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Genomics
Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
Apr 21, 2017   PLoS Genetics
Ng MCY, Graff M, Lu Y, Justice AE, Mudgal P,   . . . . . .   , Bowden DW, Cupples LA, Haiman CA, Loos RJF, North KE
Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium
Apr 21, 2017
PLoS Genetics
Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (
Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases
Apr 22, 2017   Parkinsonism & Related Disorders
Malek N, Lawton MA, Grosset KA, Bajaj N, Barker RA, Ben-Shlomo Y, Burn DJ, Foltynie T, Hardy J, Morris HR, Williams NM, Wood N, Grosset DG, PRoBaND clinical consortium
Utility of the new Movement Disorder Society clinical diagnostic criteria for Parkinson's disease applied retrospectively in a large cohort study of recent onset cases
Apr 22, 2017
Parkinsonism & Related Disorders
To examine the utility of the new Movement Disorder Society (MDS) diagnostic criteria in a large cohort of Parkinson's disease (PD) patients. Recently diagnosed (
Gene structure and expression characteristic of a novel odorant receptor gene cluster in the parasitoid wasp Microplitis mediator (Hymenoptera: Braconidae)
Apr 22, 2017   Insect Molecular Biology
Wang SN, Shan S, Zheng Y, Peng Y, Lu ZY, Yang YQ, Li RJ, Zhang YJ, Guo YY
Gene structure and expression characteristic of a novel odorant receptor gene cluster in the parasitoid wasp Microplitis mediator (Hymenoptera: Braconidae)
Apr 22, 2017
Insect Molecular Biology
Odorant receptors (ORs) expressed in the antennae of parasitoid wasps are responsible for detection of various lipophilic airborne molecules. In the present study, 107 novel OR genes were identified from Microplitis mediator antennal transcriptome data. Phylogenetic analysis of the set of OR genes from M. mediator and Microplitis demolitor revealed that M. mediator OR (MmedOR) genes can be classified into different subfamilies, and the majority of MmedORs in each subfamily shared high sequence identities and clear orthologous relationships to M. demolitor ORs. Within a subfamily, six MmedOR genes, MmedOR98, 124, 125, 126, 131 and 155, shared a similar gene structure and were tightly linked in the genome. To evaluate whether the clustered MmedOR genes share common regulatory features, the transcription profile and expression characteristics of the six closely related OR genes were investigated in M. mediator. Rapid amplification of cDNA ends-PCR experiments revealed that the OR genes within the cluster were transcribed as single mRNAs, and a bicistronic mRNA for two adjacent genes (MmedOR124 and MmedOR98) was also detected in female antennae by reverse transcription PCR. In situ hybridization experiments indicated that each OR gene within the cluster was expressed in a different number of cells. Moreover, there was no co-expression of the two highly related OR genes, MmedOR124 and MmedOR98, which appeared to be individually expressed in a distinct population of neurons. Overall, there were distinct expression profiles of closely related MmedOR genes from the same cluster in M. mediator. These data provide a basic understanding of the olfactory coding in parasitoid wasps. © 2017 The Royal Entomological Society.
Low-cost, Low-bias and Low-input RNA-seq with High Experimental Verifiability based on Semiconductor Sequencing
Apr 22, 2017   Scientific Reports
Mai Z, Xiao C, Jin J, Zhang G
Low-cost, Low-bias and Low-input RNA-seq with High Experimental Verifiability based on Semiconductor Sequencing
Apr 22, 2017
Scientific Reports
Low-input RNA-seq is powerful to represent the gene expression profiles with limited number of cells, especially when single-cell variations are not the aim. However, pre-amplification-based and molecule index-based library construction methods boost bias or require higher throughput. Here we demonstrate a simple, low-cost, low-bias and low-input RNA-seq with ion torrent semiconductor sequencing (LIEA RNA-seq). We also developed highly accurate and error-tolerant spliced mapping algorithm FANSe2splice to accurately map the single-ended reads to the reference genome with better experimental verifiability than the previous spliced mappers. Combining the experimental and computational advancements, our solution is comparable with the bulk mRNA-seq in quantification, reliably detects splice junctions and minimizes the bias with much less mappable reads.
