bluuebunny/crossref_metadata_2025 huggingface dataset:
Arteriovenous Lesions of the Internal Auditory Canal
Authors: Anzalone Charles L. , Lane John I. , Link Michael J. , Carlson Matthew L.
Published: March 2017

Objective:

To describe a unique case of an asymptomatic arteriovenous lesion of the internal auditory canal (IAC) and present the associated imaging findings.

Methods:

Retrospective case report and review of the literature.

Results:

A 55-year-old man presented for further evaluation of a left-sided sudden sensorineural hearing loss that occurred 8 years earlier. Careful review of outside serial magnetic resonance (MR) imaging revealed a contralateral, ill-defined right-sided IAC mass with low T2 signal and subtle peripheral enhancement on postcontrast T1-weighted sequencing. The patient had no history of right-sided otologic symptoms.

Subsequent dedicated IAC MR imaging confirmed the presence of a space-occupying lesion adjacent to a complexity of vasculature. The presence of prominent flow voids, paucity of avid enhancement on previous studies, and marked signal within the lesion on time-of-flight MR angiography and MR venography was consistent with the diagnosis of a solitary arteriovenous lesion of the IAC. There was no radiological evidence of recent or remote parenchymal or subarachnoid hemorrhage or stroke.

Conclusion:

We report a novel case of an occult asymptomatic IAC arteriovenous lesion. Vascular anomalies confined to the IAC are rare. To date, there have been only four reports in the literature of IAC arteriovenous lesions and our case is the first to present asymptomatically. A high index of suspicion and dedicated imaging is required to identify and accurately diagnose these lesions to guide appropriate counseling and potential intervention.
Association of Pediatric Cardiac Surgical Volume and Mortality After Cardiac ECMO
Authors: Barrett Cindy S. , Chan Titus T. , Wilkes Jacob , Bratton Susan L. , Thiagarajan Ravi R.
Published: March 2017

Centers with higher surgical and extracorporeal membrane oxygenation (ECMO) volumes have improved survival for children undergoing pediatric cardiac surgery and ECMO, respectively. We examined the relationship between both cardiac surgical and cardiac ECMO volumes, with survival. Using data from the Pediatric Health Information System, we reviewed patients who underwent ECMO during the hospitalization for cardiac surgery or heart transplantation from January 2003 to June 2014. Among 106,967 patients in 43 centers undergoing a Risk Adjustment for Congenital Heart Surgery-1 1–6 procedure (n = 104,951) or cardiac transplantation (n = 2,016), 2.9% (n = 3,069) underwent ECMO support. Centers were categorized into volume quartiles based on annual ECMO and cardiac surgical volumes. Multivariable logistic regression models controlling for clustering by center and adjusting for factors associated with mortality were constructed. Although mortality was lower in ECMO centers that performed ≥7 ECMO runs (odds ratio [OR]: 0.44, 95% confidence interval [CI]: 0.22–0.88)] and centers performing ≥158 cardiac surgical cases (OR: 0.37, 95% CI: 0.22–0.63), surgical volume was more strongly associated with ECMO mortality. Centers with higher cardiac surgical volume had fewer ECMO complications. Cardiac surgical volume, compared with ECMO volume, is more strongly associated with cardiac ECMO survival.
Adherence to Celiac Disease and Eosinophilic Esophagitis Biopsy Guidelines Is Poor in Children
Authors: Wallach Thomas , Genta Robert M. , Lebwohl Benjamin , Green Peter H.R. , Reilly Norelle R.
Published: March 2017

Objectives:

Celiac disease (CD) and eosinophilic esophagitis (EoE) are underdiagnosed gastrointestinal conditions, which adversely affect children's health. Previous studies have shown that diagnostic guidelines for CD are not consistently followed in adults. The aims of the present study are to assess the frequency with which endoscopists comply with diagnostic guidelines for CD and EoE in children, and to determine whether an association exists between adherence to biopsy guidelines and disease detection in pediatric patients.

Methods:

We reviewed pathology reports from 9171 children (ages 0–18) with at least 1 duodenal biopsy, and 8280 children with at least 1 esophageal biopsy, with specimens submitted to a national pathology laboratory. Frequency of adherence to diagnostic guidelines and recommendations for CD and EoE were determined, and the effect of this upon detection of CD and EoE.

Results:

Overall, 35% of cases were biopsied according to the 2006 American Gastroenterological Association guidelines for CD diagnosis; 8% were biopsied according to the 2007 American Gastroenterological Association EoE consensus recommendations. Detection of CD and EoE increased with the number of biopsies collected (P for trend in each <0.001). Adherence to diagnostic guidelines was particularly poor among those found to have histologically normal mucosa in both cohorts. The likelihood of CD and EoE diagnosis was significantly associated with adherence to diagnostic guidelines (odds ratio for CD 6.3, 95% confidence interval 4.4–8.9; odds ratio for EoE 2.4, 95% confidence interval 1.9–2.9).

Conclusion:

Adherence to established guidelines is poor, and improved guideline adherence is associated with greater disease detection rates for CD and EoE.
Management of Pediatric Nonalcoholic Fatty Liver Disease by Academic Hepatologists in Canada
Authors: Mouzaki Marialena , Ling Simon C. , Schreiber Richard A. , Kamath Binita M.
Published: March 2017

Background:

The literature on the optimal clinical management of pediatric patients with nonalcoholic fatty liver disease (NAFLD) is limited. The objective of this study was to identify discrepancies in the care provided to patients with NAFLD by hepatologists practicing in academic centers across Canada.

