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Genetics
Database of evidence for precision oncology portal.
Dec 11, 2018   Bioinformatics (Oxford, England)
Sun SQ, Mashl RJ, Sengupta S, Scott AD, Wang W, Batra P, Wang LB, Wyczalkowski MA, Ding L
Database of evidence for precision oncology portal.
Dec 11, 2018
Bioinformatics (Oxford, England)
Summary: A database of curated genomic variants with clinically supported drug therapies and other oncological annotations is described. The accompanying web portal provides a search engine with two modes: one that allows users to query gene, cancer type, variant type or position for druggable mutations, and another to search for and to visualize, on three-dimensional protein structures, putative druggable sites that cluster with known druggable mutations. Availability and implementation: http://dinglab.wustl.edu/depo.
Single tube liquid biopsy for advanced non-small cell lung cancer.
Dec 11, 2018   International Journal Of Cancer
de Wit S, Rossi E, Weber S, Tamminga M, Manicone M,   . . . . . .   , Hiltermann TJN, Speicher MR, Heitzer E, Terstappen LWMM, Groen HJM
Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
Dec 11, 2018   Cancer Cell
Gerhauser C, Favero F, Risch T, Simon R, Feuerbach L,   . . . . . .   , Plass C, Yaspo ML, Korbel JO, Schlomm T, Weischenfeldt J
Molecular Evolution of Early-Onset Prostate Cancer Identifies Molecular Risk Markers and Clinical Trajectories.
Dec 11, 2018
Cancer Cell
Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples.
Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally.
Dec 11, 2018   Cancer Cell
Brown JA, Ferrando A
Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: BIM Finally.
Dec 11, 2018
Cancer Cell
Glucocorticoid resistance represents a major challenge in treating acute lymphoblastic leukemia. In this issue of Cancer Cell, Jing and colleagues show epigenetic deregulation of glucocorticoid-induced BIM activation in glucocorticoid-resistant leukemia cells, and restore glucocorticoid-receptor-induced BIM upregulation with DNA demethylating agents to effectively enhance glucocorticoid response.
A quantitative trait locus, qSE3, promotes seed germination and seedling establishment under salinity stress in rice.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
He Y, Yang B, He Y, Zhan C, Cheng Y, Zhang J, Zhang H, Cheng J, Wang Z
A quantitative trait locus, qSE3, promotes seed germination and seedling establishment under salinity stress in rice.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
Seed germination is a complex trait determined by both quantitative trait loci (QTLs) and environmental factors and also their interactions. In this study, we mapped one major QTL qSE3 for seed germination and seedling establishment under salinity stress in rice. To understand the molecular basis of this QTL, we isolated qSE3 by map-based cloning and found that it encodes a K+ transporter gene, OsHAK21. The expression of qSE3 was significantly up-regulated by salinity stress in germinating seeds. Physiological analysis suggested that qSE3 significantly increased K+ and Na+ uptake in germinating seeds under salinity stress, resulting in increased abscisic acid (ABA) biosynthesis and activated ABA signaling responses. Furthermore, qSE3 significantly decreased the H2 O2 level in germinating seeds under salinity stress. All of these seed physiological changes modulated by qSE3 might contribute to seed germination and seedling establishment under salinity stress. Based on analysis of single-nucleotide polymorphism data of rice accessions, we identified a HAP3 haplotype of qSE3 that was positively correlated with seed germination under salinity stress. This study provides important insights into the roles of qSE3 in seed germination and seedling establishment under salinity stress and facilitates the practical use of qSE3 in rice breeding. This article is protected by copyright. All rights reserved.
Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders.
Dec 11, 2018   American Journal Of Medical Genetics. Part A
Li Y, Jia X, Wu H, Xun G, Ou J, Zhang Q, Li H, Bai T, Hu Z, Zou X, Xia K, Guo H
Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders.