Mycobacterium tuberculosis Lineage Distribution in Xinjiang and Gansu Provinces, China
Apr 22, 2017   Scientific Reports
Chen H, He L, Huang H, Shi C, Ni X, Dai G, Ma L, Li W
Mycobacterium tuberculosis Lineage Distribution in Xinjiang and Gansu Provinces, China
Apr 22, 2017
Scientific Reports
Mycobacterium tuberculosis (M. tuberculosis) genotyping has dramatically improved the understanding of the epidemiology of tuberculosis (TB). In this study, 187 M. tuberculosis isolates from Xinjiang Uygur Autonomous Region (Xinjiang) and Gansu province in China were genotyped using large sequence polymorphisms (LSPs) and variable number tandem repeats (VNTR). Ten isolates, which represent major nodes of VNTR-based minimum spanning tree, were selected and subsequently subjected to multi-locus sequence analyses (MLSA) that include 82 genes. Based on a robust lineage assignment, we tested the association between lineages and clinical characteristics by logistic regression. There are three major lineages of M. tuberculosis prevalent in Xinjiang, viz. the East Asian Lineage 2 (42.1%; 56/133), the Euro-American Lineage 4 (33.1%; 44/133), and the Indian and East African Lineage 3 (24.8%; 33/133); two lineages prevalent in Gansu province, which are the Lineage 2 (87%; 47/54) and the Lineage 4 (13%; 7/54). The topological structures of the MLSA-based phylogeny support the LSP-based identification of M. tuberculosis lineages. The statistical results suggest an association between the Lineage 2 and the hemoptysis/bloody sputum symptom, fever in Uygur patients. The pathogenicity of the Lineage 2 remains to be further investigated.
Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes
Apr 22, 2017   The Biochemical Journal
Basu M, Sengupta I, Khan W, Srivastava DK, Chakrabarti P, Roy S, Das C
Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes
Apr 22, 2017
The Biochemical Journal
Enhanced migratory potential and invasiveness of cancer cells attribute crucially.in cancer progression. These phenotypes are achieved by precise alteration of invasion-associated genes through local epigenetic modifications which are recognized by a class of proteins termed as chromatin reader. ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a key component of transcription regulatory network, has been recently shown to be a novel reader of H3.1K36Me2/H4K16Ac marks. Through differential gene expression analysis upon silencing this chromatin reader, we identified a subset of genes involved in cell proliferation and invasion/migration regulated by ZMYND8. Detailed analysis uncovered its anti-proliferative activity through BrdU incorporation, alteration in the expression of proliferation markers and cell cycle regulating genes and cell viability assays. In addition, performing wound healing and invasion/migration assays, its anti-invasive nature is evident. Interestingly, epithelial-mesenchymal transition, a key mechanism of cellular invasion, is regulated by ZMYND8 where we identified its selective enrichment on promoters of CLDN1 / CDH1 genes, rich in H3K36Me2/H4K16Ac marks, leading to their upregulation. Thus, presence of ZMYND8 could be implicated in maintaining the epithelial phenotype of cells. Further, syngeneic mice, injected with ZMYND8-overexpressed invasive breast cancer cells showed reduction in tumor volume and weight. In concert with this, we observed a significant downregulation of ZMYND8 in invasive ductal and lobular breast cancer tissues compared to normal one. Taken together, our study elucidates a novel function of ZMYND8 in regulating EMT and invasion of cancer cells, possibly through its chromatin reader function. ©2017 The Author(s).
