates and the inclusion of PFGE-matched, but epidemiologically unrelated, isolates demonstrate the high resolution of WGS. The prevalence and enumeration data could contribute to our further understanding of the risk associated with
Listeria monocytogenes
contamination, especially among high-risk populations.