165 research outputs found

    A new negative control gene for amino acid biosynthesis in Saccharomyces cerevisiae

    Full text link
    Enzyme levels in multiple amino acid biosynthetic pathways in yeast are coregulated. This control is effected largely at the transcriptional level by a number. of regulatory genes. We report the isolation and characterization of a new negative regulatory gene, GCD4 , for this general control system. GCD4 mutations are recessive and define a single Mendelian gene on chromosome 111. A gcd4 mutation results in resistance to different amino acid analogs and elevated, but fully inducible, mRNA levels of genes under general control. Epistasis analysis indicates that GCD4 acts more directly than the positive regulators GCN1, GCN2, GCN3 and GCN5 , but less directly than GCN4 , on the transcription of the amino acid biosynthetic genes. These data imply that GCD4 is a negative regulator of the positive effector, GCN4 . Although GCD4 occupies the same position relative to the GCN genes as other GCD genes, it produces a unique phenotype. These results illustrate the diversity of function of negative regulators in general control.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46958/1/294_2004_Article_BF00447382.pd

    Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

    Get PDF
    Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

    Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

    Get PDF
    Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

    Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

    Get PDF
    This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

    Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

    Get PDF
    Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

    Height-diameter allometry and above ground biomass in tropical montane forests: Insights from the Albertine Rift in Africa

    Get PDF
    Tropical montane forests provide an important natural laboratory to test ecological theory. While it is well-known that some aspects of forest structure change with altitude, little is known on the effects of altitude on above ground biomass (AGB), particularly with regard to changing height-diameter allometry. To address this we investigate (1) the effects of altitude on height-diameter allometry, (2) how different height-diameter allometric models affect above ground biomass estimates; and (3) how other forest structural, taxonomic and environmental attributes affect above ground biomass using 30 permanent sample plots (1-ha; all trees ≥ 10 cm diameter measured) established between 1250 and 2600 m asl in Kahuzi Biega National Park in eastern Democratic Republic of Congo. Forest structure and species composition differed with increasing altitude, with four forest types identified. Different height-diameter allometric models performed better with the different forest types, as trees got smaller with increasing altitude. Above ground biomass ranged from 168 to 290 Mg ha-1, but there were no significant differences in AGB between forests types, as tree size decreased but stem density increased with increasing altitude. Forest structure had greater effects on above ground biomass than forest diversity. Soil attributes (K and acidity, pH) also significantly affected above ground biomass. Results show how forest structural, taxonomic and environmental attributes affect above ground biomass in African tropical montane forests. They particularly highlight that the use of regional height-diameter models introduces significant biases in above ground biomass estimates, and that different height-diameter models might be preferred for different forest types, and these should be considered in future studies

    Sensory Communication

    Get PDF
    Contains table of contents for Section 2, an introduction and reports on fourteen research projects.National Institutes of Health Grant RO1 DC00117National Institutes of Health Grant RO1 DC02032National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant R01 DC00126National Institutes of Health Grant R01 DC00270National Institutes of Health Contract N01 DC52107U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-95-K-0014U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0003U.S. Navy - Office of Naval Research Grant N00014-96-1-0379U.S. Air Force - Office of Scientific Research Grant F49620-95-1-0176U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0202U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0002National Institutes of Health Grant R01-NS33778U.S. Navy - Office of Naval Research Grant N00014-92-J-184

    Формирование эмоциональной культуры как компонента инновационной культуры студентов

    Get PDF
    Homozygosity has long been associated with rare, often devastating, Mendelian disorders1 and Darwin was one of the first to recognise that inbreeding reduces evolutionary fitness2. However, the effect of the more distant parental relatedness common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity, ROH), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power3,4. Here we use ROH to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts and find statistically significant associations between summed runs of homozygosity (SROH) and four complex traits: height, forced expiratory lung volume in 1 second (FEV1), general cognitive ability (g) and educational attainment (nominal p<1 × 10−300, 2.1 × 10−6, 2.5 × 10−10, 1.8 × 10−10). In each case increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing convincing evidence for the first time that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples5,6, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein (LDL) cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection7, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been
    corecore