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Sample records for additional genetic alterations

  1. Molecular basis of inherited antithrombin deficiency in Portuguese families: identification of genetic alterations and screening for additional thrombotic risk factors.

    PubMed

    David, Dezsö; Ribeiro, Sofia; Ferrão, Lénia; Gago, Teresa; Crespo, Francisco

    2004-06-01

    Antithrombin (AT), the most important coagulation serine proteases inhibitor, plays an important role in maintaining the hemostatic balance. Inherited AT deficiency, mainly characterized by predisposition to recurrent venous thromboembolism, is transmitted in an autosomal dominant manner. In this study, we analyzed the underlying genetic alterations in 12 unrelated Portuguese thrombophilic families with AT deficiency. At the same time, the modulating effect of the FV Leiden mutation, PT 20210A, PAI-1 4G, and MTHFR 677T allelic variants, on the thrombotic risk of AT deficient patients was also evaluated. Three novel frameshift alterations, a 4-bp deletion in exon 4 and two 1-bp insertions in exon 6, were identified in six unrelated type I AT deficient families. A novel missense mutation in exon 3a, which changes the highly conserved F147 residue, and a novel splice site mutation in the invariant acceptor AG dinucleotide of intron 2 were also identified in unrelated type I AT deficient families. In addition to these, two previously reported missense mutations changing the AT reactive site bond (R393-S394) and leading to type II-RS deficiency, and a previously reported cryptic splice site mutation (IVS4-14G-->A), were also identified. In these families, increased thrombotic risk associated with co-inheritance of the FV Leiden mutation and of the PAI-1 4G variant was also observed. In conclusion, we present the first data regarding the underlying genetic alterations in Portuguese thrombophilic families with AT deficiency, and confirm that the FV Leiden mutation and probably the PAI-1 4G variant represent additional thrombotic risk factors in these families.

  2. Genetically Altered Plant Species

    NASA Technical Reports Server (NTRS)

    2003-01-01

    Researchers in Robert Ferl's lab at the University of Florida in Gainesville, genetically altered this Arabdopsis Thaliana (a brassica species) plant to learn how extreme environments, such as the low atmospheric pressure on Mars, affect plant genes. They inserted green fluorescent protein (GFP) near the on/off switches for anoxia and drought genes. When those genes were turned on after exposure to reduced atmospheric pressure, GFP was turned on as well, causing cells expressing those genes to glow green under a blue light. The natural fluorescence of chlorophyll accounts for the red glow.

  3. Genetic and Epigenetic Alterations in Bladder Cancer

    PubMed Central

    2016-01-01

    Bladder cancer is one of the most common cancers worldwide, with a high rate of recurrence and poor outcomes as a result of relapse. Bladder cancer patients require lifelong invasive monitoring and treatment, making bladder cancer one of the most expensive malignancies. Lines of evidence increasingly point to distinct genetic and epigenetic alteration patterns in bladder cancer, even between the different stages and grades of disease. In addition, genetic and epigenetic alterations have been demonstrated to play important roles during bladder tumorigenesis. This review will focus on bladder cancer-associated genomic and epigenomic alterations, which are common in bladder cancer and provide potential diagnostic markers and therapeutic targets for bladder cancer treatment. PMID:27915480

  4. Genetic alterations and epigenetic alterations of cancer-associated fibroblasts

    PubMed Central

    Du, Heng; Che, Guowei

    2017-01-01

    Cancer-associated fibroblasts (CAFs) are one major type of component identified in the tumor microenvironment. Studies have focused on the genetic and epigenetic status of CAFs, since they are critical in tumor progression and differ phenotypically and functionally from normal fibroblasts. The present review summarizes the recent achievements in understanding the gene profiles of CAFs and pays special attention to their possible epigenetic alterations. A total of 7 possible genetic alterations and epigenetic changes in CAFs are discussed, including gene differential expression, karyotype analysis, gene copy number variation, loss of heterozygosis, allelic imbalance, microsatellite instability, post-transcriptional control and DNA methylation. These genetic and epigenetic characteristics are hypothesized to provide a deep understanding of CAFs and a perspective on their clinical significance. PMID:28123515

  5. Characterizing neuromorphologic alterations with additive shape functionals

    NASA Astrophysics Data System (ADS)

    Barbosa, M. S.; Costa, L. Da F.; Bernardes, E. S.; Ramakers, G.; van Pelt, J.

    2004-01-01

    The complexity of a neuronal cell shape is known to be related to its function. Specifically, among other indicators, a decreased complexity in the dendritic trees of cortical pyramidal neurons has been associated with mental retardation. In this paper we develop a procedure to address the characterization of morphological changes induced in cultured neurons by over-expressing a gene involved in mental retardation. Measures associated with the multiscale connectivity, an additive image functional, are found to give a reasonable separation criterion between two categories of cells. One category consists of a control group and two transfected groups of neurons, and the other, a class of cat ganglionary cells. The reported framework also identified a trend towards lower complexity in one of the transfected groups. Such results establish the suggested measures as an effective descriptors of cell shape.

  6. Genetic alterations in hepatocellular carcinoma: An update

    PubMed Central

    Niu, Zhao-Shan; Niu, Xiao-Jun; Wang, Wen-Hong

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC. PMID:27895396

  7. 13. BUILDING 239. ARTILLERY PRIMER SHOP. ADDITIONS AND ALTERATIONS. FIRST ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    13. BUILDING 239. ARTILLERY PRIMER SHOP. ADDITIONS AND ALTERATIONS. FIRST FLOOR PLAN AND ELEVATIONS. May 12, 1920. - Frankford Arsenal, Building Nos. 239-239A, Southeast corner of Clay Street & Cray Road, Philadelphia, Philadelphia County, PA

  8. Distinct Genetic Alterations in Colorectal Cancer

    PubMed Central

    Ashktorab, Hassan; Schäffer, Alejandro A.; Daremipouran, Mohammad; Smoot, Duane T.; Lee, Edward; Brim, Hassan

    2010-01-01

    Background Colon cancer (CRC) development often includes chromosomal instability (CIN) leading to amplifications and deletions of large DNA segments. Epidemiological, clinical, and cytogenetic studies showed that there are considerable differences between CRC tumors from African Americans (AAs) and Caucasian patients. In this study, we determined genomic copy number aberrations in sporadic CRC tumors from AAs, in order to investigate possible explanations for the observed disparities. Methodology/Principal Findings We applied genome-wide array comparative genome hybridization (aCGH) using a 105k chip to identify copy number aberrations in samples from 15 AAs. In addition, we did a population comparative analysis with aCGH data in Caucasians as well as with a widely publicized list of colon cancer genes (CAN genes). There was an average of 20 aberrations per patient with more amplifications than deletions. Analysis of DNA copy number of frequently altered chromosomes revealed that deletions occurred primarily in chromosomes 4, 8 and 18. Chromosomal duplications occurred in more than 50% of cases on chromosomes 7, 8, 13, 20 and X. The CIN profile showed some differences when compared to Caucasian alterations. Conclusions/Significance Chromosome X amplification in male patients and chromosomes 4, 8 and 18 deletions were prominent aberrations in AAs. Some CAN genes were altered at high frequencies in AAs with EXOC4, EPHB6, GNAS, MLL3 and TBX22 as the most frequently deleted genes and HAPLN1, ADAM29, SMAD2 and SMAD4 as the most frequently amplified genes. The observed CIN may play a distinctive role in CRC in AAs. PMID:20126641

  9. ALTERATIONS AND ADDITIONS TO THE GATE HOUSE, United Engineering Company ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    ALTERATIONS AND ADDITIONS TO THE GATE HOUSE, United Engineering Company Ltd., Alameda Shipyard. Plan, elevations, and details of expanded structure. No architect noted. Drawn by "J.B.H." (John Hudspeth?). Sheet 2 of 2. Plan no. 10,504. Scale 1/4 inch to the foot. November 28, 1942, last revised 5/5/45. pencil on vellum - United Engineering Company Shipyard, Gate House, 2900 Main Street, Alameda, Alameda County, CA

  10. 10. Photocopy of 1940 architectural drawing titled: 'Alterations & Additions ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    10. Photocopy of 1940 architectural drawing titled: 'Alterations & Additions to (4290) Hosital, Schedules' includes 'Typical Door Elevations' and 'Metal Door Frames.' Dated 4-12-40. HABS film is a high-contrast 8x10' negative made from original drawing in the collection of Housing and Engineering Services, Fort Lewis, WA. - Fort Lewis, Post Hospital, Near Ninth Division Drive & Idaho Avenue, DuPont, Pierce County, WA

  11. Explaining additional genetic variation in complex traits

    PubMed Central

    Robinson, Matthew R.; Wray, Naomi R.; Visscher, Peter M.

    2015-01-01

    Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits, discovering >6000 variants associated with >500 quantitative traits and common complex diseases in humans. The associations identified so far represent only a fraction of those which influence phenotype, as there are likely to be very many variants across the entire frequency spectrum, each of which influences multiple traits, with only a small average contribution to the phenotypic variance. This presents a considerable challenge to further dissection of the remaining unexplained genetic variance within populations, which limits our ability to predict disease risk, identify new drug targets, improve and maintain food sources, and understand natural diversity. This challenge will be met within the current framework through larger sample size, better phenotyping including recording of non-genetic risk factors, focused study designs, and an integration of multiple sources of phenotypic and genetic information. The current evidence supports the application of quantitative genetic approaches, and we argue that one should retain simpler theories until simplicity can be traded for greater explanatory power. PMID:24629526

  12. Unnatural reactive amino acid genetic code additions

    SciTech Connect

    Deiters, Alexander; Cropp, T Ashton; Chin, Jason W; Anderson, J Christopher; Schultz, Peter G

    2011-02-15

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  13. Unnatural reactive amino acid genetic code additions

    SciTech Connect

    Deiters, Alexander; Cropp, Ashton T; Chin, Jason W; Anderson, Christopher J; Schultz, Peter G

    2013-05-21

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  14. Unnatural reactive amino acid genetic code additions

    SciTech Connect

    Deiters, Alexander; Cropp, T. Ashton; Chin, Jason W.; Anderson, J. Christopher; Schultz, Peter G.

    2011-08-09

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNAsyn-thetases, pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  15. Unnatural reactive amino acid genetic code additions

    SciTech Connect

    Deiters, Alexander; Cropp, T. Ashton; Chin, Jason W.; Anderson, J. Christopher; Schultz, Peter G.

    2014-08-26

    This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.

  16. Raman spectroscopic study of a genetically altered kidney cell

    NASA Astrophysics Data System (ADS)

    Joshi, Joel; Garcia, Francisco; Centeno, Silvia P.; Joshi, N. V.

    2008-02-01

    A Raman spectroscopic investigation of a genetically altered Human Embryonic Kidney Cell (HEK293) along with a pathologically normal cell has been carried out by a conventional method. The genetic alteration was carried out with a standard protocol by using a Green Fluorescence Protein (GFP). Raman spectra show that there are dramatic differences between the spectrum obtained from a genetically altered cell and that obtained from a pathologically normal cell. The former shows three broad bands; meanwhile the latter shows several sharp peaks corresponding to the ring vibrational modes of Phen, GFP and DNA. The present analysis provides an indication that the force field near Phen located at 64, 65 and 66 was altered during the genetic transformation. The Raman spectrum could be a direct experimental evidence for substantial modifications triggered due to the expression of specific genes.

  17. [Autism, genetics and synaptic function alterations].

    PubMed

    Perche, O; Laumonnier, F; Baala, L; Ardourel, M-Y; Menuet, A; Robin, V; Mortaud, S; Montécot-Dubourg, C; Richard, O; Pichon, J; Briault, S

    2010-10-01

    Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.

  18. Genetic alterations in syndromes with oral manifestations.

    PubMed

    Anuthama, Krishnamurthy; Prasad, Harikrishnan; Ramani, Pratibha; Premkumar, Priya; Natesan, Anuja; Sherlin, Herald J

    2013-11-01

    Ever since Gregor Johan Mendel proposed the law of inheritance, genetics has transcended the field of health and has entered all walks of life in its application. Thus, the gene is the pivoting factor for all happenings revolving around it. Knowledge of gene mapping in various diseases would be a valuable tool in prenatally diagnosing the condition and averting the future disability and stigma for the posterity. This article includes an array of genetically determined conditions in patients seen at our college out-patient department with complete manifestation, partial manifestation and array of manifestations not fitting into a particular syndrome.

  19. Genetic alterations in syndromes with oral manifestations

    PubMed Central

    Anuthama, Krishnamurthy; Prasad, Harikrishnan; Ramani, Pratibha; Premkumar, Priya; Natesan, Anuja; Sherlin, Herald J.

    2013-01-01

    Ever since Gregor Johan Mendel proposed the law of inheritance, genetics has transcended the field of health and has entered all walks of life in its application. Thus, the gene is the pivoting factor for all happenings revolving around it. Knowledge of gene mapping in various diseases would be a valuable tool in prenatally diagnosing the condition and averting the future disability and stigma for the posterity. This article includes an array of genetically determined conditions in patients seen at our college out-patient department with complete manifestation, partial manifestation and array of manifestations not fitting into a particular syndrome. PMID:24379857

  20. Genetic Alterations in Pesticide Exposed Bolivian Farmers

    PubMed Central

    Jørs, Erik; Gonzáles, Ana Rosa; Ascarrunz, Maria Eugenia; Tirado, Noemi; Takahashi, Catharina; Lafuente, Erika; Dos Santos, Raquel A; Bailon, Natalia; Cervantes, Rafael; O, Huici; Bælum, Jesper; Lander., Flemming

    2007-01-01

    Background Pesticides are of concern in Bolivia because of increasing use. Frequent intoxications have been demonstrated due to use of very toxic pesticides, insufficient control of distribution and sale and little knowledge among farmers of protective measures and hygienic procedures. Method Questionnaires were applied and blood tests taken from 81 volunteers from La Paz County, of whom 48 were pesticide exposed farmers and 33 non-exposed controls. Sixty males and 21 females participated with a mean age of 37.3 years (range 17–76). Data of exposure and possible genetic damage were collected and evaluated by well known statistical methods, controlling for relevant confounders. To measure genetic damage chromosomal aberrations and the comet assay analysis were performed. Results Pesticide exposed farmers had a higher degree of genetic damage compared to the control group. The number of chromosomal aberrations increased with the intensity of pesticide exposure. Females had a lower number of chromosomal aberrations than males, and people living at altitudes above 2500 metres seemed to exhibit more DNA damage measured by the comet assay. Conclusions Bolivian farmers showed signs of genotoxic damage, probably related to exposure to pesticides. Due to the potentially negative long term health effects of genetic damage on reproduction and the development of cancer, preventive measures are recommended. Effective control with imports and sales, banning of the most toxic pesticides, education and information are possible measures, which could help preventing the negative effects of pesticides on human health and the environment. PMID:19662224

  1. Molecular reconstruction of a fungal genetic code alteration.

    PubMed

    Mateus, Denisa D; Paredes, João A; Español, Yaiza; Ribas de Pouplana, Lluís; Moura, Gabriela R; Santos, Manuel A S

    2013-06-01

    Fungi of the CTG clade translate the Leu CUG codon as Ser. This genetic code alteration is the only eukaryotic sense-to-sense codon reassignment known to date, is mediated by an ambiguous serine tRNA (tRNACAG(Ser)), exposes unanticipated flexibility of the genetic code and raises major questions about its selection and fixation in this fungal lineage. In particular, the origin of the tRNACAG(Ser) and the evolutionary mechanism of CUG reassignment from Leu to Ser remain poorly understood. In this study, we have traced the origin of the tDNACAG(Ser) gene and studied critical mutations in the tRNACAG(Ser) anticodon-loop that modulated CUG reassignment. Our data show that the tRNACAG(Ser) emerged from insertion of an adenosine in the middle position of the 5'-CGA-3'anticodon of a tRNACGA(Ser) ancestor, producing the 5'-CAG-3' anticodon of the tRNACAG(Ser), without altering its aminoacylation properties. This mutation initiated CUG reassignment while two additional mutations in the anticodon-loop resolved a structural conflict produced by incorporation of the Leu 5'-CAG-3'anticodon in the anticodon-arm of a tRNA(Ser). Expression of the mutant tRNACAG(Ser) in yeast showed that it cannot be expressed at physiological levels and we postulate that such downregulation was essential to maintain Ser misincorporation at sub-lethal levels during the initial stages of CUG reassignment. We demonstrate here that such low level CUG ambiguity is advantageous in specific ecological niches and we propose that misreading tRNAs are targeted for degradation by an unidentified tRNA quality control pathway.

