bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing Self-management for Adults With Functional Abdominal Pain
Authors: Niesen Cynthia R. , Olson Donna M. , Nowdesha Kimberly D. , Tynsky Desiree A. , Loftus Conor G. , Meiers Sonja J.
Published: July 2018

Chronic disease accounts for three-quarters of today's medical expenditures. Functional abdominal pain (FAP) syndrome and associated gastrointestinal symptoms affect 0.5% to 2% of North Americans. Persons with FAP routinely seek healthcare, with little resolution of symptoms, despite high costs. National reports advocate for innovative redesign of ambulatory care services. Cognitive-behavioral therapy (CBT) is a low-cost, effective self-management approach. The objective of this study was to implement a registered nurse-led CBT approach to enhance self-management and satisfaction with care for adults with functional gastrointestinal disorder (FGID). We conducted a pre- and postintervention group comparison study in an outpatient gastroenterology subspecialty clinic within a large medical center. Twelve patients (seen May to July 2015) received nurse-led education about the pain phenomenon and CBT techniques to self-manage pain and associated symptoms of FAP. Methods and effectiveness of CBT for promoting self-management of chronic pain symptoms were reviewed. Subsequently, we conducted a project that incorporated nurse-led CBT into standard practice. Pre- and post-CBT questionnaire data showed patients had improved symptoms, well-being, and satisfaction. Registered nurses practicing at the highest level of their scope of practice within ambulatory care service models can enhance care management by educating, coaching, and counseling to improve self-care for patients with FGID.
Bowel Preparation for Gastrointestinal Endoscopic Procedures With Sodium Picosulphate-Magnesium Citrate Is an Effective, Safe, and Well-Tolerated Option in Pediatric Patients
Authors: Cisarò Fabio , Andrealli Alida , Calvo Pierluigi , Guanà Riccardo , Pinon Michele , Barletti Claudio
Published: July 2018

To obtain optimal visualization of the colonic mucosa during gastrointestinal endoscopic procedures, an adequate bowel preparation is mandatory, but a standardized protocol is still lacking for pediatric patients. Polyethylene glycol (PEG) is currently the most used laxative, but the amount of liquid to be taken orally is a large volume for the pediatric population and it may not be well tolerated. The aim of our preliminary trial was to evaluate efficacy, tolerability, and safety of sodium picosulphate-magnesium citrate (SPMC) used as bowel preparation before colonoscopy in children. Fifty children who needed a colonoscopy were prospectively enrolled between April and December 2013 and SPMC was administered to them as bowel preparation. A questionnaire about the product tolerance was completed by the patients' parents. The grade of bowel preparation and any related side effect were evaluated. The mean value of the Boston Bowel Preparation Scale was 7, out of a maximum of 9. Only 5 patients had an inadequate bowel preparation. Seventy percent of the patients considered the taste of the preparation very palatable. The remaining 26% considered it not palatable or not palatable at all. During the preparation, 18% of children complained of nausea, 20% abdominal pain, 2% vomiting, and 2% manifested headache. Bowel preparation with SPMC offers an efficient alternative to PEG and allows, on equal terms of efficacy, tolerability and safety, a much lower amount of laxative to ingest, and remarkable quality, especially in infants and toddlers.
Human Sound Localization Depends on Sound Intensity: Implications for Sensory Coding
Authors: Ihlefeld Antje , Alamatsaz Nima , Shapley Robert M
Published: July 2018

A fundamental question of human perception is how we perceive target locations in space. Through our eyes and skin, the activation patterns of sensory organs provide rich spatial cues. However, for other sensory dimensions, including sound localization and visual depth perception, spatial locations must be computed by the brain. For instance, interaural time differences (ITDs) of the sounds reaching the ears allow listeners to localize sound in the horizontal plane. Our experiments tested two prevalent theories on how ITDs affect human sound localization: 1) the labelled-line model, encoding space through tuned representations of spatial location; versus 2) the hemispheric-difference model, representing space through spike-rate distances relative to a perceptual anchor. Unlike the labelled-line model, the hemispheric-difference model predicts that with decreasing intensity, sound localization should collapse toward midline reference, and this is what we observed behaviorally. These findings cast doubt on models of human sound localization that rely on a spatially tuned map. Moreover, analogous experimental results in vision indicate that perceived depth depends upon the contrast of the target. Based on our findings, we propose that the brain uses a canonical computation of location across sensory modalities: perceived location is encoded through population spike rate relative to baseline.
Biotrophic interactions disentangled: In situ localisation of mRNAs to decipher plant and algal pathogen – host interactions at the single cell level
Authors: Badstöber Julia , Gachon Claire M. M. , Ludwig-Müller Jutta , Sandbichler Adolf M. , Neuhauser Sigrid
Published: July 2018