Methods:

A nationwide survey was distributed electronically to all pediatric hepatologists practicing in university‐affiliated hospitals using the infrastructure of the Canadian Pediatric Hepatology Research Group. The responses were anonymous.

Results:

The response rate to the survey was 79%. Everyone reported diagnosing NAFLD based on a combination of elevated transaminases and imaging suggestive of steatosis in the context of an otherwise negative workup for other liver diseases. Only 14% use liver biopsy to confirm the diagnosis. There are significant discrepancies in the frequency of screening for other comorbidities (eg, hypertension, sleep apnea, etc) and in the frequency of laboratory investigations (eg, lipid profile, transaminases, international normalized ratio, etc). Frequency of outpatient clinic follow‐up varies significantly. Treatment is consistently based on lifestyle modifications; however, reported patient outcomes in terms of body mass index improvements are poor.

Conclusions:

There are significant discrepancies in the care provided to children with NAFLD by hepatologists practicing in academic centers across Canada.
Classification of Acute Pancreatitis in the Pediatric Population
Authors: Abu‐El‐Haija Maisam , Kumar Soma , Szabo Flora , Werlin Steven , Conwell Darwin , Banks Peter , Morinville Veronique D. ,   NASPGHAN Pancreas Committee
Published: March 2017

Introduction:

Acute pancreatitis (AP) is an emerging problem in pediatrics, with most cases resolving spontaneously. Approximately 10% to 30%, however, are believed to develop “severe acute pancreatitis” (SAP).

Methods:

This consensus statement on the classification of AP in pediatrics was developed through a working group that performed an evidence‐based search for classification of AP in adult pancreatitis, definitions and criteria of systemic inflammatory response syndrome, and organ failure in pediatrics.

Results and Discussion:

Severity in pediatric AP is classified as mild, moderately severe, or severe. Mild AP is defined by AP without organ failure, local or systemic complications, and usually resolves in the first week. Moderately SAP is defined by the presence of transient organ failure that resolves in no >48 hours, or local complications or exacerbation of co‐morbid disease. SAP is defined by persistent organ failure that lasts <48 hours. The presence of systemic inflammatory response syndrome is associated with increased risk for persistent organ dysfunction. Criteria to define organ failure must be pediatric‐ and age‐based.

Conclusions:

Classifying AP in pediatrics in a uniform fashion will help define outcomes and encourage the development of future studies in the field of pediatric pancreatitis.
Case Report: Immune-mediated Complete Response in a Patient With Recurrent Advanced Ewing Sarcoma (EWS) After Vigil Immunotherapy
Authors: Ghisoli Maurizio , Rutledge McCarley , Stephens Philip J. , Mennel Robert , Barve Minal , Manley Meghan , Oliai Bahram R. , Murphy Kathleen M. , Manning Luisa , Gutierrez Belen , Rangadass Priyanka , Walker Ashli , Wang Zhaohui , Rao Donald , Adams Ned , Wallraven Gladice , Senzer Neil , Nemunaitis John
Published: March 2017

Ewing sarcoma is a highly resistant disease with a <10% chance of survival at 5 years after failure of frontline chemotherapy. This is a case report of an Ewing sarcoma patient with metastatic disease recurrence <2 years after standard chemotherapy/radiation who achieved a durable and sustained complete response after 2 series of treatments with Vigil (GMCSF/bi-shRNA furin DNA autologous tumor immunotherapy) serially manufactured from first and second recurrences with ELISPOT assay correlation. Results support justification of further testing of Vigil with ELISPOT assay as a biomarker to assess level of immune response and correlation with disease control.
High-Quality Randomized Controlled Trials in Pediatric Critical Care: A Survey of Barriers and Facilitators*
Authors: Duffett Mark , Choong Karen , Foster Jennifer , Meade Maureen , Menon Kusum , Parker Melissa , Cook Deborah J.
Published: March 2017

Objectives:

High-quality, adequately powered, randomized controlled trials are needed to inform the care of critically ill children. Unfortunately, such evidence is not always available. Our objective was to identify barriers and facilitators of conducting high-quality randomized controlled trials in pediatric critical care, from the perspective of trialists in this field.

Design:

Self-administered online survey. Respondents rated the importance of barriers and effectiveness of facilitators on seven-point scales.

Setting:

Authors of 294 pediatric critical care randomized controlled trials (published 1986 to June 2015).

Subjects:

One hundred sixteen researchers from 25 countries participated.

Interventions:

None.

Measurements and Main Results:

Respondents reported a median (Q1, Q3) of 21 years (15, 26 yr) of experience and 41 (36%) had authored more than one randomized controlled trial. More survey respondents, compared with nonrespondents, had published more than one trial (35% vs 26%; p = 0.002) and their trials were more often cited (median citations/yr, 2.4 vs 1.5; p < 0.001). Of the barriers listed, the five most important were primarily related to lack of funding. The five facilitators perceived as most effective were protected time for research, ability to recruit participants 24 hours per day/7 days per week, conducting randomized controlled trials in collaboration with a research network, funding from government agencies specifically for randomized controlled trials in critically ill children, and academic department support for conducting randomized controlled trials. Respondent experience and country income level were associated with differences in importance ratings for eight of 41 barriers. There were fewer such differences for facilitators.