  2. Molecular reconstruction of a fungal genetic code alteration

    PubMed Central

    Mateus, Denisa D.; Paredes, João A.; Español, Yaiza; Ribas de Pouplana, Lluís; Moura, Gabriela R.; Santos, Manuel A.S.

    2013-01-01

    Fungi of the CTG clade translate the Leu CUG codon as Ser. This genetic code alteration is the only eukaryotic sense-to-sense codon reassignment known to date, is mediated by an ambiguous serine tRNA (tRNACAGSer), exposes unanticipated flexibility of the genetic code and raises major questions about its selection and fixation in this fungal lineage. In particular, the origin of the tRNACAGSer and the evolutionary mechanism of CUG reassignment from Leu to Ser remain poorly understood. In this study, we have traced the origin of the tDNACAGSer gene and studied critical mutations in the tRNACAGSer anticodon-loop that modulated CUG reassignment. Our data show that the tRNACAGSer emerged from insertion of an adenosine in the middle position of the 5′-CGA-3′anticodon of a tRNACGASer ancestor, producing the 5′-CAG-3′ anticodon of the tRNACAGSer, without altering its aminoacylation properties. This mutation initiated CUG reassignment while two additional mutations in the anticodon-loop resolved a structural conflict produced by incorporation of the Leu 5′-CAG-3′anticodon in the anticodon-arm of a tRNASer. Expression of the mutant tRNACAGSer in yeast showed that it cannot be expressed at physiological levels and we postulate that such downregulation was essential to maintain Ser misincorporation at sub-lethal levels during the initial stages of CUG reassignment. We demonstrate here that such low level CUG ambiguity is advantageous in specific ecological niches and we propose that misreading tRNAs are targeted for degradation by an unidentified tRNA quality control pathway. PMID:23619021

  3. Addition of electrophilic lipids to actin alters filament structure

    SciTech Connect

    Gayarre, Javier; Sanchez, David; Sanchez-Gomez, Francisco J.; Terron, Maria C.; Llorca, Oscar; Perez-Sala, Dolores . E-mail: dperezsala@cib.csic.es

    2006-11-03

    Pathophysiological processes associated with oxidative stress lead to the generation of reactive lipid species. Among them, lipids bearing unsaturated aldehyde or ketone moieties can form covalent adducts with cysteine residues and modulate protein function. Through proteomic techniques we have identified actin as a target for the addition of biotinylated analogs of the cyclopentenone prostaglandins 15-deoxy-{delta}{sup 12,14}-PGJ{sub 2} (15d-PGJ{sub 2}) and PGA{sub 1} in NIH-3T3 fibroblasts. This modification could take place in vitro and mapped to the protein C-terminal end. Other electrophilic lipids, like the isoprostane 8-iso-PGA{sub 1} and 4-hydroxy-2-nonenal, also bound to actin. The C-terminal region of actin is important for monomer-monomer interactions and polymerization. Electron microscopy showed that actin treated with 15d-PGJ{sub 2} or 4-hydroxy-2-nonenal formed filaments which were less abundant and displayed shorter length and altered structure. Streptavidin-gold staining allowed mapping of biotinylated 15d-PGJ{sub 2} at sites of filament disruption. These results shed light on the structural implications of actin modification by lipid electrophiles.

  4. Addition of electrophilic lipids to actin alters filament structure.

    PubMed

    Gayarre, Javier; Sánchez, David; Sánchez-Gómez, Francisco J; Terrón, María C; Llorca, Oscar; Pérez-Sala, Dolores

    2006-11-03

    Pathophysiological processes associated with oxidative stress lead to the generation of reactive lipid species. Among them, lipids bearing unsaturated aldehyde or ketone moieties can form covalent adducts with cysteine residues and modulate protein function. Through proteomic techniques we have identified actin as a target for the addition of biotinylated analogs of the cyclopentenone prostaglandins 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and PGA(1) in NIH-3T3 fibroblasts. This modification could take place in vitro and mapped to the protein C-terminal end. Other electrophilic lipids, like the isoprostane 8-iso-PGA(1) and 4-hydroxy-2-nonenal, also bound to actin. The C-terminal region of actin is important for monomer-monomer interactions and polymerization. Electron microscopy showed that actin treated with 15d-PGJ(2) or 4-hydroxy-2-nonenal formed filaments which were less abundant and displayed shorter length and altered structure. Streptavidin-gold staining allowed mapping of biotinylated 15d-PGJ(2) at sites of filament disruption. These results shed light on the structural implications of actin modification by lipid electrophiles.

  5. Genetic alterations in salivary gland cancers.

    PubMed

    Yin, Linda X; Ha, Patrick K

    2016-06-15

    Salivary gland cancers are an incredibly heterogeneous group of tumors that include 24 histologically distinct tumor types. The use of new genetic methods has paved the way for promising advancements in our understanding of the molecular biology underlying each type of tumor. The objective of this review was to highlight common oncogenes, tumor suppressor genes, and cytogenetic and epigenetic changes associated with the most common tumor types: mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, mammary analogue secretory carcinoma, hyalinizing clear cell carcinoma, carcinoma ex pleomorphic adenoma, and acinic cell carcinoma. Recent insights into the pathogenesis of each cancer subtype have helped better define and classify these tumors. Further research in salivary gland cancers should focus on determining the key genes involved in the tumorigenesis of each distinct malignancy and identifying individualized chemotherapies directed at these targets. Cancer 2016;122:1822-31. © 2016 American Cancer Society.

  6. Genetic alterations of HER genes in chromophobe renal cell carcinoma

    PubMed Central

    WENG, WEN HUI; CHEN, YING TZU; YU, KAI JIE; CHANG, YING HSU; CHUANG, CHENG KENG; PANG, SEE TONG

    2016-01-01

    Chromophobe (ch) renal cell carcinoma (RCC) is the 3rd most common subtype of RCC and occurs in 5% of all RCCs. Although chRCC generally demonstrates more favorable outcomes compared with other subtypes of RCC, there is a 6–7% probability of tumor progression and metastasis in this disease. The subclassification of a more aggressive subtype of chRCC may be useful for the management of this cancer. The Erb-B2 receptor tyrosine kinase 2 [also known as human epidermal growth factor receptor (HER) 2] gene has been reported to be important in chRCC. The present study aimed to further investigate the abnormalities of the HER family genes and their potential association with chRCC. Fluorescence in situ hybridization was performed on 11 chRCC tissue specimens, and the Spearman's rank correlation coefficient analysis was used to assess the results. The loss of one copy of the HER2 and HER4 genes was observed to be the major alteration of the tumor cells in all chRCC cases. Statistical data indicated that loss of the HER2 gene was strongly correlated with loss of the HER4 gene (P=0.019). The findings of previous studies were also combined for analysis, and were consistent with those of the present study. In addition, the amplification of HER1 was also strongly correlated with the amplification of HER4 (P=0.004). Furthermore, a high percentage of genetic structural rearrangements was observed in HER3 genes, which was significantly associated with amplification of HER2 (P=0.005). Certain alterations in the HER gene family were also noted as a phenomenom in chRCC. Therefore, the characterization of the underlying aberrant functions of HER genes may be of interest for additional studies in the context of using HER genes to distinguish between RCC subtypes in order to establish improved treatment guidelines. PMID:26998131

  7. Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations.

    PubMed

    Nishida, Naoshi; Kudo, Masatoshi

    Accumulation of genetic and epigenetic alterations is a hallmark of cancer genomes, including those in hepatocellular carcinoma (HCC). Particularly, in human HCC, epigenetic changes are more frequently observed than genetic changes in a variety of cancer-related genes, suggesting a potential role for epigenetic alterations during hepatocarcinogenesis. Several environmental factors, such as inflammation, obesity, and steatosis, are reported to affect the epigenetic status in hepatocytes, which could play a role in HCC development. In addition, genetic mutations in histone modulators and chromatin regulators would be critical for the acceleration of epigenetic alteration. It is also possible that major genetic mutations of HCC, such as TP53 and CNTTB1 mutations, are associated with the disturbance of epigenetic integrity. For example, specific TP53 mutations frequently induced by aflatoxin B1 exposure might affect histone modifiers and nucleosome remodelers. Generally, epigenetic alteration is reversible, because of which dysregulation of transcription takes place, without affecting protein structure. Therefore, differentiation therapy is one of the potential approaches for HCC with advanced epigenetic alterations. On the other hand, a tumor carrying an accumulation of genetic mutations would result in many abnormal proteins that could be recognized as non-self and could be targets for immune reactions; thus, immune-checkpoint blockers should be effective for HCCs with genetic hypermutation. Although the emergence of genetic and epigenetic alterations could be linked to each other and there could be some crossover or convergence between these cancer pathways, characterization of the mutation spectrum of genetic and epigenetic alterations could influence future HCC treatment.

  8. Genetic/molecular alterations of meningiomas and the signaling pathways targeted

    PubMed Central

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2015-01-01

    Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features. PMID:25965831

  9. The Expression of Additive and Nonadditive Genetic Variation under Stress

    PubMed Central

    Blows, M. W.; Sokolowski, M. B.

    1995-01-01

    Experimental lines of Drosophila melanogaster derived from a natural population, which had been isolated in the laboratory for ~70 generations, were crossed to determine if the expression of additive, dominance and epistatic genetic variation in development time and viability was associated with the environment. No association was found between the level of additive genetic effects and environmental value for either trait, but nonadditive genetic effects increased at both extremes of the environmental range for development time. The expression of high levels of dominance and epistatic genetic variation at environmental extremes may be a general expectation for some traits. The disruption of the epistatic gene complexes in the parental lines resulted in hybrid breakdown toward faster development and there was some indication of hybrid breakdown toward higher viability. A combination of genetic drift and natural selection had therefore resulted in different epistatic gene complexes being selected after ~70 generations from a common genetic base. After crossing, the hybrid populations were observed for 10 generations. Epistasis contributed on average 12 hr in development time. Fluctuating asymmetry in sternopleural bristle number also evolved in the hybrid populations, decreasing by >18% in the first seven generations after hybridization. PMID:7672585

  10. Addition of Cryoprotectant Significantly Alters the Epididymal Sperm Proteome

    PubMed Central

    Yoon, Sung-Jae; Rahman, Md Saidur; Kwon, Woo-Sung; Park, Yoo-Jin; Pang, Myung-Geol

    2016-01-01

    Although cryopreservation has been developed and optimized over the past decades, it causes various stresses, including cold shock, osmotic stress, and ice crystal formation, thereby reducing fertility. During cryopreservation, addition of cryoprotective agent (CPA) is crucial for protecting spermatozoa from freezing damage. However, the intrinsic toxicity and osmotic stress induced by CPA cause damage to spermatozoa. To identify the effects of CPA addition during cryopreservation, we assessed the motility (%), motion kinematics, capacitation status, and viability of epididymal spermatozoa using computer-assisted sperm analysis and Hoechst 33258/chlortetracycline fluorescence staining. Moreover, the effects of CPA addition were also demonstrated at the proteome level using two-dimensional electrophoresis. Our results demonstrated that CPA addition significantly reduced sperm motility (%), curvilinear velocity, viability (%), and non-capacitated spermatozoa, whereas straightness and acrosome-reacted spermatozoa increased significantly (p < 0.05). Ten proteins were differentially expressed (two decreased and eight increased) (>3 fold, p < 0.05) after CPA, whereas NADH dehydrogenase flavoprotein 2, f-actin-capping protein subunit beta, superoxide dismutase 2, and outer dense fiber protein 2 were associated with several important signaling pathways (p < 0.05). The present study provides a mechanistic basis for specific cryostresses and potential markers of CPA-induced stress. Therefore, these might provide information about the development of safe biomaterials for cryopreservation and basic ground for sperm cryopreservation. PMID:27031703

  11. Additive and nonadditive genetic variation in avian personality traits.

    PubMed

    van Oers, K; Drent, P J; de Jong, G; van Noordwijk, A J

    2004-11-01

    Individuals of all vertebrate species differ consistently in their reactions to mildly stressful challenges. These typical reactions, described as personalities or coping strategies, have a clear genetic basis, but the structure of their inheritance in natural populations is almost unknown. We carried out a quantitative genetic analysis of two personality traits (exploration and boldness) and the combination of these two traits (early exploratory behaviour). This study was carried out on the lines resulting from a two-directional artificial selection experiment on early exploratory behaviour (EEB) of great tits (Parus major) originating from a wild population. In analyses using the original lines, reciprocal F(1) and reciprocal first backcross generations, additive, dominance, maternal effects ands sex-dependent expression of exploration, boldness and EEB were estimated. Both additive and dominant genetic effects were important determinants of phenotypic variation in exploratory behaviour and boldness. However, no sex-dependent expression was observed in either of these personality traits. These results are discussed with respect to the maintenance of genetic variation in personality traits, and the expected genetic structure of other behavioural and life history traits in general.

  12. Genetic Alterations in Hungarian Patients with Papillary Thyroid Cancer.

    PubMed

    Tobiás, Bálint; Halászlaki, Csaba; Balla, Bernadett; Kósa, János P; Árvai, Kristóf; Horváth, Péter; Takács, István; Nagy, Zsolt; Horváth, Evelin; Horányi, János; Járay, Balázs; Székely, Eszter; Székely, Tamás; Győri, Gabriella; Putz, Zsuzsanna; Dank, Magdolna; Valkusz, Zsuzsanna; Vasas, Béla; Iványi, Béla; Lakatos, Péter

    2016-01-01

    The incidence of thyroid cancers is increasing worldwide. Some somatic oncogene mutations (BRAF, NRAS, HRAS, KRAS) as well as gene translocations (RET/PTC, PAX8/PPAR-gamma) have been associated with the development of thyroid cancer. In our study, we analyzed these genetic alterations in 394 thyroid tissue samples (197 papillary carcinomas and 197 healthy). The somatic mutations and translocations were detected by Light Cycler melting method and Real-Time Polymerase Chain Reaction techniques, respectively. In tumorous samples, 86 BRAF (44.2%), 5 NRAS (3.1%), 2 HRAS (1.0%) and 1 KRAS (0.5%) mutations were found, as well as 9 RET/PTC1 (4.6%) and 1 RET/PTC3 (0.5%) translocations. No genetic alteration was seen in the non tumorous control thyroid tissues. No correlation was detected between the genetic variants and the pathological subtypes of papillary cancer as well as the severity of the disease. Our results are only partly concordant with the data found in the literature.

  13. Additional mechanisms conferring genetic susceptibility to Alzheimer’s disease

    PubMed Central

    Calero, Miguel; Gómez-Ramos, Alberto; Calero, Olga; Soriano, Eduardo; Avila, Jesús; Medina, Miguel

    2015-01-01

    Familial Alzheimer’s disease (AD), mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1, and PSEN2) involved in the production of the amyloid β peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies there is a mounting list of genetic risk factors associated with common genetic variants that have been associated with sporadic AD. Besides apolipoprotein E, that presents a strong association with the disease (OR∼4), the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated with AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways, and networks rather than the contribution of specific genes. PMID:25914626

  14. Safety assessment of genetically modified plants with deliberately altered composition.

    PubMed

    Halford, Nigel G; Hudson, Elizabeth; Gimson, Amy; Weightman, Richard; Shewry, Peter R; Tompkins, Steven

    2014-08-01

    The development and marketing of 'novel' genetically modified (GM) crops in which composition has been deliberately altered poses a challenge to the European Union (EU)'s risk assessment processes, which are based on the concept of substantial equivalence with a non-GM comparator. This article gives some examples of these novel GM crops and summarizes the conclusions of a report that was commissioned by the European Food Safety Authority on how the EU's risk assessment processes could be adapted to enable their safety to be assessed.

