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Sample records for temperature-dependent somatic mutation

  1. Age- and temperature-dependent somatic mutation accumulation in Drosophila melanogaster.

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    Ana Maria Garcia

    2010-05-01

    Full Text Available Using a transgenic mouse model harboring a mutation reporter gene that can be efficiently recovered from genomic DNA, we previously demonstrated that mutations accumulate in aging mice in a tissue-specific manner. Applying a recently developed, similar reporter-based assay in Drosophila melanogaster, we now show that the mutation frequency at the lacZ locus in somatic tissue of flies is about three times as high as in mouse tissues, with a much higher fraction of large genome rearrangements. Similar to mice, somatic mutations in the fly also accumulate as a function of age, but they do so much more quickly at higher temperature, a condition which in invertebrates is associated with decreased life span. Most mutations were found to accumulate in the thorax and less in abdomen, suggesting the highly oxidative flight muscles as a possible source of genotoxic stress. These results show that somatic mutation loads in short-lived flies are much more severe than in the much longer-lived mice, with the mutation rate in flies proportional to biological rather than chronological aging.

  2. Somatic mutations in aging, cancer and neurodegeneration.

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    Kennedy, Scott R; Loeb, Lawrence A; Herr, Alan J

    2012-04-01

    The somatic mutation theory of aging posits that the accumulation of mutations in the genetic material of somatic cells as a function of time results in a decrease in cellular function. In particular, the accumulation of random mutations may inactivate genes that are important for the functioning of the somatic cells of various organ systems of the adult, result in a decrease in organ function. When the organ function decreases below a critical level, death occurs. A significant amount of research has shown that somatic mutations play an important role in aging and a number of age related pathologies. In this review, we explore evidence for increases in somatic nuclear mutation burden with age and the consequences for aging, cancer, and neurodegeneration. We then review evidence for increases in mitochondrial mutation burden and the consequences for dysfunction in the disease processes. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  3. Somatic mutations in cerebral cortical malformations.

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    Jamuar, Saumya S; Lam, Anh-Thu N; Kircher, Martin; D'Gama, Alissa M; Wang, Jian; Barry, Brenda J; Zhang, Xiaochang; Hill, Robert Sean; Partlow, Jennifer N; Rozzo, Aldo; Servattalab, Sarah; Mehta, Bhaven K; Topcu, Meral; Amrom, Dina; Andermann, Eva; Dan, Bernard; Parrini, Elena; Guerrini, Renzo; Scheffer, Ingrid E; Berkovic, Samuel F; Leventer, Richard J; Shen, Yiping; Wu, Bai Lin; Barkovich, A James; Sahin, Mustafa; Chang, Bernard S; Bamshad, Michael; Nickerson, Deborah A; Shendure, Jay; Poduri, Annapurna; Yu, Timothy W; Walsh, Christopher A

    2014-08-21

    Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated. Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing. Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria. Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

  4. Domain landscapes of somatic mutations in cancer.

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    Nehrt, Nathan L; Peterson, Thomas A; Park, DoHwan; Kann, Maricel G

    2012-06-18

    Large-scale tumor sequencing projects are now underway to identify genetic mutations that drive tumor initiation and development. Most studies take a gene-based approach to identifying driver mutations, highlighting genes mutated in a large percentage of tumor samples as those likely to contain driver mutations. However, this gene-based approach usually does not consider the position of the mutation within the gene or the functional context the position of the mutation provides. Here we introduce a novel method for mapping mutations to distinct protein domains, not just individual genes, in which they occur, thus providing the functional context for how the mutation contributes to disease. Furthermore, aggregating mutations from all genes containing a specific protein domain enables the identification of mutations that are rare at the gene level, but that occur frequently within the specified domain. These highly mutated domains potentially reveal disruptions of protein function necessary for cancer development. We mapped somatic mutations from the protein coding regions of 100 colon adenocarcinoma tumor samples to the genes and protein domains in which they occurred, and constructed topographical maps to depict the "mutational landscapes" of gene and domain mutation frequencies. We found significant mutation frequency in a number of genes previously known to be somatically mutated in colon cancer patients including APC, TP53 and KRAS. In addition, we found significant mutation frequency within specific domains located in these genes, as well as within other domains contained in genes having low mutation frequencies. These domain "peaks" were enriched with functions important to cancer development including kinase activity, DNA binding and repair, and signal transduction. Using our method to create the domain landscapes of mutations in colon cancer, we were able to identify somatic mutations with high potential to drive cancer development. Interestingly, the

  5. Coherent Somatic Mutation in Autoimmune Disease

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    Ross, Kenneth Andrew

    2014-01-01

    Background Many aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation. Results Protein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (). Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed. Conclusions The results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases. PMID:24988487

  6. Progression inference for somatic mutations in cancer

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    Leif E. Peterson

    2017-04-01

    Full Text Available Computational methods were employed to determine progression inference of genomic alterations in commonly occurring cancers. Using cross-sectional TCGA data, we computed evolutionary trajectories involving selectivity relationships among pairs of gene-specific genomic alterations such as somatic mutations, deletions, amplifications, downregulation, and upregulation among the top 20 driver genes associated with each cancer. Results indicate that the majority of hierarchies involved TP53, PIK3CA, ERBB2, APC, KRAS, EGFR, IDH1, VHL, etc. Research into the order and accumulation of genomic alterations among cancer driver genes will ever-increase as the costs of nextgen sequencing subside, and personalized/precision medicine incorporates whole-genome scans into the diagnosis and treatment of cancer.

  7. High-throughput Phenotyping of Lung Cancer Somatic Mutations.

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    Berger, Alice H; Brooks, Angela N; Wu, Xiaoyun; Shrestha, Yashaswi; Chouinard, Candace; Piccioni, Federica; Bagul, Mukta; Kamburov, Atanas; Imielinski, Marcin; Hogstrom, Larson; Zhu, Cong; Yang, Xiaoping; Pantel, Sasha; Sakai, Ryo; Watson, Jacqueline; Kaplan, Nathan; Campbell, Joshua D; Singh, Shantanu; Root, David E; Narayan, Rajiv; Natoli, Ted; Lahr, David L; Tirosh, Itay; Tamayo, Pablo; Getz, Gad; Wong, Bang; Doench, John; Subramanian, Aravind; Golub, Todd R; Meyerson, Matthew; Boehm, Jesse S

    2016-08-08

    Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant-impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset of the impactful mutations induces xenograft tumor formation in mice and/or confers resistance to cellular EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and multiple BRAF variants, demonstrating that rare mutations can be functionally important in cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Clinical significance of somatic mutation in unexplained blood cytopenia

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    Gallì, Anna; Travaglino, Erica; Ambaglio, Ilaria; Rizzo, Ettore; Molteni, Elisabetta; Elena, Chiara; Ferretti, Virginia Valeria; Catricalà, Silvia; Bono, Elisa; Todisco, Gabriele; Bianchessi, Antonio; Rumi, Elisa; Zibellini, Silvia; Pietra, Daniela; Boveri, Emanuela; Camaschella, Clara; Toniolo, Daniela; Papaemmanuil, Elli; Ogawa, Seishi; Cazzola, Mario

    2017-01-01

    Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of, developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 or more mutations, had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and comutation patterns involving TET2, DNMT3A, or ASXL1 had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio = 13.9, P neoplasms. PMID:28424163

  9. Somatic point mutation calling in low cellularity tumors.

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    Karin S Kassahn

    Full Text Available Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/ for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.

  10. The NF1 somatic mutational landscape in sporadic human cancers.

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    Philpott, Charlotte; Tovell, Hannah; Frayling, Ian M; Cooper, David N; Upadhyaya, Meena

    2017-06-21

    Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1. Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context. As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is

  11. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.

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    Nangalia, J; Massie, C E; Baxter, E J; Nice, F L; Gundem, G; Wedge, D C; Avezov, E; Li, J; Kollmann, K; Kent, D G; Aziz, A; Godfrey, A L; Hinton, J; Martincorena, I; Van Loo, P; Jones, A V; Guglielmelli, P; Tarpey, P; Harding, H P; Fitzpatrick, J D; Goudie, C T; Ortmann, C A; Loughran, S J; Raine, K; Jones, D R; Butler, A P; Teague, J W; O'Meara, S; McLaren, S; Bianchi, M; Silber, Y; Dimitropoulou, D; Bloxham, D; Mudie, L; Maddison, M; Robinson, B; Keohane, C; Maclean, C; Hill, K; Orchard, K; Tauro, S; Du, M-Q; Greaves, M; Bowen, D; Huntly, B J P; Harrison, C N; Cross, N C P; Ron, D; Vannucchi, A M; Papaemmanuil, E; Campbell, P J; Green, A R

    2013-12-19

    Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay

  12. Somatic Mutation Theory - Why it's Wrong for Most Cancers

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    Björn L.D.M. Brücher

    2016-05-01

    Full Text Available Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT: the first (somatic mutation occurs only after the second (onset of cancer and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.

  13. Biallelic BRCA2 Mutations Shape the Somatic Mutational Landscape of Aggressive Prostate Tumors.

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    Decker, Brennan; Karyadi, Danielle M; Davis, Brian W; Karlins, Eric; Tillmans, Lori S; Stanford, Janet L; Thibodeau, Stephen N; Ostrander, Elaine A

    2016-05-05

    To identify clinically important molecular subtypes of prostate cancer (PCa), we characterized the somatic landscape of aggressive tumors via deep, whole-genome sequencing. In our discovery set of ten tumor/normal subject pairs with Gleason scores of 8-10 at diagnosis, coordinated analysis of germline and somatic variants, including single-nucleotide variants, indels, and structural variants, revealed biallelic BRCA2 disruptions in a subset of samples. Compared to the other samples, the PCa BRCA2-deficient tumors exhibited a complex and highly specific mutation signature, featuring a 2.88-fold increased somatic mutation rate, depletion of context-specific C>T substitutions, and an enrichment for deletions, especially those longer than 10 bp. We next performed a BRCA2 deficiency-targeted reanalysis of 150 metastatic PCa tumors, and each of the 18 BRCA2-mutated samples recapitulated the BRCA2 deficiency-associated mutation signature, underscoring the potent influence of these lesions on somatic mutagenesis and tumor evolution. Among all 21 individuals with BRCA2-deficient tumors, only about half carried deleterious germline alleles. Importantly, the somatic mutation signature in tumors with one germline and one somatic risk allele was indistinguishable from those with purely somatic mutations. Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive PCa, highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker. Further, any test designed to leverage BRCA2 status as a biomarker for PCa must consider both germline and somatic mutations and all types of deleterious mutations. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  14. Evaluation of Nine Somatic Variant Callers for Detection of Somatic Mutations in Exome and Targeted Deep Sequencing Data

    DEFF Research Database (Denmark)

    Krøigård, Anne Bruun; Thomassen, Mads; Lænkholm, Anne-Vibeke

    2016-01-01

    and matched normal tissue in order to detect somatic mutations. The advent of many new somatic variant callers creates a need for comparison and validation of the tools, as no de facto standard for detection of somatic mutations exists and only limited comparisons have been reported. We have performed......Next generation sequencing is extensively applied to catalogue somatic mutations in cancer, in research settings and increasingly in clinical settings for molecular diagnostics, guiding therapy decisions. Somatic variant callers perform paired comparisons of sequencing data from cancer tissue...... a comprehensive evaluation using exome sequencing and targeted deep sequencing data of paired tumor-normal samples from five breast cancer patients to evaluate the performance of nine publicly available somatic variant callers: EBCall, Mutect, Seurat, Shimmer, Indelocator, Somatic Sniper, Strelka, VarScan 2...

  15. Simultaneous DNA and RNA mapping of somatic mitochondrial mutations across diverse human cancers

    DEFF Research Database (Denmark)

    Stewart, James B.; Alaei-Mahabadi, Babak; Radhakrishnan, Sabarinathan

    2015-01-01

    Somatic mutations in the nuclear genome are required for tumor formation, but the functional consequences of somatic mitochondrial DNA (mtDNA) mutations are less understood. Here we identify somatic mtDNA mutations across 527 tumors and 14 cancer types, using an approach that takes advantage of e...

  16. Determination of somatic mutations in human erythrocytes by cytometry

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    Jensen, R.H.; Langlois, R.G.; Bigbee, W.L.

    1985-06-21

    Flow cytometric assays of human erythrocytes labeled with monoclonal antibodies specific for glycophorin A were used to enumerate variant cells that appear in peripheral blood as a result of somatic gene-loss mutations in erythrocyte precursor cells. The assay was performed on erythrocytes from 10 oncology patients who had received at least one treatment from radiation or mutagenic chemotherapy at least 3 weeks before being assayed. The patients were suffering from many different malignancies (e.g., breast, renal, bone, colon and lung), and were treated with several different mutagenic therapeutics (e.g., cisplatinum, adriamycin, daunomycin, or cyclophosphamide). The frequency of these variant cells is an indication of the amount of mutagenic damage accumulated in the individual's erythropoietic cell population. Comparing these results to HPRT clonogenic assays, we find similar baseline frequencies of somatic mutation as well as similar correlation with mutagenic exposures. 9 refs., 3 figs., 1 tab.

  17. Improving the Performance of Somatic Mutation Identification by Recovering Circulating Tumor DNA Mutations.

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    Fu, Yu; Jovelet, Cécile; Filleron, Thomas; Pedrero, Marion; Motté, Nelly; Boursin, Yannick; Luo, Yufei; Massard, Christophe; Campone, Mario; Levy, Christelle; Diéras, Véronique; Bachelot, Thomas; Garrabey, Julie; Soria, Jean-Charles; Lacroix, Ludovic; André, Fabrice; Lefebvre, Celine

    2016-10-15

    DNA extracted from cancer patients' whole blood may contain somatic mutations from circulating tumor DNA (ctDNA) fragments. In this study, we introduce cmDetect, a computational method for the systematic identification of ctDNA mutations using whole-exome sequencing of a cohort of tumor and corresponding peripheral whole-blood samples. Through the analysis of simulated data, we demonstrated an increase in sensitivity in calling somatic mutations by combining cmDetect to two widely used mutation callers. In a cohort of 93 breast cancer metastatic patients, cmDetect identified ctDNA mutations in 54% of the patients and recovered somatic mutations in cancer genes EGFR, PIK3CA, and TP53 We further showed that cmDetect detected ctDNA in 89% of patients with confirmed mutated cell-free tumor DNA by plasma analyses (n = 9) within 46 pan-cancer patients. Our results prompt immediate consideration of the use of this method as an additional step in somatic mutation calling using whole-exome sequencing data with blood samples as controls. Cancer Res; 76(20); 5954-61. ©2016 AACR. ©2016 American Association for Cancer Research.

  18. Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer

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    Kämpjärvi, K; Mäkinen, N; Kilpivaara, O; Arola, J; Heinonen, H-R; Böhm, J; Abdel-Wahab, O; Lehtonen, H J; Pelttari, L M; Mehine, M; Schrewe, H; Nevanlinna, H; Levine, R L; Hokland, P; Böhling, T; Mecklin, J-P; Bützow, R; Aaltonen, L A; Vahteristo, P

    2012-01-01

    Background: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. Methods: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). Results: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7% Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5% Gly44Cys, Ala67Val). Conclusion: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis. PMID:23132392

  19. Identification of frequent somatic mutations in inflammatory breast cancer.

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    Matsuda, Naoko; Lim, Bora; Wang, Ying; Krishnamurthy, Savitri; Woodward, Wendy; Alvarez, Ricardo H; Lucci, Anthony; Valero, Vicente; Reuben, James M; Meric-Bernstam, Funda; Ueno, Naoto T

    2017-06-01

    Inflammatory breast cancer is an aggressive form of breast cancer that shows distinct clinical features from non-inflammatory breast cancer. Genomic understanding of inflammatory breast cancer will shed light on biological targets for this disease. Our objective was to identify targeted hotspot mutations using multiplex genome sequencing in inflammatory breast cancer and compare the findings with those for patients with non-inflammatory breast cancer to further recognize novel targets. We studied 400 patients with metastatic breast cancer who had somatic hotspot mutation testing using a 46- or 50-gene multiplex platform from March 2012 to December 2014. Among this population, 24 patients had inflammatory breast cancer and 376 patients had non-inflammatory breast cancer. We tested a total of 26 samples from 24 patients with inflammatory breast cancer. The average number of mutations per patient was higher in inflammatory breast cancer than in non-inflammatory breast cancer (1.23 vs. 0.65, respectively). Identified somatic mutations in inflammatory breast cancer were TP53 (n = 18, 75%), PIK3CA (n = 10, 41.7%), and ERBB2 (n = 4, 16.7%). TP53 and ERBB2 mutations were significantly more prevalent in inflammatory breast cancer than in non-inflammatory breast cancer (P breast cancer patients. While the inflammatory breast cancer TP53 and PIK3CA mutations mirrored previously reported data for metastatic non-inflammatory breast cancer, this is the first report of higher frequency of ERBB2 mutation in inflammatory breast cancer, especially in the HR+ subtype. Once validated in a larger cohort of inflammatory breast cancer patients, this novel finding could lead to development of treatments for HR+ inflammatory breast cancer.

  20. Somatic mutations of PIK3R1 promote gliomagenesis.

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    Steven N Quayle

    Full Text Available The phosphoinositide 3-kinase (PI3K pathway is targeted for frequent alteration in glioblastoma (GBM and is one of the core GBM pathways defined by The Cancer Genome Atlas. Somatic mutations of PIK3R1 are observed in multiple tumor types, but the tumorigenic activity of these mutations has not been demonstrated in GBM. We show here that somatic mutations in the iSH2 domain of PIK3R1 act as oncogenic driver events. Specifically, introduction of a subset of the mutations identified in human GBM, in the nSH2 and iSH2 domains, increases signaling through the PI3K pathway and promotes tumorigenesis of primary normal human astrocytes in an orthotopic xenograft model. Furthermore, we show that cells that are dependent on mutant P85α-mediated PI3K signaling exhibit increased sensitivity to a small molecule inhibitor of AKT. Together, these results suggest that GBM patients whose tumors carry mutant PIK3R1 alleles may benefit from treatment with inhibitors of AKT.

  1. [AML treatment strategy based on cytogenetic abnormalities and somatic mutations].

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    Imai, Yoichi

    2015-10-01

    In addition to morphological and histocytochemical analyses of acute myeloid leukemia (AML), data on cytogenetic abnormalities and somatic mutations are used for classification of AML. The risk stratification based on these examinations facilitates determining the treatment strategy for AML. Cytogenetic risk category definitions by the Southwest Oncology Group (SWOG), Cancer and Leukemia Group B (CALGB), and The Medical Research Council (MRC) classify AML patients into favorable, intermediate, and adverse groups. Approximately 80% of patients in the intermediate group have a normal karyotype and the importance of molecular genetic analyses in these patients is increasing. Somatic mutations of NPM1, CEBPA, and FLT3 are known to be related to the prognosis of AML patients. The European LeukemiaNet (ELN) introduced risk stratification for AML patients based on cytogenetic abnormalities and NPM1, CEBPA, and FLT3 mutations. This risk stratification can be used to select only chemotherapy or chemotherapy with allogeneic hematopoietic stem cell transplantation as consolidation therapy for individual AML patients. Development of molecular targeted therapies against FLT3 or IDH mutations is in progress and these novel therapies are expected to contribute to improving the prognosis of AML patients.

  2. Somatic Mutations of tradescantia 4430 treated with radiation and mercury

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    Park, Hee Jeon; Kim, Jin Kyu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Lee, Young Yup [Dept.of Science and Biotechnology, Jeonju University, Jeonju (Korea, Republic of)

    2007-11-15

    Tradescantia 4430 clone is an interspecific hybrid made by artificially crossing T. hirsutiflora with T. subacaulis. It has hereditary heteromorphy in its flower color, blue dominant and pink recessive. The hybrid clone is exttremely sensitive to ionizing radiation and chemical mutagens. Groups of inflorescence cuttings were irradiated with 0.3, 0.5, 1.0, 1.5 and 2.0 Gy. After irradiation, the cuttings were maintained at 24 degrees C under a controlled light:dark (14 : 10) cycle. Five days after irradiation, mutations started to increase rapidly and reached a maximum rate during 8⁓10 days after irradiation. Mutation frequencies increased with radiation dose and with mercury concentration. In conclusion irradiation as well as mercury caused a dose- or concentration-response relationship in the somatic mutation frequencies of Tradescantia 4430. Tradescantia 4430 proved to be a good material for studying the combined effect of radiation and mercury.

  3. Inference of Tumor Phylogenies with Improved Somatic Mutation Discovery

    KAUST Repository

    Salari, Raheleh

    2013-01-01

    Next-generation sequencing technologies provide a powerful tool for studying genome evolution during progression of advanced diseases such as cancer. Although many recent studies have employed new sequencing technologies to detect mutations across multiple, genetically related tumors, current methods do not exploit available phylogenetic information to improve the accuracy of their variant calls. Here, we present a novel algorithm that uses somatic single nucleotide variations (SNVs) in multiple, related tissue samples as lineage markers for phylogenetic tree reconstruction. Our method then leverages the inferred phylogeny to improve the accuracy of SNV discovery. Experimental analyses demonstrate that our method achieves up to 32% improvement for somatic SNV calling of multiple related samples over the accuracy of GATK\\'s Unified Genotyper, the state of the art multisample SNV caller. © 2013 Springer-Verlag.

  4. Oxidative stress is not a major contributor to somatic mitochondrial DNA mutations.

    Directory of Open Access Journals (Sweden)

    Leslie S Itsara

    2014-02-01

    Full Text Available The accumulation of somatic mitochondrial DNA (mtDNA mutations is implicated in aging and common diseases of the elderly, including cancer and neurodegenerative disease. However, the mechanisms that influence the frequency of somatic mtDNA mutations are poorly understood. To develop a simple invertebrate model system to address this matter, we used the Random Mutation Capture (RMC assay to characterize the age-dependent frequency and distribution of mtDNA mutations in the fruit fly Drosophila melanogaster. Because oxidative stress is a major suspect in the age-dependent accumulation of somatic mtDNA mutations, we also used the RMC assay to explore the influence of oxidative stress on the somatic mtDNA mutation frequency. We found that many of the features associated with mtDNA mutations in vertebrates are conserved in Drosophila, including a comparable somatic mtDNA mutation frequency (∼10(-5, an increased frequency of mtDNA mutations with age, and a prevalence of transition mutations. Only a small fraction of the mtDNA mutations detected in young or old animals were G∶C to T∶A transversions, a signature of oxidative damage, and loss-of-function mutations in the mitochondrial superoxide dismutase, Sod2, had no detectable influence on the somatic mtDNA mutation frequency. Moreover, a loss-of-function mutation in Ogg1, which encodes a DNA repair enzyme that removes oxidatively damaged deoxyguanosine residues (8-hydroxy-2'-deoxyguanosine, did not significantly influence the somatic mtDNA mutation frequency of Sod2 mutants. Together, these findings indicate that oxidative stress is not a major cause of somatic mtDNA mutations. Our data instead suggests that somatic mtDNA mutations arise primarily from errors that occur during mtDNA replication. Further studies using Drosophila should aid in the identification of factors that influence the frequency of somatic mtDNA mutations.

  5. Oxidative Stress Is Not a Major Contributor to Somatic Mitochondrial DNA Mutations

    Science.gov (United States)

    Itsara, Leslie S.; Kennedy, Scott R.; Fox, Edward J.; Yu, Selina; Hewitt, Joshua J.; Sanchez-Contreras, Monica; Cardozo-Pelaez, Fernando; Pallanck, Leo J.

    2014-01-01

    The accumulation of somatic mitochondrial DNA (mtDNA) mutations is implicated in aging and common diseases of the elderly, including cancer and neurodegenerative disease. However, the mechanisms that influence the frequency of somatic mtDNA mutations are poorly understood. To develop a simple invertebrate model system to address this matter, we used the Random Mutation Capture (RMC) assay to characterize the age-dependent frequency and distribution of mtDNA mutations in the fruit fly Drosophila melanogaster. Because oxidative stress is a major suspect in the age-dependent accumulation of somatic mtDNA mutations, we also used the RMC assay to explore the influence of oxidative stress on the somatic mtDNA mutation frequency. We found that many of the features associated with mtDNA mutations in vertebrates are conserved in Drosophila, including a comparable somatic mtDNA mutation frequency (∼10−5), an increased frequency of mtDNA mutations with age, and a prevalence of transition mutations. Only a small fraction of the mtDNA mutations detected in young or old animals were G∶C to T∶A transversions, a signature of oxidative damage, and loss-of-function mutations in the mitochondrial superoxide dismutase, Sod2, had no detectable influence on the somatic mtDNA mutation frequency. Moreover, a loss-of-function mutation in Ogg1, which encodes a DNA repair enzyme that removes oxidatively damaged deoxyguanosine residues (8-hydroxy-2′-deoxyguanosine), did not significantly influence the somatic mtDNA mutation frequency of Sod2 mutants. Together, these findings indicate that oxidative stress is not a major cause of somatic mtDNA mutations. Our data instead suggests that somatic mtDNA mutations arise primarily from errors that occur during mtDNA replication. Further studies using Drosophila should aid in the identification of factors that influence the frequency of somatic mtDNA mutations. PMID:24516391

  6. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Krauthammer, Michael; Kong, Yong; Ha, Byung Hak; Evans, Perry; Bacchiocchi, Antonella; McCusker, James P.; Cheng, Elaine; Davis, Matthew J.; Goh, Gerald; Choi, Murim; Ariyan, Stephan; Narayan, Deepak; Dutton-Regester, Ken; Capatana, Ana; Holman, Edna C.; Bosenberg, Marcus; Sznol, Mario; Kluger, Harriet M.; Brash, Douglas E.; Stern, David F.; Materin, Miguel A.; Lo, Roger S.; Mane, Shrikant; Ma, Shuangge; Kidd, Kenneth K.; Hayward, Nicholas K.; Lifton, Richard P.; Schlessinger, Joseph; Boggon, Titus J.; Halaban, Ruth (Yale-MED); (UCLA); (Queens)

    2012-10-11

    We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1{sup P29S}) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1{sup P29S} showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

  7. 40 CFR 798.5300 - Detection of gene mutations in somatic cells in culture.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Detection of gene mutations in somatic....5300 Detection of gene mutations in somatic cells in culture. (a) Purpose. Mammalian cell culture systems may be used to detect mutations induced by chemical substances. Widely used cell lines include...

  8. Temperature-dependent sex-reversal by a transformer-2 gene-edited mutation in the spotted wing drosophila, Drosophila suzukii.

    Science.gov (United States)

    Li, Jianwei; Handler, Alfred M

    2017-09-28

    Female to male sex reversal was achieved in an emerging agricultural insect pest, Drosophila suzukii, by creating a temperature-sensitive point mutation in the sex-determination gene, transformer-2 (tra-2), using CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated) homology-directed repair gene-editing. Ds-tra-2 ts2 mutants developed as normal fertile XX and XY adults at permissive temperatures below 20 °C, but at higher restrictive temperatures (26 to 29 °C) chromosomal XX females developed as sterile intersexuals with a predominant male phenotype, while XY males developed with normal morphology, but were sterile. The temperature-dependent function of the Ds-TRA-2 ts2 protein was also evident by the up- and down-regulation of female-specific Ds-Yolk protein 1 (Ds-Yp1) gene expression by temperature shifts during adulthood. This study confirmed the temperature-dependent function of a gene-edited mutation and provides a new method for the more general creation of conditional mutations for functional genomic analysis in insects, and other organisms. Furthermore, it provides a temperature-dependent system for creating sterile male populations useful for enhancing the efficacy of biologically-based programs, such as the sterile insect technique (SIT), to control D. suzukii and other insect pest species of agricultural and medical importance.

  9. A pathway-centric survey of somatic mutations in Chinese patients with colorectal carcinomas.

    Directory of Open Access Journals (Sweden)

    Chao Ling

    Full Text Available Previous genetic studies on colorectal carcinomas (CRC have identified multiple somatic mutations in four candidate pathways (TGF-β, Wnt, P53 and RTK-RAS pathways on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene APC, TCF7L2, and PIK3CA that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene SMAD4, APC, FBXW7, BRAF and PTEN in Chinese CRC patients. While most were previously reported in CRC, one mutation in PTEN was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.

  10. Somatic cell mutation induced by sunlight in Drosophila.

    Science.gov (United States)

    Negishi, T; Takinami, S; Nikaido, O; Mochizuki, M; Toyoshima, M

    1999-12-01

    There is ample epidemiological evidence showing that sunlight can cause skin cancer in the human. In experimental studies, simulated sunlight or UV lamps are used for demonstrating carcinogenesis and other biological effects. Little studies, however, have been performed using natural sunlight itself. In this work, we have examined the mutagenicity of natural sunlight in Drosophila. The Drosophila wing spot test is useful to detect somatic cell mutations. Third instar larvae in petri dishes were exposed to sunlight (ultraviolet region with induction of mutant spot observed was 1.98 total spots/wing on June 25, 1998, and the lowest was 0.64 on December 29, 1998, while non-exposure spontaneous spots were 0.29 and 0.32 on these days, respectively. Thus, solar radiation was mutagenic both in summer and in winter.

  11. Landscape of somatic mutations in 560 breast cancer whole-genome sequences

    NARCIS (Netherlands)

    S. Nik-Zainal (Serena); H. Davies (Helen); J. Staaf (Johan); M. Ramakrishna (Manasa); D. Glodzik (Dominik); X. Zou (Xueqing); I. Martincorena (Inigo); L.B. Alexandrov (Ludmil); S. Martin (Sandra); D.C. Wedge (David); P. van Loo (Peter); Y.S. Ju (Young Seok); M. Smid (Marcel); A.B. Brinkman (Arie B.); S. Morganella (Sandro); Aure, M.R. (Miriam R.); Lingjærde, O.C. (Ole Christian); A. Langerød (Anita); Ringnér, M. (Markus); Ahn, S.-M. (Sung-Min); S. Boyault (Sandrine); Brock, J.E. (Jane E.); A. Broeks (Annegien); A. Butler (Adam); C. Desmedt (Christine); L.Y. Dirix (Luc); S. Dronov (Serge); A. Fatima (Aquila); J.A. Foekens (John); M. Gerstung (Moritz); J. Hooijer; Jang, S.J. (Se Jin); Jones, D.R. (David R.); H.-Y. Kim (Hyung-Yong); King, T.A. (Tari A.); Krishnamurthy, S. (Savitri); Lee, H.J. (Hee Jin); Lee, J.-Y. (Jeong-Yeon); Y. Li (Yilong); S. McLaren (Stuart); D. Menzies; Mustonen, V. (Ville); S. O'Meara (Sarah); I. Pauporté (Iris); X. Pivot (Xavier); C.A. Purdie (Colin A.); J.W. Raine (John); Ramakrishnan, K. (Kamna); F.G. Rodriguez-Gonzalez (F. German); Romieu, G. (Gilles); A.M. Sieuwerts (Anieta); Simpson, P.T. (Peter T.); Shepherd, R. (Rebecca); L.A. Stebbings (Lucy); Stefansson, O.A. (Olafur A.); J. Teague (Jon); Tommasi, S. (Stefania); I. Treilleux (Isabelle); G. van den Eynden; P.B. Vermeulen; A. Vincent-Salomon (Anne); L.R. Yates (Lucy); C. Caldas (Carlos); L.J. van 't Veer (Laura); A. Tutt (Andrew); S. Knappskog (Stian); Tan, B.K.T. (Benita Kiat Tee); J. Jonkers (Jos); Å. Borg (Åke); Ueno, N.T. (Naoto T.); C. Sotiriou (Christos); Viari, A. (Alain); P.A. Futreal (Andrew); P.J. Campbell (Peter); P.N. Span (Paul); S.J. van Laere (Steven); S. Lakhani (Sunil); J. Eyfjord; A.M. Thompson (Alastair M.); E. Birney (Ewan); H. Stunnenberg (Henk); M.J. Vijver (Marc ); J.W.M. Martens (John); A.-L. Borresen-Dale (Anne-Lise); A.L. Richardson (Andrea); G. Kong (Gu); G. Thomas (Gilles); M.R. Stratton (Michael)

    2016-01-01

    textabstractWe analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding

  12. Are the Somatic Mutation and Tissue Organization Field Theories of Carcinogenesis Incompatible?

    OpenAIRE

    Simon Rosenfeld

    2013-01-01

    Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research. These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT). The essence of SMT is that cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations, and that those mutations occur on genes which control cell proliferation and cell cycle. Thus, according to SMT, neoplastic lesions are the r...

  13. Low prevalence of the somatic M918T RET mutation in micro-medullary thyroid cancer.

    Science.gov (United States)

    Romei, Cristina; Ugolini, Clara; Cosci, Barbara; Torregrossa, Liborio; Vivaldi, Agnese; Ciampi, Raffaele; Tacito, Alessia; Basolo, Fulvio; Materazzi, Gabriele; Miccoli, Paolo; Vitti, Paolo; Pinchera, Aldo; Elisei, Rossella

    2012-05-01

    The prevalence of RET somatic mutations in sporadic medullary thyroid cancer (MTCs) is ∼40%-50%, and the most frequent somatic mutation is M918T. RET-positive MTCs have been demonstrated to have a more advanced stage at diagnosis and a worse outcome. The aim of the present work was to compare the prevalence of RET somatic mutations in sporadic microMTCs (1 and 2 and 3 cm. The overall prevalence of the somatic M918T RET mutation was 19.4% (31/160). RET mutations were distributed differently among the four groups. The prevalence was 11.3% (6/53) in group A, 11.8% (8/68) in group B, 31.8% (7/22) in group C, and 58.8% (10/17) in group D, exhibiting an increase with increasing size of the tumor. When comparing the prevalence of mutations in the four groups, we found a lower prevalence in microMTCs (p<0.0001). The overall prevalence of RET somatic mutations was lower than expected, and the prevalence of the somatic M918T RET mutation was significantly lower in microMTCs than in larger tumors. To explain this finding, we can hypothesize either that other oncogene(s) might be responsible for the majority of microMTC, thus identifying a tumor subset, or that the RET mutation might, or might not, occur later during tumor progression.

  14. Age related shift in the mutation spectra of germline and somatic NF2 mutations: hypothetical role of DNA repair mechanisms

    National Research Council Canada - National Science Library

    Evans, D G R; Maher, E R; Baser, M E

    2005-01-01

    It has been suggested that somatic mutations that accumulate due to an age related decline in the efficiency of DNA repair mechanisms might contribute to the increased incidence of cancer in older people...

  15. Mutational History of a Human Cell Lineage from Somatic to Induced Pluripotent Stem Cells.

    Directory of Open Access Journals (Sweden)

    Foad J Rouhani

    2016-04-01

    Full Text Available The accuracy of replicating the genetic code is fundamental. DNA repair mechanisms protect the fidelity of the genome ensuring a low error rate between generations. This sustains the similarity of individuals whilst providing a repertoire of variants for evolution. The mutation rate in the human genome has recently been measured to be 50-70 de novo single nucleotide variants (SNVs between generations. During development mutations accumulate in somatic cells so that an organism is a mosaic. However, variation within a tissue and between tissues has not been analysed. By reprogramming somatic cells into induced pluripotent stem cells (iPSCs, their genomes and the associated mutational history are captured. By sequencing the genomes of polyclonal and monoclonal somatic cells and derived iPSCs we have determined the mutation rates and show how the patterns change from a somatic lineage in vivo through to iPSCs. Somatic cells have a mutation rate of 14 SNVs per cell per generation while iPSCs exhibited a ten-fold lower rate. Analyses of mutational signatures suggested that deamination of methylated cytosine may be the major mutagenic source in vivo, whilst oxidative DNA damage becomes dominant in vitro. Our results provide insights for better understanding of mutational processes and lineage relationships between human somatic cells. Furthermore it provides a foundation for interpretation of elevated mutation rates and patterns in cancer.

  16. IDENTIFY CANCER DRIVER GENES THROUGH SHARED MENDELIAN DISEASE PATHOGENIC VARIANTS AND CANCER SOMATIC MUTATIONS.

    Science.gov (United States)

    Ma, Meng; Wang, Changchang; Glicksberg, Benjamin S; Schadt, Eric E; Li, Shuyu D; Chen, Rong

    2017-01-01

    Genomic sequencing studies in the past several years have yielded a large number of cancer somatic mutations. There remains a major challenge in delineating a small fraction of somatic mutations that are oncogenic drivers from a background of predominantly passenger mutations. Although computational tools have been developed to predict the functional impact of mutations, their utility is limited. In this study, we applied an alternative approach to identify potentially novel cancer drivers as those somatic mutations that overlap with known pathogenic mutations in Mendelian diseases. We hypothesize that those shared mutations are more likely to be cancer drivers because they have the established molecular mechanisms to impact protein functions. We first show that the overlap between somatic mutations in COSMIC and pathogenic genetic variants in HGMD is associated with high mutation frequency in cancers and is enriched for known cancer genes. We then attempted to identify putative tumor suppressors based on the number of distinct HGMD/COSMIC overlapping mutations in a given gene, and our results suggest that ion channels, collagens and Marfan syndrome associated genes may represent new classes of tumor suppressors. To elucidate potentially novel oncogenes, we identified those HGMD/COSMIC overlapping mutations that are not only highly recurrent but also mutually exclusive from previously characterized oncogenic mutations in each specific cancer type. Taken together, our study represents a novel approach to discover new cancer genes from the vast amount of cancer genome sequencing data.

  17. Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer

    Directory of Open Access Journals (Sweden)

    Wang Yu-Fen

    2006-04-01

    Full Text Available Abstract Background The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer. Methods The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE, followed by direct DNA sequencing to identify the mutations. Results Fourteen somatic mtDNA mutations were identified in 55% (11/20 of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64% were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status. Conclusion Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations.

  18. Single amino acid mutation alters thermostability of the alkaline protease from Bacillus pumilus: thermodynamics and temperature dependence.

    Science.gov (United States)

    Huang, Rong; Yang, Qingjun; Feng, Hong

    2015-02-01

    Dehairing alkaline protease (DHAP) from Bacillus pumilus BA06 has been demonstrated to have high catalytic efficiency and good thermostability, with potential application in leather processing. In order to get insights into its catalytic mechanism, two mutants with single amino acid substitution according to the homology modeling and multiple sequence alignment were characterized in thermodynamics of thermal denaturation and temperature dependence of substrate hydrolysis. The results showed that both mutants of V149I and R249E have a systematic increase in catalytic efficiency (kcat/Km) in a wide range of temperatures, mainly due to an increase of k1 (substrate diffusion) and k2 (acylation) for V149I and of k2 and k3 (deacylation) for R249E. In comparison with the wild-type DHAP, the thermostability is increased for V149I and decreased for R249E. Thermodynamic analysis indicated that the free energy (ΔGa°) of activation for thermal denaturation may govern the thermostability. The value of ΔGa° is increased for V149I and decreased for R249E. Based on these data and the structural modeling, it is suggested that substitution of Val149 with Ile may disturb the local flexibility in the substrate-binding pocket, leading to enhancement of binding affinity for the substrate. In contrast, substitution of Arg249 with Glu leads to interruption of interaction with the C-terminal of enzyme, thus resulting in less thermostability. This study indicates that amino acid residues in the active center or in the substrate-binding pocket may disturb the catalytic process and can be selected as the target for protein engineering in the bacterial alkaline proteases. © The Author 2014. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

  19. Systematic analysis of somatic mutations impacting gene expression in 12 tumour types

    Science.gov (United States)

    Ding, Jiarui; McConechy, Melissa K.; Horlings, Hugo M.; Ha, Gavin; Chun Chan, Fong; Funnell, Tyler; Mullaly, Sarah C.; Reimand, Jüri; Bashashati, Ali; Bader, Gary D.; Huntsman, David; Aparicio, Samuel; Condon, Anne; Shah, Sohrab P.

    2015-01-01

    We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles. We establish the theoretical framework and robust inference characteristics of the method using computational benchmarking. We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles. We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation. Analysis of trans-effects of mutations and copy number alterations with xseq identifies mutations in 150 genes impacting expression networks, with 89 novel predictions. We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types. These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer. PMID:26436532

  20. No evidence of somatic aryl hydrocarbon receptor interacting protein mutations in sporadic endocrine neoplasia

    DEFF Research Database (Denmark)

    Raitila, A; Georgitsi, M; Karhu, A

    2007-01-01

    . Here, we have analyzed 32 pituitary adenomas and 79 other tumors of the endocrine system for somatic AIP mutations by direct sequencing. No somatic mutations were identified. However, two out of nine patients with prolactin-producing adenoma were shown to harbor a Finnish founder mutation (Q14X...... as non-secreting pituitary adenomas have been reported, most mutation-positive patients have had growth hormone-producing adenomas diagnosed at relatively young age. Pituitary adenomas are also component tumors of some familial endocrine neoplasia syndromes such as multiple endocrine neoplasia type 1...... (MEN1) and Carney complex (CNC). Genes underlying MEN1 and CNC are rarely mutated in sporadic pituitary adenomas, but more often in other lesions contributing to these two syndromes. Thus far, the occurrence of somatic AIP mutations has not been studied in endocrine tumors other than pituitary adenomas...

  1. [A male case of subcortical band heterotopia with somatic mosaicism of DCX mutation].

    Science.gov (United States)

    Igarashi, Aiko; Kawatani, Masao; Ohta, Genrei; Kometani, Hiroshi; Ohshima, Yusei; Kato, Mitsuhiro

    2013-09-01

    This report describes a male case of subcortical band heterotopia (SBH) with somatic mosaicism of doublecortin (DCX) mutation. His brain MRI revealed bilateral SBH with anterior dominant pachygyria. Although he had infantile spasms from 5-months old and showed mild developmental delay, he responded well to vitamin B6 and ACTH therapy. We conducted DCX mutation analysis using peripheral blood lymphocytes of the proband and his parents. Only the present case showed the mixture pattern of missense mutation (c. 167 G>C) and normal sequence of DCX gene indicating that the present case resulted from somatic mosaicism of de novo DCX mutation. Male patients with DCX mutations generally present with the classical type of lissencephaly, severe developmental delay, and intractable epilepsy. However, somatic mosaic mutation of DCX can lead to SBH in males.

  2. Pinot blanc and Pinot gris arose as independent somatic mutations of Pinot noir

    National Research Council Canada - National Science Library

    Vezzulli, Silvia; Leonardelli, Lorena; Malossini, Umberto; Stefanini, Marco; Velasco, Riccardo; Moser, Claudio

    2012-01-01

    .... Layer-specific molecular characterization of the Pinot family of grape cultivars was conducted to provide an evolutionary explanation for the somatic mutations that have affected the locus of berry colour...

  3. Pinot blanc and Pinot gris arose as independent somatic mutations of Pinot noir

    OpenAIRE

    Vezzulli, S.; Leonardelli, L.; Malossini, U.; Stefanini, M.; Velasco, R.; Moser, C.

    2012-01-01

    Somatic mutation is a natural mechanism which allows plant growers to develop new cultivars. As a source of variation within a uniform genetic background, it also represents an ideal tool for studying the genetic make-up of important traits and for establishing gene functions. Layer-specific molecular characterization of the Pinot family of grape cultivars was conducted to provide an evolutionary explanation for the somatic mutations that have affected the locus of berry colour. Through the s...

  4. Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer

    OpenAIRE

    van Haaften, Gijs; Dalgliesh, Gillian L; Davies, Helen; Chen, Lina; Bignell, Graham; Greenman, Chris; Edkins, Sarah; Hardy, Claire; O?Meara, Sarah; Teague, Jon; Butler, Adam; Hinton, Jonathan; Latimer, Calli; Andrews, Jenny; Barthorpe, Syd

    2009-01-01

    Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase, UTX, pointing to histone H3 lysine methylation deregulation in multiple tumour types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX a...

  5. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

    DEFF Research Database (Denmark)

    Møller, Rikke S; Weckhuysen, Sarah; Chipaux, Mathilde

    2016-01-01

    OBJECTIVE: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. METHODS: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel...... sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR. RESULTS: We...... frontal lobe epilepsy. CONCLUSIONS: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly....

  6. Classification of Cancer Primary Sites Using Machine Learning and Somatic Mutations

    Directory of Open Access Journals (Sweden)

    Yukun Chen

    2015-01-01

    Full Text Available An accurate classification of human cancer, including its primary site, is important for better understanding of cancer and effective therapeutic strategies development. The available big data of somatic mutations provides us a great opportunity to investigate cancer classification using machine learning. Here, we explored the patterns of 1,760,846 somatic mutations identified from 230,255 cancer patients along with gene function information using support vector machine. Specifically, we performed a multiclass classification experiment over the 17 tumor sites using the gene symbol, somatic mutation, chromosome, and gene functional pathway as predictors for 6,751 subjects. The performance of the baseline using only gene features is 0.57 in accuracy. It was improved to 0.62 when adding the information of mutation and chromosome. Among the predictable primary tumor sites, the prediction of five primary sites (large intestine, liver, skin, pancreas, and lung could achieve the performance with more than 0.70 in F-measure. The model of the large intestine ranked the first with 0.87 in F-measure. The results demonstrate that the somatic mutation information is useful for prediction of primary tumor sites with machine learning modeling. To our knowledge, this study is the first investigation of the primary sites classification using machine learning and somatic mutation data.

  7. Classification of Cancer Primary Sites Using Machine Learning and Somatic Mutations.

    Science.gov (United States)

    Chen, Yukun; Sun, Jingchun; Huang, Liang-Chin; Xu, Hua; Zhao, Zhongming

    2015-01-01

    An accurate classification of human cancer, including its primary site, is important for better understanding of cancer and effective therapeutic strategies development. The available big data of somatic mutations provides us a great opportunity to investigate cancer classification using machine learning. Here, we explored the patterns of 1,760,846 somatic mutations identified from 230,255 cancer patients along with gene function information using support vector machine. Specifically, we performed a multiclass classification experiment over the 17 tumor sites using the gene symbol, somatic mutation, chromosome, and gene functional pathway as predictors for 6,751 subjects. The performance of the baseline using only gene features is 0.57 in accuracy. It was improved to 0.62 when adding the information of mutation and chromosome. Among the predictable primary tumor sites, the prediction of five primary sites (large intestine, liver, skin, pancreas, and lung) could achieve the performance with more than 0.70 in F-measure. The model of the large intestine ranked the first with 0.87 in F-measure. The results demonstrate that the somatic mutation information is useful for prediction of primary tumor sites with machine learning modeling. To our knowledge, this study is the first investigation of the primary sites classification using machine learning and somatic mutation data.

  8. Discriminating somatic and germline mutations in tumor DNA samples without matching normals

    NARCIS (Netherlands)

    S. Hiltemann (Saskia); G.W. Jenster (Guido); J. Trapman (Hans); P.J. van der Spek (Peter); A. Stubbs (Andrew)

    2015-01-01

    textabstractTumor analyses commonly employ a correction with a matched normal (MN), a sample from healthy tissue of the same individual, in order to distinguish germline mutations from somatic mutations. Since the majority of variants found in an individual are thought to be common within the

  9. Statistical method on nonrandom clustering with application to somatic mutations in cancer

    Directory of Open Access Journals (Sweden)

    Rejto Paul A

    2010-01-01

    Full Text Available Abstract Background Human cancer is caused by the accumulation of tumor-specific mutations in oncogenes and tumor suppressors that confer a selective growth advantage to cells. As a consequence of genomic instability and high levels of proliferation, many passenger mutations that do not contribute to the cancer phenotype arise alongside mutations that drive oncogenesis. While several approaches have been developed to separate driver mutations from passengers, few approaches can specifically identify activating driver mutations in oncogenes, which are more amenable for pharmacological intervention. Results We propose a new statistical method for detecting activating mutations in cancer by identifying nonrandom clusters of amino acid mutations in protein sequences. A probability model is derived using order statistics assuming that the location of amino acid mutations on a protein follows a uniform distribution. Our statistical measure is the differences between pair-wise order statistics, which is equivalent to the size of an amino acid mutation cluster, and the probabilities are derived from exact and approximate distributions of the statistical measure. Using data in the Catalog of Somatic Mutations in Cancer (COSMIC database, we have demonstrated that our method detects well-known clusters of activating mutations in KRAS, BRAF, PI3K, and β-catenin. The method can also identify new cancer targets as well as gain-of-function mutations in tumor suppressors. Conclusions Our proposed method is useful to discover activating driver mutations in cancer by identifying nonrandom clusters of somatic amino acid mutations in protein sequences.

  10. Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation.

    Science.gov (United States)

    Yu, Lijian; Kim, Haesook T; Kasar, Siddha; Benien, Parul; Du, Wei; Hoang, Kevin; Aw, Andrew; Tesar, Bethany; Improgo, Reina; Fernandes, Stacey; Radhakrishnan, Saranya; Klitgaard, Josephine; Lee, Charles; Getz, Gad; Setlur, Sunita R; Brown, Jennifer R

    2017-02-01

    Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity. We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735-45. ©2016 AACR. ©2016 American Association for Cancer Research.

  11. Frequent somatic mutations of mitochondrial DNA in esophageal squamous cell carcinoma.

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    Kumimoto, Hiroshi; Yamane, Yoshihiro; Nishimoto, Yoshio; Fukami, Hiroko; Shinoda, Masayuki; Hatooka, Shunzo; Ishizaki, Kanji

    2004-01-10

    Recent studies of various cancers, such as those of the breast, head and neck, bladder and lung, reported that 46-64% of somatic mutations in the D-loop region of mitochondrial DNA (mtDNA) are observed. However, in esophageal cancer, only a low rate (5%) of somatic mutations has so far been reported in one article (Hibi, K. et al., Int J Cancer 2001;92:319-321). Thus, to confirm this we analyzed the somatic mutations for hypervariable regions (HVR-I and HVR-II) in the D-loop of mtDNA to reevaluate the possibility of mitochondrial genetic instability in this cancer. We amplified both HVRs by PCR and DNA samples obtained from 38 esophageal tumors and matched normal tissues, and then sequenced them. Comparing the sequences of tumors to those of normal tissues, we found 14 somatic mutations in 13 patients (34.2%). Eleven mutations were at the C consecutive stretch from position 303 to 309 of MITOMAP in the mitochondria databank (http://www.mitomap.org/), 1 at position 215 in HVR-II and 2 at positions 16,304 and 16,324 in HVR-I. There were 41 types of germ line variations in HVR-I including 2 not so far recorded in the mtDNA databank and 17 in HVR-II including 1 not yet recorded. We also determined nuclear genome instability of these 38 specimens by analyzing 3 independent microsatellite sequences. While 4 specimens showed a single microsatellite change, which is tumor specific, we did not find any co-relation between a somatic mtDNA mutation and microsatellite instability of nuclear genome DNA. These results suggest that mtDNA mutations might show a genetic instability in esophageal cancer independently from a nuclear genome instability. Copyright 2003 Wiley-Liss, Inc.

  12. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy

    Science.gov (United States)

    Møller, Rikke S.; Weckhuysen, Sarah; Chipaux, Mathilde; Marsan, Elise; Taly, Valerie; Bebin, E. Martina; Hiatt, Susan M.; Prokop, Jeremy W.; Bowling, Kevin M.; Mei, Davide; Conti, Valerio; de la Grange, Pierre; Ferrand-Sorbets, Sarah; Dorfmüller, Georg; Lambrecq, Virginie; Larsen, Line H.G.; Leguern, Eric; Guerrini, Renzo; Rubboli, Guido; Cooper, Gregory M.

    2016-01-01

    Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators allowed us to ascertain additional germline variants in MTOR. Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, with or without moderate intellectual disability. In addition, an inherited variant was found in a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and without brain malformation or macrocephaly. PMID:27830187

  13. Analysis of Parkinson's disease brain-derived DNA for alpha-synuclein coding somatic mutations.

    Science.gov (United States)

    Proukakis, Christos; Shoaee, Maryiam; Morris, James; Brier, Timothy; Kara, Eleanna; Sheerin, Una-Marie; Charlesworth, Gavin; Tolosa, Eduardo; Houlden, Henry; Wood, Nicholas W; Schapira, Anthony H

    2014-07-01

    Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD. Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible. We did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA. Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations. © 2014 The Authors. International Parkinson and Movement Disorder Society published by Wiley Periodicals, Inc.

  14. Novel Genetic Diversity Through Somatic Mutations: Fuel for Adaptation of Reef Corals?

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    Emily J. Howells

    2011-08-01

    Full Text Available Adaptation of reef corals to climate change is an issue of much debate, and often viewed as too slow a process to be of relevance over decadal time scales. This notion is based on the long sexual generation times typical for some coral species. However, the importance of somatic mutations during asexual reproduction and growth on evolution and adaptation (i.e., cell lineage selection is rarely considered. Here we review the existing literature on cell lineage selection and show that the scope for somatic mutations to arise in the coral animal and associated Symbiodinium is large. For example, we estimate that ~100 million somatic mutations can arise within a branching Acropora coral colony of average size. Similarly, the large population sizes and rapid turn-over times of in hospite Symbiodinium likely result in considerable numbers of somatic mutations. While the fate of new mutations depends on many factors, including ploidy level and force and direction of selection, we argue that they likely play a key role in the evolution of reef corals.

  15. Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

    Science.gov (United States)

    Moura, M M; Cavaco, B M; Pinto, A E; Domingues, R; Santos, J R; Cid, M O; Bugalho, M J; Leite, V

    2009-01-01

    Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet. We analysed RET exons 5, 8, 10–16 in fifty-one sporadic MTC, and found somatic mutations in thirty-three (64.7%) tumours. Among the RET-positive cases, exon 16 was the most frequently affected (60.6%). Two novel somatic mutations (Cys630Gly, c.1881del18) were identified. MTC patients were divided into three groups: group 1, with mutations in RET exons 15 and 16; group 2, with other RET mutations; group 3, having no RET mutations. Group 1 had higher prevalence (P=0.0051) and number of lymph node metastases (P=0.0017), and presented more often multifocal tumours (P=0.037) and persistent disease at last control (P=0.0242) than group 2. Detectable serum calcitonin levels at last screening (P=0.0119) and stage IV disease (P=0.0145) were more frequent in group 1, than in the other groups. Our results suggest that, among the sporadic MTC, cases with RET mutations in exons 15 and 16 are associated with the worst prognosis. Cases with other RET mutations have the most indolent course, and those with no RET mutations have an intermediate risk. PMID:19401695

  16. Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome.

    Science.gov (United States)

    Rahner, N; Friedrichs, N; Steinke, V; Aretz, S; Friedl, W; Buettner, R; Mangold, E; Propping, P; Walldorf, C

    2008-01-01

    Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1. We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using combined bisulphite restriction analysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome.

  17. Somatic mutations in breast and serous ovarian cancer young patients : a systematic review and meta-analysis

    NARCIS (Netherlands)

    Encinas, Giselly; Maistro, Simone; Pasini, Fatima Solange; Hirata Katayama, Maria Lucia; Brentani, Maria Mitzi; de Bock, Geertruida Hendrika; Azevedo Koike Folgueira, Maria Aparecida

    2015-01-01

    Objective: our aim was to evaluate whether somatic mutations in five genes were associated with an early age at presentation of breast cancer (BC) or serous ovarian cancer (SOC). Methods: COSMIC database was searched for the five most frequent somatic mutations in BC and SOC. A systematic review of

  18. Designing a high-throughput somatic mutation profiling panel specifically for gynaecological cancers.

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    Vivian M Spaans

    Full Text Available Somatic mutations play a major role in tumour initiation and progression. The mutation status of a tumour may predict prognosis and guide targeted therapies. The majority of techniques to study oncogenic mutations require high quality and quantity DNA or are analytically challenging. Mass-spectrometry based mutation analysis however is a relatively simple and high-throughput method suitable for formalin-fixed, paraffin-embedded (FFPE tumour material. Targeted gene panels using this technique have been developed for several types of cancer. These current cancer hotspot panels are not focussed on the genes that are most relevant in gynaecological cancers. In this study, we report the design and validation of a novel, mass-spectrometry based panel specifically for gynaecological malignancies and present the frequencies of detected mutations. Using frequency data from the online Catalogue of Somatic Mutations in Cancer, we selected 171 somatic hotspot mutations in the 13 most important genes for gynaecological cancers, being BRAF, CDKN2A, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A and PTEN. A total of 546 tumours (205 cervical, 227 endometrial, 89 ovarian, and 25 vulvar carcinomas were used to test and validate our panel, and to study the prevalence and spectrum of somatic mutations in these types of cancer. The results were validated by testing duplicate samples and by allele-specific qPCR. The panel presented here using mass-spectrometry shows to be reproducible and high-throughput, and is usefull in FFPE material of low quality and quantity. It provides new possibilities for studying large numbers of gynaecological tumour samples in daily practice, and could be useful in guided therapy selection.

  19. Profiling of Somatic Mutations in Phaeochromocytoma and Paraganglioma by Targeted Next Generation Sequencing Analysis

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    Andrea Luchetti

    2015-01-01

    Full Text Available At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL have been implicated in inherited predisposition to phaeochromocytoma (PCC, paraganglioma (PGL, or head and neck paraganglioma (HNPGL and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse “mutation hotspots” in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R in 7.1% (6/85; for BRAF (c.1799T>A; p.V600E in 1.2% (1/85 of tumours; and for TP53 (c.1010G>A; p.R337H in 2.35% (2/85 of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269 and in PCC/PGL with an inherited gene mutation 0% (0/148 suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL.

  20. Detection of somatic mutations by high-resolution DNA melting (HRM analysis in multiple cancers.

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    Jesus Gonzalez-Bosquet

    Full Text Available Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM curve analysis represents a fast, post-PCR high-throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each. HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples.

  1. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance.

    Science.gov (United States)

    Kwok, Brian; Hall, Jeff M; Witte, John S; Xu, Yin; Reddy, Prashanti; Lin, Keming; Flamholz, Rachel; Dabbas, Bashar; Yung, Aine; Al-Hafidh, Jenan; Balmert, Emily; Vaupel, Christine; El Hader, Carlos; McGinniss, Matthew J; Nahas, Shareef A; Kines, Julie; Bejar, Rafael

    2015-11-19

    Establishing a diagnosis in patients suspected of having a myelodysplastic syndrome (MDS) can be challenging and could be informed by the identification of somatic mutations. We performed a prospective study to examine the frequency and types of mutations encountered in 144 patients with unexplained cytopenias. Based on bone marrow findings, 17% were diagnosed with MDS, 15% with idiopathic cytopenias of undetermined significance (ICUS) and some evidence of dysplasia, and 69% with ICUS and no dysplasia. Bone marrow DNA was sequenced for mutations in 22 frequently mutated myeloid malignancy genes. Somatic mutations were identified in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients and no dysplasia. In total, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis. We validated these results in a cohort of 91 lower-risk MDS and 249 ICUS cases identified over a 6-month interval. Mutations were found in 79% of those with MDS, in 45% of those with ICUS with dysplasia, and in 17% of those with ICUS without dysplasia. The spectrum of mutated genes was similar with the exception of SF3B1 which was rarely mutated in patients without dysplasia. Variant allele fractions were comparable between clonal ICUS (CCUS) and MDS as were mean age and blood counts. We demonstrate that CCUS is a more frequent diagnosis than MDS in cytopenic patients. Clinical and mutational features are similar in these groups and may have diagnostic utility once outcomes in CCUS patients are better understood. © 2015 by The American Society of Hematology.

  2. BRAF and KIT somatic mutations are present in amelanotic melanoma.

    Science.gov (United States)

    Massi, Daniela; Pinzani, Pamela; Simi, Lisa; Salvianti, Francesca; De Giorgi, Vincenzo; Pizzichetta, Maria A; Mirri, Francesco; Steffan, Agostino; Orlando, Claudio; Santucci, Marco; Canzonieri, Vincenzo

    2013-10-01

    The genotypic profile of rare amelanotic melanomas (AMs) has been poorly investigated, thus preventing either an accurate identification as a distinctive melanoma subtype or therapy stratification. Here, we investigated the presence of the BRAF(V600E) mutation by real-time quantitative PCR and KIT mutations (exons 11 and 17) by sequencing analysis in 33 AMs. AMs included 'truly' amelanotic lesions (n = 19), with no melanin pigmentation upon dermoscopic inspection and hypomelanotic lesions (n = 14), by definition partially pigmented lesions showing a melanin pigmentation area of less than 25% of the total surface area. The frequency of the BRAF(V600E) mutation was 70.3% in the 33 cases, a percentage that increased to 89% when only the subgroup of thin melanomas (≤ 1 mm in thickness, n = 9) was considered. KIT mutations were found in 12.1% of AMs, all of which developed in nonacral sites. The identification of a relatively high frequency of BRAF(V600E) and KIT mutations in AMs may have important consequences for implementation of the novel targeted therapies now available to treat this life-threatening disease.

  3. Nonsynonymous somatic mitochondrial mutations occur in the majority of cutaneous melanomas.

    Science.gov (United States)

    Mithani, Suhail K; Smith, Ian M; Topalian, Suzanne L; Califano, Joseph A

    2008-06-01

    Earlier studies of mitochondrial mutations in melanoma have focused on analysis of selected mitochondrial genes and the displacement loop (D-loop) region using conventional sequencing. In this study we use data from a whole mitochondria-sequencing array, the MitoChip v2.0, to characterize the mutations that are present throughout the mitochondrial genome. The mitochondrial genome of DNA derived from 14 fresh melanoma specimens and two melanoma cell lines, and autologous lymphocytes or immortalized B cells, respectively, were sequenced using the MitoChip v2.0. Paired comparative sequence analysis was carried out to define somatic mutations. Somatic mitochondrial DNA mutations were identified in 12/16 (75%) melanomas, compared with germline lymphocyte DNA. One hundred mutations were present among these 12 melanomas. A disproportionate number of mutations occurred in the D-loop. Furthermore, 9/16 (56.3%) melanomas carried mutations, which resulted in amino acid substitutions in functional genes. In the 10 samples carrying nicotinamide adenine dinucleotide dehydrogenase (ND) complex mutations, multiple mutations were present at a rate significantly greater than the expected frequency based on the size of ND complex genes (P=0.028, Fisher's exact test). Mitochondrial mutation is a frequent occurrence in melanoma. The high rate of missense mutations and the propensity for the ND complex implicate a role for alterations in mitochondrial respiratory function in melanoma carcinogenesis. Mutations of the noncoding D-loop are of unclear significance, but may be associated with alterations in transcription or replication. Further studies are needed to delineate the timing and functional significance of these mutations, and their role in the pathogenesis of this disease.

  4. Factors affecting the spontaneous mutational spectra in somatic mammalian cells

    Directory of Open Access Journals (Sweden)

    О.А. Ковальова

    2006-04-01

    Full Text Available  In our survey of references we are discussed the influence of factors biological origin on the spontaneous mutation specters in mammalian. Seasonal and age components influence on the frequence of cytogenetic anomalies. The immune and endocrinous systems are take part in control of the alteration of the spontaneous mutation specters. Genetical difference of sensibility in animal and human at the alteration of factors enviroment as and  genetical differences of repair systems activity are may influence on individual variation of spontaneous destabilization characters of chromosomal apparatus.

  5. Characterization of Somatic Mutations in Air Pollution-Related Lung Cancer

    Directory of Open Access Journals (Sweden)

    Xian-Jun Yu

    2015-06-01

    Full Text Available Air pollution has been classified as Group 1 carcinogenic to humans, but the underlying tumorigenesis remains unclear. In Xuanwei City of Yunnan Province, the lung cancer incidence is among the highest in China attributed to severe air pollution generated by combustion of smoky coal, providing a unique opportunity to dissect lung carcinogenesis of air pollution. Here we analyzed the somatic mutations of 164 non-small cell lung cancers (NSCLCs from Xuanwei and control regions (CR where smoky coal was not used. Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the frequent C:G → A:T nucleotide substitutions in Xuanwei NSCLCs. Exome sequencing of 2010 genes showed that Xuanwei and CR NSCLCs had a mean of 68 and 22 mutated genes per tumor, respectively (p < 0.0001. We found 167 genes (including TP53, RYR2, KRAS, CACNA1E which had significantly higher mutation frequencies in Xuanwei than CR patients, and mutations in most genes in Xuanwei NSCLCs differed from those in CR cases. The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E were associated with patients' lifetime benzo(apyrene exposure. This study uncovers the mutation spectrum of air pollution-related lung cancers, and provides evidence for pollution exposure–genomic mutation relationship at a large scale.

  6. Polycythemia and paraganglioma with a novel somatic HIF2A mutation in a male.

    Science.gov (United States)

    Toyoda, Hidemi; Hirayama, Jyunya; Sugimoto, Yuka; Uchida, Keiichi; Ohishi, Kohshi; Hirayama, Masahiro; Komada, Yoshihiro

    2014-06-01

    Recently, a new syndrome of paraganglioma, somatostatinoma, and polycythemia has been discovered (known as Pacak-Zhuang syndrome). This new syndrome, with somatic HIF2A gain-of-function mutations, has never been reported in male patients. We describe a male patient with Pacak-Zhuang syndrome who carries a newly discovered HIF2A mutation. Congenital polycythemias have diverse etiologies, including germline mutations in the oxygen-sensing pathway. These include von Hippel-Lindau (Chuvash polycythemia), prolyl hydroxylase domain-containing protein-2, and hypoxia-inducible factor-2α (HIF-2α). Somatic gain-of-function mutations in the gene encoding HIF-2α were reported in patients with paraganglioma and polycythemia and have been found exclusively in female patients. Through sequencing of the HIF2A using DNA from paraganglioma in 15-year-old male patient, we identified a novel mutation of HIF2A: a heterozygous C to A substitution at base 1589 in exon 12 of HIF2A. The mutation was not found in germline DNA from leukocytes. The C1589A mutations resulted in substitution of alanine 530 in the HIF-2α protein with glutamic acid. This mutation is undoubtedly associated with increased HIF-2α activity and increased protein half-life, because it affects the vicinity of the prolyl hydroxylase target residue, proline 531. To our knowledge, this is the first report describing Pacak-Zhuang syndrome with somatic gain-of-function mutation in HIF2A in a male patient. Congenital polycythemia of unknown origin should raise suspicion for the novel disorder Pacak-Zhuang syndrome, even in male patients. Copyright © 2014 by the American Academy of Pediatrics.

  7. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.