Plant-pathogen interactions follow spatiotemporal developmental dynamics where gene expression in pathogen and host undergo crucial changes. It is of great interest to detect, quantify and localise where and when key genes are active or inactive. Here, we adapt single molecule FISH techniques to demonstrate presence and activity of mRNAs using phytomyxids in their plant and algal host from laboratory and field materials. This allowed to monitor and quantify the expression of genes from the clubroot pathogen Plasmodiophora brassicae, several species of its Brassica hosts, and of several brown algae, including the genome model Ectocarpus siliculosus, infected with the phytomyxid Maullinia ectocarpii. We show that mRNAs are localised along a spatiotemporal gradient, thus providing proof-of-concept of the usefulness of these methods. These methods are easily adaptable to any interaction between microbes and their algal or plant host, and have the potential to increase our understanding of processes underpinning complex plant-microbe interactions.
Evolution of limb development in cephalopod mollusks
Authors: Tarazona Oscar A. , Lopez Davys H. , Slota Leslie A. , Cohn Martin J.
Published: July 2018

Cephalopod mollusks evolved numerous anatomical novelties, including arms and tentacles, but little is known about the developmental mechanisms underlying cephalopod limb evolution. Here we show that all three axes of cuttlefish limbs are patterned by the same signaling networks that act in vertebrates and arthropods, although they evolved limbs independently. In cuttlefish limb buds,Hedgehogis expressed anteriorly. Posterior transplantation ofHedgehog-expressing cells induced mirror-image limb duplications. Bmp and Wnt signals, which establish dorsoventral polarity in vertebrate and arthropod limbs, are similarly polarized in cuttlefish. Inhibition of Bmp2/4 dorsally caused ectopic expression ofNotum,which marks the ventral sucker field, and ectopic sucker development. Cuttlefish also show proximodistal regionalization ofHth,Exd, Dll,Dac,Sp8/9, andWntexpression, which delineates arm and tentacle sucker fields. These results suggest that cephalopod limbs evolved by parallel activation of a genetic program for appendage development that was present in the bilaterian common ancestor.
SuperFreq: Integrated mutation detection and clonal tracking in cancer
Authors: Flensburg Christoffer , Sargeant Tobias , Oshlack Alicia , Majewski Ian
Published: July 2018

Analysing multiple cancer samples from an individual patient can provide insight into the way the disease evolves. Monitoring the expansion and contraction of distinct clones helps to reveal the mutations that initiate the disease and those that drive progression. Existing approaches for clonal tracking from sequencing data typically require the user to combine multiple tools that are not purpose-built for this task. Furthermore, most methods require a matched normal (non-tumour) sample, which limits the scope of application. We developed SuperFreq, a cancer exome sequencing analysis pipeline that integrates identification of somatic single nucleotide variants (SNVs) and copy number alterations (CNAs) and clonal tracking for both. SuperFreq does not require a matched normal and instead relies on unrelated controls. When analysing multiple samples from a single patient, SuperFreq cross checks variant calls to improve clonal tracking, which helps to separate somatic from germline variants, and to resolve overlapping CNA calls. To demonstrate our software we analysed 304 cancer-normal exome samples across 33 cancer types in The Cancer Genome Atlas (TCGA) and evaluated the quality of the SNV and CNA calls. We simulated clonal evolution through in silico mixing of cancer and normal samples in known proportion. We found that SuperFreq identified 93% of clones with a cellular fraction of at least 50% and mutations were assigned to the correct clone with high recall and precision. In addition, SuperFreq maintained a similar level of performance for most aspects of the analysis when run without a matched normal. SuperFreq is highly versatile and can be applied in many different experimental settings for the analysis of exomes and other capture libraries. We demonstrate an application of SuperFreq to leukaemia patients with diagnosis and relapse samples.

SuperFreq is implemented in R and available on github at https://github.com/ChristofferFlensburg/SuperFreq.
Studying the fate of tumor extracellular vesicles at high spatio-temporal resolution using the zebrafish embryo
Authors: Hyenne Vincent , Ghoroghi Shima , Collot Mayeul , Harlepp Sébastien , Bauer Jack , Mercier Luc , Busnelli Ignacio , Lefebvre Olivier , Fekonja Nina , Machado Pedro , Bons Joanna , Delalande François , Amor Ana Isabel , Silva Susana Garcia , Verweij Frederik J. , Niel Guillaume Van , Schwab Yannick , Peinado Héctor , Carapito Christine , Klymchenko Andrey S. , Goetz Jacky G.
Published: July 2018

Tumor extracellular vesicles (tumor EVs) mediate the communication between tumor and stromal cells mostly to the benefit of tumor progression. Notably, tumor EVs have been reported to travel in the blood circulation, reach specific distant organs and locally modify the microenvironment. However, visualizing these eventsin vivostill faces major hurdles. Here, we show a new method for tracking individual circulating tumor EVs in a living organism: we combine novel, bright and specific fluorescent membrane probes, MemBright, with the transparent zebrafish embryo as an animal model. We provide the first description of tumor EVs’ hemodynamic behavior and document their arrest before internalization. Using transgenic lines, we show that circulating tumor EVs are uptaken by endothelial cells and blood patrolling macrophages, but not by leukocytes, and subsequently stored in acidic degradative compartments. Finally, we prove that the MemBright can be used to follow naturally released tumor EVsin vivo. Overall, our study demonstrates the usefulness and prospects of zebrafish embryo to track tumor EVsin vivo.

