bluuebunny/crossref_metadata_2025_split huggingface dataset:
The stress-inducible peroxidaseTSA2 enables Chromosome IV duplication to be conditionally beneficial inSaccharomyces cerevisiae
Authors: Linder Robert A. , Greco John P. , Seidl Fabian , Matsui Takeshi , Ehrenreich Ian M. 
Published: January 2017

AbstractAlthough chromosomal duplications are often deleterious, in some cases they enhance cells’ abilities to tolerate specific genetic or environmental challenges. Identifying the genes that cause particular chromosomal duplications to confer these conditionally beneficial effects can improve our understanding of the genetic and molecular mechanisms that enable certain aneuploidies to persist in cell populations and contribute to disease and evolution. Here, we perform a screen for spontaneous mutations that improve the tolerance of haploidSaccharomyces cerevisiaeto hydrogen peroxide. Chromosome IV duplication is the most frequent mutation, as well as the only change in chromosomal copy number, seen in the screen. Using a genetic mapping strategy that involves systematically deleting segments of a duplicated chromosome, we show that the Chromosome IV duplication’s effect is largely due to the generation of a second copy of the stress-inducible cytoplasmic thioredoxin peroxidaseTSA2. This finding is consistent with a growing literature indicating that the conditionally beneficial effects of chromosomal duplications tend to reflect the contributions of small numbers of genes that enhance tolerance to specific stresses when their copy number is increased.Article summaryChanges in karyotype play an important role in evolution and health. Although these aneuploidization events are usually deleterious, in some instances they show conditionally beneficial effects by enabling cells to tolerate specific mutations or environmental stresses. The mechanisms underlying these protective effects of aneuploidization are not fully understood. To provide insights into this problem, we identify and characterize a conditionally beneficial chromosomal duplication that makes haploid yeast more tolerant to oxidative stress. We determine that the effect of the chromosomal duplication on oxidative stress tolerance is largely explained by duplication of a single stress-inducible gene.
Efficient and flexible strategies for gene cloning and vector construction using overlap PCR
Authors: Liu Zhongtian , Zhang Tingting , Xu Kun 
Published: January 2017

AbstractGene cloning and vector construction are basic technologies in modern molecular biology for gene functional study. Here, we present flexible and efficient strategies for gene cloning and vector construction using overlap PCR. We firstly cloned the open reading frames (ORFs) of the porcineMSTN, chickenOVAand humanα-glucosidasegenes by overlap PCR-based assembling of their exons, which could be amplified with genomic DNAs as the templates without RNA extraction and RT-PCR reaction. Secondly, we generated additionally three designed functional cassettes by overlap PCR-based assembling of different DNA elements, which facilitated the construction their expression vectors greatly. Moreover, we further developed an interesting overlap-circled PCR method for fast plasmid vector construction without any cutting and ligating procedure. These advanced applications of overlap PCR provide useful alternative tools for gene cloning and vector construction.
Fragile dynamics enable diverse genomic determinants to influence arrhythmia propensity
Authors: Kamerzell Tim J , Sobie Eric A , Yang Kai-Chen , Nerbonne Jeanne M , MacRae Calum A , Iyengar Ravi 
Published: January 2017

AbstractGenotype-phenotype relationships are determinants of human diseases. Often, we know little about why so many genes are involved in complex common diseases. We hypothesized that this multigene effect arises from the relationship between genes and physiological dynamics. We tested this hypothesis for arrhythmias as physiological dynamics define this disease. We integrated graph theory analysis of genomic and protein-protein interaction networks with dynamical models of ion channel function to identify the physiological dynamics of genome wide variation for five different arrhythmias. Regulatory networks for the cardiac conduction system and arrhythmias were constructed from GWAS and known disease genes. Electrophysiological models of myocyte action potentials were used to conduct extensive parameter variations to identify robust and fragile kinetic parameters that were then, using regulatory networks, associated with genomic determinants. We find that genome-wide determinants of arrhythmias that represent many cellular processes are selectively associated with fragile physiological dynamics of ion channel kinetics. This association predicts disease propensity. Deep RNA sequencing from human left ventricular tissue of arrhythmia and control subjects confirmed the predictive relationship. Taken together these studies show that the varied multigene effects of arrhythmias arises because of associations with fragile kinetic parameters of cardiac electrophysiology.Significance StatementOur understanding of the genetics of common diseases has advanced exponentially over the past decade. We now know that differences and variation in multiple genes contribute to disease susceptibility with significant heterogeneity in the phenotype. However, how genetic variation contributes to disease phenotypes remains unknown. We hypothesized that the relationships between physiological dynamics and genetic architecture is a fundamental determinant of disease susceptibility and genetic heterogeneity. To test our hypothesis, we integrated mathematical models of cardiac electrophysiology with genetic network models of cardiac arrhythmias. We found that disease related genome variants were selectively associated with fragile kinetic parameters that predict disease propensity and identified several novel cellular processes associated with arrhythmogenesis.
Promoter-Enhancer Interactions Identified from Hi-C Data using Probabilistic Models and Hierarchical Topological Domains
Authors: Ron Gil , Moran Dror , Kaplan Tommy 
Published: January 2017