    Science.gov (United States)

    Ju, Young Seok; Alexandrov, Ludmil B; Gerstung, Moritz; Martincorena, Inigo; Nik-Zainal, Serena; Ramakrishna, Manasa; Davies, Helen R; Papaemmanuil, Elli; Gundem, Gunes; Shlien, Adam; Bolli, Niccolo; Behjati, Sam; Tarpey, Patrick S; Nangalia, Jyoti; Massie, Charles E; Butler, Adam P; Teague, Jon W; Vassiliou, George S; Green, Anthony R; Du, Ming-Qing; Unnikrishnan, Ashwin; Pimanda, John E; Teh, Bin Tean; Munshi, Nikhil; Greaves, Mel; Vyas, Paresh; El-Naggar, Adel K; Santarius, Tom; Collins, V Peter; Grundy, Richard; Taylor, Jack A; Hayes, D Neil; Malkin, David; Foster, Christopher S; Warren, Anne Y; Whitaker, Hayley C; Brewer, Daniel; Eeles, Rosalind; Cooper, Colin; Neal, David; Visakorpi, Tapio; Isaacs, William B; Bova, G Steven; Flanagan, Adrienne M; Futreal, P Andrew; Lynch, Andy G; Chinnery, Patrick F; McDermott, Ultan; Stratton, Michael R; Campbell, Peter J

    2014-10-01

    Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.

  8. Pinot blanc and Pinot gris arose as independent somatic mutations of Pinot noir.

    Science.gov (United States)

    Vezzulli, Silvia; Leonardelli, Lorena; Malossini, Umberto; Stefanini, Marco; Velasco, Riccardo; Moser, Claudio

    2012-11-01

    Somatic mutation is a natural mechanism which allows plant growers to develop new cultivars. As a source of variation within a uniform genetic background, it also represents an ideal tool for studying the genetic make-up of important traits and for establishing gene functions. Layer-specific molecular characterization of the Pinot family of grape cultivars was conducted to provide an evolutionary explanation for the somatic mutations that have affected the locus of berry colour. Through the study of the structural dynamics along chromosome 2, a very large deletion present in a single Pinot gris cell layer was identified and characterized. This mutation reveals that Pinot gris and Pinot blanc arose independently from the ancestral Pinot noir, suggesting a novel parallel evolutionary model. This proposed 'Pinot-model' represents a breakthrough towards the full understanding of the mechanisms behind the formation of white, grey, red, and pink grape cultivars, and eventually of their specific enological aptitude.

  9. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation

    Science.gov (United States)

    Béguelin, Wendy; Popovic, Relja; Teater, Matt; Jiang, Yanwen; Bunting, Karen L.; Rosen, Monica; Shen, Hao; Yang, Shao Ning; Wang, Ling; Ezponda, Teresa; Martinez-Garcia, Eva; Zhang, Haikuo; Zhang, Yupeng; Verma, Sharad K.; McCabe, Michael T.; Ott, Heidi M.; Van Aller, Glenn S.; Kruger, Ryan G.; Liu, Yan; McHugh, Charles F.; Scott, David W.; Chung, Young Rock; Kelleher, Neil; Shaknovich, Rita; Creasy, Caretha L.; Gascoyne, Randy D.; Wong, Kwok-Kin; Cerchietti, Leandro C.; Levine, Ross L.; Abdel-Wahab, Omar; Licht, Jonathan D.; Elemento, Olivier; Melnick, Ari M.

    2013-01-01

    The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. PMID:23680150

  10. An investigation of the association of genetic susceptibility risk with somatic mutation burden in breast cancer.

    Science.gov (United States)

    Zhu, Bin; Mukherjee, Anwesha; Machiela, Mitchell J; Song, Lei; Hua, Xing; Shi, Jianxin; Garcia-Closas, Montserrat; Chanock, Stephen J; Chatterjee, Nilanjan

    2016-09-06

    Genome-wide association studies have reported nearly 100 common germline susceptibility loci associated with the risk for breast cancer. Tumour sequencing studies have characterised somatic mutation profiles in breast cancer patients. The relationship between breast cancer susceptibility loci and somatic mutation patterns in breast cancer remains largely unexplored. We used single-nucleotide polymorphism (SNP) genotyping array data and tumour exome sequencing data available from 638 breast cancer patients of European ancestry from The Cancer Genome Atlas (TCGA) project. We analysed both genotype data and, when necessary, imputed genotypes for 90 known breast cancer susceptibility loci. We performed linear regression models to investigate possible associations between germline risk variants with total somatic mutation count (TSMC), as well as specific mutation types. We examined individual SNP genotypes, as well as a multi-SNP polygenic risk score (PRS). Models were statistically adjusted for age at diagnosis, stage, oestrogen-receptor (ER) and progesterone-receptor (PR) status of breast cancer. We also performed stratified analyses by ER and PR status. We observed a significant inverse association (P=8.75 × 10(-6); FDR=0.001) between the risk allele in rs2588809 of the gene RAD51B and TSMC across all breast cancer patients, for both ER(+) and ER(-) tumours. This association was also evident for different types of mutations. The PRS analysis for all patients, with or without rs2588809, showed a significant inverse association (P=0.01 and 0.04, respectively) with TSMC. This inverse association was significant in ER(+) patients with the ER(+)-specific PRS (P=0.02), but not among ER(-) patients for the ER(-)-specific PRS (P=0.39). We observed an inverse association between common germline risk variants and TSMC, which, if confirmed, could provide new insights into how germline variation informs our understanding of somatic mutation patterns in breast cancer.

  11. Suppression of different classes of somatic mutations in Arabidopsis by vir gene-expressing Agrobacterium strains.

    Science.gov (United States)

    Shah, Jasmine M; Ramakrishnan, Anantha Maharasi; Singh, Amit Kumar; Ramachandran, Subalakshmi; Unniyampurath, Unnikrishnan; Jayshankar, Ajitha; Balasundaram, Nithya; Dhanapal, Shanmuhapreya; Hyde, Geoff; Baskar, Ramamurthy

    2015-08-26

    Agrobacterium infection, which is widely used to generate transgenic plants, is often accompanied by T-DNA-linked mutations and transpositions in flowering plants. It is not known if Agrobacterium infection also affects the rates of point mutations, somatic homologous recombinations (SHR) and frame-shift mutations (FSM). We examined the effects of Agrobacterium infection on five types of somatic mutations using a set of mutation detector lines of Arabidopsis thaliana. To verify the effect of secreted factors, we exposed the plants to different Agrobacterium strains, including wild type (Ach5), its derivatives lacking vir genes, oncogenes or T-DNA, and the heat-killed form for 48 h post-infection; also, for a smaller set of strains, we examined the rates of three types of mutations at multiple time-points. The mutation detector lines carried a non-functional β-glucuronidase gene (GUS) and a reversion of mutated GUS to its functional form resulted in blue spots. Based on the number of blue spots visible in plants grown for a further two weeks, we estimated the mutation frequencies. For plants co-cultivated for 48 h with Agrobacterium, if the strain contained vir genes, then the rates of transversions, SHRs and FSMs (measured 2 weeks later) were lower than those of uninfected controls. In contrast, co-cultivation for 48 h with any of the Agrobacterium strains raised the transposition rates above control levels. The multiple time-point study showed that in seedlings co-cultivated with wild type Ach5, the reduced rates of transversions and SHRs after 48 h co-cultivation represent an apparent suppression of an earlier short-lived increase in mutation rates (peaking for plants co-cultivated for 3 h). An increase after 3 h co-cultivation was also seen for rates of transversions (but not SHR) in seedlings exposed to the strain lacking vir genes, oncogenes and T-DNA. However, the mutation rates in plants co-cultivated for longer times with this strain subsequently

  12. JAK2V617F Somatic Mutation In The General Population

    DEFF Research Database (Denmark)

    Nielsen, Camilla; Bojesen, Stig E; Nordestgaard, Børge G

    2014-01-01

    Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease....... In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation...... in the time period 2003-2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity...

  13. MSIseq: Software for Assessing Microsatellite Instability from Catalogs of Somatic Mutations.

    Science.gov (United States)

    Huang, Mi Ni; McPherson, John R; Cutcutache, Ioana; Teh, Bin Tean; Tan, Patrick; Rozen, Steven G

    2015-08-26

    Microsatellite instability (MSI) is a form of hypermutation that occurs in some tumors due to defects in cellular DNA mismatch repair. MSI is characterized by frequent somatic mutations (i.e., cancer-specific mutations) that change the length of simple repeats (e.g., AAAAA…., GATAGATAGATA...). Clinical MSI tests evaluate the lengths of a handful of simple repeat sites, while next-generation sequencing can assay many more sites and offers a much more complete view of their somatic mutation frequencies. Using somatic mutation data from the exomes of a 361-tumor training set, we developed classifiers to determine MSI status based on four machine-learning frameworks. All frameworks had high accuracy, and after choosing one we determined that it had >98% concordance with clinical tests in a separate 163-tumor test set. Furthermore, this classifier retained high concordance even when classifying tumors based on subsets of whole-exome data. We have released a CRAN R package, MSIseq, based on this classifier. MSIseq is faster and simpler to use than software that requires large files of aligned sequenced reads. MSIseq will be useful for genomic studies in which clinical MSI test results are unavailable and for detecting possible misclassifications by clinical tests.

  14. Age-associated alterations in the somatic mutation and DNA methylation levels in plants.

    Science.gov (United States)

    Dubrovina, A S; Kiselev, K V

    2016-03-01

    Somatic mutations of the nuclear and mitochondrial DNA and alterations in DNA methylation levels in mammals are well known to play important roles in ageing and various diseases, yet their specific contributions await further investigation. For plants, it has also been proposed that unrepaired DNA damage and DNA polymerase errors accumulate in plant cells and lead to increased somatic mutation rate and alterations in transcription, which eventually contribute to plant ageing. A number of studies also show that DNA methylation levels vary depending on the age of plant tissue and chronological age of a whole plant. Recent studies reveal that prolonged cultivation of plant cells in vitro induces single nucleotide substitutions and increases global DNA methylation level in a time-dependent fashion. Changes in DNA methylation are known to influence DNA repair and can lead to altered mutation rates, and, therefore, it is interesting to investigate both the genetic and epigenetic integrity in relationship to ageing in plants. This review will summarise and discuss the current studies investigating somatic DNA mutation and DNA methylation levels in relation to plant ageing and senescence. The analysis has shown that there still remains a lack of clarity concerning plant biological ageing and the role of the genetic and epigenetic instabilities in this process. © 2015 German Botanical Society and The Royal Botanical Society of the Netherlands.

  15. Transgenerational genomic instability as revealed by a somatic mutation assay using the medaka fish

    Energy Technology Data Exchange (ETDEWEB)

    Shimada, Atsuko; Shima, Akihiro

    2004-08-18

    We previously established a somatic mutation assay of the medaka wl (white leucophores) locus based on visual inspection, and showed that somatic mutations at paternally derived alleles frequently arise during the development of F{sub 1} embryos fertilized by sperm/late spermatids that had been exposed to {gamma}-rays. To further study such delayed mutations, we determined the frequency of mutant embryos obtained from three different crosses between irradiated males and non-irradiated females. When sperm and late spermatids were irradiated, the mutant frequency within non-irradiated maternally derived alleles was {approx}3 times higher than in the control group. In the F{sub 2} generation, however, no increase in mutant frequency was observed. Similarly, there was no significant increase in the F{sub 1}mutant frequency when stem spermatogonia were irradiated. These data suggest that irradiation of sperm and late spermatids can induce indirect mutations in F{sub 1} somatic cells, supporting the idea that genomic instability arises during F{sub 1} embryonic development. Moreover, such instability apparently arises most frequently when eggs are fertilized just after the sperm are irradiated.

  16. Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4.

    Directory of Open Access Journals (Sweden)

    Jenifer L Marks

    2007-05-01

    Full Text Available Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis.We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16 of FGFR4 (Glu681Lys, identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr in a lung adenocarcinoma cell line.This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

  17. DeepGene: an advanced cancer type classifier based on deep learning and somatic point mutations.

    Science.gov (United States)

    Yuan, Yuchen; Shi, Yi; Li, Changyang; Kim, Jinman; Cai, Weidong; Han, Zeguang; Feng, David Dagan

    2016-12-23

    With the developments of DNA sequencing technology, large amounts of sequencing data have become available in recent years and provide unprecedented opportunities for advanced association studies between somatic point mutations and cancer types/subtypes, which may contribute to more accurate somatic point mutation based cancer classification (SMCC). However in existing SMCC methods, issues like high data sparsity, small volume of sample size, and the application of simple linear classifiers, are major obstacles in improving the classification performance. To address the obstacles in existing SMCC studies, we propose DeepGene, an advanced deep neural network (DNN) based classifier, that consists of three steps: firstly, the clustered gene filtering (CGF) concentrates the gene data by mutation occurrence frequency, filtering out the majority of irrelevant genes; secondly, the indexed sparsity reduction (ISR) converts the gene data into indexes of its non-zero elements, thereby significantly suppressing the impact of data sparsity; finally, the data after CGF and ISR is fed into a DNN classifier, which extracts high-level features for accurate classification. Experimental results on our curated TCGA-DeepGene dataset, which is a reformulated subset of the TCGA dataset containing 12 selected types of cancer, show that CGF, ISR and DNN all contribute in improving the overall classification performance. We further compare DeepGene with three widely adopted classifiers and demonstrate that DeepGene has at least 24% performance improvement in terms of testing accuracy. Based on deep learning and somatic point mutation data, we devise DeepGene, an advanced cancer type classifier, which addresses the obstacles in existing SMCC studies. Experiments indicate that DeepGene outperforms three widely adopted existing classifiers, which is mainly attributed to its deep learning module that is able to extract the high level features between combinatorial somatic point mutations and

  18. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis.

    Science.gov (United States)

    Holstege, Henne; Pfeiffer, Wayne; Sie, Daoud; Hulsman, Marc; Nicholas, Thomas J; Lee, Clarence C; Ross, Tristen; Lin, Jue; Miller, Mark A; Ylstra, Bauke; Meijers-Heijboer, Hanne; Brugman, Martijn H; Staal, Frank J T; Holstege, Gert; Reinders, Marcel J T; Harkins, Timothy T; Levy, Samuel; Sistermans, Erik A

    2014-05-01

    The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

  19. The Frequency of Granulocytes with Spontaneous Somatic Mutations: A Wide Distribution in a Normal Human Population

    Science.gov (United States)

    Peruzzi, Benedetta; Boni, Luca; Caporale, Roberto; Dolara, Piero; Notaro, Rosario; Luzzatto, Lucio

    2013-01-01

    Germ-line mutation rate has been regarded classically as a fundamental biological parameter, as it affects the prevalence of genetic disorders and the rate of evolution. Somatic mutation rate is also an important biological parameter, as it may influence the development and/or the course of acquired diseases, particularly of cancer. Estimates of this parameter have been previously obtained in few instances from dermal fibroblasts and lymphoblastoid cells. However, the methodology required has been laborious and did not lend itself to the analysis of large numbers of samples. We have previously shown that the X-linked gene PIG-A, since its product is required for glycosyl-phosphatidylinositol-anchored proteins to become surface bound, is a good sentinel gene for studying somatic mutations. We now show that by this approach we can accurately measure the proportion of PIG-A mutant peripheral blood granulocytes, which we call mutant frequency, ƒ. We found that the results are reproducible, with a variation coefficient (CV) of 45%. Repeat samples from 32 subjects also had a CV of 44%, indicating that ƒ is a relatively stable individual characteristic. From a study of 142 normal subjects we found that log ƒ is a normally distributed variable; ƒ variability spans a 80-fold range, from less than 1×10−6 to 37.5×10−6, with a median of 4.9×10−6. Unlike other techniques commonly employed in population studies, such as comet assay, this method can detect any kind of mutation, including point mutation, as long as it causes functional inactivation of PIG-A gene. Since the test is rapid and requires only a small sample of peripheral blood, this methodology will lend itself to investigating genetic factors that underlie the variation in the somatic mutation rate, as well as environmental factors that may affect it. It will be also possible to test whether ƒ is a determinant of the risk of cancer. PMID:23342069

  20. Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle.

    Science.gov (United States)

    Juan-Mateu, J; Paradas, C; Olivé, M; Verdura, E; Rivas, E; González-Quereda, L; Rodríguez, M J; Baiget, M; Gallano, P

    2012-12-01

    X-linked dilated cardiomyopathy is a pure cardiac dystrophinopathy phenotype mainly caused by DMD mutations that present a specific transcription effect in cardiac tissue. We report a 26-year-old male who presented with severe dilated cardiomyopathy and high creatine kinase. The patient did not complain of skeletal muscle weakness. A muscle biopsy showed mild dystrophic changes and a low proportion of dystrophin-negative fibres. A molecular study identified a nonsense DMD mutation (p.Arg2098X) in somatic mosaicism. The ratio of mutant versus normal allele in blood and skeletal muscle suggests selective pressure against mutant muscle cells, a process known as genetic normalization. We hypothesize that this process may have mitigated skeletal muscle symptoms in this patient. This is the second report of a DMD somatic mosaic with evidence of genetic normalization in muscle. Somatic DMD mutations should be considered in patients presenting with idiopathic dilated cardiomyopathy. © 2011 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

  1. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands.

    Science.gov (United States)

    Nishimoto, Koshiro; Tomlins, Scott A; Kuick, Rork; Cani, Andi K; Giordano, Thomas J; Hovelson, Daniel H; Liu, Chia-Jen; Sanjanwala, Aalok R; Edwards, Michael A; Gomez-Sanchez, Celso E; Nanba, Kazutaka; Rainey, William E

    2015-08-18

    Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression. Herein, we hypothesized that APCCs have APA-related aldosterone-stimulating somatic gene mutations. APCCs were studied in 42 normal adrenals from kidney donors. To clarify APCC molecular characteristics, we used microarrays to compare the APCC transcriptome with conventional adrenocortical zones [zona glomerulosa (ZG), zona fasciculata, and zona reticularis]. The APCC transcriptome was most similar to ZG but with an enhanced capacity to produce aldosterone. To determine if APCCs harbored APA-related mutations, we performed targeted next generation sequencing of DNA from 23 APCCs and adjacent normal adrenal tissue isolated from both formalin-fixed, paraffin-embedded, and frozen tissues. Known aldosterone driver mutations were identified in 8 of 23 (35%) APCCs, including mutations in calcium channel, voltage-dependent, L-type, α1D-subunit (CACNA1D; 6 of 23 APCCs) and ATPase, Na(+)/(K+) transporting, α1-polypeptide (ATP1A1; 2 of 23 APCCs), which were not observed in the adjacent normal adrenal tissue. Overall, we show three major findings: (i) APCCs are common in normal adrenals, (ii) APCCs harbor somatic mutations known to cause excess aldosterone production, and (iii) the mutation spectrum of aldosterone-driving mutations is different in APCCs from that seen in APA. These results provide molecular support for APCC as a precursor of PA.

  2. A comparison of somatic mutational spectra in healthy study populations from Russia, Sweden and USA

    Energy Technology Data Exchange (ETDEWEB)

    Noori, P; Hou, S; Jones, I M; Thomas, C B; Lambert, B

    2004-10-27

    Comparison of mutation spectra at the hypoxanthine-phosphoribosyl transferase (HPRT) gene of peripheral blood T lymphocytes may provide insight into the aetiology of somatic mutation contributing to carcinogenesis and other diseases. To increase knowledge of mutation spectra in healthy people, we have analyzed HPRT mutant T-cells of 50 healthy Russians originally recruited as controls for a study of Chernobyl clean-up workers (Jones et al. Radiation Res. 158, 2002, 424). Reverse transcriptase polymerase chain reactions and DNA sequencing identified 161 independent mutations among 176 thioguanine resistant mutants. Forty (40) mutations affected splicing mechanisms and 27 deletions or insertions of 1 to 60 nucleotides were identified. Ninety four (94) single base substitutions were identified, including 62 different mutations at 55 different nucleotide positions, of which 19 had not previously been reported in human T-cells. Comparison of this base substitution spectrum with mutation spectra in a USA (Burkhart-Schultz et al. Carcinogenesis 17, 1996, 1871) and two Swedish populations (Podlutsky et al, Carcinogenesis 19, 1998, 557, Podlutsky et al. Mutation Res. 431, 1999, 325) revealed similarity in the type, frequency and distribution of mutations in the four spectra, consistent with aetiologies inherent in human metabolism. There were 15-19 identical mutations in the three pair-wise comparisons of Russian with USA and Swedish spectra. Intriguingly, there were 21 mutations unique to the Russian spectrum, and comparison by the Monte Carlo method of Adams and Skopek (J. Mol. Biol. 194, 1987, 391) indicated that the Russian spectrum was different from both Swedish spectra (P=0.007, 0.002) but not different from the USA spectrum (P=0.07), when Bonferroni correction for multiple comparisons was made (p < 0.008 required for significance). Age and smoking did not account for these differences. Other factors causing mutational differences need to be explored.

  3. Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis.

    Science.gov (United States)

    Erson-Omay, E Zeynep; Çağlayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S Bülent; Özduman, Koray; Köksal, Yavuz; Li, Jie; Serin Harmancı, Akdes; Clark, Victoria; Carrión-Grant, Geneive; Baranoski, Jacob; Çağlar, Caner; Barak, Tanyeri; Coşkun, Süleyman; Baran, Burçin; Köse, Doğan; Sun, Jia; Bakırcıoğlu, Mehmet; Moliterno Günel, Jennifer; Pamir, M Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J; Sander, Chris; Günel, Murat

    2015-10-01

    Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these "ultramutated" tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Targeted disruption of Ataxia-telangiectasia mutated gene in miniature pigs by somatic cell nuclear transfer

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young June; Ahn, Kwang Sung; Kim, Minjeong; Kim, Min Ju; Park, Sang-Min; Ryu, Junghyun; Ahn, Jin Seop; Heo, Soon Young; Kang, Jee Hyun; Choi, You Jung [Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan (Korea, Republic of); Choi, Seong-Jun [Institute of Tissue Regeneration Engineering, Dankook University, Cheonan (Korea, Republic of); Shim, Hosup, E-mail: shim@dku.edu [Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan (Korea, Republic of); Institute of Tissue Regeneration Engineering, Dankook University, Cheonan (Korea, Republic of); Department of Physiology, Dankook University School of Medicine, Cheonan (Korea, Republic of)

    2014-10-03

    Highlights: • ATM gene-targeted pigs were produced by somatic cell nuclear transfer. • A novel large animal model for ataxia telangiectasia was developed. • The new model may provide an alternative to the mouse model. - Abstract: Ataxia telangiectasia (A-T) is a recessive autosomal disorder associated with pleiotropic phenotypes, including progressive cerebellar degeneration, gonad atrophy, and growth retardation. Even though A-T is known to be caused by the mutations in the Ataxia telangiectasia mutated (ATM) gene, the correlation between abnormal cellular physiology caused by ATM mutations and the multiple symptoms of A-T disease has not been clearly determined. None of the existing ATM mouse models properly reflects the extent to which neurological degeneration occurs in human. In an attempt to provide a large animal model for A-T, we produced gene-targeted pigs with mutations in the ATM gene by somatic cell nuclear transfer. The disrupted allele in the ATM gene of cloned piglets was confirmed via PCR and Southern blot analysis. The ATM gene-targeted pigs generated in the present study may provide an alternative to the current mouse model for the study of mechanisms underlying A-T disorder and for the development of new therapies.

  5. Sensitive and specific KRAS somatic mutation analysis on whole-genome amplified DNA from archival tissues.

    Science.gov (United States)

    van Eijk, Ronald; van Puijenbroek, Marjo; Chhatta, Amiet R; Gupta, Nisha; Vossen, Rolf H A M; Lips, Esther H; Cleton-Jansen, Anne-Marie; Morreau, Hans; van Wezel, Tom

    2010-01-01

    Kirsten RAS (KRAS) is a small GTPase that plays a key role in Ras/mitogen-activated protein kinase signaling; somatic mutations in KRAS are frequently found in many cancers. The most common KRAS mutations result in a constitutively active protein. Accurate detection of KRAS mutations is pivotal to the molecular diagnosis of cancer and may guide proper treatment selection. Here, we describe a two-step KRAS mutation screening protocol that combines whole-genome amplification (WGA), high-resolution melting analysis (HRM) as a prescreen method for mutation carrying samples, and direct Sanger sequencing of DNA from formalin-fixed, paraffin-embedded (FFPE) tissue, from which limited amounts of DNA are available. We developed target-specific primers, thereby avoiding amplification of homologous KRAS sequences. The addition of herring sperm DNA facilitated WGA in DNA samples isolated from as few as 100 cells. KRAS mutation screening using high-resolution melting analysis on wgaDNA from formalin-fixed, paraffin-embedded tissue is highly sensitive and specific; additionally, this method is feasible for screening of clinical specimens, as illustrated by our analysis of pancreatic cancers. Furthermore, PCR on wgaDNA does not introduce genotypic changes, as opposed to unamplified genomic DNA. This method can, after validation, be applied to virtually any potentially mutated region in the genome.

  6. Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders.

    Directory of Open Access Journals (Sweden)

    Dolores González-Morón

    Full Text Available Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations.

  7. Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.

    Science.gov (United States)

    Núñez, Lucía; Gimeno-Blanes, Juan Ramón; Rodríguez-García, María Isabel; Monserrat, Lorenzo; Zorio, Esther; Coats, Caroline; McGregor, Christopher G; Hernandez del Rincón, Juan Pedro; Castro-Beiras, Alfonso; Hermida-Prieto, Manuel

    2013-01-01

    Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.

  8. Germline MC1R status influences somatic mutation burden in melanoma

    Science.gov (United States)

    Robles-Espinoza, Carla Daniela; Roberts, Nicola D.; Chen, Shuyang; Leacy, Finbarr P.; Alexandrov, Ludmil B.; Pornputtapong, Natapol; Halaban, Ruth; Krauthammer, Michael; Cui, Rutao; Timothy Bishop, D.; Adams, David J.

    2016-01-01

    The major genetic determinants of cutaneous melanoma risk in the general population are disruptive variants (R alleles) in the melanocortin 1 receptor (MC1R) gene. These alleles are also linked to red hair, freckling, and sun sensitivity, all of which are known melanoma phenotypic risk factors. Here we report that in melanomas and for somatic C>T mutations, a signature linked to sun exposure, the expected single-nucleotide variant count associated with the presence of an R allele is estimated to be 42% (95% CI, 15–76%) higher than that among persons without an R allele. This figure is comparable to the expected mutational burden associated with an additional 21 years of age. We also find significant and similar enrichment of non-C>T mutation classes supporting a role for additional mutagenic processes in melanoma development in individuals carrying R alleles. PMID:27403562

  9. The genotoxicity of nitrilotriacetic acid (NTA) in a somatic mutation and recombination test in Drosophila melanogaster.

    Science.gov (United States)

    Zordan, M; Graf, U; Singer, D; Beltrame, C; Dalla Valle, L; Osti, M; Costa, R; Levis, A G

    1991-04-01

    The genotoxicity of a chelating agent, the trisodium salt of nitrilotriacetic acid (NTA), was assessed in a somatic mutation and recombination test (SMART) in Drosophila melanogaster employing the wing hair markers mwh and flr3. The experiments were performed in parallel in two different laboratories (Padua, Italy and Schwerzenbach, Switzerland). The effectively absorbed doses of NTA, which was administered by feeding to larvae, were determined by a sensitive method employing [3H]leucine which allowed individual consumption levels to be measured. The particular pattern of clone induction produced by this compound suggests that NTA is active in inducing mitotic recombination and possibly aneuploidy in somatic cells of Drosophila. This is discussed in relation to the data present in the literature regarding the genotoxicity of NTA in a variety of experimental systems.

  10. Somatic mutations associated with MRI-derived volumetric features in glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Gutman, David A.; Dunn, William D. [Emory University School of Medicine, Departments of Neurology, Atlanta, GA (United States); Emory University School of Medicine, Biomedical Informatics, Atlanta, GA (United States); Grossmann, Patrick; Alexander, Brian M. [Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, MA (United States); Cooper, Lee A.D. [Emory University School of Medicine, Biomedical Informatics, Atlanta, GA (United States); Georgia Institute of Technology, Department of Biomedical Engineering, Atlanta, GA (United States); Holder, Chad A. [Emory University School of Medicine, Radiology and Imaging Sciences, Atlanta, GA (United States); Ligon, Keith L. [Brigham and Women' s Hospital, Harvard Medical School, Pathology, Dana-Farber Cancer Institute, Boston, MA (United States); Aerts, Hugo J.W.L. [Harvard Medical School, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women' s Hospital, Boston, MA (United States); Brigham and Women' s Hospital, Harvard Medical School, Radiology, Dana-Farber Cancer Institute, Boston, MA (United States)

    2015-12-15

    MR imaging can noninvasively visualize tumor phenotype characteristics at the macroscopic level. Here, we investigated whether somatic mutations are associated with and can be predicted by MRI-derived tumor imaging features of glioblastoma (GBM). Seventy-six GBM patients were identified from The Cancer Imaging Archive for whom preoperative T1-contrast (T1C) and T2-FLAIR MR images were available. For each tumor, a set of volumetric imaging features and their ratios were measured, including necrosis, contrast enhancing, and edema volumes. Imaging genomics analysis assessed the association of these features with mutation status of nine genes frequently altered in adult GBM. Finally, area under the curve (AUC) analysis was conducted to evaluate the predictive performance of imaging features for mutational status. Our results demonstrate that MR imaging features are strongly associated with mutation status. For example, TP53-mutated tumors had significantly smaller contrast enhancing and necrosis volumes (p = 0.012 and 0.017, respectively) and RB1-mutated tumors had significantly smaller edema volumes (p = 0.015) compared to wild-type tumors. MRI volumetric features were also found to significantly predict mutational status. For example, AUC analysis results indicated that TP53, RB1, NF1, EGFR, and PDGFRA mutations could each be significantly predicted by at least one imaging feature. MRI-derived volumetric features are significantly associated with and predictive of several cancer-relevant, drug-targetable DNA mutations in glioblastoma. These results may shed insight into unique growth characteristics of individual tumors at the macroscopic level resulting from molecular events as well as increase the use of noninvasive imaging in personalized medicine. (orig.)

  11. The Impact of Environmental and Endogenous Damage on Somatic Mutation Load in Human Skin Fibroblasts.

    Directory of Open Access Journals (Sweden)

    Natalie Saini

    2016-10-01

    Full Text Available Accumulation of somatic changes, due to environmental and endogenous lesions, in the human genome is associated with aging and cancer. Understanding the impacts of these processes on mutagenesis is fundamental to understanding the etiology, and improving the prognosis and prevention of cancers and other genetic diseases. Previous methods relying on either the generation of induced pluripotent stem cells, or sequencing of single-cell genomes were inherently error-prone and did not allow independent validation of the mutations. In the current study we eliminated these potential sources of error by high coverage genome sequencing of single-cell derived clonal fibroblast lineages, obtained after minimal propagation in culture, prepared from skin biopsies of two healthy adult humans. We report here accurate measurement of genome-wide magnitude and spectra of mutations accrued in skin fibroblasts of healthy adult humans. We found that every cell contains at least one chromosomal rearrangement and 600–13,000 base substitutions. The spectra and correlation of base substitutions with epigenomic features resemble many cancers. Moreover, because biopsies were taken from body parts differing by sun exposure, we can delineate the precise contributions of environmental and endogenous factors to the accrual of genetic changes within the same individual. We show here that UV-induced and endogenous DNA damage can have a comparable impact on the somatic mutation loads in skin fibroblasts. Trial Registration: ClinicalTrials.gov NCT01087307.

  12. Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis.

    Science.gov (United States)

    Bastian, Claire; Muller, Jean-Baptiste; Lortat-Jacob, Stephen; Nihoul-Fékété, Claire; Bignon-Topalovic, Joelle; McElreavey, Ken; Bashamboo, Anu; Brauner, Raja

    2015-05-01

    To assess genetic mutations and associated somatic anomalies in a series of patients with 46,XY gonadal dysgenesis (GD). Single center retrospective study. University pediatric hospital. Fourteen patients with 46,XY GD. None. Genotype-phenotype relationship. The presenting symptom was disorders of sex development (6 patients), primary amenorrhea (2 patients), discordance between 46,XY karyotype and female external genitalia (3 patients), discovery of Müllerian structures at surgery (2 patients), or diagnosed in the evaluation of a gonadal tumor (1 patient). Müllerian structures were shown by ultrasound evaluation in 7 of 13 patients, genitography in 3 of 6 patients and/or surgery in 8 of 10 patients (3 not seen at imaging), or only by histologic examination (1 patient). Three patients had gonadoblastoma and/or seminoma. A mutation was found in 7 patients of whom 2 had family history of reproductive problems and 5 had associated somatic anomalies. The mutations were FOG2/ZFPM2 (1 patient), SRY (2 patients), WT1 (1 patient), or deletions of distal chromosome 9p (3 patients). Among the three other patients with associated anomalies and no mutation, two had ectodermal dysplasia and one had leukemia. Mutations were observed in half of the patients with 46,XY GD with Müllerian structures. We also describe for the first time the association between GD and ectodermal dysplasia. Müllerian structures can be found in some cases only by histologic examination, which should be coupled to preventive gonadectomy because of the risk of tumor formation. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  13. Somatic mutation analysis of the SDHB, SDHC, SDHD, and RET genes in the clinical assessment of sporadic and hereditary pheochromocytoma.

    Science.gov (United States)

    Weber, Alexander; Hoffmann, Michael M; Neumann, Hartmut P H; Erlic, Zoran

    2012-08-01

    Systemic analysis of somatic mutations of other susceptibility genes in syndromic tumors as well as apparently sporadic tumors in well-characterized specimens is lacking. Its clinical relevance has not been studied. Our objective was to determine the frequency of second allele inactivation in syndromic tumors and determine the frequency and potential clinical impact of somatic mutations and loss of heterozygosity (LOH) of the known susceptibility genes in syndromic and sporadic tumors. Nine tumor specimens from clinically characterized VHL mutation, five from SDHB mutation, four from SDHD mutation, two from RET mutation carriers, and eight from apparently sporadic cases were analyzed. Tumor DNA mutation screening of the SDHx, VHL, and RET genes and LOH analyses of the SDHx and VHL genes were performed. The Yates-corrected chi-squared test was used for comparison of the clinical data and the molecular-genetic results. Second allele inactivation in tumors was identified in 83% of VHL, 80% of SDHB, and 50% of SDHD specimen. High prevalence of VHL (6/6, p=0.024) and SDHB (7/7, p=0.018) somatic mutations has been identified in the sporadic group compared to all others. In the group of the VHL tumors the SDHB somatic events were significantly lower (2/6; p=0.045). In 18/19 (95%) of cases, we were able to demonstrate the presence of at least two concomitant affected susceptibility genes. We conclude that LOH is the most prevalent second allele-inactivating event. SDHB and VHL somatic mutation might play a role in the sporadic forms of tumor development. There is no clinical impact of mutation screening or LOH analysis of tumor specimens.

  14. Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background.

    Science.gov (United States)

    Elvers, Ingegerd; Turner-Maier, Jason; Swofford, Ross; Koltookian, Michele; Johnson, Jeremy; Stewart, Chip; Zhang, Cheng-Zhong; Schumacher, Steven E; Beroukhim, Rameen; Rosenberg, Mara; Thomas, Rachael; Mauceli, Evan; Getz, Gad; Palma, Federica Di; Modiano, Jaime F; Breen, Matthew; Lindblad-Toh, Kerstin; Alföldi, Jessica

    2015-11-01

    Lymphoma is the most common hematological malignancy in developed countries. Outcome is strongly determined by molecular subtype, reflecting a need for new and improved treatment options. Dogs spontaneously develop lymphoma, and the predisposition of certain breeds indicates genetic risk factors. Using the dog breed structure, we selected three lymphoma predisposed breeds developing primarily T-cell (boxer), primarily B-cell (cocker spaniel), and with equal distribution of B- and T-cell lymphoma (golden retriever), respectively. We investigated the somatic mutations in B- and T-cell lymphomas from these breeds by exome sequencing of tumor and normal pairs. Strong similarities were evident between B-cell lymphomas from golden retrievers and cocker spaniels, with recurrent mutations in TRAF3-MAP3K14 (28% of all cases), FBXW7 (25%), and POT1 (17%). The FBXW7 mutations recurrently occur in a specific codon; the corresponding codon is recurrently mutated in human cancer. In contrast, T-cell lymphomas from the predisposed breeds, boxers and golden retrievers, show little overlap in their mutation pattern, sharing only one of their 15 most recurrently mutated genes. Boxers, which develop aggressive T-cell lymphomas, are typically mutated in the PTEN-mTOR pathway. T-cell lymphomas in golden retrievers are often less aggressive, and their tumors typically showed mutations in genes involved in cellular metabolism. We identify genes with known involvement in human lymphoma and leukemia, genes implicated in other human cancers, as well as novel genes that could allow new therapeutic options. © 2015 Elvers et al. Published by Cold Spring Harbor Laboratory Press.

  15. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations.

    Directory of Open Access Journals (Sweden)

    Laura C Greaves

    Full Text Available Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population.

  16. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations.

    Science.gov (United States)

    Greaves, Laura C; Elson, Joanna L; Nooteboom, Marco; Grady, John P; Taylor, Geoffrey A; Taylor, Robert W; Mathers, John C; Kirkwood, Thomas B L; Turnbull, Doug M

    2012-01-01

    Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown whether there are selective constraints, which have been shown to occur in the germline, on the occurrence and expansion of these mtDNA mutations within individual somatic cells. Here we compared the pattern and spectrum of mutations observed in ageing human colon to those observed in the general population (germline variants) and those associated with primary mtDNA disease. The pathogenicity of the protein encoding mutations was predicted using a computational programme, MutPred, and the scores obtained for the three groups compared. We show that the mutations associated with ageing are randomly distributed throughout the genome, are more frequently non-synonymous or frameshift mutations than the general population, and are significantly more pathogenic than population variants. Mutations associated with primary mtDNA disease were significantly more pathogenic than ageing or population mutations. These data provide little evidence for any selective constraints on the occurrence and expansion of mtDNA mutations in somatic cells of the human colon during human ageing in contrast to germline mutations seen in the general population.

  17. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.

    Science.gov (United States)

    Janoueix-Lerosey, Isabelle; Lequin, Delphine; Brugières, Laurence; Ribeiro, Agnès; de Pontual, Loïc; Combaret, Valérie; Raynal, Virginie; Puisieux, Alain; Schleiermacher, Gudrun; Pierron, Gaëlle; Valteau-Couanet, Dominique; Frebourg, Thierry; Michon, Jean; Lyonnet, Stanislas; Amiel, Jeanne; Delattre, Olivier

    2008-10-16

    Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.

  18. Somatic mutation in the HLA-B gene of a patient with acute myelogenous leukaemia.

    Science.gov (United States)

    Planelles, D; Balas, A; Gil, C; Muñoz, C; Rodríguez-Cebriá, M; Vicario, J L

    2016-07-01

    In this report we describe a case of somatic mutation in the HLA-B gene in the tumour cells of a patient with acute myelogenous leukaemia (AML). Routine human leukocyte antigen (HLA) typing of patient by serology and molecular methodologies rendered discrepant results regarding the expression of a B*15:01 antigen. Sequencing-based typing of a patient's sample including a very high percentage of blast cells revealed the presence of one nucleotide insertion at exon 3, position 440, codon 123. This insertion resulted in a reading frame shift and a premature stop codon at position 152. The mutation was absent in a sample obtained when the patient was in remission. This case report points out the relevance of the sample source for HLA typing in patients with haematological malignancies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  19. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene.

    Science.gov (United States)

    Tinschert, S; Naumann, I; Stegmann, E; Buske, A; Kaufmann, D; Thiel, G; Jenne, D E

    2000-06-01

    Segmental neurofibromatosis (NF) is generally thought to result from a postzygotic NF1 (neurofibromatosis type 1) gene mutation. However, this has not yet been demonstrated at the molecular level. Using fluorescence in situ hybridisation (FISH) we identified an NF1 microdeletion in a patient with segmental NF in whom café-au-lait spots and freckles are limited to a single body region. The mutant allele was present in a mosaic pattern in cultured fibroblasts from a café-au-lait spot lesion, but was absent in fibroblasts from normal skin as well as in peripheral blood leukocytes. These findings prove the hypothesis that the molecular basis of segmental cutaneous NF is a mutation in the NF1 gene and that the regional distribution of manifestations reflects different cell clones, commensurate with the concept of somatic mosaicism.

  20. Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge-Weber Syndrome.

    Science.gov (United States)

    Huang, Lan; Couto, Javier A; Pinto, Anna; Alexandrescu, Sanda; Madsen, Joseph R; Greene, Arin K; Sahin, Mustafa; Bischoff, Joyce

    2017-02-01

    Sturge-Weber syndrome (SWS) is a rare congenital neurocutaneous disorder characterized by facial and extracraniofacial capillary malformations and capillary-venule malformations in the leptomeninges. A somatic mosaic mutation in GNAQ (c.548G>A; p.R183Q) was found in SWS brain and skin capillary malformations. Our laboratory showed endothelial cells in skin capillary malformations are enriched for the GNAQ mutation. The purpose of this study is to determine whether the GNAQ mutation is also enriched in endothelial cells in affected SWS brain. Two human SWS brain specimens were fractionated by fluorescence-activated cell sorting into hematopoietic (CD45), endothelial (CD31, VE-Cadherin, and vascular endothelial growth factor receptor 2), and perivascular (platelet-derived growth factor receptor beta) cells and cells negative for all markers. The sorted cell populations were analyzed for GNAQ p.R183Q mutation by droplet digital polymerase chain reaction. SWS patient-derived brain endothelial cells were selected by anti-CD31-coated magnetic beads and cultured in endothelial growth medium in vitro. The GNAQ p.R183Q mutation was present in brain endothelial cells in two SWS specimens, with mutant allelic frequencies of 34.7% and 24.0%. Cells negative for all markers also harbored the GNAQ mutation. The mutant allelic frequencies in these unidentified cells were 9.2% and 8.4%. SWS patient-derived brain endothelial cells with mutant allelic frequencies of 14.7% and 21% survived and proliferated in vitro. Our study provides evidence that GNAQ p.R183Q mutation is enriched in endothelial cells in SWS brain lesions and thereby reveals endothelial cells as a source of aberrant Gαq signaling. This will help to understand the pathophysiology of SWS, to discover biomarkers for predicting cerebral involvement, and to develop therapeutic targets to prevent neurological impairments in SWS. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Temperature-dependent sex-reversal by a transformer-2 gene-edited mutation in the spotted wing drosophila, Drosophila suzukii

    Science.gov (United States)

    Female to male sex reversal was achieved in an emerging agricultural insect pest, Drosophila suzukii, by creating a temperature-sensitive point mutation in the sex-determination gene, transformer-2 (tra-2) using CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/ CRISPR-associated) hom...

  2. Somatic mosaicism in families with hemophilia B: 11% of germline mutations originate within a few cell divisions post-fertilization

    Energy Technology Data Exchange (ETDEWEB)

    Knoell, A.; Ketterling, R.P.; Vielhaber, E. [Mayo Clinic/Foundation, Rochester, MN (United States)] [and others

    1994-09-01

    Previous molecular estimates of mosaicism in the dystrophin and other genes generally have focused on the transmission of the mutated allele to two or more children by an individual without the mutation in leukocyte DNA. We have analyzed 414 families with hemophilia B by direct genomic sequencing and haplotype analysis, and have deduced the origin of mutation in 56 families. There was no origin individual who transmitted a mutant allele to more than one child. However, somatic mosaicism was detected by sequence analysis of four origin individuals (3{female} and 1{male}). The sensitivity of this analysis is typically one part in ten. In one additional female who had close to a 50:50 ratio of mutant to normal alleles, three of four noncarrier daughters inherited the haplotype associated with the mutant allele. This highlights a caveat in molecular analysis: a presumptive carrier in a family with sporadic disease does not necessarily have a 50% probability of transmitting the mutant allele to her offspring. After eliminating those families in which mosaicism could not be detected because of a total gene deletion or absence of DNA from a deduced origin individual, 5 of 43 origin individuals exhibited somatic mosaicism at a level that reflects a mutation within the first few cell divisions after fertilization. In one patient, analysis of cervical scrapings and buccal mucosa confirm the generalized distribution of somatic mutation. Are the first few cell divisions post-fertilization highly mutagenic, or do mutations at later divisions also give rise to somatic mosaicism? To address this question, DNA from origin individuals are being analyzed to detect somatic mosaicism at a sensitivity of 1:1000. Single nucleotide primer extension (SNuPE) has been utilized in eight families to date and no mosaicism has been detected. When the remaining 30 samples are analyzed, it will be possible to compare the frequency of somatic mosaicism at 0.1-10% with that of {ge}10%.

  3. SomamiR 2.0: a database of cancer somatic mutations altering microRNA-ceRNA interactions.

    Science.gov (United States)

    Bhattacharya, Anindya; Cui, Yan

    2016-01-04

    SomamiR 2.0 (http://compbio.uthsc.edu/SomamiR) is a database of cancer somatic mutations in microRNAs (miRNA) and their target sites that potentially alter the interactions between miRNAs and competing endogenous RNAs (ceRNA) including mRNAs, circular RNAs (circRNA) and long noncoding RNAs (lncRNA). Here, we describe the recent major updates to the SomamiR database. We expanded the scope of the database by including somatic mutations that impact the interactions between miRNAs and two classes of non-coding RNAs, circRNAs and lncRNAs. Recently, a large number of miRNA target sites have been discovered by newly emerged high-throughput technologies for mapping the miRNA interactome. We have mapped 388 247 somatic mutations to the experimentally identified miRNA target sites. The updated database also includes a list of somatic mutations in the miRNA seed regions, which contain the most important guiding information for miRNA target recognition. A recently developed webserver, miR2GO, was integrated with the database to provide a seamless pipeline for assessing functional impacts of somatic mutations in miRNA seed regions. Data and functions from multiple sources including biological pathways and genome-wide association studies were updated and integrated with SomamiR 2.0 to make it a better platform for functional analysis of somatic mutations altering miRNA-ceRNA interactions. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. [Point somatic mutations in bladder cancer: key carcinogenesis events, diagnostic markers and therapeutic targets].

    Science.gov (United States)

    Mikhailenko, D S; Nemtsova, M V

    2016-02-01

    Development of bladder cancer (BC) involves accumulating several genetic alterations in somatic cells: point mutations, extended deletions in the localization of tumor suppressor genes, amplification of oncogenes, aberrant DNA methylation, changes in the expression pattern of regulatory RNAs and numerous structural genes. From all of the above, point mutations have the greatest potential as diagnostic markers, as they frequently occur in carcinogenesis, characterize initiation and further clonal evolution of malignancy and represent a change in DNA detectable by routine molecular genetic methods. If we look at the clinical classification of bladder cancer, 90% of the BC presented by urothelial carcinoma, 80% of patients had superficial and 20% - of muscle-invasive tumors. The differences in morphological classification, staging and prognosis of bladder cancer represent different pathogenic pathways of tumor development. Superficial bladder cancer develops through a stage of hyperplasia involving activation of mutations in the genes FGFR3, PIK3CA, HRAS, ERBB2, TERT and others. It is shown that frequent point mutations FGFR3, PIK3CA and TERT are present in the tumor cells in the urine sediment and can be considered as markers for non-invasive molecular genetic diagnosis of primary BC and for monitoring of disease recurrence. Muscle-invasive bladder cancer develops through the stages of dysplasia and carcinoma in situ, in which mutations initially occur in key suppressor genes (TP53 and RB1) and a number of chromatin remodeling genes. This leads to genomic instability and multiple chromosome aberrations that are subjected to selection in the further clonal evolution of tumors towards predominance of more malignant subclones. This review presents systematized information about the main mutations in BC carcinogenesis, their role in the primary tumor progression, metastasizing and role as a target for diagnosis and targeted therapy.

  5. Somatic mutations in stilbene estrogen-induced Syrian hamster kidney tumors identified by DNA fingerprinting

    Directory of Open Access Journals (Sweden)

    Roy Deodutta

    2004-01-01

    Full Text Available Abstract Kidney tumors from stilbene estrogen (diethylstilbestrol-treated Syrian hamsters were screened for somatic genetic alterations by Random Amplified Polymorphic DNA-polymerase chain-reaction (RAPD-PCR fingerprinting. Fingerprints from tumor tissue were generated by single arbitrary primers and compared with fingerprints for normal tissue from the same animal, as well as normal and tumor tissues from different animals. Sixty one of the arbitrary primers amplified 365 loci that contain approximately 476 kbp of the hamster genome. Among these amplified DNA fragments, 44 loci exhibited either qualitative or quantitative differences between the tumor tissues and normal kidney tissues. RAPD-PCR loci showing decreased and increased intensities in tumor tissue DNA relative to control DNA indicate that loci have undergone allelic losses and gains, respectively, in the stilbene estrogen-induced tumor cell genome. The presence or absence of the amplified DNA fragments indicate homozygous insertions or deletions in the kidney tumor DNA compared to the age-matched normal kidney tissue DNA. Seven of 44 mutated loci also were present in the kidney tissues adjacent to tumors (free of macroscopic tumors. The presence of mutated loci in uninvolved (non-tumor surrounding tissue adjacent to tumors from stilbene estrogen-treated hamsters suggests that these mutations occurred in the early stages of carcinogenesis. The cloning and sequencing of RAPD amplified loci revealed that one mutated locus had significant sequence similarity with the hamster Cyp1A1 gene. The results show the ability of RAPD-PCR to detect and isolate, in a single step, DNA sequences representing genetic alterations in stilbene estrogen-induced cancer cells, including losses of heterozygosity, and homozygous deletion and insertion mutations. RAPD-PCR provides an alternative molecular approach for studying cancer cytogenetics in stilbene estrogen-induced tumors in humans and experimental

  6. Somatic Mutations and Genetic Heterogeneity at the CDKN1B Locus in Small Intestinal Neuroendocrine Tumors.

    Science.gov (United States)

    Crona, Joakim; Gustavsson, Tobias; Norlén, Olov; Edfeldt, Katarina; Åkerström, Tobias; Westin, Gunnar; Hellman, Per; Björklund, Peyman; Stålberg, Peter

    2015-12-01

    Until recently, the genetic landscape of small intestinal neuroendocrine tumors (SI-NETs) was limited to recurrent copy number alterations, most commonly a loss on chromosome 18. Intertumor heterogeneity with nonconcordant genotype in paired primary and metastatic lesions also is described, further contributing to the difficulty of unraveling the genetic enigma of SI-NETs. A recent study analyzing 55 SI-NET exomes nominated CDKN1B (p27) as a haploinsufficient tumor suppressor gene. This study aimed to determine the frequency of CDKN1B inactivation and to investigate genotype-phenotype correlations. It investigated 362 tumors from 200 patients. All samples were resequenced for mutations in CDKN1B using automated Sanger sequencing. The expression of p27 was investigated in 12 CDKN1B mutant and nine wild type tumors. Some 8.5 % (17/200) of patients had tumors with pathogenic mutations in CDKN1B including 13 insertion deletions, four nonsense variants, and one stop-loss variant. All variants with available nontumoral DNA were classified as somatic. Inter- and intratumor heterogeneity at the CDKN1B locus was detected respectively in six of ten and two of ten patients. Patients with CDKN1B mutated tumors had both heterogeneous disease presentation and diverse prognosis. Expression of the p27 protein did not correlate with CDKN1B mutation status, and no differences in the clinical characteristics between CDKN1B mutated and CDKN1B wild type tumor carriers were found. This study corroborates the finding of CDKN1B as a potential haplo-insufficient tumor suppressor gene characterized by inter- and intratumor heterogeneity in SI-NETs.

  7. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.

    Science.gov (United States)

    Jiang, Lu; Gu, Zhao-Hui; Yan, Zi-Xun; Zhao, Xia; Xie, Yin-Yin; Zhang, Zi-Guan; Pan, Chun-Ming; Hu, Yuan; Cai, Chang-Ping; Dong, Ying; Huang, Jin-Yan; Wang, Li; Shen, Yang; Meng, Guoyu; Zhou, Jian-Feng; Hu, Jian-Da; Wang, Jin-Fen; Liu, Yuan-Hua; Yang, Lin-Hua; Zhang, Feng; Wang, Jian-Min; Wang, Zhao; Peng, Zhi-Gang; Chen, Fang-Yuan; Sun, Zi-Min; Ding, Hao; Shi, Ju-Mei; Hou, Jian; Yan, Jin-Song; Shi, Jing-Yi; Xu, Lan; Li, Yang; Lu, Jing; Zheng, Zhong; Xue, Wen; Zhao, Wei-Li; Chen, Zhu; Chen, Sai-Juan

    2015-09-01

    Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.

  8. Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype

    Directory of Open Access Journals (Sweden)

    Li Yi

    2004-06-01

    of those cells in MMTV-Wnt1 and MMTV-Neu transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype.

  9. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts

    Science.gov (United States)

    Li, S; Li, L; Zhu, Y; Huang, C; Qin, Y; Liu, H; Ren-Heidenreich, L; Shi, B; Ren, H; Chu, X; Kang, J; Wang, W; Xu, J; Tang, K; Yang, H; Zheng, Y; He, J; Yu, G; Liang, N

    2014-01-01

    Background: Determining the somatic mutations of epidermal growth factor receptor (EGFR)-pathway networks is the key to effective treatment for non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs).The somatic mutation frequencies and their association with gender, smoking history and histology was analysed and reported in this study. Methods: Five thousand one hundred and twenty-five NSCLC patients' pathology samples were collected, and EGFR, KRAS, BRAF and PIK3CA mutations were detected by multiplex testing. The mutation status of EGFR, KRAS, BRAF and PIK3CA and their association with gender, age, smoking history and histological type were evaluated by appropriate statistical analysis. Results: EGFR, KRAS, BRAF and PIK3CA mutation rates revealed 36.2%, 8.4%, 0.5% and 3.3%, respectively, across the 5125 pathology samples. For the first time, evidence of KRAS mutations were detected in two female, non-smoking patients, age 5 and 14, with NSCLC. Furthermore, we identified 153 double and coexisting mutations and 7 triple mutations. Interestingly, the second drug-resistant mutations, T790M or E545K, were found in 44 samples from patients who had never received TKI treatments. Conclusions: EGFR exons 19, 20 and 21, and BRAF mutations tend to happen in females and non-smokers, whereas KRAS mutations were more inclined to males and smokers. Activating and resistant mutations to EGFR-TKI drugs can coexist and ‘second drug-resistant mutations', T790M or E545K, may be primary mutations in some patients. These results will help oncologists to decide candidates for mutation testing and EGFR-TKI treatment. PMID:24743704

  10. New alleles at microsatellite loci in CEPH families mainly arise from somatic mutations in the lymphoblastoid cell lines.

    Science.gov (United States)

    Banchs, I; Bosch, A; Guimerà, J; Lázaro, C; Puig, A; Estivill, X

    1994-01-01

    In the analysis of 40 CEPH families, under the EUROGEM project, with a total of 29 microsatellites (26 CA-repeats, a TCTA-repeat within the vWFII-3 gene, a TTA-repeat within the PLA-2 gene, and an AAAT-repeat intragenic to the NF1 gene) from human chromosomes 12, 17, and 21, we have detected 21 cases of abnormal segregation of alleles in 16 pedigrees for a total of 14 markers (48%). In 11 cases, the abnormal transmissions were of somatic origin, 10 of which (91%) occurred in the lymphoblastoid cell lines. In 9 other cases, it was not possible to determine if the origin of the new alleles was somatic or germline, and in one case hemizygosity in several family members was observed, so its origin was germline. The 20 new mutations detected in the 22,852 meioses analysed represent a mutation frequency of 8.7 x 10(-4) per locus per allele. The germline mutation rate could be as high as 3.9 x 10(-4) per locus per gamete (from 0 to 3.9 x 10(-4)), but the rate of somatic mutations detected in the study was much higher (4.8 x 10(-4) to 8.7 x 10(-4) per locus per allele). Individual mutation rates ranged from 0 to 3.8 x 10(-3). Among the markers analysed, all three that were tri- or tetranucleotide repeats showed one or two new alleles, compared to only 10 of the 26 (38%) CA-repeats showing mutations. Three CEPH families (102, 45 and 1333) each had several mutational events, and one individual (10210) had somatic mutations for two microsatellites from different chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Mutation of the doublecortin gene in male patients with double cortex syndrome: somatic mosaicism detected by hair root analysis.

    Science.gov (United States)

    Kato, M; Kanai, M; Soma, O; Takusa, Y; Kimura, T; Numakura, C; Matsuki, T; Nakamura, S; Hayasaka, K

    2001-10-01

    The molecular basis of double cortex syndrome was investigated in 2 male patients. Magnetic resonance imaging of the patients' heads showed diffuse subcortical band heterotopia, as is seen in female patients. We found a heterozygous mutation for Asp50Lys or Arg39Stop in both patients. Microsatellite polymorphism analysis revealed that both patients had inherited a single X chromosome from their mothers. Restriction enzyme analysis using DNA extracted from the hair roots of each patient showed four different patterns in the combination of cells carrying wild and mutant alleles, which strongly suggest somatic mosaicism. We conclude that somatic mosaic mutations in the doublecortin gene in male patients can cause subcortical band heterotopia, and that molecular analysis using hair roots is a useful method for detecting somatic mosaicism.

  12. Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing.

    Science.gov (United States)

    Zhao, Qianying; Yang, Jiaxin; Li, Lei; Cao, Dongyan; Yu, Mei; Shen, Keng

    2017-07-01

    To define genetic profiling of homologous recombination (HR) deficiency in Chinese ovarian cancer patients. we have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants. Deleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, pgenes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively. our results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.

  13. Comparison of mitochondrial mutation spectra in ageing human colonic epithelium and disease: absence of evidence for purifying selection in somatic mitochondrial DNA point mutations

    NARCIS (Netherlands)

    Greaves, L.C.; Elson, J.L.; Nooteboom, M.; Grady, J.P.; Taylor, G.A.; Taylor, R.W.; Mathers, J.C.; Kirkwood, T.B.; Turnbull, D.M.

    2012-01-01

    Human ageing has been predicted to be caused by the accumulation of molecular damage in cells and tissues. Somatic mitochondrial DNA (mtDNA) mutations have been documented in a number of ageing tissues and have been shown to be associated with cellular mitochondrial dysfunction. It is unknown

  14. Human aging and somatic point mutations in mtDNA: a comparative study of generational differences (grandparents and grandchildren

    Directory of Open Access Journals (Sweden)

    Anderson Nonato do Rosário Marinho

    2011-01-01

    Full Text Available The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years and their 62 grandchildren (mean age: 15 ± 4.1 years, the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old mutations (homoplasia and heteroplasmy. It is possible that both of these situations (homoplasia and heteroplasmy were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.

  15. Human aging and somatic point mutations in mtDNA: A comparative study of generational differences (grandparents and grandchildren).

    Science.gov (United States)

    do Rosário Marinho, Anderson Nonato; de Moraes, Milene Raiol; Santos, Sidney; Ribeiro-Dos-Santos, Andrea

    2011-01-01

    The accumulation of somatic mutations in mtDNA is correlated with aging. In this work, we sought to identify somatic mutations in the HVS-1 region (D-loop) of mtDNA that might be associated with aging. For this, we compared 31 grandmothers (mean age: 63 ± 2.3 years) and their 62 grandchildren (mean age: 15 ± 4.1 years), the offspring of their daughters. Direct DNA sequencing showed that mutations absent in the grandchildren were detected in a presumably homoplasmic state in three grandmothers and in a heteroplasmic state in an additional 13 grandmothers; no mutations were detected in the remaining 15 grandmothers. However, cloning followed by DNA sequencing in 12 grandmothers confirmed homoplasia in only one of the three mutations previously considered to be homoplasmic and did not confirm heteroplasmy in three out of nine grandmothers found to be heteroplasmic by direct sequencing. Thus, of 12 grandmothers in whom mtDNA was analyzed by cloning, eight were heteroplasmic for mutations not detected in their grandchildren. In this study, the use of genetically related subjects allowed us to demonstrate the occurrence of age-related (> 60 years old) mutations (homoplasia and heteroplasmy). It is possible that both of these situations (homoplasia and heteroplasmy) were a long-term consequence of mitochondrial oxidative phosphorylation that can lead to the accumulation of mtDNA mutations throughout life.

  16. Distinct subtype distribution and somatic mutation spectrum of lymphomas in East Asia.

    Science.gov (United States)

    Ren, Weicheng; Li, Wei; Ye, Xiaofei; Liu, Hui; Pan-Hammarström, Qiang

    2017-07-01

    Here, we give an updated overview of the subtype distribution of lymphomas in East Asia and also present the genome sequencing data on two major subtypes of these tumors. The distribution of lymphoma types/subtypes among East Asian countries is very similar, with a lower proportion of B-cell malignancies and a higher proportion of T/natural killer (NK)-cell lymphomas as compared to Western populations. Extranodal NK/T-cell lymphoma is more frequently observed in East Asia, whereas follicular lymphoma and chronic lymphocytic leukemia, are proportionally lower. The incidence rate of lymphoma subtypes in Asians living in the US was generally intermediate to the general rate in US and Asia, suggesting that both genetic and environmental factors may underlie the geographical variations observed.Key cancer driver mutations have been identified in Asian patients with diffuse large B-cell lymphoma or extranodal NK/T-cell lymphoma through genome sequencing. A distinct somatic mutation profile has also been observed in Chinese diffuse large B-cell lymphoma patients. The incidence and distribution of lymphoma subtypes differed significantly between patients from East Asia and Western countries, suggesting subtype-specific etiologic mechanisms. Further studies on the mechanism underlying these geographical variations may give new insights into our understanding of lymphomagenesis.

  17. Somatic PIK3CA mutations in seven patients with PIK3CA-related overgrowth spectrum.

    Science.gov (United States)

    Yeung, Kit San; Ip, Janice Jing Kun; Chow, Chin Pang; Kuong, Evelyn Yue Ling; Tam, Paul Kwong-Hang; Chan, Godfrey Chi-Fung; Chung, Brian Hon-Yin

    2017-04-01

    Somatic mutations in PIK3CA cause many overgrowth syndromes that have been recently coined the "PIK3CA-Related Overgrowth Spectrum." Here, we present seven molecularly confirmed patients with PIK3CA-Related Overgrowth Spectrum, including patients with Congenital Lipomatous Overgrowth, Vascular Malformations, Epidermal Nevi, Scoliosis/Skeletal and Spinal syndrome, Klippel-Trenaunay syndrome, lymphatic malformation and two with atypical phenotypes that cannot be classified into existing disease categories. The literature on PIK3CA-Related Overgrowth Spectrum, suggests that PIK3CA c.1258T>C; p.(Cys420Arg), c.1624G>A; p.(Glu542Lys), c.1633G>A; p.(Glu545Lys), c.3140A>G; p.(His1047Arg), and c.3140A>T; p.(His1047Leu) can be identified in approximately 90% of patients without brain overgrowth. Therefore, droplet digital polymerase chain reaction targeting these mutation hotspots could be used as the first-tier genetic test on patients with PIK3CA-Related Overgrowth Spectrum who do not have signs of overgrowth in their central nervous system. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  18. Glycophorin A somatic cell mutation frequencies in Finnish reinforced plastics workers exposed to styrene.

    Science.gov (United States)

    Bigbee, W L; Grant, S G; Langlois, R G; Jensen, R H; Anttila, A; Pfäffli, P; Pekari, K; Norppa, H

    1996-10-01

    We have used the glycophorin A (GPA) in vivo somatic cell mutation assay to assess the genotoxic potential of styrene exposure in 47 reinforced plastics workers occupationally exposed to styrene and 47 unexposed controls matched for age, gender, and active smoking status. GPA variant erythrocyte frequencies (Vf), reflecting GPA allele loss (phi/N) and allele loss and duplication (N/N) somatic mutations arising in vivo in the erythroid progenitor cells of individuals of GPA M/N heterozygous genotype, were flow cytometrically determined in peripheral blood samples from these subjects. Measurements of styrene exposure of the workers at the time of blood sampling showed a mean 8-h time-weighted average (TWA8-h) styrene concentration of 155 mg/m3 (37 ppm) in the breathing zone. Mean urinary concentrations of the styrene metabolites mandelic acid (MA) and mandelic acid plus phenyl glyoxylic acid (MA+PGA) were 4.4 mmol/liter (after workshift) and 2.1 mmol/liter (next morning), respectively. Multivariate analysis of covariance on log-transformed GPA Vf data with models allowing adjustment for age, gender, smoking status, and styrene exposure showed that N/N Vf were nearly significantly increased among all of the exposed workers (adjusted geometric mean, 6.3 per million versus 5.0 in the controls; P = 0.058) and were statistically significantly elevated (adjusted geometric mean, 6.8 versus 5.0 in the controls; P = 0.036) among workers classified into a high-exposure group according to personal TWA8-h concentration of styrene in the breathing zone of > or = 85 mg/m3 (20 ppm; Finnish threshold limit value). Women in this high exposure group showed especially elevated N/N Vf (adjusted geometric mean 8.5 versus 5.3 in control women; P = 0.020); this elevation was also significant if urinary MA+PGA of > or = 1.2 mmol/liter was used as the basis of classification (adjusted geometric mean, 8.3; P = 0.030). The occupational exposure could not be shown to influence phi/N Vf

  19. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia.

    Science.gov (United States)

    Lim, Young H; Ovejero, Diana; Sugarman, Jeffrey S; Deklotz, Cynthia M C; Maruri, Ann; Eichenfield, Lawrence F; Kelley, Patrick K; Jüppner, Harald; Gottschalk, Michael; Tifft, Cynthia J; Gafni, Rachel I; Boyce, Alison M; Cowen, Edward W; Bhattacharyya, Nisan; Guthrie, Lori C; Gahl, William A; Golas, Gretchen; Loring, Erin C; Overton, John D; Mane, Shrikant M; Lifton, Richard P; Levy, Moise L; Collins, Michael T; Choate, Keith A

    2014-01-15

    Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.