Dec 11, 2018
American Journal Of Medical Genetics. Part A
SHANK3 has been identified as the causative gene of 22q13.3 microdeletion syndrome phenotype. De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID). Although broad developmental phenotypes of these patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with SHANK3 DNMs. In this study, we identified a de novo splice mutation (NM_033517.1: c.2265+1G>A) that functionally impairs mRNA splicing, produces multiple splice variants, and results in the reduction of the amounts of mRNA. To analyze the genotype and phenotype correlations for SHANK3 DNMs, we reviewed 37 previously published patients with 28 SHANK3 DNMs. Our results revealed that haploinsufficiency of SHANK3 causes a broad spectrum of neurodevelopmental phenotypes with impaired social interaction, repetitive behavior, speech impairment, ID, and regression as the most common observations. Seizures, hypotonia, global development delay, dysmorphic features, and several other features also occurred recurrently. Specific phenotypes are also observed in certain genotypes. Our study provides the frequency of the heterogeneous co-occurring conditions caused by SHANK3 DNMs, which will be beneficial for diagnosis and clinical management.
Linear mixed models for association analysis of quantitative traits with next-generation sequencing data.
Dec 11, 2018   Genetic Epidemiology
Chiu CY, Yuan F, Zhang BS, Yuan A, Li X,   . . . . . .   , Cook RJ, McMahon FJ, Amos CI, Xiong M, Fan R
Linear mixed models for association analysis of quantitative traits with next-generation sequencing data.
Dec 11, 2018
Genetic Epidemiology
We develop linear mixed models (LMMs) and functional linear mixed models (FLMMs) for gene-based tests of association between a quantitative trait and genetic variants on pedigrees. The effects of a major gene are modeled as a fixed effect, the contributions of polygenes are modeled as a random effect, and the correlations of pedigree members are modeled via inbreeding/kinship coefficients. F -statistics and χ 2 likelihood ratio test (LRT) statistics based on the LMMs and FLMMs are constructed to test for association. We show empirically that the F -distributed statistics provide a good control of the type I error rate. The F -test statistics of the LMMs have similar or higher power than the FLMMs, kernel-based famSKAT (family-based sequence kernel association test), and burden test famBT (family-based burden test). The F -statistics of the FLMMs perform well when analyzing a combination of rare and common variants. For small samples, the LRT statistics of the FLMMs control the type I error rate well at the nominal levels α = 0.01 and 0.05 . For moderate/large samples, the LRT statistics of the FLMMs control the type I error rates well. The LRT statistics of the LMMs can lead to inflated type I error rates. The proposed models are useful in whole genome and whole exome association studies of complex traits.
Functional analysis of DNA methylation of the PACSIN1 promoter in pig peripheral blood mononuclear cells.
Dec 11, 2018   Journal Of Cellular Biochemistry
Feng W, Zhou L, Wang H, Hu Z, Wang X, Fu J, Wang A, Liu JF
Functional analysis of DNA methylation of the PACSIN1 promoter in pig peripheral blood mononuclear cells.
Dec 11, 2018
Journal Of Cellular Biochemistry
DNA methylation plays essential roles in regulating the activity of genes and may contribute to understanding the potential epigenetic biomarkers response to viruses. To explore the function of DNA methylation of protein kinase C and casein kinase substrate in neurons 1 (PACSNI1) promoter, herein we performed the bisulfite sequencing polymerase chain reaction and Western blot analysis to verify hypermethylation and downregulation of PACSIN1 expression in peripheral blood mononuclear cells of pig as the vitro model. Promoter methylation could reduce the transcriptional activity of the PACSIN1 gene potentially by affecting the binding of transcription factor Sp1. In addition, downregulation of the PACSIN1 gene expression could facilitate the production of interleukin-6 (IL-6), IL-8, tumor necrosis factor α, and NECAP2. The comprehensive analysis of PACSIN1 methylation and its function will help us to understand the gene to be served as an important candidate gene in pig for disease resistance breeding and aid in the identification of potential epigenetic biomarkers associated with responsiveness to viruses.
Gene-environment interactions and colorectal cancer risk: an umbrella review of systematic reviews and meta-analyses of observational studies.
Dec 11, 2018   International Journal Of Cancer
Yang T, Li X, Montazeri Z, Little J, Farrington SM, Ioannidis JP, Dunlop MG, Campbell H, Timofeeva M, Theodoratou E
Gene-environment interactions and colorectal cancer risk: an umbrella review of systematic reviews and meta-analyses of observational studies.
