bluuebunny/crossref_metadata_2025_split huggingface dataset:
EFCAB9 is a pH-Dependent Ca2+Sensor that Regulates CatSper Channel Activity and Sperm Motility
Authors: Hwang Jae Yeon , Nadja Mannowetz , Zhang Yongdeng , Everley Robert A. , Gygi Steven P. , Bewersdorf Joerg , Lishko Polina V. , Chung Jean-Ju 
Published: November 2018

SummaryVarying pH of luminal fluid along the female reproductive tract is a physiological cue that modulates sperm motility. CatSper is a sperm-specific, pH-sensitive calcium channel essential for hyperactivated motility and male fertility. Multi-subunit CatSper channel complexes organize linear Ca2+signaling nanodomains along the sperm tail. Here, we identify EF-hand calciumbinding domain-containing protein 9 (EFCAB9) as a dual function, cytoplasmic machine modulating the channel activity and the domain organization of CatSper. Knockout mice studies demonstrate that EFCAB9, in complex with the CatSper subunit, CAT SPERζ, is essential for pH-dependent and Ca2+sensitive activation of the CatSper channel. In the absence of EFCAB9, sperm motility and fertility is compromised and the linear arrangement of the Ca2+signaling domains is disrupted. EFCAB9 interacts directly with CATSPERζ in a Ca2+dependent manner and dissociates at elevated pH.These observations suggest that EFCAB9 is a long-sought, intracellular, pH-dependent Ca2+sensor that triggers changes in sperm motility.HighlightsEfcab9encodes an evolutionarily conserved, sperm-specific EF-hand domain proteinEfcab9-deficient mice have sperm motility defects and reduced male fertilityEFCAB9 is a pH-tuned Ca2+sensor for flagellar CatSper Ca2+channelEFCAB9 is a dual function machine in gatekeeping and domain organization of CatSper
Experimental Human Challenge Reveals Distinct Mechanisms of Acquisition or Protection Against Pneumococcal Colonization
Authors: Nikolaou Elissavet , Jochems Simon P. , Mitsi Elena , Pojar Sherin , Negera Edessa , Reiné Jesús , Carniel Beatriz , Soares-Schanoski Alessandra , Connor Victoria , Adler Hugh , Zaidi Seher Raza , Hales Caz , Hill Helen , Hyder-Wright Angela , Gordon Stephen B. , Rylance Jamie , Ferreira Daniela M. 
Published: November 2018

AbstractColonization of the upper respiratory tract with Streptococcus pneumoniae is the precursor of pneumococcal pneumonia and invasive disease. Following exposure, however, it is unclear which human immune mechanisms determine whether a pathogen will colonize. We used a human challenge model to investigate host-pathogen interactions in the first hours and days following intranasal exposure to Streptococcus pneumoniae. Using a novel home sampling method, we measured early immune responses and bacterial density dynamics in the nose and saliva after pneumococcal exposure. We found that nasal colonization can take up to 24 hours to become established. Also, two distinct bacterial clearance profiles were associated with protection: nasal clearers with immediate clearance of bacteria in the nose by the activity of pre-existent mucosal neutrophils and saliva clearers with detectable pneumococcus in saliva at one-hour post challenge and delayed clearance mediated by an inflammatory response and increased neutrophil activity 24 hours post bacterial encounter.
Functional Interrogation of Lynch Syndrome Associated MSH2 Missense Variants Using CRISPR-Cas9 Gene Editing in Human Embryonic Stem Cells
Authors: Rath Abhijit , Mishra Akriti , Ferreira Victoria Duque , Hu Chaoran , Grady James P. , Heinen Christopher D. 
Published: November 2018