  15. Safety assessment of genetically modified plants with deliberately altered composition

    PubMed Central

    Halford, Nigel G; Hudson, Elizabeth; Gimson, Amy; Weightman, Richard; Shewry, Peter R; Tompkins, Steven

    2014-01-01

    The development and marketing of ‘novel’ genetically modified (GM) crops in which composition has been deliberately altered poses a challenge to the European Union (EU)'s risk assessment processes, which are based on the concept of substantial equivalence with a non-GM comparator. This article gives some examples of these novel GM crops and summarizes the conclusions of a report that was commissioned by the European Food Safety Authority on how the EU's risk assessment processes could be adapted to enable their safety to be assessed. PMID:24735114

  16. DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer.

    PubMed

    Samuelsson, Johanna K; Alonso, Sergio; Yamamoto, Fumiichiro; Perucho, Manuel

    2010-11-10

    Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in carcinogenesis. Epigenetic regulation mechanisms underlie the maintenance of cell identity crucial for development and differentiation. These epigenetic regulatory mechanisms have been found substantially altered during cancer development and progression. In this review, we discuss approaches designed to analyze genetic and epigenetic alterations in colorectal cancer, especially DNA fingerprinting approaches to detect changes in DNA copy number and methylation. DNA fingerprinting techniques, despite their modest throughput, played a pivotal role in significant discoveries in the molecular basis of colorectal cancer. The aim of this review is to revisit the fingerprinting technologies employed and the oncogenic processes that they unveiled.

  17. How the Magnitude of Prey Genetic Variation Alters Predator-Prey Eco-Evolutionary Dynamics.

    PubMed

    Cortez, Michael H

    2016-09-01

    Evolution can alter the stability and dynamics of ecological communities; for example, prey evolution can drive cyclic dynamics in predator-prey systems that are not possible in the absence of evolution. However, it is unclear how the magnitude of additive genetic variation in the evolving species mediates those effects. In this study, I explore how the magnitude of prey additive genetic variation determines what effects prey evolution has on the dynamics and stability of predator-prey systems. I use linear stability analysis to decompose the stability of a general eco-evolutionary predator-prey model into components representing the stabilities of the ecological and evolutionary subsystems as well as the interactions between those subsystems. My results show that with low genetic variation, the cyclic dynamics and stability of the system are determined by the ecological subsystem. With increased genetic variation, disruptive selection always destabilizes stable communities, stabilizing selection can stabilize or destabilize communities, and prey evolution can alter predator-prey phase lags. Stability changes occur approximately when the magnitude of genetic variation balances the (in)stabilities of the ecological and evolutionary subsystems. I discuss the connections between my stability results and prior results from the theory of adaptive dynamics.

  18. Research to support sterile-male-release and genetic alteration techniques for sea lamprey control

    USGS Publications Warehouse

    Bergstedt, Roger A.; Twohey, Michael B.

    2007-01-01

    Integrated pest management of sea lampreys in the Laurentian Great Lakes has recently been enhanced by addition of a sterile-male-release program, and future developments in genetic approaches may lead to additional methods for reducing sea lamprey reproduction. We review the development, implementation, and evaluation of the sterile-male-release technique (SMRT) as it is being applied against sea lampreys in the Great Lakes, review the current understanding of SMRT efficacy, and identify additional research areas and topics that would increase either the efficacy of the SMRT or expand its geographic potential for application. Key areas for additional research are in the sterilization process, effects of skewed sex ratios on mating behavior, enhancing attractiveness of sterilized males, techniques for genetic alteration of sea lampreys, and sources of animals to enhance or expand the use of sterile lampreys.

  19. Efficient Improvement of Silage Additives by Using Genetic Algorithms

    PubMed Central

    Davies, Zoe S.; Gilbert, Richard J.; Merry, Roger J.; Kell, Douglas B.; Theodorou, Michael K.; Griffith, Gareth W.

    2000-01-01

    The enormous variety of substances which may be added to forage in order to manipulate and improve the ensilage process presents an empirical, combinatorial optimization problem of great complexity. To investigate the utility of genetic algorithms for designing effective silage additive combinations, a series of small-scale proof of principle silage experiments were performed with fresh ryegrass. Having established that significant biochemical changes occur over an ensilage period as short as 2 days, we performed a series of experiments in which we used 50 silage additive combinations (prepared by using eight bacterial and other additives, each of which was added at six different levels, including zero [i.e., no additive]). The decrease in pH, the increase in lactate concentration, and the free amino acid concentration were measured after 2 days and used to calculate a “fitness” value that indicated the quality of the silage (compared to a control silage made without additives). This analysis also included a “cost” element to account for different total additive levels. In the initial experiment additive levels were selected randomly, but subsequently a genetic algorithm program was used to suggest new additive combinations based on the fitness values determined in the preceding experiments. The result was very efficient selection for silages in which large decreases in pH and high levels of lactate occurred along with low levels of free amino acids. During the series of five experiments, each of which comprised 50 treatments, there was a steady increase in the amount of lactate that accumulated; the best treatment combination was that used in the last experiment, which produced 4.6 times more lactate than the untreated silage. The additive combinations that were found to yield the highest fitness values in the final (fifth) experiment were assessed to determine a range of biochemical and microbiological quality parameters during full-term silage

  20. Efficient improvement of silage additives by using genetic algorithms.

    PubMed

    Davies, Z S; Gilbert, R J; Merry, R J; Kell, D B; Theodorou, M K; Griffith, G W

    2000-04-01

    The enormous variety of substances which may be added to forage in order to manipulate and improve the ensilage process presents an empirical, combinatorial optimization problem of great complexity. To investigate the utility of genetic algorithms for designing effective silage additive combinations, a series of small-scale proof of principle silage experiments were performed with fresh ryegrass. Having established that significant biochemical changes occur over an ensilage period as short as 2 days, we performed a series of experiments in which we used 50 silage additive combinations (prepared by using eight bacterial and other additives, each of which was added at six different levels, including zero [i.e. , no additive]). The decrease in pH, the increase in lactate concentration, and the free amino acid concentration were measured after 2 days and used to calculate a "fitness" value that indicated the quality of the silage (compared to a control silage made without additives). This analysis also included a "cost" element to account for different total additive levels. In the initial experiment additive levels were selected randomly, but subsequently a genetic algorithm program was used to suggest new additive combinations based on the fitness values determined in the preceding experiments. The result was very efficient selection for silages in which large decreases in pH and high levels of lactate occurred along with low levels of free amino acids. During the series of five experiments, each of which comprised 50 treatments, there was a steady increase in the amount of lactate that accumulated; the best treatment combination was that used in the last experiment, which produced 4.6 times more lactate than the untreated silage. The additive combinations that were found to yield the highest fitness values in the final (fifth) experiment were assessed to determine a range of biochemical and microbiological quality parameters during full-term silage fermentation. We

  1. Non-myogenic tumors display altered expression of dystrophin (DMD) and a high frequency of genetic alterations

    PubMed Central

    Luce, Leonela N.; Abbate, Mercedes

    2017-01-01

    DMD gene mutations have been associated with the development of Dystrophinopathies. Interestingly, it has been recently reported that DMD is involved in the development and progression of myogenic tumors, assigning DMD a tumor suppressor activity in these types of cancer. However, there are only few reports that analyze DMD in non-myogenic tumors. Our study was designed to examine DMD expression and genetic alterations in non-myogenic tumors using public repositories. We also evaluated the overall survival of patients with and without DMD mutations. We studied 59 gene expression microarrays (GEO database) and RNAseq (cBioPortal) datasets that included 9817 human samples. We found reduced DMD expression in 15/27 (56%) pairwise comparisons performed (Fold-Change (FC) ≤ 0.70; p-value range = 0.04-1.5×10−20). The analysis of RNAseq studies revealed a median frequency of DMD genetic alterations of 3.4%, higher or similar to other well-known tumor suppressor genes. In addition, we observed significant poorer overall survival for patients with DMD mutations. The analyses of paired tumor/normal tissues showed that the majority of tumor specimens had lower DMD expression compared to their normal adjacent counterpart. Interestingly, statistical significant over-expression of DMD was found in 6/27 studies (FC ≥ 1.4; p-value range = 0.03-3.4×10−15). These results support that DMD expression and genetic alterations are frequent and relevant in non-myogenic tumors. The study and validation of DMD as a new player in tumor development and as a new prognostic factor for tumor progression and survival are warranted. PMID:27391342

  2. Genetic alterations in Krebs cycle and its impact on cancer pathogenesis.

    PubMed

    Sajnani, Karishma; Islam, Farhadul; Smith, Robert Anthony; Gopalan, Vinod; Lam, Alfred King-Yin

    2017-04-01

    Cancer cells exhibit alterations in many cellular processes, including oxygen sensing and energy metabolism. Glycolysis in non-oxygen condition is the main energy production process in cancer rather than mitochondrial respiration as in benign cells. Genetic and epigenetic alterations of Krebs cycle enzymes favour the shift of cancer cells from oxidative phosphorylation to anaerobic glycolysis. Mutations in genes encoding aconitase, isocitrate dehydrogenase, succinate dehydrogenase, fumarate hydratase, and citrate synthase are noted in many cancers. Abnormalities of Krebs cycle enzymes cause ectopic production of Krebs cycle intermediates (oncometabolites) such as 2-hydroxyglutarate, and citrate. These oncometabolites stabilize hypoxia inducible factor 1 (HIF1), nuclear factor like 2 (Nrf2), inhibit p53 and prolyl hydroxylase 3 (PDH3) activities as well as regulate DNA/histone methylation, which in turn activate cell growth signalling. They also stimulate increased glutaminolysis, glycolysis and production of reactive oxygen species (ROS). Additionally, genetic alterations in Krebs cycle enzymes are involved with increased fatty acid β-oxidations and epithelial mesenchymal transition (EMT) induction. These altered phenomena in cancer could in turn promote carcinogenesis by stimulating cell proliferation and survival. Overall, epigenetic and genetic changes of Krebs cycle enzymes lead to the production of oncometabolite intermediates, which are important driving forces of cancer pathogenesis and progression. Understanding and applying the knowledge of these mechanisms opens new therapeutic options for patients with cancer.

  3. Imaging genetics in obsessive-compulsive disorder: linking genetic variations to alterations in neuroimaging.

    PubMed

    Grünblatt, Edna; Hauser, Tobias U; Walitza, Susanne

    2014-10-01

    Obsessive-compulsive disorder (OCD) occurs in ∼1-3% of the general population, and its often rather early onset causes major disabilities in the everyday lives of patients. Although the heritability of OCD is between 35 and 65%, many linkage, association, and genome-wide association studies have failed to identify single genes that exhibit high effect sizes. Several neuroimaging studies have revealed structural and functional alterations mainly in cortico-striato-thalamic loops. However, there is also marked heterogeneity across studies. These inconsistencies in genetic and neuroimaging studies may be due to the heterogeneous and complex phenotypes of OCD. Under the consideration that genetic variants may also influence neuroimaging in OCD, researchers have started to combine both domains in the field of imaging genetics. Here, we conducted a systematic search of PubMed and Google Scholar literature for articles that address genetic imaging in OCD and related disorders (published through March 2014). We selected 8 publications that describe the combination of imaging genetics with OCD, and extended it with 43 publications of comorbid psychiatric disorders. The most promising findings of this systematic review point to the involvement of variants in genes involved in the serotonergic (5-HTTLPR, HTR2A), dopaminergic (COMT, DAT), and glutamatergic (SLC1A1, SAPAP) systems. However, the field of imaging genetics must be further explored, best through investigations that combine multimodal imaging techniques with genetic profiling, particularly profiling techniques that employ polygenetic approaches, with much larger sample sizes than have been used up to now.

  4. Non-additive and additive genetic effects on extraversion in 3314 Dutch adolescent twins and their parents.

    PubMed

    Rettew, David C; Rebollo-Mesa, Irene; Hudziak, James J; Willemsen, Gonneke; Boomsma, Dorret I

    2008-05-01

    The influence of non-additive genetic influences on personality traits has been increasingly reported in adult populations. Less is known, however, with respect to younger samples. In this study, we examine additive and non-additive genetic contributions to the personality trait of extraversion in 1,689 Dutch twin pairs, 1,505 mothers and 1,637 fathers of the twins. The twins were on average 15.5 years (range 12-18 years). To increase statistical power to detect non-additive genetic influences, data on extraversion were also collected in parents and simultaneously analyzed. Genetic modeling procedures incorporating age as a potential modifier of heritability showed significant influences of additive (20-23%) and non-additive genetic factors (31-33%) in addition to unshared environment (46-48%) for adolescents and for their parents. The additive genetic component was slightly and positively related to age. No significant sex differences were found for either extraversion means or for the magnitude of the genetic and environmental influences. There was no evidence of non-random mating for extraversion in the parental generation. Results show that in addition to additive genetic influences, extraversion in adolescents is influenced by non-additive genetic factors.

  5. Detected microsatellite polymorphisms in genetically altered inbred mouse strains.

    PubMed

    Du, Xiaoyan; Cui, Jing; Wang, Chao; Huo, Xueyun; Lu, Jing; Li, Yichen; Chen, Zhenwen

    2013-08-01

    Microsatellites are 50-200 repetitive DNA sequences composed of 1- to 6-base-pair-long reiterative motifs within the genome. They are vulnerable to DNA modifications, such as recombination and/or integration, and are recognized as "sentinel" DNA. Our previous report indicated that the genotypes of the microsatellite loci could change from mono- to poly-morphisms (CMP) in gene knockout (KO) mice, implying that genetic modification induces microsatellite mutation. However, it is still unclear whether the random insertion of DNA fragments into mice genomes produced via transgene (Tg) or N-ethyl-N-nitrosourea (ENU) would also result in microsatellite mutations or microsatellite loci genotypes changes. This study was designed to find possible clues to answer this question. In brief, 198 microsatellite loci that were distributed among almost all of the chromosomes (except for the Y) were examined through polymerase chain reaction to screen possible CMPs in six Tg strains. First, for each strain, the microsatellite sequences of all loci were compared between Tg and the corresponding background strain to exclude genetic interference. Simultaneously, to exclude spontaneous mutation-related CMPs that might exist in the examined six strains, mice from five spontaneously mutated inbred strains were used as the negative controls. Additionally, the sequences of all loci in these spontaneous mutated mice were compared to corresponding genetic background controls. The results showed that 40 of the 198 (20.2%) loci were identified as having CMPs in the examined Tg mice strains. The CMP genotypes were either homozygous or heterozygous compared to the background controls. Next, we applied the 40 CMP positive loci in ENU-mutated mice and their corresponding background controls. After that, a general comparison of CMPs that exist among Tg, ENU-treated and KO mouse strains was performed. The results indicated that four (D11mit258, D13mit3, D14mit102 and DXmit172) of the 40 (10%) CMP

  6. Image-based computational quantification and visualization of genetic alterations and tumour heterogeneity

    PubMed Central

    Zhong, Qing; Rüschoff, Jan H.; Guo, Tiannan; Gabrani, Maria; Schüffler, Peter J.; Rechsteiner, Markus; Liu, Yansheng; Fuchs, Thomas J.; Rupp, Niels J.; Fankhauser, Christian; Buhmann, Joachim M.; Perner, Sven; Poyet, Cédric; Blattner, Miriam; Soldini, Davide; Moch, Holger; Rubin, Mark A.; Noske, Aurelia; Rüschoff, Josef; Haffner, Michael C.; Jochum, Wolfram; Wild, Peter J.

    2016-01-01

    Recent large-scale genome analyses of human tissue samples have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions (PTEN) and amplifications (19q12, HER2) in diverse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility. PMID:27052161

  7. Curious cases: Altered dose-response relationships in addiction genetics.

    PubMed

    Uhl, George R; Drgonova, Jana; Hall, F Scott

    2014-03-01

    Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics.

  8. ICLAS Working Group on Harmonization: international guidance concerning the production care and use of genetically-altered animals.

    PubMed

    Rose, M; Everitt, J; Hedrich, H; Schofield, J; Dennis, M; Scott, E; Griffin, G

    2013-07-01

    Replacement, Reduction and Refinement, the ‘Three Rs’ of Russell & Burch, are accepted worldwide as fundamental to the ethics of animal experimentation. The production, care and use of genetically-altered animals can pose particular challenges to the implementation of the Three Rs,1 necessitating additional considerations by those responsible for overseeing the ethical use and appropriate care of animals involved in science. The International Council for Laboratory Animal Science brings representatives of the international laboratory animal science community together to recommend acceptance of guidance documents.The harmonization of guidance concerning genetically-altered animals was seen as a priority because of the increasing globalization of research involving these animals.