AbstractProximity-ligation methods as Hi-C allow us to map physical DNA-DNA interactions along the genome, and reveal its organization in topologically associating domains (TADs). As Hi-C data accumulate, computational methods were developed for identifying domain borders in multiple cell types and organisms.Here, we present PSYCHIC, a computational approach for analyzing Hi-C data and identifying Promoter-Enhancer interactions. We use a unified probabilistic model to segment the genome into domains, which we merge hierarchically and fit the Hi-C interaction map with a local background model. This allows us to estimate the expected number of interactions for every DNA-DNA pair, thus identifying over-represented interactions across the genome.By analyzing published Hi-C data in human and mouse, we identified hundreds of thousands of putative enhancers and their target genes in multiple cell types, and compiled an extensive genome-wide catalog of gene regulation in human and mouse.
Automated Detection of Records in Biological Sequence Databases that are Inconsistent with the Literature
Authors: Bouadjenek Mohamed Reda , Verspoor Karin , Zobel Justin 
Published: January 2017

AbstractWe investigate and analyse the data quality of nucleotide sequence databases with the objective of automatic detection of data anomalies and suspicious records. Specifically, we demonstrate that the published literature associated with each data record can be used to automatically evaluate its quality, by cross-checking the consistency of the key content of the database record with the referenced publications. Focusing on GenBank, we describe a set of quality indicators based on the relevance paradigm of information retrieval (IR). Then, we use these quality indicators to train an anomaly detection algorithm to classify records as“confident”or“suspicious”.Our experiments on the PubMed Central collection show assessing the coherence between the literature and database records, through our algorithms, is an effective mechanism for assisting curators to perform data cleansing. Although fewer than 0.25% of the records in our data set are known to be faulty, we would expect that there are many more in GenBank that have not yet been identified. By automated comparison with literature they can be identified with a precision of up to 10% and a recall of up to 30%, while strongly outperforming several baselines. While these results leave substantial room for improvement, they reflect both the very imbalanced nature of the data, and the limited explicitly labelled data that is available. Overall, the obtained results show promise for the development of a new kind of approach to detecting low-quality and suspicious sequence records based on literature analysis and consistency. From a practical point of view, this will greatly help curators in identifying inconsistent records in large-scale sequence databases by highlighting records that are likely to be inconsistent with the literature.
Systematic analysis of the effects of the DNA damage response network in telomere defective budding yeast
Authors: Holstein Eva-Maria , Ngo Greg , Lawless Conor , Banks Peter , Greetham Matthew , Wilkinson Darren , Lydall David 
Published: January 2017