Highlights

MemBright, a new family of membrane probes, allows for bright and specific staining of EVs

Zebrafish melanoma EVs are very similar to human and mouse melanoma EVs in morphology and protein content

The zebrafish embryo is an adapted model to precisely track tumor EVs dynamics and fate in a living organism from light to electron microscopy

Circulating tumor EVs are rapidly uptaken by endothelial cells and patrolling macrophages

Correlated light and electron microscopy can be used in zebrafish to identify cells and compartments uptaking tumor EVs

Blurb

Dispersion of tumor extracellular vesicles (EVs) throughout the body promotes tumor progression. However the behavior of tumor EVs in body fluids remains mysterious due to their small size and the absence of adapted animal model. Here we show that the zebrafish embryo can be used to track circulating tumor EVsin vivoand provide the first high-resolution description of their dissemination and uptake.
Bumblebee visual allometry results in locally improved resolution and globally improved sensitivity
Authors: Taylor Gavin J. , Tichit Pierre , Schmidt Marie D. , Bodey Andrew J. , Rau Christoph , Baird Emily
Published: July 2018

The quality of visual information that is available to an animal is limited by the size of its eyes. Differences in eye size can be observed even between closely related individuals but we understand little about how this affects visual quality. Insects are good models for exploring the effects of size on visual systems because many species exhibit size polymorphism, which modifies both the size and shape of their eyes. Previous work in this area has been limited, however, due to the challenge of determining the 3D structure of eyes. To address this, we have developed a novel method based on x-ray tomography to measure the 3D structure of insect eyes and calculate their visual capabilities. We investigated visual allometry in the bumblebeeBombus terrestrisand found that size affects specific aspects of visual quality including binocular overlap, optical sensitivity across the field of view, and visual resolution in the dorsofrontal visual field. This holistic study on eye allometry reveals that differential scaling between different eye areas provides substantial flexibility for larger bumblebees to have improved visual capabilities.
Exogenous attention facilitates performance through dissociable sensitivity and bias mechanisms
Authors: Sagar Vishak , Sengupta Ranit , Sridharan Devarajan
Published: July 2018

Selective attention enables prioritizing the most important information for differential sensory processing and decision-making. Here, we address an active debate regarding whether attention reflects a unitary phenomenon or involves the operation of dissociable sensory enhancement (perceptual sensitivity) and decisional gating (choice bias) processes. We developed a multialternative task in which participants detected and localized orientation changes in gratings at one of four spatial locations. Exogenous attention cues (high contrast flashes) preceded or followed the change events in close temporal proximity. Analysis of participants’ behavior with a multidimensional signal detection model revealed markedly distinct effects of exogenous cueing on perceptual sensitivity and choice bias. Whereas sensitivity enhancement was localized to the stimulus proximal to the exogenous cue, bias enhancement occurred even for distal stimuli in the cued hemifield. Modulations of sensitivity and bias were uncorrelated at both cued and uncued locations. Finally, exogenous cueing produced reaction time benefits only at the cued location and costs only at locations contralateral to the cue. These disparate effects of exogenous cueing on sensitivity, bias and reaction times could be parsimoniously explained within the framework of a diffusion-decision model, in which the drift rate was determined by a linear combination of sensitivity and bias at each location. Exogenous cueing effects on sensitivity and bias differed systematically from previously reported effects of endogenous cueing. We propose that the search for shared neural substrates of exogenous and endogenous attention would benefit from investigating neural correlates of their component sensory and decisional mechanisms.

Significance statement

When we voluntarily direct attention “endogenously”, we are able to better perceive stimuli at the attended location (sensitivity), and to prioritize information from that location for guiding behavioral decisions (bias). But when a salient stimulus, such as a flash of lightning, captures our attention “exogenously”, does it also produce these same effects? To answer this question, we designed a multiple alternative task in which task events occurred in close conjunction with salient exogenous cues (high contrast flashes). We discovered that exogenous attention enhanced both sensitivity and bias for cued stimuli, but each of these changes followed distinct spatial patterns across locations. Our results provide novel insights into component processes of exogenous attention and motivate the search for their neural correlates.
Using machine learning to predict antimicrobial minimum inhibitory concentrations and associated genomic features for nontyphoidalSalmonella
Authors: Nguyen Marcus , Long S. Wesley , McDermott Patrick F. , Olsen Randall J. , Olson Robert , Stevens Rick L. , Tyson Gregory H. , Zhao Shaohua , Davis James J.
Published: July 2018

NontyphoidalSalmonellaspecies are the leading bacterial cause of food-borne disease in the United States. Whole genome sequences and paired antimicrobial susceptibility data are available forSalmonellastrains because of surveillance efforts from public health agencies. In this study, a collection of 5,278 nontyphoidalSalmonellagenomes, collected over 15 years in the United States, were used to generate XGBoost-based machine learning models for predicting minimum inhibitory concentrations (MICs) for 15 antibiotics. The MIC prediction models have average accuracies between 95-96% within ± 1 two-fold dilution factor and can predict MICs with noa prioriinformation about the underlying gene content or resistance phenotypes of the strains. By selecting diverse genomes for training sets, we show that highly accurate MIC prediction models can be generated with fewer than 500 genomes. We also show that our approach for predicting MICs is stable over time despite annual fluctuations in antimicrobial resistance gene content in the sampled genomes. Finally, using feature selection, we explore the important genomic regions identified by the models for predicting MICs. To date, this is one of the largest MIC modeling studies to be published. Our strategy for developing whole genome sequence-based models for surveillance and clinical diagnostics can be readily applied to other important human pathogens.
Genome sequence of the wheat stem sawfly, Cephus cinctus, a primitive hymenopteran and wheat pest, illuminates evolution of hymenopteran chemoreceptors
Authors: Robertson Hugh M. , Waterhouse Robert M. , Walden Kimberly K. O. , Ruzzante Livio , Reijnders Maarten J. M. F. , Coates Brad S. , Legeai Fabrice , Gress Joanna C. , Biyiklioglu Sezgi , Weaver David K. , Wanner Kevin W. , Budak Hikmet
Published: July 2018