Conclusions:

Lack of funding and time are major barriers to conducting pediatric critical care randomized controlled trials worldwide. Although barriers varied among country income levels, the facilitators of such trials were more consistent. In addition to increased funding, respondents identified other strategies such as research networks that are within the purview of the pediatric critical care research community, to facilitate the conduct of rigorous randomized controlled trials.
Proteasome inhibitor-induced gastrointestinal toxicity
Authors: Stansborough Romany L. , Gibson Rachel J.
Published: March 2017

Purpose of review

Gastrointestinal toxicities are commonly reported following treatment with proteasome inhibitors. The first-generation proteasome inhibitor, bortezomib, induces significant gastrointestinal side effects including nausea, vomiting, diarrhoea, and constipation, occurring in up to 84% of patients. Despite the development of safer proteasome inhibitors, such as carfilzomib, gastrointestinal toxicities remain some of the most common side effects. This review aims to summarize the previous literature on proteasome inhibitor-induced gastrointestinal toxicities, report on recent updates in the field, and investigate possible mechanisms of this toxicity.

Recent findings

Updates in the literature have included a direct comparison of the safety of approved proteasome inhibitors, bortezomib and carfilzomib, reporting less neurotoxicity and similar gastrointestinal toxicity, from carfilzomib when compared with bortezomib. Many recent studies have investigated the safety of orally bioavailable proteasome inhibitors, such as ixazomib and oprozomib. However, little progress has been made in understanding the possible mechanisms of proteasome inhibitor-induced gastrointestinal toxicities.

Although recent studies have continued to report gastrointestinal toxicities resulting from proteasome inhibitor treatment, particularly when combined with other agents or when administered orally, the mechanisms of proteasome inhibitor-induced gut toxicity remain largely unexplored. Further studies are needed to investigate the pathophysiology of this toxicity to improve the safety of existing and novel proteasome inhibitors.
LncATLAS database for subcellular localisation of long noncoding RNAs
Authors: Mas-Ponte David , Carlevaro-Fita Joana , Palumbo Emilio , Hermoso Toni , Guigo Roderic , Johnson Rory
Published: March 2017

Background

The subcellular localisation of long noncoding RNAs (lncRNAs) holds valuable clues to their molecular function. However, measuring localisation of newly-discovered lncRNAs involves time-consuming and costly experimental methods.

Results

We have created “LncATLAS”, a comprehensive resource of lncRNA localisation in human cells based on RNA-sequencing datasets. Altogether, 6768 GENCODE-annotated lncRNAs are represented across various compartments of 15 cell lines. We introduce “Relative concentration index” (RCI) as a useful measure of localisation derived from ensemble RNAseq measurements. LncATLAS is accessible through an intuitive and informative webserver, from which lncRNAs of interest are accessed using identifiers or names. Localisation is presented across cell types and organelles, and may be compared to the distribution of all other genes. Publication-quality figures and raw data tables are automatically generated with each query, and the entire dataset is also available to download.

Conclusions

LncATLAS makes lncRNA subcellular localisation data available to the widest possible number of researchers. It is available at lncATLAS.crg.eu.
Comprehensive mapping of HIV-1 escape from a broadly neutralizing antibody
Authors: Dingens Adam S. , Haddox Hugh K. , Overbaugh Julie , Bloom Jesse D.
Published: March 2017

Precisely defining how viral mutations affect HIV’s sensitivity to antibodies is vital to the development and evaluation of vaccines and antibody immunotherapeutics. But despite great effort, a full map of escape mutants has not yet been delineated for even a single anti-HIV antibody. Here we describe a massively parallel experimental approach to quantify how all single amino-acid mutations to Envelope (Env) affect HIV’s sensitivity to a neutralizing antibody. We applied this approach to PGT151 and identified novel sites of escape in addition to those previously defined by structural and functional studies, such as glycans at sites 611 and 637, residue 647, and sites in the fusion peptide. Evaluating the effect of each amino acid at each site lends insight into the biochemical basis of escape throughout the epitope. Thus, comprehensive mapping of HIV antibody escape gives a quantitative, mutation-level view of the ways that Env can evade neutralization.
Single-cell RNA-Sequencing uncovers transcriptional states and fate decisions in haematopoiesis
Authors: Athanasiadis Emmanouil I. , Botthof Jan G. , Andres Helena , Ferreira Lauren , Lio Pietro , Cvejic Ana
Published: March 2017