Age-related effects and sex differences in gray matter density, volume, mass, and cortical thickness from childhood to young adulthood
Apr 22, 2017   The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Gennatas ED, Avants BB, Wolf DH, Satterthwaite TD, Ruparel K, Ciric R, Hakonarson H, Gur RE, Gur RC
Age-related effects and sex differences in gray matter density, volume, mass, and cortical thickness from childhood to young adulthood
Apr 22, 2017
The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience
Developmental structural neuroimaging studies in humans have long described decreases in gray matter volume and cortical thickness during adolescence. Gray matter density, a measure often assumed to be highly related to volume, has not been systematically investigated in development. We used T1 imaging data collected on the Philadelphia Neurodevelopmental Cohort to study age-related effects and sex differences in four regional gray matter measures in 1189 youths aged 8 to 23 years. Custom T1 segmentation and a novel high-resolution gray matter parcellation were used to extract gray matter density (GMD), gray matter volume (GMV), gray matter mass (GMM, defined as GMD * GMV), and cortical thickness (CT) from 1625 brain regions. Non-linear models revealed that each modality exhibits unique age-related effects and sex differences. While GMV and CT generally decrease with age, GMD increases and shows the strongest age-related effects, while GMM shows slight decline overall. Females have lower GMV but higher GMD than males throughout the brain. Our findings suggest that GMD is a prime phenotype for assessment of brain development and likely cognition and that periadolescent gray matter loss may be less pronounced than previously thought. This work highlights the need for combined quantitative histological-MRI studies. Copyright © 2017 the authors.
Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma
Apr 22, 2017   The Journal Of Biological Chemistry
Dolezal JM, Wang H, Kulkarni S, Jackson L, Lu J, Ranganathan S, Goetzman ES, Bharathi S, Beezhold K, Byersdorfer CA, Prochownik EV
Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma
Apr 22, 2017
The Journal Of Biological Chemistry
Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC progression, regression and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain Complexes I and II to respiration. The uncoupling of Complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA-Seq studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity and further metabolic re-programming. Only a subset of functions deregulated in initial tumors were similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical and molecular events accompanying HCC evolution, regression and recurrence in the absence of any potentially confounding therapies. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
A genome-wide investigation on biofilm formation in Bacillus cereus
Apr 22, 2017   Applied And Environmental Microbiology
Yan F, Yu Y, Gozzi K, Chen Y, Guo JH, Chai Y
A genome-wide investigation on biofilm formation in Bacillus cereus
Apr 22, 2017
Applied And Environmental Microbiology
Bacillus cereus is a soil-dwelling Gram-positive bacterium capable of forming structured multicellular communities, or biofilms. However, the regulatory pathways controlling biofilm formation are less well understood in B. cereus In this work, we developed a method to study B. cereus biofilms formed at the air-liquid interface. We applied two genome-wide approaches, random transposon insertion mutagenesis to identify genes that are potentially important for biofilm formation, and transcriptome analyses by RNA-seq to characterize genes that are differentially expressed in B. cereus when cells were grown in a biofilm-inducing medium. For the first approach, we identified 23 genes whose disruption by transposon insertion led to altered biofilm phenotypes. Based on the predicted function, they included genes involved in processes such as nucleotide biosynthesis, iron salvage, and antibiotic production, as well as genes encoding an ATP-dependent protease and transcription regulators. Transcriptome analyses identified about 500 genes that were differentially expressed in cells grown under biofilm-inducing conditions. One particular set of those genes may contribute to major metabolic shifts, leading to elevated production of small volatile molecules. Selected volatile molecules were shown to stimulate robust biofilm formation in B. cereus Our studies represent a genome-wide investigation on B. cereus biofilm formation.Importance In this work, we established a robust method for B. cereus biofilm studies and applied two genome-wide approaches, transposon insertion mutagenesis and transcriptome analyses by RNA-seq, to identify genes and pathways that are potentially important for biofilm formation in B. cereus We discovered dozens of genes and two major metabolic shifts that seem to be important for biofilm formation in B. cereus Our study represents a genome-wide investigation on B. cereus biofilm formation. Copyright © 2017 American Society for Microbiology.
Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production
Apr 22, 2017   Journal Of Leukocyte Biology
Shinde P, Liu W, Ménoret A, Luster AD, Vella AT
Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production
Apr 22, 2017
Journal Of Leukocyte Biology
LPS is a powerful adjuvant, and although LPS-mediated TLR4 signaling has been exquisitely delineated, the in vivo mechanism of how TLR4 responses impact T cell priming is far less clear. Besides costimulation, TNF and type 1 IFN are dominant cytokines released after TLR4 activation and can shape T cell responses, but other downstream factors have not been examined extensively. Depending on context, we show that IFNαR1 blockade resulted in minor to major effects on specific CD4 T cell clonal expansion. To help explain these differences, it was hypothesized that IFNαR1 blockade would inhibit specific T cell migration by reducing chemokine receptor signaling, but specific CD4 T cells from IFNαR1-blocked mice were readily able to migrate in response to specific chemokines. Next, we examined downstream factors and found that type 1 IFN signaling was necessary for chemokine production, even when mice were immunized with specific Ag with LPS and CD134 costimulation. IFNαR1 signaling promoted CXCL9 and CXCL10 synthesis, suggesting that these chemokines might be involved in the LPS and CD134 costimulation response. After immunization, we show that CXCL9 blockade inhibited CD4 T cell accumulation in the liver but also in LNs, even in the presence of elevated serum IFN-β levels. Thus, whereas type 1 IFN might have direct effects on primed CD4 T cells, the downstream chemokines that play a role during migration also impact accumulation. In sum, CXCL9 production is a key benchmark for productive CD4 T cell vaccination strategies. © Society for Leukocyte Biology.
Genomic Instability in Cancer: Teetering on the Limit of Tolerance
Apr 22, 2017   Cancer Research
Andor N, Maley CC, Ji HP
Genomic Instability in Cancer: Teetering on the Limit of Tolerance
Apr 22, 2017
Cancer Research
Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection, and enables the extensive phenotypic diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared with intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor's burden of genetic aberrations is distributed among coexisting clones, genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor's sensitivity to DNA-damaging therapies. We primarily focus on studies of epithelial-derived solid tumors. Cancer Res; 77(9); 1-7. ©2017 AACR. ©2017 American Association for Cancer Research.
Transcriptome comparison reveals insights into muscle response to hypoxia in blunt snout bream (Megalobrama amblycephala)
Apr 22, 2017   Gene
Chen BX, Yi SK, Wang WF, He Y, Huang Y, Gao ZX, Liu H, Wang WM, Wang HL
Transcriptome comparison reveals insights into muscle response to hypoxia in blunt snout bream (Megalobrama amblycephala)
Apr 22, 2017
Gene
The economic and biological significance of blunt snout bream (Megalobrama amblycephala) makes this species important to explore the underlying molecular mechanism of hypoxia response. In the present study, we compared the transcriptional responses to serious hypoxia in skeletal muscle among hypoxia tolerant (MT), sensitive (MS) and control (without hypoxia treatment, MC) M. amblycephala obtained according to the time difference of losing balance after hypoxia treatment. A total of 88,200,889 clean reads were generated and assembled into 44,493 unigenes. Transcriptomic comparison revealed 463 genes differentially expressed among different groups. A similar hypoxia-induced transcription patterns suggested a common hypoxia response involved in cell cycle, p53 signaling pathway, apoptosis, heart contraction and blood circulation. Interesting, four genes, heat shock protein beta-8 (hspb8), cysteine/serine-rich nuclear protein 1 (csrnp1), salt-inducible kinase 1 (sik1), and visinin-like 1a (vsnl1a) were up-regulated in MT Vs MC but down-regulated in MS Vs MC. Additionally, FoxO signaling pathway was significantly enriched only in MT Vs MC. These results not only provided the first insights into the mechanism that muscle tissue coped with the hypoxia stress in cyprinid species, but offered a theory base for breeding of M. amblycephala with hypoxia-resistant traits. Copyright © 2017. Published by Elsevier B.V.
Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes
Apr 22, 2017   Schizophrenia Research
Li J, Yoshikawa A, Brennan MD, Ramsey TL, Meltzer HY
Genetic predictors of antipsychotic response to lurasidone identified in a genome wide association study and by schizophrenia risk genes
Apr 22, 2017
Schizophrenia Research
Biomarkers which predict response to atypical antipsychotic drugs (AAPDs) increases their benefit/risk ratio. We sought to identify common variants in genes which predict response to lurasidone, an AAPD, by associating genome-wide association study (GWAS) data and changes (Δ) in Positive And Negative Syndrome Scale (PANSS) scores from two 6-week randomized, placebo-controlled trials of lurasidone in schizophrenia (SCZ) patients. We also included SCZ risk SNPs identified by the Psychiatric Genomics Consortium using a polygenic risk analysis. The top genomic loci, with uncorrected p
Large-scale collection of full-length cDNA and transcriptome analysis in Hevea brasiliensis
Apr 21, 2017   DNA Research : An International Journal For Rapid Publication Of Reports On Genes And Genomes
Makita Y, Ng KK, Veera Singham G, Kawashima M, Hirakawa H, Sato S, Othman AS, Matsui M
Large-scale collection of full-length cDNA and transcriptome analysis in Hevea brasiliensis
Apr 21, 2017
DNA Research : An International Journal For Rapid Publication Of Reports On Genes And Genomes
Natural rubber has unique physical properties that cannot be replaced by products from other latex-producing plants or petrochemically produced synthetic rubbers. Rubber from Hevea brasiliensis is the main commercial source for this natural rubber that has a cis-polyisoprene configuration. For sustainable production of enough rubber to meet demand elucidation of the molecular mechanisms involved in the production of latex is vital. To this end, we firstly constructed rubber full-length cDNA libraries of RRIM 600 cultivar and sequenced around 20,000 clones by the Sanger method and over 15,000 contigs by Illumina sequencer. With these data, we updated around 5,500 gene structures and newly annotated around 9,500 transcription start sites. Second, to elucidate the rubber biosynthetic pathways and their transcriptional regulation, we carried out tissue- and cultivar-specific RNA-Seq analysis. By using our recently published genome sequence, we confirmed the expression patterns of the rubber biosynthetic genes. Our data suggest that the cytoplasmic mevalonate (MVA) pathway is the main route for isoprenoid biosynthesis in latex production. In addition to the well-studied polymerization factors, we suggest that rubber elongation factor 8 (REF8) is a candidate factor in cis-polyisoprene biosynthesis. We have also identified 39 transcription factors that may be key regulators in latex production. Expression profile analysis using two additional cultivars, RRIM 901 and PB 350, via an RNA-Seq approach revealed possible expression differences between a high latex-yielding cultivar and a disease-resistant cultivar. © The Author 2017. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.
Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation
Apr 22, 2017   Particle And Fibre Toxicology
Cai X, Lee A, Ji Z, Huang C, Chang CH, Wang X, Liao YP, Xia T, Li R
Reduction of pulmonary toxicity of metal oxide nanoparticles by phosphonate-based surface passivation
Apr 22, 2017
Particle And Fibre Toxicology
The wide application of engineered nanoparticles has induced increasing exposure to humans and environment, which led to substantial concerns on their biosafety. Some metal oxides (MOx) have shown severe toxicity in cells and animals, thus safe designs of MOx with reduced hazard potential are desired. Currently, there is a lack of a simple yet effective safe design approach for the toxic MOx. In this study, we determined the key physicochemical properties of MOx that lead to cytotoxicity and explored a safe design approach for toxic MOx by modifying their hazard properties. THP-1 and BEAS-2B cells were exposed to 0-200 μg/mL MOx for 24 h, we found some toxic MOx including CoO, CuO, Ni2O3 and Co3O4, could induce reactive oxygen species (ROS) generation and cell death due to the toxic ion shedding and/or oxidative stress generation from the active surface of MOx internalized into lysosomes. We thus hypothesized that surface passivation could reduce or eliminate the toxicity of MOx. We experimented with a series of surface coating molecules and discovered that ethylenediamine tetra (methylene phosphonic acid) (EDTMP) could form stable hexadentate coordination with MOx. The coating layer can effectively reduce the surface activity of MOx with 85-99% decrease of oxidative potential, and 65-98% decrease of ion shedding. The EDTMP coated MOx show negligible ROS generation and cell death in THP-1 and BEAS-2B cells. The protective effect of EDTMP coating was further validated in mouse lungs exposed to 2 mg/kg MOx by oropharyngeal aspiration. After 40 h exposure, EDTMP coated MOx show significant decreases of neutrophil counts, lactate dehydrogenase (LDH) release, MCP-1, LIX and IL-6 in bronchoalveolar lavage fluid (BALF), compared to uncoated particles. The haematoxylin and eosin (H&E) staining results of lung tissue also show EDTMP coating could significantly reduce the pulmonary inflammation of MOx. The surface reactivity of MOx including ion shedding and oxidative potential is the dominated physicochemical property that is responsible for the cytotoxicity induced by MOx. EDTMP coating could passivate the surface of MOx, reduce their cytotoxicity and pulmonary hazard effects. This coating would be an effective safe design approach for a broad spectrum of toxic MOx, which will facilitate the safe use of MOx in commercial nanoproducts.
Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans
Apr 21, 2017   Cell
Scott TA, Quintaneiro LM, Norvaisas P, Lui PP, Wilson MP,   . . . . . .   , Velagapudi V, Mills PB, Typas A, Greene NDE, Cabreiro F
Host-Microbe Co-metabolism Dictates Cancer Drug Efficacy in C. elegans
Apr 21, 2017
Cell
Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B6, B9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Building a Translational Microbiome Toolbox
Apr 21, 2017   Cell
Joglekar P, Segre JA
Building a Translational Microbiome Toolbox
Apr 21, 2017
Cell
Designing successful microbiota-based therapies requires in-depth understanding of the ecological foundations of this community. In this issue, two studies by Whitaker et al. and Lim et al. provide refined genetic tools for dissecting the spatial organization and temporal dynamics of bacterial communities at the single-cell and -gene levels. Published by Elsevier Inc.
Functional Enhancer Screening in Single Cells
Apr 21, 2017   Molecular Cell
van Arensbergen J, van Steensel B
Functional Enhancer Screening in Single Cells
Apr 21, 2017
Molecular Cell
In this issue of Molecular Cell, Xie et al. (2017) introduce Mosaic-seq, a powerful technology that combines CRISPRi and single-cell RNA-seq. This method enables the high-throughput assessment of contributions of enhancers to gene regulation. Copyright © 2017 Elsevier Inc. All rights reserved.
Interferon-γ Released by Activated CD8+ T Lymphocytes Impairs the Calcium Resorption Potential of Osteoclasts in Calcified Human Aortic Valves
Apr 21, 2017   The American Journal Of Pathology
Nagy E, Lei Y, Martínez-Martínez E, Body SC, Schlotter F, Creager M, Assmann A, Khabbaz K, Libby P, Hansson GK, Aikawa E
Interferon-γ Released by Activated CD8+ T Lymphocytes Impairs the Calcium Resorption Potential of Osteoclasts in Calcified Human Aortic Valves
Apr 21, 2017
The American Journal Of Pathology
Calcium content in patients with calcific aortic valve disease (CAVD) correlates with the severity of stenosis. In CAVD, activated T lymphocytes localize with osteoclast regions; however, the functional consequences of this association remain unknown. We hypothesized that CD8+ T cells modulate calcification in CAVD. Explanted CAVD valves (n = 52) dissected into noncalcified and calcified portions were subjected to mRNA extraction, real-time quantitative PCR, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Compared with noncalcified portions, calcified regions exhibited significantly elevated transcripts for CD8, interferon (IFN)-γ, CXCL9, Perforin 1, Granzyme B, and heat shock protein 60. Osteoclast-associated receptor activator of NK-κB ligand (RANKL), tartrate-resistant acid phosphatase (TRAP), and osteoclast-associated receptor increased significantly, whereas Cathepsin K remained unchanged. The stimulation of tissue segments with phorbol-12-myristate-13-acetate and ionomycin resulted in IFN-γ release, recapitulating CAVD microenvironment. Real-time quantitative PCR detected signature mRNAs for CD8+ T-cell activation (Perforin 1, Granzyme B). In stimulated versus unstimulated organoid cultures, elevated IFN-γ reduced the mRNAs encoding for RANKL, TRAP, and Cathepsin K. Molecular imaging showed increased calcium signal intensity in stimulated versus unstimulated parts. Human CD14+ monocytes treated either with recombinant human IFN-γ or with conditioned media-derived IFN-γ exhibited low levels of Cathepsin K, TRAP, RANK, and tumor necrosis factor receptor-associated factor 6 mRNAs, whereas concentrations of the T-cell co-activators CD80 and CD86 increased in parallel with reduced osteoclast resorptive function, effects abrogated by neutralizing anti-IFN-γ antibodies. CD8+ cell-derived IFN-γ suppresses osteoclast function and may thus favor calcification in CAVD. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Apr 21, 2017   ELife
Park HB, Perez CE, Barber KW, Rinehart J, Crawford JM
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
Apr 21, 2017
ELife