The wheat stem sawfly, Cephus cinctus, is a major pest of wheat and key ecological player in the grasslands of western North America. It also represents a distinctive lineage of sawflies that appeared early during the hymenopteran radiation, but after the clade of Eusymphyta sawflies that is the sister lineage of all other Hymenoptera. We present a high-quality draft genome assembly of 162 Mbp in 1,976 scaffolds with a scaffold N50 of 622 kbp. Automated gene annotation identified 11,210 protein-coding gene models and 1,307 non-coding RNA models. Thirteen percent of the assembly consists of ~58,000 transposable elements partitioned equally between Class-I and Class-II elements. Orthology analysis reveals that 86% of Cephus proteins have identifiable orthologs in other insects. Phylogenomic analysis of conserved subsets of these proteins supports the placement of the Cephidae between the Eusymphyta and the parasitic woodwasp superfamily Orussoidea. Manual annotation and phylogenetic analysis of families of odorant, gustatory, and ionotropic receptors, plus odorant binding proteins, shows that Cephus has representatives for most conserved and expanded gene lineages in the Apocrita (wasps, ants, and bees). Cephus has also maintained several insect gene lineages that have been lost from the Apocrita, most prominently the carbon dioxide receptor subfamily. Furthermore, Cephus encodes a few small lineage-specific chemoreceptor gene family expansions that might be involved in adaptations to new grasses including wheat. These comparative analyses identify gene family members likely to have been present in the hymenopteran ancestor and provide a new perspective on the evolution of the chemosensory gene repertoire.
Heterozygous mutations in p97 and resistance to p97 inhibitors
Authors: Bastola Prabhakar , Minn Kay , Chien Jeremy
Published: July 2018

In recent years, multiple studies including ours have reported on the mechanism of resistance towards p97 inhibitors. While all these studies outline target alteration via mutations in p97 as the primary mechanism of resistance, discrepancies persist in the current literature due to the occurrence of both heterozygous and homozygous mutations when using HCT116 cells. Here, we report a pre-existing heterozygous frameshift mutation at codon 616 (N616fs*) in one of the p97 alleles in HCT116 cells and show that this mutant allele is subjected to nonsense-mediated decay. Furthermore, we independently generated p97 inhibitor (CB-5083) resistant HCT116 cells, and we observed a single heterozygous mutation at codon 526 (L526S) in genomic DNA sequencing but a homozygous L526S mutation in complementary DNA sequencing, indicating that the missense mutation (L526S) occurs in the allele that does not harbor the frameshift N616fs* mutation. Our results underscore the importance of performing simultaneous genomic and complementary DNA sequencing when confirming mutations in p97.
Molecular Diversity of Intrinsically Photosensitive Ganglion Cells
Authors: Berg Daniel , Kartheiser Katherine , Leyrer Megan , Saali Alexandra , Berson David
Published: July 2018

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are rare mammalian photoreceptors essential for non-image-forming vision functions, such as circadian photoentrainment and the pupillary light reflex. They comprise multiple subtypes distinguishable by morphology, physiology, projections, and levels of expression of melanopsin (Opn4), their photopigment. The molecular programs that differentiate ipRGCs from other ganglion cells and ipRGC subtypes from one another remain elusive. Here, we present comprehensive gene expression profiles of early postnatal and adult mouse ipRGCs purified from two lines of reporter mice marking different sets of ipRGC subtypes. We find dozens of novel genes highly enriched in ipRGCs. We reveal that Rasgrp1 and Tbx20 are selectively expressed in subsets of ipRGCs, though these molecularly defined groups imperfectly match established ipRGC subtypes. We demonstrate that the ipRGCs regulating circadian photoentrainment are unexpectedly diverse at the molecular level. Our findings reveal unexpected complexity in gene expression patterns across mammalian ipRGC subtypes.
High-resolution 4D spatiotemporal analysis reveals the contributions of local growth dynamics to contrasting maize root architectures
Authors: Jiang Ni , Floro Eric , Bray Adam L. , Laws Benjamin , Duncan Keith E. , Topp Christopher N.
Published: July 2018

Root systems are branched networks that develop from simple growth properties of their individual roots. Yet a mature maize root system has many thousands of roots that each interact with soil structures, water and nutrient patches, and microbial ecologies in the micro-environments surrounding each root tip. Although the plasticity of root growth to these and other environmental factors is well known, how the many local processes contribute over time to global features of root system architecture is hardly understood. We employ an automated 3D root imaging pipeline to capture the growth of maize roots every four hours throughout seven days of seedling development. We model the contrasting architectures of two maize inbred genotypes and their hybrid to derive key parameters that distinguish complex growth patterns as a function of time. The statistical characteristics of local root growth defined the global system properties despite a large range of trait values. “Computational dissection” of a single root from each root system identified differences in the size of the root branching zone and lateral branching densities, but not radial patterns, that drove the contrasting root architectures from seedling to maturity. X-ray imaging of mature field-grown root crowns showed that seedling growth trajectories persisted throughout development and could predict eventual architectures, suggesting a strong genetic basis. The work connects individual and systemwide scales of root growth dynamics, providing the means for a function-valued approach to understanding the genetic and genetic x environment conditioning of root growth that will enable breeding for enhanced root traits.