The success of marker-based approaches for dissecting haematopoiesis in mouse and human is reliant on the presence of well-defined cell-surface markers specific for diverse progenitor populations. An inherent problem with this approach is that the presence of specific cell surface markers does not directly reflect the transcriptional state of a cell. Here we used a marker-free approach to computationally reconstruct the blood lineage tree in zebrafish and order cells along their differentiation trajectory, based on their global transcriptional differences. Within the population of transcriptionally similar stem and progenitor cells our analysis revealed considerable cell-to-cell differences in their probability to transition to another, committed state. Once fate decision was executed, the suppression of transcription of ribosomal genes and up-regulation of lineage specific factors coordinately controlled lineage differentiation. Evolutionary analysis further demonstrated that this haematopoietic program was highly conserved between zebrafish and higher vertebrates.
A framework to identify modifier genes in patients with Phelan-McDermid syndrome
Authors: Tabet Anne-Claude , Rolland Thomas , Ducloy Marie , Lévy Jonathan , Buratti Julien , Mathieu Alexandre , Haye Damien , Perrin Laurence , Dupont Céline , Passemard Sandrine , Capri Yline , Verloes Alain , Drunat Séverine , Keren Boris , Mignot Cyril , Marey Isabelle , Jacquette Aurélia , Whalen Sandra , Pipiras Eva , Benzacken Brigitte , Chantot-Bastaraud Sandra , Afenjar Alexandra , Héron Delphine , Le Caignec Cédric , Beneteau Claire , Pichon Olivier , Isidor Bertrand , David Albert , Dupont Jean-Michel , Kemeny Stephan , Gouas Laetitia , Vago Philippe , Mosca-Boidron Anne-Laure , Faivre Laurence , Missirian Chantal , Philip Nicole , Sanlaville Damien , Edery Patrick , Satre Véronique , Coutton Charles , Devillard Françoise , Dieterich Klaus , Vuillaume Marie-Laure , Rooryck Caroline , Lacombe Didier , Pinson Lucile , Gatinois Vincent , Puechberty Jacques , Chiesa Jean , Lespinasse James , Dubourg Christèle , Quelin Chloé , Fradin Mélanie , Journel Hubert , Toutain Annick , Martin Dominique , Benmansour Abdelamdjid , Toro Roberto , Amsellem Frédérique , Delorme Richard , Bourgeron Thomas
Published: March 2017

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability, speech impairment, and autism spectrum disorders (ASD). It results from a deletion of the 22q13 locus that in most cases includes theSHANK3gene.SHANK3is considered a major gene for PMS, but the factors modulating the severity of the syndrome remain largely unknown. In this study, we investigated 85 PMS patients with different 22q13 rearrangements (78 deletions, 7 duplications). We first explored their clinical features and provide evidence for frequent corpus callosum abnormalities. We then mapped candidate genomic regions at the 22q13 locus associated with risk of clinical features, and suggest a second locus associated with absence of speech. Finally, in some cases, we identified additional rearrangements at loci associated with ASD, potentially modulating the severity of the syndrome. We also report the firstSHANK3deletion transmitted to five affected daughters by a mother without intellectual disability nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
GROOLS: reactive graph reasoning for genome annotation through biological processes
Authors: Mercier Jonathan , Josso Adrien , Médigue Claudine , Vallenet David
Published: March 2017

Background

High quality functional annotation is essential for understanding the phenotypic consequences encoded in a genome. Despite improvements in bioinformatics methods, millions of sequences in databanks are not assigned reliable functions. The curation of protein functions in the context of biological processes is a way to evaluate and improve their annotation.

Results

We developed an expert system using paraconsistent logic, named GROOLS (Genomic Rule Object-Oriented Logic System), that evaluates the completeness and the consistency of predicted functions through biological processes like metabolic pathways. Using a generic and hierarchical representation of knowledge, biological processes are modeled in a graph from which observations (i.e. predictions and expectations) are propagated by rules. At the end of the reasoning, conclusions are assigned to biological process components and highlight uncertainties and inconsistencies. Results on 14 microbial organisms are presented.

Conclusions

GROOLS software is designed to evaluate the overall accuracy of functional unit and pathway predictions according to organism experimental data like growth phenotypes. It assists biocurators in the functional annotation of proteins by focusing on missing or contradictory observations.
Genomic basis and evolutionary potential for extreme drought adaptation inArabidopsis thaliana
Authors: Exposito-Alonso Moises , Vasseur François , Ding Wei , Wang George , Burbano Hernán A. , Weigel Detlef
Published: March 2017

Because earth is currently experiencing unprecedented climate change, it is important to predict how species will respond to it. However, geographically-explicit predictive studies frequently ignore that species are comprised of genetically diverse individuals that can vary in their degree of adaptation to extreme local environments; properties that will determine the species’ ability to withstand climate change. Because an increase in extreme drought events is expected to challenge plant communities with global warming, we carried out a greenhouse experiment to investigate which genetic variants predict surviving an extreme drought event and how those variants are distributed across EurasianArabidopsis thalianaindividuals. Genetic variants conferring higher drought survival showed signatures of polygenic adaptation, and were more frequently found in Mediterranean and Scandinavian regions. Using geoenvironmental models, we predicted that Central European populations might lag behind in adaptation by the end of the 21stcentury. Further analyses showed that a population decline could nevertheless be compensated by natural selection acting efficiently over standing variation or by migration of adapted individuals from populations at the margins of the species’ distribution. These findings highlight the importance of within-species genetic heterogeneity in facilitating an evolutionary response to a changing climate.