Dec 11, 2018
International Journal Of Cancer
The cause of colorectal cancer (CRC) is multifactorial, involving both genetic variants and environmental risk factors. We systematically searched the MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases from inception to December 2016, to identify systematic reviews and meta-analyses of observational studies that investigated gene-environment (G × E) interactions in CRC risk. Then, we critically evaluated the cumulative evidence for the G × E interactions using an extension of the Human Genome Epidemiology Network's Venice criteria. Overall, 15 articles reporting systematic reviews of observational studies on 89 G × E interactions, 20 articles reporting meta-analyses of candidate gene- or single-nucleotide polymorphisms-based studies on 521 G × E interactions, and 8 articles reporting 33 genome-wide G × E interaction analyses were identified. On the basis of prior and observed scores, only the interaction between rs6983267 (8q24) and aspirin use was found to have a moderate overall credibility score as well as main genetic and environmental effects. Though 5 other interactions were also found to have moderate evidence, these interaction effects were tenuous due to the lack of main genetic effects and/or environmental effects. We did not find highly convincing evidence for any interactions, but several associations were found to have moderate or weak strength of evidence. Our conclusions are based on application of the Venice criteria which were designed to provide a conservative assessment of gene-environment interactions and thus do not include an evaluation of biological plausibility of an observed joint effect. This article is protected by copyright. All rights reserved.
Deciphering global gene expression and regulation strategy in Escherichia coli during carbon limitation.
Dec 11, 2018   Microbial Biotechnology
Li Z, Pan Q, Xiao Y, Fang X, Shi R, Fu C, Danchin A, You C
Deciphering global gene expression and regulation strategy in Escherichia coli during carbon limitation.
Dec 11, 2018
Microbial Biotechnology
Despite decades of studies meant to analyse the bacterial response to carbon limitation, we still miss a high-resolution overview of the situation. All gene expression changes observed in such conditions cannot solely be accounted for by the global regulator Crp either free or bound to its effector, cyclic AMP. Here, for the first time, we evaluated the response of both CDS (protein-coding sequence) and ncRNA (non-coding RNA) genes to carbon limitation, revealed cellular functions of differentially expressed genes systematically, quantified the contribution of Crp-cAMP and other factors to regulation and deciphered regulation strategies at a genomewide scale. Approximately one-third of the differentially expressed genes we identified responded to Crp-cAMP via its direct or indirect control, while the remaining genes were subject to growth rate-dependent control or were controlled by other regulators, especially RpoS. Importantly, gene regulation mechanisms can be established by expression pattern studies. Here, we propose a comprehensive picture of how cells respond to carbon scarcity. The global regulation strategies thus exposed illustrate that the response of cell to carbon scarcity is not limited to maintaining sufficient carbon metabolism via cAMP signalling while the main response is to adjust metabolism to cope with a slow growth rate.
A dissection model for mapping complex traits.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
Sang M, Shi H, Wei K, Ye M, Jiang L, Sun L, Wu R
A dissection model for mapping complex traits.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
Many quantitative traits are composites of other traits that contribute differentially to genetic variation. QTL mapping of these composite traits can benefit by incorporating the mechanistic process of how their formation is mediated by the underlying components. We propose a dissection model by which to map these interconnected components traits under a joint likelihood setting. The model can test how a composite trait is determined by pleiotropic QTLs for its component traits or jointly by different sets of QTLs each responsible for a different component. The model can visualize the pattern of time-varying genetic effects for individual components and their impacts on composite traits. The dissection model was used to map two composite traits, stemwood volume growth decomposed into its stem height, stem diameter and stem form components for Euramerican poplar adult trees, and total lateral root length constituted by its average lateral root length and lateral root number components for Euphrates poplar seedlings. We found the pattern of how QTLs for different components contribute to phenotypic variation in composite traits. The detailed understanding of the genetic machineries of composite traits will not only help in the design of molecular breeding in plants and animals, but also shed light on the evolutionary processes of quantitative traits under natural selection. This article is protected by copyright. All rights reserved.
Heart failure with reduced ejection fraction: comparison of patient characteristics and clinical outcomes within Asia and between Asia, Europe and the Americas.
Dec 11, 2018   European Journal Of Heart Failure
Dewan P, Jhund PS, Shen L, Petrie MC, Abraham WT,   . . . . . .   , Sritara P, Swedberg K, Tsutsui H, Zile MR, McMurray JJV
Heart failure with reduced ejection fraction: comparison of patient characteristics and clinical outcomes within Asia and between Asia, Europe and the Americas.