  9. Impact of Zn, Mg, Ni and Co elements on glass alteration: Additive effects

    NASA Astrophysics Data System (ADS)

    Aréna, H.; Godon, N.; Rébiscoul, D.; Podor, R.; Garcès, E.; Cabie, M.; Mestre, J.-P.

    2016-03-01

    The minor elements present in the nuclear glass composition or coming from the groundwater of the future repository may impact glass alteration. In this study, the effects of Zn, Mg, Ni and Co on the International Simple Glass (ISG) alteration were studied throughout 511 days of aqueous leaching experiments. The aim was to determine their additive or competitive effect on glass alteration and the nature of the alteration products. The four elements were introduced separately or altogether in solution as XCl2 chloride salts (X = Zn, Mg, Ni or Co) with monthly additions to compensate for their consumption. The alteration kinetics were determined by leachate analyses (ICP-AES) and alteration products were characterized in terms of composition, morphology and microstructure (SEM, TEM-EDX, ToF-SIMS and XRD). Results indicate that when they are introduced separately, Zn, Mg, Ni and Co have the same qualitative and quantitative effect on glass alteration kinetics and on pH: they form secondary phases leading to a pH decrease and a significant increase in glass alteration. The secondary phases were identified as silicates of the added X element: trioctahedral smectites with a stoichiometry of[(Si(4-a) Ala) (X(3-b) Alb) O10 (OH)2](a+b)- [Xc Nad Cae] (2c+d+2e) + with a = 0.11 to 0.45, b = 0.00 to 0.29, c = 0, d = 0.19 to 0.74 and e = 0.10 to 0.14. . It was shown that as pH stabilizes at a minimum value, X-silicates no longer precipitate, thus leading to a significant drop in the glass alteration rate. This pH value depends on X and it has been identified as being 8 for Mg-silicates, probably around 7.3 for Ni and Co-silicates and less than 6.2 for Zn-silicates. When tested together, the effects of these four elements on glass alteration are additive and lead to the formation of a mix of X-silicates that precipitate as long as their constitutive elements are available and the pH is above their respective minimum value. This study brings new quantitative information about the

  10. Genetic alterations in lung adenocarcinoma with a micropapillary component

    PubMed Central

    FURUKAWA, MASASHI; TOYOOKA, SHINICHI; ICHIMURA, KOUICHI; YAMAMOTO, HIROMASA; SOH, JUNICHI; HASHIDA, SHINSUKE; OUCHIDA, MAMORU; SHIEN, KAZUHIKO; ASANO, HIROAKI; TSUKUDA, KAZUNORI; MIYOSHI, SHINICHIRO

    2016-01-01

    Pulmonary adenocarcinoma (PA) with a micropapillary component (PA-MPC) is known as an aggressive subtype of PA. The molecular profiles of PA-MPC have not been well characterized. the pathological reports of patients who underwent surgical resection for lung cancer between April, 2004 and May, 2012 were reviewed. Of the 674 patients diagnosed with PA, 28 were found to have MPC. A total of 138 resected PAs without MPC were selected in the same period to serve as age-, gender- and smoking status-matched controls to the PA-MPC group. Mutational status was determined by the following two methods: SNaPshot assay based on multiplex polymerase chain reaction (PCR), primer extension and capillary electrophoresis that was designed to assess 38 somatic mutations in 8 genes [AKT1, BRAF, endothelial growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), mitogen-activated protein kinase kinase 1, neuroblastoma RAS viral oncogene homolog, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α (PIK3CA) and phosphatase and tensin homolog]; and a PCR-based sizing assay that assesses EGFR exon 19 (deletions), EGFR exon 20 (insertions) and human epidermal growth factor receptor 2 exon 20 (insertions). echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion gene (EML4-ALK) was screened by ALK immunohistochemistry and confirmed using the reverse transcription PCR assay and the break-apart fluorescence in situ hybridization assay. Regarding genetic alterations, 13 (46.4%) of the 28 PA-MPCs harbored mutually exclusive mutations: 9 (32.1%) EGFR mutations, 1 (3.6%) KRAS mutation and 3 (10.7%) EML4-ALK fusion genes. PAs without MPC harbored 42 (30.4%) EGFR mutations, 17 (12.3%) KRAS mutations, 3 (2.2%) EML4-ALK fusion genes and 1 (0.7%) PIK3CA mutation. EML4-ALK fusion genes appeared to occur significantly more frequently in PA-MPCs compared with PAs without MPC (P=0.027). Although the sample size was small, our study

  11. The hyperactive syndrome: metanalysis of genetic alterations, pharmacological treatments and brain lesions which increase locomotor activity.

    PubMed

    Viggiano, Davide

    2008-12-01

    The large number of transgenic mice realized thus far with different purposes allows addressing new questions, such as which animals, over the entire set of transgenic animals, show a specific behavioural abnormality. In the present study, we have used a metanalytical approach to organize a database of genetic modifications, brain lesions and pharmacological interventions that increase locomotor activity in animal models. To further understand the resulting data set, we have organized a second database of the alterations (genetic, pharmacological or brain lesions) that reduce locomotor activity. Using this approach, we estimated that 1.56% of the genes in the genome yield to hyperactivity and 0.75% of genes produce hypoactivity when altered. These genes have been classified into genes for neurotransmitter systems, hormonal, metabolic systems, ion channels, structural proteins, transcription factors, second messengers and growth factors. Finally, two additional classes included animals with neurodegeneration and inner ear abnormalities. The analysis of the database revealed several unexpected findings. First, the genes that, when mutated, induce hyperactive behaviour do not pertain to a single neurotransmitter system. In fact, alterations in most neurotransmitter systems can give rise to a hyperactive phenotype. In contrast, fewer changes can decrease locomotor activity. Specifically, genetic and pharmacological alterations that enhance the dopamine, orexin, histamine, cannabinoids systems or that antagonize the cholinergic system induce an increase in locomotor activity. Similarly, imbalances in the two main neurotransmitters of the nervous system, GABA and glutamate usually result in hyperactive behaviour. It is remarkable that no genetic alterations pertaining to the GABA system have been reported to reduce locomotor behaviour. Other neurotransmitters, such as norepinephrine and serotonin, have a more complex influence. For instance, a decrease in norepinephrine

  12. Premalignant Genetic and Epigenetic Alterations in Tubal Epithelium from Women with BRCA1 Mutations

    DTIC Science & Technology

    2010-10-14

    Premalignant Genetic and Epigenetic Alterations in Tubal Epithelium from Women with BRCA1 Mutations PRINCIPAL INVESTIGATOR: Anton Krumm, Ph.D...REPORT TYPE 3. DATES COVERED (From - To) 15 Sept 2009 – 14 Sept 2010 4. TITLE AND SUBTITLE Premalignant Genetic and Epigenetic Alterations in Tubal 5a...Appendices…………………………………………………………………………… 8-33 10/14/2010 Anton Krumm 1 Premalignant Genetic and Epigenetic Alterations in Tubal Epithelium from Women

  13. Genetic Assessment of Additional Endophenotypes from the Consortium on the Genetics of Schizophrenia Family Study

    PubMed Central

    Greenwood, Tiffany A.; Lazzeroni, Laura C.; Calkins, Monica E.; Freedman, Robert; Green, Michael F.; Gur, Raquel E.; Gur, Ruben C.; Light, Gregory A.; Nuechterlein, Keith H.; Olincy, Ann; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Stone, William S.; Sugar, Catherine A.; Swerdlow, Neal R.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Braff, David L.

    2015-01-01

    The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. PMID:26597662

  14. Augmented genetic decoding: global, local and temporal alterations of decoding processes and codon meaning.

    PubMed

    Baranov, Pavel V; Atkins, John F; Yordanova, Martina M

    2015-09-01

    The non-universality of the genetic code is now widely appreciated. Codes differ between organisms, and certain genes are known to alter the decoding rules in a site-specific manner. Recently discovered examples of decoding plasticity are particularly spectacular. These examples include organisms and organelles with disruptions of triplet continuity during the translation of many genes, viruses that alter the entire genetic code of their hosts and organisms that adjust their genetic code in response to changing environments. In this Review, we outline various modes of alternative genetic decoding and expand existing terminology to accommodate recently discovered manifestations of this seemingly sophisticated phenomenon.

  15. Additive genetic contribution to symptom dimensions in major depressive disorder.

    PubMed

    Pearson, Rahel; Palmer, Rohan H C; Brick, Leslie A; McGeary, John E; Knopik, Valerie S; Beevers, Christopher G

    2016-05-01

    Major depressive disorder (MDD) is a phenotypically heterogeneous disorder with a complex genetic architecture. In this study, genomic-relatedness-matrix restricted maximum-likelihood analysis (GREML) was used to investigate the extent to which variance in depression symptoms/symptom dimensions can be explained by variation in common single nucleotide polymorphisms (SNPs) in a sample of individuals with MDD (N = 1,558) who participated in the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A principal components analysis of items from the Hamilton Rating Scale for Depression (HRSD) obtained prior to treatment revealed 4 depression symptom components: (a) appetite, (b) core depression symptoms (e.g., depressed mood, anhedonia), (c) insomnia, and (d) anxiety. These symptom dimensions were associated with SNP-based heritability (hSNP2) estimates of 30%, 14%, 30%, and 5%, respectively. Results indicated that the genetic contribution of common SNPs to depression symptom dimensions were not uniform. Appetite and insomnia symptoms in MDD had a relatively strong genetic contribution whereas the genetic contribution was relatively small for core depression and anxiety symptoms. While in need of replication, these results suggest that future gene discovery efforts may strongly benefit from parsing depression into its constituent parts. (PsycINFO Database Record

  16. Nitrogen Addition Altered the Effect of Belowground C Allocation on Soil Respiration in a Subtropical Forest

    PubMed Central

    He, Tongxin; Wang, Qingkui; Wang, Silong; Zhang, Fangyue

    2016-01-01

    The availabilities of carbon (C) and nitrogen (N) in soil play an important role in soil carbon dioxide (CO2) emission. However, the variation in the soil respiration (Rs) and response of microbial community to the combined changes in belowground C and N inputs in forest ecosystems are not yet fully understood. Stem girdling and N addition were performed in this study to evaluate the effects of C supply and N availability on Rs and soil microbial community in a subtropical forest. The trees were girdled on 1 July 2012. Rs was monitored from July 2012 to November 2013, and soil microbial community composition was also examined by phospholipid fatty acids (PLFAs) 1 year after girdling. Results showed that Rs decreased by 40.5% with girdling alone, but N addition only did not change Rs. Interestingly, Rs decreased by 62.7% under the girdling with N addition treatment. The reducing effect of girdling and N addition on Rs differed between dormant and growing seasons. Girdling alone reduced Rs by 33.9% in the dormant season and 54.8% in the growing season compared with the control. By contrast, girdling with N addition decreased Rs by 59.5% in the dormant season and 65.4% in the growing season. Girdling and N addition significantly decreased the total and bacterial PLFAs. Moreover, the effect of N addition was greater than girdling. Both girdling and N addition treatments separated the microbial groups on the basis of the first principal component through principal component analysis compared with control. This indicated that girdling and N addition changed the soil microbial community composition. However, the effect of girdling with N addition treatment separated the microbial groups on the basis of the second principal component compared to N addition treatment, which suggested N addition altered the effect of girdling on soil microbial community composition. These results suggest that the increase in soil N availability by N deposition alters the effect of

  17. Cancer type-dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types

    PubMed Central

    Park, Solip; Lehner, Ben

    2015-01-01

    Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or unrecognized cancer subtypes. Rather, it suggests that how genomic alterations interact cooperatively or partially redundantly to driver cancer changes in different types of cancers. This re-wiring of epistasis across cell types is likely to be a basic feature of genetic architecture, with important implications for understanding the evolution of multicellularity and human genetic diseases. In addition, if this plasticity of epistasis across cell types is also true for synthetic lethal interactions, a synthetic lethal strategy to kill cancer cells may frequently work in one type of cancer but prove ineffective in another. PMID:26227665

  18. Genetically altered mice for evaluation of mode-of-action (MOA)

    EPA Science Inventory

    Genetically altered mice for evaluation of mode-of-action (MOA). Barbara D. Abbott, Cynthia J. Wolf, Kaberi P. Das, Christopher S. Lau. (Presented by B. Abbott). This presentation provides an example of the use of genetically modified mice to determine the mode-of-action of r...

  19. Genetic Evolution of Shape-Altering Programs for Supersonic Aerodynamics

    NASA Technical Reports Server (NTRS)

    Kennelly, Robert A., Jr.; Bencze, Daniel P. (Technical Monitor)

    2002-01-01

    Two constrained shape optimization problems relevant to aerodynamics are solved by genetic programming, in which a population of computer programs evolves automatically under pressure of fitness-driven reproduction and genetic crossover. Known optimal solutions are recovered using a small, naive set of elementary operations. Effectiveness is improved through use of automatically defined functions, especially when one of them is capable of a variable number of iterations, even though the test problems lack obvious exploitable regularities. An attempt at evolving new elementary operations was only partially successful.

  20. Genetic Alterations in Medullary Thyroid Cancer: Diagnostic and Prognostic Markers

    PubMed Central

    A, Taccaliti; F, Silvetti; G, Palmonella; M, Boscaro

    2011-01-01

    Medullary thyroid carcinoma (MTC) is a rare calcitonin producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, with consequently essential roles in cell survival, differentiation and proliferation. Somatic or germline mutations of the RET gene play an important role in this neoplasm in development of sporadic and familial forms, respectively. Genetic diagnosis has an important role in differentiating sporadic from familiar MTC. Furthermore, depending on the location of the mutation, patients can be classified into risk classes. Therefore, genetic screening of the RET gene plays a critical role not only in diagnosis but also in assessing the prognosis and course of MTC. PMID:22654561

  1. How Obstacles Perturb Population Fronts and Alter Their Genetic Structure

    PubMed Central

    Möbius, Wolfram; Murray, Andrew W.; Nelson, David R.

    2015-01-01

    As populations spread into new territory, environmental heterogeneities can shape the population front and genetic composition. We focus here on the effects of an important building block of heterogeneous environments, isolated obstacles. With a combination of experiments, theory, and simulation, we show how isolated obstacles both create long-lived distortions of the front shape and amplify the effect of genetic drift. A system of bacteriophage T7 spreading on a spatially heterogeneous Escherichia coli lawn serves as an experimental model system to study population expansions. Using an inkjet printer, we create well-defined replicates of the lawn and quantitatively study the population expansion of phage T7. The transient perturbations of the population front found in the experiments are well described by a model in which the front moves with constant speed. Independent of the precise details of the expansion, we show that obstacles create a kink in the front that persists over large distances and is insensitive to the details of the obstacle’s shape. The small deviations between experimental findings and the predictions of the constant speed model can be understood with a more general reaction-diffusion model, which reduces to the constant speed model when the obstacle size is large compared to the front width. Using this framework, we demonstrate that frontier genotypes just grazing the side of an isolated obstacle increase in abundance, a phenomenon we call ‘geometry-enhanced genetic drift’, complementary to the founder effect associated with spatial bottlenecks. Bacterial range expansions around nutrient-poor barriers and stochastic simulations confirm this prediction. The effect of the obstacle on the genealogy of individuals at the front is characterized by simulations and rationalized using the constant speed model. Lastly, we consider the effect of two obstacles on front shape and genetic composition of the population illuminating the effects

  2. Salt additions alter short-term nitrogen and carbon mobilization in a coastal Oregon Andisol.

    PubMed

    Compton, Jana E; Church, M Robbins

    2011-01-01

    Deposition of sea salts is commonly elevated along the coast relative to inland areas, yet little is known about the effects on terrestrial ecosystem biogeochemistry. We examined the influence of NaCl concentrations on N, C, and P leaching from a coastal Oregon forest Andisol in two laboratory studies: a rapid batch extraction (approximately 1 d) and a month-long incubation using microlysimeters. In the rapid extractions, salt additions immediately mobilized significant amounts of ammonium and phosphate but not nitrate. In the month-long incubations, salt additions at concentrations in the range of coastal precipitation increased nitrate leaching from the microcosms by nearly 50% and reduced the mobility of dissolved organic carbon. Our findings suggest that coupled abiotic-biotic effects increase nitrate mobility in these soils: exchange of sodium for ammonium, then net nitrification. Changes in sea salt deposition to land and the interactions with coastal soils could alter the delivery of N and C to sensitive coastal waters.