AbstractLynch syndrome (LS) is a hereditary cancer predisposition condition caused by inactivating germline mutations in one of the DNA mismatch repair (MMR) genes. Identifying a deleterious germline mutation by DNA sequencing is important for confirming an LS diagnosis. Frameshift and nonsense mutations significantly alter the protein product and likely impair MMR function. However, the implication of a missense mutation is often difficult to interpret. Referred to as variants of uncertain significance (VUS), their discovery hampers the definitive LS diagnosis. To determine the pathogenic significance of a VUS it is helpful to know its impact on protein function. Functional studies in the test tube and in cellular models have been performed for some VUS, however, these studies have been limited by the artificial nature of the assays. We report here an improved functional assay in which we engineered site-specific MSH2 VUS using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 gene editing in human embryonic stem cells. This approach introduces the variant into the endogenous MSH2 loci, while simultaneously eliminating the wild-type gene. We then characterized the impact of the variants on cellular MMR functions including DNA damage response signaling upon challenge with a DNA alkylating agent and the repair of DNA microsatellites. We classified the MMR functional capability of 8 of 10 VUS under study providing valuable information for determining their likelihood of being bona fide LS mutations. This improved human cell-based assay system for functionally testing MMR gene VUS will facilitate the identification of high risk LS patients.Significance StatementUnderstanding how cancer-associated missense variants in MMR genes affect function helps determine whether they truly contribute to disease. Laboratory assays previously utilized are limited by their artificial nature. To improve this, we introduced variants directly into the endogenous MMR loci in hESCs using CRISPR-Cas9 gene editing. This approach allows us to assess each variant while being expressed by its normal regulatory elements in a cellular environment. Our results will help guide the management of patients world-wide who carry these variants. At the same time, this study provides a technical road map for assessing the functional effects of all LS-associated variants, as well as variants linked to other genetic diseases where a cell-based functional assay is available.
Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer
Authors: Kang Yun Pyo , Torrente Laura , Liu Min , Asara John M. , Dibble Christian C. , DeNicola Gina M. 
Published: November 2018

SummaryNRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably,CDO1is preferentially silenced by promoter methylation in non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite, and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.
A pilot study of the effects ofMycoplasma ovipneumoniaeexposure on domestic lamb growth and performance
Authors: Besser Thomas E. , Levy Jessica , Ackerman Melissa , Nelson Danielle , Manlove Kezia , Potter Kathleen A. , Busboom Jan , Benson Margaret 
Published: November 2018

AbstractMycoplasma ovipneumoniaeis a globally distributed pathogen that has been associated with pneumonia in both domestic and wild Caprinae. It is closely related toM. hyopneumoniae, a respiratory pathogen of swine that is associated with decreased growth rates of pigs as well as clinical respiratory disease. In order to assess the effects ofM. ovipneumoniaeon lamb performance, we generated a cohort of lambs free ofM. ovipneumoniaeby segregation of test negative ewes after lambing, then compared the growth and carcass quality traits ofM. ovipneumoniae-freeand -colonized lambs from weaning to harvest. Some signs of respiratory disease were observed during the feeding trial in both lamb groups, but theM. ovipneumoniae-exposedgroup included more affected lambs and higher average disease scores. At harvest, lungs of lambs in both groups showed few grossly visible lesions, although theM. ovipneumoniae-exposedgroup did exhibit increased microscopic lung lesions (P<0.05). In addition,M. ovipneumoniaeexposed lambs produced lower average daily gains (P<0.05), and lower yield grade carcasses (P<0.05) compared to those of non-exposed lambs. The results demonstrated the feasibility of test and segregation for elimination ofM. ovipneumoniaefrom groups of sheep and suggested that this pathogen may impair lamb growth and productivity even in the absence of overt respiratory disease.
The effect of heavy metal contamination on human and animal health in the vicinity of a zinc smelter
Authors: Shen Xiaoyun , Chi Yongkuan , Xiong Kangning 
Published: November 2018