Dec 11, 2018
European Journal Of Heart Failure
AIMS: Nearly 60% of the world's population lives in Asia but little is known about the characteristics and outcomes of Asian patients with heart failure with reduced ejection fraction (HFrEF) compared to other areas of the world. METHODS AND RESULTS: We pooled two, large, global trials, with similar design, in 13 174 patients with HFrEF (patient distribution: China 833, India 1390, Japan 209, Korea 223, Philippines 223, Taiwan 199 and Thailand 95, Western Europe 3521, Eastern Europe 4758, North America 613, and Latin America 1110). Asian patients were younger (55.0-63.9 years) than in Western Europe (67.9 years) and North America (66.6 years). Diuretics and devices were used less, and digoxin used more, in Asia. Mineralocorticoid receptor antagonist use was higher in China (66.3%), the Philippines (64.1%) and Latin America (62.8%) compared to Europe and North America (range 32.8% to 49.6%). The rate of cardiovascular death/heart failure hospitalization was higher in Asia (e.g. Taiwan 17.2, China 14.9 per 100 patient-years) than in Western Europe (10.4) and North America (12.8). However, the adjusted risk of cardiovascular death was higher in many Asian countries than in Western Europe (except Japan) and the risk of heart failure hospitalization was lower in India and in the Philippines than in Western Europe, but significantly higher in China, Japan, and Taiwan. CONCLUSION: Patient characteristics and outcomes vary between Asia and other regions and between Asian countries. These variations may reflect several factors, including geography, climate and environment, diet and lifestyle, health care systems, genetics and socioeconomic influences.
Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations.
Dec 11, 2018   International Journal Of Cancer
Sa JK, Choi SW, Zhao J, Lee Y, Zhang J, Kong DS, Choi JW, Seol HJ, Lee JI, Iavarone A, Rabadan R, Nam DH
Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations.
Dec 11, 2018
International Journal Of Cancer
Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)-induced mutagenesis. In present study, we have identified a rare subset of treatment-naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment-induced hypermutagenesis. We conducted Whole-Exome Sequencing (WES), Whole-Transcriptome Sequencing (WTS), and Single-Cell Sequencing (SCS) of TMZ-naïve and post-TMZ treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ-naïve hypermutated tumors were marked by absence of IDH1 somatic mutation and MGMT promoter (pMGMT) methylation, two genomic traits that were significantly associated with TMZ-induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ-naive hypermutated glioma patients were also previous diagnosed with cancer development history, suggesting that germline dysfunction of the MMR pathway could potentially pose hereditary risk to genetic predisposition of carcinogenesis in gliomas. Lastly, both TMZ-naïve and post-TMZ treated hypermutated tumors exhibited a significant increase in neoantigen load suggesting immunotherapeutic alternatives. Our results present new and unique understanding of hypermutagenic process in adult gliomas and an important step towards clinical implication of immunotherapy in glioma treatment. This article is protected by copyright. All rights reserved.
Development and user evaluation of a rare disease gene prioritization workflow based on cognitive ergonomics.
Dec 11, 2018   Journal Of The American Medical Informatics Association : JAMIA
Lee JJY, van Karnebeek CDM, Wasserman WW
Development and user evaluation of a rare disease gene prioritization workflow based on cognitive ergonomics.
Dec 11, 2018
Journal Of The American Medical Informatics Association : JAMIA
Objective: The clinical diagnosis of genetic disorders is undergoing transformation, driven by whole exome sequencing and whole genome sequencing (WES/WGS). However, such nucleotide-level resolution technologies create an interpretive challenge. Prior literature suggests that clinicians may employ characteristic cognitive processes during WES/WGS investigations to identify disruptions in genes causal for the observed disease. Based on cognitive ergonomics, we designed and evaluated a gene prioritization workflow that supported these cognitive processes. Materials and Methods: We designed a novel workflow in which clinicians recalled known genetic diseases with similarity to patient phenotypes to inform WES/WGS data interpretation. This prototype-based workflow was evaluated against the common computational approach based on physician-specified sets of individual patient phenotypes. The evaluation was conducted as a web-based user study, in which 18 clinicians analyzed 2 simulated patient scenarios using a randomly assigned workflow. Data analysis compared the 2 workflows with respect to accuracy and efficiency in diagnostic interpretation, efficacy in collecting detailed phenotypic information, and user satisfaction. Results: Participants interpreted genetic diagnoses faster using prototype-based workflows. The 2 workflows did not differ in other evaluated aspects. Discussion: The user study findings indicate that prototype-based approaches, which are designed to model experts' cognitive processes, can expedite gene prioritization and provide utility in synergy with common phenotype-driven variant/gene prioritization approaches. However, further research of the extent of this effect across diverse genetic diseases is required. Conclusion: The findings demonstrate potential for prototype-based phenotype description to accelerate computer-assisted variant/gene prioritization through complementation of skills and knowledge of clinical experts via human-computer interaction.