  3. The Unilateral Mean Luminance Alters Additive Internal Noise in Normal Vision.

    PubMed

    Li, Lin; Yu, Yongqiang; Zhou, Yifeng

    2015-01-01

    Luminance has been found to play a modulating role in the processes of many visual tasks. However, the mechanisms underlying the modulation role of luminance have been little studied, and the conclusions have been controversial. Here, using a dichoptic viewing paradigm by varying the luminance in one eye while measuring the contrast-detection threshold in the other eye, we studied the effect of different unilateral mean luminance values on the detectability of sine wave gratings against backgrounds of various levels of white noise in normal subjects. We found that unilateral luminance altered the additive internal noise within a perceptual template model framework, with low luminance increasing the additive internal noise and high luminance reducing it. This finding helps to reveal how luminance modulates contrast detection and its relative mechanisms.

  4. Somatic retrotransposition alters the genetic landscape of the human brain

    PubMed Central

    Baillie, J. Kenneth; Barnett, Mark W.; Upton, Kyle R.; Gerhardt, Daniel J.; Richmond, Todd A.; De Sapio, Fioravante; Brennan, Paul; Rizzu, Patrizia; Smith, Sarah; Fell, Mark; Talbot, Richard T.; Gustincich, Stefano; Freeman, Thomas C.; Mattick, John S.; Hume, David A.; Heutink, Peter; Carninci, Piero; Jeddeloh, Jeffrey A.; Faulkner, Geoffrey J.

    2011-01-01

    Retrotransposons are mobile genetic elements that employ a germ line “copy-and-paste” mechanism to spread throughout metazoan genomes1. At least 50% of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease2-3. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells4-5, excluding early embryo development and some malignancies6-7. Recent reports of L1 expression8-9 and copy number variation10-11 (CNV) in the human brain suggest L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germ line mutations, as well as 7,743 putative somatic L1 insertions in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 and 1,350 somatic Alu and SVA insertions, respectively. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes. PMID:22037309

  5. Chromosomal and genetic alterations in human hepatocellular adenomas associated with type Ia glycogen storage disease.

    PubMed

    Kishnani, Priya S; Chuang, Tzu-Po; Bali, Deeksha; Koeberl, Dwight; Austin, Stephanie; Weinstein, David A; Murphy, Elaine; Chen, Ying-Ting; Boyette, Keri; Liu, Chu-Hao; Chen, Yuan-Tsong; Li, Ling-Hui

    2009-12-15

    Hepatocellular adenoma (HCA) is a frequent long-term complication of glycogen storage disease type I (GSD I) and malignant transformation to hepatocellular carcinoma (HCC) is known to occur in some cases. However, the molecular pathogenesis of tumor development in GSD I is unclear. This study was conducted to systematically investigate chromosomal and genetic alterations in HCA associated with GSD I. Genome-wide SNP analysis and mutation detection of target genes was performed in ten GSD Ia-associated HCA and seven general population HCA cases for comparison. Chromosomal aberrations were detected in 60% of the GSD Ia HCA and 57% of general population HCA. Intriguingly, simultaneous gain of chromosome 6p and loss of 6q were only seen in GSD Ia HCA (three cases) with one additional GSD I patient showing submicroscopic 6q14.1 deletion. The sizes of GSD Ia adenomas with chromosome 6 aberrations were larger than the sizes of adenomas without the changes (P = 0.012). Expression of IGF2R and LATS1 candidate tumor suppressor genes at 6q was reduced in more than 50% of GSD Ia HCA that were examined (n = 7). None of the GSD Ia HCA had biallelic mutations in the HNF1A gene. These findings give the first insight into the distinct genomic and genetic characteristics of HCA associated with GSD Ia. These results strongly suggest that chromosome 6 alterations could be an early event in the liver tumorigenesis in GSD I, and may be in general population. These results also suggest an interesting relationship between GSD Ia HCA and steps to HCC transformation.

  6. A Molecular Genetic Basis Explaining Altered Bacterial Behavior in Space

    PubMed Central

    Prasad, Nripesh; Levy, Shawn E.; Stodieck, Louis; Jones, Angela; Shrestha, Shristi; Klaus, David

    2016-01-01

    Bacteria behave differently in space, as indicated by reports of reduced lag phase, higher final cell counts, enhanced biofilm formation, increased virulence, and reduced susceptibility to antibiotics. These phenomena are theorized, at least in part, to result from reduced mass transport in the local extracellular environment, where movement of molecules consumed and excreted by the cell is limited to diffusion in the absence of gravity-dependent convection. However, to date neither empirical nor computational approaches have been able to provide sufficient evidence to confirm this explanation. Molecular genetic analysis findings, conducted as part of a recent spaceflight investigation, support the proposed model. This investigation indicated an overexpression of genes associated with starvation, the search for alternative energy sources, increased metabolism, enhanced acetate production, and other systematic responses to acidity—all of which can be associated with reduced extracellular mass transport. PMID:27806055

  7. Melanoma: From Melanocyte to Genetic Alterations and Clinical Options

    PubMed Central

    Bertolotto, Corine

    2013-01-01

    Metastatic melanoma remained for decades without any effective treatment and was thus considered as a paradigm of cancer resistance. Recent progress with understanding of the molecular mechanisms underlying melanoma initiation and progression revealed that melanomas are genetically and phenotypically heterogeneous tumors. This recent progress has allowed for the development of treatment able to improve for the first time the overall disease-free survival of metastatic melanoma patients. However, clinical responses are still either too transient or limited to restricted patient subsets. The complete cure of metastatic melanoma therefore remains a challenge in the clinic. This review aims to present the recent knowledge and discoveries of the molecular mechanisms involved in melanoma pathogenesis and their exploitation into clinic that have recently facilitated bench to bedside advances. PMID:24416617

  8. Additive and non-additive genetic components of the jack male life history in Chinook salmon (Oncorhynchus tshawytscha).

    PubMed

    Forest, Adriana R; Semeniuk, Christina A D; Heath, Daniel D; Pitcher, Trevor E

    2016-08-01

    Chinook salmon, Oncorhynchus tshawytscha, exhibit alternative reproductive tactics (ARTs) where males exist in two phenotypes: large "hooknose" males and smaller "jacks" that reach sexual maturity after only 1 year in seawater. The mechanisms that determine "jacking rate"-the rate at which males precociously sexually mature-are known to involve both genetics and differential growth rates, where individuals that become jacks exhibit higher growth earlier in life. The additive genetic components have been studied and it is known that jack sires produce significantly more jack offspring than hooknose sires, and vice versa. The current study was the first to investigate both additive and non-additive genetic components underlying jacking through the use of a full-factorial breeding design using all hooknose sires. The effect of dams and sires descendant from a marker-assisted broodstock program that identified "high performance" and "low performance" lines using growth- and survival-related gene markers was also studied. Finally, the relative growth of jack, hooknose, and female offspring was examined. No significant dam, sire, or interaction effects were observed in this study, and the maternal, additive, and non-additive components underlying jacking were small. Differences in jacking rates in this study were determined by dam performance line, where dams that originated from the low performance line produced significantly more jacks. Jack offspring in this study had a significantly larger body size than both hooknose males and females starting 1 year post-fertilization. This study provides novel information regarding the genetic architecture underlying ARTs in Chinook salmon that could have implications for the aquaculture industry, where jacks are not favoured due to their small body size and poor flesh quality.

  9. A genetic code alteration generates a proteome of high diversity in the human pathogen Candida albicans

    PubMed Central

    Gomes, Ana C; Miranda, Isabel; Silva, Raquel M; Moura, Gabriela R; Thomas, Benjamin; Akoulitchev, Alexandre; Santos, Manuel AS

    2007-01-01

    Background Genetic code alterations have been reported in mitochondrial, prokaryotic, and eukaryotic cytoplasmic translation systems, but their evolution and how organisms cope and survive such dramatic genetic events are not understood. Results Here we used an unusual decoding of leucine CUG codons as serine in the main human fungal pathogen Candida albicans to elucidate the global impact of genetic code alterations on the proteome. We show that C. albicans decodes CUG codons ambiguously and tolerates partial reversion of their identity from serine back to leucine on a genome-wide scale. Conclusion Such codon ambiguity expands the proteome of this human pathogen exponentially and is used to generate important phenotypic diversity. This study highlights novel features of C. albicans biology and unanticipated roles for codon ambiguity in the evolution of the genetic code. PMID:17916231

  10. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.

    PubMed

    Soejima, Hidenobu; Higashimoto, Ken

    2013-07-01

    Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders.

  11. Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner.

    PubMed

    Lachance-Touchette, Pamela; Choudhury, Mayukh; Stoica, Ana; Di Cristo, Graziella; Cossette, Patrick

    2014-01-01

    Mutations in genes encoding for GABAA receptor subunits is a well-established cause of genetic generalized epilepsy. GABA neurotransmission is implicated in several developmental processes including neurite outgrowth and synapse formation. Alteration in excitatory/inhibitory synaptic activities plays a critical role in epilepsy, thus here we investigated whether mutations in α1 subunit of GABAA receptor may affect dendritic spine and GABAergic bouton formation. In particular, we examined the effects of three mutations of the GABRA1 gene (D219N, A322D and K353delins18X) that were found in a cohort of French Canadian families with genetic generalized epilepsy. We used a novel single-cell genetic approach, by preparing cortical organotypic cultures from GABRA1 (flox/flox) mice and simultaneously inactivating endogenous GABRA1 and transfecting mutant α1 subunits in single glutamatergic pyramidal cells and basket GABAergic interneurons by biolistic transfection. We found that GABRA1 (-/-) GABAergic cells showed reduced innervation field, which was rescued by co-expressing α1-A322D and α1-WT but not α1-D219N. We further found that the expression of the most severe GABRA1 missense mutation (α1-A322D) induced a striking increase of spine density in pyramidal cells along with an increase in the number of mushroom-like spines. In addition, α1-A322D expression in GABAergic cells slightly increased perisomatic bouton density, whereas other mutations did not alter bouton formation. All together, these results suggest that the effects of different GABAAR mutations on GABAergic bouton and dendritic spine formation are specific to the mutation and cannot be always explained by a simple loss-of-function gene model. The use of single cell genetic manipulation in organotypic cultures may provide a better understanding of the specific and distinct neural circuit alterations caused by different GABAA receptor subunit mutations and will help define the pathophysiology of genetic

  12. Single-cell genetic expression of mutant GABAA receptors causing Human genetic epilepsy alters dendritic spine and GABAergic bouton formation in a mutation-specific manner

    PubMed Central

    Lachance-Touchette, Pamela; Choudhury, Mayukh; Stoica, Ana; Di Cristo, Graziella; Cossette, Patrick

    2014-01-01

    Mutations in genes encoding for GABAA receptor subunits is a well-established cause of genetic generalized epilepsy. GABA neurotransmission is implicated in several developmental processes including neurite outgrowth and synapse formation. Alteration in excitatory/inhibitory synaptic activities plays a critical role in epilepsy, thus here we investigated whether mutations in α1 subunit of GABAA receptor may affect dendritic spine and GABAergic bouton formation. In particular, we examined the effects of three mutations of the GABRA1 gene (D219N, A322D and K353delins18X) that were found in a cohort of French Canadian families with genetic generalized epilepsy. We used a novel single-cell genetic approach, by preparing cortical organotypic cultures from GABRA1flox/flox mice and simultaneously inactivating endogenous GABRA1 and transfecting mutant α1 subunits in single glutamatergic pyramidal cells and basket GABAergic interneurons by biolistic transfection. We found that GABRA1−/− GABAergic cells showed reduced innervation field, which was rescued by co-expressing α1-A322D and α1-WT but not α1-D219N. We further found that the expression of the most severe GABRA1 missense mutation (α1-A322D) induced a striking increase of spine density in pyramidal cells along with an increase in the number of mushroom-like spines. In addition, α1-A322D expression in GABAergic cells slightly increased perisomatic bouton density, whereas other mutations did not alter bouton formation. All together, these results suggest that the effects of different GABAAR mutations on GABAergic bouton and dendritic spine formation are specific to the mutation and cannot be always explained by a simple loss-of-function gene model. The use of single cell genetic manipulation in organotypic cultures may provide a better understanding of the specific and distinct neural circuit alterations caused by different GABAA receptor subunit mutations and will help define the pathophysiology of genetic

  13. Linking neocortical, cognitive, and genetic variability in autism with alterations of brain plasticity: the Trigger-Threshold-Target model.

    PubMed

    Mottron, Laurent; Belleville, Sylvie; Rouleau, Guy A; Collignon, Olivier

    2014-11-01

    The phenotype of autism involves heterogeneous adaptive traits (strengths vs. disabilities), different domains of alterations (social vs. non-social), and various associated genetic conditions (syndromic vs. nonsyndromic autism). Three observations suggest that alterations in experience-dependent plasticity are an etiological factor in autism: (1) the main cognitive domains enhanced in autism are controlled by the most plastic cortical brain regions, the multimodal association cortices; (2) autism and sensory deprivation share several features of cortical and functional reorganization; and (3) genetic mutations and/or environmental insults involved in autism all appear to affect developmental synaptic plasticity, and mostly lead to its upregulation. We present the Trigger-Threshold-Target (TTT) model of autism to organize these findings. In this model, genetic mutations trigger brain reorganization in individuals with a low plasticity threshold, mostly within regions sensitive to cortical reallocations. These changes account for the cognitive enhancements and reduced social expertise associated with autism. Enhanced but normal plasticity may underlie non-syndromic autism, whereas syndromic autism may occur when a triggering mutation or event produces an altered plastic reaction, also resulting in intellectual disability and dysmorphism in addition to autism. Differences in the target of brain reorganization (perceptual vs. language regions) account for the main autistic subgroups. In light of this model, future research should investigate how individual and sex-related differences in synaptic/regional brain plasticity influence the occurrence of autism.

  14. The Evolution of Human Intelligence and the Coefficient of Additive Genetic Variance in Human Brain Size

    ERIC Educational Resources Information Center

    Miller, Geoffrey F.; Penke, Lars

    2007-01-01

    Most theories of human mental evolution assume that selection favored higher intelligence and larger brains, which should have reduced genetic variance in both. However, adult human intelligence remains highly heritable, and is genetically correlated with brain size. This conflict might be resolved by estimating the coefficient of additive genetic…

  15. Ontogeny of additive and maternal genetic effects: lessons from domestic mammals.

    PubMed

    Wilson, Alastair J; Reale, Denis

    2006-01-01

    Evolution of size and growth depends on heritable variation arising from additive and maternal genetic effects. Levels of heritable (and nonheritable) variation might change over ontogeny, increasing through "variance compounding" or decreasing through "compensatory growth." We test for these processes using a meta-analysis of age-specific weight traits in domestic ungulates. Generally, mean standardized variance components decrease with age, consistent with compensatory growth. Phenotypic convergence among adult sheep occurs through decreasing environmental and maternal genetic variation. Maternal variation similarly declines in cattle. Maternal genetic effects are thus reduced with age (both in absolute and relative terms). Significant trends in heritability (decreasing in cattle, increasing in sheep) result from declining maternal and environmental components rather than from changing additive variation. There was no evidence for increasing standardized variance components. Any compounding must therefore be masked by more important compensatory processes. While extrapolation of these patterns to processes in natural population is difficult, our results highlight the inadequacy of assuming constancy in genetic parameters over ontogeny. Negative covariance between direct and maternal genetic effects was common. Negative correlations with additive and maternal genetic variances indicate that antagonistic pleiotropy (between additive and maternal genetic effects) may maintain genetic variance and limit responses to selection.