  20. Identification of two poorly prognosed ovarian carcinoma subtypes associated with CHEK2 germ-line mutation and non-CHEK2 somatic mutation gene signatures

    Science.gov (United States)

    Ow, Ghim Siong; Ivshina, Anna V; Fuentes, Gloria; Kuznetsov, Vladimir A

    2014-01-01

    High-grade serous ovarian cancer (HG-SOC), a major histologic type of epithelial ovarian cancer (EOC), is a poorly-characterized, heterogeneous and lethal disease where somatic mutations of TP53 are common and inherited loss-of-function mutations in BRCA1/2 predispose to cancer in 9.5–13% of EOC patients. However, the overall burden of disease due to either inherited or sporadic mutations is not known.     We performed bioinformatics analyses of mutational and clinical data of 334 HG-SOC tumor samples from The Cancer Genome Atlas to identify novel tumor-driving mutations, survival-significant patient subgroups and tumor subtypes potentially driven by either hereditary or sporadic factors. We identified a sub-cluster of high-frequency mutations in 22 patients and 58 genes associated with DNA damage repair, apoptosis and cell cycle. Mutations of CHEK2, observed with the highest intensity, were associated with poor therapy response and overall survival (OS) of these patients (P = 8.00e-05), possibly due to detrimental effect of mutations at the nuclear localization signal. A 21-gene mutational prognostic signature significantly stratifies patients into relatively low or high-risk subgroups with 5-y OS of 37% or 6%, respectively (P = 7.31e-08). Further analysis of these genes and high-risk subgroup revealed 2 distinct classes of tumors characterized by either germline mutations of genes such as CHEK2, RPS6KA2 and MLL4, or somatic mutations of other genes in the signature. Our results could provide improvement in prediction and clinical management of HG-SOC, facilitate our understanding of this complex disease, guide the design of targeted therapeutics and improve screening efforts to identify women at high-risk of hereditary ovarian cancers distinct from those associated with BRCA1/2 mutations. PMID:24879340

  1. Genotyping analysis of 3 RET polymorphisms demonstrates low somatic mutation rate in Chinese Hirschsprung disease patients.

    Science.gov (United States)

    Zhang, Zhen; Jiang, Qian; Li, Qi; Cheng, Wei; Qiao, Guoliang; Xiao, Ping; Gan, Liang; Su, Lin; Miao, Chunyue; Li, Long

    2015-01-01

    Genetic mosaicism has been reported for both coding and non-coding sequences in the RET gene in Hirschsprung disease (HSCR) patients. This study aimed to investigate somatic mutation rate in Chinese population by comparing both homozygous genotype percentage and risk allele frequency of 3 RET single nucleotide polymorphisms (SNPs) among blood and colon samples. DNA was extracted from 59 HSCR blood samples, 59 control blood samples and 76 fresh frozen colon tissue samples (grouped into ganglionic, transitional and aganglionic level). Genotype status of rs2435357 and rs2506030 was examined by competitive allele specific hydrolysis probes (Taqman) PCR technology, and rs2506004 was examined by Sanger sequencing. Homozygous genotype percentage and risk allele frequency were calculated for each type of sample and compared by chi-square test. P<0.05 was regarded as being statistically significant. Colon tissue DNA samples showed similar frequency of SNPs as that of the blood DNA samples in HSCR patients, both of which are significantly higher than the control blood group (rs2435357 TT genotype: 71.2%, 74.7% versus 22.0% in HSCR blood, HSCR colon and control blood DNA respectively, P=0.000; rs2506004 AA genotype: 72.4%, 83.1% versus 25.5%, P=0.000; rs2506030 GG genotype: 79.7%, 77.2% versus 54.2%, P=0.000 and 0.004). With respect to DNA extracted from ganglionic, transitional and aganglionic levels, no statistically significant difference was demonstrated in those 3 regions (rs2435357: P=0.897; rs2506004: P=0.740; rs2506030: P=0.901). Our data does not support the notion that high frequency of somatic changes as an underlying etiology of Chinese HSCR population.

  2. Failure to Identify Somatic Mutations in Monozygotic Twins Discordant for Schizophrenia by Whole Exome Sequencing

    Directory of Open Access Journals (Sweden)

    Nan Lyu

    2016-01-01

    Conclusions: This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.

  3. Pitfalls of improperly procured adjacent non-neoplastic tissue for somatic mutation analysis using next-generation sequencing

    Directory of Open Access Journals (Sweden)

    Lei Wei

    2016-10-01

    Full Text Available Abstract Background The rapid adoption of next-generation sequencing provides an efficient system for detecting somatic alterations in neoplasms. The detection of such alterations requires a matched non-neoplastic sample for adequate filtering of non-somatic events such as germline polymorphisms. Non-neoplastic tissue adjacent to the excised neoplasm is often used for this purpose as it is simultaneously collected and generally contains the same tissue type as the neoplasm. Following NGS analysis, we and others have frequently observed low-level somatic mutations in these non-neoplastic tissues, which may impose additional challenges to somatic mutation detection as it complicates germline variant filtering. Methods We hypothesized that the low-level somatic mutation observed in non-neoplastic tissues may be entirely or partially caused by inadvertent contamination by neoplastic cells during the surgical pathology gross assessment or tissue procurement process. To test this hypothesis, we applied a systematic protocol designed to collect multiple grossly non-neoplastic tissues using different methods surrounding each single neoplasm. The procedure was applied in two breast cancer lumpectomy specimens. In each case, all samples were first sequenced by whole-exome sequencing to identify somatic mutations in the neoplasm and determine their presence in the adjacent non-neoplastic tissues. We then generated ultra-deep coverage using targeted sequencing to assess the levels of contamination in non-neoplastic tissue samples collected under different conditions. Results Contamination levels in non-neoplastic tissues ranged up to 3.5 and 20.9 % respectively in the two cases tested, with consistent pattern correlated with the manner of grossing and procurement. By carefully controlling the conditions of various steps during this process, we were able to eliminate any detectable contamination in both patients. Conclusion The results demonstrated that the

  4. Database of somatic mutations in EGFR with analyses revealing indel hotspots but no smoking-associated signature.

    Science.gov (United States)

    Gu, Dongqing; Scaringe, William A; Li, Kai; Saldivar, Juan-Sebastian; Hill, Kathleen A; Chen, Zhenbin; Gonzalez, Kelly D; Sommer, Steve S

    2007-08-01

    We created an Epidermal Growth Factor Receptor (EGFR) Mutation Database (http://www.cityofhope.org/cmdl/egfr_db) that curates a convenient compilation of somatic EGFR mutations in non-small-cell lung cancer (NSCLC) and associated epidemiological and methodological data, including response to the tyrosine kinase inhibitors Gefitinib and Erlotinib. Herein, we analyze 809 mutations collected from 26 publications. Four super hotspots account for 70% of reported mutations while two-thirds of 131 unique mutations have been reported only once and account for only 11% of reported mutations. Consistent with strong biological selection for gain of function, the reported mutations are virtually all missense substitutions or in-frame microdeletions, microinsertions, or microindels (colocalized insertion and deletion with a net gain or loss of 1-50 nucleotides). Microdeletions and microindels are common in a region of exon 19. Microindels, which account for 8% of mutations, have smaller inserted sequences (95% are 1 to 5 bp) and are elevated 16-fold relative to mouse somatic microindels and to human germline microindels. Microdeletions/microindels are significantly more frequent in responders to Gefitinib or Erlotinib (P = 0.003). In addition, EGFR mutations in smokers do not carry signatures of mutagens in cigarette smoke. Otherwise, the mutation pattern does not differ significantly with respect to gender, age, or tumor histology. The EGFR Mutation Database is a central resource of EGFR sequence variant data for clinicians, geneticists, and other researchers. Authors are encouraged to submit new publications with EGFR sequence variants to be included in the database or to provide direct submissions via The WayStation submission and publication process (http://www.centralmutations.org). (c) 2007 Wiley-Liss, Inc.

  5. Somatic mutation footprinting reveals a unique tetranucleotide signature associated with intron-exon boundaries in lung cancer.

    Science.gov (United States)

    Wormald, Samuel; Lerch, Anita; Mouradov, Dmitri; O'Connor, Liam

    2018-02-09

    Cigarette smoke comprises a large number of carcinogenic substances that can increase DNA mutation load in epithelial cells of the mouth, throat and lungs. While a strong C:A substitution preference is abundant in tobacco-related cancer genomes, detection of complex or less abundant somatic mutation signatures may be confounded by the heterogeneity of carcinogens present in smoke. Trinucleotide signatures are defined for a variety of somatic mutation processes, yet the extent to which this configuration optimally defines and discriminates between mutational processes is not clear. Here, we describe a method that determines whether trinucleotide patterns do a good job at encapsulating a mutation signature or whether they mask underlying heterogeneity that alternative pattern structures would better define. The approach works by mapping the dependency of trinucleotide signatures in relation to sequence context to establish a 'footprint' of context dependency. Applying this technique to smoke-associated cancers, we show that a robust tetranucleotide substitution is prevalent in 17% of lung squamous cell carcinoma genomes. The signature is dominated by the substitution CT(C:A)G and is strongly associated with gene expression level and intron-exon junctions. Intriguingly, its distribution across the genome is biased towards 5' splice junctions, suggesting a novel mechanism of mutation. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Somatic mutations of the RET proto-oncogene are not required for tumor development in multiple endocrine neoplasia type 2 (MEN 2) gene carriers

    NARCIS (Netherlands)

    Landsvater, RM; deWit, MJ; Zewald, RA; Hofstra, RMW; Buys, CHCM; vanAmstel, HKP; Hoppener, JWM; Lips, CJM

    1996-01-01

    Germ line mutations in one allele of the RET proto-oncogene predispose to the multiple endocrine neoplasia type 2 (MEN 2) syndromes, To investigate whether these inherited mutations alone can cause the development of tumors in vivo (oncogene model) or whether somatic mutations in the homologous RET

  7. TumorTracer: a method to identify the tissue of origin from the somatic mutations of a tumor specimen

    DEFF Research Database (Denmark)

    Marquard, Andrea Marion; Birkbak, Nicolai Juul; Thomas, Cecilia Engel

    2015-01-01

    A substantial proportion of cancer cases present with a metastatic tumor and require further testing to determine the primary site; many of these are never fully diagnosed and remain cancer of unknown primary origin (CUP). It has been previously demonstrated that the somatic point mutations...... detected in a tumor can be used to identify its site of origin with limited accuracy. We hypothesized that higher accuracy could be achieved by a classification algorithm based on the following feature sets: 1) the number of nonsynonymous point mutations in a set of 232 specific cancer-associated genes, 2...... to aid clinical diagnosis of cancers of unknown primary origin....

  8. Prevalence of somatic mitochondrial mutations and spatial distribution of mitochondria in non-small cell lung cancer.

    Science.gov (United States)

    Kazdal, Daniel; Harms, Alexander; Endris, Volker; Penzel, Roland; Kriegsmann, Mark; Eichhorn, Florian; Muley, Thomas; Stenzinger, Albrecht; Pfarr, Nicole; Weichert, Wilko; Warth, Arne

    2017-07-11

    Mitochondria are considered relevant players in many tumour entities and first data indicate beneficial effects of mitochondria-targeted antioxidants in both cancer prevention and anticancer therapies. To further dissect the potential roles of mitochondria in NSCLC we comprehensively analysed somatic mitochondrial mutations, determined the spatial distribution of mitochondrial DNA within complete tumour sections and investigated the mitochondrial load in a large-scale approach. Whole mitochondrial genome sequencing of 26 matched tumour and non-neoplastic tissue samples extended by reviewing published data of 326 cases. Systematical stepwise real-time PCR quantification of mitochondrial DNA covering 16 whole surgical tumour sections. Immunohistochemical determination of the mitochondrial load in 171 adenocarcinoma and 145 squamous cell carcinoma. Our results demonstrate very low recurrences (max. 1.7%) and a broad distribution of 456 different somatic mitochondrial mutations. Large inter- and intra-tumour heterogeneity were seen for mitochondrial DNA copy numbers in conjunction with a correlation to the predominant histological growth pattern. Furthermore, tumour cells had significantly higher mitochondrial level compared to adjacent stroma, whereas differences between tumour entities were negligible. Non-evident somatic mitochondrial mutations and highly varying mitochondrial DNA level delineate challenges for the approach of mitochondria-targeted anticancer therapies in NSCLC.

  9. ExScalibur: A High-Performance Cloud-Enabled Suite for Whole Exome Germline and Somatic Mutation Identification.

    Science.gov (United States)

    Bao, Riyue; Hernandez, Kyle; Huang, Lei; Kang, Wenjun; Bartom, Elizabeth; Onel, Kenan; Volchenboum, Samuel; Andrade, Jorge

    2015-01-01

    Whole exome sequencing has facilitated the discovery of causal genetic variants associated with human diseases at deep coverage and low cost. In particular, the detection of somatic mutations from tumor/normal pairs has provided insights into the cancer genome. Although there is an abundance of publicly-available software for the detection of germline and somatic variants, concordance is generally limited among variant callers and alignment algorithms. Successful integration of variants detected by multiple methods requires in-depth knowledge of the software, access to high-performance computing resources, and advanced programming techniques. We present ExScalibur, a set of fully automated, highly scalable and modulated pipelines for whole exome data analysis. The suite integrates multiple alignment and variant calling algorithms for the accurate detection of germline and somatic mutations with close to 99% sensitivity and specificity. ExScalibur implements streamlined execution of analytical modules, real-time monitoring of pipeline progress, robust handling of errors and intuitive documentation that allows for increased reproducibility and sharing of results and workflows. It runs on local computers, high-performance computing clusters and cloud environments. In addition, we provide a data analysis report utility to facilitate visualization of the results that offers interactive exploration of quality control files, read alignment and variant calls, assisting downstream customization of potential disease-causing mutations. ExScalibur is open-source and is also available as a public image on Amazon cloud.

  10. Proteome-Scale Investigation of Protein Allosteric Regulation Perturbed by Somatic Mutations in 7,000 Cancer Genomes.

    Science.gov (United States)

    Shen, Qiancheng; Cheng, Feixiong; Song, Huili; Lu, Weiqiang; Zhao, Junfei; An, Xiaoli; Liu, Mingyao; Chen, Guoqiang; Zhao, Zhongming; Zhang, Jian

    2017-01-05

    The allosteric regulation triggering the protein's functional activity via conformational changes is an intrinsic function of protein under many physiological and pathological conditions, including cancer. Identification of the biological effects of specific somatic variants on allosteric proteins and the phenotypes that they alter during tumor initiation and progression is a central challenge for cancer genomes in the post-genomic era. Here, we mapped more than 47,000 somatic missense mutations observed in approximately 7,000 tumor-normal matched samples across 33 cancer types into protein allosteric sites to prioritize the mutated allosteric proteins and we tested our prediction in cancer cell lines. We found that the deleterious mutations identified in cancer genomes were more significantly enriched at protein allosteric sites than tolerated mutations, suggesting a critical role for protein allosteric variants in cancer. Next, we developed a statistical approach, namely AlloDriver, and further identified 15 potential mutated allosteric proteins during pan-cancer and individual cancer-type analyses. More importantly, we experimentally confirmed that p.Pro360Ala on PDE10A played a potential oncogenic role in mediating tumorigenesis in non-small cell lung cancer (NSCLC). In summary, these findings shed light on the role of allosteric regulation during tumorigenesis and provide a useful tool for the timely development of targeted cancer therapies. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  11. Lack of somatic mutations in the catalytic domains of CREBBP and EP300 genes implies a role for histone deacetylase inhibition in myeloproliferative neoplasms

    DEFF Research Database (Denmark)

    Andersen, C.L.; Grønbæk, K.; Hasselbalch, H.

    2012-01-01

    with myeloproliferative neoplasms (MPNs) has not previously been performed. DNA was purified from diagnostic samples of 56 MPN patients. We designed a mutation screening assay based on denaturing gradient gel electrophoresis and direct sequencing. Our results suggest that CREBBP and EP300 mutations are not major......Somatic mutations of the two genes coding for the histone acetyltransferase genes, CREEBP and EP300 have been identified as a pathogenetic mechanism shared by common forms of B-cell non-Hodgkinós lymphomas. A screening for somatic mutations in CREEBP and EP300 genes in patients...

  12. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

    Directory of Open Access Journals (Sweden)

    Yana Pikman

    2006-07-01

    Full Text Available The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV, essential thrombocytosis (ET, and myelofibrosis with myeloid metaplasia (MF. Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR, the thrombopoietin receptor (MPL, or the granulocyte-colony stimulating factor receptor (GCSFR.DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L in 9% (4/45 of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12/L, marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis.Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD exhibits certain features of

  13. Identification of Somatic Mutations in the von Hippel–Lindau (VHL Gene in a Patient With Renal Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Wen-Chung Wang

    2009-11-01

    Full Text Available One of the known causal molecular events in renal cell carcinoma is somatic mutation in the von Hippel–Lindau (VHL gene. Our study describes a 51-year-old Taiwanese man who had bilateral renal cell carcinoma. The patient underwent radical nephrectomy without postoperative chemotherapy or radiotherapy, and is still alive after renal transplantation without tumor recurrence after > 5 years. To clarify his predisposition for bilateral tumors, we performed molecular genetic analysis of the VHL gene in this study. Polymerase chain reaction–single-strand conformation polymorphism and direct sequencing were performed on DNA of blood samples and paraffin-embedded tumor specimens from this patient. DNA from peripheral blood lymphocytes tested negative for germline mutations. However, there were two heterozygous alleles in the promoter and 3′ untranslated regions of this gene. Nonetheless, the DNA from his tumors showed loss of heterozygosity (LOH in these two loci. In addition to the LOH, we identified some different somatic mutations in his tumor tissues: C287T and G460A in the right-sided tumor, and G244A and G390A in the left-sided tumor. The possible roles of these genetic polymorphisms and point mutations in his renal tumorigenesis are discussed. This report provides new insights into renal cell carcinoma that result from VHL gene alterations in Taiwan.

  14. Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter.

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    Tobias Åkerström

    Full Text Available Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%. Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005 and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005.Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the

  15. Somatic hypermutation in immunity and cancer: Critical analysis of strand-biased and codon-context mutation signatures.

    Science.gov (United States)

    Steele, Edward J

    2016-09-01

    For 30 years two general mechanisms have competed to explain somatic hypermutation of immunoglobulin (Ig) genes. The first, the DNA-based model, is focused only on DNA substrates. The modern form is the Neuberger "DNA Deamination Model" based on activation-induced cytidine deaminase (AID) and short-patch error-prone DNA repair by DNA Polymerase-η operating around AID C-to-U lesions. The other is an RNA-based mechanism or the "Reverse Transcriptase Model" of SHM which produces strand-biased mutations at A:T and G:C base pairs. This involves error-prone cDNA synthesis via an RNA-dependent DNA polymerase copying the Ig pre-mRNA template and integrating the now error-filled cDNA copy back into the normal chromosomal site. The modern form of this mechanism depends on AID dC-to-dU lesions and long tract error-prone cDNA synthesis of the transcribed strand by DNA Polymerase-η acting as a reverse transcriptase. The evidence for and against each mechanism is critically evaluated. The conclusion is that all the SHM molecular data gathered since 1980 supports directly or indirectly the RNA/RT-based mechanism. All the data and critical analyses are systematically laid out so the reader can evaluate this conclusion for themselves. Recently we have investigated whether similar RNA/RT-based mutator mechanisms explain how de novo mutations arise in somatic tissues (cancer genomes). The data analyses indeed suggest that cancers arise via dysregulated "Ig-like SHM responses" involving rogue DNA and RNA deaminations coupled to genome-wide RT events. Further, Robyn Lindley has recently shown that the strand-biased mutations in cancer genome genes are also in "codon-context." This has been termed Targeted Somatic Mutation (TSM) to highlight that mutations are far more targeted than previously thought in somatic tissues associated with disease. The TSM process implies an "in-frame DNA reader" whereby DNA and RNA deaminases at transcribed regions are guided in their mutagenic action

  16. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings

    Science.gov (United States)

    Wada, Taizo; Konno, Akihiro; Schurman, Shepherd H.; Garabedian, Elizabeth K.; Anderson, Stacie M.; Kirby, Martha; Nelson, David L.; Candotti, Fabio

    2003-01-01

    Revertant mosaicism due to true back mutations or second-site mutations has been identified in several inherited disorders. The occurrence of revertants is considered rare, and the underlying genetic mechanisms remain mostly unknown. Here we describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS). The original mutation causing disease in this family is a single base insertion (1305insG) in the WAS protein (WASP) gene, which results in frameshift and abrogates protein expression. Both patients, however, showed expression of WASP in a fraction of their T cells that were demonstrated to carry a second-site mutation causing the deletion of 19 nucleotides from nucleotide 1299 to 1316. This deletion abrogated the effects of the original mutation and restored the WASP reading frame. In vitro expression studies indicated that mutant protein encoded by the second-site mutation was expressed and functional, since it was able to bind to cellular partners and mediate T cell receptor/CD3 downregulation. These observations were consistent with evidence of in vivo selective advantage of WASP-expressing lymphocytes. Molecular analysis revealed that the sequence surrounding the deletion contained two 4-bp direct repeats and that a hairpin structure could be formed by five GC pairs within the deleted fragment. These findings strongly suggest that slipped mispairing was the cause of this second-site mutation and that selective accumulation of WASP-expressing T lymphocytes led to revertant mosaicism in these patients. PMID:12727931

  17. An Analysis of the Sensitivity of Proteogenomic Mapping of Somatic Mutations and Novel Splicing Events in Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ruggles, Kelly V.; Tang, Zuojian; Wang, Xuya; Grover, Himanshu; Askenazi, Manor; Teubl, Jennifer; Cao, Song; McLellan, Michael D.; Clauser, Karl R.; Tabb, David L.; Mertins, Philipp; Slebos, Robbert; Erdmann-Gilmore, Petra; Li, Shunqiang; Gunawardena, Harsha P.; Xie, Ling; Liu, Tao; Zhou, Jian-Ying; Sun, Shisheng; Hoadley, Katherine A.; Perou, Charles M.; Chen, Xian; Davies, Sherri R.; Maher, Christopher A.; Kinsinger, Christopher R.; Rodland, Karen D.; Zhang, Hui; Zhang, Zhen; Ding, Li; Townsend, R. Reid; Rodriguez, Henry; Chan, Daniel; Smith, Richard D.; Liebler, Daniel C.; Carr, Steven A.; Payne, Samuel; Ellis, Matthew J.; Fenyő, David

    2015-12-02

    Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations and splice variants identified in cancer cells are translated. Herein we therefore describe a proteogenomic data integration tool (QUILTS) and illustrate its application to whole genome, transcriptome and global MS peptide sequence datasets generated from a pair of luminal and basal-like breast cancer patient derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS process replicates. Despite over thirty sample replicates, only about 10% of all SNV (somatic and germline) were detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNV without a detectable mRNA transcript were also observed demonstrating the transcriptome coverage was also incomplete (~80%). In contrast to germ-line variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than the luminal tumor raising the possibility of differential translation or protein degradation effects. In conclusion, the QUILTS program integrates DNA, RNA and peptide sequencing to assess the degree to which somatic mutations are translated and therefore biologically active. By identifying gaps in sequence coverage QUILTS benchmarks current technology and assesses progress towards whole cancer proteome and transcriptome analysis.

  18. Temperature dependence of surface nanobubbles

    NARCIS (Netherlands)

    Berkelaar, R.P.; Seddon, James Richard Thorley; Zandvliet, Henricus J.W.; Lohse, Detlef

    2012-01-01

    The temperature dependence of nanobubbles was investigated experimentally using atomic force microscopy. By scanning the same area of the surface at temperatures from 51 °C to 25 °C it was possible to track geometrical changes of individual nanobubbles as the temperature was decreased.

  19. Environmental modulation of somatic mutations: nature of interactions. Final report, 1 June 1974--31 May 1977. [Effects of diurnal temperature changes in Tradescantia

    Energy Technology Data Exchange (ETDEWEB)

    Mericle, L.W.

    1977-05-01

    Research on this project has had as a major goal a combined ecologic-genetic investigation of somatic mutations in order to evaluate the impacts of certain changing environmental parameters. The ultimate aim, to better understand how such environmental-mutation interactions operate and to assure the information obtained be extrapolatable to conditions and events in nature. Higher plants delineate reproductive tissues late in development from meristematic, somatic tissues. Moreover, the prevailing method of reproduction may be without sexual fusion of gametes and/or wholly asexual (vegetative). Therefore, somatic mutations can have as far-reaching genetic significance for a plant population as when germ cells, themselves, are directly affected. Our data show diurnal temperature differences (DTD) of greater than or equal to 22.2 C-degrees to be very effective mutagenic agents in the Tradescantia somatic mutation system. Further, these ranges of DTD were found to occur often in important seed production areas. A DTD of 22.2 in magnitude can increase mutations 10-fold. And, durations short as 1-day can induce significant increases in mutation rate. Whether interaction of 22.2 DTD with low-level radiation (800 mR/day) is synergistic or attenuative is still debatable. We believe, however, that spontaneous, and 22.2 DTD induced, mutations occur mainly via the genetic mechanism of somatic crossing-over; mutations from acute ionizing radiation (e.g., 30-60 R ..gamma..) via chromosome breakage, producing micronuclei. Requirements for maximizing the Discriminatory Response Capability (DRC) in the Tradescantia somatic mutation system are set forth.

  20. Epidermal growth factor receptor somatic mutation analysis in 354 Chinese patients with non-small cell lung cancer.

    Science.gov (United States)

    Quan, Xueping; Gao, Hongjun; Wang, Zhikuan; Li, Jie; Zhao, Wentao; Liang, Wei; Yu, Qiang; Guo, Dongliang; Hao, Zhanping; Liu, Jingxin

    2018-02-01

    Lung cancer is one of the most common types of cancer worldwide, with the highest mortality rate of all types of cancer. In the present study, epidermal growth factor receptor (EGFR) mutations of 354 primary patients with non-small cell lung cancer (NSCLC) of Chinese ethnicity were detected following formalin-fixed and paraffin-embedded specimen DNA extraction, polymerase chain reaction amplification, and sanger sequencing. The total rate of occurrence of EGFR somatic mutation in these 354 patients was 48.02%. Of these detected EGFR mutations, 27.40% were located in exon 19 and 25.99% in exon 21. The most frequent mutation in exon 19 was E746-A750del (8.47%), and in exon 21, L858R (10.17%). EGFR mutation rates were significantly associated with sex [female vs. male: 60.13 vs. 38.81%; adjusted odds ratio (OR), 1.93, 95% confidence interval (CI), 1.07-3.51, P=0.029], age (<60 vs. ≥60; 58.62 vs. 40.67%; adjusted OR, 1.87; 95% CI, 1.20-2.92; P=0.006) and histology [adenocarcinoma (ADC) vs. non-ADC; 52.76 vs. 26.56%; adjusted OR, 2.35; 95% CI, 1.28-4.50; P=0.007]. The frequency of E746_A750del, Q787Q and L858R mutations were significantly different in ADC patients compared with squamous cell carcinoma patients (P<0.001). Furthermore, a novel EGFR mutation, M793K, was detected in 7 NSCLC patients with possible gefitinib resistance. The present study analyzed the EGFR exon 18-21 mutation occurrence profile for Chinese patients with NSCLC and identified significant associations between different EGFR mutations with demographic and histological factors. These results may offer clinical benefits and potential novel treatments.

  1. An integrated inspection of the somatic mutations in a lung squamous cell carcinoma using next-generation sequencing.

    Directory of Open Access Journals (Sweden)

    Lucy F Stead

    Full Text Available Squamous cell carcinoma (SCC of the lung kills over 350,000 people annually worldwide, and is the main lung cancer histotype with no targeted treatments. High-coverage whole-genome sequencing of the other main subtypes, small-cell and adenocarcinoma, gave insights into carcinogenic mechanisms and disease etiology. The genomic complexity within the lung SCC subtype, as revealed by The Cancer Genome Atlas, means this subtype is likely to benefit from a more integrated approach in which the transcriptional consequences of somatic mutations are simultaneously inspected. Here we present such an approach: the integrated analysis of deep sequencing data from both the whole genome and whole transcriptome (coding and non-coding of LUDLU-1, a SCC lung cell line. Our results show that LUDLU-1 lacks the mutational signature that has been previously associated with tobacco exposure in other lung cancer subtypes, and suggests that DNA-repair efficiency is adversely affected; LUDLU-1 contains somatic mutations in TP53 and BRCA2, allelic imbalance in the expression of two cancer-associated BRCA1 germline polymorphisms and reduced transcription of a potentially endogenous PARP2 inhibitor. Functional assays were performed and compared with a control lung cancer cell line. LUDLU-1 did not exhibit radiosensitisation or an increase in sensitivity to PARP inhibitors. However, LUDLU-1 did exhibit small but significant differences with respect to cisplatin sensitivity. Our research shows how integrated analyses of high-throughput data can generate hypotheses to be tested in the lab.

  2. SOMATIC MUTATIONS OF THE VON HIPPEL-LINDAU DISEASE TUMOR-SUPPRESSOR GENE IN NONFAMILIAL CLEAR-CELL RENAL-CARCINOMA

    NARCIS (Netherlands)

    FOSTER, K; PROWSE, A; van den Berg, Anke; FLEMING, S; HULSBEEK, MMF; CROSSEY, PA; RICHARDS, FM; CAIRNS, P; FERGUSONSMITH, MA; BUYS, CHCM; MAHER, ER

    1994-01-01

    Loss of heterozygosity (LOH) studies have suggested that somatic mutations of a tumour suppressor gene or genes on chromosome 3p are a critical event in the pathogenesis of non-familial renal cell carcinoma (RCC). Germline mutations of the von Hippel - Lindau (VHL) disease gene predispose to early

  3. Somatic mosaicism for the COL7A1 mutation p.Gly2034Arg in the unaffected mother of a patient with dystrophic epidermolysis bullosa pruriginosa

    NARCIS (Netherlands)

    van den Akker, P. C.; Pasmooij, A. M. G.; Meijer, R.; Scheffer, H.; Jonkman, M. F.

    Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder caused by mutations in the type VII collagen gene, COL7A1. Although revertant mosaicism is well known in DEB, 'forward' somatic mosaicism, in which a pathogenic mutation arises on a wild-type (WT) background, extending beyond

  4. Somatic mosaicism for the COL7A1 mutation p.Gly2034Arg in the unaffected mother of a patient with dystrophic epidermolysis bullosa pruriginosa

    NARCIS (Netherlands)

    Akker, P.C. van den; Pasmooij, A.M.; Meijer, R.; Scheffer, H.; Jonkman, M.F.

    2015-01-01

    Dystrophic epidermolysis bullosa (DEB) is a heritable blistering disorder caused by mutations in the type VII collagen gene, COL7A1. Although revertant mosaicism is well known in DEB, 'forward' somatic mosaicism, in which a pathogenic mutation arises on a wild-type (WT) background, extending beyond

  5. Routine use of the Ion Torrent AmpliSeq™ Cancer Hotspot Panel for identification of clinically actionable somatic mutations.

    Science.gov (United States)

    Tsongalis, Gregory J; Peterson, Jason D; de Abreu, Francine B; Tunkey, Christopher D; Gallagher, Torrey L; Strausbaugh, Linda D; Wells, Wendy A; Amos, Christopher I

    2014-05-01

    Somatic mutation analysis is standard of practice for solid tumors in order to identify therapeutic sensitizing and resistance mutations. Our laboratory routinely performed standalone PCR-based methods for mutations in several genes. Rapid discovery and introduction of new therapeutics has demanded additional genomic information for adequate management of the cancer patient. We evaluated a next generation sequencing assay, the Ion Torrent AmpliSeq Cancer Hotspot Panelv2 (CHPv2), capable of identifying multiple somatic mutations in 50 genes in a single assay. Accuracy, precision, limit of detection, and specificity were evaluated using DNA from well-characterized cell lines, genetically engineered cell lines fixed and embedded in paraffin, and previously tested mutation positive or negative, formalin-fixed, paraffin-embedded (FFPE) tissues. Normal kidney, tonsil and colon FFPE tissues were used as controls. Accuracy studies showed 100% concordance in each patient sample between previous PCR results and the corresponding variants identified using the Ion Torrent panel. Precision studies gave consistent results when libraries were prepared from the same original DNA and were run on multiple 316 chips. The limit of detection was determined to be 5% for single nucleotide variants (SNVs) and 20% for insertions and deletions (indels). Specificity studies using normal FFPE tissue previously tested by PCR methods were also 100%. We have evaluated the performance of the AmpliSeq Cancer Panel Hotspotv2 and show that it is suitable for clinical testing. This next generation sequencing panel has allowed the laboratory to consolidate a broader range of molecular oncology testing to a single platform and single assay.

  6. Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis.

    Directory of Open Access Journals (Sweden)

    Bernd Timmermann

    Full Text Available BACKGROUND: Colorectal cancer (CRC is with approximately 1 million cases the third most common cancer worldwide. Extensive research is ongoing to decipher the underlying genetic patterns with the hope to improve early cancer diagnosis and treatment. In this direction, the recent progress in next generation sequencing technologies has revolutionized the field of cancer genomics. However, one caveat of these studies remains the large amount of genetic variations identified and their interpretation. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the first work on whole exome NGS of primary colon cancers. We performed 454 whole exome pyrosequencing of tumor as well as adjacent not affected normal colonic tissue from microsatellite stable (MSS and microsatellite instable (MSI colon cancer patients and identified more than 50,000 small nucleotide variations for each tissue. According to predictions based on MSS and MSI pathomechanisms we identified eight times more somatic non-synonymous variations in MSI cancers than in MSS and we were able to reproduce the result in four additional CRCs. Our bioinformatics filtering approach narrowed down the rate of most significant mutations to 359 for MSI and 45 for MSS CRCs with predicted altered protein functions. In both CRCs, MSI and MSS, we found somatic mutations in the intracellular kinase domain of bone morphogenetic protein receptor 1A, BMPR1A, a gene where so far germline mutations are associated with juvenile polyposis syndrome, and show that the mutations functionally impair the protein function. CONCLUSIONS/SIGNIFICANCE: We conclude that with deep sequencing of tumor exomes one may be able to predict the microsatellite status of CRC and in addition identify potentially clinically relevant mutations.

  7. JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate

    Science.gov (United States)

    Nielsen, Camilla; Bojesen, Stig E.; Nordestgaard, Børge G.; Kofoed, Klaus F.; Birgens, Henrik S.

    2014-01-01

    Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease. In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003–2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased by 0.55% per year, erythrocyte volume fraction increased by 1.19% per year, and erythrocyte mean corpuscular volume increased by 1.25% per year, while there was no change in platelet count or erythropoietin levels. Furthermore, we established a JAK2V617F mutation burden cut-off point of 2% indicative of disease versus no disease; however, individuals with a mutation burden below 2% may suffer from a latent form of myeloproliferative disease revealed by a slightly larger spleen and/or slightly higher lactic acid dehydrogenase concentration compared to controls. Of all 63 JAK2V617F positive individuals, 48 were eventually diagnosed with a myeloproliferative neoplasm. PMID:24907356

  8. PPM1D Mosaic Truncating Variants in Ovarian Cancer Cases May Be Treatment-Related Somatic Mutations

    Science.gov (United States)

    Pharoah, Paul D. P.; Song, Honglin; Dicks, Ed; Intermaggio, Maria P.; Harrington, Patricia; Baynes, Caroline; Alsop, Kathryn; Bogdanova, Natalia; Cicek, Mine S.; Cunningham, Julie M.; Fridley, Brooke L.; Gentry-Maharaj, Aleksandra; Hillemanns, Peter; Lele, Shashi; Lester, Jenny; McGuire, Valerie; Moysich, Kirsten B.; Poblete, Samantha; Sieh, Weiva; Sucheston-Campbell, Lara; Widschwendter, Martin; Whittemore, Alice S.; Dörk, Thilo; Menon, Usha; Odunsi, Kunle; Goode, Ellen L.; Karlan, Beth Y.; Bowtell, David D.; Gayther, Simon A.; Ramus, Susan J.

    2016-01-01

    Mosaic truncating mutations in the protein phosphatase, Mg2+/Mn2+-dependent, 1D (PPM1D) gene have recently been reported with a statistically significantly greater frequency in lymphocyte DNA from ovarian cancer case patients compared with unaffected control patients. Using massively parallel sequencing (MPS) we identified truncating PPM1D mutations in 12 of 3236 epithelial ovarian cancer (EOC) case patients (0.37%) but in only one of 3431 unaffected control patients (0.03%) (P = .001). All statistical tests were two-sided. A combination of Sanger sequencing, pyrosequencing, and MPS data suggested that 12 of the 13 mutations were mosaic. All mutations were identified in post-chemotherapy treatment blood samples from case patients (n = 1827) (average 1234 days post-treatment in carriers) rather than from cases collected pretreatment (less than 14 days after diagnosis, n = 1384) (P = .002). These data suggest that PPM1D variants in EOC cases are primarily somatic mosaic mutations caused by treatment and are not associated with germline predisposition to EOC. PMID:26823519

  9. Confirmation of homozygosity for a single nucleotide substitution mutation in a Cockayne syndrome patient using monoallelic mutation analysis in somatic cell hybrids.

    Science.gov (United States)

    McDaniel, L D; Legerski, R; Lehmann, A R; Friedberg, E C; Schultz, R A

    1997-01-01

    The identification of individuals homozygous for a specific mutation offers advantages for the elucidation of molecular mechanisms of hereditary disease states. Cockayne syndrome is a rare autosomal recessive disorder, the molecular basis of which is complicated by significant genetic and clinical heterogeneity. The genes associated with both genetic complementation groups, CSA and CS-B, have been identified. We have previously identified a number of CSA mutations, including a single base substitution that introduces a stop codon (322Tyr-->Stop) mutation in the C-terminal region for at least one allele of the CSA gene in a severely affected patient. We now present data confirming the existence of homozygosity in this patient using a strategy with general applicability. Somatic cell hybrids were established by fusing patient cells with mouse A9 cells. Screening with chromosome 5 specific polymorphic markers facilitated identification of hybrid clones bearing only one of the distinct CSA alleles. Sequencing of a portion of the human CSA gene in a subset of these hybrids permitted monoallelic mutation analysis and confirmed the presence of the 322Tyr-->Stop mutation in both alleles.

  10. Detection of somatic mutations of the PIG-A gene in Brazilian patients with paroxysmal nocturnal hemoglobinuria

    Directory of Open Access Journals (Sweden)

    Franco de Carvalho R.

    2001-01-01

    Full Text Available Paroxysmal nocturnal hemoglobinuria (PNH is an acquired clonal syndrome characterized by intravascular hemolysis mediated by complement, thrombotic events and alterations in hematopoiesis. Basically, the molecular events which underlie the complexity of the syndrome consist of the absence of the glycosylphosphatidylinositol (GPI anchor as a consequence of somatic mutations in the PIG-A gene, located on the X chromosome. The GPI group is responsible for the attachment of many proteins to the cytoplasmic membrane. Two of them, CD55 and CD59, have a major role in the inhibition of the action of complement on the cellular membrane of blood cells. The absence of GPI biosynthesis can lead to PNH. Since mutations in the PIG-A gene are always present in patients with PNH, the aim of this study was to characterize the mutations in the PIG-A gene in Brazilian patients. The analysis of the PIG-A gene was performed using DNA samples derived from bone marrow and peripheral blood. Conformation-sensitive gel electrophoresis was used for screening the mutation and sequencing methods were used to identify the mutations. Molecular analysis permitted the identification of three point mutations in three patients: one G->A transition in the 5' portion of the second intron, one T->A substitution in the second base of codon 430 (Leu430->stop, and one deletion deltaA in the third base of codon 63. This study represents the first description of mutations in the PIG-A gene in a Brazilian population.

  11. Synthetic Circulating Cell-free DNA as Quality Control Materials for Somatic Mutation Detection in Liquid Biopsy for Cancer.

    Science.gov (United States)

    Zhang, Rui; Peng, Rongxue; Li, Ziyang; Gao, Peng; Jia, Shiyu; Yang, Xin; Ding, Jiansheng; Han, Yanxi; Xie, Jiehong; Li, Jinming

    2017-09-01

    Detection of somatic genomic alterations in tumor-derived cell-free DNA (cfDNA) in the plasma is challenging owing to the low concentrations of cfDNA, variable detection methods, and complex workflows. Moreover, no proper quality control materials are available currently. We developed a set of synthetic cfDNA quality control materials (SCQCMs) containing spike-in cfDNA on the basis of micrococcal nuclease digestion carrying somatic mutations as simulated cfDNA and matched genomic DNA as genetic background to emulate paired tumor-normal samples in real clinical tests. Site-directed mutagenesis DNA that contained 1500-2000 bases with single-nucleotide variants or indels and genomic DNA from CRISPR/Cas9 edited cells with EML4-ALK rearrangements was fragmented, quantified, and added into micrococcal nuclease-digested DNA derived from HEK293T cells. To prove their suitability, the SCQCMs were compared with patient-derived plasma samples and validated in a collaborative study that encompassed 11 laboratories. The results of SCQCM analysis by next-generation sequencing showed strong agreement with those of patient-derived plasma samples, including the size profile of cfDNA and the quality control metrics of the sequencing data. More than 95% of laboratories correctly detected the SCQCMs with EGFR T790M, L858R, KRAS G12D, and a deletion in exon 19, as well as with EML4-ALK variant 2. The SCQCMs were successfully applied in a broad range of settings, methodologies, and informatics techniques. We conclude that SCQCMs can be used as optimal quality controls in test performance assessments for circulating tumor DNA somatic mutation detection. © 2017 American Association for Clinical Chemistry.

  12. Somatic mutation in larvae of the silkworm, Bombyx mori, induced by heavy ion irradiation to diapause eggs

    Energy Technology Data Exchange (ETDEWEB)

    Kotani, Eiji; Furusawa, Toshiharu [Kyoto Inst. of Tech. (Japan). Faculty of Textile Science; Nagaoka, Shunji [Fujita Health Univ., Toyoake, Aichi (Japan). School of Health Sciences] [and others

    2002-12-01

    In order to investigate whether eggs of the black-striped strain (P{sup S}) of the silkworm, Bombyx mori, represent an appropriate model for estimating the biological effect of cosmic radiation, radiosensitivity of the eggs against X-rays and heavy ion particles was examined as ground-based experiments. The exposure of diapause eggs to X-rays or heavy ion particles resulted in somatic mutations appearing as a white spot on the black integument during larval stage. Irradiation of non-diapause eggs with X-rays demonstrated a significant difference in frequency of the mutation between fractionated and single administration doses, but no difference was observed in diapause eggs. Incidence of the mutation as induced by carbon ion beams for 15-day old eggs was higher for eggs that had been kept at 15 deg C than those kept at 25 deg C. Neon beam irradiation of diapause eggs displayed dose- and linear energy transfer (LET)-dependent effects, causing a maximal rate of the mutation at 150 keV/{mu}m. These results confirm that B. mori eggs represent valid models for estimating the biological effects of cosmic radiation. (author)

  13. NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis.

    Science.gov (United States)

    Le Morvan, Marine; Zinovyev, Andrei; Vert, Jean-Philippe

    2017-06-01

    Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passenger events that hide the contribution of driver events. Here we propose a method, NetNorM, to represent whole-exome somatic mutation data in a form that enhances cancer-relevant information using a gene network as background knowledge. We evaluate its relevance for two tasks: survival prediction and unsupervised patient stratification. Using data from 8 cancer types from The Cancer Genome Atlas (TCGA), we show that it improves over the raw binary mutation data and network diffusion for these two tasks. In doing so, we also provide a thorough assessment of somatic mutations prognostic power which has been overlooked by previous studies because of the sparse and binary nature of mutations.

  14. NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis.

    Directory of Open Access Journals (Sweden)

    Marine Le Morvan

    2017-06-01

    Full Text Available Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passenger events that hide the contribution of driver events. Here we propose a method, NetNorM, to represent whole-exome somatic mutation data in a form that enhances cancer-relevant information using a gene network as background knowledge. We evaluate its relevance for two tasks: survival prediction and unsupervised patient stratification. Using data from 8 cancer types from The Cancer Genome Atlas (TCGA, we show that it improves over the raw binary mutation data and network diffusion for these two tasks. In doing so, we also provide a thorough assessment of somatic mutations prognostic power which has been overlooked by previous studies because of the sparse and binary nature of mutations.

  15. NetNorM: Capturing cancer-relevant information in somatic exome mutation data with gene networks for cancer stratification and prognosis

    Science.gov (United States)

    2017-01-01

    Genome-wide somatic mutation profiles of tumours can now be assessed efficiently and promise to move precision medicine forward. Statistical analysis of mutation profiles is however challenging due to the low frequency of most mutations, the varying mutation rates across tumours, and the presence of a majority of passenger events that hide the contribution of driver events. Here we propose a method, NetNorM, to represent whole-exome somatic mutation data in a form that enhances cancer-relevant information using a gene network as background knowledge. We evaluate its relevance for two tasks: survival prediction and unsupervised patient stratification. Using data from 8 cancer types from The Cancer Genome Atlas (TCGA), we show that it improves over the raw binary mutation data and network diffusion for these two tasks. In doing so, we also provide a thorough assessment of somatic mutations prognostic power which has been overlooked by previous studies because of the sparse and binary nature of mutations. PMID:28650955

  16. Somatic frameshift mutations in the Bloom syndrome BLM gene are frequent in sporadic gastric carcinomas with microsatellite mutator phenotype

    Directory of Open Access Journals (Sweden)

    Matei Irina

    2001-08-01

    Full Text Available Abstract Background Genomic instability has been reported at microsatellite tracts in few coding sequences. We have shown that the Bloom syndrome BLM gene may be a target of microsatelliteinstability (MSI in a short poly-adenine repeat located in its coding region. To further characterize the involvement of BLM in tumorigenesis, we have investigated mutations in nine genes containing coding microsatellites in microsatellite mutator phenotype (MMP positive and negative gastric carcinomas (GCs. Methods We analyzed 50 gastric carcinomas (GCs for mutations in the BLM poly(A tract aswell as in the coding microsatellites of the TGFβ1-RII, IGFIIR, hMSH3, hMSH6, BAX, WRN, RECQL and CBL genes. Results BLM mutations were found in 27% of MMP+ GCs (4/15 cases but not in any of the MMP negative GCs (0/35 cases. The frequency of mutations in the other eight coding regions microsatellite was the following: TGFβ1-RII (60 %, BAX (27%, hMSH6 (20%,hMSH3 (13%, CBL (13%, IGFIIR (7%, RECQL (0% and WRN (0%. Mutations in BLM appear to be more frequently associated with frameshifts in BAX and in hMSH6and/or hMSH3. Tumors with BLM alterations present a higher frequency of unstable mono- and trinucleotide repeats located in coding regions as compared with mutator phenotype tumors without BLM frameshifts. Conclusions BLM frameshifts are frequent alterations in GCs specifically associated with MMP+tumors. We suggest that BLM loss of function by MSI may increase the genetic instability of a pre-existent unstable genotype in gastric tumors.

  17. Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti.

    Science.gov (United States)

    Choate, Keith A; Lu, Yin; Zhou, Jing; Elias, Peter M; Zaidi, Samir; Paller, Amy S; Farhi, Anita; Nelson-Williams, Carol; Crumrine, Debra; Milstone, Leonard M; Lifton, Richard P

    2015-04-01

    Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected subjects have red, scaly skin at birth, experience worsening palmoplantar keratoderma in childhood, and develop hundreds of normal skin spots, beginning at around 20 years of age, that increase in size and number over time. We identified a causal de novo mutation in keratin 1 (KRT1). Similar to IWC-causing KRT10 mutations, this mutation in KRT1 resulted in a C-terminal frameshift, replacing 22 C-terminal amino acids with an alternate 30-residue peptide. Mutant KRT1 caused partial collapse of the cytoplasmic intermediate filament network and mislocalized to the nucleus. As with KRT10 mutations causing IWC, reversion of KRT1 mutations occurred via mitotic recombination. Because reversion is not observed with other disease-causing keratin mutations, the results of this study implicate KRT1 and KRT10 C-terminal frameshift mutations in the high frequency of revertant mosaicism in IWC.

  18. Somatic mutations of the ret Protooncogene in sporadic medullary thyroid carcinoma are not restricted to exon 16 and are associated with tumor recurrence

    Energy Technology Data Exchange (ETDEWEB)

    Romei, C.; Elisei, R.; Pinchera, A. [Univ. of Pisa (Italy)] [and others

    1996-04-01

    Germline point mutations in exons 10, 11, and 16 of the ret protooncogene have been identified as causative in multiple endocrine neoplasia type 2 and in familial medullary thyroid carcinoma (MTC). Somatic point mutations of the same gene, exclusively associated with codon 918 of exon 16, have also been reported in few cases of sporadic medullary thyroid carcinoma. We analyzed the blood and tumor DNA of 19 patients with sporadic MTC and 6 patients with primary parathyroid adenoma for point mutations at exons 10, 11, and 16 of the ret protooncogene by restriction analysis of the PCR-amplified product and by sequence analysis of exons 10 and 11. A Cys{sup 634}{r_arrow}Tyr mutation was found in both the tumoral and blood DNA of one patient, indicating that he was affected by an hereditary form of MTC, erroneously considered sporadic. In the other 18 patients with MTC, somatic point mutations of ret were found in 8 cases (44.4%). In 5 cases the mutation affected exon 16 (Met{sup 918}{r_arrow}Thr), and in 3 cases it affected exon 11 (Cys{sup 634}{r_arrow}Arg in 1 and Cys{sup 634}{r_arrow}Trp in 2); these 3 mutations were confirmed by sequence analysis. The remaining 10 patients had no mutation in exon 10 by either restriction analysis or sequence analysis. Clinical data showed that 75% of the patients whose tumor carried ret mutation had tumor recurrence and/or increased serum calcitonin concentrations during the postsurgical follow-up period as opposed to 10% of the patients without mutations (P < 0.02, by {chi}{sup 2} analysis). No ret mutation was found in the tumoral DNA from parathyroid adenomas. Our findings indicate that the somatic ret point mutation frequently found in sporadic MTC may affect not only exon 16 but also exon 11 and is associated with less favorable clinical outcome. 14 refs., 2 figs., 3 tabs.

  19. Somatic mutation of EZH2 (Y641) in follicular and diffuse large B-cell lymphomas of germinal center origin | Office of Cancer Genomics

    Science.gov (United States)

    Morin et al. describe recurrent somatic mutations in EZH2, a polycomb group oncogene. The mutation, found in the SET domain of this gene encoding a histone methyltransferase, is found only in a subset of lymphoma samples. Specifically, EZH2 mutations are found in about 12% of follicular lymphomas (FL) and almost 23% of diffuse large B-cell lymphomas (DLBCL) of germinal center origin. This paper goes on to demonstrate that altered EZH2 proteins, corresponding to the most frequent mutations found in human lymphomas, have reduced activity using in vitro histone methylation assays.

  20. Somatic cell mutation frequency at the HPRT, T-cell antigen receptor and glycophorin A loci in Cockayne syndrome.

    Science.gov (United States)

    Lin, Y W; Kubota, M; Hirota, H; Furusho, K; Tomiwa, K; Ochi, J; Kasahara, Y; Sasaki, H; Ohta, S

    1995-07-01

    Skin fibroblasts of patients with Cockayne syndrome (CS) are hypersensitive to the lethal or mutagenic effect of ultraviolet light, which may cause genetic instability. Up to now, however, no systematic study of in vivo somatic cell mutation in CS cells has been reported. This article describes our investigation of the mutation frequencies (Mfs) at three different loci, i.e. hypoxanthine-guanine phosphoribosyl transferase (HPRT), T-cell antigen receptor (TCR) and glycophorin A (GPA), in six patients with CS. Mfs at the HPRT and TCR loci were found to be within the normal range as determined in age-matched controls. In the GPA locus of two patients, there was a slight increase, but it was much smaller than that reported in other DNA repair deficient syndromes. The frequency of spontaneous HPRT mutation in Epstein-Barr virus transformed B-lymphoblastoid cells derived from CS patients was similar to that in cells from normal children. The molecular characterization of the representative HPRT mutant T cell clones from CS patients did not show any structural alterations. These results may explain, at least in part, why CS is not associated with predisposition to cancer.

  1. In situ sequencing identifies TMPRSS2-ERG fusion transcripts, somatic point mutations and gene expression levels in prostate cancers.

    Science.gov (United States)

    Kiflemariam, Sara; Mignardi, Marco; Ali, Muhammad Akhtar; Bergh, Anders; Nilsson, Mats; Sjöblom, Tobias

    2014-10-01

    Translocations contribute to the genesis and progression of epithelial tumours and in particular to prostate cancer development. To better understand the contribution of fusion transcripts and visualize the clonal composition of multifocal tumours, we have developed a technology for multiplex in situ detection and identification of expressed fusion transcripts. When compared to immunohistochemistry, TMPRSS2-ERG fusion-negative and fusion-positive prostate tumours were correctly classified. The most prevalent TMPRSS2-ERG fusion variants were visualized, identified, and quantitated in human prostate cancer tissues, and the ratio of the variant fusion transcripts could for the first time be directly determined by in situ sequencing. Further, we demonstrate concurrent in situ detection of gene expression, point mutations, and gene fusions of the prostate cancer relevant targets AMACR, AR, TP53, and TMPRSS2-ERG. This unified approach to in situ analyses of somatic mutations can empower studies of intra-tumoural heterogeneity and future tissue-based diagnostics of mutations and translocations. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  2. Estimating Exceptionally Rare Germline and Somatic Mutation Frequencies via Next Generation Sequencing.

    Directory of Open Access Journals (Sweden)

    Jordan Eboreime

    Full Text Available We used targeted next generation deep-sequencing (Safe Sequencing System to measure ultra-rare de novo mutation frequencies in the human male germline by attaching a unique identifier code to each target DNA molecule. Segments from three different human genes (FGFR3, MECP2 and PTPN11 were studied. Regardless of the gene segment, the particular testis donor or the 73 different testis pieces used, the frequencies for any one of the six different mutation types were consistent. Averaging over the C>T/G>A and G>T/C>A mutation types the background mutation frequency was 2.6x10-5 per base pair, while for the four other mutation types the average background frequency was lower at 1.5x10-6 per base pair. These rates far exceed the well documented human genome average frequency per base pair (~10-8 suggesting a non-biological explanation for our data. By computational modeling and a new experimental procedure to distinguish between pre-mutagenic lesion base mismatches and a fully mutated base pair in the original DNA molecule, we argue that most of the base-dependent variation in background frequency is due to a mixture of deamination and oxidation during the first two PCR cycles. Finally, we looked at a previously studied disease mutation in the PTPN11 gene and could easily distinguish true mutations from the SSS background. We also discuss the limits and possibilities of this and other methods to measure exceptionally rare mutation frequencies, and we present calculations for other scientists seeking to design their own such experiments.

  3. Estimating Exceptionally Rare Germline and Somatic Mutation Frequencies via Next Generation Sequencing

    Science.gov (United States)

    Yoon, Song-Ro; Arnheim, Norman; Calabrese, Peter

    2016-01-01

    We used targeted next generation deep-sequencing (Safe Sequencing System) to measure ultra-rare de novo mutation frequencies in the human male germline by attaching a unique identifier code to each target DNA molecule. Segments from three different human genes (FGFR3, MECP2 and PTPN11) were studied. Regardless of the gene segment, the particular testis donor or the 73 different testis pieces used, the frequencies for any one of the six different mutation types were consistent. Averaging over the C>T/G>A and G>T/C>A mutation types the background mutation frequency was 2.6x10-5 per base pair, while for the four other mutation types the average background frequency was lower at 1.5x10-6 per base pair. These rates far exceed the well documented human genome average frequency per base pair (~10−8) suggesting a non-biological explanation for our data. By computational modeling and a new experimental procedure to distinguish between pre-mutagenic lesion base mismatches and a fully mutated base pair in the original DNA molecule, we argue that most of the base-dependent variation in background frequency is due to a mixture of deamination and oxidation during the first two PCR cycles. Finally, we looked at a previously studied disease mutation in the PTPN11 gene and could easily distinguish true mutations from the SSS background. We also discuss the limits and possibilities of this and other methods to measure exceptionally rare mutation frequencies, and we present calculations for other scientists seeking to design their own such experiments. PMID:27341568

  4. Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia.

    Science.gov (United States)

    Palomba, Grazia; Colombino, Maria; Contu, Antonio; Massidda, Bruno; Baldino, Giovanni; Pazzola, Antonio; Ionta, MariaTeresa; Capelli, Francesca; Trova, Vittorio; Sedda, Tito; Sanna, Giovanni; Tanda, Francesco; Budroni, Mario; Palmieri, Giuseppe; Cossu, Antonio; Contu, Marta; Cuccu, Angelo; Farris, Antonio; Macciò, Antonio; Mameli, Giuseppe; Olmeo, Nina; Ortu, Salvatore; Petretto, Elisabetta; Pusceddu, Valeria; Virdis, Luciano

    2012-08-29

    Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. Overall, KRAS tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation in BRAF gene; PIK3CA was found mutated in 67 (17%) patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern vs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. Our findings support the hypothesis that differences in patients' origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

  5. Is Increased Low-dose somatic Radiosensitivity Associated with Increased Transgenerational Germline Mutation

    Energy Technology Data Exchange (ETDEWEB)

    Brenner, David J.

    2008-10-02

    Using single-molecule polymerase chain reaction, the frequency of spontaneous and radiation-induced mutation at an expanded simple tandem repeat (ESTR) locus was studied in DNA samples extracted from sperm and bone marrow of Atm knockout (Atm+/–) heterozygous male mice. The frequency of spontaneous mutation in sperm and bone marrow in Atm+/– males did not significantly differ from that in wild-type BALB/c mice. Acute gamma-ray exposure did not affect ESTR mutation frequency in bone marrow and resulted in similar increases in sperm samples taken from Atm+/– and BALB/c males. Taken together, these results suggest that the Atm haploinsufficiency analyzed in our study does not affect spontaneous and radiation-induced ESTR mutation frequency in mice.

  6. Inspecting Targeted Deep Sequencing of Whole Genome Amplified DNA Versus Fresh DNA for Somatic Mutation Detection: A Genetic Study in Myelodysplastic Syndrome Patients.

    Science.gov (United States)

    Palomo, Laura; Fuster-Tormo, Francisco; Alvira, Daniel; Ademà, Vera; Armengol, María Pilar; Gómez-Marzo, Paula; de Haro, Nuri; Mallo, Mar; Xicoy, Blanca; Zamora, Lurdes; Solé, Francesc

    2017-08-01

    Whole genome amplification (WGA) has become an invaluable method for preserving limited samples of precious stock material and has been used during the past years as an alternative tool to increase the amount of DNA before library preparation for next-generation sequencing. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by presenting somatic mutations in several myeloid-related genes. In this work, targeted deep sequencing has been performed on four paired fresh DNA and WGA DNA samples from bone marrow of MDS patients, to assess the feasibility of using WGA DNA for detecting somatic mutations. The results of this study highlighted that, in general, the sequencing and alignment statistics of fresh DNA and WGA DNA samples were similar. However, after variant calling and when considering variants detected at all frequencies, there was a high level of discordance between fresh DNA and WGA DNA (overall, a higher number of variants was detected in WGA DNA). After proper filtering, a total of three somatic mutations were detected in the cohort. All somatic mutations detected in fresh DNA were also identified in WGA DNA and validated by whole exome sequencing.

  7. Prevalence of KRAS, BRAF, and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia

    Directory of Open Access Journals (Sweden)

    Palomba Grazia

    2012-08-01

    Full Text Available Abstract Background Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. Methods From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478 were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. Results Overall, KRAS tumour mutation rate was 30% (145/478 positive cases. Distribution of mutation carriers was surprisingly different within the island: 87/204 (43% in North Sardinia vs. 58/274 (21% in Middle-South Sardinia (pBRAF gene; PIK3CA was found mutated in 67 (17% patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10% cases from northern vs. 48/201 (24% cases from central-southern island (pKRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. Conclusions Our findings support the hypothesis that differences in patients’ origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

  8. A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events.

    Directory of Open Access Journals (Sweden)

    Angela N Brooks

    Full Text Available Although recurrent somatic mutations in the splicing factor U2AF1 (also known as U2AF35 have been identified in multiple cancer types, the effects of these mutations on the cancer transcriptome have yet to be fully elucidated. Here, we identified splicing alterations associated with U2AF1 mutations across distinct cancers using DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA. Using RNA-Seq data from 182 lung adenocarcinomas and 167 acute myeloid leukemias (AML, in which U2AF1 is somatically mutated in 3-4% of cases, we identified 131 and 369 splicing alterations, respectively, that were significantly associated with U2AF1 mutation. Of these, 30 splicing alterations were statistically significant in both lung adenocarcinoma and AML, including three genes in the Cancer Gene Census, CTNNB1, CHCHD7, and PICALM. Cell line experiments expressing U2AF1 S34F in HeLa cells and in 293T cells provide further support that these altered splicing events are caused by U2AF1 mutation. Consistent with the function of U2AF1 in 3' splice site recognition, we found that S34F/Y mutations cause preferences for CAG over UAG 3' splice site sequences. This report demonstrates consistent effects of U2AF1 mutation on splicing in distinct cancer cell types.

  9. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias

    DEFF Research Database (Denmark)

    Andersson, Anna K; Ma, Jing; Wang, Jianmin

    2015-01-01

    Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older childr...

  10. The landscape of somatic mutations in Down syndrome-related myeloid disorders.

    Science.gov (United States)

    Yoshida, Kenichi; Toki, Tsutomu; Okuno, Yusuke; Kanezaki, Rika; Shiraishi, Yuichi; Sato-Otsubo, Aiko; Sanada, Masashi; Park, Myoung-ja; Terui, Kiminori; Suzuki, Hiromichi; Kon, Ayana; Nagata, Yasunobu; Sato, Yusuke; Wang, RuNan; Shiba, Norio; Chiba, Kenichi; Tanaka, Hiroko; Hama, Asahito; Muramatsu, Hideki; Hasegawa, Daisuke; Nakamura, Kazuhiro; Kanegane, Hirokazu; Tsukamoto, Keiko; Adachi, Souichi; Kawakami, Kiyoshi; Kato, Koji; Nishimura, Ryosei; Izraeli, Shai; Hayashi, Yasuhide; Miyano, Satoru; Kojima, Seiji; Ito, Etsuro; Ogawa, Seishi

    2013-11-01

    Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

  11. Somatic mtDNA mutation spectra in the aging human putamen.

    Directory of Open Access Journals (Sweden)

    Siôn L Williams

    Full Text Available The accumulation of heteroplasmic mitochondrial DNA (mtDNA deletions and single nucleotide variants (SNVs is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. To address this, we have used next generation sequencing of mtDNA-enriched libraries (Mito-Seq to investigate mtDNA mutation spectra of putamen from young and aged donors. Frequencies of the "common" deletion and other "major arc" deletions were significantly increased in the aged cohort with the fold increase in the frequency of the common deletion exceeding that of major arc deletions. SNVs also increased with age with the highest rate of accumulation in the non-coding control region which contains elements necessary for translation and replication. Examination of predicted amino acid changes revealed a skew towards pathogenic SNVs in the coding region driven by mutation bias. Levels of the pathogenic m.3243A>G tRNA mutation were also found to increase with age. Novel multimeric tandem duplications that resemble murine control region multimers and yeast ρ(- mtDNAs, were identified in both young and aged specimens. Clonal ∼50 bp deletions in the control region were found at high frequencies in aged specimens. Our results reveal the complex manner in which the mitochondrial genome alters with age and provides a foundation for studies of other tissues and disease states.

  12. Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis.

    Science.gov (United States)

    Marchesi, Vincent T

    2016-02-01

    Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes. © FASEB.

  13. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension

    DEFF Research Database (Denmark)

    Beuschlein, Felix; Boulkroun, Sheerazed; Osswald, Andrea

    2013-01-01

    Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na+/K+ ATPase α...... subunit) and ATP2B3 (encoding a Ca2+ ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced...... affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation...

  14. Frequent somatic reversion of KRT1 mutations in ichthyosis with confetti

    OpenAIRE

    Keith A. Choate; Lu, Yin; Zhou, Jing; Elias, Peter M.; Zaidi, Samir; Paller, Amy S; Farhi, Anita; Nelson-Williams, Carol; Crumrine, Debra; Milstone, Leonard M.; Lifton, Richard P

    2015-01-01

    Widespread reversion of genetic disease is rare; however, such events are particularly evident in some skin disorders in which normal clones develop on a background of affected skin. We previously demonstrated that mutations in keratin 10 (KRT10) cause ichthyosis with confetti (IWC), a severe dominant disorder that is characterized by progressive development of hundreds of normal skin spots via revertant mosaicism. Here, we report on a clinical and histological IWC subtype in which affected s...

  15. Is selection required for the accumulation of somatic mitochondrial DNA mutations in post-mitotic cells?

    Science.gov (United States)

    Durham, S E; Samuels, D C; Chinnery, P F

    2006-06-01

    Mitochondrial DNA (mtDNA) mutations accumulate in the skeletal muscle of patients with mtDNA disease, and also as part of healthy ageing. Simulations of human muscle fibres suggest that, over many decades, the continuous destruction and copying of mtDNA (relaxed replication) can lead to dramatic changes in the percentage level of mutant mtDNA in non-dividing cells through random genetic drift. This process should apply to both pathogenic and neutral mutations. To test this hypothesis we sequenced the entire mitochondrial genome for 20 muscle fibres from a healthy elderly 85-year-old individual, chosen because of the low frequency of cytochrome c oxidase negative fibres. Phenotypically neutral single base substitutions were detected in 15% of the healthy fibres, supporting the hypothesis that positive selection is not essential for the clonal expansion of mtDNA point mutations during human life. Treatments that enhance mtDNA replication, such as vigorous excercise, could amplify this process, with potentially detrimental long-term consequences.

  16. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population

    DEFF Research Database (Denmark)

    Nielsen, Camilla; Birgens, Henrik S; Nordestgaard, Børge G

    2011-01-01

    JAK2 V617F is present in the majority of patients with myeloproliferative cancer; however, its prevalence and clinical significance in the general population is unknown. We screened for presence of the mutation in 10,507 participants from the Copenhagen City Heart Study with up to 17.6 years.......8-1.1) for 1-year age increases. In the general population, JAK2 V617F is associated with increased morbidity and mortality, although only present in 18 of 10,507 (0.2%)....