Applying the handicap principle to biofilms: condition-dependent signaling in Bacillus subtilis microbial communities.
Dec 11, 2018   Environmental Microbiology
Harris KD, Kolodkin-Gal I
Applying the handicap principle to biofilms: condition-dependent signaling in Bacillus subtilis microbial communities.
Dec 11, 2018
Environmental Microbiology
Bacteria in nature often reside in differentiated communities termed biofilms. These communities, which are composed of a number of functionally distinct cell types, are an interesting example of division of labor in microbes, and as such have been used as a system to study the evolution of cooperation. The structured population of the biofilm also plays a critical role in the persistence of infections, and biofouling of medical and industrial devices. Biofilm formation involves several stages of differentiation, which are mediated by extracellular factors secreted by cells composing the biofilm. The developmental model of biofilm formation describes this process mechanistically: specific subpopulations of cells synthesize signals within the biofilm, and promote the differentiation of other subpopulations. The handicap principle suggests that signals function because they provide reliable information regarding the state of the signaler; here we apply the handicap principle to signaling among cells composing Bacillus subtilis biofilms, emphasizing the perspective of secreted factors as sources of information rather than solely as mediators of development. Such information could facilitate competition among phenotypically similar cells composing the biofilm, affecting local organizational patterns within defined subpopulations. This article is protected by copyright. All rights reserved.
Mitochondrial DNA mutation m.3243A>G is associated with altered mitochondrial function in peripheral blood mononuclear cells, with heteroplasmy levels and with clinical phenotypes.
Dec 11, 2018   Diabetic Medicine : A Journal Of The British Diabetic Association
Geng X, Zhang Y, Yan J, Chu C, Gao F, Jiang Z, Zhang X, Chen Y, Wei X, Feng Y, Lu H, Wang C, Zeng F, Jia W
Mitochondrial DNA mutation m.3243A>G is associated with altered mitochondrial function in peripheral blood mononuclear cells, with heteroplasmy levels and with clinical phenotypes.
Dec 11, 2018
Diabetic Medicine : A Journal Of The British Diabetic Association
AIMS: To investigate the associations among heteroplasmy levels (i.e. the proportions of mutant and wild-type mitochondrial DNA in the same cell), mitochondrial function and clinical severity of the m.3243A>G mutation. METHODS: A total of 17 participants carrying the m.3243A>G mutation and 17 sex- and age-matched healthy controls were included in this study. Heteroplasmy levels of the m.3243A>G mutation in leukocytes, saliva and urine sediment were determined by pyrosequencing. The clinical evaluation included endocrinological, audiological and ophthalmological examinations. Mitochondrial function was determined in peripheral blood mononuclear cells isolated from participants. RESULTS: Heteroplasmy levels in urine sediment were higher than those in leukocytes and saliva. Reduced levels of adenosine triphosphate and mitochondrial membrane potential, and increased reactive oxygen species production were observed in mutant peripheral blood mononuclear cells (all P < 0.05). Linear regression analysis indicated that higher heteroplasmy levels in peripheral blood leukocytes were associated with increased levels of glycated albumin and HbA1c , and decreased total hip bone mineral density T-score after adjustment for age and sex (all P < 0.05). Furthermore, mitochondrial membrane potential was independently associated with bone mineral density T-score at the femoral neck (P < 0.05). CONCLUSIONS: Heteroplasmy levels in peripheral blood leukocytes and mitochondrial membrane potential in peripheral blood mononuclear cells were closely associated with clinical manifestations and were valuable for evaluation of the clinical severity of the m.3243A>G mutation. This article is protected by copyright. All rights reserved.