SIGNIFICANCE STATEMENT

When and where roots grow determines their ability to capture short-lived and patchy water and nutrient resources to support the aboveground organs of the plant. Roots have no known long-distance external sensing mechanisms, but form branched networks that blindly explore the soil and respond to encountered local stimuli. How global architectures form from the many thousands of these local responses, and how they are controlled genetically are major open questions. Here we quantify differences in local root growth patterns of two inbred genotypes of maize that control contrasting systemwide properties. Measurements at the seedling stage were highly correlated with the complex architectures of mature root systems, paving the way for the development of crops with greater resource uptake capacity.
A Robust Method to Estimate the Largest Lyapunov Exponent of Noisy Signals: A Revision to the Rosenstein’s Algorithm
Authors: Mehdizadeh Sina
Published: July 2018

Aim

This study proposed a revision to the Rosenstein’s method of numerical calculation of largest Lyapunov exponent (LyE) to make it more robust to noise.

Methods

To this aim, the effect of increasing number of initial neighboring points on the LyE value was investigated and compared to the values obtained by filtering the time series. Both simulated (Lorenz and passive dynamic walker) and experimental (human walking) time series were used to calculate LyE. The number of initial neighbors used to calculate LyE for all time series was 1 (the original Rosenstein’s method), 2, 3, 4, 5, 10, 15, 20, 25, and 30 data points.

Results

The results demonstrated that the LyE graph reached a plateau at the 15-point neighboring condition inferring that the LyE values calculated using at least 15 neighboring points were consistent and reliable.

Conclusion

The proposed method could be used to calculate LyE more reliably in experimental time series acquired from biological systems where noise is omnipresent.
Mitochondrial RNA capping: highly efficient 5’-RNA capping with NAD+ and NADH by yeast and human mitochondrial RNA polymerase
Authors: Bird Jeremy G. , Basu Urmimala , Kuster David , Ramachandran Aparna , Grudzien-Nogalska Ewa , Kiledjian Megerditch , Temiakov Dmitry , Patel Smita S. , Ebright Richard H. , Nickels Bryce E.
Published: July 2018

Bacterial and eukaryotic nuclear RNA polymerases (RNAPs) cap RNA with the oxidized and reduced forms of the metabolic effector nicotinamide adenine dinucleotide, NAD+ and NADH, using NAD+ and NADH as non-canonical initiating nucleotides for transcription initiation. Here, we show that mitochondrial RNAPs (mtRNAPs) cap RNA with NAD+ and NADH, and do so more efficiently than nuclear RNAPs. Direct quantitation of NAD+- and NADH-capped RNA demonstrates remarkably high levels of capping in vivo: up to ~60% NAD+ and NADH capping of yeast mitochondrial transcripts, and up to ~10% NAD+ capping of human mitochondrial transcripts. The capping efficiency is determined by promoter sequence at, and upstream of, the transcription start site and, in yeast and human cells, by intracellular NAD+ and NADH levels. Our findings indicate mtRNAPs serve as both sensors and actuators in coupling cellular metabolism to mitochondrial gene expression, sensing NAD+ and NADH levels and adjusting transcriptional outputs accordingly.
In silicoprioritization of transporter-drug relationships from drug sensitivity screens
Authors: César-Razquin A. , Girardi E. , Yang M. , Brehme M. , Sáez-Rodríguez J. , Superti-Furga G.
Published: July 2018

The interplay between drugs and cell metabolism is a key factor in determining both compound potency and toxicity. In particular, how and to what extent transmembrane transporters affect drug uptake and disposition is currently only partially understood. Most transporter proteins belong to two protein families: the ATP-Binding Cassette (ABC) transporter family, whose members are often involved in xenobiotic efflux and drug resistance, and the large and heterogeneous family of Solute carriers (SLCs). We recently argued that SLCs are collectively a rather neglected gene group, with most of its members still poorly characterized, and thus likely to include many yet-to-be-discovered associations with drugs. We searched publicly available resources and literature to define the currently known set of drugs transported by ABCs or SLCs, which involved ~500 drugs and more than 100 transporters. In order to extend this set, we then mined the largest publicly available pharmacogenomics dataset, which involves approximately 1000 molecularly annotated cancer cell lines and their response to 265 chemical compounds, and used regularized linear regression models (Elastic Net, LASSO) to predict drug responses based on SLC and ABC data (expression levels, SNVs, CNVs). The most predictive models included both known and previously unidentified associations between drugs and transporters. To our knowledge, this represents the first application of regularized linear regression to this set of genes, providing an extensive prioritization of potentially pharmacologically interesting interactions.
Mitochondrial biogenesis is transcriptionally repressed in lysosomal lipid storage diseases
Authors: Yambire King Faisal , Fernandez-Mosquera Lorena , Steinfeld Robert , Muehle Christiane , Ikonen Elina , Milosevic Ira , Raimundo Nuno
Published: July 2018