AbstractA diagnosis of heavy metal poisoning in sheep living on pasture in the vicinity of a zinc smelter was made based on laboratory tests and clinical signs in livestock in the Wumeng mountain area of China. Heavy metal contamination has generated serious harm to the health of local farmers after passing through the food chain. The levels of copper, zinc, cadmium, and lead in irrigation water, soil, forages, and animal tissues were measured in samples taken from within the vicinity of a zinc smelter and control samples. Heavy metal concentrations in foods (corn, rice, and wheat) and human tissues (blood and hair) from local farmers living in affected areas and controls were also determined. Hematological values were determined in human and animal samples. The copper, zinc, cadmium, and lead concentrations in irrigation water, soils, and forages were markedly higher than the levels in healthy pastures. Cadmium and lead concentrations were 177.82 and 16.61 times greater in forages than controls, respectively, and 68.71 and 15.66 times greater in soils than controls, respectively. Heavy metal concentrations in food (corn, rice, and wheat) in affected areas were markedly higher than in the control samples. Cadmium and lead concentrations in the tissues of affected sheep were markedly higher than in control animals (P< 0.01). Cadmium and lead concentrations in blood and hair samples from affected farmers were markedly higher than the control samples (P < 0.01). The occurrence of anemia in affected persons and animals followed a hypochromic and microcytic pattern. The intake of cadmium and lead was estimated according to herbage ingestion rates. It was found that the levels of cadmium and lead accumulated in sheep through the ingestion of vegetation growing in the sites closest to the zinc smelter were approximately 3.36 mg Cd/kg body wt./day and 38.47 mg Pb/kg body wt./day. This surpassed the fatal dosages for sheep of 1.13 mg Cd/kg body wt/day and 4.42 mg Pb/kg body wt./day. Serum total antioxidant capacity in affected humans and animals was significantly lower than in the controls (P < 0.01). The serum protein parameters in affected humans and animals were significantly reduced (P < 0.01). It was therefore concluded that heavy metal contamination has caused serious harm to sheep in this area. The heavy metal concentrations in food and grain also pose a significant risk to human health in the Chinese Wumeng mountain area.
Inferring novel lncRNA associated with Ventricular septal defect by DNA methylation interaction network
Authors: Zhang Min , Gu Yue , Su Mu , Zhang Shumei , Chen Chuangeng , Lv Wenhua , Zhang Yan 
Published: November 2018

AbstractVentricular septal defect (VSD) is one of the most common types of congenital heart disease. To find more and more molecular alteration is conducive to explore the mechanism and biomarker in VSD. Herein we devised a predictive strategy to uncover novel lncRNA of VSD integrating DNA methylation, gene expression and lncRNA expression of early embryo and VSD by profiles from GEO database. In totally, 175 lncRNAs, 7290 genes and 3002 DNA methylation genes were obtained by logistic regression analysis associated with embryonic development. Moreover, 7304 DMGs were significant differential methylated by Wilcoxon rank test and Student’s test in VSD. We constructed the lncRNA-mRNA co-expression network in embryo (LMCNe). Then, a reconstructed co-expression weighted network (RCWN) was built integrated LMCNe and the DNA methylation associated network (DMAN) based on the correlation of the DNA methylation level and protein interaction network between embryonic development and VSD. We extracted top 10 lncRNAs with higher score performing DRaWR from the weight network, which as potential VSD related lncRNAs. Six lncRNAs showed a high level of expression in the heart tissue recorded in the NONOCOND database. Furthermore, associated lncRNA genes DCAF8L1, NIT1, SH2D7 and DOCK9-AS2 in validated samples showed a prominently association with VSD. These outcomes provide a reference for lncRNA involved in VSD initialization and a new insight for studies of VSD-associated lncRNAs.Author SummaryVentricular septal defect (VSD) is one of the most common types of congenital heart disease and has a high mortality rate in infants. Many molecular markers have proved effective as biomarker in VSD like DNA methylation and lncRNA. lncRNA is a type of non-coding RNA which has important effect in regulation gene expression and disease occurrence. VSD is an embryonic stage developmental disease. Therefore we hypothesized that lncRNA which was associated with DNA methylation and mRNA in early embryonic development may also affect the occurrence of VSD. So in this work, from the perspective of embryonic development, we devised a predictive strategy to uncovering novel lncRNA of VSD. In our result, four lncRNA associated genes were found differential expressed in VSD and normal samples by qPCR validation. The identification of lncRNA associated with ventricular septal defect is beneficial to further study the mechanism of VSD from the molecular level and also provides a good molecular marker for clinical therapeutic and diagnosis. At the same time, it also provides a new insight for the researches of lncRNA associated with VSD.
Aneuvis: Web-based exploration of numerical chromosomal variation in single cells
Authors: Piqué Daniel G , Andriani Grasiella A , Maggi Elaine , Zimmerman Samuel E , Greally John M , Montagna Cristina , Mar Jessica C. 
Published: November 2018