Functional mapping of N deficiency-induced response in wheat yield-component traits by implementing high-throughput phenotyping.
Dec 11, 2018   The Plant Journal : For Cell And Molecular Biology
Jiang L, Sun L, Ye M, Wang J, Wang Y, Bogard M, Lacaze X, Fournier A, Beauchêne K, Gouache D, Wu R
Functional mapping of N deficiency-induced response in wheat yield-component traits by implementing high-throughput phenotyping.
Dec 11, 2018
The Plant Journal : For Cell And Molecular Biology
As overfertilization leads to environmental concerns and the cost of N-fertilizer increases, the issue of how to select crop cultivars that can produce high yield on N-deficient lands has become crucially important. However, little is known about the genetic mechanisms by which crops respond to environmental changes induced by N signaling. Here, we dissected the genetic architecture of N-induced phenotypic plasticity in bread wheat (Triticum aestivum L.) by integrating functional mapping and semi-automatic high-throughput phenotyping data of yield-related canopy architecture. We identified a set of quantitative trait loci (QTLs) that determined the pattern and magnitude of how wheat cultivars responded to low N stress from normal N supply throughout wheat life cycle. This analysis highlighted the phenological landscape of genetic effects exerted by individual QTLs, as well as their interactions with N-induced signals and with canopy measurement angles. This information may shed light on our mechanistic understanding of plant adaptation and provide valuable information for the breeding of N-deficiency tolerant wheat varieties. This article is protected by copyright. All rights reserved.
Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.
Dec 11, 2018   Journal Of Cardiovascular Translational Research
Xu YJ, Wang ZS, Yang CX, Di RM, Qiao Q, Li XM, Gu JN, Guo XJ, Yang YQ
Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.
Dec 11, 2018
Journal Of Cardiovascular Translational Research
Dilated cardiomyopathy (DCM) is the most prevalent cause of non-ischemic cardiac failure and the commonest indication for cardiac transplantation. Compelling evidence highlights the pivotal roles of genetic defects in the occurrence of DCM. Nevertheless, the genetic determinants underpinning DCM remain largely obscure. In this study, the coding regions of ISL1, which encodes a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling, were sequenced in 216 unrelated patients with DCM, and a novel heterozygous ISL1 mutation, NM_002202.2: c.631A>T; p.(Lys211*), was identified in a proband. The mutation, which co-segregated with DCM in the family, was absent in 238 unrelated controls, as well as in the Genome Aggregation and the Exome Aggregation Consortium population databases. Functional analyses unveiled that the mutant ISL1 protein lost transcriptional activity alone or in synergy with TBX20 or GATA4, two other transcription factors associated with DCM. These findings indicate ISL1 as a new gene of DCM.
The Nature of the Shared Environment.
Dec 11, 2018   Behavior Genetics
Kendler KS, Ohlsson H, Lichtenstein P, Sundquist J, Sundquist K
The Nature of the Shared Environment.
Dec 11, 2018
Behavior Genetics
While a standard part of twin modeling, the magnitude of shared environment (c2) is rarely examined by comparing estimates obtained using other methods. To clarify these effects on familial resemblance, we estimated c2 for 20 diverse phenotypes in: (i) monozygotic and dizygotic twins, (ii) all step-siblings, and (iii) reared together and apart half-siblings, ascertained from the Swedish general population. The mean c2 estimates (± 95% CIs) differed across methods and were higher from twins (0.18; 0.13-0.23) than from the step (0.12; 0.09-0.14) and half-sibs (0.09; 0.06-0.13). c2 estimates correlated moderately across these three methods (ICC = + 0.28). When step-siblings from blended (each sib biologically related to one parent) and adoption-like families (one sib offspring of both parents and one of neither), were examined separately, resemblance was much lower in the latter. We need to clarify the range of environmental processes now considered together under the term "shared environment."
Cytotoxic Tolerance of Healthy and Cancerous Bone Cells to Anti-microbial Phenolic Compounds Depend on Culture Conditions.
Dec 11, 2018   Applied Biochemistry And Biotechnology
Karadas O, Mese G, Ozcivici E
Cytotoxic Tolerance of Healthy and Cancerous Bone Cells to Anti-microbial Phenolic Compounds Depend on Culture Conditions.