  17. Association between targeted somatic mutation (TSM) signatures and HGS-OvCa progression.

    Science.gov (United States)

    Lindley, Robyn A; Humbert, Patrick; Larner, Cliff; Akmeemana, Eric H; Pendlebury, Christopher R R

    2016-09-01

    Evidence already exists that the activation-induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence ("motif") surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis. If successful, a secondary objective is to investigate if such changes are associated with disease progression indicators that include disease stage and progression-free survival time. Using a discovery cohort of 194 high-grade serous ovarian adenocarcinoma (HGS-OvCa) exomes, the results confirm the ability of the novel in silico approach used to identify changes in the preferred target motifs for AID, APOBEC3G, APOBEC3B, and ADAR1 during oncogenesis. Using this approach, a set of new cancer-progression associated signatures (C-PASs) were identified. Furthermore, it was found that the C-PAS identified can be used to differentiate between the cohort of patients that remained progression-free for longer than 60 months, from those in which disease progressed within 60 months (sensitivity 95%, specificity 90%). The spectrum of outcomes observed here could provide a foundation for future clinical assessment of susceptibility variants in ovarian, and several other cancers as disease progresses. The ability of the in silico methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  18. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in "paternal age-effect" syndromes.

    Science.gov (United States)

    Goriely, Anne; Lord, Helen; Lim, Jasmine; Johnson, David; Lester, Tracy; Firth, Helen V; Wilkie, Andrew O M

    2010-08-01

    Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age ("paternal age effect"). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occur. Here we describe the first molecularly documented evidence of germline and somatic mosaicism for FGFR2 mutation, identified in the mother of a child with Crouzon syndrome caused by a heterozygous c.1007A>G (p.Asp336Gly) substitution. Levels of maternal somatic mosaicism for this mutation, estimated by pyrosequencing, ranged from 3.3% in hair roots to 14.1% in blood. Our observation underlines the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon, and other paternal age-effect syndromes.

  19. [THE SOMATIC MUTATIONS AND ABERRANT METHYLATION AS POTENTIAL GENETIC MARKERS OF URINARY BLADDER CANCER].

    Science.gov (United States)

    Mikhailenko, D S; Kushlinskii, N E

    2016-02-01

    All around the world, more than 330 thousands cases of bladder cancer are registered annually hence representing actual problem of modern oncology. Still in demand are search and characteristic of new molecular markers of bladder cancer detecting in tumor cells from urinary sediment and having high diagnostic accuracy. The studies of last decade, especially using methods of genome-wide sequencing, permitted to receive a large amount of experimental data concerning development and progression of bladder cancer The review presents systematic analysis of publications available in PubMed data base mainly of last five years. The original studies of molecular genetic disorders under bladder cancer and meta-analyzes were considered This approach permitted to detected the most common local alterations of DNA under bladder cancer which can be detected using routine genetic methods indifferent clinical material and present prospective interest for development of test-systems. The molecular genetic markers of disease can be activating missense mutations in 7 and 10 exons of gene of receptor of growth factor of fibroblasts 3 (FGFR3), 9 and 20 exons of gene of Phosphatidylinositol-4,5-bi-phosphate-3-kinase (PIK3CA) and mutation in -124 and -146 nucleotides in promoter of gene of catalytic subunit telomerase (TERT). The development of test-systems on the basis of aberrant methylation of CpG-islets of genes-suppressors still is seemed as a difficult task because of differences in pattern of methylation of different primary tumors at various stages of clonal evolution of bladder cancer though they can be considered as potential markers.

  20. A complex form of hereditary spastic paraplegia in three siblings due to somatic mosaicism for a novel SPAST mutation in the mother.

    Science.gov (United States)

    Aulitzky, Anna; Friedrich, Katrin; Gläser, Dieter; Gastl, Regina; Kubisch, Christian; Ludolph, Albert C; Volk, Alexander E

    2014-12-15

    Hereditary spastic paraplegias (HSPs) represent a clinically and genetically heterogeneous group of diseases. Major symptoms comprise progressive bilateral leg stiffness, spasticity at rest and diffuse muscle weakness. Complex forms are characterized by additional symptoms like dementia, cerebellar dysfunction or seizures. Autosomal dominant, autosomal recessive, X-linked recessive and possibly mitochondrial inheritance have been described in familial HSP. The most frequently mutated gene in familial cases of uncomplicated autosomal dominant HSP is SPAST, however de novo mutations in SPAST are rarely found. Here, we report on the clinical and genetic findings in a family with three children afflicted by complex HSP and their unaffected parents. Although autosomal dominant inheritance seemed unlikely in this family, genetic testing revealed a novel SPAST mutation, c.1837G>C (p.Asp613His), in a heterozygous state in all affected individuals and somatic mosaicism of this mutation in the unaffected mother. Our study thus expands the knowledge on SPAST-associated HSP and emphasizes that de novo mutations and somatic mosaicism should be taken into consideration in HSP families presenting with a family history not suggestive for an autosomal dominant inheritance pattern. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Somatic point mutations in mtDNA control region are influenced by genetic background and associated with healthy aging: a GEHA study

    DEFF Research Database (Denmark)

    Rose, Giuseppina; Romeo, Giuseppe; Dato, Serena

    2010-01-01

    Tissue specific somatic mutations occurring in the mtDNA control region have been proposed to provide a survival advantage. Data on twins and on relatives of long-lived subjects suggested that the occurrence/accumulation of these mutations may be genetically influenced. To further investigate....... We found a significant correlation of the mtDNA control region heteroplasmy between sibs, confirming a genetic influence on this phenomenon. Furthermore, many subjects showed heteroplasmy due to mutations different from the C150T transition. In these cases heteroplasmy was correlated within sibpairs...... in Finnish and northern Italian samples, but not in southern Italians. This suggested that the genetic contribution to control region mutations may be population specific. Finally, we observed a possible correlation between heteroplasmy and Hand Grip strength, one of the best markers of physical performance...

  2. A novel missense mutation in LIS1 in a child with subcortical band heterotopia and pachygyria inherited from his mildly affected mother with somatic mosaicism.

    Science.gov (United States)

    Mineyko, Aleksandra; Doja, Asif; Hurteau, Julie; Dobyns, William B; Das, Soma; Boycott, Kym M

    2010-06-01

    Mutations in the LIS1 gene result in isolated lissencephaly or subcortical band heterotopia. We report a 5-year-old male who presented with seizures and global developmental delay. Magnetic resonance imaging (MRI) demonstrated posteriorly predominant pachygyria and subcortical band heterotopia. His mother had a history of epilepsy, with onset in her teenage years. Her MRI revealed no abnormalities. Sequence analysis of the LIS1 gene identified a novel p.H389Y mutation in exon 11 (c.1165C>T). The child's mother was found to have the identical mutation as her son, with the signal intensity of the mutant allele being much lower than the normal allele, suggesting somatic mosaicism. This patient is one of only a few reported with a missense mutation in LIS1 associated with subcortical band heterotopia, and this is the first report of a mosaic individual having an affected child.

  3. Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting.

    Science.gov (United States)

    Dougherty, Brian A; Lai, Zhongwu; Hodgson, Darren R; Orr, Maria C M; Hawryluk, Matthew; Sun, James; Yelensky, Roman; Spencer, Stuart K; Robertson, Jane D; Ho, Tony W; Fielding, Anitra; Ledermann, Jonathan A; Barrett, J Carl

    2017-07-04

    To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had >80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo- and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.

  4. The use of PIG-A as a sentinel gene for the study of the somatic mutation rate and of mutagenic agents in vivo.

    Science.gov (United States)

    Peruzzi, Benedetta; Araten, David J; Notaro, Rosario; Luzzatto, Lucio

    2010-01-01

    Mutations are an inherent risk of cell duplication. On one hand, inheritable mutations are the driving force of biological evolution; on the other hand, their accumulation in somatic cells plays a key role in the development of cancer. The frequency of mutants (f) and the rate of mutation (mu) are biological features of any cell population: their measurement could provide important information about the risk of oncogenesis and the exposure to carcinogenic agents. However, the measurement of these parameters is not trivial. To measure f and mu, a potential sentinel gene is the PIG-A gene, which encodes one of the subunits of an enzyme essential in the biosynthesis of glycosylphosphatidylinositol (GPI). Since PIG-A is X-linked, mutational inactivation of the one single copy active in somatic cells entails absence from the cell surface of all the proteins that require GPI for attachment to the membrane: thus, mutant cells display a GPI-negative surface phenotype that can be easily detected by flow cytometry. The measurement of PIG-A mutants by counting cells with the GPI-negative phenotype has proved to be effective to measure mutant frequency in peripheral blood cells of humans and of others animals. Up to now, mu has been exceedingly difficult to measure in human cells; however, by using as a sentinel the PIG-A gene in lymphoblastoid cell lines we now have a test that makes it practical to measure mu in human cells. 2009 Elsevier B.V. All rights reserved.

  5. A Site Specific Model And Analysis Of The Neutral Somatic Mutation Rate In Whole-Genome Cancer Data

    DEFF Research Database (Denmark)

    Bertl, Johanna; Guo, Qianyun; Rasmussen, Malene Juul

    2017-01-01

    Detailed modelling of the neutral mutational process in cancer cells is crucial for identifying driver mutations and understanding the mutational mechanisms that act during cancer development. The neutral mutational process is very complex: whole-genome analyses have revealed that the mutation ra...

  6. A Somatic HIF2α Mutation-Induced Multiple and Recurrent Pheochromocytoma/Paraganglioma with Polycythemia: Clinical Study with Literature Review.

    Science.gov (United States)

    Liu, Qiuli; Wang, Yan; Tong, Dali; Liu, Gaolei; Yuan, Wenqiang; Zhang, Jun; Ye, Jin; Zhang, Yao; Yuan, Gang; Feng, Qingxing; Zhang, Dianzheng; Jiang, Jun

    2017-03-01

    A syndrome known as pheochromocytomas (PCC)/paragangliomas (PGL) and polycythemia resulted from gain-of-function mutation of hypoxia-inducible factor 2α (HIF2α) has been reported recently. However, clinical features of this syndrome vary from patient to patient. In our study, we described the clinical features of the patient within 15-year follow-up with a literature review. The patient presented with "red face" since childhood and was diagnosed with polycythemia and pheochromocytoma in 2000, and then, tumor was removed at his age of 27 (year 2000). However, 13 years later (2013), he was diagnosed with multiple paragangliomas. Moreover, 2 years later (2015), another two paragangaliomas were also confirmed. Genetic analysis of hereditary PCC/PGL-related genes was conducted. A somatic heterozygous missense mutation of HIF2α (c.1589C>T) was identified at exon 12, which is responsible for the elevated levels of HIF2α and erythropoietin (EPO) and subsequent development of paragangaliomas. However, this mutation was only found in the tumors from three different areas, not in the blood. So far, 13 cases of PCC/PGL with polycythemia have been reported. Among them, somatic mutations of HIF2α at exon 12 are responsible for 12 cases, and only 1 case was caused by germline mutation of HIF2α at exon 9. The HIF2α mutation-induced polycythemia with PCC/PGL is a rare syndrome with no treatment for cure. Comprehensive therapies for this disease include removal of the tumors and intermittent phlebotomies; administration of medications to control blood pressure and to prevent complications or death resulted from high concentration of red blood cell (RBC). Genetic test is strongly recommended for patients with early onset of polycythemia and multiple/recurrent PCC/PGL.

  7. Recent advances in understanding Cushing disease: resistance to glucocorticoid negative feedback and somatic USP8 mutations [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Eleni Daniel

    2017-05-01

    Full Text Available Cushing’s disease is a rare disease with a characteristic phenotype due to significant hypercortisolism driven by over-secretion of adrenocorticotropic hormone and to high morbidity and mortality if untreated. It is caused by a corticotroph adenoma of the pituitary, but the exact mechanisms leading to tumorigenesis are not clear. Recent advances in molecular biology such as the discovery of somatic mutations of the ubiquitin-specific peptidase 8 (USP8 gene allow new insights into the pathogenesis, which could be translated into exciting and much-needed therapeutic applications.

  8. Correlation between temperature-dependent permittivity dispersion ...

    Indian Academy of Sciences (India)

    The results indicate that the poling temperature plays a crucial role in the domains' alignment process, as expected. The temperature-dependent permittivity frequency dispersion and depolarization behaviours may have same origin. The aligned domains' break up into random state/nanodomains at depoling temperature ...

  9. Temperature Dependent Models of Semiconductor Devices for ...

    African Journals Online (AJOL)

    The paper presents an investigation of the temperature dependent model of a diode and bipolar transistor built-in to the NAP-2 program and comparison of these models with experimentally measured characteristics of the BA 100 diode and BC 109 transistor. The detail of the modelling technique has been discussed and ...

  10. Measurements of temperature dependence of 'localized susceptibility'

    CERN Document Server

    Shiozawa, H; Ishii, H; Takayama, Y; Obu, K; Muro, T; Saitoh, Y; Matsuda, T D; Sugawara, H; Sato, H

    2003-01-01

    The magnetic susceptibility of some rare-earth compounds is estimated by measuring magnetic circular dichroism (MCD) of rare-earth 3d-4f absorption spectra. The temperature dependence of the magnetic susceptibility obtained by the MCD measurement is remarkably different from the bulk susceptibility in most samples, which is attributed to the strong site selectivity of the core MCD measurement.

  11. Temperature dependence of the MDT gas gain

    CERN Document Server

    Gaudio, G; Treichel, M

    1999-01-01

    This note describes the measurements taken in the Gamma Irradiation Facility (GIF) in the X5 test beam area at CERN to investigate the temperature dependence of the MDT drift gas (Ar/CO2 - 90:10). Spectra were taken with an Americium-241 source during the aging studies. We analysed the effects of temperature changes on the pulse height spectrum.

  12. Investigation Of Temperature Dependent Characteristics Of ...

    African Journals Online (AJOL)

    The structure, magnetization and magnetostriction of Laves phase compound TbCo2 were investigated by temperature dependent high resolution neutron powder diffraction. The compound crystallizes in the cubic Laves phase C15 structure above its Curie temperature, TC and exhibits a rhombohedral distortion (space ...

  13. Oncogenic potential is related to activating effect of cancer single and double somatic mutations in receptor tyrosine kinases

    Science.gov (United States)

    Hashimoto, Kosuke; Rogozin, Igor B.; Panchenko, Anna R.

    2012-01-01

    Aberrant activation of receptor tyrosine kinases (RTKs) is a common feature of many cancer cells. It was previously suggested that the mechanisms of kinase activation in cancer might be linked to transitions between active and inactive states. Here we estimate the effects of single and double cancer mutations on the stability of active and inactive states of the kinase domains from different RTKs. We show that singleton cancer mutations destabilize active and inactive states, however inactive states are destabilized more than the active ones leading to kinase activation. We show that there exists a relationship between the estimate of oncogenic potential of cancer mutation and kinase activation. Namely, more frequent mutations have a higher activating effect, which might allow us to predict the activating effect of the mutations from the mutation spectra. Independent evolutionary analysis of mutation spectra complements this observation and finds the same frequency threshold defining mutation hot spots. We analyze double mutations and report a positive epistasis and additional advantage of doublets with respect to cancer cell fitness. The activation mechanisms of double mutations differ from those of single mutations and double mutation spectrum is found to be dissimilar to the mutation spectrum of singletons. PMID:22753356

  14. Somatic mutation and recombination induced with reactor thermal neutrons in Drosophila melanogaster; Mutacion y recombinacion somaticas inducidas con neutrones termicos de reactor en Drosophila melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Zambrano A, F.; Guzman R, J.; Paredes G, L.; Delfin L, A. [Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

    1997-07-01

    The SMART test of Drosophila melanogaster was used to quantify the effect over the somatic mutation and recombination induced by thermal and fast neutrons at the TRIGA Mark III reactor of the ININ at the power of 300 k W for times of 30, 60 and 120 minutes with total equivalent doses respectively of 20.8, 41.6 and 83.2 Sv. A linear relation between the radiation equivalent dose and the frequency of the genetic effects such as mutation and recombination was observed. The obtained results allow to conclude that SMART is a sensitive system to the induced damage by neutrons, so this can be used for studying its biological effects. (Author)

  15. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension

    NARCIS (Netherlands)

    Azizan, E.A.; Poulsen, H.; Tuluc, P.; Zhou, J; Clausen, M.V.; Lieb, A.; Maniero, C.; Garg, S.; Bochukova, E.G.; Zhao, W.; Shaikh, L.H.; Brighton, C.A.; Teo, A.E.; Davenport, A.P.; Dekkers, T.; Tops, B.; Kusters, B.; Ceral, J.; Yeo, G.S.; Neogi, S.G.; McFarlane, I.; Rosenfeld, N.; Marass, F.; Hadfield, J.; Margas, W.; Chaggar, K.; Solar, M.; Deinum, J.; Dolphin, A.C.; Farooqi, I.S.; Striessnig, J.; Nissen, P.; Brown, M.J.

    2013-01-01

    At least 5% of individuals with hypertension have adrenal aldosterone-producing adenomas (APAs). Gain-of-function mutations in KCNJ5 and apparent loss-of-function mutations in ATP1A1 and ATP2A3 were reported to occur in APAs. We find that KCNJ5 mutations are common in APAs resembling

  16. A mutation of cdc-25.1 causes defects in germ cells but not in somatic tissues in C. elegans.

    Science.gov (United States)

    Kim, Jiyoung; Lee, Ah-Reum; Kawasaki, Ichiro; Strome, Susan; Shim, Yhong-Hee

    2009-07-31

    By screening C. elegans mutants for severe defects in germline proliferation, we isolated a new loss-of-function allele of cdc-25.1, bn115. bn115 and another previously identified loss-of-function allele nr2036 do not exhibit noticeable cell division defects in the somatic tissues but have reduced numbers of germ cells and are sterile, indicating that cdc-25.1 functions predominantly in the germ line during postembryonic development, and that cdc-25.1 activity is probably not required in somatic lineages during larval development. We analyzed cell division of germ cells and somatic tissues in bn115 homozygotes with germline-specific anti-PGL-1 immunofluorescence and GFP transgenes that express in intestinal cells, in distal tip cells, and in gonadal sheath cells, respectively. We also analyzed the expression pattern of cdc-25.1 with conventional and quantitative RT-PCR. In the presence of three other family members of cdc-25 in C. elegans defects are observed only in the germ line but not in the somatic tissues in cdc-25.1 single mutants, and cdc-25.1 is expressed predominantly, if not exclusively, in the germ line during postembryonic stages. Our findings indicate that the function of cdc-25.1 is unique in the germ line but likely redundant with other members in the soma.

  17. Abiotic stress leads to somatic and heritable changes in homologous recombination frequency, point mutation frequency and microsatellite stability in Arabidopsis plants

    Energy Technology Data Exchange (ETDEWEB)

    Yao Youli, E-mail: youli.yao@uleth.ca [Department of Biological Sciences, University of Lethbridge, Lethbridge, T1K 3M4 Alberta (Canada); Kovalchuk, Igor, E-mail: igor.kovalchuk@uleth.ca [Department of Biological Sciences, University of Lethbridge, Lethbridge, T1K 3M4 Alberta (Canada)

    2011-02-10

    In earlier studies, we showed that abiotic stresses, such as ionizing radiation, heavy metals, temperature and water, trigger an increase in homologous recombination frequency (HRF). We also demonstrated that many of these stresses led to inheritance of high-frequency homologous recombination, HRF. Although an increase in recombination frequency is an important indicator of genome rearrangements, it only represents a minor portion of possible stress-induced mutations. Here, we analyzed the influence of heat, cold, drought, flood and UVC abiotic stresses on two major types of mutations in the genome, point mutations and small deletions/insertions. We used two transgenic lines of Arabidopsis thaliana, one allowing an analysis of reversions in a stop codon-containing inactivated {beta}-glucuronidase transgene and another one allowing an analysis of repeat stability in a microsatellite-interrupted {beta}-glucuronidase transgene. The transgenic Arabidopsis line carrying the {beta}-glucuronidase-based homologous recombination substrate was used as a positive control. We showed that the majority of stresses increased the frequency of point mutations, homologous recombination and microsatellite instability in somatic cells, with the frequency of homologous recombination being affected the most. The analysis of transgenerational changes showed an increase in HRF to be the most prominent effect observed in progeny. Significant changes in recombination frequency were observed upon exposure to all types of stress except drought, whereas changes in microsatellite instability were observed upon exposure to UVC, heat and cold. The frequency of point mutations in the progeny of stress-exposed plants was the least affected; an increase in mutation frequency was observed only in the progeny of plants exposed to UVC. We thus conclude that transgenerational changes in genome stability in response to stress primarily involve an increase in recombination frequency.

  18. Non-coding cancer driver candidates identified with a sample- and position-specific model of the somatic mutation rate

    Science.gov (United States)

    Juul, Malene; Bertl, Johanna; Guo, Qianyun; Nielsen, Morten Muhlig; Świtnicki, Michał; Hornshøj, Henrik; Madsen, Tobias; Hobolth, Asger; Pedersen, Jakob Skou

    2017-01-01

    Non-coding mutations may drive cancer development. Statistical detection of non-coding driver regions is challenged by a varying mutation rate and uncertainty of functional impact. Here, we develop a statistically founded non-coding driver-detection method, ncdDetect, which includes sample-specific mutational signatures, long-range mutation rate variation, and position-specific impact measures. Using ncdDetect, we screened non-coding regulatory regions of protein-coding genes across a pan-cancer set of whole-genomes (n = 505), which top-ranked known drivers and identified new candidates. For individual candidates, presence of non-coding mutations associates with altered expression or decreased patient survival across an independent pan-cancer sample set (n = 5454). This includes an antigen-presenting gene (CD1A), where 5’UTR mutations correlate significantly with decreased survival in melanoma. Additionally, mutations in a base-excision-repair gene (SMUG1) correlate with a C-to-T mutational-signature. Overall, we find that a rich model of mutational heterogeneity facilitates non-coding driver identification and integrative analysis points to candidates of potential clinical relevance. DOI: http://dx.doi.org/10.7554/eLife.21778.001 PMID:28362259

  19. Somatic Mutation of the 5′ Noncoding Region of the BCL-6 Gene Is Associated with Intraclonal Diversity and Clonal Selection in Histological Transformation of Follicular Lymphoma

    Science.gov (United States)

    Szereday, Zoltán; Csernus, Balázs; Nagy, Monika; László, Terézia; Warnke, Roger A.; Matolcsy, András

    2000-01-01

    Follicular lymphoma (FL) is a B cell non-Hodgkin’s lymphoma (NHL) that frequently displays a t(14;18) translocation. Clonal evolution and histological transformation of FL is frequently associated with the accumulation of secondary genetic alterations. It has been demonstrated that the BCL-6 gene can be altered by chromosomal rearrangements and by mutations clustering in its 5′ noncoding region in a significant fraction of FL and diffuse large cell lymphoma (DLCL). To elucidate the role of the BCL-6 gene alterations in the histological transformation and clonal progression of FL, we analyzed serial biopsy specimens from 12 patients with FL. Two cases of FL showed no histological alteration in the second biopsy, and 10 cases of FL showed morphological transformation to DLCL in the second biopsy. Southern blot analysis was used to detect rearrangement of the BCL-6 gene, polymerase chain reaction-single strand conformation polymorphism and sequence analysis were performed for identification of mutations in the 5′ noncoding region of the BCL-6 gene, and immunohistochemical analysis was applied to reveal the BCL-6 protein expression. No BCL-6 gene rearrangement was detected in any of the samples, but a total of 58 mutations were found in the 5′ noncoding region of the BCL-6 gene in seven cases. In five cases, both the FL and the clonally related FL or DLCL, and in two cases only the DLCL samples were mutated. The mutations were identical in multiple biopsy specimens of FL that did not show morphological transformation. In six patients where FL cells underwent morphological transformation, considerable intraclonal sequence heterogeneity was observed, indicating an ongoing type of somatic mutation. Based on the pattern of shared and nonshared mutations, the genealogical relationship of neoplastic clones could be established. In all of these cases, the histological transformation of FL was associated with the emergence of a subpopulation marked by new sites of

  20. Somatic mutation of the 5' noncoding region of the BCL-6 gene is associated with intraclonal diversity and clonal selection in histological transformation of follicular lymphoma.

    Science.gov (United States)

    Szereday, Z; Csernus, B; Nagy, M; László, T; Warnke, R A; Matolcsy, A

    2000-03-01

    Follicular lymphoma (FL) is a B cell non-Hodgkin's lymphoma (NHL) that frequently displays a t(14;18) translocation. Clonal evolution and histological transformation of FL is frequently associated with the accumulation of secondary genetic alterations. It has been demonstrated that the BCL-6 gene can be altered by chromosomal rearrangements and by mutations clustering in its 5' noncoding region in a significant fraction of FL and diffuse large cell lymphoma (DLCL). To elucidate the role of the BCL-6 gene alterations in the histological transformation and clonal progression of FL, we analyzed serial biopsy specimens from 12 patients with FL. Two cases of FL showed no histological alteration in the second biopsy, and 10 cases of FL showed morphological transformation to DLCL in the second biopsy. Southern blot analysis was used to detect rearrangement of the BCL-6 gene, polymerase chain reaction-single strand conformation polymorphism and sequence analysis were performed for identification of mutations in the 5' noncoding region of the BCL-6 gene, and immunohistochemical analysis was applied to reveal the BCL-6 protein expression. No BCL-6 gene rearrangement was detected in any of the samples, but a total of 58 mutations were found in the 5' noncoding region of the BCL-6 gene in seven cases. In five cases, both the FL and the clonally related FL or DLCL, and in two cases only the DLCL samples were mutated. The mutations were identical in multiple biopsy specimens of FL that did not show morphological transformation. In six patients where FL cells underwent morphological transformation, considerable intraclonal sequence heterogeneity was observed, indicating an ongoing type of somatic mutation. Based on the pattern of shared and nonshared mutations, the genealogical relationship of neoplastic clones could be established. In all of these cases, the histological transformation of FL was associated with the emergence of a subpopulation marked by new sites of mutations in

  1. Visualization portal for genetic variation (VizGVar): a tool for interactive visualization of SNPs and somatic mutations in exons, genes and protein domains.

    Science.gov (United States)

    Román, Antonio Solano; Alfaro, Verónica; Cruz, Carlos; Solano, Allan Orozco

    2017-10-30

    VizGVar was designed to meet the growing need of the research community for improved genomic and proteomic data viewers that benefit from better information visualization. We implemented a new information architecture and applied user centered design principles to provide a new improved way of visualizing genetic information and protein data related to human disease. VizGVar connects the entire database of Ensembl protein motifs, domains, genes and exons with annotated SNPs and somatic variations from PharmGKB and COSMIC. VizGVar precisely represents genetic variations and their respective location by colored curves to designate different types of variations. The structured hierarchy of biological data is reflected in aggregated patterns through different levels, integrating several layers of information at once. VizGVar provides a new interactive, web-based JavaScript visualization of somatic mutations and protein variation, enabling fast and easy discovery of clinically relevant variation patterns. VizGVar is accessible at http://vizport.io/vizgvar. http://vizport.io/vizgvar/doc/. asolano@broadinstitute.org, allan.orozcosolano@ucr.ac.cr.

  2. Temperature dependence of optically induced cell deformations

    Science.gov (United States)

    Fritsch, Anatol; Kiessling, Tobias R.; Stange, Roland; Kaes, Josef A.

    2012-02-01

    The mechanical properties of any material change with temperature, hence this must be true for cellular material. In biology many functions are known to undergo modulations with temperature, like myosin motor activity, mechanical properties of actin filament solutions, CO2 uptake of cultured cells or sex determination of several species. As mechanical properties of living cells are considered to play an important role in many cell functions it is surprising that only little is known on how the rheology of single cells is affected by temperature. We report the systematic temperature dependence of single cell deformations in Optical Stretcher (OS) measurements. The temperature is changed on a scale of about 20 minutes up to hours and compared to defined temperature shocks in the range of milliseconds. Thereby, a strong temperature dependence of the mechanics of single suspended cells is revealed. We conclude that the observable differences arise rather from viscosity changes of the cytosol than from structural changes of the cytoskeleton. These findings have implications for the interpretation of many rheological measurements, especially for laser based approaches in biological studies.

  3. Somatic Mutation in Immunoglobulin Gene Variable Region in Patients With Chronic Lymphoid Leukemia and Its Influence on Disease Prognosis

    Directory of Open Access Journals (Sweden)

    Sadighi

    2016-03-01

    Full Text Available Background Chronic lymphocytic leukemia (CLL is a common blood cancer in people aged over 40. In addition to clinical and pathologic staging and blood tests, immunoglobulin variable heavy chain (IgVH mutation analysis is a relevant prognostic factor for CLL. Finding the most prevalent mutation type and conducting a molecular analysis of immunoglobulin in the majority of the patients can contribute to identifying the disease pattern. Objectives In the present study, we used molecular detection methods to find the relationship between clinical and pathologic findings with immunoglobulin heavy chain mutations in CLL patients in Iran. Patients and Methods Patients with CLL were randomly selected from patients referred to Imam Khomeini hospital, Tehran, Iran. All patients underwent a clinical staging of the disease and had flow cytometric analysis performed on their blood samples. The panels of cell surface markers used for the diagnosis of chronic lymphoid leukemia include CD19, CD3, CD23, CD10, and CD5. The diagnosis confirmed a minimum of 20% positive expression of dual CD5 and CD19 markers. Genomic DNA was then extracted from the patients’ blood and IgVH mutation analysis was conducted with pGEM-T (easy vector cloning kit followed by IgVH sequencing. Results Study patients were 42 to 80 years old, with their mean age of 62 (SE = 1.87 years. About 73% of them were male. The mean white blood cell (WBC count, lymphocytes percentage, average hemoglobin level, and platelet count were 56,000/µL, 85%, 12 g/dL, and 150,000/µL, respectively. According to their molecular analysis, 38.9% of patients were unmutated and 61.1% showed mutation in the variable heavy chain locus. The most common mutation had occurred in IgVH3 allele (66.66%. The mean overall survival rate of patients, mutated and unmutated, was, respectively, 39 (95% CI, 32 to 46 and 31 (95% CI, 26 to 36 months (P = 0.4. Binet stage had statistically significant relationship with patients

  4. Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation.

    Science.gov (United States)

    Stavnezer, Janet; Linehan, Erin K; Thompson, Mikayla R; Habboub, Ghaith; Ucher, Anna J; Kadungure, Tatenda; Tsuchimoto, Daisuke; Nakabeppu, Yusaku; Schrader, Carol E

    2014-06-24

    Somatic hypermutation (SHM) of antibody variable region genes is initiated in germinal center B cells during an immune response by activation-induced cytidine deaminase (AID), which converts cytosines to uracils. During accurate repair in nonmutating cells, uracil is excised by uracil DNA glycosylase (UNG), leaving abasic sites that are incised by AP endonuclease (APE) to create single-strand breaks, and the correct nucleotide is reinserted by DNA polymerase β. During SHM, for unknown reasons, repair is error prone. There are two APE homologs in mammals and, surprisingly, APE1, in contrast to its high expression in both resting and in vitro-activated splenic B cells, is expressed at very low levels in mouse germinal center B cells where SHM occurs, and APE1 haploinsufficiency has very little effect on SHM. In contrast, the less efficient homolog, APE2, is highly expressed and contributes not only to the frequency of mutations, but also to the generation of mutations at A:T base pair (bp), insertions, and deletions. In the absence of both UNG and APE2, mutations at A:T bp are dramatically reduced. Single-strand breaks generated by APE2 could provide entry points for exonuclease recruited by the mismatch repair proteins Msh2-Msh6, and the known association of APE2 with proliferating cell nuclear antigen could recruit translesion polymerases to create mutations at AID-induced lesions and also at A:T bp. Our data provide new insight into error-prone repair of AID-induced lesions, which we propose is facilitated by down-regulation of APE1 and up-regulation of APE2 expression in germinal center B cells.

  5. Prospective blinded study of somatic mutation detection in cell-free DNA utilizing a targeted 54-gene next generation sequencing panel in metastatic solid tumor patients.

    Science.gov (United States)

    Kim, Seung Tae; Lee, Won-Suk; Lanman, Richard B; Mortimer, Stefanie; Zill, Oliver A; Kim, Kyoung-Mee; Jang, Kee Taek; Kim, Seok-Hyung; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Eltoukhy, Helmy; Kang, Won Ki; Lee, Woo Yong; Kim, Hee-Cheol; Park, Keunchil; Lee, Jeeyun; Talasaz, AmirAli

    2015-11-24

    Sequencing of the mutant allele fraction of circulating cell-free DNA (cfDNA) derived from tumors is increasingly utilized to detect actionable genomic alterations in cancer. We conducted a prospective blinded study of a comprehensive cfDNA sequencing panel with 54 cancer genes. To evaluate the concordance between cfDNA and tumor DNA (tDNA), sequencing results were compared between cfDNA from plasma and genomic tumor DNA (tDNA). Utilizing next generation digital sequencing technology (DST), we profiled approximately 78,000 bases encoding 512 complete exons in the targeted genes in cfDNA from plasma. Seventy-five patients were prospectively enrolled between February 2013 and March 2014, including 61 metastatic cancer patients and 14 clinical stage II CRC patients with matched plasma and tissue samples. Using the 54-gene panel, we detected at least one somatic mutation in 44 of 61 tDNA (72.1%) and 29 of 44 (65.9%) cfDNA. The overall concordance rate of cfDNA to tDNA was 85.9%, when all detected mutations were considered. We collected serial cfDNAs during cetuximab-based treatment in 2 metastatic KRAS wild-type CRC patients, one with acquired resistance and one with primary resistance. We demonstrate newly emerged KRAS mutation in cfDNA 1.5 months before radiologic progression. Another patient had a newly emerged PIK3CA H1047R mutation on cfDNA analysis at progression during cetuximab/irinotecan chemotherapy with gradual increase in allele frequency from 0.8 to 2.1%. This blinded, prospective study of a cfDNA sequencing showed high concordance to tDNA suggesting that the DST approach may be used as a non-invasive biopsy-free alternative to conventional sequencing using tumor biopsy.

  6. Temperature Dependent Wire Delay Estimation in Floorplanning

    DEFF Research Database (Denmark)

    Winther, Andreas Thor; Liu, Wei; Nannarelli, Alberto

    2011-01-01

    Due to large variations in temperature in VLSI circuits and the linear relationship between metal resistance and temperature, the delay through wires of the same length can be different. Traditional thermal aware floorplanning algorithms use wirelength to estimate delay and routability....... In this work, we show that using wirelength as the evaluation metric does not always produce a floorplan with the shortest delay. We propose a temperature dependent wire delay estimation method for thermal aware floorplanning algorithms, which takes into account the thermal effect on wire delay. The experiment...... results show that a shorter delay can be achieved using the proposed method. In addition, we also discuss the congestion and reliability issues as they are closely related to routing and temperature....

  7. Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

    NARCIS (Netherlands)

    de Kock, Leanne; Rivera, Barbara; Revil, Timothée; Thorner, Paul; Goudie, Catherine; Bouron-Dal Soglio, Dorothée; Choong, Catherine S.; Priest, John R.; Van Diest, Paul J.; Tanboon, Jantima; Wagner, Anja; Ragoussis, Jiannis; Choong, Peter F.M.; Foulkes, William D

    2017-01-01

    Background:Sarcomas are rare and heterogeneous cancers. We assessed the contribution of DICER1 mutations to sarcoma development.Methods:The coding region of DICER1 was sequenced in 67 sarcomas using a custom Fluidigm Access Array. The RNase III domains were Sanger sequenced in six additional

  8. The reliable assurance of detecting somatic mutations in cancer-related genes by next-generation sequencing: the results of external quality assessment in China

    Science.gov (United States)

    Han, Yanxi; Yi, Lang; Xie, Jiehong; Yang, Xin; Fan, Gaowei; Wang, Guojing; Hao, Mingju; Zhang, Dong; Zhang, Kuo; Lin, Guigao; Li, Jinming

    2016-01-01

    To evaluate the proficiencies of laboratories utilizing next-generation sequencing (NGS) to detect somatic mutations in cancer-related genes, an external quality assessment (EQA) was implemented by the National Center for Clinical Laboratories of China in 2015. We prepared a panel of samples that comprised eight samples made by mixing synthetic mutated DNA fragments with normal human genomic DNA and one reference sample containing only genomic DNA. We validated our sample panel, and then distributed it to laboratories across China. We received complete results from 64 laboratories. The performances of 51.6 % (33/64) respondent labs were acceptable and 26.6 % (17/64) of the labs returned perfect results. In total, 449 mistakes were reported, including 201 false-negatives (201/449, 44.8 %) and 222 false-positives (222/449, 49.4 %) and 26 slightly discordant results (26/449, 5.8 %). We believe these unsatisfactory results and varied performances are mainly due to the enrichment methods used, the diverse sequencing chemistries of the different NGS platforms, and other errors within the sequencing process. The results indicate that our sample panel is suitable for use in EQA studies, and that further laboratory training in targeted NGS testing is urgently required. To address this, we propose a targeted NGS workflow with details on quality assurance procedures according to the current guidelines. PMID:27542269

  9. Somatic-cell selection is a major determinant of the blood-cell phenotype in heterozygotes for glucose-6-phosphate dehydrogenase mutations causing severe enzyme deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Filosa, S.; Giacometti, N.; Wangwei, C.; Martini, G. [Istituto Internazionale di Genetica e Biofisica, Naples (Italy)] [and others

    1996-10-01

    X-chromosome inactivation in mammals is regarded as an essentially random process, but the resulting somatic-cell mosaicism creates the opportunity for cell selection. In most people with red-blood-cell glucose-6-phosphate dehydrogenase (G6PD) deficiency, the enzyme-deficient phenotype is only moderately expressed in nucleated cells. However, in a small subset of hemizygous males who suffer from chronic nonspherocytic hemolytic anemia, the underlying mutations (designated class I) cause more-severe G6PD deficiency, and this might provide an opportunity for selection in heterozygous females during development. In order to test this possibility we have analyzed four heterozygotes for class I G6PD mutations: two with G6PD Portici (1178G{r_arrow}A) and two with G6PD Bari (1187C{r_arrow}T). We found that in fractionated blood cell types (including erythroid, myeloid, and lymphoid cell lineages) there was a significant excess of G6PD-normal cells. The significant concordance that we have observed in the degree of imbalance in the different blood-cell lineages indicates that a selective mechanism is likely to operate at the level of pluripotent blood stem cells. Thus, it appears that severe G6PD deficiency affects adversely the proliferation or the survival of nucleated blood cells and that this phenotypic characteristic is critical during hematopoiesis. 65 refs., 6 figs., 3 tabs.

  10. Binding of CLL subset 4 B-cell receptor immunoglobulins to viable human memory B lymphocytes requires a distinctive IGKV somatic mutation.

    Science.gov (United States)

    Catera, Rosa; Liu, Yun; Gao, Chao; Yan, Xiao-Jie; Magli, Amanda; Allen, Steven L; Kolitz, Jonathan E; Rai, Kanti R; Chu, Charles C; Feizi, Ten; Stamatopoulos, Kostas; Chiorazzi, Nicholas

    2017-01-12

    Amino acid replacement mutations in certain CLL stereotyped B-cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34+ IGs, we found IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bind naïve B cells. However, only subset 4 IGs react with memory B cells. Furthermore, subset 4 IGs do not bind DNA nor i or I carbohydrate antigens, common targets of IGHV4-34-utilizing antibodies in systemic lupus erythematosus and cold agglutinin disease, respectively. Notably, we found that subset 4 IG binding to memory B lymphocytes depends on an aspartic acid at position 66 of FR3 in the rearranged IGKV2-30 gene; this amino acid residue is acquired by somatic mutation. Our findings illustrate the importance of positive and negative selection criteria for structural elements in CLL IGs and suggest that autoantigens driving normal B cells to become subset 4 CLL cells differ from those driving IGHV4-34+ B cells in other diseases.

  11. Detection of somatic TP53 mutations in tampons of patients with high-grade serous ovarian cancer.

    Science.gov (United States)

    Erickson, Britt K; Kinde, Isaac; Dobbin, Zachary C; Wang, Yuxuan; Martin, Jovana Y; Alvarez, Ronald D; Conner, Michael G; Huh, Warner K; Roden, Richard B S; Kinzler, Kenneth W; Papadopoulos, Nickolas; Vogelstein, Bert; Diaz, Luis A; Landen, Charles N

    2014-11-01

    To investigate whether tumor cells could be detected in the vagina of women with serous ovarian cancer through TP53 analysis of DNA samples collected by placement of a vaginal tampon. Women undergoing surgery for a pelvic mass were identified in the gynecologic oncology clinic. They placed a vaginal tampon before surgery, which was removed in the operating room. Cells were isolated and DNA was extracted from both the cells trapped within the tampon and the primary tumor. In patients with serous carcinoma, the DNA was interrogated for the presence of TP53 mutations using a method capable of detecting rare mutant alleles in a mixture of mutant and wild-type DNA. Thirty-three patients were enrolled. Eight patients with advanced serous ovarian cancer were included for analysis. Three had a prior tubal ligation. TP53 mutations were identified in all eight tumor samples. Analysis of the DNA from the tampons revealed mutations in three of the five patients with intact tubes (sensitivity 60%) and in none of the three patients with tubal ligation. In all three participants with mutation detected in the tampon specimen, the tumor and the vaginal DNA harbored the exact same TP53 mutation. The fraction of DNA derived from exfoliated tumor cells ranged from 0.01% to 0.07%. In this pilot study, DNA derived from tumor was detected in the vaginas of 60% of patients with ovarian cancer with intact fallopian tubes. With further development, this approach may hold promise for the early detection of this deadly disease.

  12. Witches' brooms in Siberian stone pine as somatic mutations and initial genetic material for breeding of nut-bearing and ornamental cultivars

    Directory of Open Access Journals (Sweden)

    M. S. Yamburov

    2013-12-01

    Full Text Available For the raising of the Siberian stone pine (Pinus sibirica Du Tour nut-bearing and ornamental cultivars, the most important traits are adense crown, slow growth and precocity. Generative mutations of this kind are eliminated by natural selection, therefore, somatic mutationrsearch is important. Among somatic mutations, the most promising one is the so-called 'witches' brooms' (WB where crown fragments demonstrate slowed growth and intensive branching. WB occasionally occurs in native populations. According to phytopathology textbooks, WB are caused by various pathogen species (viruses, mycoplasmas, fungi. The WB of this kind are characterized by a sickly look, full suppression of reproductive functions, a short life and a nidus patternof distribution. There are also WB of different types: with a high vitality and fertility, a long life and sporadic distribution. They occur very rarely(about 1 per 10 000 trees across the species' range. We investigated 18 trees with WB of this type. The size of WB ranged from 0.3 to 30 m, age varied from 30 to 300 years. Male cones were absent inall WB. Female cone initiation was normal if the WB was located in the top part of a crown. Scions from WB and a normal crown (NC of the same tree were grafted on identical rootstocks. On average,the height of 7-year-old WB grafts (WBG was 2 times lower, and the stem diameter was 2 times higher than in the NC grafts (NCG. It wasachieved due to the fundamental differences in the shoot system morphogenesis. Here are three principal differences in decreasing order of importance: (i WBGs were characterized by the absence or near absence of apical dominance. The NCG had no more than 3 orders of branching, and the length of the 1st order axis was on average 5times larger than the axis of the 3rd order. The WBG had 6-7 orders of branching, and the length of shoots of 5-6th orders averaged 80-90% of the length of the first orders. (ii At an

  13. Inducing Somatic Pkd1 Mutations in Vivo in a Mouse Model of Autosomal-Dominant Polycystic Kidney Disease

    Science.gov (United States)

    2016-10-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the world’s most common life-threatening genetic diseases. Over 95% of diagnosed cases of... genetic models to induce mutations: one during embryogenesis (Six2-cre) and one in the adult (Villin-cre). The embryonic model has generated clones of...wildtype and mutant cells that persist in the adult. The adult model has failed to induce sufficient recombination . In this report we summarize the

  14. Temperature dependences of hydrous species in feldspars

    Science.gov (United States)

    Liu, W. D.; Yang, Y.; Zhu, K. Y.; Xia, Q. K.

    2018-01-01

    Feldspars are abundant in the crust of the Earth. Multiple hydrogen species such as OH, H2O and NH4 + can occur in the structure of feldspars. Hydrogen species play a critical role in influencing some properties of the host feldspars and the crust, including mechanical strength, electrical property of the crust, and evolution of the crustal fluids. Knowledge of hydrous species in feldspars to date has been mostly derived from spectroscopic studies at ambient temperature. However, the speciation and sites of hydrous species at high temperatures may not be quenchable. Here, we investigated the temperature dependences of several typical hydrous components (e.g., type IIa OH, type IIb OH and type I H2O) in feldspars by measuring the in situ FTIR spectra at elevated temperatures up to 800 °C. We found that the hydrous species demonstrated different behaviors at elevated temperatures. With increasing temperature, type IIa OH redistributes on the various sites in the anorthoclase structure. Additionally, O-H vibration frequencies increase for types IIa and IIb OH, and they decrease for type I H2O with increasing temperature. In contrast to type I H2O which drastically dehydrates during the heating process, types IIa and IIb OH show negligible loss; however, the bulk integral absorption coefficients drastically decrease with increasing temperature. These results may have implications in understanding the properties of hydrous species and feldspars at non-ambient temperatures, not only under geologic conditions but also at cold planetary surface conditions.

  15. Temperature dependent terahertz properties of Ammonium Nitrate

    Science.gov (United States)

    Rahman, Abdur; Azad, Abul; Moore, David

    Terahertz spectroscopy has been demonstrated as an ideal nondestructive method for identifying hazardous materials such as explosives. Many common explosives exhibit distinct spectral signatures at terahertz range (0.1-6.0 THz) due to the excitations of their low frequency vibrational modes. Ammonium nitrate (AN), an easily accessible oxidizer often used in improvised explosive, exhibits strong temperature dependence. While the room temperature terahertz absorption spectrum of AN is featureless, it reveals distinct spectral features below 240 K due to the polymorphic phase transition. We employed terahertz time domain spectroscopy to measure the effective dielectric properties of AN embedded in polytetrafluoroethylene (PTFE) binder. The dielectric properties of pure AN were extracted using three different effective medium theories (EMT), simple effective medium approach, Maxwell-Garnett (MG) model, and Bruggeman (BR) model. In order to understand the effect of temperature on the dielectric properties, we varied the sample temperature from 5K to 300K. This study indicates presence of additional vibrational modes at low temperature. These results may greatly enhance the detectability of AN and facilitate more accurate theoretical modeling.

  16. Temperature dependence of phonons in photosynthesis proteins

    Science.gov (United States)

    Xu, Mengyang; Myles, Dean; Blankenship, Robert; Markelz, Andrea

    Protein long range vibrations are essential to biological function. For many proteins, these vibrations steer functional conformational changes. For photoharvesting proteins, the structural vibrations play an additional critical role in energy transfer to the reaction center by both phonon assisted energy transfer and energy dissipation. The characterization of these vibrations to understand how they are optimized to balance photoharvesting and photoprotection is challenging. To date this characterization has mainly relied on fluorescence line narrowing measurements at cryogenic temperatures. However, protein dynamics has a strong temperature dependence, with an apparent turn on in anharmonicity between 180-220 K. If this transition affects intramolecular vibrations, the low temperature measurements will not represent the phonon spectrum at biological temperatures. Here we use the new technique of anisotropic terahertz microscopy (ATM) to measure the intramolecular vibrations of FMO complex. ATM is uniquely capable of isolating protein vibrations from isotropic background. We find resonances both red and blue shift with temperature above the dynamical transition. The results indicate that the characterization of vibrations must be performed at biologically relevant temperatures to properly understand the energy overlap with the excitation energy transfer. This work was supported by NSF:DBI 1556359, BioXFEL seed Grant funding from NSF:DBI 1231306, DOE: DE-SC0016317, and the Bruce Holm University at Buffalo Research Foundation Grant.

  17. Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1) gene reveals association with early age of diagnosis in colorectal cancer patients.

    Science.gov (United States)

    Shull, Austin Y; Clendenning, Megan L; Ghoshal-Gupta, Sampa; Farrell, Christopher L; Vangapandu, Hima V; Dudas, Larry; Wilkerson, Brent J; Buckhaults, Phillip J

    2013-01-01

    The Cub and Sushi Multiple Domains 1 (CSMD1) gene, located on the short arm of chromosome 8, codes for a type I transmembrane protein whose function is currently unknown. CSMD1 expression is frequently lost in many epithelial cancers. Our goal was to characterize the relationships between CSMD1 somatic mutations, allele imbalance, DNA methylation, and the clinical characteristics in colorectal cancer patients. We sequenced the CSMD1 coding regions in 54 colorectal tumors using the 454FLX pyrosequencing platform to interrogate 72 amplicons covering the entire coding sequence. We used heterozygous SNP allele ratios at multiple CSMD1 loci to determine allelic balance and infer loss of heterozygosity. Finally, we performed methylation-specific PCR on 76 colorectal tumors to determine DNA methylation status for CSMD1 and known methylation targets ALX4, RUNX3, NEUROG1, and CDKN2A. Using 454FLX sequencing and confirming with Sanger sequencing, 16 CSMD1 somatic mutations were identified in 6 of the 54 colorectal tumors (11%). The nonsynonymous to synonymous mutation ratio of the 16 somatic mutations was 15:1, a ratio significantly higher than the expected 2:1 ratio (p = 0.014). This ratio indicates a presence of positive selection for mutations in the CSMD1 protein sequence. CSMD1 allelic imbalance was present in 19 of 37 informative cases (56%). Patients with allelic imbalance and CSMD1 mutations were significantly younger (average age, 41 years) than those without somatic mutations (average age, 68 years). The majority of tumors were methylated at one or more CpG loci within the CSMD1 coding sequence, and CSMD1 methylation significantly correlated with two known methylation targets ALX4 and RUNX3. C:G>T:A substitutions were significantly overrepresented (47%), suggesting extensive cytosine methylation predisposing to somatic mutations. Deep amplicon sequencing and methylation-specific PCR reveal that CSMD1 alterations can correlate with earlier clinical presentation

  18. Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1 gene reveals association with early age of diagnosis in colorectal cancer patients.

    Directory of Open Access Journals (Sweden)

    Austin Y Shull

    Full Text Available BACKGROUND: The Cub and Sushi Multiple Domains 1 (CSMD1 gene, located on the short arm of chromosome 8, codes for a type I transmembrane protein whose function is currently unknown. CSMD1 expression is frequently lost in many epithelial cancers. Our goal was to characterize the relationships between CSMD1 somatic mutations, allele imbalance, DNA methylation, and the clinical characteristics in colorectal cancer patients. METHODS: We sequenced the CSMD1 coding regions in 54 colorectal tumors using the 454FLX pyrosequencing platform to interrogate 72 amplicons covering the entire coding sequence. We used heterozygous SNP allele ratios at multiple CSMD1 loci to determine allelic balance and infer loss of heterozygosity. Finally, we performed methylation-specific PCR on 76 colorectal tumors to determine DNA methylation status for CSMD1 and known methylation targets ALX4, RUNX3, NEUROG1, and CDKN2A. RESULTS: Using 454FLX sequencing and confirming with Sanger sequencing, 16 CSMD1 somatic mutations were identified in 6 of the 54 colorectal tumors (11%. The nonsynonymous to synonymous mutation ratio of the 16 somatic mutations was 15:1, a ratio significantly higher than the expected 2:1 ratio (p = 0.014. This ratio indicates a presence of positive selection for mutations in the CSMD1 protein sequence. CSMD1 allelic imbalance was present in 19 of 37 informative cases (56%. Patients with allelic imbalance and CSMD1 mutations were significantly younger (average age, 41 years than those without somatic mutations (average age, 68 years. The majority of tumors were methylated at one or more CpG loci within the CSMD1 coding sequence, and CSMD1 methylation significantly correlated with two known methylation targets ALX4 and RUNX3. C:G>T:A substitutions were significantly overrepresented (47%, suggesting extensive cytosine methylation predisposing to somatic mutations. CONCLUSIONS: Deep amplicon sequencing and methylation-specific PCR reveal that CSMD1

  19. Yeast mother cell-specific ageing, genetic (in)stability, and the somatic mutation theory of ageing.

    Science.gov (United States)

    Laun, Peter; Bruschi, Carlo V; Dickinson, J Richard; Rinnerthaler, Mark; Heeren, Gino; Schwimbersky, Richard; Rid, Raphaela; Breitenbach, Michael

    2007-01-01

    Yeast mother cell-specific ageing is characterized by a limited capacity to produce daughter cells. The replicative lifespan is determined by the number of cell cycles a mother cell has undergone, not by calendar time, and in a population of cells its distribution follows the Gompertz law. Daughter cells reset their clock to zero and enjoy the full lifespan characteristic for the strain. This kind of replicative ageing of a cell population based on asymmetric cell divisions is investigated as a model for the ageing of a stem cell population in higher organisms. The simple fact that the daughter cells can reset their clock to zero precludes the accumulation of chromosomal mutations as the cause of ageing, because semiconservative replication would lead to the same mutations in the daughters. However, nature is more complicated than that because, (i) the very last daughters of old mothers do not reset the clock; and (ii) mutations in mitochondrial DNA could play a role in ageing due to the large copy number in the cell and a possible asymmetric distribution of damaged mitochondrial DNA between mother and daughter cell. Investigation of the loss of heterozygosity in diploid cells at the end of their mother cell-specific lifespan has shown that genomic rearrangements do occur in old mother cells. However, it is not clear if this kind of genomic instability is causative for the ageing process. Damaged material other than DNA, for instance misfolded, oxidized or otherwise damaged proteins, seem to play a major role in ageing, depending on the balance between production and removal through various repair processes, for instance several kinds of proteolysis and autophagy. We are reviewing here the evidence for genetic change and its causality in the mother cell-specific ageing process of yeast.

  20. Transcriptome analysis of an apple (Malus × domestica) yellow fruit somatic mutation identifies a gene network module highly associated with anthocyanin and epigenetic regulation.

    Science.gov (United States)

    El-Sharkawy, Islam; Liang, Dong; Xu, Kenong

    2015-12-01

    Using RNA-seq, this study analysed an apple (Malus×domestica) anthocyanin-deficient yellow-skin somatic mutant 'Blondee' (BLO) and its red-skin parent 'Kidd's D-8' (KID), the original name of 'Gala', to understand the molecular mechanisms underlying the mutation. A total of 3299 differentially expressed genes (DEGs) were identified between BLO and KID at four developmental stages and/or between two adjacent stages within BLO and/or KID. A weighted gene co-expression network analysis (WGCNA) of the DEGs uncovered a network module of 34 genes highly correlated (r=0.95, P=9.0×10(-13)) with anthocyanin contents. Although 12 of the 34 genes in the WGCNA module were characterized and known of roles in anthocyanin, the remainder 22 appear to be novel. Examining the expression of ten representative genes in the module in 14 diverse apples revealed that at least eight were significantly correlated with anthocyanin variation. MdMYB10 (MDP0000259614) and MdGST (MDP0000252292) were among the most suppressed module member genes in BLO despite being undistinguishable in their corresponding sequences between BLO and KID. Methylation assay of MdMYB10 and MdGST in fruit skin revealed that two regions (MR3 and MR7) in the MdMYB10 promoter exhibited remarkable differences between BLO and KID. In particular, methylation was high and progressively increased alongside fruit development in BLO while was correspondingly low and constant in KID. The methylation levels in both MR3 and MR7 were negatively correlated with anthocyanin content as well as the expression of MdMYB10 and MdGST. Clearly, the collective repression of the 34 genes explains the loss-of-colour in BLO while the methylation in MdMYB10 promoter is likely causal for the mutation. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  1. SubClonal Hierarchy Inference from Somatic Mutations: Automatic Reconstruction of Cancer Evolutionary Trees from Multi-region Next Generation Sequencing.

    Directory of Open Access Journals (Sweden)

    Noushin Niknafs

    2015-10-01

    Full Text Available Recent improvements in next-generation sequencing of tumor samples and the ability to identify somatic mutations at low allelic fractions have opened the way for new approaches to model the evolution of individual cancers. The power and utility of these models is increased when tumor samples from multiple sites are sequenced. Temporal ordering of the samples may provide insight into the etiology of both primary and metastatic lesions and rationalizations for tumor recurrence and therapeutic failures. Additional insights may be provided by temporal ordering of evolving subclones--cellular subpopulations with unique mutational profiles. Current methods for subclone hierarchy inference tightly couple the problem of temporal ordering with that of estimating the fraction of cancer cells harboring each mutation. We present a new framework that includes a rigorous statistical hypothesis test and a collection of tools that make it possible to decouple these problems, which we believe will enable substantial progress in the field of subclone hierarchy inference. The methods presented here can be flexibly combined with methods developed by others addressing either of these problems. We provide tools to interpret hypothesis test results, which inform phylogenetic tree construction, and we introduce the first genetic algorithm designed for this purpose. The utility of our framework is systematically demonstrated in simulations. For most tested combinations of tumor purity, sequencing coverage, and tree complexity, good power (≥ 0.8 can be achieved and Type 1 error is well controlled when at least three tumor samples are available from a patient. Using data from three published multi-region tumor sequencing studies of (murine small cell lung cancer, acute myeloid leukemia, and chronic lymphocytic leukemia, in which the authors reconstructed subclonal phylogenetic trees by manual expert curation, we show how different configurations of our tools can

  2. Somatic Symptoms

    DEFF Research Database (Denmark)

    Eliasen, Marie; Kreiner, Svend; Ebstrup, Jeanette F

    2016-01-01

    A high number of somatic symptoms have been associated with poor health status and increased health care use. Previous studies focused on number of symptoms without considering the specific symptoms. The aim of the study was to investigate 1) the prevalence of 19 somatic symptoms, 2......) the associations between the symptoms, and 3) the associations between the somatic symptoms, self-perceived health and limitations due to physical health accounting for the co-occurrence of symptoms. Information on 19 somatic symptoms, self-perceived health and limitations due to physical health was achieved from.......9% of the respondents were bothered by one or more of the 19 somatic symptoms. The symptoms were associated in a complex structure. Still, recognisable patterns were identified within organ systems/body parts. When accounting for symptom co-occurrence; dizziness, pain in legs, respiratory distress and tiredness were...

  3. Inclusion of temperature dependent shell corrections in Landau ...

    Indian Academy of Sciences (India)

    Abstract. Landau theory used for studying hot rotating nuclei usually uses zero temperature Struti- nsky smoothed total energy for the temperature dependent shell corrections. This is replaced in this work by the temperature dependent Strutinsky smoothed free energy. Our results show that this re- placement has only ...

  4. Inclusion of temperature dependent shell corrections in Landau ...

    Indian Academy of Sciences (India)

    Landau theory used for studying hot rotating nuclei usually uses zero temperature Strutinsky smoothed total energy for the temperature dependent shell corrections. This is replaced in this work by the temperature dependent Strutinsky smoothed free energy. Our results show that this replacement has only marginal effect for ...

  5. Temperature dependence of ferromagnetic resonance measurements in nanostructured line arrays

    Directory of Open Access Journals (Sweden)

    Raposo V.

    2014-07-01

    Full Text Available We report the effect of temperature on the ferromagnetic resonance (FMR spectra of nanostructured line arrays. Different temperature dependences are observed for permalloy an nickel based samples. The qualitative features of the temperature dependence of the resonance field and linewidth can be described by the usual expression of slow relaxing linewidth mechanism and Bloch equation.

  6. Temperature dependence of the magnetization of canted spin structures

    DEFF Research Database (Denmark)

    Jacobsen, Henrik; Lefmann, Kim; Brok, Erik

    2012-01-01

    for the temperature dependence of the magnetization of a simple canted spin structure in which relaxation can take place at finite temperatures between spin configurations with different canting angles. We show that the saturation magnetization may either decrease or increase with decreasing temperature, depending...

  7. Somatic diversification of immunoglobulins.

    Science.gov (United States)

    Rudikoff, S; Pawlita, M; Pumphrey, J; Heller, M

    1984-04-01

    A series of three IgM, kappa monoclonal antibodies arising from a fusion of BALB/c spleen cells from mice immunized with beta-(1,6)-galactan-containing antigens have been analyzed. These three lines were found (i) to have homologous protein sequences in the heavy chain D region and at the sites of recombination between the heavy chain variable and D segment (VH-D) and the D and joining segment (D-JH), although amino acid substitutions were observed in both the heavy and light chain variable regions; (ii) to use identical heavy and light chain joining segments; and (iii) to demonstrate two identical (productive and nonproductive) kappa-chain rearrangements. A likely explanation for these observations is that the three lines are clonally related (arise from a common precursor) and that the observed heavy and light chain variable segment substitutions represent somatic point mutations. Because these antibodies are all of the IgM class, the results indicate that a somatic mutational mechanism is activated early in B-cell ontogeny and operates at both the heavy and light chain loci. Furthermore, the somatic mutation process appears to continue during the development of a given cell line, but is independent of class switching.

  8. Modeling temperature dependence of trace element concentrations in groundwater using temperature dependent distribution coefficient

    Science.gov (United States)

    Saito, H.; Saito, T.; Hamamoto, S.; Komatsu, T.

    2015-12-01

    In our previous study, we have observed trace element concentrations in groundwater increased when groundwater temperature was increased with constant thermal loading using a 50-m long vertical heat exchanger installed at Saitama University, Japan. During the field experiment, 38 degree C fluid was circulated in the heat exchanger resulting 2.8 kW thermal loading over 295 days. Groundwater samples were collected regularly from 17-m and 40-m deep aquifers at four observation wells located 1, 2, 5, and 10 m, respectively, from the heat exchange well and were analyzed with ICP-MS. As a result, concentrations of some trace elements such as boron increased with temperature especially at the 17-m deep aquifer that is known as marine sediment. It has been also observed that the increased concentrations have decreased after the thermal loading was terminated indicating that this phenomenon may be reversible. Although the mechanism is not fully understood, changes in the liquid phase concentration should be associated with dissolution and/or desorption from the solid phase. We therefore attempt to model this phenomenon by introducing temperature dependence in equilibrium linear adsorption isotherms. We assumed that distribution coefficients decrease with temperature so that the liquid phase concentration of a given element becomes higher as the temperature increases under the condition that the total mass stays constant. A shape function was developed to model the temperature dependence of the distribution coefficient. By solving the mass balance equation between the liquid phase and the solid phase for a given element, a new term describing changes in the concentration was implemented in a source/sink term of a standard convection dispersion equation (CDE). The CDE was then solved under a constant ground water flow using FlexPDE. By calibrating parameters in the newly developed shape function, the changes in element concentrations observed were quite well predicted. The

  9. Hysteresis and Temperature Dependency of Moisture Sorption – New Measurements

    DEFF Research Database (Denmark)

    Rode, Carsten; Hansen, Kurt Kielsgaard

    2011-01-01

    It is well known that sorption characteristics of building materials exhibit hysteresis in the way the equilibrium curves develop between adsorption and desorption, and that the sorption curves are also somewhat temperature dependent. However, these two facts are most often neglected in models...... measurements of hysteresis and temperature dependency of the moisture sorption characteristics of three different porous building materials: aerated concrete, cement paste and spruce. Scanning curves are measured for all three materials where periods with adsorption and desorption interrupt each other...

  10. Germline and somatic mosaicism for FGFR2 mutation in the mother of a child with Crouzon syndrome: Implications for genetic testing in ?paternal age-effect? syndromes

    OpenAIRE

    Goriely, Anne; Lord, Helen; Lim, Jasmine; Johnson, David; Lester, Tracy; Firth, Helen V.; Wilkie, Andrew OM

    2010-01-01

    Crouzon syndrome is a dominantly inherited disorder characterized by craniosynostosis and facial dysostosis, caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene; it belongs to a class of disorders that mostly arise as de novo mutations and exhibit a near-exclusive paternal origin of mutation and elevated paternal age (?paternal age effect?). However, even if this is the major mode of origin of mutations in paternal age-effect disorders, germline mosaicism may also occu...

  11. Temperature dependence of the HNO3 UV absorption cross sections

    Science.gov (United States)

    Burkholder, James B.; Talukdar, Ranajit K.; Ravishankara, A. R.; Solomon, Susan

    1993-01-01

    The temperature dependence of the HNO3 absorption cross sections between 240 and 360 K over the wavelength range 195 to 350 nm has been measured using a diode array spectrometer. Absorption cross sections were determined using both (1) absolute pressure measurements at 298 K and (2) a dual absorption cell arrangement in which the absorption spectrum at various temperatures is measured relative to the room temperature absorption spectrum. The HNO3 absorption spectrum showed a temperature dependence which is weak at short wavelengths but stronger at longer wavelengths which are important for photolysis in the lower stratosphere. The 298 K absorption cross sections were found to be larger than the values currently recommended for atmospheric modeling (DeMore et al., 1992). Our absorption cross section data are critically compared with the previous measurements of both room temperature and temperature-dependent absorption cross sections. Temperature-dependent absorption cross sections of HNO3 are recommended for use in atmospheric modeling. These temperature dependent HNO3 absorption cross sections were used in a two-dimensional dynamical-photochemical model to demonstrate the effects of the revised absorption cross sections on loss rate of HNO3 and the abundance of NO2 in the stratosphere.

  12. Temperature dependent optical properties of PbS nanocrystals.

    Science.gov (United States)

    Nordin, M N; Li, Juerong; Clowes, S K; Curry, R J

    2012-07-11

    A comprehensive study of the optical properties of PbS nanocrystals (NCs) is reported that includes the temperature dependent absorption, photoluminescence (PL) and PL lifetime in the range of 3-300 K. The absorption and PL are found to display different temperature dependent behaviour though both redshift as temperature is reduced. This results in a temperature dependent Stokes shift which increases from ∼75 meV at 300 K with reducing temperature until saturating at ∼130 meV below ∼150 K prior to a small reduction to 125 meV upon cooling from 25 to 3 K. The PL lifetime is found to be single exponential at 3 K with a lifetime of τ(1) = 6.5 μs. Above 3 K biexponential behaviour is observed with the lifetime for each process displaying a different temperature dependence. The Stokes shift is modelled using a three-level rate equation model incorporating temperature dependent parameter values obtained via fitting phenomenological relationships to the observed absorption and PL behaviour. This results in a predicted energy difference between the two emitting states of ∼6 meV which is close to the excitonic exchange energy splitting predicted theoretically for these systems.