Perturbations in mitochondrial function and homeostasis are pervasive in lysosomal storage diseases, but the underlying mechanisms remain unknown. Here, we report a transcriptional program that represses mitochondrial biogenesis and function in lysosomal storage diseases Niemann-Pick type C (NPC) and acid sphingomyelinase deficiency (ASM), in patient cells and mouse tissues. This mechanism is mediated by the transcription factors KLF2 and ETV1, which are both induced in NPC and ASM patient cells. Mitochondrial biogenesis and function defects in these cells are rescued by the silencing of KLF2 or ETV1. Increased ETV1 expression is regulated by KLF2, while the increase of KLF2 protein levels in NPC and ASM stems from impaired signaling downstream sphingosine-1-phosphate receptor 1 (S1PR1), which normally represses KLF2. In patient cells, S1PR1 is undetectable at the plasma membrane and thus unable to repress KLF2. This manuscript provides a mechanistic pathway for the prevalent mitochondrial defects in lysosomal storage diseases.
Quick and efficient approach to develop genomic resources in orphan species: application inLavandula angustifolia
Authors: Fomeju Berline Fopa , Brunel Dominique , Bérard Aurélie , Rivoal Jean-Baptiste , Gallois Philippe , Le Paslier Marie-Christine , Bouverat-Bernier Jean-Pierre
Published: July 2018

Next-Generation Sequencing (NGS) technologies, by reducing the cost and increasing the throughput of sequencing, have opened doors of research efforts to generate genomic data to a range of previously poorly studied species. In this study, we proposed a method for the rapid development of a large scale molecular resources for orphan species. We studied as an exampleLavandula angustifolia, a perennial sub-shrub plant native from the Mediterranean region and whose essential oil have numerous applications in cosmetics, pharmaceuticals, and alternative medicines.

We first built a ‘Maillette’ reference Unigene, compound of coding sequences, thanks tode novoRNA-seq assembly. Then, we reconstructed the complete genes sequences (with exons and introns) using a transcriptome-guided DNA-seq assembly approach in order to maximize the possibilities of finding polymorphism between genetically close individuals. Finally, we used these resources for SNP mining within a collection of 16 lavender clones and tested the SNP within the scope of a phylogeny analysis. We obtained a cleaned reference of 8, 030 functionally annotated ‘genes’ (in silicoannotation). We found up to 400K polymorphic sites, depending on the genotype analyzed, and observed a high SNP frequency (mean of 1 SNP per 90 bp) and a high level of heterozygosity (more than 60% of heterozygous SNP per genotype). We found similar genetic distances between pairs of clones, related to the out-crossing nature of the species, the restricted area of cultivation and the clonal propagation of the varieties.

The method propose is transferable to other orphan species, requires little bioinformatics resources and can be realized within a year. This is the first reported large-scale SNP development on Lavandula angustifolia. All this data provides a rich pool of molecular resource to explore and exploit biodiversity in breeding programs.
Genome-wide silencing screen in mesothelioma cells reveals that loss of function of BAP1 induces chemoresistance to ribonucleotide reductase inhibition: implication for therapy
Authors: Okonska Agata , Bühler Saskja , Rao Vasundhara , Ronner Manuel , Blijlevens Maxime , Meulen-Muileman Ida Van der , Menezes Renee de , Smit Egbert , Weder Walter , Stahel Rolf , Penengo Lorenza , Beusechem Victor van , Felley-Bosco Emanuela
Published: July 2018

Introduction

Loss of function of BRCA1 associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy.

Methods

A genetically engineered model was established expressing either functional or nonfunctional BAP1 and whole-genome siRNA screens were performed assessing impaired survival between the two cell lines. Cytotoxity induced by gemcitabine and hydroxyurea were assessed in a panel of BAP1-WT and BAP1-mut/del cell lines. Functional studies were carried out in BAP1 mut/del cell line reconstituted with BAP1 WT or BAP1 C91A (catalytically dead mutant) and in BAP1 WT cell line upon siRNA-mediated knock-down of BAP1.

Results

The whole-genome siRNA screen unexpectedly revealed 11 hits (FDR<0.05) more cytotoxic for BAP1-proficient cells. Two actionable targets, RRM1 and RRM2, were validated and their inhibition mediated by gemcitabine or hydroxyurea respectively, was more cytotoxic in BAP1-proficient cell lines. Upregulation of RRM2 upon gemcitabine and hydroxyurea was more profound in BAP1 mut/del cell lines. Increased lethality mediated by gemcitabine and hydroxyurea was observed in NCI-H2452 cells reconstituted with BAP1 WT but not with C91A mutant and upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared to control or C91A mutant. Finally, the opposite was observed after BAP1 knockdown in BAP1-proficient SPC111 cell line.