One-sentence summary

“Future genetic changes inA. thalianapopulations can be forecast by combining climate change models with genomic predictions based on experimental phenotypic data.”
SQANTI: extensive characterization of long read transcript sequences for quality control in full-length transcriptome identification and quantification
Authors: Tardaguila Manuel , Fuente Lorena de la , Marti Cristina , Pereira Cécile , Pardo-Palacios Francisco Jose , Risco Hector del , Ferrell Marc , Mellado Maravillas , Macchietto Marissa , Verheggen Kenneth , Edelmann Mariola , Ezkurdia Iakes , Vazquez Jesus , Tress Michael , Mortazavi Ali , Martens Lennart , Rodriguez-Navarro Susana , Moreno Victoria , Conesa Ana
Published: March 2017

High-throughput sequencing of full-length transcripts using long reads has paved the way for the discovery of thousands of novel transcripts, even in very well annotated organisms as mice and humans. Nonetheless, there is a need for studies and tools that characterize these novel isoforms. Here we present SQANTI, an automated pipeline for the classification of long-read transcripts that computes 47 descriptors that can be used to assess the quality of the data and of the preprocessing pipelines. We applied SQANTI to a neuronal mouse transcriptome using PacBio long reads and illustrate how the tool is effective in readily describing the composition of and characterizing the full-length transcriptome. We perform extensive evaluation of ToFU PacBio transcripts by PCR to reveal that an important number of the novel transcripts are technical artifacts of the sequencing approach, and that SQANTI quality descriptors can be used to engineer a filtering strategy to remove them. Most novel transcripts in this curated transcriptome are novel combinations of existing splice sites, result more frequently in novel ORFs than novel UTRs and are enriched in both general metabolic and neural specific functions. We show that these new transcripts have a major impact in the correct quantification of transcript levels by state-of-the-art short-read based quantification algorithms. By comparing our iso-transcriptome with public proteomics databases we find that alternative isoforms are elusive to proteogenomics detection and are variable in protein changes with respect to the principal isoform of their genes. SQANTI allows the user to maximize the analytical outcome of long read technologies by providing the tools to deliver quality-evaluated and curated full-length transcriptomes. SQANTI is available athttps://bitbucket.org/ConesaLab/sqanti.
CNN-based Encoding and Decoding of Visual Object Recognition in Space and Time
Authors: Seeliger K. , Fritsche M. , Güçlü U. , Schoenmakers S. , Schoffelen J.-M. , Bosch S. E. , van Gerven M. A. J.
Published: March 2017

Deep convolutional neural networks (CNNs) have been put forward as neurobiologically plausible models of the visual hierarchy. Using functional magnetic resonance imaging, CNN representations of visual stimuli have previously been shown to correspond to processing stages in the ventral and dorsal streams of the visual system. Whether this correspondence between models and brain signals also holds for activity acquired at high temporal resolution has been explored less exhaustively. Here, we addressed this question by combining CNN-based encoding models with magnetoencephalography (MEG). Human participants passively viewed 1000 images of objects while MEG signals were acquired. We modelled their high temporal resolution source-reconstructed cortical activity with CNNs, and observed a feedforward sweep across the visual hierarchy between 75-200 ms after stimulus onset. This spatiotemporal cascade was captured by the network layer representations, where the increasingly abstract stimulus representation in the hierarchical network model was reflected in different parts of the visual cortex, following the visual ventral stream. We further validated the accuracy of our encoding model by decoding stimulus identity in a left-out validation set of viewed objects, achieving state-of-the-art decoding accuracy.
A Species-Specific Nematocide that Results in Terminal Embryogenesis
Authors: Renahan Tess , Hong Ray L.
Published: March 2017

Nematode-insect interactions are ubiquitous, complex, and constantly changing as the host and nematode coevolve. The entomophilic nematodePristionchus pacificusis found on a myriad of beetle species worldwide, though the molecular dynamics of this relationship are largely unknown. To better understand how host cues affectP. pacificusembryogenesis, we characterized the threshold of sensitivity to the pheromone (Z)-7-tetradecen-2-one (ZTDO) by determining the minimum exposure duration and developmental window that results inP. pacificusembryonic lethality. We found early-stage embryos exposed to volatile ZTDO for as few as four hours all display terminal embryogenesis, characterized by punctuated development up to 48 hours later, with abnormal morphology and limited lumen formation. To determine if the pheromone arrests pre-hatching development by suffocating or permeabilizing the eggshells, we raised embryos under anoxic condition as well as examined eggshell permeability using the lipophilic dye FM4-64. We found that asphyxiating the embryos arrested embryogenesis in a reversible manner but did not phenocopy the effects of ZTDO exposure, whereas the ZTDO-induced disruption of embryogenesis did correlate with increased eggshell permeability. The effects of ZTDO are also highly specific, as other lipid insect compounds do not produce any detectable embryocidal effect. The high specificity and unusual teratogenic effect of ZTDO may be important in mediating the host-nematode relationship by regulatingP. pacificusdevelopment.