Nonribosomal peptides represent a large class of metabolites with pharmaceutical relevance. Pteridines, such as pterins, folates, and flavins, are heterocyclic metabolites that often serve as redox-active cofactors. The biosynthetic machineries for construction of these distinct classes of small molecules operate independently in the cell. Here, we discovered an unprecedented nonribosomal peptide synthetase-like-pteridine synthase hybrid biosynthetic gene cluster in Photorhabdus luminescens using genome synteny analysis. P. luminescens is a Gammaproteobacterium that undergoes phenotypic variation and can have both pathogenic and mutualistic roles. Through extensive gene deletion, pathway-targeted molecular networking, quantitative proteomic analysis, and NMR, we show that the genetic locus affects the regulation of quorum sensing and secondary metabolic enzymes and encodes new pteridine metabolites functionalized with cis-amide acyl-side chains, termed pepteridine A (1) and B (2). The pepteridines are produced in the pathogenic phenotypic variant and represent the first reported metabolites to be synthesized by a hybrid NRPS-pteridine pathway. These studies expand our view of the combinatorial biosynthetic potential available in bacteria.
Revealing the biochemical and genetic basis of colour variation in a polymorphic lizard
Apr 21, 2017   Molecular Biology And Evolution
McLean CA, Lutz A, Rankin KJ, Stuart-Fox D, Moussalli A
Revealing the biochemical and genetic basis of colour variation in a polymorphic lizard
Apr 21, 2017
Molecular Biology And Evolution
Determining the mechanistic and genetic basis of animal coloration is essential to understand the costs and constraints on colour production, and the evolution and maintenance of phenotypic variation. However, genes underlying structural colour and widespread pigment classes apart from melanin remain largely uncharacterised, in part due to restricted taxonomic focus. We combined liquid chromatography-mass spectrometry and RNA-seq gene expression analyses to characterise the pigments and genes associated with skin colour in the polymorphic lizard, Ctenophorus decresii. Throat coloration in male C. decresii may be a combination of orange, yellow, grey or ultra-violet blue. We confirmed the presence of two biochemically different pigment classes, pteridines (self-synthesised) and carotenoids (acquired through the diet), in all skin colours. Orange skin had the highest levels of pteridine pigments while yellow skin tended to have higher levels of carotenoids, of which the vitamin A precursors β-carotene and β-cryptoxanthin have not been previously confirmed in reptiles. These results were confirmed by gene expression analyses, which detected 489 genes differentially expressed between the skin colours, including genes associated with pteridine production, provitamin A carotenoid metabolism, iridophore-specific synthesis, melanin synthesis and steroid hormone pathways. For the majority of these 489 genes, however, our study reveals a new association with colour production in vertebrates. These data represent a significant contribution to understanding the genetic basis of colour variation in vertebrates and a rich resource for further studies. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge
Apr 21, 2017   Europace : European Pacing, Arrhythmias, And Cardiac Electrophysiology : Journal Of The Working Groups On Cardiac Pacing, Arrhythmias, And Cardiac Cellular Electrophysiology Of The European Society Of Cardiology
Antzelevitch C, Yan GX, Ackerman MJ, Borggrefe M, Corrado D,   . . . . . .   , Nam GB, Sacher F, Shimizu W, Viskin S, Wilde AAM
J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge
Apr 21, 2017
Europace : European Pacing, Arrhythmias, And Cardiac Electrophysiology : Journal Of The Working Groups On Cardiac Pacing, Arrhythmias, And Cardiac Cellular Electrophysiology Of The European Society Of Cardiology
Cis-regulatory divergence in gene expression between two thermally divergent yeast species
Apr 21, 2017   Genome Biology And Evolution
Li XC, Fay JC
Cis-regulatory divergence in gene expression between two thermally divergent yeast species
Apr 21, 2017
Genome Biology And Evolution