Conclusion

We found that BAP1 is involved in the regulation of RRM2 levels during replication stress. These observations reveal a potential therapeutic approach where MPM patients to be stratified depending on BAP status for gemcitabine treatment.
Low genetic variation is associated with low mutation rate in the giant duckweed
Authors: Xu Shuqing , Stapley Jessica , Gablenz Saskia , Boyer Justin , Appenroth Klaus J. , Sree K. Sowjanya , Gershenzon Jonathan , Widmer Alex , Huber Meret
Published: July 2018

Mutation rate and effective population size (Ne) jointly determine intraspecific genetic diversity, but the role of mutation rate is often ignored. We investigate genetic diversity, spontaneous mutation rate andNein the giant duckweed (Spirodela polyrhiza). Despite its large census population size, whole-genome sequencing of 68 globally sampled individuals revealed extremely low within-species genetic diversity. Assessed under natural conditions, the genome-wide spontaneous mutation rate is at least seven times lower than estimates made for other multicellular eukaryotes, whereasNeis large. These results demonstrate that low genetic diversity can be associated with large-Nespecies, where selection can reduce mutation rates to very low levels, and accurate estimates of mutation rate can help to explain seemingly counterintuitive patterns of genome-wide variation.

One Sentence Summary

The low-down on a tiny plant: extremely low genetic diversity in an aquatic plant is associated with its exceptionally low mutation rate.
Investigating the unknown functions in the minimal bacterial genome reveals many transporter proteins
Authors: Antczak Magdalena , Michaelis Martin , Wass Mark N
Published: July 2018

The recent identification of the minimal bacterial genome revealed that nearly one third (149) of the 473 encoded genes were of unknown function, demonstrating our limited understanding of the essential functions of life. Application of state of the art in silico methods for functional annotation demonstrated that these proteins of unknown function lack orthologs, known protein domains, and templates to model their structure. Combination of the results from different complementary approaches enabled functions to be assigned to 94 of the 149 proteins, although often with general terms such as transporter or DNA binding. 22 likely transporter proteins were identified indicating the importance of nutrient uptake into and waste disposal out of the minimal bacterial cell, where many metabolic enzymes have been removed. These results advance our understanding of the minimal bacterial genome and therefore aid synthetic biology and its application to biotechnology.
Alcohol-responsive genes identified in human iPSC-derived neural cultures
Authors: Jensen Kevin P. , Lieberman Richard , Kranzler Henry R. , Gelernter Joel , Covault Jonathan
Published: July 2018

Alcohol use contributes to numerous diseases and injuries. The nervous system is affected by alcohol in diverse ways, though the molecular mechanisms of these effects are not clearly understood. Using human-induced pluripotent stem cells (iPSCs), we developed a neural cell culture model to identify the mechanisms of alcohol’s effects. iPSCs were generated from fibroblasts and differentiated into forebrain neural cells cultures that were treated with 50 mM alcohol or sham conditions (same media lacking alcohol) for 7 days. We analyzed gene expression using total RNA sequencing (RNA-seq) for 34 samples derived from 11 subjects and for 10 samples from 5 subjects in an independent experiment that had intermittent exposure to the same dose of alcohol. We also analyzed genetic effects on gene expression and conducted a weighted correlation network analysis. We found that differentiated neural cell cultures have the capacity to recapitulate gene regulatory effects previously observed in specific primary neural tissues and identified 226 genes that were differentially expressed (FDR< 0.1) after alcohol treatment. The effects on expression included decreases inINSIG1andLDLR,two genes involved in cholesterol homeostasis. We also identified a module of 58 co-expressed genes that were uniformly decreased following alcohol exposure. The majority of these effects were supported in the independent alcohol exposure experiment. Enrichment analysis linked the alcohol responsive genes to cell cycle, notch signaling, and cholesterol biosynthesis pathways, which are disrupted in several neurological disorders. Our findings suggest that there is convergence between these disorders and the effects of alcohol exposure.
Architecture of parallel adaptation to freshwater in multiple populations of threespine stickleback
Authors: Terekhanova Nadezhda V. , Barmintseva Anna E. , Kondrashov Alexey S. , Bazykin Georgii A. , Mugue Nikolai S.
Published: July 2018

Threespine sticklebacks adapted to freshwater environments all over the Northern Hemisphere. This adaptation involved parallel recruitment of freshwater alleles in clusters of closely linked sites, or divergence islands (DIs). However, it is unclear to what extent the DIs involved in adaptation and the alleles within them coincide between populations adapting to similar environments. Here, we examine 10 freshwater populations of similar ages from the White Sea basin, and study the repeatability of patterns of adaptation in them. Overall, the 65 detected DIs tend to reside in regions of low recombination, underlining the role of reduced recombination in their establishment. Moreover, the DIs are clustered in the genome to the extent that is not explainable by the recombination rate alone, consistent with the divergence hitchhiking model. 21 out of the 65 DIs are universal; i.e., the frequency of freshwater alleles in them is increased in all analyzed populations. Universal DIs tend to have longer core region shared between populations, and the divergence between the marine and the freshwater haplotypes in them is higher, implying that they are older, also consistently with divergence hitchhiking. Within most DIs, the same set of sites distinguished the marine and the freshwater haplotypes in all populations; however, in some of the DIs, the genetic architecture of the freshwater haplotype differed between populations, suggesting that they could have been established by soft selective sweeps.
Lesion Attributes Segmentation for Melanoma Detection with Deep Learning
Authors: Chen Eric Z. , Dong Xu , Wu Junyan , Jiang Hongda , Li Xiaoxiao , Rong Ruichen
Published: July 2018