Summary Statement

Insect-associated nematodes coordinate their development using host cues to “walk the line” between mutualism and pathogenesis. A host pheromone causes terminal embryogenesis by permeablizing the nematode eggshell.
Positive interactions support complex networks
Authors: Losapio Gianalberto , de la Cruz Marcelino , Escudero Adrián , Schmid Bernhard , Schöb Christian
Published: March 2017

Ecologists have recognised the effects of biotic interactions on the spatial distribution of living organisms. Yet, the spatial structure of plant interaction networks in real-world ecosystems has remained elusive so far. Using spatial pattern and network analyses, we found that alpine plant communities are organised in spatially variable and complex networks. Specifically, the cohesiveness of complex networks is promoted by short-distance positive plant interactions. At fine spatial scale, where positive mutual interactions prevailed, networks were characterised by a large connected component. With increasing scale, when negative interactions took over, network architecture became more hierarchical with many detached components that show a network collapse. This study highlights the crucial role of positive interactions for maintaining species diversity and the resistance of communities in the face of environmental perturbations.
Eyes closed or Eyes open? Exploring the alpha desynchronization hypothesis in resting state functional connectivity networks with intracranial EEG
Authors: Gómez-Ramírez Jaime , Freedman Shelagh , Mateos Diego , Pérez-Velázquez José Luis , Valiante Taufik
Published: March 2017

This paper addresses a fundamental question, are eyes closed and eyes open resting states equivalent baseline conditions, or do they have consistently different electrophysiological signatures? We compare the functional connectivity patterns in an eyes closed resting state with an eyes open resting state, and show that functional connectivity in the alpha band decreases in the eyes open condition compared to eyes closed. This "alpha desynchronization " or reduction in the number of connections from eyes closed to eyes open, is here, for the first time, studied with intracranial recordings. We provide two calculations of the wiring cost, local and mesoscopic, defined in terms of the distance between the electrodes and the likelihood that they are functionally connected. We find that, in agreement with the "alpha desynchronization" hypothesis, the local wiring cost decreases going from eyes closed to eyes open. However, when the wiring cost calculation takes into account the connectivity pattern, the wiring cost variation from eyes closed to eyes open is not as consistent and shows regional specificity. The wiring cost measure defined here, provides a new avenue for understanding the electrophysiology of resting state.
Characterization of nitrogen deposition by means of atmospheric biomonitors
Authors: Díaz-Álvarez E. A. , de la Barrera E.
Published: March 2017

An increase of nitrogen deposition resulting from human activities is not only a major threat for global biodiversity, but also for human health, especially in highly populated regions. It is thus important and in some instances legally mandated to monitor reactive nitrogen species in the atmosphere. The utilization of widely distributed biological species suitable for biomonitoring may be a good alternative. We assessed the suitability of an ensemble of atmospheric biomonitors of nitrogen deposition by means of an extensive sampling of a lichen, two mosses, and a bromeliad throughout the Valley of Mexico, whose population reaches 30 million, and subsequent measurements of nitrogen metabolism parameters. In all cases we found significant responses of nitrogen content, C:N ratio and the δ15N to season and site. In turn, the δ15N for the mosses responded linearly to the wet deposition. Also, the nitrogen content (R2= 0.7), the C:N ratio (R2= 0.6), and δ15N (R2= 0.5) for the bromeliad had a linear response to NOx. However, the bromeliad was not found in sites with NOx concentrations exceeding 80 ppb, apparently of as a consequence of exceeding nitrogen. These biomonitors can be utilized in tandem to determine the status of atmospheric nitrogenous pollution in regions without monitoring networks for avoiding health problems for ecosystems and humans.
ChIPSeqFPro, a pipeline for sequential processing of ChIP-Seq fastq to bigwig files
Authors: Pjanic Milos
Published: March 2017

ChIPSeqFPro is a pipeline that automates processing of a collection of ChIPSeq or ATAC-Seq data starting from the gzip compressed fastq files. It performs the quality control using FastQC, mapping to the human genome hg19 or mouse mm10 using BWA mapper, for both single read or paired end sequencing fastq files, followed with sam to bam conversion using samtools view, creates statistics on bam files using samtools flagstat, peak calling with MACS, and finally creates high resolution bigwig files from bam files using a custom script bam2bigwig that invokes bedtools bamtobed and UCSC scripts, bedItemOverlapCount, bedGraphToBigWig and fetchChromSizes.
Genetic and epigenetic insight into morphospecies in a reef coral
Authors: Dimond James L. , Gamblewood Sanoosh K. , Roberts Steven B.
Published: March 2017

Incongruence between conventional and molecular systematics has left the delineation of many species unresolved. Reef-building corals are no exception, with phenotypic plasticity among the most plausible explanations for alternative morphospecies. As potential molecular signatures of phenotypic plasticity, epigenetic processes may contribute to our understanding of morphospecies. We compared genetic and epigenetic variation in Caribbean branchingPoritesspp., testing the hypothesis that epigenetics— specifically, differential patterns of DNA methylation—play a role in alternative morphotypes of a group whose taxonomic status has been questioned. We used reduced representation genome sequencing to analyze over 1,000 single nucleotide polymorphisms and CpG sites in 27Poritesspp. exhibiting a range of morphotypes from a variety of habitats in Belize. We found stronger evidence for genetic rather than epigenetic structuring, identifying three well-defined genetic groups. One of these groups exhibited significantly thicker branches, and branch thickness was a better predictor of genetic groups than depth, habitat, or symbiont type. Epigenetic patterns were more subtle, with no clear groups. The more thickly branched individuals in one of the genetic groups exhibited some epigenetic similarity, suggesting potential covariation of genetics and epigenetics. This covariation was further supported by a positive association between pairwise genetic and epigenetic distance. We speculate that epigenetic patterns are a complex mosaic reflecting inheritance and diverse environmental histories. Given the role of genetics in branchingPoritesspp. morphospecies we were able to detect with genome-wide sequencing, use of such techniques throughout the geographic range may help settle their phylogeny.
Antibody-mediated depletion of protein variant expression in living cells (Protein interference)
Authors: Ulaganathan Vijay K. , Ullrich Axel
Published: March 2017