  16. Nitrogen addition alters elemental stoichiometry within soil aggregates in a temperate steppe

    NASA Astrophysics Data System (ADS)

    Yin, Jinfei; Wang, Ruzhen; Liu, Heyong; Feng, Xue; Xu, Zhuwen; Jiang, Yong

    2016-11-01

    Ongoing increases in anthropogenic nitrogen (N) inputs have largely affected soil carbon (C) and nutrient cycling in most terrestrial ecosystems. Numerous studies have concerned the effects of elevated N inputs on soil dissolved organic carbon (DOC), dissolved inorganic N (DIN), available phosphorus (AP), exchangeable calcium (Ca) and magnesium (Mg), and available iron (Fe) and manganese (Mn). However, few have emphasized the stoichiometric traits of these soil parameters, especially within different soil aggregate fractions. In a semiarid grassland of Inner Mongolia, we studied the effect of N addition on the ratios of DOC : DIN, DOC : AP, DIN : AP, exchangeable Ca : Mg, available Fe : Mn within three soil aggregate classes of large macroaggregates (> 2000 µm), small macroaggregates (250-2000 µm), and microaggregates (< 250 µm). Elevated N inputs significantly decreased the DOC : DIN ratio within three soil aggregates. The soil DOC : AP ratio significantly decreased along with increasing N gradients within large macroaggregates and microaggregates. Nitrogen significantly decreased the ratio of exchangeable Ca : Mg within soil macroaggregates. The ratio of available Fe : Mn decreased with N addition within three soil aggregate classes. Alteration of elemental stoichiometry within soil fractions that are characterized by different nutrient retention capacity will influence the chemical composition of soil microorganisms and plant quality.

  17. Accounting for additive genetic mutations on litter size in Ripollesa sheep.

    PubMed

    Casellas, J; Caja, G; Piedrafita, J

    2010-04-01

    Little is known about mutational variability in livestock, among which only a few mutations with relatively large effects have been reported. In this manuscript, mutational variability was analyzed in 1,765 litter size records from 404 Ripollesa ewes to characterize the magnitude of this genetic source of variation and check the suitability of including mutational effects in genetic evaluations of this breed. Threshold animal models accounting for additive genetic mutations were preferred to models without mutational contributions, with an average difference in the deviance information criterion of more than 5 units. Moreover, the statistical relevance of the additive genetic mutation term was checked through a Bayes factor approach, which showed that the models with mutational variability were 8.5 to 22.7 times more probable than the others. The mutational heritability (percentage of the phenotypic variance accounted for by mutational variance) was 0.6 or 0.9%, depending on whether genetic dominance effects were accounted for by the analytical model. The inclusion of mutational effects in the genetic model for evaluating litter size in Ripollesa ewes called for some minor modifications in the genetic merit order of the individuals evaluated, which suggested that the continuous uploading of new additive mutations could be taken into account to optimize the selection scheme. This study is the first attempt to estimate mutational variances in a livestock species and thereby contribute to better characterization of the genetic background of productive traits of interest.

  18. Role of Genetic Alterations in the NLRP3 and CARD8 Genes in Health and Disease

    PubMed Central

    Paramel, G. V.; Sirsjö, A.; Fransén, K.

    2015-01-01

    The complexity of a common inflammatory disease is influenced by multiple genetic and environmental factors contributing to the susceptibility of disease. Studies have reported that these exogenous and endogenous components may perturb the balance of innate immune response by activating the NLRP3 inflammasome. The multimeric NLRP3 complex results in the caspase-1 activation and the release of potent inflammatory cytokines, like IL-1β. Several studies have been performed on the association of the genetic alterations in genes encoding NLRP3 and CARD8 with the complex diseases with inflammatory background, like inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis, and type 1 diabetes. The aim of the present review is therefore to summarize the literature regarding genetic alterations in these genes and their association with health and disease. PMID:25788762

  19. Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

    PubMed Central

    Czapiewski, Piotr; Kunc, Michał; Haybaeck, Johannes

    2016-01-01

    Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosis-related pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high- and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data. PMID:27256979

  20. Detection of complex genetic alterations in human glioblastoma multiforme using comparative genomic hybridization

    SciTech Connect

    Schlegel, J.; Stumm, G.; Scherthan, H.; Arens, N.

    1996-01-01

    The aim of the present study was to detect complex genetic alterations in human glioblastoma multiforme (GBM) by comparative genomic in situ hybridization (CGH). Of the 24 GBM that were examined, increased fluorescence intensities indicating chromosomal polysomy of chromosome 7 and gene amplification at chromosome 7p were found in 42% of the tumors. In addition, signal enhancement of chromosome 19 was present in 29% and at 12q13-15 in 21% of the tumors. We also detected reduction of fluorescence intensities indicating gross deletions on chromosomes 10 (58%), 9p (46%), and 13 (29%). There was a close correlation of CGH results when compared with Southern analysis of the EGFR gene localized on chromosome 7 and loss of heterozygosity detection of chromosome 9 and 10 by microsatellite PCR. A close correlation was also observed between copy number changes of chromosome 7 and deletions of chromosome 10. Amplification of chromosome 12q and deletions of chromosomes 9p and 13 seemed to be complementary in the tumors investigated in the present study. 44 refs., 3 figs., 1 tab.

  1. Utility of Dexrazoxane for the Attenuation of Epirubicin-Induced Genetic Alterations in Mouse Germ Cells

    PubMed Central

    Ahmad, Sheikh F.; Ansaria, Mushtaq A.; Nadeem, Ahmed; Al-Shabanah, Othman A.; Al-Harbi, Mohammed M.; Bakheet, Saleh A.

    2016-01-01

    Dexrazoxane has been approved to treat anthracycline-induced cardiomyopathy and extravasation. However, the effect of dexrazoxane on epirubicin-induced genetic alterations in germ cells has not yet been reported. Thus, the aim of this study was to determine whether dexrazoxane modulates epirubicin-induced genetic damage in the germ cells of male mice. Our results show that dexrazoxane was not genotoxic at the tested doses. Furthermore, it protected mouse germ cells against epirubicin-induced genetic alterations as detected by the reduction in disomic and diploid sperm, spermatogonial chromosomal aberrations, and abnormal sperm heads. The attenuating effect of dexrazoxane was greater at higher dose, indicating a dose-dependent effect. Moreover, sperm motility and count were ameliorated by dexrazoxane pretreatment. Epirubicin induced marked biochemical changes characteristic of oxidative DNA damage including elevated 8-hydroxy-2ʹ-deoxyguanosine levels and reduction in reduced glutathione. Pretreatment of mice with dexrazoxane before epirubicin challenge restored these altered endpoints. We conclude that dexrazoxane may efficiently mitigate the epirubicin insult in male germ cells, and prevent the enhanced risk of abnormal reproductive outcomes and associated health risks. Thus, pretreating patients with dexrazoxane prior to epirubicin may efficiently preserve not only sperm quality but also prevent the transmission of genetic damage to future generations. PMID:27690233

  2. Commentary on Zohar's "Prospects for 'genetic therapy' -- can a person benefit from being altered?

    PubMed

    Kahn, Jeffrey P

    1991-10-01

    In his paper on the effects of Prenatal Genetic Intervention (PGI) on personal identity, Noam Zohar comes to a conclusion about genetic makeup and the uses of gene therapy quite different from the one I reach in another piece in this issue. Zohar's argument rests on the contention that personal identity changes with alteration of the genome, following what I have identified as the "constitutive" view. To see that this is the pillar supporting the weight of his argument, consider the following. Questions of identity aside, how can it be that altering the genome of children suffering from Lesch-Nyhan syndrome or Tay-Sachs disease so that they now produce the enzyme that they formerly lacked does not benefit them? Clearly, if their identities were not changed, such individuals would in fact realize great benefit from PGI, since the devastating bad effects of the genetic flaw would be avoided. Such a change would certainly make the altered individuals better off, that is, it would benefit them. On this, Zohar and I do not disagree. Persistence of identity through such genetic change is the sticking point.

  3. Genetic findings in schizophrenia patients related to alterations in the intracellular Ca-homeostasis.

    PubMed

    Giegling, Ina; Genius, Just; Benninghoff, Jens; Rujescu, Dan

    2010-12-01

    There is a relatively high genetic heritability of schizophrenia as shown by family, twin and adoption studies. A large number of hypotheses on the causes of schizophrenia occurred over time. In this review we focus on genetic findings related to potential alterations of intracellular Ca-homeostasis in association with schizophrenia. First, we provide evidence for the NMDA/glutamatergic theory of schizophrenia including calcium processes. We mainly focus on genes including: DAO (D-amino acid oxidase), DAOA (D-amino acid oxidase activator), DTNBP1 (Dysbindin 1, dystrobrevin-binding protein 1), NRG1 (Neuregulin 1), ERBB4 (v-erb-a erythroblastic leukemia viral oncogene homolog 4, avian), NOS1 (nitric oxide synthase 1, neuronal) and NRGN (Neurogranin). Furthermore, a gene coding for a calcium channel subunit (CACNA1C: calcium channel, voltage-dependent, L type, alpha 1C subunit) is discussed in the light of schizophrenia whereas genetic findings related to alterations in the intracellular Ca-homeostasis associated specifically with dopaminergic and serotonergic neurotransmission in schizophrenia are not herein closer reviewed. Taken together there is converging evidence for the contribution of genes potentially related to alterations in intracellular Ca-homeostasis to the risk of schizophrenia. Replications and functional studies will hopefully provide further insight into these genetic variants and the underlying processes.

  4. Genetic analysis in post-mortem samples with micro-ischemic alterations.

    PubMed

    Campuzano, Oscar; Sanchez-Molero, Olallo; Mademont-Soler, Irene; Coll, Monica; Allegue, Catarina; Ferrer-Costa, Carles; Mates, Jesus; Perez-Serra, Alexandra; Del Olmo, Bernat; Iglesias, Anna; Sarquella-Brugada, Georgia; Brugada, Josep; Borondo, Juan Carlos; Castella, Josep; Medallo, Jordi; Brugada, Ramon

    2017-02-01

    Sudden cardiac arrest is a leading cause of death worldwide. Most cardiac arrests happen in patients who have previously suffered a myocardial infarct. The risk of sudden death after infarction may increase in people who carry a pathogenic genetic alteration in cardiac ion channels. We hypothesized that micro-ischemia could trigger lethal arrhythmogenesis, thus we sought to identify genetic alterations in cardiac ion channels in patients with micro-ischemic disease. We studied a cohort of 56 post-mortem samples. Autopsy studies identified myocardial infarction as the cause of death in each case. We used both Sanger sequencing and next-generation sequencing to screen candidate genes associated with sudden cardiac death. We identified six rare missense genetic variations in five unrelated patients. Two variants have been previously reported; one is associated with atrial fibrillation (SCN5A_p.H445D), and the other is predicted to be benign (ANK2_p.T2059M). The novel variants were predicted in silico as benign, except for one (RyR2_p.M4019T), which was classified as deleterious. Our post-mortem, micro-infarction cohort displayed a rate of nearly 10% non-common genetic variants. However, the clinical significance of most of the identified variants remains unknown due to lack of family assessment. Further analyses should be performed in large cohorts to clarify the role of ion-channel gene analysis in samples showing microscopic ischemic alterations.

  5. Estimation of Additive, Dominance, and Imprinting Genetic Variance Using Genomic Data

    PubMed Central

    Lopes, Marcos S.; Bastiaansen, John W. M.; Janss, Luc; Knol, Egbert F.; Bovenhuis, Henk

    2015-01-01

    Traditionally, exploration of genetic variance in humans, plants, and livestock species has been limited mostly to the use of additive effects estimated using pedigree data. However, with the development of dense panels of single-nucleotide polymorphisms (SNPs), the exploration of genetic variation of complex traits is moving from quantifying the resemblance between family members to the dissection of genetic variation at individual loci. With SNPs, we were able to quantify the contribution of additive, dominance, and imprinting variance to the total genetic variance by using a SNP regression method. The method was validated in simulated data and applied to three traits (number of teats, backfat, and lifetime daily gain) in three purebred pig populations. In simulated data, the estimates of additive, dominance, and imprinting variance were very close to the simulated values. In real data, dominance effects account for a substantial proportion of the total genetic variance (up to 44%) for these traits in these populations. The contribution of imprinting to the total phenotypic variance of the evaluated traits was relatively small (1–3%). Our results indicate a strong relationship between additive variance explained per chromosome and chromosome length, which has been described previously for other traits in other species. We also show that a similar linear relationship exists for dominance and imprinting variance. These novel results improve our understanding of the genetic architecture of the evaluated traits and shows promise to apply the SNP regression method to other traits and species, including human diseases. PMID:26438289

  6. The contribution of additive genetic variation to personality variation: heritability of personality.

    PubMed

    Dochtermann, Ned A; Schwab, Tori; Sih, Andrew

    2015-01-07

    Individual animals frequently exhibit repeatable differences from other members of their population, differences now commonly referred to as 'animal personality'. Personality differences can arise, for example, from differences in permanent environmental effects--including parental and epigenetic contributors--and the effect of additive genetic variation. Although several studies have evaluated the heritability of behaviour, less is known about general patterns of heritability and additive genetic variation in animal personality. As overall variation in behaviour includes both the among-individual differences that reflect different personalities and temporary environmental effects, it is possible for personality to be largely genetically influenced even when heritability of behaviour per se is quite low. The relative contribution of additive genetic variation to personality variation can be estimated whenever both repeatability and heritability are estimated for the same data. Using published estimates to address this issue, we found that approximately 52% of animal personality variation was attributable to additive genetic variation. Thus, while the heritability of behaviour is often moderate or low, the heritability of personality is much higher. Our results therefore (i) demonstrate that genetic differences are likely to be a major contributor to variation in animal personality and (ii) support the phenotypic gambit: that evolutionary inferences drawn from repeatability estimates may often be justified.

  7. Genetic algorithm-guided discovery of additive combinations that direct quantum dot assembly.

    PubMed

    Bawazer, Lukmaan A; Ihli, Johannes; Comyn, Timothy P; Critchley, Kevin; Empson, Christopher J; Meldrum, Fiona C

    2015-01-14

    The use of combinations of organic additives to control crystallization, as occurs in biomineralization, is rarely investigated due to the vast potential reaction space. It is demonstrated here that combinatorial approaches led by genetic algorithm heuristics can enable identification of active additive combinations, and four key organic molecules are rapidly identified, which generate highly fluorescent CdS quantum dot superstructures.

  8. Genetically modified animal models recapitulating molecular events altered in human hepatocarcinogenesis.

    PubMed

    Sánchez, Aránzazu; Fabregat, Isabel

    2009-04-01

    New advancements have been made in recent years in the understanding of the molecular mechanisms that govern human liver tumorigenesis. Experimental animal models have been widely used, especially mouse models. In this review we highlight some of the genetically engineered mouse models that have proved to be excellent tools to study the intracellular signalling pathways altered in hepatocarcinogenesis and establish potential correlations with data from humans, with special focus on hepatocellular carcinoma (HCC), the most common type of primary liver cancer. Information obtained from these animal models will help to design future therapeutic approaches to HCC, particularly those that explore drugs that specifically target the altered molecular pathways.

  9. A review of genetic alterations in the serotonin pathway and their correlation with psychotic diseases and response to atypical antipsychotics.

    PubMed

    Baou, Maria; Boumba, Vassiliki A; Petrikis, Petros; Rallis, Georgios; Vougiouklakis, Theodore; Mavreas, Venetsanos

    2016-01-01

    Serotonin is a neurotransmitter that plays a predominant role in mood regulation. The importance of the serotonin pathway in controlling behavior and mental status is well recognized. All the serotonin elements - serotonin receptors, serotonin transporter, tryptophan hydroxylase and monoamine oxidase proteins - can show alterations in terms of mRNA or protein levels and protein sequence, in schizophrenia and bipolar disorder. Additionally, when examining the genes sequences of all serotonin elements, several single nucleotide polymorphisms (SNPs) have been found to be more prevalent in schizophrenic or bipolar patients than in healthy individuals. Several of these alterations have been associated either with different phenotypes between patients and healthy individuals or with the response of psychiatric patients to the treatment with atypical antipsychotics. The complex pattern of genetic diversity within the serotonin pathway hampers efforts to identify the key variations contributing to an individual's susceptibility to the disease. In this review article, we summarize all genetic alterations found across the serotonin pathway, we provide information on whether and how they affect schizophrenia or bipolar disorder phenotypes, and, on the contribution of familial relationships on their detection frequencies. Furthermore, we provide evidence on whether and how specific gene polymorphisms affect the outcome of schizophrenic or bipolar patients of different ethnic groups, in response to treatment with atypical antipsychotics. All data are discussed thoroughly, providing prospective for future studies.