AbstractMotivationAberrations in chromosomal copy number are one of the most common molecular features observed in cancer. Quantifying the degree of numerical chromosomal variation in single cells across a population of cells is of interest to researchers studying whole chromosomal instability (W-CIN). W-CIN, a state of high numerical chromosomal variation, contributes to treatment resistance in cancer.ResultsHere, we introduce aneuvis, a web application that allows users to determine whether numerical chromosomal variation exists between experimental treatment groups. The web interface allows users to upload molecular cytogenetic or processed whole-genome sequencing data in a cell-by-chromosome matrix format and automatically generates visualizations and summary statistics that reflect the degree of numeric chromosomal variability. Aneuvis is the first user-friendly web application to help researchers identify the genetic and environmental perturbations that promote numerical chromosomal variation.Availability and ImplementationAneuvis is freely available as a web application at https://dpique.shinyapps.io/aneuvis/. Website implemented using Shiny version 1.0.5 with all major browsers supported. All source code for the application is available at https://github.com/dpique/aneuvis.
Inhalation of marijuana affects Drosophila heart function
Authors: Gómez IM , Rodríguez MA , Santalla M , Kassis G , Colman Lerner JE , Aranda O , Sedán D , Andrinolo D , Valverde CA , Ferrero P 
Published: November 2018

AbstractMedical uses of marijuana have been recently approved in many countries, and after a long ban on research, there is despicable scientific evidence regarding its action and side effects. We investigated the effect of inhalation of vaporized marijuana on cardiac function in Drosophila melanogaster, a suitable genetic model for assessing cardiovascular function. Chronic exposure of adult flies to vaporized marijuana reduces heart rate, increments contractility and prolongs relaxation. These changes are manifested in the cardiomyocytes with no effect in calcium handling, and in the absence of the canonical cannabinoids receptors identified in mammals. Our results are the first evidence of the in vivo impact of phytocannabinoids in D. melanogaster and open new paths for genetic screenings using vaporized compounds, providing a simple and affordable platform prior to mammalian models.
The landscape of antigen-specific T cells in human cancers
Authors: Li Bo , Liu Longchao , Zhang Jian , Chen Jiahui , Ye Jianfeng , Filatenkov Alexander , Shukla Sachet , Qiao Jian , Zhan Xiaowei , Wu Catherine , Fu Yang-Xin 
Published: November 2018

AbstractAntigen-specific T cells can be orchestrated to kill cancer cells in immunotherapies but the utilities of the TCR information have not been fully explored. Here, we leveraged previous efforts on tumor TCR repertoire, and developed a novel algorithm to characterize antigen-specific TCR clusters. Joint analysis with gene expression revealed novel regulators for T cell activation. Investigation of single-cell sequencing data revealed a novel subset of tissue-resident memory T cell population with elevated metabolic status. Integrative analysis of TCR clusters with HLA alleles and cancer genomics data identified candidate antigens derived from missense mutations, frameshift indels, and tumor-associated gene overexpression. Predicted antigenHSFX1was further validated using vaccinated humanized HLA-A*02:01 mice. Finally, high abundant cancer-associated TCRs were observed in the blood repertoire of early breast cancer patients, suggesting new avenues for noninvasive early detection. Thus, our analysis identified cancer-associated T cells with broad utilities in immune monitoring and cancer immunotherapies.
Chiral twisting in cytoskeletal polymers regulates filament size and orientation
Authors: Shi Handuo , Quint David , Gopinathan Ajay , Huang Kerwyn Casey 
Published: November 2018