AbstractFunctional telomeres are critically important to eukaryotic genetic stability. Budding yeast is a powerful model organism for genetic analysis and yeast telomeres are maintained by very similar mechanisms to human telomeres. Scores of proteins and pathways are known to affect telomere function. Here, we report a series of related genome-wide genetic interaction screens performed on budding yeast cells with acute or chronic telomere defects. We examined genetic interactions in cells defective in Cdc13 and Stn1, affecting two components of CST, a single stranded DNA (ssDNA) binding complex that binds telomeric DNA. We investigated genetic interactions in cells with defects in Rfa3, affecting the major ssDNA binding protein, RPA, which has overlapping functions with CST at telomeres. We also examined genetic interactions in cells lackingEXO1orRAD9,affecting different aspects of the DNA damage response in acdc13-1background. Comparing fitness profiles across the data sets allows us build up a picture of the specific responses to different types of dysfunctional telomeres. Our results show that there is no universal response to telomere defects. To help others engage with the large volumes of data we make the data available via two interactive web-based tools: Profilyzer and DIXY. Among numerous genetic interactions we found thechk1Δ mutation improved fitness ofcdc13-1 exo1Δ cells more than other checkpoint mutations (ddc1Δ,rad9Δ,rad17Δ,rad24Δ), whereas incdc13-1cells the effects of all checkpoint mutations were similar. We find that Chk1 stimulates resection at defective telomeres, revealing a new role for Chk1 in the eukaryotic DNA damage response network.
Targeted gene correction ofFKRPby CRISPR/Cas9 restores functional glycosylation of α-dystroglycan in cortical neurons derived from human induced pluripotent stem cells
Authors: Lana Beatrice , Kim Jihee , Ryan David , Konstantinidis Evangelos , Louzada Sandra , Fu Beiyuan , Yang Fengtang , Stemple Derek L. , Liu Pentao , Muntoni Francesco , Lin Yung-Yao 
Published: January 2017

SummaryMutations in genes required for functional glycosylation of α-dystroglycan cause a group of congenital muscular dystrophies associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic, physiology-relevant human cellular models has limited our understanding of the cortical abnormalities in dystroglycanopathies. Here we generate induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous mutations in the ribitol-5-phosphate transferase gene,FKRP. We carry out targeted gene correction in FKRP-iPSCs using CRISPR/Cas9-mediated genome editing. We characterise the directed differentiation of FKRP- and corrected-iPSCs to neural stem cells, cortical progenitors and cortical neurons. Importantly, we show that targeted gene correction ofFKRPrestores functional glycosylation of α-dystroglycan in iPSC-derived cortical neurons. We independently validate this result by showing targeted gene mutation ofFKRPdisrupts functional glycosylation of α-dystroglycan. This work demonstrates the feasibility of using CRISPR/Cas9-engineered human iPSCs for modelling dystroglycanopathies and provides a foundation for therapeutic development.HighlightsGeneration of FKRP-iPSCs for modelling cortical abnormalities in dystroglycanopathiesPrecise gene correction by CRISPR/Cas9-mediated genome editingDirected differentiation of isogenic control and FKRP-iPSC to cortical neuronsFunctional glycosylation of α-dystroglycan is restored in cortical neurons derived from CRISPR/Cas9-corrected iPSCsTargeted gene mutation of FKRP disrupts functional glycosylation of α-dystroglycan in cortical neurons
Wilm’s tumor 1 promotes memory flexibility
Authors: Mariottini Chiara , Munari Leonardo , Gunzel Ellen , Seco Joseph M. , Tzavaras Nikos , Hansen Jens , Stern Sarah A. , Gao Virginia , Aleyasin Hossein , Azeloglu Evren U. , Hodes Georgia E. , Russo Scott J. , Huff Vicki , Birtwistle Marc , Blitzer Robert D. , Alberini Cristina M. , Iyengar Ravi 
Published: January 2017

AbstractUnder physiological conditions, strength and persistence of memory must be regulated in order to produce behavioral flexibility. In fact, impairments in memory flexibility are associated with pathologies such as post-traumatic stress disorder or autism; however the underlying mechanisms that enable memory flexibility are still poorly understood. Here we identified the transcriptional repressor Wilm’s Tumor 1 (WT1) as a critical synaptic plasticity regulator that decreases memory strength, promoting memory flexibility. WT1 was activated in the hippocampus following induction of long-term potentiation (LTP) or learning. WT1 knockdown enhanced CA1 neuronal excitability, LTP and long-term memory whereas its over-expression weakened memory retention. Moreover, forebrain WT1-deficient mice showed deficits in both reversal, sequential learning tasks and contextual fear extinction, exhibiting impaired memory flexibility. We conclude that WT1 limits memory strength or promotes memory weakening, thus enabling memory flexibility, a process that is critical for learning from new experience.
Genome Graphs
Authors: Novak Adam M. , Hickey Glenn , Garrison Erik , Blum Sean , Connelly Abram , Dilthey Alexander , Eizenga Jordan , Elmohamed M. A. Saleh , Guthrie Sally , Kahles André , Keenan Stephen , Kelleher Jerome , Kural Deniz , Li Heng , Lin Michael F. , Miga Karen , Ouyang Nancy , Rakocevic Goran , Smuga-Otto Maciek , Zaranek Alexander Wait , Durbin Richard , McVean Gil , Haussler David , Paten Benedict 
Published: January 2017