  10. Genetic Alterations in Prostate Cancers among African-American Men and Comparisons with Cancers from European and Asian Patients

    DTIC Science & Technology

    2015-10-01

    1 AWARD NUMBER: W81XWH-14-1-0303 TITLE: Genetic Alterations in Prostate Cancers among African-American Men and Comparisons with Cancers from...REPORT TYPE Annual 3. DATES COVERED 29 Sep 2014 – 28 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Genetic Alterations in Prostate Cancers... genetics 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON USAMRMC a. REPORT U b

  11. Generation of Infectious Poliovirus with Altered Genetic Information from Cloned cDNA.

    PubMed

    Bujaki, Erika

    2016-01-01

    The effect of specific genetic alterations on virus biology and phenotype can be studied by a great number of available assays. The following method describes the basic protocol to generate infectious poliovirus with altered genetic information from cloned cDNA in cultured cells.The example explained here involves generation of a recombinant poliovirus genome by simply replacing a portion of the 5' noncoding region with a synthetic gene by restriction cloning. The vector containing the full length poliovirus genome and the insert DNA with the known mutation(s) are cleaved for directional cloning, then ligated and transformed into competent bacteria. The recombinant plasmid DNA is then propagated in bacteria and transcribed to RNA in vitro before RNA transfection of cultured cells is performed. Finally, viral particles are recovered from the cell culture.

  12. Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification

    PubMed Central

    Bezerra, Ana R.; Simões, João; Lee, Wanseon; Rung, Johan; Weil, Tobias; Gut, Ivo G.; Gut, Marta; Bayés, Mónica; Rizzetto, Lisa; Cavalieri, Duccio; Giovannini, Gloria; Bozza, Silvia; Romani, Luigina; Kapushesky, Misha; Moura, Gabriela R.; Santos, Manuel A. S.

    2013-01-01

    Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research. PMID:23776239

  13. Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification.

    PubMed

    Bezerra, Ana R; Simões, João; Lee, Wanseon; Rung, Johan; Weil, Tobias; Gut, Ivo G; Gut, Marta; Bayés, Mónica; Rizzetto, Lisa; Cavalieri, Duccio; Giovannini, Gloria; Bozza, Silvia; Romani, Luigina; Kapushesky, Misha; Moura, Gabriela R; Santos, Manuel A S

    2013-07-02

    Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research.

  14. Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture

    PubMed Central

    Monir, Md. Mamun; Zhu, Jun

    2017-01-01

    Most of the genome-wide association studies (GWASs) for human complex diseases have ignored dominance, epistasis and ethnic interactions. We conducted comparative GWASs for total cholesterol using full model and additive models, which illustrate the impacts of the ignoring genetic variants on analysis results and demonstrate how genetic effects of multiple loci could differ across different ethnic groups. There were 15 quantitative trait loci with 13 individual loci and 3 pairs of epistasis loci identified by full model, whereas only 14 loci (9 common loci and 5 different loci) identified by multi-loci additive model. Again, 4 full model detected loci were not detected using multi-loci additive model. PLINK-analysis identified two loci and GCTA-analysis detected only one locus with genome-wide significance. Full model identified three previously reported genes as well as several new genes. Bioinformatics analysis showed some new genes are related with cholesterol related chemicals and/or diseases. Analyses of cholesterol data and simulation studies revealed that the full model performs were better than the additive-model performs in terms of detecting power and unbiased estimations of genetic variants of complex traits. PMID:28079101

  15. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  16. Product versus additive threshold models for analysis of reproduction outcomes in animal genetics.

    PubMed

    David, I; Bodin, L; Gianola, D; Legarra, A; Manfredi, E; Robert-Granié, C

    2009-08-01

    The phenotypic observation of some reproduction traits (e.g., insemination success, interval from lambing to insemination) is the result of environmental and genetic factors acting on 2 individuals: the male and female involved in a mating couple. In animal genetics, the main approach (called additive model) proposed for studying such traits assumes that the phenotype is linked to a purely additive combination, either on the observed scale for continuous traits or on some underlying scale for discrete traits, of environmental and genetic effects affecting the 2 individuals. Statistical models proposed for studying human fecundability generally consider reproduction outcomes as the product of hypothetical unobservable variables. Taking inspiration from these works, we propose a model (product threshold model) for studying a binary reproduction trait that supposes that the observed phenotype is the product of 2 unobserved phenotypes, 1 for each individual. We developed a Gibbs sampling algorithm for fitting a Bayesian product threshold model including additive genetic effects and showed by simulation that it is feasible and that it provides good estimates of the parameters. We showed that fitting an additive threshold model to data that are simulated under a product threshold model provides biased estimates, especially for individuals with high breeding values. A main advantage of the product threshold model is that, in contrast to the additive model, it provides distinct estimates of fixed effects affecting each of the 2 unobserved phenotypes.

  17. Common genetic variants, acting additively, are a major source of risk for autism

    PubMed Central

    2012-01-01

    Background Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. Methods By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. Results By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. Conclusions Our results, when viewed in the context of results from genome

  18. Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

    PubMed Central

    Chowdhury, Susmita; Henneman, Lidewij; Dent, Tom; Hall, Alison; Burton, Alice; Pharoah, Paul; Pashayan, Nora; Burton, Hilary

    2015-01-01

    There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention. PMID:26068647

  19. Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

    PubMed

    Chowdhury, Susmita; Henneman, Lidewij; Dent, Tom; Hall, Alison; Burton, Alice; Pharoah, Paul; Pashayan, Nora; Burton, Hilary

    2015-06-09

    There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention.

  20. Additive genetic breeding values correlate with the load of partially deleterious mutations.

    PubMed

    Tomkins, Joseph L; Penrose, Marissa A; Greeff, Johan; LeBas, Natasha R

    2010-05-14

    The mutation-selection-balance model predicts most additive genetic variation to arise from numerous mildly deleterious mutations of small effect. Correspondingly, "good genes" models of sexual selection and recent models for the evolution of sex are built on the assumption that mutational loads and breeding values for fitness-related traits are correlated. In support of this concept, inbreeding depression was negatively genetically correlated with breeding values for traits under natural and sexual selection in the weevil Callosobruchus maculatus. The correlations were stronger in males and strongest for condition. These results confirm the role of existing, partially recessive mutations in maintaining additive genetic variation in outbred populations, reveal the nature of good genes under sexual selection, and show how sexual selection can offset the cost of sex.

  1. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology.

    PubMed

    Qaddoumi, Ibrahim; Orisme, Wilda; Wen, Ji; Santiago, Teresa; Gupta, Kirti; Dalton, James D; Tang, Bo; Haupfear, Kelly; Punchihewa, Chandanamali; Easton, John; Mulder, Heather; Boggs, Kristy; Shao, Ying; Rusch, Michael; Becksfort, Jared; Gupta, Pankaj; Wang, Shuoguo; Lee, Ryan P; Brat, Daniel; Peter Collins, V; Dahiya, Sonika; George, David; Konomos, William; Kurian, Kathreena M; McFadden, Kathryn; Serafini, Luciano Neder; Nickols, Hilary; Perry, Arie; Shurtleff, Sheila; Gajjar, Amar; Boop, Fredrick A; Klimo, Paul D; Mardis, Elaine R; Wilson, Richard K; Baker, Suzanne J; Zhang, Jinghui; Wu, Gang; Downing, James R; Tatevossian, Ruth G; Ellison, David W

    2016-06-01

    Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

  2. A genetic algorithms approach for altering the membership functions in fuzzy logic controllers

    NASA Technical Reports Server (NTRS)

    Shehadeh, Hana; Lea, Robert N.

    1992-01-01

    Through previous work, a fuzzy control system was developed to perform translational and rotational control of a space vehicle. This problem was then re-examined to determine the effectiveness of genetic algorithms on fine tuning the controller. This paper explains the problems associated with the design of this fuzzy controller and offers a technique for tuning fuzzy logic controllers. A fuzzy logic controller is a rule-based system that uses fuzzy linguistic variables to model human rule-of-thumb approaches to control actions within a given system. This 'fuzzy expert system' features rules that direct the decision process and membership functions that convert the linguistic variables into the precise numeric values used for system control. Defining the fuzzy membership functions is the most time consuming aspect of the controller design. One single change in the membership functions could significantly alter the performance of the controller. This membership function definition can be accomplished by using a trial and error technique to alter the membership functions creating a highly tuned controller. This approach can be time consuming and requires a great deal of knowledge from human experts. In order to shorten development time, an iterative procedure for altering the membership functions to create a tuned set that used a minimal amount of fuel for velocity vector approach and station-keep maneuvers was developed. Genetic algorithms, search techniques used for optimization, were utilized to solve this problem.

  3. Neuroendocrine carcinoma of the pancreas with similar genetic alterations to invasive ductal adenocarcinoma.

    PubMed

    Kimura, Tetsuo; Miyamoto, Hiroshi; Fukuya, Akira; Kitamura, Shinji; Okamoto, Koichi; Kimura, Masako; Muguruma, Naoki; Ikemoto, Tetsuya; Shimada, Mitsuo; Yoneda, Akiko; Bando, Yoshimi; Takishita, Makoto; Takayama, Tetsuji

    2016-08-01

    Neuroendocrine carcinoma (NEC) of the pancreas is very rare, and its origin is not fully elucidated. Here, we present a case of a small-size NEC of the pancreas that is genetically similar to invasive ductal adenocarcinoma (IDA). A 65-year-old man was referred to our hospital due to obstructive jaundice and found to have a 12-mm solid tumor in the pancreas head. The tumor exhibited low vascularity on enhanced computed tomography, and endoscopic retrograde pancreatographic imaging revealed an irregular obstruction in a branch duct of the pancreas. The patient was thereby diagnosed with a pancreatic ductal cancer, and stomach-preserving pancreaticoduodenectomy with regional lymph node resection was performed. Histochemical analysis of the resected tumor showed that the neoplastic cells with scanty cytoplasm and hyperchromatic nuclei strongly expressed chromogranin A and synaptophysin. The Ki-67 index was 40 % in the most proliferative tumor regions, and the tumor was diagnosed as a NEC of the pancreas. However, in the analysis of genetic alterations of the tumor tissue, the neoplastic cells showed altered KRAS, TP53, and SMAD4/DPC4, suggesting that the NEC in our case is genetically related to IDA. Our data suggest that poorly differentiated IDAs may transform into NECs.

  4. Aeromonas proteolyrica bacteria in aerospace environments. [possible genetic alterations and effects on man

    NASA Technical Reports Server (NTRS)

    Foster, B. G.

    1974-01-01

    Preflight studies on Aeromonas proteolytica are reported to investigate the possibility of genetic alterations resulting in increased proteolysis in spacecraft environments. This organism may be present on human tissue and could pose medical problems if its endopeptidase and a hemolysin were to be produced in ususually high quantities or altered in such a way as to be more effective in their activities. Considered are: (1) Development of a nutrative holding medium for suspension of organisms; (2) the establishment of baseline information for the standardization of the assay for endopeptidase levels and hemolytic titers; (3) formulation of a method by which intracutaneous hemorrhage could be quantitated in guinea pig tissue; and (4) the responses of these organisms to parameters of spaceflight and experimentation.

  5. Simultaneous Estimation of Additive and Mutational Genetic Variance in an Outbred Population of Drosophila serrata

    PubMed Central

    McGuigan, Katrina; Aguirre, J. David; Blows, Mark W.

    2015-01-01

    How new mutations contribute to genetic variation is a key question in biology. Although the evolutionary fate of an allele is largely determined by its heterozygous effect, most estimates of mutational variance and mutational effects derive from highly inbred lines, where new mutations are present in homozygous form. In an attempt to overcome this limitation, middle-class neighborhood (MCN) experiments have been used to assess the fitness effect of new mutations in heterozygous form. However, because MCN populations harbor substantial standing genetic variance, estimates of mutational variance have not typically been available from such experiments. Here we employ a modification of the animal model to analyze data from 22 generations of Drosophila serrata bred in an MCN design. Mutational heritability, measured for eight cuticular hydrocarbons, 10 wing-shape traits, and wing size in this outbred genetic background, ranged from 0.0006 to 0.006 (with one exception), a similar range to that reported from studies employing inbred lines. Simultaneously partitioning the additive and mutational variance in the same outbred population allowed us to quantitatively test the ability of mutation-selection balance models to explain the observed levels of additive and mutational genetic variance. The Gaussian allelic approximation and house-of-cards models, which assume real stabilizing selection on single traits, both overestimated the genetic variance maintained at equilibrium, but the house-of-cards model was a closer fit to the data. This analytical approach has the potential to be broadly applied, expanding our understanding of the dynamics of genetic variance in natural populations. PMID:26384357

  6. Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease

    PubMed Central

    Soderquest, Katrina; Hertweck, Arnulf; Mohamed, Rami; Goldberg, Rimma; Perucha, Esperanza; Franke, Lude; Herrero, Javier; Lord, Graham M.

    2017-01-01

    The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner. PMID:28187197

  7. Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1.

    PubMed Central

    Tada, Kenji; Kochi, Masato; Saya, Hideyuki; Kuratsu, Jun-ichi; Shiraishi, Shoji; Kamiryo, Takanori; Shinojima, Naoki; Ushio, Yukitaka

    2003-01-01

    Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that predisposes sufferers to various forms of neoplasia. Among affected individuals, 15%-20% develop astrocytomas, especially pilocytic astrocytomas (PA), which are benign and classified as grade I by the World Health Organization. They are generally well circumscribed, and their progression is slow. NF1-associated PAs (NF1-PAs) occasionally behave as aggressive tumors. To elucidate underlying genetic events in clinically progressive NF1-PAs, we performed molecular genetic analysis on 12 PAs, including 3 NF1-PAs, for pS3, p16, and epidermal growth factor receptor genes, as well as loss of heterozygosity (LOH) on chromosome 1p, 10, 17, and 19q. None of the obvious genetic alterations typically seen in higher grade astrocytomas were found in 9 sporadic PAs. However, in 2 of 3 NF1-PAs, microsatellite analysis showed LOH10, including the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene locus, despite the diagnosis of pilocytic astrocytoma;one of these also manifested homozygous deletion of the p16 gene. The other NF1-PA harbored only LOH of the NF1 gene locus (17q). Our preliminary results support the hypothesis that some NF1-PAs differ genetically from sporadic PAs. PMID:14565158

  8. Does Addition of Propolis to Glass Ionomer Cement Alter its Physicomechanical Properties? An In Vitro Study.

    PubMed

    Subramaniam, P; Girish Babu, K L; Neeraja, G; Pillai, S

    Propolis is a natural resinous substance produced by honey bees. The antimicrobial effects of glass ionomer cement have been shown to improve with the addition of propolis; however its effect on the physicomechanical properties of the cement is not known.