  13. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Directory of Open Access Journals (Sweden)

    Virijevic Marijana

    2016-12-01

    Full Text Available Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2 genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK. The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up.

  14. BUCKLING OF A COLUMN WITH TEMPERATURE DEPENDENT MATERIAL PROPERTIES

    Directory of Open Access Journals (Sweden)

    Ömer SOYKASAP

    2001-01-01

    Full Text Available Buckling of a column with temperature dependent material properties is investigated. Euler-Bernoulli theory of thin beams is used to derive the element matrices by means of the minimum potential energy principle. Temperature dependency of material properties is taken into account in the formulation. The column is divided into finite elements with the axial degrees of freedom defined at the outer fiber of the column. Column elements have simpler derivations and compact element matrices than those of classical beam-bending element. Some illustrative examples are presented to show the convergence of numerical results obtained by the use of new elements. The results are compared with those of the classical beam-bending element and analytical solution. The new element converges to the analytical results as powerful as the classical beam-bending element. The temperature effects on the buckling loads of the column with temperature dependent material properties are also examined.

  15. Temperature dependent climate projection deficiencies in CMIP5 models

    DEFF Research Database (Denmark)

    Christensen, Jens H.; Boberg, Fredrik

    2012-01-01

    Monthly mean temperatures for 34 GCMs available from the CMIP5 project are compared with observations from CRU for 26 different land regions covering all major land areas in the world for the period 1961-2000 by means of quantile-quantile (q-q) diagrams. A warm period positive temperature dependent...... bias is identified for many of the models within many of the chosen climate regions. However, the exact temperature dependence varies considerably between the models. We analyse the role of this difference as a contributing factor for some models to project stronger regional warming than others...... that in general models with a positive temperature dependent bias tend to have a large projected temperature change, and these tendencies increase with increasing global warming level. We argue that this appears to be linked with the ability of models to capture complex feedbacks accurately. In particular land...

  16. On the Temperature Dependence of the UNIQUAC/UNIFAC Models

    DEFF Research Database (Denmark)

    Skjold-Jørgensen, Steen; Rasmussen, Peter; Fredenslund, Aage

    1980-01-01

    Local composition models for the description of the properties of liquid mixtures do not in general give an accurate representation of excess Gibbs energy and excess enthalpy simultaneously. The introduction of temperature dependent interaction parameters leads to considerable improvements...... of the simultaneous correlation. The temperature dependent parameters have, however, little physical meaning and very odd results are frequently obtained when the interaction parameters obtained from excess enthalpy information alone are used for the prediction of vapor-liquid equilibria. The UNIQUAC/UNIFAC models...... are modified in this work by the introduction of a general temperature dependence of the coordination number. The modified UNIQUAC/UNIFAC models are especially suited for the representation of mixtures containing non-associating components. The modified models contain the same number of interaction parameters...

  17. EGFR somatic mutations in lung tumors: radon exposure and passive smoking in former- and never-smoking U.S. women.

    Science.gov (United States)

    Taga, Masataka; Mechanic, Leah E; Hagiwara, Nobutoshi; Vähäkangas, Kirsi H; Bennett, William P; Alavanja, Michael C R; Welsh, Judith A; Khan, Mohammed A; Lee, Adam; Diasio, Robert; Edell, Eric; Bungum, Aaron; Jang, Jin Sung; Yang, Ping; Jen, Jin; Harris, Curtis C

    2012-06-01

    Patients with lung cancer with mutations in EGF receptor (EGFR) tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke. This hypothesis was investigated by analyzing EGFR mutations in 70 lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic. Overall, the frequency of EGFR mutation was 41% [95% confidence interval (CI), 32%-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors. The results suggest that EGFR mutations are common in female, never-smoking lung cancer cases from the United States, and EGFR mutations are unlikely due to exposure to radon or passive smoking.

  18. The temperature dependent amide I band of crystalline acetanilide

    Energy Technology Data Exchange (ETDEWEB)

    Cruzeiro, Leonor [CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro (Portugal); Physics Department, FCT, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro (Portugal); Freedman, Holly [CCMAR, Universidade do Algarve, Campus de Gambelas, 8005-139 Faro (Portugal)

    2013-10-01

    The temperature dependent anomalous peak in the amide I band of crystalline acetanilide is thought to be due to self-trapped states. On the contrary, according to the present model, the anomalous peak comes from the fraction of ACN molecules strongly hydrogen-bonded to a neighboring ACN molecule, and its intensity decreases because, on average, this fraction decreases as temperature increases. This model provides, for the first time, an integrated and theoretically consistent view of the temperature dependence of the full amide I band and a qualitative explanation of some of the features of nonlinear pump–probe experiments.

  19. Somatic mutations of isocitrate dehydrogenases 1 and 2 are prognostic and follow-up markers in patients with acute myeloid leukaemia with normal karyotype

    Science.gov (United States)

    Karan-Djurasevic, Teodora; Marjanovic, Irena; Tosic, Natasa; Mitrovic, Mirjana; Djunic, Irena; Colovic, Natasa; Vidovic, Ana; Suvajdzic-Vukovic, Nada; Tomin, Dragica; Pavlovic, Sonja

    2016-01-01

    Abstract Background Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes are frequent molecular lesions in acute myeloid leukaemia with normal karyotype (AML-NK). The effects of IDH mutations on clinical features and treatment outcome in AML-NK have been widely investigated, but only a few studies monitored these mutations during follow-up. Patients and methods In our study samples from 110 adult de novo AML-NK were studied for the presence of IDH1 and IDH2 mutations, their associations with other prognostic markers and disease outcome. We also analyzed the stability of these mutations during the course of the disease in complete remission (CR) and relapse. Results IDH mutations were found in 25 (23%) patients. IDH+ patients tend to have lower CR rate compared to IDH-patients (44% vs 62.2%, p = 0.152), and had slightly lower disease free survival (12 months vs 17 months; p = 0.091). On the other hand, the presence of IDH mutations had significant impact on overall survival (2 vs 7 months; p = 0.039). The stability of IDH mutations were studied sequentially in 19 IDH+ patients. All of them lost the mutation in CR, and the same IDH mutations were detected in relapsed samples. Conclusions Our study shows that the presence of IDH mutations confer an adverse effect in AML-NK patients, which in combination with other molecular markers can lead to an improved risk stratification and better treatment. Also, IDH mutations are very stable during the course of the disease and can be potentially used as markers for minimal residual disease detection. PMID:27904446

  20. Temperature dependence of electromechanical properties of PLZT x ...

    Indian Academy of Sciences (India)

    Administrator

    the temperature dependence of electromechanical proper- ties of PLZT. It has been observed that the compositions of PLZT ceramics with Zr/Ti 57/43 show enhanced piezoelectric response at room temperature and can be used in low power transducer devices (Shukla et al 2004). Keeping the device application in view, ...

  1. Temperature dependence of exciton diffusion in conjugated polymers

    NARCIS (Netherlands)

    Mikhnenko, O.V.; Cordella, F.; Sieval, A.B.; Hummelen, J.C.; Blom, P.W.M.; Loi, M.A.

    2008-01-01

    The temperature dependence of the exciton dynamics in a conjugated polymer is studied using time-resolved spectroscopy. Photoluminescence decays were measured in heterostructured samples containing a sharp polymer-fullerene interface, which acts as an exciton quenching wall. Using a ID diffusion

  2. Temperature dependence of electromechanical properties of PLZT x ...

    Indian Academy of Sciences (India)

    The compositions of lead lanthanum zirconate titanate PLZT [Pb(Zr0.57Ti0.43)O3 + at% of La, where = 3, 5, 6, 10 and 12] have been synthesized using mixed oxide route. The temperature dependent electromechanical parameters have been determined using vector impedance spectroscopy (VIS). The charge constant ...

  3. Temperature-dependent gas transport and its correlation with kinetic ...

    Indian Academy of Sciences (India)

    2017-05-20

    May 20, 2017 ... Temperature-dependent gas transport and its correlation with kinetic diameter in polymer nanocomposite membrane. N K ACHARYA. Applied Physics Department, Faculty of Technology and Engineering, The M S University of Baroda,. Vadodara 390 001, India sarnavee@gmail.com. MS received 18 May ...

  4. Temperature dependence studies on the electro-oxidation of ...

    Indian Academy of Sciences (India)

    Cyclic voltammetry; electrochemical impedance spectroscopy; activation energy; fuel cell; alcohol. Abstract. Temperature dependence on the electro-oxidation of methanol, ethanol and 1-propanol in 0.5 M H2SO4 were investigated with Pt and PtRu electrodes. Tafel slope and apparent activation energy were evaluated ...

  5. Electronically induced nuclear transitions - temperature dependence and Rabi oscillations

    CERN Document Server

    Niez, J J

    2002-01-01

    This paper deals with a nucleus electromagnetically coupled with the bound states of its electronic surroundings. It describes the temperature dependence of its dynamics and the onset of potential Rabi oscillations by means of a Master Equation. The latter is generalized in order to account for possible strong resonances. Throughout the paper the approximation schemes are discussed and tested. (authors)

  6. Temperature dependence of postmortem MR quantification for soft tissue discrimination

    Energy Technology Data Exchange (ETDEWEB)

    Zech, Wolf-Dieter; Schwendener, Nicole; Jackowski, Christian [University of Bern, From the Institute of Forensic Medicine, Bern (Switzerland); Persson, Anders; Warntjes, Marcel J. [University of Linkoeping, The Center for Medical Image Science and Visualization (CMIV), Linkoeping (Sweden)

    2015-08-15

    To investigate and correct the temperature dependence of postmortem MR quantification used for soft tissue characterization and differentiation in thoraco-abdominal organs. Thirty-five postmortem short axis cardiac 3-T MR examinations were quantified using a quantification sequence. Liver, spleen, left ventricular myocardium, pectoralis muscle and subcutaneous fat were analysed in cardiac short axis images to obtain mean T1, T2 and PD tissue values. The core body temperature was measured using a rectally inserted thermometer. The tissue-specific quantitative values were related to the body core temperature. Equations to correct for temperature differences were generated. In a 3D plot comprising the combined data of T1, T2 and PD, different organs/tissues could be well differentiated from each other. The quantitative values were influenced by the temperature. T1 in particular exhibited strong temperature dependence. The correction of quantitative values to a temperature of 37 C resulted in better tissue discrimination. Postmortem MR quantification is feasible for soft tissue discrimination and characterization of thoraco-abdominal organs. This provides a base for computer-aided diagnosis and detection of tissue lesions. The temperature dependence of the T1 values challenges postmortem MR quantification. Equations to correct for the temperature dependence are provided. (orig.)

  7. On the effect of temperature dependent thermal conductivity on ...

    African Journals Online (AJOL)

    We consider the effect of temperature dependent thermal conductivity on temperature rise in biologic tissues during microwave heating. The method of asymptotic expansion is used for finding solution. An appropriate matching procedure was used in our method. Our result reveals the possibility of multiple solutions and it ...

  8. Extraction of temperature dependent interfacial resistance of thermoelectric modules

    DEFF Research Database (Denmark)

    Chen, Min

    2011-01-01

    This article discusses an approach for extracting the temperature dependency of the electrical interfacial resistance associated with thermoelectric devices. The method combines a traditional module-level test rig and a nonlinear numerical model of thermoelectricity to minimize measurement errors...... on the interfacial resistance. The extracted results represent useful data to investigating the characteristics of thermoelectric module resistance and comparing performance of various modules....

  9. Pressure–temperature dependence of thermodynamic properties of ...

    Indian Academy of Sciences (India)

    properties of materials under high pressures and temperatures for microscopic under- standing as well as technological applications. In this paper, we report our theoretical study of both pressure and temperature dependences of the thermal properties of rutile within the Debye and Debye–Grüneisen models with and ...

  10. Arrhenius temperature dependence of in vitro tissue plasminogen activator thrombolysis

    Energy Technology Data Exchange (ETDEWEB)

    Shaw, George J [Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Dhamija, Ashima [Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Bavani, Nazli [Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Wagner, Kenneth R [Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States); Holland, Christy K [Department of Biomedical Engineering, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0769 (United States)

    2007-06-07

    Stroke is a devastating disease and a leading cause of death and disability. Currently, the only FDA approved therapy for acute ischemic stroke is the intravenous administration of the thrombolytic medication, recombinant tissue plasminogen activator (tPA). However, this treatment has many contraindications and can have dangerous side effects such as intra-cerebral hemorrhage. These treatment limitations have led to much interest in potential adjunctive therapies, such as therapeutic hypothermia (T {<=} 35 deg. C) and ultrasound enhanced thrombolysis. Such interest may lead to combining these therapies with tPA to treat stroke, however little is known about the effects of temperature on the thrombolytic efficacy of tPA. In this work, we measure the temperature dependence of the fractional clot mass loss {delta}m(T) resulting from tPA exposure in an in vitro human clot model. We find that the temperature dependence is well described by an Arrhenius temperature dependence with an effective activation energy E{sub eff} of 42.0 {+-} 0.9 kJ mole{sup -1}. E{sub eff} approximates the activation energy of the plasminogen-to-plasmin reaction of 48.9 kJ mole{sup -1}. A model to explain this temperature dependence is proposed. These results will be useful in predicting the effects of temperature in future lytic therapies.

  11. Investigation of temperature dependence of development and aging

    Science.gov (United States)

    Sacher, G. A.

    1969-01-01

    Temperature dependence of maturation and metabolic rates in insects, and the failure of vital processes during development were investigated. The paper presented advances the general hypothesis that aging in biological systems is a consequence of the production of entropy concomitant with metabolic activity.

  12. Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Juan Feng

    2017-02-01

    Full Text Available Abstract Target-specific next-generation sequencing technology was used to analyze 112 genes in adult patients with acute lymphoblastic leukemia (ALL. This sequencing mainly focused on the specific mutational hotspots. Among the 121 patients, 93 patients were B-ALL (76.9%, and 28 patients (23.1% were T-ALL. Of the 121 patients, 110 (90.9% harbored at least one mutation. The five most frequently mutated genes in T-ALL are NOTCH1, JAK3, FBXW7, FAT1, and NRAS. In B-ALL, FAT1, SF1, CRLF2, TET2, and PTPN1 have higher incidence of mutations. Gene mutations are different between Ph+ALL and Ph−ALL patients. B-ALL patients with PTPN11 mutation and T-ALL patients with NOTCH1 and/or FBXW7 mutations showed better survival. But B-ALL with JAK1/JAK2 mutations showed worse survival. The results suggest that gene mutations exist in adult ALL patients universally, they are related with prognosis.

  13. The Number of Point Mutations in Induced Pluripotent Stem Cells and Nuclear Transfer Embryonic Stem Cells Depends on the Method and Somatic Cell Type Used for Their Generation.

    Science.gov (United States)

    Araki, Ryoko; Mizutani, Eiji; Hoki, Yuko; Sunayama, Misato; Wakayama, Sayaka; Nagatomo, Hiroaki; Kasama, Yasuji; Nakamura, Miki; Wakayama, Teruhiko; Abe, Masumi

    2017-05-01

    Induced pluripotent stem cells hold great promise for regenerative medicine but point mutations have been identified in these cells and have raised serious concerns about their safe use. We generated nuclear transfer embryonic stem cells (ntESCs) from both mouse embryonic fibroblasts (MEFs) and tail-tip fibroblasts (TTFs) and by whole genome sequencing found fewer mutations compared with iPSCs generated by retroviral gene transduction. Furthermore, TTF-derived ntESCs showed only a very small number of point mutations, approximately 80% less than the number observed in iPSCs generated using retrovirus. Base substitution profile analysis confirmed this greatly reduced number of point mutations. The point mutations in iPSCs are therefore not a Yamanaka factor-specific phenomenon but are intrinsic to genome reprogramming. Moreover, the dramatic reduction in point mutations in ntESCs suggests that most are not essential for genome reprogramming. Our results suggest that it is feasible to reduce the point mutation frequency in iPSCs by optimizing various genome reprogramming conditions. We conducted whole genome sequencing of ntES cells derived from MEFs or TTFs. We thereby succeeded in establishing TTF-derived ntES cell lines with far fewer point mutations. Base substitution profile analysis of these clones also indicated a reduced point mutation frequency, moving from a transversion-predominance to a transition-predominance. Stem Cells 2017;35:1189-1196. © 2017 AlphaMed Press.

  14. Efficient Generation of Somatic Cell Nuclear Transfer-Competent Porcine Cells with Mutated Alleles at Multiple Target Loci by Using CRISPR/Cas9 Combined with Targeted Toxin-Based Selection System.

    Science.gov (United States)

    Sato, Masahiro; Miyoshi, Kazuchika; Nakamura, Shingo; Ohtsuka, Masato; Sakurai, Takayuki; Watanabe, Satoshi; Kawaguchi, Hiroaki; Tanimoto, Akihide

    2017-12-04

    The recent advancement in genome editing such a CRISPR/Cas9 system has enabled isolation of cells with knocked multiple alleles through a one-step transfection. Somatic cell nuclear transfer (SCNT) has been frequently employed as one of the efficient tools for the production of genetically modified (GM) animals. To use GM cells as SCNT donor, efficient isolation of transfectants with mutations at multiple target loci is often required. The methods for the isolation of such GM cells largely rely on the use of drug selection-based approach using selectable genes; however, it is often difficult to isolate cells with mutations at multiple target loci. In this study, we used a novel approach for the efficient isolation of porcine cells with at least two target loci mutations by one-step introduction of CRISPR/Cas9-related components. A single guide (sg) RNA targeted to GGTA1 gene, involved in the synthesis of cell-surface α-Gal epitope (known as xenogenic antigen), is always a prerequisite. When the transfected cells were reacted with toxin-labeled BS-I-B₄ isolectin for 2 h at 37 C to eliminate α-Gal epitope-expressing cells, the surviving clones lacked α-Gal epitope expression and were highly expected to exhibit induced mutations at another target loci. Analysis of these α-Gal epitope-negative surviving cells demonstrated a 100% occurrence of genome editing at target loci. SCNT using these cells as donors resulted in the production of cloned blastocysts with the genotype similar to that of the donor cells used. Thus, this novel system will be useful for SCNT-mediated acquisition of GM cloned piglets, in which multiple target loci may be mutated.

  15. Efficient Generation of Somatic Cell Nuclear Transfer-Competent Porcine Cells with Mutated Alleles at Multiple Target Loci by Using CRISPR/Cas9 Combined with Targeted Toxin-Based Selection System

    Directory of Open Access Journals (Sweden)

    Masahiro Sato

    2017-12-01

    Full Text Available The recent advancement in genome editing such a CRISPR/Cas9 system has enabled isolation of cells with knocked multiple alleles through a one-step transfection. Somatic cell nuclear transfer (SCNT has been frequently employed as one of the efficient tools for the production of genetically modified (GM animals. To use GM cells as SCNT donor, efficient isolation of transfectants with mutations at multiple target loci is often required. The methods for the isolation of such GM cells largely rely on the use of drug selection-based approach using selectable genes; however, it is often difficult to isolate cells with mutations at multiple target loci. In this study, we used a novel approach for the efficient isolation of porcine cells with at least two target loci mutations by one-step introduction of CRISPR/Cas9-related components. A single guide (sg RNA targeted to GGTA1 gene, involved in the synthesis of cell-surface α-Gal epitope (known as xenogenic antigen, is always a prerequisite. When the transfected cells were reacted with toxin-labeled BS-I-B4 isolectin for 2 h at 37 C to eliminate α-Gal epitope-expressing cells, the surviving clones lacked α-Gal epitope expression and were highly expected to exhibit induced mutations at another target loci. Analysis of these α-Gal epitope-negative surviving cells demonstrated a 100% occurrence of genome editing at target loci. SCNT using these cells as donors resulted in the production of cloned blastocysts with the genotype similar to that of the donor cells used. Thus, this novel system will be useful for SCNT-mediated acquisition of GM cloned piglets, in which multiple target loci may be mutated.

  16. Somatic Host Cell Alterations in HPV Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Tamara R. Litwin

    2017-08-01

    Full Text Available High-risk human papilloma virus (HPV infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements. HPV-associated cancers have recurrent somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA and phosphatase and tensin homolog (PTEN, human leukocyte antigen A and B (HLA-A and HLA-B-A/B, and the transforming growth factor beta (TGFβ pathway, and rarely have mutations in the tumor protein p53 (TP53 and RB transcriptional corepressor 1 (RB1 tumor suppressor genes. There are some variations by tumor site, such as NOTCH1 mutations which are primarily found in head and neck cancers. Understanding the somatic events following HPV infection and persistence can aid the development of early detection biomarkers, particularly when mutations in precancers are characterized. Somatic mutations may also influence prognosis and treatment decisions.

  17. Somatic Host Cell Alterations in HPV Carcinogenesis.

    Science.gov (United States)

    Litwin, Tamara R; Clarke, Megan A; Dean, Michael; Wentzensen, Nicolas

    2017-08-03

    High-risk human papilloma virus (HPV) infections cause cancers in different organ sites, most commonly cervical and head and neck cancers. While carcinogenesis is initiated by two viral oncoproteins, E6 and E7, increasing evidence shows the importance of specific somatic events in host cells for malignant transformation. HPV-driven cancers share characteristic somatic changes, including apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC)-driven mutations and genomic instability leading to copy number variations and large chromosomal rearrangements. HPV-associated cancers have recurrent somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) and phosphatase and tensin homolog ( PTEN ), human leukocyte antigen A and B ( HLA-A and HLA-B ) -A/B , and the transforming growth factor beta (TGFβ) pathway, and rarely have mutations in the tumor protein p53 ( TP53 ) and RB transcriptional corepressor 1 ( RB1 ) tumor suppressor genes. There are some variations by tumor site, such as NOTCH1 mutations which are primarily found in head and neck cancers. Understanding the somatic events following HPV infection and persistence can aid the development of early detection biomarkers, particularly when mutations in precancers are characterized. Somatic mutations may also influence prognosis and treatment decisions.

  18. Temperature-dependent structure evolution in liquid gallium

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, L. H.; Wang, X. D.; Yu, Q.; Zhang, H.; Zhang, F.; Sun, Y.; Cao, Q. P.; Xie, H. L.; Xiao, T. Q.; Zhang, D. X.; Wang, C. Z.; Ho, K. M.; Ren, Y.; Jiang, J. Z.

    2017-04-01

    Temperature-dependent atomistic structure evolution of liquid gallium (Ga) has been investigated by using in situ high energy X-ray diffraction experiment and ab initio molecular dynamics simulation. Both experimental and theoretical results reveal the existence of a liquid structural change around 1000 K in liquid Ga. Below and above this temperature the liquid exhibits differences in activation energy for selfdiffusion, temperature-dependent heat capacity, coordination numbers, density, viscosity, electric resistivity and thermoelectric power, which are reflected from structural changes of the bond-orientational order parameter Q6, fraction of covalent dimers, averaged string length and local atomic packing. This finding will trigger more studies on the liquid-to-liquid crossover in metallic melts.

  19. Temperature-dependent enthalpy of oxygenation in Antarctic fish hemoglobins

    DEFF Research Database (Denmark)

    Fago, A.; Wells, R.M.G.; Weber, Roy E.

    1997-01-01

    The effect of temperature on the oxygen-binding properties of the hemoglobins of three cold-adapted Antarctic fish species, Dissostichus mawsoni, Pagothenia borchgrevinki and Trematomus, sp., has been investigated under different pH values and buffer conditions. A clear non linear van't Hoff plot...... oxygen binding. The degree of the temperature dependence of the heat of oxygenation observed in these hemoglobins seems to reflect the differences in their allosteric effects rather than a specific molecular adaptation to low temperatures. Moreover, this study indicates that the disagreement between...... (logP(50) vs 1/T) of D. mawsoni hemoglobin indicates that the enthalpy of oxygenation (slope of the plot) is temperature dependent and that at high temperatures oxygen-binding becomes less exothermic. Nearly linear relationships were found in the hemoglobins of the other two species. The data were...

  20. Temperature dependencies of frequency characteristics of HTSC RLC curcuit

    Science.gov (United States)

    Buniatyan, Vahe V.; Aroutiounian, V. M.; Shmavonyan, G. Sh.; Buniatyan, Vaz. V.

    2006-05-01

    Analytical expressions of temperature dependencies of magnitude-frequency and phase-frequency characteristics of a HTSC RLC parallel circuit are obtained, where the resistance and inductance are non-linearly depended on the optical signal modulated by the intensity. It is shown that the magnitude-frequency and phase-frequency characteristics of circuits can be controlled by choosing the parameters of the HTSC thin film and optical "pump".

  1. AlN Bandgap Temperature Dependence from its Optical Properties

    Science.gov (United States)

    2008-06-07

    AlN bandgap temperature dependence from its optical properties E. Silveira a,, J.A. Freitas b, S.B. Schujman c, L.J. Schowalter c a Depto. de Fisica ...literature could, in part, be lifted in terms of selection rules for the optical transitions [5]. Further experimental investigations corroborated with...CL, transmission/ absorption and OR measurements at different temperatures. 2. Experimental details The high-quality large bulk AlN single crystals

  2. Temperature dependence of the fundamental band gap parameters ...

    Indian Academy of Sciences (India)

    Abstract. Thin films of ternary ZnxCd1 xSe were deposited on GaAs (100) substrate using metal- organic-chemical-vapour-deposition (MOCVD) technique. Temperature dependence of the near- band-edge emission from these Cd-rich ZnxCd1 xSe (for x = 0.025, 0.045) films has been studied using photoluminescence ...

  3. Combination of RNA- and exome-sequencing efficiently eliminates false-positive somatic point mutations and indels – exemplified by cases of CN-AML

    DEFF Research Database (Denmark)

    Herborg, Laura Laine; Hansen, Marcus Celik; Roug, Anne Stidsholt

    Thorough annotation as a means of detecting highly relevant mutations, and aberrated genes, is becoming more feasible as the evidence of biological pathways underlying malignant transformation compiles. However, there is a continuous risk of misinterpretating both true and false positive...

  4. The normally expressed kappa immunoglobulin light chain gene repertoire and somatic mutations studied by single-sided specific polymerase chain reaction (PCR); frequent occurrence of features often assigned to autoimmunity

    DEFF Research Database (Denmark)

    Juul, L; Hougs, L; Andersen, V

    1997-01-01

    The expressed human kappa light chain gene repertoire utilized by healthy individuals was studied by two different single-sided specific PCR techniques to avoid bias for certain V genes. A total of 103 rearranged kappa sequences from peripheral blood mononuclear cells from healthy individuals were...... cloned from cDNA and assigned to the Vkappa and Jkappa germ-line genes with the closest overall homology. The use of cDNA rather than genomic DNA focused the analysis on activated B cells rich in mRNA. Accordingly, the sequences represented the applied repertoire and almost all were somatically mutated......% and 21% of the sequences, respectively. Extended CDR3s more than nine residues in length were found in 18% of the sequences, and in 71% of cases this was due to insertion of an extra proline residue. This proline was usually explained from the germ-line sequences involved. These results are in good...

  5. Temperature dependence of the elastocaloric effect in natural rubber

    Energy Technology Data Exchange (ETDEWEB)

    Xie, Zhongjian, E-mail: zhongjian.xie521@gmail.com; Sebald, Gael; Guyomar, Daniel

    2017-07-12

    The temperature dependence of the elastocaloric (eC) effect in natural rubber (NR) has been studied. This material exhibits a large eC effect over a broad temperature range from 0 °C to 49 °C. The maximum adiabatic temperature change (ΔT) occurred at 10 °C and the behavior could be predicted by the temperature dependence of the strain-induced crystallization (SIC) and the temperature-induced crystallization (TIC). The eC performance of NR was then compared with that of shape memory alloys (SMAs). This study contributes to the SIC research of NR and also broadens the application of elastomers. - Highlights: • A large elastocaloric effect over a broad temperature range was found in natural rubber (NR). • The caloric performance of NR was compared with that of shape memory alloys. • The temperature dependence of the elastocaloric effect in NR can be prediced by the theory of strain-induced crystallization.

  6. Iron mapping using the temperature dependency of the magnetic susceptibility.

    Science.gov (United States)

    Birkl, Christoph; Langkammer, Christian; Krenn, Heinz; Goessler, Walter; Ernst, Christina; Haybaeck, Johannes; Stollberger, Rudolf; Fazekas, Franz; Ropele, Stefan

    2015-03-01

    The assessment of iron content in brain white matter (WM) is of high importance for studying neurodegenerative diseases. While R2 * mapping and quantitative susceptibility mapping is suitable for iron mapping in gray matter, iron mapping in WM still remains an unsolved problem. We propose a new approach for iron mapping, independent of diamagnetic contributions of myelin by assessing the temperature dependency of the paramagnetic susceptibility. We used unfixed human brain slices for relaxometry and calculated R2 ' as a measure for microscopic susceptibility variations at several temperatures (4°C-37°C) at 3 Tesla. The temperature coefficient of R2 ' (TcR2p) was calculated by linear regression and related to the iron concentration found by subsequent superconducting quantum interference device (SQUID) magnetometry and by inductively coupled plasma mass spectrometry. In line with SQUID measurements, R2 ' mapping showed a linear temperature dependency of the bulk susceptibility with the highest slope in gray matter. Even in WM, TcR2p yielded a high linear correlation with the absolute iron concentration. According to Curie's law, only paramagnetic matter exhibits a temperature dependency while the diamagnetism shows no effect. We have demonstrated that the temperature coefficient (TcR2p) can be used as a measure of the paramagnetic susceptibility despite of an unknown diamagnetic background. © 2014 Wiley Periodicals, Inc.

  7. MO-DE-207B-01: JACK FOWLER JUNIOR INVESTIGATOR COMPETITION WINNER: Between Somatic Mutations and PET-Based Radiomic Features in Non-Small Cell Lung Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Yip, S; Coroller, T; Rios Velazquez, E; Parmar, C; Mak, R; Aerts, H [Brigham and Women’s Hospital, Dana Farber Cancer Institute, and Harvard Medical School, Boston, MA (United States); Kim, J [Brigham and Women’s Hospital, Boston Children’s Hospital and Harvard Medical School, Boston, MA (United States)

    2016-06-15

    Purpose: Although PET-based radiomic features have been proposed to quantify tumor heterogeneity and shown promise in outcome prediction, little is known about their relationship with tumor genetics. This study assessed the association of [{sup 18}F]fluorodeoxyglucose (FDG)-PET-based radiomic features with non-small cell lung cancer (NSCLC) mutations. Methods: 348 NSCLC patients underwent FDG-PET/CT scans before treatment and were tested for genetic mutations. 13% (44/348) and 28% (96/348) patients were found to harbor EGFR (EGFR+) and KRAS (KRAS+) mutations, respectively. We evaluated nineteen PET-based radiomic features quantifying phenotypic traits, and compared them with conventional PET features (metabolic tumor volume (MTV) and maximum-SUV). The association between the feature values and mutation status was evaluated using the Wilcoxcon-rank-sum-test. The ability of each measure to predict mutations was assessed by the area under the receiver operating curve (AUC). Noether’s test was used to determine if the AUCs were significantly from random (AUC=0.50). All p-values were corrected for multiple testing by controlling the false discovery rate (FDR{sub Wilcoxon} and FDR{sub Noether}) of 10%. Results: Eight radiomic features, MTV, and maximum-SUV, were significantly associated with the EGFR mutation (FDR{sub Wilcoxon}=0.01–0.10). However, KRAS+ demonstrated no significantly distinctive imaging features compared to KRAS− (FDR{sub Wilcoxon}≥0.92). EGFR+ and EGFR− were significantly discriminated by conventional PET features (AUC=0.61, FDR{sub Noether}=0.04 for MTV and AUC=0.64, FDR{sub Noether}=0.01 for maximum-SUV). Eight radiomic features were significantly predictive for EGFR+ compared to EGFR− (AUC=0.59–0.67, FDR{sub Noether}=0.0032–0.09). Normalized-inverse-difference-moment outperformed all features in predicting EGFR mutation (AUC=0.67, FDR{sub Noether}=0.0032). Moreover, only the radiomic feature normalized-inverse-difference-moment could

  8. First insight into the somatic mutation burden of neurofibromatosis type 2-associated grade I and grade II meningiomas: a case report comprehensive genomic study of two cranial meningiomas with vastly different clinical presentation.

    Science.gov (United States)

    Dewan, Ramita; Pemov, Alexander; Dutra, Amalia S; Pak, Evgenia D; Edwards, Nancy A; Ray-Chaudhury, Abhik; Hansen, Nancy F; Chandrasekharappa, Settara C; Mullikin, James C; Asthagiri, Ashok R; Heiss, John D; Stewart, Douglas R; Germanwala, Anand V

    2017-02-13

    Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined. Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient. While the grade I tumor was asymptomatic, the grade II tumor exhibited an unusually high growth rate: expanding to 335 times its initial volume within one year. The genomes of both tumors were examined by whole-exome sequencing (WES) complemented with spectral karyotyping (SKY) and SNP-array copy-number analyses. To better understand the clonal composition of the atypical meningioma, the tumor was divided in four sections and each section was investigated independently. Both tumors had second copy inactivation of NF2, confirming the central role of the gene in meningioma formation. The genome of the benign tumor closely resembled that of a normal diploid cell and had only one other deleterious mutation (EPHB3). In contrast, the chromosomal architecture of the grade II tumor was highly re-arranged, yet uniform among all analyzed fragments, implying that this large and fast growing tumor was composed of relatively few clones. Besides multiple gains and losses, the grade II meningioma harbored numerous chromosomal translocations. WES analysis of the atypical tumor identified deleterious mutations in two genes: ADAMTSL3 and CAPN5 in all fragments, indicating that the mutations were present in the cell undergoing fast clonal expansion CONCLUSIONS: This is the first WES study of NF2-associated meningiomas. Besides second NF2 copy inactivation, we found low somatic burden in both tumors and high level of genomic instability in the atypical meningioma. Genomic instability resulting in altered gene

  9. Downregulation but lack of promoter hypermethylation or somatic mutations of the potential tumor suppressor CXXC5 in MDS and AML with deletion 5q

    DEFF Research Database (Denmark)

    Treppendahl, Marianne Bach; Möllgård, L; Hellström-Lindberg, E

    2013-01-01

    During recent years mutations in epigenetic modulators have been identified in several human cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)[1]. CXXC5 has been found to be necessary for retinoic acid induced differentiation of myelocytic leukemia cells, identify......During recent years mutations in epigenetic modulators have been identified in several human cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)[1]. CXXC5 has been found to be necessary for retinoic acid induced differentiation of myelocytic leukemia cells...

  10. Temperature dependence of the Brewer global UV measurements

    Science.gov (United States)

    Fountoulakis, Ilias; Redondas, Alberto; Lakkala, Kaisa; Berjon, Alberto; Bais, Alkiviadis F.; Doppler, Lionel; Feister, Uwe; Heikkila, Anu; Karppinen, Tomi; Karhu, Juha M.; Koskela, Tapani; Garane, Katerina; Fragkos, Konstantinos; Savastiouk, Volodya

    2017-11-01

    Spectral measurements of global UV irradiance recorded by Brewer spectrophotometers can be significantly affected by instrument-specific optical and mechanical features. Thus, proper corrections are needed in order to reduce the associated uncertainties to within acceptable levels. The present study aims to contribute to the reduction of uncertainties originating from changes in the Brewer internal temperature, which affect the performance of the optical and electronic parts, and subsequently the response of the instrument. Until now, measurements of the irradiance from various types of lamps at different temperatures have been used to characterize the instruments' temperature dependence. The use of 50 W lamps was found to induce errors in the characterization due to changes in the transmissivity of the Teflon diffuser as it warms up by the heat of the lamp. In contrast, the use of 200 or 1000 W lamps is considered more appropriate because they are positioned at longer distances from the diffuser so that warming is negligible. Temperature gradients inside the instrument can cause mechanical stresses which can affect the instrument's optical characteristics. Therefore, during the temperature-dependence characterization procedure warming or cooling must be slow enough to minimize these effects. In this study, results of the temperature characterization of eight different Brewer spectrophotometers operating in Greece, Finland, Germany and Spain are presented. It was found that the instruments' response changes differently in different temperature regions due to different responses of the diffusers' transmittance. The temperature correction factors derived for the Brewer spectrophotometers operating at Thessaloniki, Greece, and Sodankylä, Finland, were evaluated and were found to remove the temperature dependence of the instruments' sensitivity.

  11. Gas diffusion and temperature dependence of bubble nucleation during irradiation

    DEFF Research Database (Denmark)

    Foreman, A. J. E.; Singh, Bachu Narain

    1986-01-01

    of the diatomic nucleation of helium bubbles, assuming helium to diffuse substitutionally, with radiation-enhanced diffusion at lower temperatures. The calculated temperature dependence of the bubble density shows excellent agreement with that observed in 600 MeV proton irradiations, including a reduction...... in activation energy below Tm/2. The coalescence of diatomic nuclei due to Brownian motion markedly improves the agreement and also provides a well-defined terminal density. Bubble nucleation by this mechanism is sufficiently fast to inhibit any appreciable initial loss of gas to grain boundaries during...

  12. Temperature dependent Raman scattering in YCrO3

    Science.gov (United States)

    Mall, A. K.; Mukherjee, S.; Sharma, Y.; Garg, A.; Gupta, R.

    2014-04-01

    High quality polycrystalline YCrO3 samples were synthesized using solid-state-reaction method. The samples were subsequently characterized using X-ray diffraction and magnetometry. Further, temperature dependent Raman spectroscopy over a spectral range from 100 to 800 cm-1 was used to examine the variation of phonons as a function of temperature from 90 to 300 K. In the low temperature ferroelectric phase of YCrO3, the observed phonon spectra showed softening of some Raman modes below the magnetic ordering temperature (TN ˜ 142K), suggesting a coupling between the spin and phonon degrees of freedom.

  13. Temperature dependence of photovoltaic cells, modules, and systems

    Energy Technology Data Exchange (ETDEWEB)

    Emery, K.; Burdick, J.; Caiyem, Y. [National Renewable Energy Lab., Golden, CO (United States)] [and others

    1996-05-01

    Photovoltaic (PV) cells and modules are often rated in terms of a set of standard reporting conditions defined by a temperature, spectral irradiance, and total irradiance. Because PV devices operates over a wide range of temperatures and irradiances, the temperature and irradiance related behavior must be known. This paper surveys the temperature dependence of crystalline and thin-film, state-of-the-art, research-size cells, modules, and systems measured by a variety of methods. The various error sources and measurement methods that contribute to cause differences in the temperature coefficient for a given cell or module measured with various methods are discussed.

  14. Ultra-capacitor electrical modeling using temperature dependent parameters

    Energy Technology Data Exchange (ETDEWEB)

    Lajnef, W.; Briat, O.; Azzopardi, S.; Woirgard, E.; Vinassa, J.M. [Bordeaux-1 Univ., Lab. IXL CNRS UMR 5818 - ENSEIRB, 33 - Talence (France)

    2004-07-01

    This paper deals with ultra-capacitor electrical modeling. For a proper characterization and identification, a dedicated test bench is designed. First, the ultra-capacitor electric behavior is presented and an electrical model is proposed. The model parameters are identified using a combination of constant currents and frequency response measurements. Then, the temperature dependence of the ultra-capacitor parameters is investigated. Therefore, constant currents and impedance spectroscopy tests are done at different ambient temperatures. Finally, the electrical model parameters are adjusted according to temperature. (authors)

  15. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

    NARCIS (Netherlands)

    Wolach, Baruch; Scharf, Yitshak; Gavrieli, Ronit; de Boer, Martin; Roos, Dirk

    2005-01-01

    Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91(phox), a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme

  16. A cancer cell-line titration series for evaluating somatic classification

    National Research Council Canada - National Science Library

    Denroche, Robert E; Mullen, Laura; Timms, Lee; Beck, Timothy; Yung, Christina K; Stein, Lincoln; McPherson, John D; Brown, Andrew M K

    2015-01-01

    .... We present here a cell-line titration series dataset that can be used to evaluate somatic variant calling pipelines with the goal of reliably calling true somatic mutations at low allele frequencies...

  17. Temperature-dependent photoluminescence from CdS/Si nanoheterojunctions

    Energy Technology Data Exchange (ETDEWEB)

    Song, Yue Li; Li, Yong; Ji, Peng Fei; Zhou, Feng Qun; Sun, Xiao Jun; Yuan, Shu Qing; Wan, Ming Li [Pingdingshan University, Department of Physics, Solar New Energy Research Center, Pingdingshan (China); Ling, Hong [North China University of Water Resources and Electric Power, Department of Mathematics and Information Science, Zhengzhou (China)

    2016-12-15

    CdS/Si nanoheterojunctions have been fabricated by growing nanocrystal CdS (nc-CdS) on the silicon nanoporous pillar array (Si-NPA) through using a chemical bath deposition method. The nanoheterojunctions have been constructed by three layers: the upper layer being a nc-CdS thin films, the intermediate layer being the interface region including nc-CdS and nanocrystal silicon (nc-Si), and the bottom layer being nc-Si layer grown on sc-Si substrate. The room temperature and temperature-dependent photoluminescence (PL) have been measured and analyzed to provide some useful information of defect states. Utilizing the Gauss-Newton fitting method, five emission peaks from the temperature-dependent PL spectra can be determined. From the high energy to low energy, these five peaks are ascribed to the some luminescence centers which are formed by the oxygen-related deficiency centers in the silicon oxide layer of Si-NPA, the band gap emission of nc-CdS, the transition from the interstitial cadmium (I{sub Cd}) to the valence band, the recombination from I{sub Cd} to cadmium vacancies (V{sub Cd}), and from sulfur vacancies (V{sub s}) to the valence band, respectively. Understanding of the defect states in the CdS/Si nanoheterojunctions is very meaningful for the performance of devices based on CdS/Si nanoheterojunctions. (orig.)

  18. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia.

    Science.gov (United States)

    Cao, Y; Hunter, Z R; Liu, X; Xu, L; Yang, G; Chen, J; Patterson, C J; Tsakmaklis, N; Kanan, S; Rodig, S; Castillo, J J; Treon, S P

    2015-01-01

    CXCR4(WHIM) somatic mutations are common Waldenstrom's Macroglobulinemia (WM), and are associated with clinical resistance to ibrutinib. We engineered WM cells to express the most common WHIM (Warts, Hypogammaglobulinemia, Infections and Myelokathexis), CXCR(S338X) mutation in WM. Following SDF-1a stimulation, CXCR4(S338X) WM cells exhibited decreased receptor internalization, enhanced and sustained AKT kinase (AKT) and extracellular regulated kinase (ERK) signaling, decreased poly (ADP-ribose) polymerase and caspase 3 cleavage, and decreased Annexin V staining versus CXCR4 wild-type (WT) cells. CXCR4(S338X)-related signaling and survival effects were blocked by the CXCR4 inhibitor AMD3100. SDF-1a-treated CXCR4(S338X) WM cells showed sustained AKT and ERK activation and decreased apoptotic changes versus CXCR4(WT) cells following ibrutinib treatment, findings which were also reversed by AMD3100. AKT or ERK antagonists restored ibrutinib-triggered apoptotic changes in SDF-1a-treated CXCR4(S338X) WM cells demonstrating their role in SDF-1a-mediated ibrutinib resistance. Enhanced bone marrow pAKT staining was also evident in CXCR4(WHIM) versus CXCR4(WT) WM patients, and remained active despite ibrutinib therapy in CXCR4(WHIM) patients. Last, CXCR4(S338X) WM cells showed varying levels of resistance to other WM relevant therapeutics, including bendamustine, fludarabine, bortezomib and idelalisib in the presence of SDF-1a. These studies demonstrate a functional role for CXCR4(WHIM) mutations, and provide a framework for investigation of CXCR4 inhibitors in WM.

  19. Not All Next Generation Sequencing Diagnostics are Created Equal: Understanding the Nuances of Solid Tumor Assay Design for Somatic Mutation Detection

    Energy Technology Data Exchange (ETDEWEB)

    Gray, Phillip N., E-mail: pgray@ambrygen.com; Dunlop, Charles L.M.; Elliott, Aaron M. [Ambry Genetics, 15 Argonaut, Aliso Viejo, CA 92656 (United States)

    2015-07-17

    The molecular characterization of tumors using next generation sequencing (NGS) is an emerging diagnostic tool that is quickly becoming an integral part of clinical decision making. Cancer genomic profiling involves significant challenges including DNA quality and quantity, tumor heterogeneity, and the need to detect a wide variety of complex genetic mutations. Most available comprehensive diagnostic tests rely on primer based amplification or probe based capture methods coupled with NGS to detect hotspot mutation sites or whole regions implicated in disease. These tumor panels utilize highly customized bioinformatics pipelines to perform the difficult task of accurately calling cancer relevant alterations such as single nucleotide variations, small indels or large genomic alterations from the NGS data. In this review, we will discuss the challenges of solid tumor assay design/analysis and report a case study that highlights the need to include complementary technologies (i.e., arrays) and germline analysis in tumor testing to reliably identify copy number alterations and actionable variants.

  20. Somatic Mutation of the 5′ Noncoding Region of the BCL-6 Gene Is Associated with Intraclonal Diversity and Clonal Selection in Histological Transformation of Follicular Lymphoma

    OpenAIRE

    Szereday, Zoltán; Csernus, Balázs; Nagy, Monika; László, Terézia; Warnke, Roger A.; Matolcsy, András

    2000-01-01

    Follicular lymphoma (FL) is a B cell non-Hodgkin’s lymphoma (NHL) that frequently displays a t(14;18) translocation. Clonal evolution and histological transformation of FL is frequently associated with the accumulation of secondary genetic alterations. It has been demonstrated that the BCL-6 gene can be altered by chromosomal rearrangements and by mutations clustering in its 5′ noncoding region in a significant fraction of FL and diffuse large cell lymphoma (DLCL). To elucidate the role of th...

  1. Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context of SMARCB1 Deficiency

    Directory of Open Access Journals (Sweden)

    Johanna Sandgren

    2015-01-01

    Full Text Available Background. AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodeling complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease. Results. A de novo germline variant in SMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hitting SEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, and IFNA8. All were found with subclonal allele frequencies (range 5.7–17% and none were expressed. However, besides SMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, and PCM1. Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system. FGFR1, CXCR4, and MDK were upregulated and may represent possible drug targets. Conclusion. The loss of SMARCB1 function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies.

  2. Temperature Dependent Variations of Phonon Interactions in Nanocrystalline Cerium Oxide

    Directory of Open Access Journals (Sweden)

    Sugandha Dogra Pandey

    2015-01-01

    Full Text Available The temperature dependent anharmonic behavior of the phonon modes of nanocrystalline CeO2 was investigated in the temperature range of 80–440 K. The anharmonic constants have been derived from the shift in phonon modes fitted to account for the anharmonic contributions as well as the thermal expansion contribution using the high pressure parameters derived from our own high pressure experimental data reported previously. The total anharmonicity has also been estimated from the true anharmonicity as well as quasiharmonic component. In the line-width variation analysis, the cubic anharmonic term was found to dominate the quartic term. Finally, the phonon lifetime also reflected the trend so observed.

  3. Temperature dependence effect of viscosity on ultrathin lubricant film melting

    Directory of Open Access Journals (Sweden)

    A.V.Khomenko

    2006-01-01

    Full Text Available We study the melting of an ultrathin lubricant film under friction between atomically flat surfaces at temperature dependencies of viscosity described by Vogel-Fulcher relationship and by power expression, which are observed experimentally. It is shown that the critical temperature exists in both cases the exceeding of which leads to the melting of lubricant and, as a result, the sliding mode of friction sets in. The values of characteristic parameters of lubricant are defined, which are needed for friction reduction. In the systems, where the Vogel-Fulcher dependence is fulfilled, it is possible to choose the parameters at which the melting of lubricant takes place even at zero temperature of friction surfaces. The deformational defect of the shear modulus is taken into account in describing the lubricant melting according to the mechanism of the first-order transition.

  4. Temperature Dependence of the Viscosity of Isotropic Liquids

    Science.gov (United States)

    Jadzyn, J.; Czechowski, G.; Lech, T.

    1999-04-01

    Temperature dependence of the shear viscosity measured for isotropic liquids belonging to the three homologous series: 4-(trans-4'-n-alkylcyclohexyl) isothiocyanatobenzenes (Cn H2n+1 CyHx Ph NCS; nCHBT, n=0-12), n-alkylcyanobiphenyls (CnH2n+1 Ph Ph CN; nCB, n=2-12) and 1,n-alkanediols (HO(CH2)nOH; 1,nAD, n=2-10) were analysed with the use of Arrhenius equation and its two modifications: Vogel--Fulcher and proposed in this paper. The extrapolation of the isothermal viscosity of 1,n-alkanediols (n=2-10) to n=1 leads to an interesting conclusion concerning the expected viscosity of methanediol, HOCH2OH, the compound strongly unstable in a pure state.

  5. Temperature-dependent thermal properties of spark plasma sintered alumina

    Directory of Open Access Journals (Sweden)

    Saheb Nouari

    2017-01-01

    Full Text Available In this work, we report temperature-dependent thermal properties of alumina powder and bulk alumina consolidated by spark plasma sintering method. The properties were measured between room temperature and 250ºC using a thermal constants analyzer. Alumina powder had very low thermal properties due to the presence of large pores and absence of bonding between its particles. Fully dense alumina with a relative density of 99.6 % was obtained at a sintering temperature of 1400°C and a holding time of 10 min. Thermal properties were found to mainly dependent on density. Thermal conductivity, thermal diffusivity, and specific heat of the fully dense alumina were 34.44 W/mK, 7.62 mm2s-1, and 1.22 J/gK, respectively, at room temperature. Thermal conductivity and thermal diffusivity decreased while specific heat increased with the increase in temperature from room temperature to 250ºC.

  6. Temperature dependence of contact resistance at metal/MWNT interface

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sang-Eui; Moon, Kyoung-Seok; Sohn, Yoonchul, E-mail: yoonchul.son@samsung.com [Materials Research Center, Samsung Advanced Institute of Technology, Samsung Electronics, Suwon 443-803 (Korea, Republic of)

    2016-07-11

    Although contact resistance of carbon nanotube (CNT) is one of the most important factors for practical application of electronic devices, a study regarding temperature dependence on contact resistance of CNTs with metal electrodes has not been found. Here, we report an investigation of contact resistance at multiwalled nanotube (MWNT)/Ag interface as a function of temperature, using MWNT/polydimethylsiloxane (PDMS) composite. Electrical resistance of MWNT/PDMS composite revealed negative temperature coefficient (NTC). Excluding the contact resistance with Ag electrode, the NTC effect became less pronounced, showing lower intrinsic resistivity with the activation energy of 0.019 eV. Activation energy of the contact resistance of MWNT/Ag interface was determined to be 0.04 eV, two times larger than that of MWNT-MWNT network. The increase in the thermal fluctuation assisted electron tunneling is attributed to conductivity enhancement at both MWNT/MWNT and MWNT/Ag interfaces with increasing temperature.

  7. Nonlinear temperature dependent failure analysis of finite width composite laminates

    Science.gov (United States)

    Nagarkar, A. P.; Herakovich, C. T.

    1979-01-01

    A quasi-three dimensional, nonlinear elastic finite element stress analysis of finite width composite laminates including curing stresses is presented. Cross-ply, angle-ply, and two quasi-isotropic graphite/epoxy laminates are studied. Curing stresses are calculated using temperature dependent elastic properties that are input as percent retention curves, and stresses due to mechanical loading in the form of an axial strain are calculated using tangent modulii obtained by Ramberg-Osgood parameters. It is shown that curing stresses and stresses due to tensile loading are significant as edge effects in all types of laminate studies. The tensor polynomial failure criterion is used to predict the initiation of failure. The mode of failure is predicted by examining individual stress contributions to the tensor polynomial.

  8. Measurement system for temperature dependent noise characterization of magnetoresistive sensors

    Science.gov (United States)

    Nording, F.; Weber, S.; Ludwig, F.; Schilling, M.

    2017-03-01

    Magnetoresistive (MR) sensors and sensor systems are used in a large variety of applications in the field of industrial automation, automotive business, aeronautic industries, and instrumentation. Different MR sensor technologies like anisotropic magnetoresistive, giant magnetoresistive, and tunnel magnetoresistive sensors show strongly varying properties in terms of magnetoresistive effect, response to magnetic fields, achievable element miniaturization, manufacturing effort, and signal-to-noise ratio. Very few data have been reported so far on the comparison of noise performance for different sensor models and technologies, especially including the temperature dependence of their characteristics. In this paper, a stand-alone measurement setup is presented that allows a comprehensive characterization of MR sensors including sensitivity and noise over a wide range of temperatures.

  9. Temperature dependence of topological susceptibility using gradient flow

    CERN Document Server

    Taniguchi, Yusuke; Kanaya, Kazuyuki; Kitazawa, Masakiyo; Suzuki, Hiroshi; Umeda, Takashi; Iwami, Ryo; Wakabayashi, Naoki

    2016-01-01

    We study temperature dependence of the topological susceptibility with the $N_{f}=2+1$ flavors Wilson fermion. We have two major interests in this paper. One is a comparison of gluonic and fermionic definitions of the topological susceptibility. Two definitions are related by the chiral Ward-Takahashi identity but their coincidence is highly non-trivial for the Wilson fermion. By applying the gradient flow both for the gauge and quark fields we find a good agreement of these two measurements. The other is a verification of a prediction of the dilute instanton gas approximation at low temperature region $T_{pc}< T<1.5T_{pc}$, for which we confirm the prediction that the topological susceptibility decays with power $\\chi_{t}\\propto(T/T_{pc})^{-8}$ for three flavors QCD.

  10. Temperature dependence of the dielectric constant of acrylic dielectric elastomer

    Energy Technology Data Exchange (ETDEWEB)

    Sheng, Junjie; Chen, Hualing; Li, Bo; Chang, Longfei [Xi' an Jiaotong University, State Key Laboratory for Strength and Vibration of Mechanical Structures, Xi' an (China); Xi' an Jiaotong University, School of Mechanical Engineering, Xi' an (China)

    2013-02-15

    The dielectric constant is an essential electrical parameter to the achievable voltage-induced deformation of the dielectric elastomer. This paper primarily focuses on the temperature dependence of the dielectric constant (within the range of 173 K to 373 K) for the most widely used acrylic dielectric elastomer (VHB 4910). First the dielectric constant was investigated experimentally with the broadband dielectric spectrometer (BDS). Results showed that the dielectric constant first increased with temperature up to a peak value and then dropped to a relative small value. Then by analyzing the fitted curves, the Cole-Cole dispersion equation was found better to characterize the rising process before the peak values than the Debye dispersion equation, while the decrease process afterward can be well described by the simple Debye model. Finally, a mathematical model of dielectric constant of VHB 4910 was obtained from the fitted results which can be used to further probe the electromechanical stability of the dielectric elastomers. (orig.)

  11. Temperature dependence of the dielectric constant of acrylic dielectric elastomer

    Science.gov (United States)

    Sheng, Junjie; Chen, Hualing; Li, Bo; Chang, Longfei

    2013-02-01

    The dielectric constant is an essential electrical parameter to the achievable voltage-induced deformation of the dielectric elastomer. This paper primarily focuses on the temperature dependence of the dielectric constant (within the range of 173 K to 373 K) for the most widely used acrylic dielectric elastomer (VHB 4910). First the dielectric constant was investigated experimentally with the broadband dielectric spectrometer (BDS). Results showed that the dielectric constant first increased with temperature up to a peak value and then dropped to a relative small value. Then by analyzing the fitted curves, the Cole-Cole dispersion equation was found better to characterize the rising process before the peak values than the Debye dispersion equation, while the decrease process afterward can be well described by the simple Debye model. Finally, a mathematical model of dielectric constant of VHB 4910 was obtained from the fitted results which can be used to further probe the electromechanical stability of the dielectric elastomers.

  12. Apparatus for temperature-dependent cathodoluminescence characterization of materials

    Science.gov (United States)

    Bok, Jan; Schauer, Petr

    2014-07-01

    An apparatus for characterization of temperature-dependent cathodoluminescence (CL) of solid-state materials is presented. This device excites a specimen using an electron beam and the CL emission is collected from the specimen side opposite the e-beam irradiation. The design of the temperature-controlled specimen holder that enables cooling down to 100 K and heating up to 500 K is described. The desired specimen temperature is automatically stabilized using a PID controller, which is the proportional-integral-derivative control feedback loop. Moreover, the specimen holder provides in situ e-beam current measurement during the specimen excitation. The apparatus allows the measurement of the CL intensity, the CL spectrum, or the CL intensity decay depending on the specimen temperature, or on a variety of excitation conditions, such as excitation energy, electron current (dose), or excitation duration. The apparatus abilities are demonstrated by an example of the CL measurements of the YAG:Ce single-crystal scintillator.

  13. Temperature dependence of the electronic structure of semiconductors and insulators

    Energy Technology Data Exchange (ETDEWEB)

    Poncé, S., E-mail: samuel.pon@gmail.com; Gillet, Y.; Laflamme Janssen, J.; Gonze, X. [European Theoretical Spectroscopy Facility and Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, Chemin des étoiles 8, bte L07.03.01, B-1348 Louvain-la-neuve (Belgium); Marini, A. [Consiglio Nazionale delle Ricerche (CNR), Via Salaria Km 29.3, CP 10, 00016 Monterotondo Stazione (Italy); Verstraete, M. [European Theoretical Spectroscopy Facility and Physique des matériaux et nanostructures, Université de Liège, Allée du 6 Août 17, B-4000 Liège (Belgium)

    2015-09-14

    The renormalization of electronic eigenenergies due to electron-phonon coupling (temperature dependence and zero-point motion effect) is sizable in many materials with light atoms. This effect, often neglected in ab initio calculations, can be computed using the perturbation-based Allen-Heine-Cardona theory in the adiabatic or non-adiabatic harmonic approximation. After a short description of the recent progresses in this field and a brief overview of the theory, we focus on the issue of phonon wavevector sampling convergence, until now poorly understood. Indeed, the renormalization is obtained numerically through a slowly converging q-point integration. For non-zero Born effective charges, we show that a divergence appears in the electron-phonon matrix elements at q → Γ, leading to a divergence of the adiabatic renormalization at band extrema. This problem is exacerbated by the slow convergence of Born effective charges with electronic wavevector sampling, which leaves residual Born effective charges in ab initio calculations on materials that are physically devoid of such charges. Here, we propose a solution that improves this convergence. However, for materials where Born effective charges are physically non-zero, the divergence of the renormalization indicates a breakdown of the adiabatic harmonic approximation, which we assess here by switching to the non-adiabatic harmonic approximation. Also, we study the convergence behavior of the renormalization and develop reliable extrapolation schemes to obtain the converged results. Finally, the adiabatic and non-adiabatic theories, with corrections for the slow Born effective charge convergence problem (and the associated divergence) are applied to the study of five semiconductors and insulators: α-AlN, β-AlN, BN, diamond, and silicon. For these five materials, we present the zero-point renormalization, temperature dependence, phonon-induced lifetime broadening, and the renormalized electronic band structure.

  14. Not All Next Generation Sequencing Diagnostics are Created Equal: Understanding the Nuances of Solid Tumor Assay Design for Somatic Mutation Detection

    Directory of Open Access Journals (Sweden)

    Phillip N. Gray

    2015-07-01

    Full Text Available The molecular characterization of tumors using next generation sequencing (NGS is an emerging diagnostic tool that is quickly becoming an integral part of clinical decision making. Cancer genomic profiling involves significant challenges including DNA quality and quantity, tumor heterogeneity, and the need to detect a wide variety of complex genetic mutations. Most available comprehensive diagnostic tests rely on primer based amplification or probe based capture methods coupled with NGS to detect hotspot mutation sites or whole regions implicated in disease. These tumor panels utilize highly customized bioinformatics pipelines to perform the difficult task of accurately calling cancer relevant alterations such as single nucleotide variations, small indels or large genomic alterations from the NGS data. In this review, we will discuss the challenges of solid tumor assay design/analysis and report a case study that highlights the need to include complementary technologies (i.e., arrays and germline analysis in tumor testing to reliably identify copy number alterations and actionable variants.

  15. Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes.

    Science.gov (United States)

    Müller-Höcker, Josef; Schäfer, Sabine; Krebs, Stefan; Blum, Helmut; Zsurka, Gábor; Kunz, Wolfram S; Prokisch, Holger; Seibel, Peter; Jung, Andreas

    2014-11-01

    Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome c oxidase (COX)-positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (P cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (P cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the MT-CO1 and MT-CO3 genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity-impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.

  16. 'Haruna': uma nova mutação somática natural da videira 'Itália' 'Haruna': a new natural somatic mutation of 'Italia' grapevine

    Directory of Open Access Journals (Sweden)

    Adriane Marinho de Assis

    2013-03-01

    Full Text Available O objetivo deste estudo foi descrever as principais características físico-químicas e produtivas da uva fina de mesa 'Haruna', uma nova mutação natural originada da cv. Itália, em Uraí-PR, Brasil. O formato das bagas, elipsoide alongado bastante expressivo, é uma das características que mais difere essa nova mutação da uva 'Itália'. As bagas apresentam coloração verde-clara, tendendo ao amarelo na maturação plena, com pincel e polpa verde, crocante, firme, textura carnosa e de sabor moscatel, enquanto os cachos apresentam formato cilíndrico-cônico. O ciclo, bem como o desempenho produtivo e a suscetibilidade às doenças fúngicas assemelham- se aos da cv. Itália. Durante a maturação plena, apresenta teor médio de sólidos solúveis de 16,2ºBrix, superior à 'Itália, 0,5% de ácido tartárico e índice de maturação de 31,2. Trata-se de uma nova cultivar de uva fina de mesa com bom potencial de cultivo no Brasil.The aim of this study was to describe the main physical -chemical and productive characteristics of 'Haruna' table grape, a new natural mutation originated from cv. Italia, in Uraí, PR, Brazil. The berries present a very expressive large oval shape, which is the main characteristic that differ this new mutation from 'Italia' grape. The berries color is light green, tending to yellow at full maturity, with brush and flesh green, crunchy, firm, with fleshy texture and moscatel flavor, while the clusters present cylindrical-conical shape. The cycle, as well as the production performance and the susceptibility to fungal diseases is similar to the cv. Italia. During the full maturation, it has an average content of soluble solids of 16.2ºBrix, higher than 'Italia', 0.5% of tartaric acid and maturation index of 31.2. This is a new cultivar of fine table grape with potential for cultivation in Brazil.

  17. Competitive interactions modify the temperature dependence of damselfly growth rates.

    Science.gov (United States)

    Nilsson-Ortman, Viktor; Stoks, Robby; Johansson, Frank

    2014-05-01

    Individual growth rates and survival are major determinants of individual fitness, population size structure, and community dynamics. The relationships between growth rate, survival, and temperature may thus be important for predicting biological responses to climate change. Although it is well known that growth rates and survival are affected by competition and predation in addition to temperature, the combined effect of these factors on growth rates, survival, and size structure has rarely been investigated simultaneously in the same ecological system. To address this question, we conducted experiments on the larvae of two species of damselflies and determined the temperature dependence of growth rate, survival, and cohort size structure under three scenarios of increasing ecological complexity: no competition, intraspecific competition, and interspecific competition. In one species, the relationship between growth rate and temperature became steeper in the presence of competitors, whereas that of survival remained unchanged. In the other species, the relationship between growth rate and temperature was unaffected by competitive interactions, but survival was greatly reduced at high temperatures in the presence of interspecific competitors. The combined effect of competitive interactions and temperature on cohort size structure differed from the effects of these factors in isolation. Together, these findings suggest that it will be challenging to scale up information from single-species laboratory studies to the population and community level.

  18. Temperature dependent bacteriophages of a tropical bacterial pathogen

    Directory of Open Access Journals (Sweden)

    Martha Rebecca Jane Clokie

    2014-11-01

    Full Text Available There is an increasing awareness of the multiple ways that bacteriophages (phages influence bacterial evolution, population dynamics, physiology and pathogenicity. By studying a novel group of phages infecting a soil borne pathogen, we revealed a paradigm shifting observation that the phages switch their lifestyle according to temperature. We sampled soil from an endemic area of the serious tropical pathogen Burkholderia pseudomallei, and established that podoviruses infecting the pathogen are frequently present in soil, and many of them are naturally occurring variants of a common virus type. Experiments on one phage in the related model Burkholderia thailandensis demonstrated that temperature defines the outcome of phage-bacteria interactions. At higher temperatures (37°C, the phage predominantly goes through a lytic cycle, but at lower temperatures (25°C, the phage remains temperate. This is the first report of a naturally occurring phage that follows a lytic or temperate lifestyle according to temperature. These observations fundamentally alter the accepted views on the abundance, population biology and virulence of B. pseudomallei. Furthermore, when taken together with previous studies, our findings suggest that the phenomenon of temperature dependency in phages is widespread. Such phages are likely to have a profound effect on bacterial life, and on our ability to culture and correctly enumerate viable bacteria.

  19. A Temperature-Dependent Battery Model for Wireless Sensor Networks.

    Science.gov (United States)

    Rodrigues, Leonardo M; Montez, Carlos; Moraes, Ricardo; Portugal, Paulo; Vasques, Francisco

    2017-02-22

    Energy consumption is a major issue in Wireless Sensor Networks (WSNs), as nodes are powered by chemical batteries with an upper bounded lifetime. Estimating the lifetime of batteries is a difficult task, as it depends on several factors, such as operating temperatures and discharge rates. Analytical battery models can be used for estimating both the battery lifetime and the voltage behavior over time. Still, available models usually do not consider the impact of operating temperatures on the battery behavior. The target of this work is to extend the widely-used Kinetic Battery Model (KiBaM) to include the effect of temperature on the battery behavior. The proposed Temperature-Dependent KiBaM (T-KiBaM) is able to handle operating temperatures, providing better estimates for the battery lifetime and voltage behavior. The performed experimental validation shows that T-KiBaM achieves an average accuracy error smaller than 0.33%, when estimating the lifetime of Ni-MH batteries for different temperature conditions. In addition, T-KiBaM significantly improves the original KiBaM voltage model. The proposed model can be easily adapted to handle other battery technologies, enabling the consideration of different WSN deployments.