AbstractThere is increasing recognition that a single, monoploid reference genome is a poor universal reference structure for human genetics, because it represents only a tiny fraction of human variation. Adding this missing variation results in a structure that can be described as a mathematical graph: a genome graph. We demonstrate that, in comparison to the existing reference genome (GRCh38), genome graphs can substantially improve the fractions of reads that map uniquely and perfectly. Furthermore, we show that this fundamental simplification of read mapping transforms the variant calling problem from one in which many non-reference variants must be discovered de-novo to one in which the vast majority of variants are simply re-identified within the graph. Using standard benchmarks as well as a novel reference-free evaluation, we show that a simplistic variant calling procedure on a genome graph can already call variants at least as well as, and in many cases better than, a state-of-the-art method on the linear human reference genome. We anticipate that graph-based references will supplant linear references in humans and in other applications where cohorts of sequenced individuals are available.
Multiplexed dynamic imaging of genomic loci in single cells by combined CRISPR imaging and DNA sequential FISH
Authors: Takei Yodai , Shah Sheel , Harvey Sho , Qi Lei S. , Cai Long 
Published: January 2017

ABSTRACTVisualization of chromosome dynamics allows the investigation of spatiotemporal chromatin organization and its role in gene regulation and other cellular processes. However, current approaches to label multiple genomic loci in live cells have a fundamental limitation in the number of loci that can be labelled and uniquely identified. Here we describe an approach we call “track first and identify later” for multiplexed visualization of chromosome dynamics by combining two techniques: CRISPR labeling and DNA sequential fluorescencein situhybridization (DNA seqFISH). Our approach first labels and tracks chromosomal loci in live cells with the CRISPR system, then barcodes those loci by DNA seqFISH in fixed cells and resolves their identities. We demonstrate our approach by tracking telomere dynamics, identifying 12 unique subtelomeric regions with variable detection efficiencies, and tracking back the telomere dynamics of respective chromosomes in mouse embryonic stem cells.
The impact of human papillomavirus type on colposcopy performance in women offered HPV immunisation in a catch‐up vaccine programme: a two‐centre observational study
Authors: Munro A , Gillespie C , Cotton S , Busby‐Earle C , Kavanagh K , Cuschieri K , Cubie H , Robertson C , Smart L , Pollock K , Moore C , Palmer T , Cruickshank ME 
Published: January 2017

ObjectiveTo determine whether human papillomavirus (HPV) immunisation has affected the prevalence of HPV genotypes and colposcopic features of cervical intraepithelial neoplasia (CIN) in young women referred for colposcopy.DesignA two‐centre observational study including vaccinated and unvaccinated women.SettingColposcopy clinics serving two health regions in Scotland, UK.PopulationA total of 361 women aged 20–25 years attending colposcopy following an abnormal cervical cytology result at routine cervical screening.MethodsCervical samples were obtained from women for HPV DNA genotyping and mRNA E6/E7 expression of HPV 16, 18, 31, 33, and 45. Demographic data, cytology, and histology results and colposcopic features were recorded. Chi‐square analysis was conducted to identify associations between vaccine status, HPV genotypes, and colposcopic features.Main outcome measuresColposcopic features, HPV genotypes, mRNA expression, and cervical histology.ResultsThe prevalence of HPV 16 was significantly lower in the vaccinated group (8.6%) compared with the unvaccinated group (46.7%) (P = 0.001). The number of cases of CIN2+ was significantly lower in women who had been vaccinated (P = 0.006). The HPV vaccine did not have a statistically significant effect on commonly recognised colposcopic features, but there was a slight reduction in the positive predictive value (PPV) of colposcopy for CIN2+, from 74% (unvaccinated) to 66.7% (vaccinated).ConclusionsIn this group of young women with abnormal cytology referred to colposcopy, HPV vaccination via a catch‐up programme reduced the prevalence of CIN2+ and HPV 16 infection. The reduced PPV of colposcopy for the detection of CIN2+ in women who have been vaccinated is at the lower acceptable level of the UK national cervical screening programme guidelines.Tweetable abstractReduction of hrHPV positivity and CIN in immunised women consistent with lower PPV of colposcopy for CIN2+.
Intravitreal ranibizumab for diabetic macular oedema in previously vitrectomized eyes
Authors: Laugesen Caroline Schmidt , Ostri Christoffer , Brynskov Troels , Lund‐Andersen Henrik , Larsen Michael , Vorum Henrik , Sørensen Torben L. 
Published: January 2017