Dec 11, 2018
Applied Biochemistry And Biotechnology
Carnosol and carnosic acid are polyphenolic compounds found in rosemary and sage with known anti-oxidant, anti-inflammatory, and anti-microbial properties. Here, we addressed the potential use of carnosol and carnosic acid for in vitro bone tissue engineering applications, specifically depending on their cytotoxic effects on bone marrow stromal and stem cells, and osteosarcoma cells in monolayer and 3D cultures. Carnosol and carnosic acid displayed a bacteriostatic effect on Gram-positive bacteria, especially on S. aureus. The viability results indicated that bone marrow stromal cells and bone marrow stem cells were more tolerant to the presence of carnosol compared to osteosarcoma cells. 3D culture conditions increased this tolerance further for healthy cells, while not affecting the cytotoxic potential of carnosol for osteosarcoma cells. Carnosic acid was found to be more cytotoxic for all cell types used in the study. Results suggest that phenolic compounds might have potential use as anti-microbial and anti-carcinogenic agents for bone tissue engineering with further optimization for controlled release.
Probing BAK and BAX Activation and Pore Assembly with Cytochrome c Release, Limited Proteolysis, and Oxidant-Induced Linkage.
Dec 11, 2018   Methods In Molecular Biology (Clifton, N.J.)
Iyer S, Uren RT, Kluck RM
Probing BAK and BAX Activation and Pore Assembly with Cytochrome c Release, Limited Proteolysis, and Oxidant-Induced Linkage.
Dec 11, 2018
Methods In Molecular Biology (Clifton, N.J.)
Mitochondrial permeabilization is a key event in the intrinsic pathway of apoptosis, and is mediated by either of the BCL-2 family members BAK or BAX. These two proteins generate pores in the mitochondrial outer membrane that release factors such as cytochrome c into the cytosol to trigger caspase activation and apoptotic cell death. To generate pores, BAK and BAX undergo major changes including BAX translocation to the outer membrane, and partial unfolding, dimerization, and oligomerization. Here we describe biochemical protocols that can be used on most cell types to gain a population overview of BAK and BAX status.
Over-expression of GmKR3, a TIR-NBS-LRR type R gene, confers resistance to multiple viruses in soybean.
Dec 11, 2018   Plant Molecular Biology
Xun H, Yang X, He H, Wang M, Guo P, Wang Y, Pang J, Dong Y, Feng X, Wang S, Liu B
Over-expression of GmKR3, a TIR-NBS-LRR type R gene, confers resistance to multiple viruses in soybean.
Dec 11, 2018
Plant Molecular Biology
KEY MESSAGE: That overexpression of GmKR3 enhances innate virus resistance by stimulating. Soybean mosaic virus (SMV) is found in many soybean production areas, and SMV infection is one of the prevalent viral diseases that can cause significant yield losses in soybean. In plants, resistance (R) genes are involved in pathogen reorganization and innate immune response activation. Most R proteins have nucleotide-binding site and leucine-rich repeat (NBS-LRR) domains, and some of the NBS-LRR type R proteins in dicots have Toll/Interleukin-1 Receptor (TIR) motifs. We report here the analysis of the over-expression of GmKR3, a soybean TIR-NBS-LRR type R gene on virus resistance in soybean. When over-expressed in soybean, GmKR3 enhanced the plant's resistance to several strains of SMV, the closely related potyviruses bean common mosaic virus (BCMV) and watermelon mosaic virus (WMV), and the secovirus bean pod mottle virus (BPMV). Importantly, over-expression of GmKR3 did not affect plant growth and development, including yield and qualities of the seeds. HPLC analysis showed that abscisic acid (ABA) content increased in the 35S:GmKR3 transgenic plants, and in both wild-type and 35S:GmKR3 transgenic plants in response to virus inoculation. Consistent with this observation, we found that the expression of two ABA catabolism genes was down-regulated in 35S:GmKR3 transgenic plants. We also found that the expression of Gm04.3, an ABA responsive gene encoding BURP domain-containing protein, was up-regulated in 35S:GmKR3 transgenic plants. Taken together, our results suggest that overexpression of GmKR3 enhanced virus resistance in soybean, which was achieved at least in part via ABA signaling.