  20. A Temperature-Dependent Battery Model for Wireless Sensor Networks

    Science.gov (United States)

    Rodrigues, Leonardo M.; Montez, Carlos; Moraes, Ricardo; Portugal, Paulo; Vasques, Francisco

    2017-01-01

    Energy consumption is a major issue in Wireless Sensor Networks (WSNs), as nodes are powered by chemical batteries with an upper bounded lifetime. Estimating the lifetime of batteries is a difficult task, as it depends on several factors, such as operating temperatures and discharge rates. Analytical battery models can be used for estimating both the battery lifetime and the voltage behavior over time. Still, available models usually do not consider the impact of operating temperatures on the battery behavior. The target of this work is to extend the widely-used Kinetic Battery Model (KiBaM) to include the effect of temperature on the battery behavior. The proposed Temperature-Dependent KiBaM (T-KiBaM) is able to handle operating temperatures, providing better estimates for the battery lifetime and voltage behavior. The performed experimental validation shows that T-KiBaM achieves an average accuracy error smaller than 0.33%, when estimating the lifetime of Ni-MH batteries for different temperature conditions. In addition, T-KiBaM significantly improves the original KiBaM voltage model. The proposed model can be easily adapted to handle other battery technologies, enabling the consideration of different WSN deployments. PMID:28241444

  1. [Revertant somatic mosaicism in primary immunodeficiency diseases].

    Science.gov (United States)

    Wada, Taizo

    2014-01-01

    Revertant somatic mosaicism has been described in an increasing number of genetic disorders including primary immunodeficiency diseases. Both back mutations leading to restoration of wild-type sequences and second-site mutations resulting in compensatory changes have been demonstrated in mosaic individuals. Recent studies identifying revertant somatic mosaicism caused by multiple independent genetic changes further support its frequent occurrence in primary immunodeficiency diseases. Revertant mosaicism acquires a particular clinical relevance because it may lead to selective growth advantage of the corrected cells, resulting in improvement of disease symptoms or atypical clinical presentations. This phenomenon also provides us unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. Here we review the recent findings of revertant somatic mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

  2. Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenström Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutation Status.

    Science.gov (United States)

    Cea, Michele; Cagnetta, Antonia; Acharya, Chirag; Acharya, Prakrati; Tai, Yu-Tzu; Yang, Cao; Lovera, Davide; Soncini, Debora; Miglino, Maurizio; Fraternali-Orcioni, Giulio; Mastracci, Luca; Nencioni, Alessio; Montecucco, Fabrizio; Monacelli, Fiammetta; Ballestrero, Alberto; Hideshima, Teru; Chauhan, Dharminder; Gobbi, Marco; Lemoli, Roberto M; Munshi, Nikhil; Treon, Steven P; Anderson, Kenneth C

    2016-12-15

    Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD+ pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD+ levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the antitumor effects of Nampt inhibition in Waldenström macroglobulinemia. We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo RESULTS: We found that Waldenström macroglobulinemia cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in Waldenström macroglobulinemia cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-Waldenström macroglobulinemia cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: (i) activation of caspase-3, PARP and downregulation of Mcl-1, (ii) enhanced intracellular ATP and NAD+ depletion, (iii) inhibition of NF-κB signaling, and (iv) inhibition of multiple prosurvival signaling pathways. In a murine xenograft Waldenström macroglobulinemia model, low-dose combination FK866 and ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Our results show intracellular NAD+ level as crucial for proliferation and survival of Waldenström macroglobulinemia cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in Waldenström macroglobulinemia. Clin Cancer Res; 22(24); 6099-109. ©2016 AACR. ©2016 American Association for Cancer Research.

  3. Dual NAMPT and BTK Targeting Leads to Synergistic Killing of Waldenstrom's Macroglobulinemia Cells Regardless of MYD88 and CXCR4 Somatic Mutations Status

    Science.gov (United States)

    Cea, Michele; Cagnetta, Antonia; Acharya, Chirag; Acharya, Prakrati; Tai, Yu-Tzu; Yang, Guang; Lovera, Davide; Soncini, Debora; Miglino, Maurizio; Fraternali-Orcioni, Giulio; Mastracci, Luca; Nencioni, Alessio; Montecucco, Fabrizio; Ballestrero, Alberto; Hideshima, Teru; Chauhan, Dharminder; Gobbi, Marco; Lemoli, Roberto M.; Munshi, Nikhil; Treon, Steven P.; Anderson, Kenneth C.

    2018-01-01

    Purpose Nicotinamide phosphoribosyltransferase (Nampt) regulates intracellular NAD+ pool and is highly expressed in a number of malignancies. FK866, a selective inhibitor of Nampt, depletes intracellular NAD+ levels, thereby blocking cellular metabolism and triggering sensitization to other drugs and cell death. Here we characterized the anti-tumor effects of Nampt inhibition in Waldenström Macroglobulinemia (WM). Experimental Design We investigated Nampt role in MW cells using both mRNA and protein expression analyses. We have also used loss-of-function approaches to investigate the growth and survival effects of Nampt on MW cells and further tested the anti-MW activity of dual Nampt and BTK inhibition in vitro and in vivo. Results We found that WM cells exhibit high levels of Nampt compared with normal B cells. Loss of function studies suggested a potential oncogenic role of Nampt in WM cells, and BTK-inhibitor ibrutinib and FK866 resulted in a significant and synergistic anti-WM cell death, regardless of MYD88 and CXCR4 mutational status. Cell death was associated with: 1) activation of caspase-3, PARP and down-regulation of Mcl-1; 2) enhanced intracellular ATP and NAD+ depletion; 3) inhibition of NF-kappa B signaling; and 4) inhibition of multiple pro-survival signaling pathways. In a murine xenograft WM model, low-dose combination FK866 and Ibrutinib is well tolerated, significantly inhibits tumor growth, and prolongs host survival. Conclusions our results show intracellular NAD+ level as crucial for proliferation and survival of WM cells, and provides the mechanistic preclinical rationale for targeting Nampt, either alone or with Ibrutinib, to overcome drug resistance and improve patient outcome in WM. PMID:27287071

  4. ATBF1 and NQO1 as candidate targets for allelic loss at chromosome arm 16q in breast cancer: Absence of somatic ATBF1 mutations and no role for the C609T NQO1 polymorphism

    Directory of Open Access Journals (Sweden)

    Peterse Johannes L

    2008-04-01

    Full Text Available Abstract Background Loss of heterozygosity (LOH at chromosome arm 16q is frequently observed in human breast cancer, suggesting that one or more target tumor suppressor genes (TSGs are located there. However, detailed mapping of the smallest region of LOH has not yet resulted in the identification of a TSG at 16q. Therefore, the present study attempted to identify TSGs using an approach based on mRNA expression. Methods A cDNA microarray for the 16q region was constructed and analyzed using RNA samples from 39 breast tumors with known LOH status at 16q. Results Five genes were identified to show lower expression in tumors with LOH at 16q compared to tumors without LOH. The genes for NAD(PH dehydrogenase quinone (NQO1 and AT-binding transcription factor 1 (ATBF1 were further investigated given their functions as potential TSGs. NQO1 has been implicated in carcinogenesis due to its role in quinone detoxification and in stabilization of p53. One inactive polymorphic variant of NQO1 encodes a product showing reduced enzymatic activity. However, we did not find preferential targeting of the active NQO1 allele in tumors with LOH at 16q. Immunohistochemical analysis of 354 invasive breast tumors revealed that NQO1 protein expression in a subset of breast tumors is higher than in normal epithelium, which contradicts its proposed role as a tumor suppressor gene. ATBF1 has been suggested as a target for LOH at 16q in prostate cancer. We analyzed the entire coding sequence in 48 breast tumors, but did not identify somatic sequence changes. We did find several in-frame insertions and deletions, two variants of which were reported to be somatic pathogenic mutations in prostate cancer. Here, we show that these variants are also present in the germline in 2.5% of 550 breast cancer patients and 2.9% of 175 healthy controls. This indicates that the frequency of these variants is not increased in breast cancer patients. Moreover, there is no preferential LOH of

  5. Temperature-dependent dispersion model of float zone crystalline silicon

    Science.gov (United States)

    Franta, Daniel; Dubroka, Adam; Wang, Chennan; Giglia, Angelo; Vohánka, Jirí; Franta, Pavel; Ohlídal, Ivan

    2017-11-01

    In this paper, we present the temperature dependent dispersion model of float zone crystalline silicon. The theoretical background for valence electronic excitations is introduced in the theoretical part of this paper. This model is based on application of sum rules and parametrization of transition strength functions corresponding to the individual elementary phonon and electronic excitations. The parameters of the model are determined by fitting ellipsometric and spectrophotometric experimental data in the spectral range from far infrared (70 cm-1) to extreme ultraviolet (40 eV). The ellipsometric data were measured in the temperature range 5-700 K. The excitations of the valence electrons to the conduction band are divided into the indirect and direct electronic transitions. The indirect transitions are modeled by truncated Lorentzian terms, whereas the direct transitions are modeled using Gaussian broadened piecewise smooth functions representing 3D and 2D van Hove singularities modified by excitonic effects. Since the experimental data up to high energies (40 eV) are available, we are able to determine the value of the effective number of valence electrons. The Tauc-Lorentz dispersion model is used for modeling high energy electron excitations. Two slightly different values of the effective number of valence electrons are obtained for the Jellison-Modine (4.51) and Campi-Coriasso (4.37) parametrization. Our goal is to obtain the model of dielectric response of crystalline silicon which depends only on photon energy, temperature and small number of material parameters, e.g. the concentration of substituted carbon and interstitial oxygen. The model presented in this paper is accurate enough to replace tabulated values of c-Si optical constants used in the optical characterization of thin films diposited on silicon substrates. The spectral dependencies of the optical constants obtained in our work are compared to results obtained by other authors.

  6. Temperature dependent modulation of lobster neuromuscular properties by serotonin.

    Science.gov (United States)

    Hamilton, Jonna L; Edwards, Claire R; Holt, Stephen R; Worden, Mary Kate

    2007-03-01

    In cold-blooded species the efficacy of neuromuscular function depends both on the thermal environmental of the animal's habitat and on the concentrations of modulatory hormones circulating within the animal's body. The goal of this study is to examine how temperature variation within an ecologically relevant range affects neuromuscular function and its modulation by the neurohormone serotonin (5-HT) in Homarus americanus, a lobster species that inhabits a broad thermal range in the wild. The synaptic strength of the excitatory and inhibitory motoneurons innervating the lobster dactyl opener muscle depends on temperature, with the strongest neurally evoked muscle movements being elicited at cold (temperatures. However, whereas neurally evoked contractions can be elicited over the entire temperature range from 2 to >20 degrees C, neurally evoked relaxations of resting muscle tension are effective only at colder temperatures at which the inhibitory junction potentials are hyperpolarizing in polarity. 5-HT has two effects on inhibitory synaptic signals: it potentiates their amplitude and also shifts the temperature at which they reverse polarity by approximately +7 degrees C. Thus 5-HT both potentiates neurally evoked relaxations of the muscle and increases the temperature range over which neurally evoked muscle relaxations can be elicited. Neurally evoked contractions are maximally potentiated by 5-HT at warm (18 degrees C) temperatures; however, 5-HT enhances excitatory junction potentials in a temperature-independent manner. Finally, 5-HT strongly increases resting muscle tension at the coldest extent of the temperature range tested (2 degrees C) but is ineffective at 22 degrees C. These data demonstrate that 5-HT elicits several temperature-dependent physiological changes in the passive and active responses of muscle to neural input. The overall effect of 5-HT is to increase the temperature range over which neurally evoked motor movements can be elicited in this

  7. Temperature-Dependent Henry's Law Constants of Atmospheric Amines.

    Science.gov (United States)

    Leng, Chunbo; Kish, J Duncan; Roberts, Jason E; Dwebi, Iman; Chon, Nara; Liu, Yong

    2015-08-20

    There has been growing interest in understanding atmospheric amines in the gas phase and their mass transfer to the aqueous phase because of their potential roles in cloud chemistry, secondary organic aerosol formation, and the fate of atmospheric organics. Temperature-dependent Henry's law constants (KH) of atmospheric amines, a key parameter in atmospheric chemical transport models to account for mass transfer, are mostly unavailable. In this work, we investigated gas-liquid equilibria of five prevalent atmospheric amines, namely 1-propylamine, di-n-propylamine, trimethylamine, allylamine, and 4-methylmorpholine using bubble column technique. We reported effective KH, intrinsic KH, and gas phase diffusion coefficients of these species over a range of temperatures relevant to the lower atmosphere for the first time. The measured KH at 298 K and enthalpy of solution for 1-propylamine, di-n-propylamine, trimethylamine, allylamine, and 4-methylmorpholine are 61.4 ± 4.9 mol L(-1) atm(-1) and -49.0 ± 4.8 kJ mol(-1); 14.5 ± 1.2 mol L(-1) atm(-1) and -72.5 ± 6.8 kJ mol(-1); 8.9 ± 0.7 mol L(-1) atm(-1) and -49.6 ± 4.7 kJ mol(-1); 103.5 ± 10.4 mol L(-1) atm(-1) and -42.7 ± 4.3 kJ mol(-1); and 952.2 ± 114.3 mol L(-1) atm(-1) and -82.7 ± 9.7 kJ mol(-1), respectively. In addition, we evaluated amines' characteristic times to achieve gas-liquid equilibrium for partitioning between gas and aqueous phases. Results show gas-liquid equilibrium can be rapidly established at natural cloud droplets surface, but the characteristic times may be extended substantially at lower temperatures and pHs. Moreover, our findings imply that atmospheric amines are more likely to exist in cloud droplets, and ambient temperature, water content, and pH of aerosols play important roles in their partitioning.

  8. Somatic symptom disorder

    Science.gov (United States)

    ... disorders; Somatization disorder; Somatiform disorders; Briquet syndrome; Illness anxiety disorder ... JF, Fava M, et al, eds. Massachusetts General Hospital Comprehensive Clinical Psychiatry. 2nd ed. Philadelphia, PA: Elsevier; ...

  9. Temperature Dependence of Single-Event Burnout in N-Channel Power MOSFET’s

    Science.gov (United States)

    1994-03-15

    AD-A277 921 P O Temperature Dependence of Single-Event Burnout in N-Channel Power MOSFETs 15 March 1994 Prepared by G. H. JOHNSON, R. D. SCHRIMPF...Makimunm 200 words) The temperature dependence of single-event burnout (SEB) in n-channel power metal-oxide- semiconductor field effect transistors...power MOSFET is tmned off (blocking a large The temperature dependence of single-event burn drain-source bias) [3]. Previous burnout modeling has beow

  10. Temperature dependence of microwave oscillations in magnetic tunnel junctions with a perpendicularly magnetized free layer

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Peng; Feng, Jiafeng, E-mail: hxwei@iphy.ac.cn, E-mail: jiafengfeng@iphy.ac.cn; Wei, Hongxiang, E-mail: hxwei@iphy.ac.cn, E-mail: jiafengfeng@iphy.ac.cn; Han, Xiufeng [Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China); Fang, Bin; Zhang, Baoshun; Zeng, Zhongming [Key Laboratory of Nanodevices and Applications, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, Ruoshui Road 398, Suzhou 215123 (China)

    2015-01-05

    We experimentally study the temperature dependence of the spin-transfer-torque-induced microwave oscillations in MgO-based magnetic tunnel junction nanopillars with a perpendicularly magnetized free layer. We demonstrate that the oscillation frequency increases rapidly with decreasing temperature, which is mainly ascribed to the temperature dependence of both the saturation magnetization and the perpendicular magnetic anisotropy. We also find that a strong temperature dependence of the output power while a nonmonotonic temperature dependence of spectral linewidth are maintained for a constant dc bias in measured temperature range. Possible mechanisms leading to the different dependences of oscillation frequency, output power, and linewidth are discussed.

  11. Somatization, Paranoia, and Language.

    Science.gov (United States)

    Oxman, Thomas E.; And Others

    1988-01-01

    Free speech of subjects with somatization and paranoia was analyzed to identify and compare self-concept dimensions reflected in their lexical choices. The somatization disorder group conveyed a sense of negativism, distress, and preoccupation with an uncertain self-identity. The paranoid patients portrayed an artificially positive, grandiose…

  12. Prospects for cellular mutational assays in human populations

    Energy Technology Data Exchange (ETDEWEB)

    Mendelsohn, M.L.

    1984-06-29

    Practical, sensitive, and effective human cellular assays for detecting somatic and germinal mutations would have great value in environmental mutagenesis and carcinogenesis studies. Such assays would fill the void between human mutagenicity and the data that exist from short-term tests and from mutagenicity in other species. This paper discusses the following possible human cellular assays: (1) HPRT (hypoxanthine phosphoribosyltransferase) somatic cell mutation based on 6-thioguanine resistance; (2) hemoglobin somatic cell mutation assay; (3) glycophorin somatic cell mutation assay; and (4) LDH-X sperm cell mutation assay. 18 references.

  13. Parental Somatic Mosaicism Is Underrecognized and Influences Recurrence Risk of Genomic Disorders

    Science.gov (United States)

    Campbell, Ian M.; Yuan, Bo; Robberecht, Caroline; Pfundt, Rolph; Szafranski, Przemyslaw; McEntagart, Meriel E.; Nagamani, Sandesh C.S.; Erez, Ayelet; Bartnik, Magdalena; Wiśniowiecka-Kowalnik, Barbara; Plunkett, Katie S.; Pursley, Amber N.; Kang, Sung-Hae L.; Bi, Weimin; Lalani, Seema R.; Bacino, Carlos A.; Vast, Mala; Marks, Karen; Patton, Michael; Olofsson, Peter; Patel, Ankita; Veltman, Joris A.; Cheung, Sau Wai; Shaw, Chad A.; Vissers, Lisenka E.L.M.; Vermeesch, Joris R.; Lupski, James R.; Stankiewicz, Paweł

    2014-01-01

    New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics. PMID:25087610

  14. Somatic Literacy. Bringing Somatic Education into Physical Education.

    Science.gov (United States)

    Linden, Paul

    1994-01-01

    Examines the profession of physical education and what it could become if it embraced somatic work, explaining the basic concepts and processes of somatic education. Somatic education focuses on the interactions of posture, movement, emotion, thought, self-concept, and cultural values. A case study details somatic education in practice. (SM)

  15. Mutational processes molding the genomes of 21 breast cancers

    NARCIS (Netherlands)

    S. Nik-Zainal (Serena); L.B. Alexandrov (Ludmil); D.C. Wedge (David); P. van Loo (Peter); C. Greenman (Chris); J.W. Raine (John); D. Jones (David); J. Hinton (Jonathan); J. Marshall (John); L.A. Stebbings (Lucy); D. Menzies; S. Martin (Sandra); K. Leung (Kenric); L. Chen (Lina); C. Leroy (Catherine); M. Ramakrishna (Manasa); R. Rance (Richard); K.W. Lau (King Wai); L. Mudie (Laura); I. Varela (Ignacio); D.J. McBride (David); G.R. Bignell (Graham); S.L. Cooke (Susanna); A. Shlien (Adam); J. Gamble (John); I. Whitmore (Ian); M. Maddison (Mark); P.S. Tarpey (Patrick); H. Davies (Helen); E. Papaemmanuil (Elli); P.J. Stephens (Philip); S. McLaren (Stuart); A. Butler (Adam); J. Teague (Jon); G. Jönsson (Göran); J. Garber; R.A. Silver (Angus); P. Miron (Penelope); A. Fatima (Aquila); S. Boyault (Sandrine); A. Langerød (Anita); A. Tutt (Andrew); J.W.M. Martens (John); S.A.J.R. Aparicio (Samuel A. J.); Å. Borg (Åke); A.V. Salomon (Anne Vincent); G. Thomas (Gilles); A.-L. Borresen-Dale (Anne-Lise); A.L. Richardson (Andrea); M.S. Neuberger (Michael); P.A. Futreal (Andrew); P.J. Campbell (Peter); M.R. Stratton (Michael)

    2012-01-01

    textabstractAll cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers

  16. Clinical approaches to somatization.

    Science.gov (United States)

    Busch, Fredric N

    2014-05-01

    Somatization is the experience and expression of psychological distress through bodily symptoms. Somatization can be conceptualized as an emotional state that has not been represented symbolically or as a defense against intolerable emotions and fantasies. Bodily concerns can also function as a means of seeking responsiveness from others. Alexithymia refers to a difficulty identifying and symbolizing emotional states that has been found to be associated with somatization. When functioning as a defense, a focus on the body can be used to avoid frightening or intolerable feelings and fantasies, or to ward off aggressive fantasies by viewing oneself as physically damaged. Systematic studies have demonstrated the presence of the defense of somatization in mood disorders, particularly anxiety and panic disorders. In treating anxiety disorders, the therapist helps the patient to determine the nature of emotions and fantasies that the patient is defending against, particularly fears and conflicts surrounding anger and separation. © 2014 Wiley Periodicals, Inc.

  17. Insight into Temperature Dependence of GTPase Activity in Human Guanylate Binding Protein-1

    Science.gov (United States)

    Rahman, Safikur; Deep, Shashank; Sau, Apurba Kumar

    2012-01-01

    Interferon-γ induced human guanylate binding protein-1(hGBP1) belongs to a family of dynamin related large GTPases. Unlike all other GTPases, hGBP1 hydrolyzes GTP to a mixture of GDP and GMP with GMP being the major product at 37°C but GDP became significant when the hydrolysis reaction was carried out at 15°C. The hydrolysis reaction in hGBP1 is believed to involve with a number of catalytic steps. To investigate the effect of temperature in the product formation and on the different catalytic complexes of hGBP1, we carried out temperature dependent GTPase assays, mutational analysis, chemical and thermal denaturation studies. The Arrhenius plot for both GDP and GMP interestingly showed nonlinear behaviour, suggesting that the product formation from the GTP-bound enzyme complex is associated with at least more than one step. The negative activation energy for GDP formation and GTPase assay with external GDP together indicate that GDP formation occurs through the reversible dissociation of GDP-bound enzyme dimer to monomer, which further reversibly dissociates to give the product. Denaturation studies of different catalytic complexes show that unlike other complexes the free energy of GDP-bound hGBP1 decreases significantly at lower temperature. GDP formation is found to be dependent on the free energy of the GDP-bound enzyme complex. The decrease in the free energy of this complex at low temperature compared to at high is the reason for higher GDP formation at low temperature. Thermal denaturation studies also suggest that the difference in the free energy of the GTP-bound enzyme dimer compared to its monomer plays a crucial role in the product formation; higher stability favours GMP but lower favours GDP. Thus, this study provides the first thermodynamic insight into the effect of temperature in the product formation of hGBP1. PMID:22859948

  18. Insight into temperature dependence of GTPase activity in human guanylate binding protein-1.

    Directory of Open Access Journals (Sweden)

    Anjana Rani

    Full Text Available Interferon-γ induced human guanylate binding protein-1(hGBP1 belongs to a family of dynamin related large GTPases. Unlike all other GTPases, hGBP1 hydrolyzes GTP to a mixture of GDP and GMP with GMP being the major product at 37°C but GDP became significant when the hydrolysis reaction was carried out at 15°C. The hydrolysis reaction in hGBP1 is believed to involve with a number of catalytic steps. To investigate the effect of temperature in the product formation and on the different catalytic complexes of hGBP1, we carried out temperature dependent GTPase assays, mutational analysis, chemical and thermal denaturation studies. The Arrhenius plot for both GDP and GMP interestingly showed nonlinear behaviour, suggesting that the product formation from the GTP-bound enzyme complex is associated with at least more than one step. The negative activation energy for GDP formation and GTPase assay with external GDP together indicate that GDP formation occurs through the reversible dissociation of GDP-bound enzyme dimer to monomer, which further reversibly dissociates to give the product. Denaturation studies of different catalytic complexes show that unlike other complexes the free energy of GDP-bound hGBP1 decreases significantly at lower temperature. GDP formation is found to be dependent on the free energy of the GDP-bound enzyme complex. The decrease in the free energy of this complex at low temperature compared to at high is the reason for higher GDP formation at low temperature. Thermal denaturation studies also suggest that the difference in the free energy of the GTP-bound enzyme dimer compared to its monomer plays a crucial role in the product formation; higher stability favours GMP but lower favours GDP. Thus, this study provides the first thermodynamic insight into the effect of temperature in the product formation of hGBP1.

  19. Somatization in Parkinson's Disease

    DEFF Research Database (Denmark)

    Carrozzino, Danilo; Bech, Per; Patierno, Chiara

    2017-01-01

    The current systematic review study is aimed at critically analyzing from a clinimetric viewpoint the clinical consequence of somatization in Parkinson's Disease (PD). By focusing on the International Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we...... consequence of such psychiatric symptom should be further evaluated by replacing the clinically inadequate diagnostic label of psychogenic parkinsonism with the psychosomatic concept of persistent somatization as conceived by the Diagnostic Criteria for Psychosomatic Research (DCPR)....

  20. Temperature dependence of electron mobility in N-type organic molecular crystals: Theoretical study

    Science.gov (United States)

    Lin, Lili; Fan, Jianzhong; Jiang, Supu; Wang, Zhongjie; Wang, Chuan-Kui

    2017-11-01

    The temperature dependence of electron mobility in three Fx-TCNQ molecular crystals is studied. The electron mobility calculated based on Marcus charge transfer rate for all three molecules increases, as the temperature becomes high. Nevertheless, the electron mobility calculated based on quantum charge transfer rate shows opposite temperature dependence and indicates bandlike transport mechanism. Similar intrinsic transport properties are obtained for three systems. The different temperature dependence for Fx-TCNQ molecules detected should be induced by different transfer paths or external factors. Our investigation could help one better understand experimental results and provide intuitive view on the transfer mechanism in molecular crystals.

  1. Temperature-dependent gate-swing hysteresis of pentacene thin film transistors

    Directory of Open Access Journals (Sweden)

    Yow-Jon Lin

    2014-10-01

    Full Text Available The temperature-dependent hysteresis-type transfer characteristics of pentacene-based organic thin film transistors (OTFTs were researched. The temperature-dependent transfer characteristics exhibit hopping conduction behavior. The fitting data for the temperature-dependent off-to-on and on-to-off transfer characteristics of OTFTs demonstrate that the hopping distance (ah and the barrier height for hopping (qϕt control the carrier flow, resulting in the hysteresis-type transfer characteristics of OTFTs. The hopping model gives an explanation of the gate-swing hysteresis and the roles played by qϕt and ah.

  2. Pulse Radiolysis Studies of Temperature Dependent Electron Transfers among Redox Centers in ba(3)-Cytochrome c Oxidase from Thermus thermophilus

    DEFF Research Database (Denmark)

    Farver, Ole; Wherland, Scot; Antholine, William E

    2010-01-01

    in cytochrome ba(3) had no effect on the rate of this reaction whereas the II-Met160Leu Cu(A)-mutation was slower by an amount corresponding to a decreased driving force of ∼0.06 eV. The structures support the presence of a common, electron-conducting "wire" between Cu(A) and heme-a(b). The transfer......The functioning of cytochrome c oxidases involves orchestration of long-range electron transfer (ET) events among the four redox active metal centers. We report the temperature dependence of electron transfer from the Cu(A)(r) site to the low-spin heme-(a)b(o) site, i.e., Cu(A)(r) + heme...

  3. Quantitative Analysis of Temperature Dependence of Raman shift of monolayer WS2

    National Research Council Canada - National Science Library

    Huang, Xiaoting; Gao, Yang; Yang, Tianqi; Ren, Wencai; Cheng, Hui-Ming; Lai, Tianshu

    2016-01-01

    We report the temperature-dependent evolution of Raman spectra of monolayer WS2 directly CVD-grown on a gold foil and then transferred onto quartz substrates over a wide temperature range from 84 to 543 K...

  4. Integrated optic current transducers incorporating photonic crystal fiber for reduced temperature dependence.

    Science.gov (United States)

    Chu, Woo-Sung; Kim, Sung-Moon; Oh, Min-Cheol

    2015-08-24

    Optical current transducers (OCT) are indispensable for accurate monitoring of large electrical currents in an environment suffering from severe electromagnetic interference. Temperature dependence of OCTs caused by its components, such as wave plates and optical fibers, should be reduced to allow temperature-independent operation. A photonic crystal fiber with a structural optical birefringence was incorporated instead of a PM fiber, and a spun PM fiber was introduced to overcome the temperature-dependent linear birefringence of sensing fiber coil. Moreover, an integrated optic device that provides higher stability than fiber-optics was employed to control the polarization and detect the phase of the sensed optical signal. The proposed OCT exhibited much lower temperature dependence than that from a previous study. The OCT satisfied the 0.5 accuracy class (IIEC 60044-8) and had a temperature dependence less than ± 1% for a temperature range of 25 to 78 °C.

  5. Temperature-dependent structural and functional features of a hyperthermostable enzyme using elastic neutron scattering

    NARCIS (Netherlands)

    Koutsopoulos, S; van der Oost, J; Norde, W

    2005-01-01

    The dynamic behavior of an endoglucanase from the hyperthermophilic microorganism Pyrococcus furiosus was investigated using elastic neutron scattering. The temperature dependence of the atomic motions was correlated with conformational. and functional characteristics of the enzyme. The onset of

  6. Molecular players involved in temperature-dependent sex determination and sex differentiation in Teleost fish

    Science.gov (United States)

    2014-01-01

    The molecular mechanisms that underlie sex determination and differentiation are conserved and diversified. In fish species, temperature-dependent sex determination and differentiation seem to be ubiquitous and molecular players involved in these mechanisms may be conserved. Although how the ambient temperature transduces signals to the undifferentiated gonads remains to be elucidated, the genes downstream in the sex differentiation pathway are shared between sex-determining mechanisms. In this paper, we review recent advances on the molecular players that participate in the sex determination and differentiation in fish species, by putting emphasis on temperature-dependent sex determination and differentiation, which include temperature-dependent sex determination and genetic sex determination plus temperature effects. Application of temperature-dependent sex differentiation in farmed fish and the consequences of temperature-induced sex reversal are discussed. PMID:24735220

  7. Temperature dependence of the strain response of chemical composition gratings in optical fibers

    Science.gov (United States)

    Li, Guoyu; Guan, Bai-ou

    2008-11-01

    Chemical composition gratings, used as strain sensing elements at high temperature environments, show a temperature dependence of their strain response. Temperature dependence of the strain response of CCGs over a range of temperatures from 24°C to 900°C has been measured. It is found that the wavelength shift of CCGs is linear with applied tensile strain at a constant temperature, and the strain sensitivity is 0.0011nm/μɛ.

  8. Identifying driver mutations in sequenced cancer genomes

    DEFF Research Database (Denmark)

    Raphael, Benjamin J; Dobson, Jason R; Oesper, Layla

    2014-01-01

    High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise......, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA...... sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein...

  9. Mitochondrial mutations in cancer.

    Science.gov (United States)

    Brandon, M; Baldi, P; Wallace, D C

    2006-08-07

    The metabolism of solid tumors is associated with high lactate production while growing in oxygen (aerobic glycolysis) suggesting that tumors may have defects in mitochondrial function. The mitochondria produce cellular energy by oxidative phosphorylation (OXPHOS), generate reactive oxygen species (ROS) as a by-product, and regulate apoptosis via the mitochondrial permeability transition pore (mtPTP). The mitochondria are assembled from both nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) genes. The mtDNA codes for 37 genes essential of OXPHOS, is present in thousands of copies per cell, and has a very high mutations rate. In humans, severe mtDNA mutations result in multisystem disease, while some functional population-specific polymorphisms appear to have permitted humans to adapt to new environments. Mutations in the nDNA-encoded mitochondrial genes for fumarate hydratase and succinate dehydrogenase have been linked to uterine leiomyomas and paragangliomas, and cancer cells have been shown to induce hexokinase II which harnesses OXPHOS adenosine triphosphate (ATP) production to drive glycolysis. Germline mtDNA mutations at nucleotides 10398 and 16189 have been associated with breast cancer and endometrial cancer. Tumor mtDNA somatic mutations range from severe insertion-deletion and chain termination mutations to mild missense mutations. Surprisingly, of the 190 tumor-specific somatic mtDNA mutations reported, 72% are also mtDNA sequence variants found in the general population. These include 52% of the tumor somatic mRNA missense mutations, 83% of the tRNA mutations, 38% of the rRNA mutations, and 85% of the control region mutations. Some associations might reflect mtDNA sequencing errors, but analysis of several of the tumor-specific somatic missense mutations with population counterparts appear legitimate. Therefore, mtDNA mutations in tumors may fall into two main classes: (1) severe mutations that inhibit OXPHOS, increase ROS production and promote tumor

  10. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders

    NARCIS (Netherlands)

    Campbell, I.M.; Yuan, B.; Robberecht, C.; Pfundt, R.P.; Szafranski, P.; McEntagart, M.E.; Nagamani, S.C.; Erez, A.; Bartnik, M.; Wisniowiecka-Kowalnik, B.; Plunkett, K.S.; Pursley, A.N.; Kang, S.H.; Bi, W.; Lalani, S.R.; Bacino, C.A.; Vast, M.; Marks, K.; Patton, M.; Olofsson, P.; Patel, A.; Veltman, J.A.; Cheung, S.W.; Shaw, C.A.; Vissers, L.E.L.M.; Vermeesch, J.R.; Lupski, J.R.; Stankiewicz, P.

    2014-01-01

    New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such

  11. Temperature Dependence of Rheology and Polymer Diffusion in Silica/Polystyrene Nanocomposites

    Science.gov (United States)

    Tung, Wei-Shao; Clarke, Nigel; Composto, Russell; Meth, Jeffrey; Winey, Karen

    2015-03-01

    Time-temperature superposition using the WLF equation is well-established for both the zero shear viscosity and the polymer diffusion coefficient in homopolymer melts. This talk will present the temperature-dependence of polymer dynamics in polymer nanocomposites comprised of polystyrene and phenyl-capped silica nanoparticles (0 - 50 vol%). The WLF equation fits the temperature dependence of the tracer polymer diffusion coefficient and the fitting parameter (B/fo) decreases smoothly with nanoparticle concentration suggesting an increase in the thermal expansion coefficient for the free volume. The WLF equation also fits the temperature dependence of the zero shear viscosity from oscillatory shear experiments, although the fitting parameter (B/fo) increases substantially with nanoparticle concentration. This discrepancy between the diffusion and rheology will be discussed with respect to the reptation model, which predicts that the temperature dependence of polymer diffusion depends predominately on the temperature dependence of local viscosity, and the elastic response in nanocomposites. National Science Foundation DMR-12-10379.

  12. Temperature dependence of 1H NMR chemical shifts and its influence on estimated metabolite concentrations.

    Science.gov (United States)

    Wermter, Felizitas C; Mitschke, Nico; Bock, Christian; Dreher, Wolfgang

    2017-07-06

    Temperature dependent chemical shifts of important brain metabolites measured by localised 1H MRS were investigated to test how the use of incorrect prior knowledge on chemical shifts impairs the quantification of metabolite concentrations. Phantom measurements on solutions containing 11 metabolites were performed on a 7 T scanner between 1 and 43 °C. The temperature dependence of the chemical shift differences was fitted by a linear model. Spectra were simulated for different temperatures and analysed by the AQSES program (jMRUI 5.2) using model functions with chemical shift values for 37 °C. Large differences in the temperature dependence of the chemical shift differences were determined with a maximum slope of about ±7.5 × 10-4 ppm/K. For 32-40 °C, only minor quantification errors resulted from using incorrect chemical shifts, with the exception of Cr and PCr. For 1-10 °C considerable quantification errors occurred if the temperature dependence of the chemical shifts was neglected. If 1H MRS measurements are not performed at 37 °C, for which the published chemical shift values have been determined, the temperature dependence of chemical shifts should be considered to avoid systematic quantification errors, particularly for measurements on animal models at lower temperatures.

  13. Sex reversal triggers the rapid transition from genetic to temperature-dependent sex.

    Science.gov (United States)

    Holleley, Clare E; O'Meally, Denis; Sarre, Stephen D; Marshall Graves, Jennifer A; Ezaz, Tariq; Matsubara, Kazumi; Azad, Bhumika; Zhang, Xiuwen; Georges, Arthur

    2015-07-02

    Sex determination in animals is amazingly plastic. Vertebrates display contrasting strategies ranging from complete genetic control of sex (genotypic sex determination) to environmentally determined sex (for example, temperature-dependent sex determination). Phylogenetic analyses suggest frequent evolutionary transitions between genotypic and temperature-dependent sex determination in environmentally sensitive lineages, including reptiles. These transitions are thought to involve a genotypic system becoming sensitive to temperature, with sex determined by gene-environment interactions. Most mechanistic models of transitions invoke a role for sex reversal. Sex reversal has not yet been demonstrated in nature for any amniote, although it occurs in fish and rarely in amphibians. Here we make the first report of reptile sex reversal in the wild, in the Australian bearded dragon (Pogona vitticeps), and use sex-reversed animals to experimentally induce a rapid transition from genotypic to temperature-dependent sex determination. Controlled mating of normal males to sex-reversed females produces viable and fertile offspring whose phenotypic sex is determined solely by temperature (temperature-dependent sex determination). The W sex chromosome is eliminated from this lineage in the first generation. The instantaneous creation of a lineage of ZZ temperature-sensitive animals reveals a novel, climate-induced pathway for the rapid transition between genetic and temperature-dependent sex determination, and adds to concern about adaptation to rapid global climate change.

  14. A Study of the Temperature Dependence of Bienzyme Systems and Enzymatic Chains

    Directory of Open Access Journals (Sweden)

    N. V. Kotov

    2007-01-01

    Full Text Available It is known that most enzyme-facilitated reactions are highly temperature dependent processes. In general, the temperature coefficient, Q10, of a simple reaction reaches 2.0–3.0. Nevertheless, some enzyme-controlled processes have much lower Q10 (about 1.0, which implies that the process is almost temperature independent, even if individual reactions involved in the process are themselves highly temperature dependent. In this work, we investigate a possible mechanism for this apparent temperature compensation: simple mathematical models are used to study how varying types of enzyme reactions are affected by temperature. We show that some bienzyme-controlled processes may be almost temperature independent if the modules involved in the reaction have similar temperature dependencies, even if individually, these modules are strongly temperature dependent. Further, we show that in non-reversible enzyme chains the stationary concentrations of metabolites are dependent only on the relationship between the temperature dependencies of the first and last modules, whilst in reversible reactions, there is a dependence on every module. Our findings suggest a mechanism by which the metabolic processes taking place within living organisms may be regulated, despite strong variation in temperature.

  15. Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma

    Directory of Open Access Journals (Sweden)

    Xiang Chen

    2014-04-01

    Full Text Available Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs and copy number alterations (CNAs. To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%–53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods.

  16. The effect of temperature dependent tissue parameters on acoustic radiation force induced displacements

    CERN Document Server

    Suomi, Visa; Konofagou, Elisa; Cleveland, Robin

    2016-01-01

    Multiple ultrasound elastography techniques rely on acoustic radiation force (ARF) in monitoring high-intensity focused ultrasound (HIFU) therapy. However, ARF is dependent on tissue attenuation and sound speed, both of which are also known to change with temperature making the therapy monitoring more challenging. Furthermore, the viscoelastic properties of tissue are also temperature dependent, which affects the displacements induced by ARF. The aim of this study is to quantify the temperature dependent changes in the acoustic and viscoelastic properties of liver and investigate their effect on ARF induced displacements by using both experimental methods and simulations. Furthermore, the temperature dependent viscoelastic properties of liver are experimentally measured over a frequency range of 0.1-200 Hz at temperatures reaching 80 C, and both conventional and fractional Zener models are used to fit the data. The fractional Zener model was found to fit better with the experimental viscoelasticity data with ...

  17. Selecting Temperature for Protein Crystallization Screens Using the Temperature Dependence of the Second Virial Coefficient

    Science.gov (United States)

    Liu, Jun; Yin, Da-Chuan; Guo, Yun-Zhu; Wang, Xi-Kai; Xie, Si-Xiao; Lu, Qin-Qin; Liu, Yong-Ming

    2011-01-01

    Protein crystals usually grow at a preferable temperature which is however not known for a new protein. This paper reports a new approach for determination of favorable crystallization temperature, which can be adopted to facilitate the crystallization screening process. By taking advantage of the correlation between the temperature dependence of the second virial coefficient (B22) and the solubility of protein, we measured the temperature dependence of B22 to predict the temperature dependence of the solubility. Using information about solubility versus temperature, a preferred crystallization temperature can be proposed. If B22 is a positive function of the temperature, a lower crystallization temperature is recommended; if B22 shows opposite behavior with respect to the temperature, a higher crystallization temperature is preferred. Otherwise, any temperature in the tested range can be used. PMID:21479212

  18. Temperature dependence of a refractive index sensor based on a macrobending micro-plastic optical fiber.

    Science.gov (United States)

    Jing, Ning; Teng, Chuanxin; Zhao, Xiaowei; Zheng, Jie

    2015-03-10

    We investigate the temperature dependence of a refractive index (RI) sensor based on a macrobending micro-plastic optical fiber (m-POF) both theoretically and experimentally. The performance of the RI sensor at different temperatures (10°C-70°C) is measured and simulated over an RI range from 1.33 to 1.45. It is found that the temperature dependent bending loss and RI measurement deviation monotonically change with temperature, and the RI deviation has a higher gradient with temperature variation for a higher measured RI. Because of the linear trend of temperature dependence of the sensor, it is feasible to correct for changes in ambient temperature.

  19. Manipulating the temperature dependence of the thermal conductivity of graphene phononic crystal.

    Science.gov (United States)

    Hu, Shiqian; An, Meng; Yang, Nuo; Li, Baowen

    2016-07-01

    By using non-equilibrium molecular dynamics simulations, modulating the temperature dependence of thermal conductivity of graphene phononic crystals (GPnCs) is investigated. It is found that the temperature dependence of thermal conductivity of GPnCs follows ∼T (-α) behavior. The power exponents (α) can be efficiently tuned by changing the characteristic size of GPnCs. The phonon participation ratio spectra and dispersion relation reveal that the long-range phonon modes are more affected in GPnCs with larger holes (L 0). Our results suggest that constructing GPnCs is an effective method to manipulate the temperature dependence of thermal conductivity of graphene, which would be beneficial for developing GPnC-based thermal management and signal processing devices.

  20. Investigation on the effects of temperature dependency of material parameters on a thermoelastic loading problem

    Science.gov (United States)

    Kumar, Anil; Mukhopadhyay, Santwana

    2017-08-01

    The present work is concerned with the investigation of thermoelastic interactions inside a spherical shell with temperature-dependent material parameters. We employ the heat conduction model with a single delay term. The problem is studied by considering three different kinds of time-dependent temperature and stress distributions applied at the inner and outer surfaces of the shell. The problem is formulated by considering that the thermal properties vary as linear function of temperature that yield nonlinear governing equations. The problem is solved by applying Kirchhoff transformation along with integral transform technique. The numerical results of the field variables are shown in the different graphs to study the influence of temperature-dependent thermal parameters in various cases. It has been shown that the temperature-dependent effect is more prominent in case of stress distribution as compared to other fields and also the effect is significant in case of thermal shock applied at the two boundary surfaces of the spherical shell.

  1. Temperature dependence of the ClONO{sub 2} UV absorption spectrum

    Energy Technology Data Exchange (ETDEWEB)

    Burkholder, J.B.; Talukdar, R.K.; Ravishankara, A.R. [Univ. of Colorado, Boulder, CO (United States)

    1994-04-01

    The temperature dependence of the ClONO{sub 2} absorption spectrum has been measured between 220 and 298 K and between 195 and 430 nm using a diode array spectrometer. The absorption cross sections were determined using both: (1) absolute pressure measurements at 296 K and (2) measurements at various temperatures relative to 296 K using a dual absorption cell arrangement. The temperature dependence of the ClONO{sub 2} absorption spectrum shows very broad structure. The amplitude of the temperature dependence relative to that at 296 K is weak at short wavelengths, < 2% at 215 nm and 220 K, but significant at the wavelengths important in the stratosphere, {approximately} 30% at 325 nm and 220 K. The authors ClONO{sub 2} absorption cross section data are in good general agreement with the previous measurements of Molina and Molina.

  2. Temperature dependence of the ClONO2 UV absorption spectrum

    Science.gov (United States)

    Burkholder, James B.; Talukdar, Ranajit K.; Ravishankara, A. R.

    1994-01-01

    The temperature dependence of the ClONO2 absorption spectrum has been measured between 220 and 298 K and between 195 and 430 nm using a diode array spectrometer. The absorption cross sections were determined using both: (1) absolute pressure measurements at 296 K and (2) measurements at various temperatures relative to 296 K using a dual absorption cell arrangement. The temperature dependence of the ClONO2 absorption spectrum shows very broad structure. The amplitude of the temperature dependence relative to that at 296 K is weak at short wavelengths, less than 2% at 215 nm and 220 K, but significant at the wavelengths important in the stratosphere, about 30% at 325 nm and 220 K. Our ClONO2 absorption cross section data are in good general agreement with the previous measurements of Molina and Molina (1979).

  3. Temperature dependent properties of InSb and InAs nanowire field-effect transistors

    Science.gov (United States)

    Nilsson, Henrik A.; Caroff, Philippe; Thelander, Claes; Lind, Erik; Karlström, Olov; Wernersson, Lars-Erik

    2010-04-01

    We present temperature dependent electrical measurements on InSb and InAs nanowire field-effect transistors (FETs). The FETs are fabricated from InAs/InSb heterostructure nanowires, where one complete transistor is defined within each of the two segments. Both the InSb and the InAs FETs are n-type with good current saturation and low voltage operation. The off-current for the InSb FET shows a strong temperature dependence, which we attribute to a barrier lowering due to an increased band-to-band tunneling in the drain part of the channel.

  4. DETERMINATION OF TEMPERATURE DISTRIBUTION FOR ANNULAR FINS WITH TEMPERATURE DEPENDENT THERMAL CONDUCTIVITY BY HPM

    Directory of Open Access Journals (Sweden)

    Davood Domairry Ganji

    2011-01-01

    Full Text Available In this paper, homotopy perturbation method has been used to evaluate the temperature distribution of annular fin with temperature-dependent thermal conductivity and to determine the temperature distribution within the fin. This method is useful and practical for solving the nonlinear heat transfer equation, which is associated with variable thermal conductivity condition. The homotopy perturbation method provides an approximate analytical solution in the form of an infinite power series. The annular fin heat transfer rate with temperature-dependent thermal conductivity has been obtained as a function of thermo-geometric fin parameter and the thermal conductivity parameter describing the variation of the thermal conductivity.

  5. Temperature-Dependent Diffusion Coefficients from ab initio Computations: Hydrogen in Nickel

    Energy Technology Data Exchange (ETDEWEB)

    E Wimmer; W Wolf; J Sticht; P Saxe; C Geller; R Najafabadi; G Young

    2006-03-16

    The temperature-dependent mass diffusion coefficient is computed using transition state theory. Ab initio supercell phonon calculations of the entire system provide the attempt frequency, the activation enthalpy, and the activation entropy as a function of temperature. Effects due to thermal lattice expansion are included and found to be significant. Numerical results for the case of hydrogen in nickel demonstrate a strong temperature dependence of the migration enthalpy and entropy. Trapping in local minima along the diffusion path has a pronounced effect especially at low temperatures. The computed diffusion coefficients with and without trapping bracket the available experimental values over the entire temperature range between 0 and 1400 K.

  6. The Temperature Dependence of the Debye-Waller Factor of Magnesium

    DEFF Research Database (Denmark)

    Sledziewska-Blocka, D.; Lebech, Bente

    1976-01-01

    The temperature dependence of the average Debye-Waller factor for magnesium was measured by means of neutron diffraction spectrometry. The experimental results obtained in the temperature range from 5 to 256 K are compared with theoretical calculations, using the harmonic and quasi-harmonic appro......The temperature dependence of the average Debye-Waller factor for magnesium was measured by means of neutron diffraction spectrometry. The experimental results obtained in the temperature range from 5 to 256 K are compared with theoretical calculations, using the harmonic and quasi...

  7. Temperature Dependent Fracture Model and its Application to Ultra Heavy Thick Steel Plate Used for Shipbuilding

    Science.gov (United States)

    Jang, Yun Chan; Lee, Youngseog; An, Gyu Baek; Park, Joon Sik; Lee, Jong Bong; Kim, Sung Il

    In this study, experimental and numerical studies were performed to examine the effects of thickness of steel plate on the arrest fracture toughness. The ESSO tests were performed with the steel plates having temperature gradient along the crack propagation direction. A temperature dependent crack initiation criterion was proposed as well. A series of three-dimensional FEA was then carried out to simulate the ESSO test while the thickness of the steel plate varies. Results reveal that a temperature dependent brittle criterion proposed in this study can describe the fracture behavior properly.

  8. Temperature-dependent vibrational spectroscopic study and DFT calculations of the sorbic acid

    Science.gov (United States)

    Saraiva, G. D.; Nogueira, C. E. S.; Freire, P. T. C.; de Sousa, F. F.; da Silva, J. H.; Teixeira, A. M. R.; Mendes Filho, J.

    2015-02-01

    This work reports a temperature-dependent vibrational spectroscopic study of the sorbic acid (C6H8O2), as well as the mode assignment at ambient conditions, based on the density functional theory. Temperature-dependent vibrational properties have been performed in polycrystalline sorbic acid through both Raman and infrared spectroscopy in the 20-300 K and 80-300 K temperature ranges, respectively. These studies present the occurrence of some modifications in the Raman spectra that could be interpreted as a low temperature phase transition undergone by sorbic acid from the monoclinic phase to an unknown phase with conformational change of the molecules in the unit cell.

  9. Temperature dependence of photoluminescence from submonolayer deposited InGaAs/GaAs quantum dots

    DEFF Research Database (Denmark)

    Xu, Zhangcheng; Leosson, K.; Birkedal, Dan

    2002-01-01

    The temperature dependence of photoluminescence (PL) from self-assembled InGaAs quantum dots (QD's) grown by submonolayer deposition mode (non-SK mode), is investigated. It is found that the PL spectra are dominated by the ground-state transitions at low temperatures, but increasingly by the exci......The temperature dependence of photoluminescence (PL) from self-assembled InGaAs quantum dots (QD's) grown by submonolayer deposition mode (non-SK mode), is investigated. It is found that the PL spectra are dominated by the ground-state transitions at low temperatures, but increasingly...

  10. Somatic structural rearrangements in genetically engineered mouse mammary tumors

    NARCIS (Netherlands)

    Varela, I.; Klijn, C.N.; Stephens, P.J.; Mudie, L.J.; Stebbings, L.; Galappaththige, D.; Van der Gulden, H.; Schut, E.; Klarenbeek, S.; Campbell, P.J.; Wessels, L.F.A.; Stratton, M.R.; Jonkers, J.; Futreal, P.A.; Adams, D.J.

    2010-01-01

    Background: Here we present the first paired-end sequencing of tumors from genetically engineered mouse models of cancer to determine how faithfully these models recapitulate the landscape of somatic rearrangements found in human tumors. These were models of Trp53-mutated breast cancer, Brca1- and

  11. Analysis of relation between the mutation frequencies and somatic recombination induced by neutrons and the age of D. Melanogaster larvae; Analisis de la relacion entre las frecuencias de mutacion y recombinacion somaticas inducidas por neutrones y la edad de las larvas en D. Melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Guzman R, J.; Zambrano A, F.; Paredes G, L.; Delfin L, A.; Quiroz R, C. [Instituto Nacional de Investigaciones Nucleares, A.P. 18-1027, 11801 Mexico D.F. (Mexico)

    1998-07-01

    Neutrons are subatomic particles with neutral electric charge, equal zero, which are emitted during the fissile material fission in nuclear reactors. It is known a little about biological effects induced by neutrons. There is a world interest in the use of reactors and accelerators for patients radiotherapy using neutrons with the purpose to destroy malignant cells of deep tumours where traditional methods have not given satisfactory results. There for it is required to do wide studies of biological effects of neutrons as well as their dosimetry. It was used the Smart test (Somatic Mutation and Recombination Test) of D. Melanogaster for quantifying the mutation induction and somatic recombination induced by neutrons of the National Institute of Nuclear Research reactor, at power of 300 and 1000 k W, with equivalent doses calculated 95.14 and 190.2 Sv for 300 k W and of 25.64 and 51.29 Sv for 1000 k W, using larvae with 72 or 96 hours aged. It was observed a linear relation between equivalent dose and genetic effects frequency, these last were greater when the reactor power was 1000 k W than those 300 k W. It was observed too that the damage was greater in 96 hours larvae than those 72 hours. The stain size presented an inverse relation with respect to larvae age. It is concluded that the Smart system is sensitive to neutrons effect and it responds of a directly proportional form to radiation dose, as well as to dose rate. It is noted more the effect when are used larvas in pre pupa stage where the irradiation target (imagal cells) is greater. The Smart is sensitive to damage induced by neutrons , thus can be used to studying its direct biological effects or by the use of chemical modulators. (Author)

  12. A simple equation for describing the temperature dependent growth of free-floating macrophytes

    NARCIS (Netherlands)

    Heide, van Tj.; Roijackers, R.M.M.; Nes, van E.H.; Peeters, E.T.H.M.

    2006-01-01

    Temperature is one of the most important factors determining growth rates of free-floating macrophytes in the field. To analyse and predict temperature dependent growth rates of these pleustophytes, modelling may play an important role. Several equations have been published for describing

  13. The importance of temperature dependent energy gap in the understanding of high temperature thermoelectric properties

    Science.gov (United States)

    Singh, Saurabh; Pandey, Sudhir K.

    2016-10-01

    In this work, we show the importance of temperature dependent energy band gap, E g (T), in understanding the high temperature thermoelectric (TE) properties of material by considering LaCoO3 (LCO) and ZnV2O4 (ZVO) compounds as a case study. For the fix value of band gap, E g , deviation in the values of α has been observed above 360 K and 400 K for LCO and ZVO compounds, respectively. These deviation can be overcomed by consideration of temperature dependent band gap. The change in used value of E g with respect to temperature is ∼4 times larger than that of In As. This large temperature dependence variation in E g can be attributed to decrement in the effective on-site Coulomb interaction due to lattice expansion. At 600 K, the value of ZT for n and p-doped, LCO is ∼0.35 which suggest that it can be used as a potential material for TE device. This work clearly suggest that one should consider the temperature dependent band gap in predicting the high temperature TE properties of insulating materials.

  14. Temperature dependence of the in situ widths of a rotating condensate in one dimensional optical potential

    Energy Technology Data Exchange (ETDEWEB)

    Hassan, Ahmed S., E-mail: ahmedhassan117@yahoo.com; Soliman, Shemi S.M.

    2016-01-08

    In this paper, a conventional method of quantum statistical mechanics is used to study the temperature dependence of the in situ widths of a rotating condensate bosons in 1D optical potential. We trace the experimentally accessible parameters for which the temperature dependence of the in situ widths becomes perceivable. The calculated results showed that the temperature dependence of the in situ widths is completely different from that of a rotating condensate or trapped bosons in the optical lattice separately. The z-width shows distinct behavior from x- and y-widths due to the rotation effect. The obtained results provide useful qualitative theoretical results for future Bose Einstein condensation experiments in such traps. - Highlights: • The temperature dependence of the in situ widths of a rotating condensate boson in 1D optical potential is investigated. • We trace the experimentally accessible parameters for which the in situ widths become perceivable. • The above mentioned parameters exhibit a characteristic rotation rate and optical potential depth dependence. • Characteristic dependence of the effective widths on temperature is investigated. • Our results provide useful qualitatively and quantitative theoretical results for experiments in various traps.

  15. Temperature Dependence and Magnetic Properties of Injection Molding Tool Materials Used in Induction Heating

    DEFF Research Database (Denmark)

    Guerrier, Patrick; Nielsen, Kaspar Kirstein; Hattel, Jesper Henri

    2015-01-01

    To analyze the heating phase of an induction heated injection molding tool precisely, the temperature-dependent magnetic properties, B–H curves, and the hysteresis loss are necessary for the molding tool materials. Hence, injection molding tool steels, core materials among other materials have...

  16. Temperature dependence of single-event burnout in n-channel power MOSFETs

    Science.gov (United States)

    Johnson, Gregory H.; Schrimpf, Ronald D.; Galloway, Kenneth F.; Koga, Rocky

    1992-12-01

    The temperature dependence of single-event burnout (SEB) in n-channel power MOSFETs is investigated experimentally and analytically. Experimental data are presented which indicate that the SEB susceptibility of the power MOSFET decreases with increasing temperature. A previously reported analytical model that describes the SEB mechanism is updated to include temperature variations. This model is shown to agree with the experimental trends.

  17. Observed and simulated temperature dependence of the liquid water path of low clouds

    Energy Technology Data Exchange (ETDEWEB)

    Del Genio, A.D.; Wolf, A.B. [NASA Goddard Institute for Space Studies, New York, NY (United States)

    1996-04-01

    Data being acquired at the Atmospheric Radiation Measurement (ARM) Southern great Plains (SGP) Cloud and Radiation Testbed (CART) site can be used to examine the factors determining the temperature dependence of cloud optical thickness. We focus on cloud liquid water and physical thickness variations which can be derived from existing ARM measurements.

  18. Temperature-dependent dynamic mechanical properties of magnetorheological elastomers under magnetic field

    Energy Technology Data Exchange (ETDEWEB)

    Ju, Benxiang, E-mail: jubenxiang@qq.com [National Instrument Functional Materials Engineering Technology Research Center, Chongqing 400707 (China); Tang, Rui; Zhang, Dengyou; Yang, Bailian [National Instrument Functional Materials Engineering Technology Research Center, Chongqing 400707 (China); Yu, Miao; Liao, Changrong [College of Optoelectronic Engineering, Chongqing University, Chongqing 400044 (China)

    2015-01-15

    Both anisotropic and isotropic magnetorheological elastomer (MRE) samples were fabricated by using as-prepared polyurethane (PU) matrix and carbonyl iron particles. Temperature-dependent dynamic mechanical properties of MRE were investigated and analyzed. Due to the unique structural features of as-prepared matrix, temperature has a greater impact on the properties of as-prepared MRE, especially isotropic MRE. With increasing of temperature and magnetic field, MR effect of isotropic MRE can reach up to as high as 4176.5% at temperature of 80 °C, and the mechanism of the temperature-dependent in presence of magnetic field was discussed. These results indicated that MRE is a kind of temperature-dependent material, and can be cycled between MRE and MR plastomer (MRP) by varying temperature. - Highlights: • Both anisotropic and isotropic MRE were fabricated by using as-prepared matrix. • Temperature-dependent properties of MRE under magnetic field were investigated. • As-prepared MRE can transform MRE to MRP by adjusting temperature.

  19. Temperature dependence of UV radiation effects in Arctic and temperate isolates of three red macrophytes

    NARCIS (Netherlands)

    van de Poll, W.H.; Eggert, A.; Buma, A.G.J.; Breeman, Arno

    The temperature dependence of UV effects was studied for Arctic and temperate isolates of the red macrophytes Palmaria palmata, Coccotylus truncatus and Phycodrys rubens. The effects of daily repeated artificial ultraviolet B and A radiation (UVBR: 280-320 nm, UVAR: 320-400 nm) treatments were

  20. The Heated Laminar Vertical Jet in a Liquid with Power-law Temperature Dependence of Density

    OpenAIRE

    Sharifulin, V. A.

    2009-01-01

    The analytical solution of heated laminar vertical jet in a liquid with power-law temperature dependence of density was obtained in the skin-layer approximation for certain values of Prandtl number. Cases of point and linear sources were considered.

  1. Temperature-dependent infrared and calorimetric studies on arsenicals adsorption from solution to hematite nanoparticles

    Science.gov (United States)

    To address the lack of systematic and surface sensitive studies on the adsorption energetics of arsenic compounds on metal (oxyhydr)oxides, we conducted temperature-dependent ATR-FTIR studies for the adsorption of arsenate, monomethylarsonic acid, and dimethylarsinic acid on hematite nanoparticles a...

  2. Temperature Dependence of the Polariton Linewidth in a GaAs Quantum Well Microcavity

    DEFF Research Database (Denmark)

    Borri, P.; Jensen, Jacob Riis; Langbein, W.

    2000-01-01

    The temperature dependent linewidths of the polariton resonances in a GaAs/AlGaAs single quantum well microcavity are measured. Due to the dominant homogeneous broadening of the investigated resonances, a direct linewidth analysis of the reflectivity spectra allows us to investigate the role of s...

  3. Using extrathermodynamic relationships to model the temperature dependence of Henry's law constants of 209 PCB congeners.

    Science.gov (United States)

    Bamford, Holly A; Poster, Dianne L; Huie, Robert E; Baker, Joel E

    2002-10-15

    Our previous measurements of the temperature dependencies of Henry's law constants of 26 polychlorinated biphenyls (PCBs) showed a well-defined linear relationship between the enthalpy and the entropy of phase change. Within a homologue group, the Henry's law constants converged to a common value at a specific isoequilibrium temperature. We use this relationship to model the temperature dependencies of the Henry's law constants of the remaining PCB congeners. By using experimentally measured Henry's law constants at 11 degrees C for 61 PCB congeners described in this paper combined with the isoequilibrium temperatures from our previous measurements of Henry's law constants of 26 PCB congeners, we have derived an empirical relationship between the enthalpies and the entropies of phase change for these additional PCB congeners. A systematic variation in the enthalpies and entropies of phase change was found to be partially dependent on the chlorine number and substitution patterns on the biphenyl rings, allowing further estimation of the temperature dependence of Henry's law constants for the remaining 122 PCB congeners. The enthalpies of phase change for all 209 PCB congeners ranged between 10 and 169 kJ mol(-1), where the enthalpies of phase change decreased as the number of ortho chlorine substitutions on the biphenyl rings increased within homologue groups. These data are used to predict the temperature dependence of Henry's law constants for all 209 PCB congeners.

  4. Theory of Temperature Dependence of the Magnetization in Rare-Earth-Transition-Metal Alloys

    DEFF Research Database (Denmark)

    Szpunar, B.; Lindgård, Per-Anker

    1977-01-01

    It is shown that the temperature dependence of the magnetic moments and Curie and ferrimagnetic compensation temperatures for Gdl-xTx (T = Co, Ni, and Fe) and Y1-xCox can be accounted for by a simple model assuming a RKKY interaction between the rare-earth moments and the transition-metal pseudo-...

  5. PRELIMINARY s'T'u_D|Es" on TEMPERATURE DEPENDENCE 'QF ...

    African Journals Online (AJOL)

    Bartington MS2B sensor operating at low frequency. The temperature dependence of magnetic.susceptibility experiment was carried out on representative samples using the. Bartington MS2X/T system (Fig.2). The samples' were frozen in the refrigerator to nearly 0°C and then quickly transferred to the water (MS2W) sensor.

  6. Temperature dependence of the superconducting proximity effect quantified by scanning tunneling spectroscopy

    Directory of Open Access Journals (Sweden)

    A. Stępniak

    2015-01-01

    Full Text Available Here, we present the first systematic study on the temperature dependence of the extension of the superconducting proximity effect in a 1–2 atomic layer thin metallic film, surrounding a superconducting Pb island. Scanning tunneling microscopy/spectroscopy (STM/STS measurements reveal the spatial variation of the local density of state on the film from 0.38 up to 1.8 K. In this temperature range the superconductivity of the island is almost unaffected and shows a constant gap of a 1.20 ± 0.03 meV. Using a superconducting Nb-tip a constant value of the proximity length of 17 ± 3 nm at 0.38 and 1.8 K is found. In contrast, experiments with a normal conductive W-tip indicate an apparent decrease of the proximity length with increasing temperature. This result is ascribed to the thermal broadening of the occupation of states of the tip, and it does not reflect an intrinsic temperature dependence of the proximity length. Our tunneling spectroscopy experiments shed fresh light on the fundamental issue of the temperature dependence of the proximity effect for atomic monolayers, where the intrinsic temperature dependence of the proximity effect is comparably weak.

  7. Dissecting the frog inner ear with Gaussian noise .2. Temperature dependence of inner ear function

    NARCIS (Netherlands)

    vanDijk, P; Wit, HP; Segenhout, JM

    1997-01-01

    The temperature dependence of the response of single primary auditory nerve fibers (n = 31) was investigated in the European edible frog, Rana esculenta (seven ears). Nerve fiber responses were analyzed with Wiener kernel analysis and polynomial correlation. The responses were described with a

  8. Temperature dependent behaviour of lead sulfide quantum dot solar cells and films

    NARCIS (Netherlands)

    Speirs, Mark J.; Dirin, Dmitry N.; Abdu-Aguye, Mustapha; Balazs, Daniel M.; Kovalenko, Maksym V.; Loi, Maria Antonietta

    2016-01-01

    Despite increasing greatly in power conversion efficiency in recent times, lead sulfide quantum dot (PbS QD) solar cells still suffer from a low open circuit voltage (V-OC) and fill factor (FF). In this work, we explore the temperature dependent behavior of similar to 9% efficient solar cells. In

  9. Temperature dependence of electronic heat capacity in Holstein model of DNA

    Science.gov (United States)

    Fialko, N.; Sobolev, E.; Lakhno, V.

    2016-04-01

    The dynamics of charge migration was modeled to calculate temperature dependencies of its thermodynamic equilibrium values such as energy and electronic heat capacity in homogeneous adenine fragments. The energy varies from nearly polaron one at T ∼ 0 to midpoint of the conductivity band at high temperatures. The peak on the graph of electronic heat capacity is observed at the polaron decay temperature.

  10. Demonstrating the Temperature Dependence of Density via Construction of a Galilean Thermometer

    Science.gov (United States)

    Priest, Marie A.; Padgett, Lea W.; Padgett, Clifford W.