Melanoma is the most deadly form of skin cancer world-wide. Many efforts have been made for early detection of melanoma. The International Skin Imaging Collaboration (ISIC) hosted the 2018 Challenges to improve the diagnosis of melanoma based on dermoscopic images. In this paper, we describe our solution for the task 2 of ISIC 2018 Challenges. We present a multi-task U-Net model to automatically detect lesion attributes of melanoma. Our multi-task U-Net deep learning model achieves a Jaccard index of 0.433 on official test data, which ranks the 5th place on the final leaderboard.
Monetary model of exchange rate determination under floating and non-floating regimes
Authors: Ibhagui Oyakhilome Wallace
Published: July 2018

Purpose

The purpose of this paper is to empirically analyse how different exchange rate regimes affect the links between monetary fundamentals and exchange rates in Sub-Saharan Africa.

Design/methodology/approach

Using the Pedroni method for panel cointegration, mean group and pooled mean group and the panel vector autoregressive technique, this study empirically investigates whether monetary fundamentals impact exchange rates similarly in both regimes. Thus, the author acquires needed and credible empirical data.

Findings

The result suggests that the impact is dissimilar. In the floating regime, an increase in relative money supply and relative real output depreciates and appreciates the nominal exchange rate in the long run whereas in the non-floating regime, the evidence is mixed. Thus, exchange rates bear a theoretically consistent relationship with monetary fundamentals across SSA countries with floating regimes but fails under non-floating regimes. This provides evidence that regime choice is important if the relationship between monetary fundamentals and exchange rates in SSA are to be theoretically consistent.

Originality/value

This study empirically incorporates the dissimilarities in exchange rate regimes in a panel framework and study the links between exchange rates and monetary fundamentals. The focus on how exchange rate regimes might alter the equilibrium relationships between exchange rates and monetary fundamentals in SSA is a pioneering experiment.
Addressing free riders in collaborative group work
Authors: El Massah Suzanna Sobhy
Published: July 2018

Purpose

Free-riding behaviour may threaten the success of teamwork, when one or more group members receive the benefits of other members’ achievements with little effort or cost of their own. The purpose of this paper is to investigate students’ collaborative behaviour to address the problem of free riders (FRs) in university settings.

Design/methodology/approach

The research is an 11-week field study of three senior finance classes and incorporates mobile learning employing Quip and Google Docs applications to facilitate group work. A comprehensive set of quantitative and qualitative methods analysing students’ perceptions, instructors’ reflections, peer reflections and mobile learning methods are used to answer questions pertaining to group work, the work experience, FRs and ways to minimise the last.

Findings

In this paper, the author shows that students at the university level have positive views of group work despite the presence of FRs. Students like to form their own groups; consequently, peer evaluation appears to be unreliable. The study points to free riding as a serious threat to academic productivity and calls for actions and strategies from institutions and instructors to eradicate this behaviour. Mobile applications enable instructors to track FRs and to some extent discourage their behaviour.

Originality/value

There are limited studies that focus on FRs in higher education and, to the researcher’s knowledge, no such investigation has been applied in the Middle East and North Africa. Likewise, there is little research available on incorporating mobile learning to assess group work in higher education. This study aims at exploring the existence and associated experiences of free riding, along with methods to curtail the problem. The findings of this study provide a good platform for inquiry into the FR phenomenon in higher education and its impact on student learning, as well as the possible roles of instructors and mobile applications. The findings of this study could be developed further through more research with a view to providing a broader perspective of the situation in Middle Eastern and North African cultures.
Academics’ experience of contradicting institutional logics of publishing
Authors: Aksom Herman
Published: July 2018

Purpose

The purpose of this paper is to explore whether and how Ukrainian scholars recognize and react to a situation of an absence of two major institutional logics of academic writing and publishing, namely the logics of science advancement and personal career promotion and the dominance of the logic of coercive pressures to publish regardless of quality and resonance and with no material and reputational rewards. Two fundamental and essential logics that drive research activity at any university in western societies seem to be almost absent in Ukrainian context, where symbolic publishing for accountability only is taken-for-granted.

Design/methodology/approach

The study adopts qualitative interpretative research methodology. The scholars from seven universities were interviewed, including 16 senior scholars and 15 PhD students.

Findings

The study shows the dominance of a single logic of accountability which is persisted due to coercive pressures exerted on scholars. Despite the absence of instrumental value behind publishing requirements in Ukrainian higher education system, most academics do not question this policy and largely take it for granted as the only possible system.

Originality/value

Research conducted in this study contributes to institutional logics and institutional complexity literature by highlighting a unique situation of institutional complexity when logic that offers neither economic nor social benefits dominates the field. It is shown how actors recognize, interpret and respond to this situation, identifying three types of responses that range from blind adherence to taken-for-granted institutional definitions to strategic balance between coercive pressures and desired logics.