A significant development in the field of human biology is the revelation of millions of unannotated protein sequence variants emerging from the several human genotyping and genome sequencing initiatives. This presents unique opportunities as well as confounding challenges in our understanding of how molecular signalling outcomes vary among individuals in the general population. As a result the conventional ‘one drug fits all’ lines of approach in the drug discovery process is becoming obsolete. However, an innovative genotype-specific approach targeting protein sequence variants instead of a reference protein target is currently lacking. In this short communication we report a remarkable observation of antibody-mediated knockdown of intracellular protein expression. This suggests allele-specific inhibition of protein-variant expression can be achieved by intracellular delivery of lipid conjugated linear epitope-specific monoclonal antibodies. The results presented here demonstrate novel opportunities for interrogating the protein coding variations in the human genomes and new therapeutic strategies for the inhibition of pathogenic protein variants in a genotype-centric manner.
Expanding gene families helps generate the metabolic robustness required for antibiotic biosynthesis
Authors: Schniete Jana K , Cruz-Morales Pablo , Selem Nelly , Fernández-Martínez Lorena T. , Hunter Iain S , Barona-Gómez Francisco , Hoskisson Paul A
Published: March 2017

Introductory paragraph

Expanding the genetic repertoire of an organism by gene duplication or horizontal gene transfer (HGT) can aid adaptation.Streptomycesspecies are prolific producers of bioactive specialised metabolites with adaptive functions in nature and some have found utility in human medicine such as antibiotics. Whilst the biosynthesis of these specialised metabolites is directed by dedicated biosynthetic gene clusters (BGCs), little attention has been focussed on how these organisms have evolved robustness into their genomes to facilitate the metabolic plasticity required to provide chemical precursors for biosynthesis. Here we show that specific expansions of gene families in central carbon metabolism have evolved and become fixed inStreptomycesbacteria to enable plasticity and robustness that maintain cell functionality whilst costly specialised metabolites are produced. These expanded gene families, in addition to being a metabolic adaptation, make excellent targets for metabolic engineering of industrial specialised metabolite producing bacteria.
Data-Driven Prediction of CRISPR-Based Transcription Regulation for Programmable Control of Metabolic Flux
Authors: Sheng Jiayuan , Guo Weihua , Ash Christine , Freitas Brendan , Paoletti Mitchell , Feng Xueyang
Published: March 2017

Multiplex and multi-directional control of metabolic pathways is crucial for metabolic engineering to improve product yield of fuels, chemicals, and pharmaceuticals. To achieve this goal, artificial transcriptional regulators such as CRISPR-based transcription regulators have been developed to specifically activate or repress genes of interest. Here, we found that by deploying guide RNAs to target on DNA sites at different locations of genetic cassettes, we could use just one synthetic CRISPR-based transcriptional regulator to simultaneously activate and repress gene expressions. By using the pairwise datasets of guide RNAs and gene expressions, we developed a data-driven predictive model to rationally design this system for fine-tuning expression of target genes. We demonstrated that this system could achieve programmable control of metabolic fluxes when using yeast to produce versatile chemicals. We anticipate that this master CRISPR-based transcription regulator will be a valuable addition to the synthetic biology toolkit for metabolic engineering, speeding up the “design-build-test” cycle in industrial biomanufacturing as well as generating new biological insights on the fates of eukaryotic cells.
Profiling copy number variation and disease associations from 50,726 DiscovEHR Study exomes
Authors: Maxwell Evan K. , Packer Jonathan S. , O’Dushlaine Colm , McCarthy Shane E. , Hare-Harris Abby , Staples Jeffrey , Gonzaga-Jauregui Claudia , Fetterolf Samantha N. , Faucett W. Andrew , Leader Joseph B. , Moreno-De-Luca Andres , Gatta Giusy Della , Scollan Margaret , Persaud Trikaldarshi , Penn John , Hawes Alicia , Bai Xiaodong , Wolf Sarah , Lopez Alexander E. , Ulloa Rick , Sprangel Christopher , Chernomorsky Rostislav , Borecki Ingrid B. , Dewey Frederick E. , Economides Aris N. , Overton John D. , Kirchner H. Lester , Murray Michael F. , Ritchie Marylyn D. , Carey David J. , Ledbetter David H. , Yancopoulos George D. , Shuldiner Alan R. , Baras Aris , Gottesman Omri , Habegger Lukas , Martin Christa Lese , Reid Jeffrey G.
Published: March 2017