    2011-01-01

    A method for the construction of a Galilean thermometer out of common chemistry glassware is described. Students in a first-semester physical chemistry (thermodynamics) class can construct the Galilean thermometer as an investigation of the thermal expansivity of liquids and the temperature dependence of density. This is an excellent first…

  11. Indications for a changing electricity demand pattern : The temperature dependence of electricity demand in the Netherlands

    NARCIS (Netherlands)

    Hekkenberg, M.; Benders, R. M. J.; Moll, H. C.; Uiterkamp, A. J. M. Schoot

    This study assesses the electricity demand pattern in the relatively temperate climate of the Netherlands (latitude 52 degrees 30'N). Daily electricity demand and average temperature during the period from 1970 until 2007 are investigated for possible trends in the temperature dependence of

  12. The temperature dependence of Cr3+ : YAG zero-phonon lines

    NARCIS (Netherlands)

    Marceddu, Marco; Manca, Marianna; Ricci, Pier Carlo; Anedda, Alberto

    2012-01-01

    This paper deals with the photoluminescence temperature dependence of the zero-phonon lines of Cr3+ ions in an yttrium aluminium garnet (YAG) matrix. Experimental data were analysed in the framework of electron-phonon coupling in the quadratic approximation and it was found that Cr3+ ions in the YAG

  13. Analogy between temperature-dependent and concentration-dependent bacterial killing

    NARCIS (Netherlands)

    Neef, C.; van Gils, Stephanus A.; Ijzerman, W.L.

    2002-01-01

    In this article an analogy between temperature-dependent and concentration-dependent bacterial killing is described. The validation process of autoclaves uses parameters such as reduction rate constant k, decimal reduction time D and resistance coefficient z from an imaginary microorganism to

  14. Temperature dependence of CIE-x,y color coordinates in YAG:Ce single crystal phosphor

    Czech Academy of Sciences Publication Activity Database

    Rejman, M.; Babin, Vladimir; Kučerková, Romana; Nikl, Martin

    2017-01-01

    Roč. 187, Jul (2017), s. 20-25 ISSN 0022-2313 R&D Projects: GA TA ČR TA04010135 Institutional support: RVO:68378271 Keywords : YAG:Ce * single-crystal * simulation * energy level lifetime * white LED * CIE * temperature dependence Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.686, year: 2016

  15. A theoretical analysis for temperature dependences of laser-induced damage threshold

    Science.gov (United States)

    Mikami, K.; Motokoshi, S.; Somekawa, T.; Jitsuno, T.; Fujita, M.; Tanaka, K. A.

    2013-11-01

    The temperature dependence of the laser-induced damage threshold on optical coatings was studied in detail for laser pulses from 123 K to 473 K at different temperature using Nd:YAG laser (wavelength 1064 nm and pulse width 4 ns) and Ti:Sapphire laser (wavelength 800 nm and pulse width 100 fs, 2 ps, and 200 ps). The six kinds of optical monolayer coatings were prepared by electron beam evaporation and the coating materials were SiO2, Al2O3, HfO2, ZrO2, Ta2O5, and MgF2. For pulses longer than a few picoseconds, the laser-induced damage threshold of single-layer coatings increased with decreasing temperature. This temperature dependence was reversed for pulses shorter than a few picoseconds. We describe the physics models to explain the observed scaling. The electron avalanche is essential to explain the differences in the temperature dependence. In other words, the balance between linear process such as electron avalanche etc. and nonlinear process such as multiphoton ionization etc. will be able to decide the tendency of the temperature dependence. The proposed model also gives one of possibility for an extremely high LIDT optics.

  16. Temperature dependence of the electrical conductivity of amorphous V sub x Si sub 1 minus x

    Energy Technology Data Exchange (ETDEWEB)

    Boghosian, H.H.; Howson, M.A. (Department of Physics, The University of Leeds, Leeds LS2 9JT, United Kingdom (GB))

    1990-04-15

    We present results for the temperature dependence of electrical conductivity for amorphous V{sub {ital x}}Si{sub 1{minus}{ital x}} alloys. The alloys investigated span the composition range from {ital x}=0.5 to 0.1. For the alloys with more than 20 at. % V, the temperature dependence could be successfully fitted with use of the theories of quantum interference effects, and values for the spin-orbit and inelastic scattering rates are extracted from the fits. As the concentration of V is decreased, there is evidence for a metal-insulator transition seen at around 15 to 13 at. % V. The temperature dependence of the conductivity is surprisingly similar for all the alloys on the metallic side of the transition, showing a clear {ital T}{sup 1/2} dependence at the lowest temperatures while the insulating V{sub 0.1}Si{sub 0.9} alloy shows evidence for variable-range-hopping conduction. The V{sub 0.13}Si{sub 0.87} alloy, which is right at the transition, exhibits an unusual temperature dependence. The sample is metallic and seems to follow a {ital T}{sup 1/3} dependence at low temperatures.

  17. Hartmann flow with temperature-dependent physical properties. [magnetohydrodynamics of liquid metal

    Science.gov (United States)

    Linn, G. T.; Walker, J. S.

    1978-01-01

    Attention is given to the steady, fully developed, one-dimensional flow of a liquid metal in which thermal conductivity, electrical conductivity, and viscosity are functions of temperature. It is found that the properties are decreasing functions of temperature and the first differences between temperature-dependent and constant properties are discussed.

  18. Transient energy growth modulation by temperature dependent transport properties in a stratified plane Poiseuille flow

    NARCIS (Netherlands)

    Rinaldi, E.; Boersma, B.J.; Pecnik, R.

    2015-01-01

    We investigate the effect of temperature dependent thermal conductivity ? and isobaric specific heat c_P on the transient amplification of perturbations in a thermally stratified laminar plane Poiseuille flow. It is shown that for decreasing thermal conductivity the maximum transient energy growth

  19. THE TEMPERATURE DEPENDENCE OF THE EMISSION OF PERCHLORO- ETHYLENE FROM DRY CLEANED FABRICS

    Science.gov (United States)

    A study was conducted to evaluate the emission of perchloroethylene (tetrachloroethylene) from freshly dry cleaned fabrics using small environmental test chambers. The temperature dependence of the release of perchloroethylene was evaluated over a temperature range of 20 to 45°C....

  20. Habitat related variation in UV tolerance of tropical marine red macrophytes is not temperature dependent

    NARCIS (Netherlands)

    van de Poll, W.H.; Bischof, K.; Buma, A.G.J.; Breeman, Arno

    Because tropical marine macrophytes experience high ultraviolet-B radiation (UVBR: 280-320 nm) it is assumed that they have high UV tolerance. This was investigated by examining the relative UV sensitivity of five Caribbean red macrophytes. Furthermore, the possibility of temperature dependence of

  1. A Simple Method to Calculate the Temperature Dependence of the Gibbs Energy and Chemical Equilibrium Constants

    Science.gov (United States)

    Vargas, Francisco M.

    2014-01-01

    The temperature dependence of the Gibbs energy and important quantities such as Henry's law constants, activity coefficients, and chemical equilibrium constants is usually calculated by using the Gibbs-Helmholtz equation. Although, this is a well-known approach and traditionally covered as part of any physical chemistry course, the required…

  2. Temperature-dependent remineralization of organic matter - small impacts on the carbon cycle

    Science.gov (United States)

    Laufkötter, Charlotte; John, Jasmin; Stock, Charles; Dunne, John

    2017-04-01

    The temperature dependence of remineralization of organic matter is regularly mentioned as important but unconstrained factor, with the potential to cause considerable uncertainty in projections of marine export production, carbon sequestration and oceanic carbon uptake. We have recently presented evidence for a temperature dependence of the particulate organic matter (POC) flux to depth, based on a compilation of observations. Here, we explore the impacts of the new temperature dependence on net primary production, POC flux and oceanic carbon uptake in the ecosystem model COBALT coupled to GFDL's ESM2M Coupled Climate-Carbon Earth System Model. We have implemented two remineralization schemes: COBALT-R1 includes a temperature dependence using parameter values according to our data analysis. COBALT-R1 shows very high remineralization in warm surface waters. The data used to constrain it, however, comes from colder water below 150m. Colonization of sinking material occurs throughout the euphotic zone, potentially reducing remineralization in the immediate vicinity of the ocean surface relative to R1 rates [Mislan et al., 2014]. We thus considered a second model version (COBALT-R2) that decreases remineralization towards the surface but ramped up remineralization rates to R1 values below 150m. After 1300 years of spin-up, the effects of the temperature dependence are most visible in the intermediate part of the water column (150 - 1500m), with stronger remineralization in the warmer upper water but weaker remineralization below, such that the carbon flux at 2000m is barely affected. Also, both COBALT-R1 and COBALT-R2 simulate lower POC flux in the low latitudes and higher POC flux in high latitudes compared to the original model version. In terms of future changes, COBALT-R1 projects an increase in NPP while COBALT-R2 projects a moderate decrease. However, the percentaged decrease in POC flux at 100m is identical in both model versions and the original COBALT

  3. Role of temperature-dependent viscosity and surface plates in spherical shell models of mantle convection

    Science.gov (United States)

    Zhong, Shijie; Zuber, Maria T.; Moresi, Louis; Gurnis, Michael

    2000-05-01

    Layered viscosity, temperature-dependent viscosity, and surface plates have an important effect on the scale and morphology of structure in spherical models of mantle convection. We find that long-wavelength structures can be produced either by a layered viscosity with a weak upper mantle or temperature-dependent viscosity even in the absence of surface plates, corroborating earlier studies. However, combining the layered viscosity structure with a temperature-dependent viscosity results in structure with significantly shorter wavelengths. Our models show that the scale of convection is mainly controlled by the surface plates, supporting the previous two-dimensional studies. Our models with surface plates, layered and temperature-dependent viscosity, and internal heating explain mantle structures inferred from seismic tomography. The models show that hot upwellings initiate at the core-mantle boundary (CMB) with linear structures, and as they depart from CMB, the linear upwellings quickly change into quasi-cylindrical plumes that dynamically interact with the ambient mantle and surface plates while ascending through the mantle. A linear up welling structure is generated again at shallow depths (maintained throughout the mantle. The tendency for linear upwelling and downwelling structures to break into plume-like structures is stronger at higher Rayleigh numbers. Our models also show that downwellings to first-order control surface plate motions and the locations and horizontal motion of upwellings. Upwellings tend to form at stagnation points predicted solely from the buoyancy forces of downwellings. Temperature-dependent viscosity greatly enhances the ascending velocity of developed upwelling plumes, and this may reduce the influence of global mantle flow on the motion of plumes. Our results can explain the anticorrelation between hotspot distribution and fast seismic wave speed anomalies in the lower mantle and may also have significant implications to the

  4. Characteristics of gliomas in patients with somatic IDH mosaicism.

    Science.gov (United States)

    Bonnet, Charlotte; Thomas, Laure; Psimaras, Dimitri; Bielle, Franck; Vauléon, Elodie; Loiseau, Hugues; Cartalat-Carel, Stéphanie; Meyronet, David; Dehais, Caroline; Honnorat, Jérôme; Sanson, Marc; Ducray, François

    2016-03-31

    IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors. Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations. In addition to skeletal tumors, enchondromatosis patients sometimes develop gliomas. The aim of the present study was to determine whether gliomas in enchondromatosis patients might also result from somatic IDH mosaicism and whether their characteristics are similar to those of sporadic IDH-mutated gliomas. For this purpose, we analyzed the characteristics of 6 newly diagnosed and 32 previously reported cases of enchondromatosis patients who developed gliomas and compared them to those of a consecutive series of 159 patients with sporadic IDH-mutated gliomas. As was the case with sporadic IDH mutated gliomas, enchondromatosis gliomas were frequently located in the frontal lobe (54 %) and consisted of diffuse low-grade (73 %) or anaplastic gliomas (21 %). However, they were diagnosed at an earlier age (25.6 years versus 44 years, p IDH mutated gliomas (21 % versus 1 %, p IDH mutations and loss of ATRX expression. In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor. In contrast to sporadic IDH mutated gliomas, no enchondromatosis glioma harbored a 1p/19q co-deletion (0/6 versus 59/123, p = 0.03). The characteristics of gliomas in patients with enchondromatosis suggest that these tumors, as cartilaginous tumors, result from somatic IDH mosaicism and that the timing of IDH mutation acquisition might affect the location and molecular characteristics of gliomas. Early acquisition of IDH mutations could shift gliomagenesis towards the brainstem thereby mimicking the regional preference of histone mutated gliomas.

  5. Somatization in refugees: a review.

    Science.gov (United States)

    Rohlof, Hans G; Knipscheer, Jeroen W; Kleber, Rolf J

    2014-11-01

    To present a review of the literature concerning medically unexplained physical symptoms in refugees. We outline a variety of definitions and explanations of somatization, as well as the role of culture in the concept of disease. In addition, we present a review of the epidemiological literature about somatization in refugees. Refugees from non-Western countries exhibit more unexplained somatic symptoms than the general Western population. Although different studies have employed different methodologies and are therefore difficult to compare, it can be concluded that refugees form a particular population in which somatization is prominent. Potential, not mutually exclusive, explanations of the high number of somatic symptoms in the refugee population include general psychopathology, specifically traumatisation, results of torture, and stigmatisation of psychiatric care. There are implications for assessment, clinical treatment and further research concerning somatization in refugees.

  6. Deciphering Signatures of Mutational Processes Operative in Human Cancer

    Science.gov (United States)

    Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Campbell, Peter J.; Stratton, Michael R.

    2013-01-01

    Summary The genome of a cancer cell carries somatic mutations that are the cumulative consequences of the DNA damage and repair processes operative during the cellular lineage between the fertilized egg and the cancer cell. Remarkably, these mutational processes are poorly characterized. Global sequencing initiatives are yielding catalogs of somatic mutations from thousands of cancers, thus providing the unique opportunity to decipher the signatures of mutational processes operative in human cancer. However, until now there have been no theoretical models describing the signatures of mutational processes operative in cancer genomes and no systematic computational approaches are available to decipher these mutational signatures. Here, by modeling mutational processes as a blind source separation problem, we introduce a computational framework that effectively addresses these questions. Our approach provides a basis for characterizing mutational signatures from cancer-derived somatic mutational catalogs, paving the way to insights into the pathogenetic mechanism underlying all cancers. PMID:23318258

  7. The Role of Somatic L1 Retrotransposition in Human Cancers

    Directory of Open Access Journals (Sweden)

    Emma C. Scott

    2017-05-01

    Full Text Available The human LINE-1 (or L1 element is a non-LTR retrotransposon that is mobilized through an RNA intermediate by an L1-encoded reverse transcriptase and other L1-encoded proteins. L1 elements remain actively mobile today and continue to mutagenize human genomes. Importantly, when new insertions disrupt gene function, they can cause diseases. Historically, L1s were thought to be active in the germline but silenced in adult somatic tissues. However, recent studies now show that L1 is active in at least some somatic tissues, including epithelial cancers. In this review, we provide an overview of these recent developments, and examine evidence that somatic L1 retrotransposition can initiate and drive tumorigenesis in humans. Recent studies have: (i cataloged somatic L1 activity in many epithelial tumor types; (ii identified specific full-length L1 source elements that give rise to somatic L1 insertions; and (iii determined that L1 promoter hypomethylation likely plays an early role in the derepression of L1s in somatic tissues. A central challenge moving forward is to determine the extent to which L1 driver mutations can promote tumor initiation, evolution, and metastasis in humans.

  8. Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.

    Science.gov (United States)

    Campbell, Ian M; Yuan, Bo; Robberecht, Caroline; Pfundt, Rolph; Szafranski, Przemyslaw; McEntagart, Meriel E; Nagamani, Sandesh C S; Erez, Ayelet; Bartnik, Magdalena; Wiśniowiecka-Kowalnik, Barbara; Plunkett, Katie S; Pursley, Amber N; Kang, Sung-Hae L; Bi, Weimin; Lalani, Seema R; Bacino, Carlos A; Vast, Mala; Marks, Karen; Patton, Michael; Olofsson, Peter; Patel, Ankita; Veltman, Joris A; Cheung, Sau Wai; Shaw, Chad A; Vissers, Lisenka E L M; Vermeesch, Joris R; Lupski, James R; Stankiewicz, Paweł

    2014-08-07

    New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  9. Somatic sex determination.

    Science.gov (United States)

    Zarkower, David

    2006-02-10

    C. elegans occurs in two natural sexes, the XX hermaphrodite and the XO male, which differ extensively in anatomy, physiology, and behavior. All somatic differences between the sexes result from the differential activity of a "global" sex determination regulatory pathway. This pathway also controls X chromosome dosage compensation, which is coordinated with sex determination by the action of the three SDC proteins. The SDC proteins control somatic and germline sex by transcriptional repression of the her-1 gene. HER-1 is a secreted protein that controls a regulatory module consisting of a transmembrane receptor, TRA-2, three intracellular FEM proteins, and the zinc finger transcription factor TRA-1. The molecular workings of this regulatory module are still being elucidated. Similarity of TRA-2 to patched receptors and of TRA-1 to GLI proteins suggests that parts of the global pathway originally derived from a Hedgehog signaling pathway. TRA-1 controls all aspects of somatic sexual differentiation, presumably by regulating a variety of tissue- and cell-specific downstream targets, including the cell death regulator EGL-1 and the male sexual regulator MAB-3. Sex determination evolves rapidly, and conservation of sexual regulators between phyla has been elusive. An apparent exception involves DM domain proteins, including MAB-3, which control sexual differentiation in nematodes, arthropods, and vertebrates. Important issues needing more study include the detailed molecular mechanisms of the global pathway, the identities of additional sexual regulators acting in the global pathway and downstream of TRA-1, and the evolutionary history of the sex determination pathway. Recently developed genetic and genomic technologies and comparative studies in divergent species have begun to address these issues.

  10. Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors.

    Directory of Open Access Journals (Sweden)

    Joaquim Bellmunt

    Full Text Available An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS in patients with advanced urothelial carcinoma (UC treated with platinum-based chemotherapy.DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE invasive high-grade UC samples and were screened for mutations, copy number variation (CNV and gene expression analysis. Clinical data were available from 85 cases. Mutations were analyzed by mass-spectrometry based on genotyping platform (Oncomap 3 and genomic imbalances were detected by comparative genomic hybridization (CGH analysis. Regions with threshold of log2 ratio ≥0.4, or ≤0.6 were defined as either having copy number gain or loss and significantly recurrent CNV across the set of samples were determined using a GISTIC analysis. Expression analysis on selected relevant UC genes was conducted using Nanostring. To define the co-occurrence pattern of mutations and CNV, we grouped genomic events into 5 core signal transduction pathways: 1 TP53 pathway, 2 RTK/RAS/RAF pathway, 3 PI3K/AKT/mTOR pathway, 4 WNT/CTNNB1, 5 RB1 pathway. Cox regression was used to assess pathways abnormalities with survival outcomes.35 samples (41% harbored mutations on at least one gene: TP53 (16%, PIK3CA (9%, FGFR3 (2%, HRAS/KRAS (5%, and CTNNB1 (1%. 66% of patients had some sort of CNV. PIK3CA/AKT/mTOR pathway alteration (mutations+CNV had the greatest impact on OS (p=0.055. At a gene level, overexpression of CTNNB1 (p=0.0008 and PIK3CA (p=0.02 were associated with shorter OS. Mutational status on PIK3CA was not associated with survival. Among other individually found genomic alterations, TP53 mutations (p=0.07, mTOR gain (p=0.07 and PTEN overexpression (p=0.08 have a marginally significant negative impact on OS.Our study suggests that targeted therapies focusing on the PIK3CA/AKT/mTOR pathway genomic alterations can generate the greatest impact in the overall patient

  11. Temperature Dependence of Fraction of Frozen Water in Solutions of Glucose and its Oligomers, Dextrans, and Potato Starch

    National Research Council Canada - National Science Library

    PRADIPASENA, Pasawadee; TATTIAKUL, Jirarat; NAKAMURA, Keiko; MIYAWAKI, Osato

    2007-01-01

    Initial freezing point and freezable water fraction, as the two parameters to determine the temperature dependence of fraction of frozen water, were measured systematically for solutions of glucose...

  12. Septin mutations in human cancers

    Directory of Open Access Journals (Sweden)

    Elias T Spiliotis

    2016-11-01

    Full Text Available Septins are GTP-binding proteins that are evolutionarily and structurally related to the RAS oncogenes. Septin expression levels are altered in many cancers and new advances point to how abnormal septin expression may contribute to the progression of cancer. In contrast to the RAS GTPases, which are frequently mutated and actively promote tumorigenesis, little is known about the occurrence and role of septin mutations in human cancers. Here, we review septin missense mutations that are currently in the Catalog of Somatic Mutations in Cancer (COSMIC database. The majority of septin mutations occur in tumors of the large intestine, skin, endometrium and stomach. Over 25% of the annotated mutations in SEPT2, SEPT4 and SEPT9 belong to large intestine tumors. From all septins, SEPT9 and SEPT14 exhibit the highest mutation frequencies in skin, stomach and large intestine cancers. While septin mutations occur with frequencies lower than 3%, recurring mutations in several invariant and highly conserved amino acids are found across different septin paralogs and tumor types. Interestingly, a significant number of these mutations occur in the GTP-binding pocket and septin dimerization interfaces. Future studies may determine how these somatic mutations affect septin structure and function, whether they contribute to the progression of specific cancers and if they could serve as tumor-specific biomarkers.

  13. Elevated temperature dependent transport properties of phosphorus and arsenic doped zinc oxide thin films

    Science.gov (United States)

    Cai, B.; Nakarmi, M. L.; Oder, T. N.; McMaster, M.; Velpukonda, N.; Smith, A.

    2013-12-01

    Elevated temperature dependent Hall effect measurements were performed in a wide temperature range from 80 to 800 K to study transport properties of zinc oxide (ZnO) thin films heavily doped with phosphorus (P) and arsenic (As), and grown on sapphire substrates by RF magnetron sputtering. Double thermal activation processes in both P- and As-doped ZnO thin films with small activation energy of ˜0.04 eV and large activation energy of ˜0.8 eV were observed from variable temperature Hall effect measurements. The samples exhibited n-type conductivities throughout the temperature range. Based on photoluminescence measurements at 11 K and theoretical results, the large activation energy observed in the temperature dependent Hall effect measurement has been assigned to a deep donor level, which could be related to oxygen vacancy (VO) in the doped ZnO thin films.

  14. Temperature dependence of magnetically dead layers in ferromagnetic thin-films

    Directory of Open Access Journals (Sweden)

    M. Tokaç

    2017-11-01

    Full Text Available Polarized neutron reflectometry has been used to study interface magnetism and magnetic dead layers in model amorphous CoFeB:Ta alloy thin-film multilayers with Curie temperatures tuned to be below room-temperature. This allows temperature dependent variations in the effective magnetic thickness of the film to be determined at temperatures that are a significant fraction of the Curie temperature, which cannot be achieved in the material systems used for spintronic devices. In addition to variation in the effective magnetic thickness due to compositional grading at the interface with the tantalum capping layer, the key finding is that at the interface between ferromagnetic film and GaAs(001 substrate local interfacial alloying creates an additional magnetic dead-layer. The thickness of this magnetic dead-layer is temperature dependent, which may have significant implications for elevated-temperature operation of hybrid ferromagnetic metal-semiconductor spintronic devices.

  15. Study of frequency- and temperature-dependent electrical transport in heavy fermion systems

    Science.gov (United States)

    Baral, P. C.

    2017-05-01

    This paper focuses on the frequency- and temperature-dependent electrical transport properties of heavy fermion (HF) systems. For this, Kondo lattice model (KLM) with Coulomb correlation between f-f electrons at the same site is considered. The Hamiltonian is treated in mean-field approximation (MFA) for the Kondo hybridization and Heisenberg-type interaction to get mean-field Hamiltonian and it is written after the Fourier transformation. The Hartree-Fock-type approximation is considered for the Coulomb repulsion between f-f electrons, the perturbed part of the Hamiltonian. The two Green’s functions for the conduction and f-electrons are calculated to define the self-energy. Then the frequency- and temperature-dependent optical conductivity and resistivity are calculated by using the Kubo’s formula within the linear dynamical response approach. They are studied by varying the model parameters. The anomalies and results obtained are compared with experimental data.

  16. An improved stochastic algorithm for temperature-dependent homogeneous gas phase reactions

    CERN Document Server

    Kraft, M

    2003-01-01

    We propose an improved stochastic algorithm for temperature-dependent homogeneous gas phase reactions. By combining forward and reverse reaction rates, a significant gain in computational efficiency is achieved. Two modifications of modelling the temperature dependence (with and without conservation of enthalpy) are introduced and studied quantitatively. The algorithm is tested for the combustion of n-heptane, which is a reference fuel component for internal combustion engines. The convergence of the algorithm is studied by a series of numerical experiments and the computational cost of the stochastic algorithm is compared with the DAE code DASSL. If less accuracy is needed the stochastic algorithm is faster on short simulation time intervals. The new stochastic algorithm is significantly faster than the original direct simulation algorithm in all cases considered.

  17. Temperature Dependence of Faraday Effect-Induced Bias Error in a Fiber Optic Gyroscope.

    Science.gov (United States)

    Li, Xuyou; Liu, Pan; Guang, Xingxing; Xu, Zhenlong; Guan, Lianwu; Li, Guangchun

    2017-09-07

    Improving the performance of interferometric fiber optic gyroscope (IFOG) in harsh environments, such as magnetic field and temperature field variation, is necessary for its practical applications. This paper presents an investigation of Faraday effect-induced bias error of IFOG under varying temperature. Jones matrix method is utilized to formulize the temperature dependence of Faraday effect-induced bias error. Theoretical results show that the Faraday effect-induced bias error changes with the temperature in the non-skeleton polarization maintaining (PM) fiber coil. This phenomenon is caused by the temperature dependence of linear birefringence and Verdet constant of PM fiber. Particularly, Faraday effect-induced bias errors of two polarizations always have opposite signs that can be compensated optically regardless of the changes of the temperature. Two experiments with a 1000 m non-skeleton PM fiber coil are performed, and the experimental results support these theoretical predictions. This study is promising for improving the bias stability of IFOG.

  18. Determination of the built-in voltage of BHJ solar cells by temperature dependent photocurrent measurements

    Energy Technology Data Exchange (ETDEWEB)

    Mingebach, Markus; Deibel, Carsten [Experimental Physics VI, Physical Institute, Julius-Maximilians-University of Wuerzburg (Germany); Dyakonov, Vladimir [Experimental Physics VI, Physical Institute, Julius-Maximilians-University of Wuerzburg (Germany); Bavarian Center of Applied Energy Research (ZAE Bayern e.V.), Wuerzburg (Germany)

    2011-07-01

    Despite all progresses in the performance of organic BHJ solar cells (up to 8% power conversion efficiency) some very important properties such as the voltage dependent photocurrent or the built-in potential are not fully understood yet. We investigate poly(3-hexyl thiophene) (P3HT): [6,6]-phenyl-C{sub 61} butyric acid methyl ester (PCBM) solar cells by means of temperature dependent pulsed photocurrent measurements and impedance spectroscopy. We find a point of optimal symmetry (POS) that represents the case of quasi flat bands (QFB) in the bulk of the cell, which is lower than the built-in voltage. This difference is due to band bending at the contacts, which is reduced at lower temperatures. Therefore we can identify the built-in voltage by measuring the POS (confirmed by temperature dependent current voltage measurements). This leads to the conclusion that the potential determined by Mott-Schottky analysis is not the built-in potential.

  19. Temperature dependent thermoelectric properties of chemically derived gallium zinc oxide thin films

    KAUST Repository

    Barasheed, Abeer Z.

    2013-01-01

    In this study, the temperature dependent thermoelectric properties of sol-gel prepared ZnO and 3% Ga-doped ZnO (GZO) thin films have been explored. The power factor of GZO films, as compared to ZnO, is improved by nearly 17% at high temperature. A stabilization anneal, prior to thermoelectric measurements, in a strongly reducing Ar/H2 (95/5) atmosphere at 500°C was found to effectively stabilize the chemically derived films, practically eliminating hysteresis during thermoelectric measurements. Subtle changes in the thermoelectric properties of stabilized films have been correlated to oxygen vacancies and excitonic levels that are known to exist in ZnO-based thin films. The role of Ga dopants and defects, formed upon annealing, in driving the observed complex temperature dependence of the thermoelectric properties is discussed. © The Royal Society of Chemistry 2013.

  20. Probing Temperature-Dependent Recombination Kinetics in Polymer:Fullerene Solar Cells by Electric Noise Spectroscopy

    Directory of Open Access Journals (Sweden)

    Giovanni Landi

    2017-09-01

    Full Text Available The influence of solvent additives on the temperature behavior of both charge carrier transport and recombination kinetics in bulk heterojunction solar cells has been investigated by electric noise spectroscopy. The observed differences in charge carrier lifetime and mobility are attributed to a different film ordering and donor-acceptor phase segregation in the blend. The measured temperature dependence indicates that bimolecular recombination is the dominant loss mechanism in the active layer, affecting the device performance. Blend devices prepared with a high-boiling-point solvent additive show a decreased recombination rate at the donor-acceptor interface as compared to the ones prepared with the reference solvent. A clear correlation between the device performance and the morphological properties is discussed in terms of the temperature dependence of the mobility-lifetime product.

  1. Temperature-dependent piezoresistivity in an MWCNT/epoxy nanocomposite temperature sensor with ultrahigh performance

    Science.gov (United States)

    Alamusi; Li, Yuan; Hu, Ning; Wu, Liangke; Yuan, Weifeng; Peng, Xianghe; Gu, Bin; Chang, Christiana; Liu, Yaolu; Ning, Huiming; Li, Jinhua; Surina; Atobe, Satoshi; Fukunaga, Hisao

    2013-11-01

    A temperature sensor was fabricated from a polymer nanocomposite with multi-walled carbon nanotube (MWCNT) as nanofiller (i.e., MWCNT/epoxy). The electrical resistance and temperature coefficient of resistance (TCR) of the temperature sensor were characterized experimentally. The effects of temperature (within the range 333-373 K) and MWCNT content (within the range 1-5 wt%) were investigated thoroughly. It was found that the resistance increases with increasing temperature and decreasing MWCNT content. However, the resistance change ratio related to the TCR increases with increasing temperature and MWCNT content. The highest value of TCR (0.021 K-1), which was observed in the case of 5 wt% MWCNT, is much higher than those of traditional metals and MWCNT-based temperature sensors. Moreover, the corresponding numerical simulation—conducted to explain the above temperature-dependent piezoresistivity of the nanocomposite temperature sensor—indicated the key role of a temperature-dependent tunneling effect.

  2. Temperature Dependence of Sound Velocity in High-Strength Fiber-Reinforced Plastics

    Science.gov (United States)

    Nomura, Ryuji; Yoneyama, Keiichi; Ogasawara, Futoshi; Ueno, Masashi; Okuda, Yuichi; Yamanaka, Atsuhiko

    2003-08-01

    Longitudinal sound velocity in unidirectional hybrid composites or high-strength fiber-reinforced plastics (FRPs) was measured along the fiber axis over a wide temperature range (from 77 K to 420 K). We investigated two kinds of high-strength crystalline polymer fibers, polyethylene (Dyneema) and polybenzobisoxazole (Zylon), which are known to have negative thermal expansion coefficients and high thermal conductivities along the fiber axis. Both FRPs had very high sound velocities of about 9000 m/s at low temperatures and their temperature dependences were very strong. Sound velocity monotonically decreased with increasing temperature. The temperature dependence of sound velocity was much stronger in Dyneema-FRP than in Zylon-FRP.

  3. Temperature dependence of Young's modulus of titanium dioxide (TIO2) nanotubes: Molecular mechanics modeling

    Science.gov (United States)

    Lukyanov, S. I.; Bandura, A. V.; Evarestov, R. A.

    2015-12-01

    Temperature dependence of the Young's modulus of cylindrical single-wall nanotubes with zigzag and armchair chiralities and consolidated-wall nanotubes has been studied by the molecular mechanics method with the use of the atom-atom potential. The nanotubes have been obtained by rolling up of crystal layers (111) of TiO2 with fluorite structure. Calculations have been performed for isothermal conditions on the basis of calculating the Helmholtz free energy of the system. The dependence of the Helmholtz free energy of nanotubes on the period has been calculated in the quasi-harmonic approximation as a result of calculation of phonon frequencies. It has been shown that the temperature dependence of the stiffness of nanotubes is determined by their chirality, and some nanotubes exibit anomalous behavior of both the Young's modulus and the period of unit cell with variation in temperature.

  4. Temperature dependence of magnetically dead layers in ferromagnetic thin-films

    Science.gov (United States)

    Tokaç, M.; Kinane, C. J.; Atkinson, D.; Hindmarch, A. T.

    2017-11-01

    Polarized neutron reflectometry has been used to study interface magnetism and magnetic dead layers in model amorphous CoFeB:Ta alloy thin-film multilayers with Curie temperatures tuned to be below room-temperature. This allows temperature dependent variations in the effective magnetic thickness of the film to be determined at temperatures that are a significant fraction of the Curie temperature, which cannot be achieved in the material systems used for spintronic devices. In addition to variation in the effective magnetic thickness due to compositional grading at the interface with the tantalum capping layer, the key finding is that at the interface between ferromagnetic film and GaAs(001) substrate local interfacial alloying creates an additional magnetic dead-layer. The thickness of this magnetic dead-layer is temperature dependent, which may have significant implications for elevated-temperature operation of hybrid ferromagnetic metal-semiconductor spintronic devices.

  5. Temperature dependence of direct current conductivity in Ag-ED20 nanocomposite films

    Science.gov (United States)

    Novikov, G. F.; Rabenok, E. V.; Bogdanova, L. M.; Irzhak, V. I.

    2017-10-01

    The effect of silver nanoparticles (NPs) in the concentration range of ≤0.8 wt % have on direct current conductivity σdc of Ag-ED20 nanocomposite is studied by method of broadband dielectric spectroscopy (10-2-105 Hz) method of broadband dielectric spectroscopy. It is found that temperature dependence σdc consists of two sections: above the glass transition temperature ( T g), the dependence corresponds to the empirical Vogel-Fulcher-Tammann law (Vogel temperature T 0 does not depend on the NP concentration); below T g, the dependence is Arrhenius with activation energy E a ≈ 1.2 eV. In the region where T > T g, the σdc value grows along with NP concentration. It is concluded that the observed broken form of the temperature dependence is apparently due to a change in the conduction mechanism after the freezing of ion mobility at temperatures below T g.

  6. Temperature dependence of stress in CVD diamond films studied by Raman spectroscopy

    Directory of Open Access Journals (Sweden)

    Dychalska Anna

    2015-09-01

    Full Text Available Evolution of residual stress and its components with increasing temperature in chemical vapor deposited (CVD diamond films has a crucial impact on their high temperature applications. In this work we investigated temperature dependence of stress in CVD diamond film deposited on Si(100 substrate in the temperature range of 30 °C to 480 °C by Raman mapping measurement. Raman shift of the characteristic diamond band peaked at 1332 cm-1 was studied to evaluate the residual stress distribution at the diamond surface. A new approach was applied to calculate thermal stress evolution with increasing tempera­ture by using two commonly known equations. Comparison of the residts obtained from the two methods was presented. The intrinsic stress component was calculated from the difference between average values of residual and thermal stress and then its temperature dependence was discussed.

  7. EXACT SOLUTION FOR TEMPERATURE-DEPENDENT BUCKLING ANALYSIS OF FG-CNT-REINFORCED MINDLIN PLATES

    Directory of Open Access Journals (Sweden)

    Seyed Mohammad Mousavi

    2016-03-01

    Full Text Available This research deals with the buckling analysis of nanocomposite polymeric temperature-dependent plates reinforced by single-walled carbon nanotubes (SWCNTs. For the carbon-nanotube reinforced composite (CNTRC plate, uniform distribution (UD and three types of functionally graded (FG distribution patterns of SWCNT reinforcements are assumed. The material properties of FG-CNTRC plate are graded in the thickness direction and estimated based on the rule of mixture. The CNTRC is located in a elastic medium which is simulated with temperature-dependent Pasternak medium. Based on orthotropic Mindlin plate theory, the governing equations are derived using Hamilton’s principle and solved by Navier method. The influences of the volume fractions of carbon nanotubes, elastic medium, temperature and distribution type of CNTs are considered on the buckling of the plate. Results indicate that CNT distribution close to top and bottom are more efficient than those distributed nearby the mid-plane for increasing the stiffness of plates.

  8. Thermal dissociation of molten KHSO4: Temperature dependence of Raman spectra and thermodynamics

    DEFF Research Database (Denmark)

    Knudsen, Christian B.; Kalampounias, Angelos G.; Fehrmann, Rasmus

    2008-01-01

    intensities with the stoichiometric coefficients, the equilibrium constant, and the thermodynamics of the reaction equilibrium is derived. The method is used-along with the temperature-dependent features of the Raman spectra-to show that the studied equilibrium 2HSO(4)(-) (1) S2O72-(1) + H2O(g) is the only......Raman spectroscopy is used to study the thermal dissociation of molten KHSO4 at temperatures of 240-450 degrees C under static equilibrium conditions. Raman spectra obtained at 10 different temperatures for the molten phase and for the vapors thereof exhibit vibrational wavenumbers and relative...... band intensities inferring the occurrence of the temperature-dependent dissociation equilibrium 2HSO(4)(-) (1) S2O72-(1) + H2O(g). The Raman data are adequate for determining the partial pressures of H2O in the gas phase above the molten mixtures. A formalism for correlating relative Raman band...

  9. Temperature-Dependent Polarization in Field-Effect Transport and Photovoltaic Measurements of Methylammonium Lead Iodide.

    Science.gov (United States)

    Labram, John G; Fabini, Douglas H; Perry, Erin E; Lehner, Anna J; Wang, Hengbin; Glaudell, Anne M; Wu, Guang; Evans, Hayden; Buck, David; Cotta, Robert; Echegoyen, Luis; Wudl, Fred; Seshadri, Ram; Chabinyc, Michael L

    2015-09-17

    While recent improvements in the reported peak power conversion efficiency (PCE) of hybrid organic-inorganic perovskite solar cells have been truly astonishing, there are many fundamental questions about the electronic behavior of these materials. Here we have studied a set of electronic devices employing methylammonium lead iodide ((MA)PbI3) as the active material and conducted a series of temperature-dependent measurements. Field-effect transistor, capacitor, and photovoltaic cell measurements all reveal behavior consistent with substantial and strongly temperature-dependent polarization susceptibility in (MA)PbI3 at temporal and spatial scales that significantly impact functional behavior. The relative PCE of (MA)PbI3 photovoltaic cells is observed to reduce drastically with decreasing temperature, suggesting that such polarization effects could be a prerequisite for high-performance device operation.

  10. A finite element technique for non-deterministic thermal deformation analyses including temperature dependent material properties

    Science.gov (United States)

    Case, W. R., Jr.; Walston, W. H., Jr.

    1977-01-01

    A technique utilizing the finite element displacement method is developed for the static analysis of structures subjected to non-deterministic thermal loading in which the material properties, assumed isotropic, are temperature dependent. Matrix equations are developed for the first two statistical moments of the displacements using a third order series expansion for the displacements in terms of the random temperatures. Sample problems are included to demonstrate the range of applicability of the third order series solutions. These solutions are compared with results from Monte Carlo analyses and also, for some problems, with solutions obtained by numerically integrating equations for the statistical properties of the displacements. In general, it is shown that the effect of temperature dependent material properties can have a significant effect on the covariances of the displacements.

  11. A Model of Temperature-Dependent Young's Modulus for Ultrahigh Temperature Ceramics

    Directory of Open Access Journals (Sweden)

    Weiguo Li

    2011-01-01

    Full Text Available Based on the different sensitivities of material properties to temperature between ultrahigh temperature ceramics (UHTCs and traditional ceramics, the original empirical formula of temperature-dependent Young's modulus of ceramic materials is unable to describe the temperature dependence of Young's modulus of UHTCs which are used as thermal protection materials. In this paper, a characterization applied to Young's modulus of UHTC materials under high temperature which is revised from the original empirical formula is established. The applicable temperature range of the characterization extends to the higher temperature zone. This study will provide a basis for the characterization for strength and fracture toughness of UHTC materials and provide theoretical bases and technical reserves for the UHTC materials' design and application in the field of spacecraft.

  12. Temperature dependence of magnetic anisotropies in ultrathin Fe film on vicinal Si(111)

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yong-Sheng; He, Wei; Ye, Jun; Hu, Bo; Tang, Jin; Zhang, Xiang-Qun [State Key Laboratory of Magnetism and Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China); Cheng, Zhao-Hua, E-mail: zhcheng@aphy.iphy.ac.cn [State Key Laboratory of Magnetism and Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190 (China); School of Physical Sciences, University of Chinese Academy of Sciences, Beijing 100190 (China)

    2017-05-01

    The temperature dependence of magnetic anisotropy of ultrathin Fe film with different thickness epitaxially grown on vicinal Si(111) substrate has been quantitatively investigated using the anisotropic magnetoresistance(AMR) measurements. Due to the effect of the vicinal substrate, the magnetic anisotropy is the superposition of a four-fold, a two-fold and a weakly six-fold contribution. It is found that the temperature dependence of the first-order magnetocrystalline anisotropies coefficient follows power laws of the reduced magnetization m(T)(=M(T)/M(0)) being consistent with the Callen and Callen's theory. However the temperature dependence of uniaxial magnetic anisotropy (UMA) shows novel behavior that decreases roughly as a function of temperature with different power law for samples with different thickness. We also found that the six-fold magnetocrystalline anisotropy is almost invariable over a wide temperature range. Possible mechanisms leading to the different exponents are discussed.

  13. Temperature dependence of the photoluminescence of MnS/ZnS core—shell quantum dots

    Science.gov (United States)

    Fang, Dai-Feng; Ding, Xing; Dai, Ru-Cheng; Zhao, Zhi; Wang, Zhong-Ping; Zhang, Zeng-Ming

    2014-12-01

    The temperature dependence of the photoluminescence (PL) from MnS/ZnS core—shell quantum dots is investigated in a temperature range of 8 K-300 K. The orange emission from the 4T1 → 6A1 transition of Mn2+ ions and the blue emission related to the trapped surface state are observed in the MnS/ZnS core—shell quantum dots. As the temperature increases, the orange emission is shifted toward a shorter wavelength while the blue emission is shifted towards the longer wavelength. Both the orange and blue emissions reduce their intensities with the increase of temperature but the blue emission is quenched faster. The temperature-dependent luminescence intensities of the two emissions are well explained by the thermal quenching theory.

  14. Competitive adsorption equilibrium model with continuous temperature dependent parameters for naringenin enantiomers on Chiralpak AD column.

    Science.gov (United States)

    Xu, Jin; Jiang, Xiaoxiao; Guo, Jinghua; Chen, Yongtao; Yu, Weifang

    2015-11-27

    Determination of competitive adsorption equilibrium model with continuous temperature dependent parameters is important for the design and optimization of a chromatographic separation process operated under non-isothermal conditions. In this study, linear pulse experiments were first carried to determine the parameters of transport-dispersive model and their temperature dependences in the range of 283–313 K. Overloaded band profiles of naringenin enantiomers on a Chiralpak AD column were acquired under various temperatures. Three of them were first separately fitted using Langmuir, linear-Langmuir and bi-Langmuir isotherm models substituted into the transport-dispersive column model. The comparison showed that bi-Langmuir model captures more details of the experimental results. This model was then extended with three extra parameters accounting for adsorption heat effects and used to simultaneously fit the band profiles at three temperatures.

  15. Compact model of power MOSFET with temperature dependent Cauer RC network for more accurate thermal simulations

    Science.gov (United States)

    Marek, Juraj; Chvála, Aleš; Donoval, Daniel; Príbytný, Patrik; Molnár, Marián; Mikolášek, Miroslav

    2014-04-01

    A new, more accurate SPICE-like model of a power MOSFET containing a temperature dependent thermal network is described. The designed electro-thermal MOSFET model consists of several parts which represent different transistor behavior under different conditions such as reverse bias, avalanche breakdown and others. The designed model is able to simulate destruction of the device as thermal runaway and/or overcurrent destruction during the switching process of a wide variety of inductive loads. Modified thermal equivalent circuit diagrams were designed taking into account temperature dependence of thermal resistivity. The potential and limitations of the new models are presented and analyzed. The new model is compared with the standard and empirical models and brings a higher accuracy for rapid heating pulses. An unclamped inductive switching (UIS) test as a stressful condition was used to verify the proper behavior of the designed MOSFET model.

  16. A Temperature-Dependent Thermal Model of IGBT Modules Suitable for Circuit-Level Simulations

    DEFF Research Database (Denmark)

    Wu, Rui; Wang, Huai; Ma, Ke

    2014-01-01

    Thermal impedance of IGBT modules may vary with operating conditions due to that the thermal conductivity and heat capacity of materials are temperature dependent. This paper proposes a Cauer thermal model for a 1700 V/1000 A IGBT module with temperature-dependent thermal resistances and thermal...... relevant reliability aspect performance. A test bench is built up with an ultra-fast infrared (IR) camera to validate the proposed thermal impedance model....... capacitances. The temperature effect is investigated by Finite Element Method (FEM) simulation based on the geometry and material information of the IGBT module. The developed model is ready for circuit-level simulation to achieve an improved accuracy of the estimation on IGBT junction temperature and its...

  17. Unusual temperature dependence of the positron lifetime in a polymer of intrinsic microporosity

    Energy Technology Data Exchange (ETDEWEB)

    Lima de Miranda, Rodrigo; Kruse, Jan; Raetzke, Klaus; Faupel, Franz [Technische Fakultaet der Christian-Albrechts-Universitaet, Lehrstuhl fuer Materialverbunde, Kaiserstr. 2, 24143 Kiel (Germany); Fritsch, Detlev; Abetz, Volker [Institut fuer Polymerforschung, GKSS-Forschungszentrum Geesthacht GmbH, Max-Planck-Strasse 1, 21502 Geesthacht (Germany); Budd, Peter M.; Selbie, James D. [School of Chemistry, The University of Manchester, Manchester M13 9PL (United Kingdom); McKeown, Neil B.; Ghanem, Bader S. [School of Chemistry, Cardiff University, Cardiff CF10 3AT (United Kingdom)

    2007-10-15

    The performance of polymeric membranes for gas separation is mainly determined by the free volume. Polymers of intrinsic microporosity are interesting due to the high abundance of accessible free volume. We performed measurements of the temperature dependence of the positron lifetime, generally accepted for investigation of free volume, in two polymers of intrinsic microporosity (PIM-1 and PIM-7) in the range from 143 to 523 K. The mean value of the free volume calculated from the ortho-positronium lifetime is in the range of typical values for high free volume polymers. However, the temperature dependence of the local free volume is non-monotonous in contrast to the macroscopic thermal expansion. The explanation is linked to the spirocenters in the polymer. (copyright 2007 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  18. Identification of microscopic domain wall motion from temperature dependence of nonlinear dielectric response.

    Czech Academy of Sciences Publication Activity Database

    Mokrý, Pavel; Sluka, T.

    2017-01-01

    Roč. 110, č. 16 (2017), č. článku 162906. ISSN 0003-6951 R&D Projects: GA ČR(CZ) GA14-32228S Institutional support: RVO:61389021 Keywords : microscopic domain wall * electric fields * temperature dependence Subject RIV: JA - Electronics ; Optoelectronics, Electrical Engineering Impact factor: 3.411, year: 2016 http://dx.doi.org/10.1063/1.4981874

  19. Temperature dependence of single-event burnout in n-channel power MOSFET's

    Science.gov (United States)

    Johnson, G. H.; Schrimpf, R. D.; Galloway, K. F.; Koga, R.

    1994-03-01

    The temperature dependence of single-event burnout (SEB) in n-channel power metal-oxide-semiconductor field effect transistors (MOSFET's) is investigated experimentally and analytically. Experimental data are presented which indicate that the SEB susceptibility of the power MOSFET decreases with increasing temperature. A previously reported analytical model that describes the SEB mechanism is updated to include temperature variations. This model is shown to agree with the experimental trends.

  20. Temperature dependence of the kinetic isotope effect in β-pinene ozonolysis

    Science.gov (United States)

    Gensch, Iulia; Laumer, Werner; Stein, Olaf; Kammer, Beatrix; Hohaus, Thorsten; Saathoff, Harald; Wegener, Robert; Wahner, Andreas; Kiendler-Scharr, Astrid

    2011-10-01

    The temperature dependence of the kinetic isotope effect (KIE) of β-pinene ozonolysis was investigated experimentally at 258, 273 and 303 K in the AIDA atmospheric simulation chamber. Compound specific carbon isotopic analysis of gas phase samples was performed off-line with a Thermo Desorption-Gas Chromatography-Isotope Ratio Mass Spectrometry (TD-GC-IRMS) system. From the temporal behavior of the δ13C of β-pinene a KIE of 1.00358 ± 0.00013 was derived at 303 K, in agreement with literature data. Furthermore, KIE values of 1.00380 ± 0.00014 at 273 K and 1.00539 ± 0.00012 at 258 K were determined, showing an increasing KIE with decreasing temperature. A parameterization of the observed KIE temperature dependence was deduced and used in a sensitivity study carried out with the global chemistry transport model MOZART-3. Two scenarios were compared, the first neglecting, the second implementing the KIE temperature dependence in the simulations. β-Pinene stable carbon isotope ratio and concentration were computed, with emphasis on boreal zones. For early spring it is shown that when neglecting the temperature dependence of KIE, the calculated average age of β-pinene in the atmosphere can be up to two times over- or underestimated. The evolution of the isotopic composition of the major β-pinene oxidation product, nopinone, was examined using Master Chemical Mechanism (MCM) simulations. The tested hypothesis that formation of nopinone and its associated KIE are the determining factors for the observed δ13C values of nopinone is supported at high β-pinene conversion levels.

  1. Temperature-dependent photoluminescence and Raman investigation of Cu-incorporated ZnO nanorods

    Energy Technology Data Exchange (ETDEWEB)

    Yu, J.L. [Institute of Micro/Nano Devices and Solar Cells, School of Physics and Information Engineering, Fuzhou University, Fuzhou (China); Jiangsu Collaborative Innovation Center of Photovolatic Science and Engineering, Changzhou University, Changzhou 213164, Jiangsu (China); Key Laboratory of Semiconductor Materials Science, Institute of Semiconductors, Chinese Academy of Sciences, P.O. Box 912, Beijing 100083 (China); Lai, Y.F., E-mail: laiyunfeng@gmail.com [Institute of Micro/Nano Devices and Solar Cells, School of Physics and Information Engineering, Fuzhou University, Fuzhou (China); Cheng, S.Y.; Zheng, Q. [Institute of Micro/Nano Devices and Solar Cells, School of Physics and Information Engineering, Fuzhou University, Fuzhou (China); Chen, Y.H. [Key Laboratory of Semiconductor Materials Science, Institute of Semiconductors, Chinese Academy of Sciences, P.O. Box 912, Beijing 100083 (China)

    2015-05-15

    Temperature-dependent Raman and photoluminescence (PL) investigation of Cu-incorporated ZnO nanorods prepared by hydrothermal method have been investigated. A strong broad violet–blue emission has been observed in the PL spectra of Cu-incorporated ZnO nanorods, which decreases dramatically with increasing temperature. By Gaussian fitting, this peak can be resolved into two peaks centered at around 393 and 405 nm, respectively, under a temperature of 8 K. The origins of these two peaks are discussed. Temperature-dependent energies of neutral donor bound exciton (D{sup 0}X) are analyzed, and the Einstein temperature is deduced to be around 343±44 K, which do not show significant change compared with that without Cu incorporation. An activation energy of about 14±1 meV is determined from the quenching of D{sup 0}X as a function of temperature in the Cu-incorporated ZnO nanorods, which is much smaller than that deduced in the undoped ZnO nanorods (about 22±2 meV). The small activation energy can be attributed to the additional nonradiative centers introduced by Cu incorporation. The high concentration of defects and impurities in the Cu-incorporated ZnO nanorods are also confirmed by the larger value of the line width of the Raman spectra and its temperature-dependent relationship. - Highlights: • A strong violet–blue emission is observed in the PL spectra of ZnO:Cu nanorods. • This emission can be resolved into two peaks by Gaussian fitting. • Activation energy of the nonradiative centers and Einstein temperature is deduced. • The small activation energy indicates the additional nonradiative centers. • The temperature-dependent Raman spectra indicates more defects in the doping sample.

  2. Inverse temperature dependence of reverse gate leakage current in AlGaN/GaN HEMT

    Science.gov (United States)

    Kaushik, J. K.; Balakrishnan, V. R.; Panwar, B. S.; Muralidharan, R.

    2013-01-01

    The experimentally observed inverse temperature dependence of the reverse gate leakage current in AlGaN/GaN HEMT is explained using a virtual gate trap-assisted tunneling model. The virtual gate is formed due to the capture of electrons by surface states in the vicinity of actual gate. The increase and decrease in the length of the virtual gate with temperature due to trap kinetics are used to explain this unusual effect. The simulation results have been validated experimentally.

  3. Temperature dependency of the hysteresis behaviour of PZT actuators using Preisach model

    DEFF Research Database (Denmark)

    Mangeot, Charles; Zsurzsan, Tiberiu-Gabriel

    2016-01-01

    The Preisach model is a powerful tool for modelling the hysteresis phenomenon on multilayer piezo actuators under large signal excitation. In this paper, measurements at different temperatures are presented, showing the effect on the density of the Preisach matrix. An energy-based approach...... is presented, aiming at defining a temperature-dependent phenomenological model of hysteresis for a better understanding of the non-linear effects in piezo actuators....

  4. Modeling of Temperature-Dependent Noise in Silicon Nanowire FETs including Self-Heating Effects

    OpenAIRE

    Anandan, P.; Malathi, N.; Mohankumar, N.

    2014-01-01

    Silicon nanowires are leading the CMOS era towards the downsizing limit and its nature will be effectively suppress the short channel effects. Accurate modeling of thermal noise in nanowires is crucial for RF applications of nano-CMOS emerging technologies. In this work, a perfect temperature-dependent model for silicon nanowires including the self-heating effects has been derived and its effects on device parameters have been observed. The power spectral density as a function of thermal resi...

  5. Temperature dependence and mechanism of the reaction between O(3P) and chlorine dioxide

    Science.gov (United States)

    Colussi, A. J.; Sander, S. P.; Fiedl, R. R.

    1992-01-01

    Second-order rate constants for the decay of O(3P) in excess chlorine dioxide, k(II), were measured as a function of total pressure (20-600 Torr argon) and temperature (248-312 K), using flash photolysis-atomic resonance fluorescence. Results indicate that k(II) is pressure dependent with a value, K(b), that is nonzero at zero pressure, and both the third-order rate constant and k(b) have negative temperature dependences.

  6. Adomian Decomposition Method for a Nonlinear Heat Equation with Temperature Dependent Thermal Properties

    Directory of Open Access Journals (Sweden)

    Ashfaque H. Bokhari

    2009-01-01

    Full Text Available The solutions of nonlinear heat equation with temperature dependent diffusivity are investigated using the modified Adomian decomposition method. Analysis of the method and examples are given to show that the Adomian series solution gives an excellent approximation to the exact solution. This accuracy can be increased by increasing the number of terms in the series expansion. The Adomian solutions are presented in some situations of interest.

  7. Temperature-dependent respiration-growth relations in ancestral maize cultivars

    Science.gov (United States)

    Bruce N. Smith; Jillian L. Walker; Rebekka L. Stone; Angela R. Jones; Lee D. Hansen

    2001-01-01

    Shoots from 4- to 6-day old seedlings of seven ancestral or old cultivars of Zea mays L. were placed in a calorimeter. Dark metabolic heat rate (q) and CO2 production rate (RCO2) were measured at nine temperatures (5, 10, 15, 20, 25, 30, 35, 40, and 45 °C). Temperature dependencies of q and RCO2 were used to model response of both growth and substrate carbon conversion...

  8. Inferring the temperature dependence of population parameters: the effects of experimental design and inference algorithm.

    Science.gov (United States)

    Palamara, Gian Marco; Childs, Dylan Z; Clements, Christopher F; Petchey, Owen L; Plebani, Marco; Smith, Matthew J

    2014-12-01

    Understanding and quantifying the temperature dependence of population parameters, such as intrinsic growth rate and carrying capacity, is critical for predicting the ecological responses to environmental change. Many studies provide empirical estimates of such temperature dependencies, but a thorough investigation of the methods used to infer them has not been performed yet. We created artificial population time series using a stochastic logistic model parameterized with the Arrhenius equation, so that activation energy drives the temperature dependence of population parameters. We simulated different experimental designs and used different inference methods, varying the likelihood functions and other aspects of the parameter estimation methods. Finally, we applied the best performing inference methods to real data for the species Paramecium caudatum. The relative error of the estimates of activation energy varied between 5% and 30%. The fraction of habitat sampled played the most important role in determining the relative error; sampling at least 1% of the habitat kept it below 50%. We found that methods that simultaneously use all time series data (direct methods) and methods that estimate population parameters separately for each temperature (indirect methods) are complementary. Indirect methods provide a clearer insight into the shape of the functional form describing the temperature dependence of population parameters; direct methods enable a more accurate estimation of the parameters of such functional forms. Using both methods, we found that growth rate and carrying capacity of Paramecium caudatum scale with temperature according to different activation energies. Our study shows how careful choice of experimental design and inference methods can increase the accuracy of the inferred relationships between temperature and population parameters. The comparison of estimation methods provided here can increase the accuracy of model predictions, with important

  9. Modeling of Circuits with Strongly Temperature Dependent Thermal Conductivities for Cryogenic CMOS

    OpenAIRE

    Hamlet, J.; Eng, K.; Gurrieri, T.; Levy, J; Carroll, M

    2010-01-01

    When designing and studying circuits operating at cryogenic temperatures understanding local heating within the circuits is critical due to the temperature dependence of transistor and noise behavior. We have investigated local heating effects of a CMOS ring oscillator and current comparator at T=4.2K. In two cases, the temperature near the circuit was measured with an integrated thermometer. A lumped element equivalent electrical circuit SPICE model that accounts for the strongly temperature...

  10. Quark mass density- and temperature- dependent model for bulk strange quark matter

    OpenAIRE

    al, Yun Zhang et.

    2002-01-01

    It is shown that the quark mass density-dependent model can not be used to explain the process of the quark deconfinement phase transition because the quark confinement is permanent in this model. A quark mass density- and temperature-dependent model in which the quark confinement is impermanent has been suggested. We argue that the vacuum energy density B is a function of temperature. The dynamical and thermodynamical properties of bulk strange quark matter for quark mass density- and temper...

  11. Temperature-Dependent Ellipsometry Measurements of Partial Coulomb Energy in Superconducting Cuprates

    Science.gov (United States)

    Levallois, J.; Tran, M. K.; Pouliot, D.; Presura, C. N.; Greene, L. H.; Eckstein, J. N.; Uccelli, J.; Giannini, E.; Gu, G. D.; Leggett, A. J.; van der Marel, D.

    2016-07-01

    We performed an experimental study of the temperature and doping dependence of the energy-loss function of the bilayer and trilayer bismuth cuprates family. The primary aim is to obtain information on the energy stored in the Coulomb interaction between the conduction electrons, on the temperature dependence thereof, and on the change of Coulomb interaction when Cooper pairs are formed. We performed temperature-dependent ellipsometry measurements on several Bi2 Sr2 CaCu2 O8 -x single crystals: underdoped with Tc=60 , 70, and 83 K; optimally doped with Tc=91 K ; overdoped with Tc=84 , 81, 70, and 58 K; as well as optimally doped Bi2 Sr2 Ca2 Cu3 O10 +x with Tc=110 K . Our first observation is that, as the temperature drops through Tc, the loss function in the range up to 2 eV displays a change of temperature dependence as compared to the temperature dependence in the normal state. This effect at—or close to—Tc depends strongly on doping, with a sign change for weak overdoping. The size of the observed change in Coulomb energy, using an extrapolation with reasonable assumptions about its q dependence, is about the same size as the condensation energy that has been measured in these compounds. Our results therefore lend support to the notion that the Coulomb energy is an important factor for stabilizing the superconducting phase. Because of the restriction to small momentum, our observations do not exclude a possible significant contribution to the condensation energy of the Coulomb energy associated with the region of q around (π ,π ).

  12. Temperature-Dependent Ellipsometry Measurements of Partial Coulomb Energy in Superconducting Cuprates

    Directory of Open Access Journals (Sweden)

    J. Levallois

    2016-08-01

    Full Text Available We performed an experimental study of the temperature and doping dependence of the energy-loss function of the bilayer and trilayer bismuth cuprates family. The primary aim is to obtain information on the energy stored in the Coulomb interaction between the conduction electrons, on the temperature dependence thereof, and on the change of Coulomb interaction when Cooper pairs are formed. We performed temperature-dependent ellipsometry measurements on several Bi_{2}Sr_{2}CaCu_{2}O_{8-x} single crystals: underdoped with T_{c}=60, 70, and 83 K; optimally doped with T_{c}=91  K; overdoped with T_{c}=84, 81, 70, and 58 K; as well as optimally doped Bi_{2}Sr_{2}Ca_{2}Cu_{3}O_{10+x} with T_{c}=110  K. Our first observation is that, as the temperature drops through T_{c}, the loss function in the range up to 2 eV displays a change of temperature dependence as compared to the temperature dependence in the normal state. This effect at—or close to—T_{c} depends strongly on doping, with a sign change for weak overdoping. The size of the observed change in Coulomb energy, using an extrapolation with reasonable assumptions about its q dependence, is about the same size as the condensation energy that has been measured in these compounds. Our results therefore lend support to the notion that the Coulomb energy is an important factor for stabilizing the superconducting phase. Because of the restriction to small momentum, our observations do not exclude a possible significant contribution to the condensation energy of the Coulomb energy associated with the region of q around (π,π.

  13. Temperature dependency of mechanical properties for crystalline cellulose added to silicone elastomer

    Science.gov (United States)

    Kameda, Takao; Sugino, Naoto; Takei, Satoshi; Hanabata, Makoto

    2017-08-01

    A chemical cross-linked transparent film was got by a silicon compound to crystalline cellulose. Temperature dependency for the elasticity modulus of a provided film was measured. The shear elastic modulus was obtained the value of 2 x 106 [Pa] at room temperature. The sample decreases in 190 [deg. C] for the elasticity modulus at the room temperature as 60%, but approximately 10% recover when temperature rises up to 200 [deg. C] or more.

  14. Does N2 fixation amplify the temperature dependence of ecosystem metabolism?

    Science.gov (United States)

    Welter, Jill R; Benstead, Jonathan P; Cross, Wyatt F; Hood, James M; Huryn, Alexander D; Johnson, Philip W; Williamson, Tanner J

    2015-03-01

    Variation in resource supply can cause variation in temperature dependences of metabolic processes (e.g., photosynthesis and respiration). Understanding such divergence is particularly important when using metabolic theory to predict ecosystem responses to climate warming. Few studies, however, have assessed the effect of temperature-resource interactions on metabolic processes, particularly in cases where the supply of limiting resources exhibits temperature dependence. We investigated the responses of biomass accrual, gross primary production (GPP), community respiration (CR), and N2 fixation to warming during biofilm development in a streamside channel experiment. Areal rates of GPP, CR, biomass accrual, and N2 fixation scaled positively with temperature, showing a 32- to 71-fold range across the temperature gradient (approximately 7 degrees-24 degrees C). Areal N2-fixation rates exhibited apparent activation energies (1.5-2.0 eV; 1 eV = approximately 1.6 x 10(-19) J) approximating the activation energy of the nitrogenase reaction. In contrast, mean apparent activation energies for areal rates of GPP (2.1-2.2 eV) and CR (1.6-1.9 eV) were 6.5- and 2.7-fold higher than estimates based on metabolic theory predictions (i.e., 0.32 and 0.65 eV, respectively) and did not significantly differ from the apparent activation energy observed for N2 fixation. Mass-specific activation energies for N2 fixation (1.4-1.6 eV), GPP (0.3-0.5 eV), and CR (no observed temperature relationship) were near or lower than theoretical predictions. We attribute the divergence of areal activation energies from those predicted by metabolic theory to increases in N2 fixation with temperature, leading to amplified temperature dependences of biomass accrual and areal rates of GPP and R. Such interactions between temperature dependences must be incorporated into metabolic models to improve predictions of ecosystem responses to climate change.

  15. EFFECT OF TEMPERATURE-DEPENDENCY OF SURFACE EMISSIVITY ON HEAT TRANSFER USING THE PARAMETERIZED PERTURBATION METHOD

    Directory of Open Access Journals (Sweden)

    Maziar Jalaal

    2011-01-01

    Full Text Available Knowledge of the temperature dependence of the physical properties such surface emissivity, which controls the radiative problem, is fundamental for determining the thermal balance of many scientific and industrial processes. The current work studies the ability of a strong analytical method called parameterized perturbation method (PPM, which unlike classic perturbation method do not need small parameter, for nonlinear heat transfer equations. The results are compared with the numerical Runge-Kutta method showed good agreement.

  16. Genetic instability and increased mutational load: which diagnostic tool best direct patients with cancer to immunotherapy?

    Science.gov (United States)

    Palmieri, Giuseppe; Colombino, Maria; Cossu, Antonio; Marchetti, Antonio; Botti, Gerardo; Ascierto, Paolo A

    2017-01-21

    The occurrence of high rates of somatic mutations in cancer is believed to correspond to increased frequency of neo-epitope formation and tumor immunogenicity. Thus, classification of patients with cancer according to degree a somatic hyper-mutational status could be proposed as a predictive biomarker of responsiveness to immunotherapy with immune checkpoint inhibitors. Here, we discuss the suitable and reliable tests easily adoptable in clinical practice to assess somatic mutational status in patients with advanced cancer.