Gene regulation is a ubiquitous mechanism by which organisms respond to their environment. While organisms are often found to be adapted to the environments they experience, the role of gene regulation in environmental adaptation is not often known. In this study, we examine divergence in cis-regulatory effects between two Saccharomyces species, S. cerevisiae and S. uvarum, that have substantially diverged in their thermal growth profile. We measured allele specific expression (ASE) in the species' hybrid at three temperatures, the highest of which is lethal to S. uvarum but not the hybrid or S. cerevisiae. We find that S. uvarum alleles can be expressed at the same level as S. cerevisiae alleles at high temperature and most cis-acting differences in gene expression are not dependent on temperature. While a small set of 136 genes show temperature-dependent ASE, we find no indication that signatures of directional cis-regulatory evolution are associated with temperature. Within promoter regions we find binding sites enriched upstream of temperature responsive genes, but only weak correlations between binding site and expression divergence. Our results indicate that temperature divergence between S. cerevisiae and S. uvarum has not caused widespread divergence in cis-regulatory activity, but point to a small subset of genes where the species' alleles show differences in magnitude or opposite responses to temperature. The difficulty of explaining divergence in cis-regulatory sequences with models of transcription factor binding sites and nucleosome positioning highlights the importance of identifying mutations that underlie cis-regulatory divergence between species. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
Genomic data for 78 chickens from 14 populations
Apr 21, 2017   GigaScience
Li D, Che T, Chen B, Tian S, Zhou X,   . . . . . .   , Yang M, Zhou R, Li R, Zhu Q, Li M
Genomic data for 78 chickens from 14 populations
Apr 21, 2017
GigaScience
Since the domestication of the red jungle fowls ( Gallus gallus ) (dating back to ∼10,000 B.P.) in Asia, domestic chickens ( Gallus gallus domesticus ) have been subjected to the combined effects of natural selection and human-driven artificial selection; this has resulted in marked phenotypic diversity in a number of traits, including behavior, body composition, egg production and skin color. Population genomic variations through diversifying selection have not been fully investigated. The whole genomes of 78 domestic chickens were sequenced to an average of 18-fold coverage for each bird. By combining this data with publicly available genomes of 5 wild red jungle fowls and 8 Xishuangbanna game fowls, we conducted a comprehensive comparative genomics analysis of 91 chickens from 17 populations. After aligning ∼21.30 gigabases (Gb) of high quality data from each individual to the reference chicken genome, we identified ∼6.44 million (M) SNPs for each population. These SNPs included 1.10 M novel SNPs in 17 populations that were absent in the current chicken dbSNP (Build 145) entries. The current data is important for population genetics and further studies in chicken, and will serve as a valuable resource for investigating diversifying selection and candidate genes for selective breeding in chicken.
Sequencing and functional validation of the JGI Brachypodium distachyon T-DNA collection
Apr 22, 2017   The Plant Journal : For Cell And Molecular Biology
Hsia MM, O'Malley R, Cartwright A, Nieu R, Gordon SP,   . . . . . .   , Jordan M, Pauly M, Ecker JR, Gu Y, Vogel JP
Sequencing and functional validation of the JGI Brachypodium distachyon T-DNA collection
Apr 22, 2017
The Plant Journal : For Cell And Molecular Biology
Due to a large and growing collection of genomic and experimental resources, Brachypodium distachyon has emerged as a powerful experimental model for the grasses. To add to these resources we sequenced 21,165 T-DNA lines, 15,569 of which were produced in this study. This increased the number of unique insertion sites in the T-DNA collection by 21,078 bringing the overall total to 26,112. Thirty seven percent (9,754) of these insertion sites are within genes (including UTRs and introns) and 28% (7,217) are within 500 bp of a gene. Approximately 31% of the genes in the v2.1 annotation have been tagged in this population. To demonstrate the utility of this collection, we phenotypically characterized six T-DNA lines with insertions in genes previously shown in other systems to be involved in cellulose biosynthesis, hemicellulose biosynthesis, secondary cell wall development, DNA damage repair, wax biosynthesis, and chloroplast synthesis. In all cases, the phenotypes observed supported previous studies demonstrating the utility of this collection for plant functional genomics. The Brachypodium T-DNA collection can be accessed at http://jgi.doe.gov/our-science/science-programs/plant-genomics/brachypodium/brachypodium-t-dna-collection/. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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