Copy number variants (CNVs) are a substantial source of genomic variation and contribute to a wide range of human disorders. Gene-disrupting exonic CNVs have important clinical implications as they can underlie variability in disease presentation and susceptibility. The relationship between exonic CNVs and clinical traits has not been broadly explored at the population level, primarily due to technical challenges. We surveyed common and rare CNVs in the exome sequences of 50,726 adult DiscovEHR study participants with linked electronic health records (EHRs). We evaluated the diagnostic yield and clinical expressivity of known pathogenic CNVs, and performed tests of association with EHR-derived serum lipids, thereby evaluating the relationship between CNVs and complex traits and phenotypes in an unbiased, real-world clinical context. We identified CNVs from megabase to exon-level resolution, demonstrating reliable, high-throughput detection of clinically relevant exonic CNVs. In doing so, we created a catalog of high-confidence common and rare CNVs and refined population frequency estimates of known and novel gene-disrupting CNVs. Our survey among an unselected clinical population provides further evidence that neuropathy-associated duplications and deletions in 17p12 have similar population prevalence but are clinically under-diagnosed. Similarly, adults who harbor 22q11.2 deletions frequently had EHR documentation of neurodevelopmental/neuropsychiatric disorders and congenital anomalies, but not a formal genetic diagnosis (i.e., deletion). In an exome-wide association study of lipid levels, we identified a novel five-exon duplication withinLDLRsegregating in a large kindred with features of familial hypercholesterolemia. Exonic CNVs provide new opportunities to understand and diagnose human disease.
Embryonic loss of human females with partial trisomy 19 identifies region critical for the single active X
Authors: Migeon Barbara R , Beer Michael A , Bjornsson Hans T
Published: March 2017

To compensate for the sex difference in the number of X chromosomes, human females, like human males have only one active X. The other X chromosomes in cells of both sexes are silencedin uterobyXIST, theInactive X Specific Transcript gene, that is present on all X chromosomes. To investigate the means by which the human active X is protected from silencing byXIST, we updated the search for a key dosage sensitiveXISTrepressor using new cytogenetic data with more precise resolution. Here, based on a previously unknown sex bias in copy number variations, we identify a unique region in our genome, and propose candidate genes that lie within, as they could inactivateXIST. Unlike males, the females who duplicate this region of chromosome 19 (partial 19 trisomy) do not survive embryogenesis; this preimplantation loss of females may be one reason that more human males are born than females.
Signatures of long-term balancing selection in human genomes
Authors: Bitarello Bárbara Domingues , Filippo Cesare de , Teixeira João Carlos , Schmidt Joshua M. , Kleinert Philip , Meyer Diogo , Andrés Aida M.
Published: March 2017

Balancing selection maintains advantageous diversity in populations through various mechanisms. While extensively explored from a theoretical perspective, an empirical understanding of its prevalence and targets lags behind our knowledge of positive selection. Here we describe theNon-Central Deviation(NCD), a simple yet powerful statistic to detect long-term balancing selection (LTBS) that quantifies how close frequencies are to expectations under LTBS, and provides the basis for a neutrality test.NCDcan be applied to a single locus or genomic data, and can be implemented considering only polymorphisms (NCD1) or also considering fixed differences with respect to an outgroup (NCD2) species. Incorporating fixed differences improves power, andNCD2has higher power to detect LTBS in humans under different frequencies of the balanced allele(s) than other available methods. Applied to genome-wide data from African and European human populations, in both cases using chimpanzee as an outgroup,NCD2shows that, albeit not prevalent, LTBS affects a sizable portion of the genome: about 0.6% of analyzed genomic windows and 0.8% of analyzed positions. Significant windows (p< 0.0001) contain 1.6% of SNPs in the genome, which disproportionally fall within exons and change protein sequence, but are not enriched in putatively regulatory sites. These windows overlap about 8% of the protein-coding genes, and these have larger number of transcripts than expected by chance even after controlling for gene length. Our catalog includes known targets of LTBS but a majority of them (90%) are novel. As expected, immune-related genes are among those with the strongest signatures, although most candidates are involved in other biological functions, suggesting that LTBS potentially influences diverse human phenotypes.
Distinguishing among modes of convergent adaptation using population genomic data
Authors: Lee Kristin M. , Coop Graham
Published: March 2017

Geographically separated populations can convergently adapt to the same selection pressure. Convergent evolution at the level of a gene may arise via three distinct modes. The selected alleles can (1) have multiple independent mutational origins, (2) be shared due to shared ancestral standing variation, or (3) spread throughout subpopulations via gene flow. We present a model-based, statistical approach that utilizes genomic data to detect cases of convergent adaptation at the genetic level, identify the loci involved and distinguish among these modes. To understand the impact of convergent positive selection on neutral diversity at linked loci, we make use of the fact that hitchhiking can be modeled as an increase in the variance in neutral allele frequencies around a selected site within a population. We build on coalescent theory to show how shared hitchhiking events between subpopulations act to increase covariance in allele frequencies between subpopulations at loci near the selected site, and extend this theory under different models of migration and selection on the same standing variation. We incorporate this hitchhiking effect into a multivariate normal model of allele frequencies that also accounts for population structure. Based on this theory, we present a composite-likelihood-based approach that utilizes genomic data to identify loci involved in convergence, and distinguishes among alternate modes of convergent adaptation. We illustrate our method on genome-wide polymorphism data from two distinct cases of convergent adaptation. First, we investigate the adaptation for copper toxicity tolerance in two populations of the common yellow monkey flower,Mimulus guttatus. We show that selection has occurred on an allele that has been standing in these populations prior to the onset of copper mining in this region. Lastly, we apply our method to data from four populations of the killifish,Fundulus heteroclitus, that show very rapid convergent adaptation for tolerance to industrial pollutants. Here, we identify a single locus at which both independent mutation events and selection on an allele shared via gene flow, either slightly before or during selection, play a role in adaptation across the species’ range.