AbstractWhile cytoskeletal proteins in the actin family are structurally similar, as filaments they act as critical components of diverse cellular processes across all kingdoms of life. In many rod-shaped bacteria, the actin homolog MreB directs cell-wall insertion and maintains cell shape, but it remains unclear how structural changes to MreB affect its physiological function. To bridge this gap, we performed molecular dynamics simulations forCaulobacter crescentusMreB and then utilized a coarse-grained biophysical model to successfully predict MreB filament propertiesin vivo.We discovered that MreB double protofilaments exhibit left-handed twisting that is dependent on the bound nucleotide and membrane binding; the degree of twisting determines the limit length and orientation of MreB filamentsin vivo.Membrane binding of MreB also induces a stable membrane curvature that is physiologically relevant. Together, our data empower the prediction of cytoskeletal filament size from molecular dynamics simulations, providing a paradigm for connecting protein filament structure and mechanics to cellular functions.
Introducing the recovery inspiration group: promoting hope for recovery with inspirational recovery stories
Authors: Elsegood Kelly J. , Anderson Lucinda , Newton Rachel 
Published: November 2018

Purpose
The purpose of this paper is to undertake a preliminary evaluation of a novel intervention – Recovery Inspiration Group, which uses recovery stories to promote hope and inspiration for recovery among people with complex mental health difficulties.

Design/methodology/approach
The Recovery Inspiration Group was delivered to women on a specialist personality disorder inpatient unit, who were concurrently participating in a dialectical behaviour therapy (DBT) Programme. In total, 12 service users participated in the RIG and as part of the intervention, wrote down key reflections after hearing each recovery story. A thematic analysis of these reflections formed the primary basis of the evaluation. Descriptive statistics derived from a service user feedback survey (n=6) supplemented the qualitative findings.

Findings
Three themes were identified in the qualitative data, suggesting that participants had engaged with recovery-oriented reflections and experiences: recovery stories as validating and inspiring; Generalisation of DBT skills; shifting perspectives of recovery: doing better rather than being better. The survey results unanimously endorsed the RIG as a worthwhile and validating experience, which participants would recommend to other service users.

Practical implications
Recovery Inspiration Group appears to be a low-cost and easily replicable intervention with the potential to promote hope and inspiration for recovery among people with complex mental health difficulties.

Originality/value
Recovery Inspiration Group is a novel approach to harnessing the wisdom of people with lived experience of mental health difficulties, to foster hope among users of mental health inpatient services.
China’s role in the new round of restructuring of regional division of labor in East Asia
Authors: Liu Hongzhong , Shi Daqian 
Published: November 2018

PurposeThe purpose of this paper is to explain the reasons and development trend of the new round of restructuring of regional division of labor in East Asia after the global financial crisis and the role of China in the process.Design/methodology/approachThe paper probes into four factors leading to the adjustment of regional division of labor in East Asia before analyzing its development trend trough comparing the change of roles of China and ASEAN in the process.FindingsAfter the flying-geese division and regional production network, East Asia’s regional division of labor is getting a new round of structural adjustment. The analysis of this paper shows that this adjustment is mainly due to global financial crisis, post-crisis de-globalization, the rebalancing of East Asian economies and China’s economic transformation. From the adjustment direction, the main trend is ASEAN gradually replacing China to become the new assembly plant area, while China becomes a new manufacturing power by its rising status in the global value chain.Originality/valueThe paper describes the development trend of the new round of restructuring of regional division of labor in East Asia in the future and gives the policy implications for the East Asian countries.