AbstractPurposeThere is little information about the efficacy of intravitreal vascular endothelial growth factor (VEGF) inhibition in vitrectomized eyes. This study aimed to evaluate the efficacy of anti‐VEGF (ranibizumab) on diabetic macular oedema in previously vitrectomized eyes.MethodsA nationwide retrospective review of medical records from 2010 to 2013.ResultsWe identified 33 previously vitrectomized eyes in 28 patients treated with ranibizumab injections for diabetic macular oedema. Median follow‐up was 323 days (interquartile range 72–1404 days). Baseline mean visual acuity was 0.57 logMAR (95% CI 0.13–1.01) before injections. After an average of 4.7 injections (range 1–15), mean visual acuity remained stable at 0.54 logMAR (95% CI 0.13–0.95) with a mean improvement of 0.03 (p = 0. 45, 95% CI −0.12 to 0.06). In 12 eyes (36%), visual acuity improved 0.1 logMAR or more, in 12 eyes (36%), vision was unchanged (gain or loss of 0–0.05 logMAR), and in nine eyes (27%), vision decreased 0.1 logMAR or more. Mean central foveal thickness (CFT) on optical coherence tomography (OCT) scan was 412 μm (95% CI 390–434 μm) before injections. After injections, the mean CFT decreased to 352 μm (95% CI 334–370 μm). The mean reduction in CFT was 14% (95% CI 4–24%, p = 0.01). Sixteen eyes (48.5%) became devoid of oedema on the last OCT scan. Despite the significant reduction in CFT, the visual acuity remained unchanged.ConclusionIntravitreal ranibizumab can be effective in previously vitrectomized eyes with diabetic macular oedema. However, the response is variable and should be carefully monitored.
Sleep and diabetic retinopathy
Authors: Jee Donghyun , Keum Nana , Kang Seungbum , Arroyo Jorge G. 
Published: January 2017

AbstractPurposeTo investigate the association between sleep duration and diabetic retinopathy (DR).MethodsA population‐based cross‐sectional study using a nation‐wide, systemically stratified, multistage, clustered sampling method included a total of 1670 subjects aged ≥40 years with diabetes who participated in the Korean National Health and Nutrition Examination Survey during 2008–2012. All participants performed standardized interviews, including self‐reported sleep duration, and comprehensive ophthalmic examinations. Seven standard retinal fundus photographs were obtained from both eyes after pupil dilatation. Diabetic retinopathy (DR) was graded and classified as any DR and vision‐threatening DR. Participants were stratified into men and women.ResultsThe mean sleep duration was 6.71 hr/day. In men, adjusted OR of any DR was 1.88 [95% confidence interval (OR), 1.01–3.59] in those with ≤5 hr sleep, and 2.19 (95% CI, 1.01–4.89) in those with ≥9 hr sleep, compared to in subjects with 6–8 hr sleep, after adjusting for potential confounders including age, body mass index (BMI), diabetes duration, fasting glucose level, haemoglobin A1c levels and hypertension. In women, however, no significant association between sleep duration and DR was found. The vision‐threatening DR was not significantly associated with sleep duration in either men or women.ConclusionsShort and long sleep was associated with high prevalence of DR in men. Sleep deprivation may be involved in the pathogenesis of DR development.
Self‐Control in Childhood: A Synthesis of Perspectives and Focus on Early Development
Authors: Gagne Jeffrey R. 
Published: January 2017

AbstractIn this article, I describe three prominent developmental science perspectives on self‐control in childhood, discuss differences and areas of consensus, and suggest a comprehensive, early integrative approach to research on this topic. The self‐control perspectives are the self‐regulatory concepts of delay of gratification and willpower, the cognitive neuroscience executive functioning construct of inhibitory control (IC), and the behavioral and emotional temperament dimensions of effortful control and IC. The primary focus of these approaches is similar, and differences are based largely on theory, methods, and the age of the children studied. Therefore, I agree with a synthesis of these perspectives championed by other developmental scientists, and propose comprehensive, multitheoretical, multimethod empirical study that begins when self‐control emerges in toddlerhood.