  17. Thermal rectification in restructured graphene with locally modulated temperature dependence of thermal conductivity

    Science.gov (United States)

    Arora, Anuj; Hori, Takuma; Shiga, Takuma; Shiomi, Junichiro

    2017-10-01

    We study thermal rectification (TR) in a selectively restructured graphene by performing deviational phonon Monte Carlo (MC) simulations with frequency-dependent phonon transport properties obtained from first principles. The restructuring is achieved by introducing vacancy defects in a portion of graphene. The defects significantly change phonon transport properties, resulting in a modulation of temperature dependence of thermal conductivity. With this modulated temperature dependence, we predict TR ratio through a Fourier's-law-based iterative scheme (FIS), where heat flow through the system is analyzed by solving the Fourier's law of heat conduction with spatially varying temperature-dependent thermal conductivity. To identify structure parameters for maximal TR ratio, we investigate the influence of defect size, volume percentage of defects, and system (consisting of defective and nondefective regions) length through FIS analysis. As a result, we find that the TR ratio is mainly a function of length of defective and nondefective regions and volume percentage of defect, and it is mostly independent of defect size. A longer (of the order of 10 μm) nondefective side, coupled to a shorter (of the order of 100 nm) defective side, can lead to large TR ratios. Finally, MC simulation for the restructured graphene (full system) is performed to verify the predictions from FIS analysis. The full system calculations give similar trends but with enhanced TR ratios up to 70% for the temperature range of 200-500 K.

  18. Simulation of phase separation with temperature-dependent viscosity using lattice Boltzmann method.

    Science.gov (United States)

    Wang, Heping; Zang, Duyang; Li, Xiaoguang; Geng, Xingguo

    2017-12-27

    This paper presents an exploration of the phase separation behavior and pattern formation in a binary fluid with temperature-dependent viscosity via a coupled lattice Boltzmann method (LBM). By introducing a viscosity-temperature relation into the LBM, the coupling effects of the viscosity-temperature coefficient [Formula: see text] , initial viscosity [Formula: see text] and thermal diffusion coefficient [Formula: see text] , on the phase separation were successfully described. The calculated results indicated that an increase in initial viscosity and viscosity-temperature coefficient, or a decrease in the thermal diffusion coefficient, can lead to the orientation of isotropic growth fronts over a wide range of viscosity. The results showed that droplet-type phase structures and lamellar phase structures with domain orientation parallel or perpendicular to the walls can be obtained in equilibrium by controlling the initial viscosity, thermal diffusivity, and the viscosity-temperature coefficient. Furthermore, the dataset was rearranged for growth kinetics of domain growth and thermal diffusion fronts in a plot by the spherically averaged structure factor and the ratio of separated and continuous phases. The analysis revealed two different temporal regimes: spinodal decomposition and domain growth stages, which further quantified the coupled effects of temperature and viscosity on the evolution of temperature-dependent phase separation. These numerical results provide guidance for setting optimum temperature ranges to obtain expected phase separation structures for systems with temperature-dependent viscosity.

  19. Modeling and Compensating Temperature-Dependent Non-Uniformity Noise in IR Microbolometer Cameras

    Science.gov (United States)

    Wolf, Alejandro; Pezoa, Jorge E.; Figueroa, Miguel

    2016-01-01

    Images rendered by uncooled microbolometer-based infrared (IR) cameras are severely degraded by the spatial non-uniformity (NU) noise. The NU noise imposes a fixed-pattern over the true images, and the intensity of the pattern changes with time due to the temperature instability of such cameras. In this paper, we present a novel model and a compensation algorithm for the spatial NU noise and its temperature-dependent variations. The model separates the NU noise into two components: a constant term, which corresponds to a set of NU parameters determining the spatial structure of the noise, and a dynamic term, which scales linearly with the fluctuations of the temperature surrounding the array of microbolometers. We use a black-body radiator and samples of the temperature surrounding the IR array to offline characterize both the constant and the temperature-dependent NU noise parameters. Next, the temperature-dependent variations are estimated online using both a spatially uniform Hammerstein-Wiener estimator and a pixelwise least mean squares (LMS) estimator. We compensate for the NU noise in IR images from two long-wave IR cameras. Results show an excellent NU correction performance and a root mean square error of less than 0.25 ∘C, when the array’s temperature varies by approximately 15 ∘C. PMID:27447637

  20. Model analysis of temperature dependence of abnormal resistivity of a multiwalled carbon nanotube interconnection

    Directory of Open Access Journals (Sweden)

    Yi-Chen Yeh

    2010-07-01

    Full Text Available Yi-Chen Yeh1, Lun-Wei Chang2, Hsin-Yuan Miao3, Szu-Po Chen1, Jhu-Tzang Lue11Department of Physics and 2Institute of Electronics Engineering, National Tsing Hua University, Hsinchu, Taiwan; 3Department of Electrical Engineering, Tunghai University, Taichung, TaiwanAbstract: A homemade microwave plasma-enhanced chemical vapor deposition method was used to grow a multiwalled carbon nanotube between two nickel catalyst electrodes. To investigate the transport properties and electron scattering mechanism of this interconnection (of approximately fixed length and fixed diameter, we carried out a model analysis of temperature dependence of resistivity. To explain the abnormal behavior of the negative temperature coefficient of resistivity in our experimental results, we then employed theories, such as hopping conductivity theory and variable range hopping conductivity theory, to describe resistivity in the high- and low-temperature ranges, respectively. Further, the grain boundary scattering model is also provided to fit the entire measured curve of temperature dependence of resistivity.Keywords: multiwalled carbon nanotube, resistivity, hopping conductivity, temperature dependence

  1. COMPENSATION OF OUTPUT SIGNAL TEMPERATURE DEPENDENCE IN HOMODYNE DEMODULATION TECHNIQUE FOR PHASE FIBER-OPTIC SENSORS

    Directory of Open Access Journals (Sweden)

    M. V. Mekhrengin

    2015-03-01

    Full Text Available Modified phase-generated carrier homodyne demodulation technique for fiber-optic sensors is presented. Nowadays phase-generated carrier homodyne demodulation technique is one of the most widespread. One of its drawbacks is the temperature dependence of the output signal because of the modulator scale factor temperature dependence. In order to compensate this dependence an automatic adjustment of the phase modulation depth is necessary. To achieve the result, additional harmonics analysis is used with the help of the Bessel functions. For this purpose the known demodulation scheme is added with the branch, where interferometric signal is multiplied by the third harmonic of the modulation signal. The deviation of optimal ratio of odd harmonics is used as a feedback signal for adjusting the modulation depth. Unwanted emissions arise in the feedback signal, when the third harmonic possesses a value close to zero. To eliminate unwanted emission in the feedback signal, the principle scheme is added with one more branch, where interferometric signal is multiplied by the forth harmonic of the modulation signal. The deviation of optimal ratio of even harmonics is used as a feedback signal alternately with the deviation of optimal ratio of odd harmonics. A mathematical model of the algorithm is designed using the MATLAB package. Results of modeling have confirmed that suggested method gives the possibility for an automatic adjustment of the phase modulation depth and makes it possible to compensate temperature dependence for the modulator scale factor and output signal magnitude.

  2. Molecular modeling of temperature dependence of solubility parameters for amorphous polymers.

    Science.gov (United States)

    Chen, Xianping; Yuan, Cadmus; Wong, Cell K Y; Zhang, Guoqi

    2012-06-01

    A molecular modeling strategy is proposed to describe the temperature (T) dependence of solubility parameter (δ) for the amorphous polymers which exhibit glass-rubber transition behavior. The commercial forcefield "COMPASS" is used to support the atomistic simulations of the polymer. The temperature dependence behavior of δ for the polymer is modeled by running molecular dynamics (MD) simulation at temperatures ranging from 250 up to 650 K. Comparing the MD predicted δ value at 298 K and the glass transition temperature (T(g)) of the polymer determined from δ-T curve with the experimental value confirm the accuracy of our method. The MD modeled relationship between δ and T agrees well with the previous theoretical works. We also observe the specific volume (v), cohesive energy (U(coh)), cohesive energy density (E(CED)) and δ shows a similar temperature dependence characteristics and a drastic change around the T(g). Meanwhile, the applications of δ and its temperature dependence property are addressed and discussed.

  3. Comparing the temperature dependence of photosynthetic electron transfer in Chloroflexus aurantiacus and Rhodobactor sphaeroides reaction centers.

    Science.gov (United States)

    Guo, Zhi; Lin, Su; Xin, Yueyong; Wang, Haiyu; Blankenship, Robert E; Woodbury, Neal W

    2011-09-29

    The process of electron transfer from the special pair, P, to the primary electron donor, H(A), in quinone-depleted reaction centers (RCs) of Chloroflexus (Cf.) aurantiacus has been investigated over the temperature range from 10 to 295 K using time-resolved pump-probe spectroscopic techniques. The kinetics of the electron transfer reaction, P* → P(+)H(A)(-), was found to be nonexponential, and the degree of nonexponentiality increased strongly as temperature decreased. The temperature-dependent behavior of electron transfer in Cf. aurantiacus RCs was compared with that of the purple bacterium Rhodobacter (Rb.) sphaeroides . Distinct transitions were found in the temperature-dependent kinetics of both Cf. aurantiacus and Rb. sphaeroides RCs, at around 220 and 160 K, respectively. Structural differences between these two RCs, which may be associated with those differences, are discussed. It is suggested that weaker protein-cofactor hydrogen bonding, stronger electrostatic interactions at the protein surface, and larger solvent interactions likely contribute to the higher transition temperature in Cf. aurantiacus RCs temperature-dependent kinetics compared with that of Rb. sphaeroides RCs. The reaction-diffusion model provides an accurate description for the room-temperature electron transfer kinetics in Cf. aurantiacus RCs with no free parameters, using coupling and reorganization energy values previously determined for Rb. sphaeroides , along with an experimental measure of protein conformational diffusion dynamics and an experimental literature value of the free energy gap between P* and P(+)H(A)(-). © 2011 American Chemical Society

  4. Temperature dependence of amino acid side chain IR absorptions in the amide I' region.

    Science.gov (United States)

    Anderson, Benjamin A; Literati, Alex; Ball, Borden; Kubelka, Jan

    2014-05-01

    Amide I' IR spectra are widely used for studies of structural changes in peptides and proteins as a function of temperature. Temperature dependent absorptions of amino acid side-chains that overlap the amide I' may significantly complicate the structural analyses. While the side-chain IR spectra have been investigated previously, thus far their dependence on temperature has not been reported. Here we present the study of the changes in the IR spectra with temperature for side-chain groups of aspartate, glutamate, asparagine, glutamine, arginine, and tyrosine in the amide I' region (in D2O). Band fitting analysis was employed to extract the temperature dependence of the individual spectral parameters, such as peak frequency, integrated intensity, band width, and shape. As expected, the side-chain IR bands exhibit significant changes with temperature. The majority of the spectral parameters, particularly the frequency and intensity, show linear dependence on temperature, but the direction and magnitude vary depending on the particular side-chain group. The exception is arginine, which exhibits a distinctly nonlinear frequency shift with temperature for its asymmetric CN3H5(+) bending signal, although a linear fit can account for this change to within ~1/3 cm(-1). The applicability of the determined spectral parameters for estimations of temperature-dependent side-chain absorptions in peptides and proteins are discussed. Copyright © 2013 Wiley Periodicals, Inc.

  5. Investigation of temperature-dependent small-signal performances of TB SOI MOSFETs

    Science.gov (United States)

    Huang, Yuping; Liu, Jun; Lü, Kai; Chen, Jing

    2017-04-01

    This paper investigated the temperature dependence of the cryogenic small-signal ac performances of multi-finger partially depleted (PD) silicon-on-insulator (SOI) metal oxide semiconductor field effect transistors (MOSFETs), with T-gate body contact (TB) structure. The measurement results show that the cut-off frequency increases from 78 GHz at 300 K to 120 GHz at 77 K and the maximum oscillation frequency increases from 54 GHz at 300 K to 80 GHz at 77 K, and these are mainly due to the effect of negative temperature dependence of threshold voltage and transconductance. By using a simple equivalent circuit model, the temperature-dependent small-signal parameters are discussed in detail. The understanding of cryogenic small-signal performance is beneficial to develop the PD SOI MOSFETs integrated circuits for ultra-low temperature applications. Project supported by the National Natural Science Foundation of China (No. 61331006) and the National Defense Pre-Research Foundation of China (No. 9140A11040114DZ04152).

  6. Modeling and Compensating Temperature-Dependent Non-Uniformity Noise in IR Microbolometer Cameras

    Directory of Open Access Journals (Sweden)

    Alejandro Wolf

    2016-07-01

    Full Text Available Images rendered by uncooled microbolometer-based infrared (IR cameras are severely degraded by the spatial non-uniformity (NU noise. The NU noise imposes a fixed-pattern over the true images, and the intensity of the pattern changes with time due to the temperature instability of such cameras. In this paper, we present a novel model and a compensation algorithm for the spatial NU noise and its temperature-dependent variations. The model separates the NU noise into two components: a constant term, which corresponds to a set of NU parameters determining the spatial structure of the noise, and a dynamic term, which scales linearly with the fluctuations of the temperature surrounding the array of microbolometers. We use a black-body radiator and samples of the temperature surrounding the IR array to offline characterize both the constant and the temperature-dependent NU noise parameters. Next, the temperature-dependent variations are estimated online using both a spatially uniform Hammerstein-Wiener estimator and a pixelwise least mean squares (LMS estimator. We compensate for the NU noise in IR images from two long-wave IR cameras. Results show an excellent NU correction performance and a root mean square error of less than 0.25 ∘ C, when the array’s temperature varies by approximately 15 ∘ C.

  7. Estimation of the temperature dependent interaction between uncharged point defects in Si

    Energy Technology Data Exchange (ETDEWEB)

    Kamiyama, Eiji [Department of Communication Engineering, Okayama Prefectural University, 111 Kuboki, Soja-shi, Okayama-ken 719-1197 (Japan); GlobalWafers Japan Co., Ltd., 30 Soya, Hadano, Kanagawa, 257-8566 (Japan); Vanhellemont, Jan [Department of Solid State Sciences, Ghent University, Krijgslaan 281-S1, Ghent B-9000 (Belgium); Sueoka, Koji [Department of Communication Engineering, Okayama Prefectural University, 111 Kuboki, Soja-shi, Okayama-ken 719-1197 (Japan)

    2015-01-15

    A method is described to estimate the temperature dependent interaction between two uncharged point defects in Si based on DFT calculations. As an illustration, the formation of the uncharged di-vacancy V{sub 2} is discussed, based on the temperature dependent attractive field between both vacancies. For that purpose, all irreducible configurations of two uncharged vacancies are determined, each with their weight given by the number of equivalent configurations. Using a standard 216-atoms supercell, nineteen irreducible configurations of two vacancies are obtained. The binding energies of all these configurations are calculated. Each vacancy is surrounded by several attractive sites for another vacancy. The obtained temperature dependent of total volume of these attractive sites has a radius that is closely related with the capture radius for the formation of a di-vacancy that is used in continuum theory. The presented methodology can in principle also be applied to estimate the capture radius for pair formation of any type of point defects.

  8. Temperature dependence of critical currents in REBCO thin films with artificial pinning centers

    Science.gov (United States)

    Matsumoto, Kaname; Nishihara, Masaya; Kimoto, Takamasa; Horide, Tomoya; Jha, Alok Kumar; Yoshida, Yutaka; Awaji, Satoshi; Ichinose, Ataru

    2017-10-01

    Conventionally, δT c type (order parameter modulation) and δl type (mean free path modulation) pinning mechanisms have been proposed to explain the temperature dependence of the flux pinning of superconducting materials. According to previous studies, it is assumed that the temperature dependence of J c of REBa2Cu3O7 (REBCO, RE = Y, Gd, Sm, etc) films without artificial pinning centers (APCs) is δl type, but it is unidentified when APCs are introduced into the films. In this paper, GdBCO thin films doped with BaHfO3 (BHO) deposited on LaAlO3 substrates by pulsed laser deposition were studied. A target exchange method was used to alternately ablate two targets of pure GdBCO and BHO for introducing nanorods as APCs into GdBCO films. Since the insulative BHO acts as a strong pinning center, the δT c pinning mechanism is expected for the temperature dependence of J c of these thin films. However, the experimental results showed that the J c of the films with BHO nanorods was determined by the δl pinning mechanism over a wide temperature range. In order to explain these unexpected results, we examined the pinning mechanism by nanorods based on a resultant pinning force model.

  9. Surprising behaviors in the temperature dependent kinetics of diatomic interhalogens with anions and cations

    Science.gov (United States)

    Shuman, Nicholas S.; Martinez, Oscar; Ard, Shaun G.; Wiens, Justin P.; Keyes, Nicholas R.; Guo, Hua; Viggiano, Albert A.

    2017-06-01

    Rate constants and product branching fractions of reactions between diatomic interhalogens (ICl, ClF) and a series of anions (Br-, I-) and cations (Ar+, N2+) are measured using a selected ion flow tube apparatus and reported over the temperature range 200-500 K. The efficiency of both anion reactions with ICl is 2%-3% at 300 K to yield Cl-, increasing with temperature in a manner consistent with the small endothermicities of the reactions. The anion reactions with ClF are 10%-20% efficient at 300 K to yield Cl- and also show a positive temperature dependence despite being highly exothermic. The stationary points along the anion + ClF reaction coordinates were calculated using density functional theory, showing no endothermic barriers inhibiting reaction. The observed temperature dependence can be rationalized by a decreasing dipole attraction with increasing rotational energy, but confirmation requires trajectory calculations of the systems. All four cation reactions are fairly efficient at 300 K with small positive temperature dependences, despite large exothermicities to charge transfer. Three of the four reactions proceed exclusively by dissociative charge transfer to yield Cl+. The N2+ + ClF reaction proceeds by both non-dissociative and dissociative charge transfer, with the non-dissociative channel surprisingly increasing with increasing temperature. The origins of these behaviors are not clear and are discussed within the framework of charge-transfer reactions.

  10. Methane fluxes show consistent temperature dependence across microbial to ecosystem scales.

    Science.gov (United States)

    Yvon-Durocher, Gabriel; Allen, Andrew P; Bastviken, David; Conrad, Ralf; Gudasz, Cristian; St-Pierre, Annick; Thanh-Duc, Nguyen; del Giorgio, Paul A

    2014-03-27

    Methane (CH4) is an important greenhouse gas because it has 25 times the global warming potential of carbon dioxide (CO2) by mass over a century. Recent calculations suggest that atmospheric CH4 emissions have been responsible for approximately 20% of Earth's warming since pre-industrial times. Understanding how CH4 emissions from ecosystems will respond to expected increases in global temperature is therefore fundamental to predicting whether the carbon cycle will mitigate or accelerate climate change. Methanogenesis is the terminal step in the remineralization of organic matter and is carried out by strictly anaerobic Archaea. Like most other forms of metabolism, methanogenesis is temperature-dependent. However, it is not yet known how this physiological response combines with other biotic processes (for example, methanotrophy, substrate supply, microbial community composition) and abiotic processes (for example, water-table depth) to determine the temperature dependence of ecosystem-level CH4 emissions. It is also not known whether CH4 emissions at the ecosystem level have a fundamentally different temperature dependence than other key fluxes in the carbon cycle, such as photosynthesis and respiration. Here we use meta-analyses to show that seasonal variations in CH4 emissions from a wide range of ecosystems exhibit an average temperature dependence similar to that of CH4 production derived from pure cultures of methanogens and anaerobic microbial communities. This average temperature dependence (0.96 electron volts (eV)), which corresponds to a 57-fold increase between 0 and 30°C, is considerably higher than previously observed for respiration (approximately 0.65 eV) and photosynthesis (approximately 0.3 eV). As a result, we show that both the emission of CH4 and the ratio of CH4 to CO2 emissions increase markedly with seasonal increases in temperature. Our findings suggest that global warming may have a large impact on the relative contributions of CO2 and CH

  11. [Psychic disorders and somatic suffering].

    Science.gov (United States)

    Canneva, Jean

    2010-01-01

    To what extent should somatic treatment be taken into account when psychic suffering dominates? How can this care be anticipated when healthcare workers and carers are confronted with patients who do not express what they want? Greatest attention must be paid to somatic care by anticipating body function and relying on the support of the families and the skills of the professionals.

  12. Induced pluripotent stem cell lines derived from human somatic cells.

    Science.gov (United States)

    Yu, Junying; Vodyanik, Maxim A; Smuga-Otto, Kim; Antosiewicz-Bourget, Jessica; Frane, Jennifer L; Tian, Shulan; Nie, Jeff; Jonsdottir, Gudrun A; Ruotti, Victor; Stewart, Ron; Slukvin, Igor I; Thomson, James A

    2007-12-21

    Somatic cell nuclear transfer allows trans-acting factors present in the mammalian oocyte to reprogram somatic cell nuclei to an undifferentiated state. We show that four factors (OCT4, SOX2, NANOG, and LIN28) are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem (ES) cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all three primary germ layers. Such induced pluripotent human cell lines should be useful in the production of new disease models and in drug development, as well as for applications in transplantation medicine, once technical limitations (for example, mutation through viral integration) are eliminated.

  13. Mutational landscape of yeast mutator strains.

    Science.gov (United States)

    Serero, Alexandre; Jubin, Claire; Loeillet, Sophie; Legoix-Né, Patricia; Nicolas, Alain G

    2014-02-04

    The acquisition of mutations is relevant to every aspect of genetics, including cancer and evolution of species on Darwinian selection. Genome variations arise from rare stochastic imperfections of cellular metabolism and deficiencies in maintenance genes. Here, we established the genome-wide spectrum of mutations that accumulate in a WT and in nine Saccharomyces cerevisiae mutator strains deficient for distinct genome maintenance processes: pol32Δ and rad27Δ (replication), msh2Δ (mismatch repair), tsa1Δ (oxidative stress), mre11Δ (recombination), mec1Δ tel1Δ (DNA damage/S-phase checkpoints), pif1Δ (maintenance of mitochondrial genome and telomere length), cac1Δ cac3Δ (nucleosome deposition), and clb5Δ (cell cycle progression). This study reveals the diversity, complexity, and ultimate unique nature of each mutational spectrum, composed of punctual mutations, chromosomal structural variations, and/or aneuploidies. The mutations produced in clb5Δ/CCNB1, mec1Δ/ATR, tel1Δ/ATM, and rad27Δ/FEN1 strains extensively reshape the genome, following a trajectory dependent on previous events. It comprises the transmission of unstable genomes that lead to colony mosaicisms. This comprehensive analytical approach of mutator defects provides a model to understand how genome variations might accumulate during clonal evolution of somatic cell populations, including tumor cells.

  14. Mutation in Aldosterone Producing Adenoma

    Directory of Open Access Journals (Sweden)

    Jian-Jhong Wang

    2017-09-01

    Full Text Available Discoveries of somatic mutations permit the recognition of subtypes of aldosterone-producing adenomas (APAs with distinct clinical presentations and pathological features. Catenin β1 (CTNNB1 mutation in APAs has been recently described and discussed in the literature. However, significant knowledge gaps still remain regarding the prevalence, clinical characteristics, pathophysiology, and outcomes in APA patients harboring CTNNB1 mutations. Aberrant activation of the Wnt/β-catenin signaling pathway will further modulate tumorigenesis. We also discuss the recent knowledge of CTNNB1 mutation in adrenal adenomas.

  15. COSMIC: somatic cancer genetics at high-resolution.

    Science.gov (United States)

    Forbes, Simon A; Beare, David; Boutselakis, Harry; Bamford, Sally; Bindal, Nidhi; Tate, John; Cole, Charlotte G; Ward, Sari; Dawson, Elisabeth; Ponting, Laura; Stefancsik, Raymund; Harsha, Bhavana; Kok, Chai Yin; Jia, Mingming; Jubb, Harry; Sondka, Zbyslaw; Thompson, Sam; De, Tisham; Campbell, Peter J

    2017-01-04

    COSMIC, the Catalogue of Somatic Mutations in Cancer (http://cancer.sanger.ac.uk) is a high-resolution resource for exploring targets and trends in the genetics of human cancer. Currently the broadest database of mutations in cancer, the information in COSMIC is curated by expert scientists, primarily by scrutinizing large numbers of scientific publications. Over 4 million coding mutations are described in v78 (September 2016), combining genome-wide sequencing results from 28 366 tumours with complete manual curation of 23 489 individual publications focused on 186 key genes and 286 key fusion pairs across all cancers. Molecular profiling of large tumour numbers has also allowed the annotation of more than 13 million non-coding mutations, 18 029 gene fusions, 187 429 genome rearrangements, 1 271 436 abnormal copy number segments, 9 175 462 abnormal expression variants and 7 879 142 differentially methylated CpG dinucleotides. COSMIC now details the genetics of drug resistance, novel somatic gene mutations which allow a tumour to evade therapeutic cancer drugs. Focusing initially on highly characterized drugs and genes, COSMIC v78 contains wide resistance mutation profiles across 20 drugs, detailing the recurrence of 301 unique resistance alleles across 1934 drug-resistant tumours. All information from the COSMIC database is available freely on the COSMIC website. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  16. A new general model for predicting melting thermodynamics of complementary and mismatched B-form duplexes containing locked nucleic acids: application to probe design for digital PCR detection of somatic mutations.

    Science.gov (United States)

    Hughesman, Curtis; Fakhfakh, Kareem; Bidshahri, Roza; Lund, H Louise; Haynes, Charles

    2015-02-17

    Advances in real-time polymerase chain reaction (PCR), as well as the emergence of digital PCR (dPCR) and useful modified nucleotide chemistries, including locked nucleic acids (LNAs), have created the potential to improve and expand clinical applications of PCR through their ability to better quantify and differentiate amplification products, but fully realizing this potential will require robust methods for designing dual-labeled hydrolysis probes and predicting their hybridization thermodynamics as a function of their sequence, chemistry, and template complementarity. We present here a nearest-neighbor thermodynamic model that accurately predicts the melting thermodynamics of a short oligonucleotide duplexed either to its perfect complement or to a template containing mismatched base pairs. The model may be applied to pure-DNA duplexes or to duplexes for which one strand contains any number and pattern of LNA substitutions. Perturbations to duplex stability arising from mismatched DNA:DNA or LNA:DNA base pairs are treated at the Gibbs energy level to maintain statistical significance in the regressed model parameters. This approach, when combined with the model's accounting of the temperature dependencies of the melting enthalpy and entropy, permits accurate prediction of T(m) values for pure-DNA homoduplexes or LNA-substituted heteroduplexes containing one or two independent mismatched base pairs. Terms accounting for changes in solution conditions and terminal addition of fluorescent dyes and quenchers are then introduced so that the model may be used to accurately predict and thereby tailor the T(m) of a pure-DNA or LNA-substituted hydrolysis probe when duplexed either to its perfect-match template or to a template harboring a noncomplementary base. The model, which builds on classic nearest-neighbor thermodynamics, should therefore be of use to clinicians and biologists who require probes that distinguish and quantify two closely related alleles in either a

  17. Temperature dependent dynamics of DegP-trimer: A molecular dynamics study

    Directory of Open Access Journals (Sweden)

    Nivedita Rai

    2015-01-01

    Full Text Available DegP is a heat shock protein from high temperature requirement protease A family, which reacts to the environmental stress conditions in an ATP independent way. The objective of the present analysis emerged from the temperature dependent functional diversity of DegP between chaperonic and protease activities at temperatures below and above 28 °C, respectively. DegP is a multimeric protein and the minimal functional unit, DegP-trimer, is of great importance in understanding the DegP pathway. The structural aspects of DegP-trimer with respect to temperature variation have been studied using molecular dynamics simulations (for 100 ns and principal component analysis to highlight the temperature dependent dynamics facilitating its functional diversity. The DegP-trimer revealed a pronounced dynamics at both 280 and 320 K, when compared to the dynamics observed at 300 K. The LA loop is identified as the highly flexible region during dynamics and at extreme temperatures, the residues 46–80 of LA loop express a flip towards right (at 280 and left ( at 320 K with respect to the fixed β-sheet connecting the LA loop of protease for which Phe46 acts as one of the key residues. Such dynamics of LA loop facilitates inter-monomeric interaction with the PDZ1 domain of the neighbouring monomer and explains its active participation when DegP exists as trimer. Hence, the LA loop mediated dynamics of DegP-trimer is expected to provide further insight into the temperature dependent dynamics of DegP towards the understanding of its assembly and functional diversity in the presence of substrate.

  18. A Temperature-Dependent Phenology Model for Liriomyza huidobrensis (Diptera: Agromyzidae)

    Science.gov (United States)

    Sporleder, Marc; Carhuapoma, Pablo; Kroschel, Jürgen

    2017-01-01

    Abstract Liriomyza huidobrensis (Blanchard) is an economically important and highly polyphagous worldwide pest. To establish a temperature-dependent phenology model, essential for understanding the development and growth of the pest population under a variety of climates and as part of a pest risk analysis, L. huidobrensis life-table data were collected under laboratory conditions at seven constant temperatures on its host faba bean (Vicia faba L.). Several nonlinear equations were fitted to each life stage to model the temperature-dependent population growth and species life history and finally compile an overall temperature-dependent pest phenology model using the Insect Life Cycle Modeling (ILCYM) software. Liriomyza huidobrensis completed development from egg to adult in all temperatures evaluated, except at 32 °C, which was lethal to pupae. Eggs did not develop at 35 °C. Mean development time of all immature stages decreased with increasing temperature. Nonlinear models predicted optimal temperature for immature survival between 20–25 °C (32–38% mortality of all immature stages). Life-table parameters simulated at constant temperatures indicated that L. huidobrensis develops within the range of 12–28 °C. Simulated life-table for predicting the population dynamics of L. huidobrensis under two contrasting environments showed that lowland temperatures at the coast of Peru (250 m.a.s.l.) presented better conditions for a potential population increase than highland (3,400 m.a.s.l.) conditions. The presented model linked with Geographic Information Systems will allow pest risk assessments in different environmental regions to support the regulation of pest movement to prevent pest entry into not-yet invaded regions as well as to implement effective management strategies. PMID:28334271

  19. Temperature dependence of Henry's law constant in an extended temperature range.

    Science.gov (United States)

    Görgényi, Miklós; Dewulf, Jo; Van Langenhove, Herman

    2002-08-01

    The Henry's law constants H for chloroform, 1,1-dichloroethane, 1,2-dichloropropane, trichloroethene, chlorobenzene, benzene and toluene were determined by the EPICS-SPME technique (equilibrium partitioning in closed systems--solid phase microextraction) in the temperature range 275-343 K. The curvature observed in the ln H vs. 1/T plot was due to the temperature dependence of the change in enthalpy delta H0 during the transfer of 1 mol solute from the aqueous solution to the gas phase. The nonlinearity of the plot was explained by means of a thermodynamic model which involves the temperature dependence of delta H0 of the compounds and the thermal expansion of water in the three-parameter equation ln (H rho TT) = A2/T + BTB + C2, where rho T is the density of water at temperature T, TB = ln(T/298) + (298-T)/T, A2 = -delta H298(0)/R, delta H298(0) is the delta H0 value at 298 K, B = delta Cp0/R, and C2 is a constant. delta Cp0 is the molar heat capacity change in volatilization from the aqueous solution. A statistical comparison of the two models demonstrates the superiority of the three-parameter equation over the two-parameter one ln H vs. 1/T). The new, three-parameter equation allows a more accurate description of the temperature dependence of H, and of the solubility of volatile organic compounds in water at higher temperatures.

  20. The effect of temperature dependent tissue parameters on acoustic radiation force induced displacements

    Science.gov (United States)

    Suomi, Visa; Han, Yang; Konofagou, Elisa; Cleveland, Robin O.

    2016-10-01

    Multiple ultrasound elastography techniques rely on acoustic radiation force (ARF) in monitoring high-intensity focused ultrasound (HIFU) therapy. However, ARF is dependent on tissue attenuation and sound speed, both of which are also known to change with temperature making the therapy monitoring more challenging. Furthermore, the viscoelastic properties of tissue are also temperature dependent, which affects the displacements induced by ARF. The aim of this study is to quantify the temperature dependent changes in the acoustic and viscoelastic properties of liver and investigate their effect on ARF induced displacements by using both experimental methods and simulations. Furthermore, the temperature dependent viscoelastic properties of liver are experimentally measured over a frequency range of 0.1-200 Hz at temperatures reaching 80 °C, and both conventional and fractional Zener models are used to fit the data. The fractional Zener model was found to fit better with the experimental viscoelasticity data with respect to the conventional model with up to two orders of magnitude lower sum of squared errors (SSE). The characteristics of experimental displacement data were also seen in the simulations due to the changes in attenuation coefficient and lesion development. At low temperatures before thermal ablation, attenuation was found to affect the displacement amplitude. At higher temperature, the decrease in displacement amplitude occurs approximately at 60-70 °C due to the combined effect of viscoelasticity changes and lesion growth overpowering the effect of attenuation. The results suggest that it is necessary to monitor displacement continuously during HIFU therapy in order to ascertain when ablation occurs.

  1. Temperature-Dependent Modeling and Crosstalk Analysis in Mixed Carbon Nanotube Bundle Interconnects

    Science.gov (United States)

    Rai, Mayank Kumar; Garg, Harsh; Kaushik, B. K.

    2017-08-01

    The temperature-dependent circuit modeling and performance analysis in terms of crosstalk in capacitively coupled mixed carbon nanotube bundle (MCB) interconnects, at the far end of the victim line, have been analyzed with four different structures of MCBs (MCB-1, MCB-2, MCB-3 and MCB-4) constituted under case 1 and case 2 at the 22-nm technology node. The impact of tunneling and intershell coupling between adjacent shells on temperature-dependent equivalent circuit parameters of a multi-walled carbon nanotube bundle are also critically analyzed and employed for different MCB structures under case 1. A similar analysis is performed for copper interconnects and comparisons are made between results obtained through these analyses over temperatures ranging from 300 K to 500 K. The simulation program with integrated circuit emphasis simulation results reveals that, compared with all MCB structures under case 1 and case 2, with rise in temperature from 300 K to 500 K, crosstalk-induced noise voltage levels at the far end of the victim line are found to be significantly large in copper. It is also observed that due to the dominance of larger temperature-dependent resistance and ground capacitance in case 1, the MCB-2 is of lower crosstalk-induced noise voltage levels than other structures of MCBs. On the other hand, the MCB-1 has smaller time duration of victim output. Results further reveal that, compared with case 2 of MCB, with rise in temperatures, the victim line gets less prone to crosstalk-induced noise in MCB interconnects constituted under case 1, due to tunneling effects and intershell coupling between adjacent shells. Based on these comparative results, a promising MCB structure (MCB-2) has been proposed among other structures under the consideration of tunneling effects and intershell coupling (case 1).

  2. Are There Mutator Polymerases?

    Directory of Open Access Journals (Sweden)

    Miguel Garcia-Diaz

    2003-01-01

    Full Text Available DNA polymerases are involved in different cellular events, including genome replication and DNA repair. In the last few years, a large number of novel DNA polymerases have been discovered, and the biochemical analysis of their properties has revealed a long list of intriguing features. Some of these polymerases have a very low fidelity and have been suggested to play mutator roles in different processes, like translesion synthesis or somatic hypermutation. The current view of these processes is reviewed, and the current understanding of DNA polymerases and their role as mutator enzymes is discussed.

  3. The temperature-dependent expression of the desaturase gene desA in Synechocystis PCC6803.

    Science.gov (United States)

    Los, D; Horvath, I; Vigh, L; Murata, N

    1993-02-22

    We examined the temperature-dependent regulation of the expression of the desA gene, which encodes delta 12 desaturase of Synechocystis PCC6803. The level of desA transcript increased 10-fold within 1 h upon a decrease in temperature from 36 degrees C to 22 degrees C. This suggests that the low-temperature-induced desaturation of membrane lipid fatty acids is regulated at the level of the expression of the desaturase genes. The accumulation of the desA transcript depended on the extent of temperature change over a certain threshold level, but not on the absolute temperature.

  4. Calculation of the Effect of Random Superfluid Density on the Temperature Dependence of the Penetration Depth

    Energy Technology Data Exchange (ETDEWEB)

    Lippman, Thomas; Moler, Kathryn A.

    2012-07-20

    Microscopic variations in composition or structure can lead to nanoscale inhomogeneity in superconducting properties such as the magnetic penetration depth, but measurements of these properties are usually made on longer length scales. We solve a generalized London equation with a non-uniform penetration depth {lambda}(r), obtaining an approximate solution for the disorder-averaged Meissner screening. We find that the effective penetration depth is different from the average penetration depth and is sensitive to the details of the disorder. These results indicate the need for caution when interpreting measurements of the penetration depth and its temperature dependence in systems which may be inhomogeneous.

  5. Intensity and temperature-dependent photoluminescence of tris (8-hydroxyquinoline) aluminum films

    Energy Technology Data Exchange (ETDEWEB)

    Ajward, A. M.; Wang, X.; Wagner, H. P. [Department of Physics, University of Cincinnati, Cincinnati, Ohio 45221 (United States)

    2013-12-04

    We investigate the recombination of excitons in tris (8-hydroxyquinoline) aluminum films by intensity and temperature dependent time-resolved photoluminescence (PL). At low temperature (15 K) and elevated excitation intensity the radiative emission is quenched by singlet-singlet annihilation processes. With rising temperature the PL quenching is strongly reduced resulting in a PL efficiency maximum at ∼170 K. The reduced exciton annihilation is attributed to thermally activated occupation of non-quenchable trapped exciton states. Above 170 K the PL efficiency decreases due to thermal de-trapping of radiative states and subsequent migration to non-radiative centers.

  6. Thin film flow in MHD third grade fluid on a vertical belt with temperature dependent viscosity.

    Science.gov (United States)

    Gul, Taza; Islam, Saed; Shah, Rehan Ali; Khan, Ilyas; Shafie, Sharidan

    2014-01-01

    In this work, we have carried out the influence of temperature dependent viscosity on thin film flow of a magnetohydrodynamic (MHD) third grade fluid past a vertical belt. The governing coupled non-linear differential equations with appropriate boundary conditions are solved analytically by using Adomian Decomposition Method (ADM). In order to make comparison, the governing problem has also been solved by using Optimal Homotopy Asymptotic Method (OHAM). The physical characteristics of the problem have been well discussed in graphs for several parameter of interest.

  7. Physico-chemical characterization of the temperature dependent hydration kinetics of Gleditsia sinensis gum.

    Science.gov (United States)

    Jian, Hong-Lei; Lin, Xue-Jiao; Zhang, Wei-Ming; Sun, Da-Feng; Jiang, Jian-Xin

    2013-11-01

    The physico-chemical properties and hydration kinetics of Gleditsia sinensis gum were investigated to evaluate its temperature dependence. The increase of temperature resulted in improved solubility of G. sinensis gum, and the dissolved galactomannan showed decreased degree of galactose substitution (DSGal) and increased molecular weight (p0.96), and the hydration index t0.8 at different temperatures varied in the range of 51-302 min. It was found that galactomannan with low DSGal and high molecular weight exhibited slow hydration rate and poor solubility. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Analysis of the temperature dependence of the thermal conductivity of insulating single crystal oxides

    Directory of Open Access Journals (Sweden)

    E. Langenberg

    2016-10-01

    Full Text Available The temperature dependence of the thermal conductivity of 27 different single crystal oxides is reported from ≈20 K to 350 K. These crystals have been selected among the most common substrates for growing epitaxial thin-film oxides, spanning over a range of lattice parameters from ≈3.7 Å to ≈12.5 Å. Different contributions to the phonon relaxation time are discussed on the basis of the Debye model. This work provides a database for the selection of appropriate substrates for thin-film growth according to their desired thermal properties, for applications in which heat management is important.

  9. A Temperature-Dependent Thermal Model of IGBT Modules Suitable for Circuit-Level Simulations

    DEFF Research Database (Denmark)

    Wu, Rui; Wang, Huai; Pedersen, Kristian Bonderup

    2016-01-01

    A basic challenge in the IGBT transient simulation study is to obtain the realistic junction temperature, which demands not only accurate electrical simulations but also precise thermal impedance. This paper proposed a transient thermal model for IGBT junction temperature simulations during short...... circuits or overloads. The updated Cauer thermal model with varying thermal parameters is obtained by means of FEM thermal simulations with temperature-dependent physical parameters. The proposed method is applied to a case study of a 1700 V/1000 A IGBT module. Furthermore, a testing setup is built up...

  10. Computational modeling of 915 MHz microwave ablation: Comparative assessment of temperature-dependent tissue dielectric models.

    Science.gov (United States)

    Deshazer, Garron; Hagmann, Mark; Merck, Derek; Sebek, Jan; Moore, Kent B; Prakash, Punit

    2017-09-01

    The objective of this study is to develop a computational model for simulating 915 MHz microwave ablation (MWA), and verify the simulation predictions of transient temperature profiles against experimental measurements. Due to the limited experimental data characterizing temperature-dependent changes of tissue dielectric properties at 915 MHz, we comparatively assess two temperature-dependent approaches of modeling of dielectric properties: model A- piecewise linear temperature dependencies based on existing, but limited, experimental data, and model B- similar to model A, but augmented with linear decrease in electrical conductivity above 95 °C, as guided by our experimental measurements. The finite element method was used to simulate MWA procedures in liver with a clinical 915 MHz ablation applicator. A coupled electromagnetic-thermal solver incorporating temperature-dependent tissue biophysical properties of liver was implemented. Predictions of the transient temperature profiles and ablation zone dimensions for both model A and model B were compared against experimental measurements in ex vivo bovine liver tissue. Broadband dielectric properties of tissue within different regions of the ablation zone were measured and reported at 915 MHz and 2.45 GHz. Model B yielded peak tissue temperatures in closer agreement with experimental measurements, attributed to the inclusion of decrease in electrical conductivity at elevated temperature. The simulated transverse diameters of the ablation zone predicted by both models were greater than experimental measurements, which may be in part due to the lack of a tissue shrinkage model. At both considered power levels, predictions of transverse ablation zone diameters were in closer agreement with measurements for model B (max. discrepancy of 5 mm at 60 W, and 3 mm at 30 W), compared to model A (max. discrepancy of 9 mm at 60 W, and 6 mm at 30 W). Ablation zone lengths with both models were within 2 mm at 30 W, but

  11. Defect-induced change of temperature-dependent elastic constants in BCC iron

    Energy Technology Data Exchange (ETDEWEB)

    Gao, N.; Setyawan, W.; Zhang, S. H.; Wang, Z. G.

    2017-07-01

    The effects of radiation-induced defects (randomly distributed vacancies, voids, and interstitial dislocation loops) on temperature-dependent elastic constants, C11, C12, and C44 in BCC iron, are studied with molecular dynamics method. The elastic constants are found to decrease with increasing temperatures for all cases containing different defects. The presence of vacancies, voids, or interstitial loops further decreases the elastic constants. For a given number of point defects, the randomly distributed vacancies show the strongest effect compared to voids or interstitial loops. All these results are expected to provide useful information to combine with experimental results for further understanding of radiation damage.

  12. Temperature dependence of the single photon emission from interface-fluctuation GaN quantum dots.

    Science.gov (United States)

    Le Roux, F; Gao, K; Holmes, M; Kako, S; Arita, M; Arakawa, Y

    2017-11-23

    The temperature dependent single photon emission statistics of interface-fluctuation GaN quantum dots are reported. Quantum light emission is confirmed at temperatures up to ~77 K, by which point the background emission degrades the emission purity and results in a measured g(2) (0) in excess of 0.5. A discussion on the extent of the background contamination is also given through comparison to extensive data taken under various ambient and experimental conditions, revealing that the quantum dots themselves are emitting single photons with high purity.

  13. Unraveling the Transcriptional Basis of Temperature-Dependent Pinoxaden Resistance in Brachypodium hybridum.

    Science.gov (United States)

    Matzrafi, Maor; Shaar-Moshe, Lidor; Rubin, Baruch; Peleg, Zvi

    2017-01-01

    Climate change endangers food security and our ability to feed the ever-increasing human population. Weeds are the most important biotic stress, reducing crop-plant productivity worldwide. Chemical control, the main approach for weed management, can be strongly affected by temperature. Previously, we have shown that temperature-dependent non-target site (NTS) resistance of Brachypodium hybridum is due to enhanced detoxification of acetyl-CoA carboxylase inhibitors. Here, we explored the transcriptional basis of this phenomenon. Plants were characterized for the transcriptional response to herbicide application, high-temperature and their combination, in an attempt to uncover the genetic basis of temperature-dependent pinoxaden resistance. Even though most of the variance among treatments was due to pinoxaden application (61%), plants were able to survive pinoxaden application only when grown under high-temperatures. Biological pathways and expression patterns of members of specific gene families, previously shown to be involved in NTS metabolic resistance to different herbicides, were examined. Cytochrome P450, glucosyl transferase and glutathione-S-transferase genes were found to be up-regulated in response to pinoxaden application under both control and high-temperature conditions. However, biological pathways related to oxidation and glucose conjugation were found to be significantly enriched only under the combination of pinoxaden application and high-temperature. Analysis of reactive oxygen species (ROS) was conducted at several time points after treatment using a probe detecting H2O2/peroxides. Comparison of ROS accumulation among treatments revealed a significant reduction in ROS quantities 24 h after pinoxaden application only under high-temperature conditions. These results may indicate significant activity of enzymatic ROS scavengers that can be correlated with the activation of herbicide-resistance mechanisms. This study shows that up-regulation of genes

  14. Scaling of temperature dependence of charge mobility in molecular Holstein chains

    Science.gov (United States)

    Tikhonov, D. A.; Fialko, N. S.; Sobolev, E. V.; Lakhno, V. D.

    2014-03-01

    The temperature dependence of a charge mobility in a model DNA based on a Holstein Hamiltonian is calculated for four types of homogeneous sequences It has turned out that upon rescaling all four types are quite similar. Two types of rescaling, i.e., those for low and intermediate temperatures, are found. The curves obtained are approximated on a logarithmic scale by cubic polynomials. We believe that for model homogeneous biopolymers with parameters close to the designed ones, one can assess the value of the charge mobility without carrying out resource-intensive direct simulation, just by using a suitable approximating function.

  15. Molecular modeling of temperature dependence of solubility parameters for amorphous polymers

    OpenAIRE

    Chen, X.; Yuan, C.; Wong, C.K.Y.; Zhang, G

    2011-01-01

    A molecular modeling strategy is proposed to describe the temperature (T) dependence of solubility parameter (δ) for the amorphous polymers which exhibit glass-rubber transition behavior. The commercial forcefield “COMPASS” is used to support the atomistic simulations of the polymer. The temperature dependence behavior of δ for the polymer is modeled by running molecular dynamics (MD) simulation at temperatures ranging from 250 up to 650 K. Comparing the MD predicted δ value at 298 K and the ...

  16. Temperature dependence of large positive magnetoresistance in hybrid ferromagnetic/semiconductor devices

    Science.gov (United States)

    Overend, N.; Nogaret, A.; Gallagher, B. L.; Main, P. C.; Henini, M.; Marrows, C. H.; Howson, M. A.; Beaumont, S. P.

    1998-04-01

    We investigate a new type of magnetoresistance (MR) in which the resistivity of a near-surface two-dimensional electron gas is controlled by the magnetization of a submicron ferromagnetic grating defined on the surface of the device. We observe an increase in resistance of up to ˜1500% at a temperature of 4 K and ˜1% at 300 K. The magnitude and temperature dependence of the MR are well accounted for by a semiclassical theory. Optimization of device parameters is expected to increase considerably the magnitude of the room temperature MR.

  17. Temperature dependence of unitary properties of an ATP-dependent potassium channel in cardiac myocytes.

    OpenAIRE

    McLarnon, J G; Hamman, B.N.; Tibbits, G.F.

    1993-01-01

    The temperature dependence of the properties of unitary currents in cultured rat ventricular myocytes has been studied. Currents flowing through an ATP-dependent K+ channel were recorded from inside-out patches with the bath temperature varied from 10 degrees to 30 degrees C. The channel conductance was 56 pS at room temperature (22 degrees C), and the amplitudes of unitary currents and the channel conductance exhibited a relatively weak (Q10 from 1.4 to 1.6) dependence on temperature. The te...

  18. Temperature Dependent Electrical and Micromechanical Properties of Lanthanum Titanate with Additions of Yttria

    Science.gov (United States)

    Goldsby, Jon C.

    2003-01-01

    Lanthanum titanate (La2Ti2O7) a layered distorted perovskite (1) with space group Pna2(sub 1) has been shown to have potential as a high temperature piezoelectric (2). However this highly refractory oxide compound must be consolidated at relatively high temperatures approximately 1400 C. Commercial La2Ti207 powders were mechanically alloyed with additions of Y2O3 to lower the consolidation temperature by 300 C and to provide post processing mechanical stability. Temperature dependent electrical, elastic and anelastic behavior were selected as nondestructive means of evaluating the effects of yttria on the properties of this ferroceramic material.

  19. Temperature-Dependent Electrical and Micromechanical Properties of Lanthanum Titanate with Additions of Yttria

    Science.gov (United States)

    Goldsby, Jon C.

    2010-01-01

    Temperature-dependent elastic properties were determined by establishing continuous flexural vibrations in the material at its lowest resonance frequency of 31tHz. The imaginary part of the complex impedance plotted as a function of frequency and temperature reveals a thermally activated peak, which decreases in magnitude as the temperature increases. Additions of yttria do not degrade the electromechanical in particularly the elastic and anelastic properties of lanthanum titanate. Y2O3/La2Ti2O7 exhibits extremely low internal friction and hence may be more mechanical fatigue-resistant at low strains.

  20. Temperature dependent electrical properties of polyaniline film grown on paper through aniline vapor polymerization

    Energy Technology Data Exchange (ETDEWEB)

    Deb, K.; Bera, A.; Saha, B., E-mail: biswajit.physics@gmail.com [Department of Physics, National Institute of Technology Agartala, Jirania, West Tripura 799046 (India); Bhowmik, K. L. [Department of Physics, National Institute of Technology Agartala, Jirania, West Tripura 799046 (India); Department of Chemistry, Bir Bikram Memorial College, Agartala, West Tripura 799004 (India); Chattopadhyay, K. K. [Department of Physics, Jadavpur University, Kolkata 700 032 (India)

    2016-05-23

    Polyaniline thin film has been prepared on paper by aniline vapor deposition technique. Ferric chloride has been used as polymerizing agent in this approach. The prepared films were studied through electrical resistivity and optical properties measurements. The electrical resistivity of the polyaniline film shows significant temperature dependence. The resistance sharply falls with the increase in temperature. The optical absorbance measurements shows characteristics absorbance peak indicating the formation of conducting emeraldine salt form of polyaniline. The optical energy band gap of the film was calculated from the transmittance spectra. The optical energy band gap and electrical conductivity of the polyaniline film is well suited for their applications in electronic devices.

  1. Temperature dependence of universal conductance fluctuation due to development of weak localization in graphene

    Science.gov (United States)

    Terasawa, D.; Fukuda, A.; Fujimoto, A.; Ohno, Y.; Matsumoto, K.

    2017-11-01

    The temperature effect of quantum interference on resistivity is examined in monolayer graphene, with experimental results showing that the amplitude of the conductance fluctuation increases as temperature decreases. We find that this behavior can be attributed to the decrease in the inelastic scattering (dephasing) rate, which enhances the weak localization (WL) correction to resistivity. Following a previous report that explained the relationship between the universal conductance fluctuation (UCF) and WL regarding the gate voltage dependence (Terasawa et al., 2017) [19], we propose that the temperature dependence of the UCF in monolayer graphene can be interpreted by the WL theory.

  2. Reversing the temperature dependence of the sensitized Er3+ luminescence intensity

    Science.gov (United States)

    Lenz, F.; Hryciw, A.; DeCorby, R.; Meldrum, A.

    2009-08-01

    The temperature-induced quenching of the Er3+ luminescence is a significant problem in silicon-based materials systems ultimately designed for room-temperature applications. Here, we show that amorphous silicon-rich oxide, moderately annealed in order to avoid growth of Si nanocrystals, exhibits a reversed temperature dependence in which the integrated Er3+ luminescence increases in intensity upon heating from 77 up to 300 K. This behavior is attributed to a unique spectrum of interacting defects that efficiently sensitize the Er3+ levels, even in the absence of nanocrystals. The effect could have ramifications in fiber-optic emitters or amplifiers to be operated at noncryogenic temperatures.

  3. Effects of Temperature Dependence of Energy Bandgap on I-V Characteristics in CNTFETs Models

    Science.gov (United States)

    Marani, R.; Perri, A. G.

    In this paper, we analyze the effects of temperature dependence of energy bandgap on I-V characteristics in some carbon nanotube field effect transistors (CNTFETs) models proposed in literature in order to identify the one more suitable for computer aided design (CAD) applications. At first we consider a compact, semi-empirical model, already proposed by us, performing I-V characteristic simulations at different temperatures. Our results are compared with those obtained with the Stanford-Source virtual carbon nanotube field-effect transistor model (VS-CNFET), obtaining I-V characteristics comparable, but with lower CPU calculation time.

  4. Unraveling the Transcriptional Basis of Temperature-Dependent Pinoxaden Resistance in Brachypodium hybridum

    Science.gov (United States)

    Matzrafi, Maor; Shaar-Moshe, Lidor; Rubin, Baruch; Peleg, Zvi

    2017-01-01

    Climate change endangers food security and our ability to feed the ever-increasing human population. Weeds are the most important biotic stress, reducing crop-plant productivity worldwide. Chemical control, the main approach for weed management, can be strongly affected by temperature. Previously, we have shown that temperature-dependent non-target site (NTS) resistance of Brachypodium hybridum is due to enhanced detoxification of acetyl-CoA carboxylase inhibitors. Here, we explored the transcriptional basis of this phenomenon. Plants were characterized for the transcriptional response to herbicide application, high-temperature and their combination, in an attempt to uncover the genetic basis of temperature-dependent pinoxaden resistance. Even though most of the variance among treatments was due to pinoxaden application (61%), plants were able to survive pinoxaden application only when grown under high-temperatures. Biological pathways and expression patterns of members of specific gene families, previously shown to be involved in NTS metabolic resistance to different herbicides, were examined. Cytochrome P450, glucosyl transferase and glutathione-S-transferase genes were found to be up-regulated in response to pinoxaden application under both control and high-temperature conditions. However, biological pathways related to oxidation and glucose conjugation were found to be significantly enriched only under the combination of pinoxaden application and high-temperature. Analysis of reactive oxygen species (ROS) was conducted at several time points after treatment using a probe detecting H2O2/peroxides. Comparison of ROS accumulation among treatments revealed a significant reduction in ROS quantities 24 h after pinoxaden application only under high-temperature conditions. These results may indicate significant activity of enzymatic ROS scavengers that can be correlated with the activation of herbicide-resistance mechanisms. This study shows that up-regulation of genes

  5. Temperature-dependent transport mechanisms through PE-CVD coatings: comparison of oxygen and water vapour

    Science.gov (United States)

    Kirchheim, D.; Wilski, S.; Jaritz, M.; Mitschker, F.; Gebhard, M.; Brochhagen, M.; Böke, M.; Benedikt, Jan; Awakowicz, P.; Devi, A.; Hopmann, Ch; Dahlmann, R.

    2017-10-01

    When it comes to thin coatings such as plasma-enhanced chemical vapour deposition or plasma-enhanced atomic layer deposition coatings on substrates of polymeric material, existing models often describe transport through these thin coatings as mainly driven by transport through defects of different sizes. However, temperature-dependent measurements of permeation could not confirm this hypothesis and instead gaseous transport through these thin coatings was found to more likely to occur through the molecular structure. This paper correlates existing transport models with data from oxygen transmission experiments and puts recent investigations for water vapour transmission mechanisms into context for a better understanding of gaseous transport through thin coatings.

  6. Temperature dependence of dislocation-related luminescence in silicon-germanium heterostructure

    CERN Document Server

    Lee, H S

    1998-01-01

    We measured the photoluminescence spectra of very thin and partially strained Si sub 0 sub . sub 6 Ge sub 0 sub . sub 4 alloys grown on silicon substrate with varying degrees of strain relaxation. We observed photoluminescence lines, so called D-lines, which arose from dislocations in the SiGe/Si alloys. We identified the origin of the D-lines as the dislocations in Si substrate extending from the SiGe/Si interface. We also studied the temperature dependence of the Si D-lines and determined the dissociation energy of the defect energy levels.

  7. Strained silicon on SiGe: Temperature dependence of carrier effective masses

    Science.gov (United States)

    Richard, Soline; Cavassilas, Nicolas; Aniel, Frédéric; Fishman, Guy

    2003-10-01

    A strain Bir-Pikus Hamiltonian Hst, based on a 20 band sps* kṡp Hamiltonian Hkp, is used to describe the valence band and the first two conduction bands over the entire Brillouin zone. This full-band kṡp computation of the carrier dispersion relation is used to calculate electron and hole effective masses in strained silicon. Hole density of states masses are found to be very temperature dependent whereas electron effective masses can be considered temperature independent to first order.

  8. Somatic Symptom Disorders in Children

    Directory of Open Access Journals (Sweden)

    Beena Johnson

    2017-04-01

    Full Text Available Physical symptoms without any identifiable structural or biochemical abnormalities on detailed clinical examination and investigations, are common in children. Some children may have persistent physical discomfort which can lead to debilitating impact on their academic and social functioning. These children seek repeated medical consultations and are usually subjected to unnecessary invasive diagnostic procedures. It is extremely important to understand that emotional factors can contribute to the development as well as maintenance of impairing physical symptoms. There is scientific evidence for the association of anxiety and functional somatic symptoms in children. The diagnostic category which was previously called somatoform disorders is now included in somatic symptom disorders. The main feature of the somatic symptom disorders is the excessive concern with somatic symptoms. Detailed clinical examination and investigations will not reveal any abnormalities to explain the symptoms. The somatic symptom disorders are common in childhood. Cognitive behavioural therapy by experts in child guidance, will relieve the somatic symptoms related to anxiety and stress. If not intervened at the earliest, the persistent physical symptoms associated with emotional stress will cause significant functional disability in childhood. Unnecessary invasive medical interventions cause more agony to the child. These children also have high risk for developing anxiety disorders and depressive disorders in young adulthood. Hence, early intervention using cognitive behavioural techniques should be provided to all children with somatic symptom disorders, which will definitely improve their quality of life.

  9. Males with epilepsy, complete subcortical band heterotopia, and somatic mosaicism for DCX.

    Science.gov (United States)

    Poolos, N P; Das, S; Clark, G D; Lardizabal, D; Noebels, J L; Wyllie, E; Dobyns, W B

    2002-05-28

    Subcortical band heterotopia (SBH) is seen predominantly in females, resulting from mutations in the X-linked doublecortin (DCX) gene, and can present with mild mental retardation and epilepsy. Males carrying DCX mutations usually demonstrate lissencephaly and are clinically much more severely affected. This article reports two cases of males with SBH indistinguishable from the female phenotype, both resulting from somatic mosaicism for DCX mutation.

  10. A novel DCX missense mutation in a family with X-linked lissencephaly and subcortical band heterotopia syndrome inherited from a low-level somatic mosaic mother: Genetic and functional studies.

    Science.gov (United States)

    Tsai, Meng-Han; Kuo, Pei-Wen; Myers, Candace T; Li, Shih-Wen; Lin, Wei-Che; Fu, Ting-Ying; Chang, Hsin-Yun; Mefford, Heather C; Chang, Yao-Chung; Tsai, Jin-Wu

    2016-09-01

    To study the genetics and functional alteration of a family with X-linked lissencephaly and subcortical band heterotopia. Five affected patients (one male with lissencephaly, four female with subcortical band heterotopia) and their relatives were studied. Sanger sequencing of DCX gene, allele specific PCR and molecular inversion probe technique were performed. Mutant and wild type of the gene products, namely doublecortin, were expressed in cells followed by immunostaining to explore the localization of doublecortin and microtubules in cells. In vitro microtubule-binding protein spin-down assay was performed to quantify the binding ability of doublecortin to microtubules. We identified a novel DCX mutation c.785A > G, p.Asp262Gly that segregated with the affected members of the family. Allele specific PCR and molecular inversion probe technique demonstrated that the asymptomatic female carrier had an 8% mutant allele fraction in DNA derived from peripheral leukocytes. This mother had 7 children, 4 of whom were affected and all four affected siblings carried the mutation. Functional study showed that the mutant doublecortin protein had a significant reduction of its ability to bind microtubules. Low level mosaicism could be a cause of inherited risk from asymptomatic parents for DCX related lissencephaly-subcortical band heterotopia spectrum. This is particularly important in terms of genetic counselling for recurrent risk of future pregnancies. The reduced binding affinity of mutant doublecortin may contribute to developmental malformation of the cerebral cortex. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  11. Temperature-dependent yield criterion for high strength steel sheets under warm-forming conditions

    Directory of Open Access Journals (Sweden)

    Cai Zhengyang

    2015-01-01

    Full Text Available In this paper, uniaxial and biaxial tensile tests with cruciform specimens were conducted to investigate the deformation behaviour of dual phase steel sheet with a tensile strength of 590 MPa (DP590 under evaluated warm-forming temperatures (20–190 ∘C. Detailed analyses were then carried out to obtain the corresponding experimental yield loci. For the purpose of describing the temperature-dependent yield behaviour of DP590 appropriately, the Yld2000–2d yield function with temperature-dependent exponent was proposed. The identification procedures of the introduced parameters were then proposed based on Levenberg-Marquardt optimization algorithm. Afterwards, the proposed model was implemented into ABAQUS as user subroutine VUMAT with NICE (Next Increment Corrects Error explicit integration scheme. The numerical simulations of biaxial tensile tests were then conducted to confirm the validity of the proposed model. It could be concluded that the flexibility and accuracy of the proposed model guarantee the applicability in warm-forming applications.

  12. Temperature dependent rate coefficients for the reactions of Criegee biradicals with selected alcohols and sulphides

    Science.gov (United States)

    McGillen, Max; McMahon, Laura; Curchod, Basile; Shallcross, Dudley; Orr-Ewing, Andrew

    2017-04-01

    The reactions of Criegee biradicals have received much attention in recent years, yet few reactive systems have undergone direct experimental measurement, and fewer still have been measured as a function of temperature. In this study, absolute temperature-dependent rate coefficients for the gas-phase reactions of a suite of alcohols and sulphides with both formaldehyde oxide (CH2OO) and acetone oxide ((CH3)2COO) are determined experimentally between 254 and 328 K using cavity ringdown spectroscopy for detecting Criegee biradicals. Major differences in reactivity and temperature dependence are observed both in terms of the functionality (between alcohols and sulphides) and also the degree of alkyl substitution about the Criegee biradical. This diverse behaviour represents a uniquely challenging problem for atmospheric chemistry since the atmosphere contains a large variety of both functionalized compounds and Criegee biradicals, leading to a formidable parameter space which may be impossible to cover experimentally. Notwithstanding, new experimental data such as these are vital for understanding the general behaviour of Criegee biradicals in the atmosphere.

  13. Temperature dependence of the current in Schottky-barrier source-gated transistors

    Science.gov (United States)

    Sporea, R. A.; Overy, M.; Shannon, J. M.; Silva, S. R. P.

    2015-05-01

    The temperature dependence of the drain current is an important parameter in thin-film transistors. In this paper, we propose that in source-gated transistors (SGTs), this temperature dependence can be controlled and tuned by varying the length of the source electrode. SGTs comprise a reverse biased potential barrier at the source which controls the current. As a result, a large activation energy for the drain current may be present which, although useful in specific temperature sensing applications, is in general deleterious in many circuit functions. With support from numerical simulations with Silvaco Atlas, we describe how increasing the length of the source electrode can be used to reduce the activation energy of SGT drain current, while maintaining the defining characteristics of SGTs: low saturation voltage, high output impedance in saturation, and tolerance to geometry variations. In this study, we apply the dual current injection modes to obtain drain currents with high and low activation energies and propose mechanisms for their exploitation in future large-area integrated circuit designs.

  14. On the temperature dependence of H-U{sub iso} in the riding hydrogen model

    Energy Technology Data Exchange (ETDEWEB)

    Lübben, Jens; Volkmann, Christian [Institut für Anorganische Chemie, Georg-August-Universität, Tammannstrasse 4, D-37077 Göttingen (Germany); Grabowsky, Simon [School of Chemistry and Biochemistry, Stirling Highway 35, WA-6009 Crawley (Australia); Edwards, Alison [Bragg Institute, Australian Nuclear Science and Technology Organisation, Locked Bag 2001, Kirrawee DC, NSW 2232 (Australia); Morgenroth, Wolfgang [Institut für Geowissenschaften, Abteilung Kristallographie, Goethe-Universität, Altenhöferallee 1, 60438 Frankfurt am Main (Germany); Fabbiani, Francesca P. A. [GZG, Abteilung Kristallographie, Georg-August Universität, Goldschmidtstrasse 1, 37077 Göttingen (Germany); Sheldrick, George M. [Institut für Anorganische Chemie, Georg-August-Universität, Tammannstrasse 4, D-37077 Göttingen (Germany); Dittrich, Birger, E-mail: birger.dittrich@chemie.uni-hamburg.de [Institut für Anorganische und Angewandte Chemie, Martin-Luther-King-Platz 6, 20146 Hamburg (Germany); Institut für Anorganische Chemie, Georg-August-Universität, Tammannstrasse 4, D-37077 Göttingen (Germany)

    2014-07-01

    The temperature dependence of hydrogen U{sub iso} and parent U{sub eq} in the riding hydrogen model is investigated by neutron diffraction, aspherical-atom refinements and QM/MM and MO/MO cluster calculations. Fixed values of 1.2 or 1.5 appear to be underestimated, especially at temperatures below 100 K. The temperature dependence of H-U{sub iso} in N-acetyl-l-4-hydroxyproline monohydrate is investigated. Imposing a constant temperature-independent multiplier of 1.2 or 1.5 for the riding hydrogen model is found to be inaccurate, and severely underestimates H-U{sub iso} below 100 K. Neutron diffraction data at temperatures of 9, 150, 200 and 250 K provide benchmark results for this study. X-ray diffraction data to high resolution, collected at temperatures of 9, 30, 50, 75, 100, 150, 200 and 250 K (synchrotron and home source), reproduce neutron results only when evaluated by aspherical-atom refinement models, since these take into account bonding and lone-pair electron density; both invariom and Hirshfeld-atom refinement models enable a more precise determination of the magnitude of H-atom displacements than independent-atom model refinements. Experimental efforts are complemented by computing displacement parameters following the TLS+ONIOM approach. A satisfactory agreement between all approaches is found.