Use of natural language processing in electronic medical records to identify pregnant women with suicidal behavior: towards a solution to the complex classification problem.
Dec 11, 2018   European Journal Of Epidemiology
Zhong QY, Mittal LP, Nathan MD, Brown KM, Knudson González D, Cai T, Finan S, Gelaye B, Avillach P, Smoller JW, Karlson EW, Cai T, Williams MA
Use of natural language processing in electronic medical records to identify pregnant women with suicidal behavior: towards a solution to the complex classification problem.
Dec 11, 2018
European Journal Of Epidemiology
We developed algorithms to identify pregnant women with suicidal behavior using information extracted from clinical notes by natural language processing (NLP) in electronic medical records. Using both codified data and NLP applied to unstructured clinical notes, we first screened pregnant women in Partners HealthCare for suicidal behavior. Psychiatrists manually reviewed clinical charts to identify relevant features for suicidal behavior and to obtain gold-standard labels. Using the adaptive elastic net, we developed algorithms to classify suicidal behavior. We then validated algorithms in an independent validation dataset. From 275,843 women with codes related to pregnancy or delivery, 9331 women screened positive for suicidal behavior by either codified data (N = 196) or NLP (N = 9,145). Using expert-curated features, our algorithm achieved an area under the curve of 0.83. By setting a positive predictive value comparable to that of diagnostic codes related to suicidal behavior (0.71), we obtained a sensitivity of 0.34, specificity of 0.96, and negative predictive value of 0.83. The algorithm identified 1423 pregnant women with suicidal behavior among 9331 women screened positive. Mining unstructured clinical notes using NLP resulted in a 11-fold increase in the number of pregnant women identified with suicidal behavior, as compared to solely reliance on diagnostic codes.
Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.
Dec 11, 2018   Human Molecular Genetics
Belin S, Ornaghi F, Shackleford G, Wang J, Scapin C,   . . . . . .   , Fratta P, D'Antonio M, Poitelon Y, Laura Feltri M, Wrabetz L
Neuregulin 1 type III improves peripheral nerve myelination in a mouse model of congenital hypomyelinating neuropathy.
Dec 11, 2018
Human Molecular Genetics
Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.
Evaluation of porcine circovirus type 2 infection in in vitro embryo production using naturally infected oocytes.
Dec 13, 2018   Theriogenology
Weng XG, Liu Y, Zhou SH, Zhang YT, Shao YT, Xu QQ, Liu ZH
Evaluation of porcine circovirus type 2 infection in in vitro embryo production using naturally infected oocytes.
Dec 13, 2018
Theriogenology
In vitro fertilization (IVF) and somatic cell nuclear transfer (SCNT) are important breeding techniques for livestock. High-quality MII oocytes produced from in vitro maturation (IVM) are required for the two techniques listed above. The ovaries used for IVM operations are primarily acquired from commercial abattoirs, and the pathogen status of slaughtered animals becomes an unavoidable issue. Our previous monitoring data showed that porcine circovirus type 2 (PCV-2) is the main pathogen present in ovaries from abattoirs. However, the characteristics and effects of PCV-2 infection in oocyte maturation and in vitro production (IVP) of embryos are unclear, and currently there are no relevant studies. Therefore, the aim of this study was to determine the PCV-2 infection pattern and determine whether it affects oocyte in vitro maturation and IVP embryo development. More than five hundred ovaries and five thousand oocytes were utilized in the present study. Polymerase chain reaction (PCR) was used to detect PCV-2 DNA in ovaries, follicular fluid (FF), oocytes, cumulus cells and IVP embryos. The effects of viral infections on the rate of oocyte maturation and IVP embryo development were evaluated. We also analyzed the number of copies of the virus in the IVM and IVP process by absolute quantitative fluorescence PCR. Our study showed that the prevalent virus subgenotype in ovaries was PCV-2a. PCV-2a infection did not significantly affect ovarian/oocyte morphology and maturation. Moreover, virus infection did not have a significant effect on the development of the IVP embryos except for a reduction in IVF blastocyst cell numbers. Further tests showed that the viral copy numbers fluctuated at different stages between the IVP embryos and culture medium. For the first time, this study identified the infection pattern of naturally sourced PCV-2 in the course of oocyte maturation and embryo development.

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