  9. Pattern of inbreeding depression, condition dependence, and additive genetic variance in Trinidadian guppy ejaculate traits

    PubMed Central

    Gasparini, Clelia; Devigili, Alessandro; Dosselli, Ryan; Pilastro, Andrea

    2013-01-01

    In polyandrous species, a male's reproductive success depends on his fertilization capability and traits enhancing competitive fertilization success will be under strong, directional selection. This leads to the prediction that these traits should show stronger condition dependence and larger genetic variance than other traits subject to weaker or stabilizing selection. While empirical evidence of condition dependence in postcopulatory traits is increasing, the comparison between sexually selected and ‘control’ traits is often based on untested assumption concerning the different strength of selection acting on these traits. Furthermore, information on selection in the past is essential, as both condition dependence and genetic variance of a trait are likely to be influenced by the pattern of selection acting historically on it. Using the guppy (Poecilia reticulata), a livebearing fish with high levels of multiple paternity, we performed three independent experiments on three ejaculate quality traits, sperm number, velocity, and size, which have been previously shown to be subject to strong, intermediate, and weak directional postcopulatory selection, respectively. First, we conducted an inbreeding experiment to determine the pattern of selection in the past. Second, we used a diet restriction experiment to estimate their level of condition dependence. Third, we used a half-sib/full-sib mating design to estimate the coefficients of additive genetic variance (CVA) underlying these traits. Additionally, using a simulated predator evasion test, we showed that both inbreeding and diet restriction significantly reduced condition. According to predictions, sperm number showed higher inbreeding depression, stronger condition dependence, and larger CVA than sperm velocity and sperm size. The lack of significant genetic correlation between sperm number and velocity suggests that the former may respond to selection independently one from other ejaculate quality traits

  10. Warming and Nitrogen Addition Alter Photosynthetic Pigments, Sugars and Nutrients in a Temperate Meadow Ecosystem

    PubMed Central

    Zhang, Tao; Yang, Shaobo; Guo, Rui; Guo, Jixun

    2016-01-01

    Global warming and nitrogen (N) deposition have an important influence on terrestrial ecosystems; however, the influence of warming and N deposition on plant photosynthetic products and nutrient cycling in plants is not well understood. We examined the effects of 3 years of warming and N addition on the plant photosynthetic products, foliar chemistry and stoichiometric ratios of two dominant species, i.e., Leymus chinensis and Phragmites communis, in a temperate meadow in northeastern China. Warming significantly increased the chlorophyll content and soluble sugars in L. chinensis but had no impact on the carotenoid and fructose contents. N addition caused a significant increase in the carotenoid and fructose contents. Warming and N addition had little impact on the photosynthetic products of P. communis. Warming caused significant decreases in the N and phosphorus (P) concentrations and significantly increased the carbon (C):P and N:P ratios of L. chinensis, but not the C concentration or the C:N ratio. N addition significantly increased the N concentration, C:P and N:P ratios, but significantly reduced the C:N ratio of L. chinensis. Warming significantly increased P. communis C and P concentrations, and the C:N and C:P ratios, whereas N addition increased the C, N and P concentrations but had no impact on the stoichiometric variables. This study suggests that both warming and N addition have direct impacts on plant photosynthates and elemental stoichiometry, which may play a vital role in plant-mediated biogeochemical cycling in temperate meadow ecosystems. PMID:27171176

  11. Warming and Nitrogen Addition Alter Photosynthetic Pigments, Sugars and Nutrients in a Temperate Meadow Ecosystem.

    PubMed

    Zhang, Tao; Yang, Shaobo; Guo, Rui; Guo, Jixun

    2016-01-01

    Global warming and nitrogen (N) deposition have an important influence on terrestrial ecosystems; however, the influence of warming and N deposition on plant photosynthetic products and nutrient cycling in plants is not well understood. We examined the effects of 3 years of warming and N addition on the plant photosynthetic products, foliar chemistry and stoichiometric ratios of two dominant species, i.e., Leymus chinensis and Phragmites communis, in a temperate meadow in northeastern China. Warming significantly increased the chlorophyll content and soluble sugars in L. chinensis but had no impact on the carotenoid and fructose contents. N addition caused a significant increase in the carotenoid and fructose contents. Warming and N addition had little impact on the photosynthetic products of P. communis. Warming caused significant decreases in the N and phosphorus (P) concentrations and significantly increased the carbon (C):P and N:P ratios of L. chinensis, but not the C concentration or the C:N ratio. N addition significantly increased the N concentration, C:P and N:P ratios, but significantly reduced the C:N ratio of L. chinensis. Warming significantly increased P. communis C and P concentrations, and the C:N and C:P ratios, whereas N addition increased the C, N and P concentrations but had no impact on the stoichiometric variables. This study suggests that both warming and N addition have direct impacts on plant photosynthates and elemental stoichiometry, which may play a vital role in plant-mediated biogeochemical cycling in temperate meadow ecosystems.

  12. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease

    SciTech Connect

    Kamdar, Karishma; Khakpour, Samira; Chen, Jingyu; Leone, Vanessa; Brulc, Jennifer; Mangatu, Thomas; Antonopoulos, Dionysios A.; Chang, Eugene B; Kahn, Stacy A.; Kirschner, Barbara S; Young, Glenn; DePaolo, R. William

    2016-01-13

    Chronic inflammatory disorders are thought to arise due to an interplay between predisposing host genetics and environmental factors. For example, the onset of inflammatory bowel disease is associated with enteric proteobacterial infection, yet the mechanistic basis for this association is unclear. We have shown previously that genetic defiency in TLR1 promotes acute enteric infection by the proteobacteria Yersinia enterocolitica. Examining that model further, we uncovered an altered cellular immune response that promotes the recruitment of neutrophils which in turn increases metabolism of the respiratory electron acceptor tetrathionate by Yersinia. These events drive permanent alterations in anti-commensal immunity, microbiota composition, and chronic inflammation, which persist long after Yersinia clearence. Deletion of the bacterial genes involved in tetrathionate respiration or treatment using targeted probiotics could prevent microbiota alterations and inflammation. Thus, acute infection can drive long term immune and microbiota alterations leading to chronic inflammatory disease in genetically predisposed individuals.

  13. Evolution of the additive genetic variance–covariance matrix under continuous directional selection on a complex behavioural phenotype

    PubMed Central

    Careau, Vincent; Wolak, Matthew E.; Carter, Patrick A.; Garland, Theodore

    2015-01-01

    Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance–covariance matrix (G). Yet knowledge of G in a population experiencing new or altered selection is not sufficient to predict selection response because G itself evolves in ways that are poorly understood. We experimentally evaluated changes in G when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change. PMID:26582016

  14. Evolution of the additive genetic variance-covariance matrix under continuous directional selection on a complex behavioural phenotype.

    PubMed

    Careau, Vincent; Wolak, Matthew E; Carter, Patrick A; Garland, Theodore

    2015-11-22

    Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance-covariance matrix ( G: ). Yet knowledge of G: in a population experiencing new or altered selection is not sufficient to predict selection response because G: itself evolves in ways that are poorly understood. We experimentally evaluated changes in G: when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G: induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G: induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G: and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change.

  15. Evidence that both genetic instability and selection contribute to the accumulation of chromosome alterations in cancer.

    PubMed

    Gorringe, Kylie L; Chin, Suet-Feung; Pharoah, Paul; Staines, Joanne M; Oliveira, Carla; Edwards, Paul A W; Caldas, Carlos

    2005-05-01

    Cancer cells contain many genetic alterations, and genetic instability may be important in tumourigenesis. We evaluated 58 breast and ovarian cancer cell lines for microsatellite instability (MSI) and chromosomal instability (CIN). MSI was identified in 3/33 breast and 5/25 ovarian cell lines, and 7/8 MSI lines showed an inactivation of mismatch repair. Average ploidy by centromeric fluorescence in situ hybridization (FISH) of MSI (n = 8, average ploidy = 2.65) and microsatellite stable (MSS; n = 7, average ploidy = 3.01) cell lines was not different, due to the presence of three aneuploid MSI lines, and two near-diploid MSS lines. However, the variability of the centromeric FISH data was different between MSI and MSS (P = 0.049). The complexity of structural chromosomal rearrangements was not different between MSI and MSS. Thus, MSI and numerical CIN are not mutually exclusive, and structural CIN occurs independently of MSI or numerical CIN. Dynamic genetic instability was evaluated in three cell lines-MSI diploid (MT-3), MSS diploid (SUM159) and MSS aneuploid (MT-1). Ten clones of each of these cell lines were analysed by centromeric FISH and six-colour chromosome painting. The variation in chromosome number was different among all three cell lines (P < 0.001). MT-3 appeared numerically constant (94% of centromeric FISH signals matched the mode). SUM159 was 88% constant; however, 7% of cells had duplicated chromosomes. MT-1 was 82% constant; most changes were chromosomal losses. The six-colour FISH data showed that SUM159 had more stable structural chromosomal alterations (e.g. chromosomal translocations) compared with MT-3 and MT-1, but had no increase in unstable changes (e.g. chromatid breaks) when compared with MT-3. MT-1 had fewer unstable changes than both MT-3 and SUM159. These data suggest that numerical CIN may contribute to aneuploidy, but that selection plays an important role, particularly for the accumulation of structural chromosomal changes.

  16. A novel nuclear genetic code alteration in yeasts and the evolution of codon reassignment in eukaryotes

    PubMed Central

    Mühlhausen, Stefanie; Findeisen, Peggy; Plessmann, Uwe; Urlaub, Henning; Kollmar, Martin

    2016-01-01

    The genetic code is the cellular translation table for the conversion of nucleotide sequences into amino acid sequences. Changes to the meaning of sense codons would introduce errors into almost every translated message and are expected to be highly detrimental. However, reassignment of single or multiple codons in mitochondria and nuclear genomes, although extremely rare, demonstrates that the code can evolve. Several models for the mechanism of alteration of nuclear genetic codes have been proposed (including “codon capture,” “genome streamlining,” and “ambiguous intermediate” theories), but with little resolution. Here, we report a novel sense codon reassignment in Pachysolen tannophilus, a yeast related to the Pichiaceae. By generating proteomics data and using tRNA sequence comparisons, we show that Pachysolen translates CUG codons as alanine and not as the more usual leucine. The Pachysolen tRNACAG is an anticodon-mutated tRNAAla containing all major alanine tRNA recognition sites. The polyphyly of the CUG-decoding tRNAs in yeasts is best explained by a tRNA loss driven codon reassignment mechanism. Loss of the CUG-tRNA in the ancient yeast is followed by gradual decrease of respective codons and subsequent codon capture by tRNAs whose anticodon is not part of the aminoacyl-tRNA synthetase recognition region. Our hypothesis applies to all nuclear genetic code alterations and provides several testable predictions. We anticipate more codon reassignments to be uncovered in existing and upcoming genome projects. PMID:27197221

  17. Additive genetic variation in schizophrenia risk is shared by populations of African and European descent.

    PubMed

    de Candia, Teresa R; Lee, S Hong; Yang, Jian; Browning, Brian L; Gejman, Pablo V; Levinson, Douglas F; Mowry, Bryan J; Hewitt, John K; Goddard, Michael E; O'Donovan, Michael C; Purcell, Shaun M; Posthuma, Danielle; Visscher, Peter M; Wray, Naomi R; Keller, Matthew C

    2013-09-05

    To investigate the extent to which the proportion of schizophrenia's additive genetic variation tagged by SNPs is shared by populations of European and African descent, we analyzed the largest combined African descent (AD [n = 2,142]) and European descent (ED [n = 4,990]) schizophrenia case-control genome-wide association study (GWAS) data set available, the Molecular Genetics of Schizophrenia (MGS) data set. We show how a method that uses genomic similarities at measured SNPs to estimate the additive genetic correlation (SNP correlation [SNP-rg]) between traits can be extended to estimate SNP-rg for the same trait between ethnicities. We estimated SNP-rg for schizophrenia between the MGS ED and MGS AD samples to be 0.66 (SE = 0.23), which is significantly different from 0 (p(SNP-rg = 0) = 0.0003), but not 1 (p(SNP-rg = 1) = 0.26). We re-estimated SNP-rg between an independent ED data set (n = 6,665) and the MGS AD sample to be 0.61 (SE = 0.21, p(SNP-rg = 0) = 0.0003, p(SNP-rg = 1) = 0.16). These results suggest that many schizophrenia risk alleles are shared across ethnic groups and predate African-European divergence.

  18. Genetic alterations and cancer formation in a European flatfish at sites of different contaminant burdens.

    PubMed

    Lerebours, Adélaïde; Stentiford, Grant D; Lyons, Brett P; Bignell, John P; Derocles, Stéphane A P; Rotchell, Jeanette M

    2014-09-02

    Fish diseases are an indicator for marine ecosystem health since they provide a biological end-point of historical exposure to stressors. Liver cancer has been used to monitor the effects of exposure to anthropogenic pollution in flatfish for many years. The prevalence of liver cancer can exceed 20%. Despite the high prevalence and the opportunity of using flatfish to study environmentally induced cancer, the genetic and environmental factors driving tumor prevalence across sites are poorly understood. This study aims to define the link between genetic deterioration, liver disease progression, and anthropogenic contaminant exposures in the flatfish dab (Limanda limanda). We assessed genetic changes in a conserved cancer gene, Retinoblastoma (Rb), in association with histological diagnosis of normal, pretumor, and tumor pathologies in the livers of 165 fish from six sites in the North Sea and English Channel. The highest concentrations of metals (especially cadmium) and organic chemicals correlated with the presence of tumor pathology and with defined genetic profiles of the Rb gene, from these sites. Different Rb genetic profiles were found in liver tissue near each tumor phenotype, giving insight into the mechanistic molecular-level cause of the liver pathologies. Different Rb profiles were also found at sampling sites of differing contaminant burdens. Additionally, profiles indicated that histological "normal" fish from Dogger sampling locations possessed Rb profiles associated with pretumor disease. This study highlights an association between Rb and specific contaminants (especially cadmium) in the molecular etiology of dab liver tumorigenesis.

  19. Alteration of Genetic Make-up in Karnal Bunt Pathogen (Tilletia indica) of Wheat in Presence of Host Determinants

    PubMed Central

    Gupta, Atul K.; Seneviratne, J. M.; Bala, Ritu; Jaiswal, J. P.; Kumar, Anil

    2015-01-01

    Alteration of genetic make-up of the isolates and monosporidial strains of Tilletia indica causing Karnal bunt (KB) disease in wheat was analyzed using DNA markers and SDS-PAGE. The generation of new variation with different growth characteristics is not a generalized feature and is not only dependant on the original genetic make up of the base isolate/monosporidial strains but also on interaction with host. Host determinant(s) plays a significant role in the generation of variability and the effect is much pronounced in monosporidial strains with narrow genetic base as compared to broad genetic base. The most plausible explanation of genetic variation in presence of host determinant(s) are the recombination of genetic material from two different mycelial/sporidia through sexual mating as well as through para-sexual means. The morphological and development dependent variability further suggests that the variation in T. indica strains predominantly derived through the genetic rearrangements. PMID:26060428

  20. Selenium addition alters mercury uptake, bioavailability in the rhizosphere and root anatomy of rice (Oryza sativa)

    PubMed Central

    Wang, Xun; Tam, Nora Fung-Yee; Fu, Shi; Ametkhan, Aray; Ouyang, Yun; Ye, Zhihong

    2014-01-01

    Background and Aims Mercury (Hg) is an extremely toxic pollutant, especially in the form of methylmercury (MeHg), whereas selenium (Se) is an essential trace element in the human diet. This study aimed to ascertain whether addition of Se can produce rice with enriched Se and lowered Hg content when growing in Hg-contaminated paddy fields and, if so, to determine the possible mechanisms behind these effects. Methods Two cultivars of rice (Oryza sativa, japonica and indica) were grown in either hydroponic solutions or soil rhizobags with different Se and Hg treatments. Concentrations of total Hg, MeHg and Se were determined in the roots, shoots and brown rice, together with Hg uptake kinetics and Hg bioavailability in the soil. Root anatonmy was also studied. Key Results The high Se treatment (5 μg g–1) significantly increased brown rice yield by 48 % and total Se content by 2·8-fold, and decreased total Hg and MeHg by 47 and 55 %, respectively, compared with the control treatments. The high Se treatment also markedly reduced ‘water-soluble’ Hg and MeHg concentrations in the rhizosphere soil, decreased the uptake capacity of Hg by roots and enhanced the development of apoplastic barriers in the root endodermis. Conclusions Addition of Se to Hg-contaminated soil can help produce brown rice that is simultaneously enriched in Se and contains less total Hg and MeHg. The lowered accumulation of total Hg and MeHg appears to be the result of reduced bioavailability of Hg and production of MeHg in the rhizosphere, suppression of uptake of Hg into the root cells and an enhancement of the development of apoplastic barriers in the endodermis of the roots. PMID:24948669

  1. Nitrogen and phosphorus additions alter nutrient dynamics but not resorption efficiencies of Chinese fir leaves and twigs differing in age.

    PubMed

    Chen, Fu-Sheng; Niklas, Karl Joseph; Liu, Yu; Fang, Xiang-Min; Wan, Song-Ze; Wang, Huimin

    2015-10-01

    It is unclear how or even if phosphorus (P) input alters the influence of nitrogen (N) deposition in a forest. In theory, nutrients in leaves and twigs differing in age may show different responses to elevated nutrient input. To test this possibility, we selected Chinese fir (Cunninghamia lanceolata) for a series of N and P addition experiments using treatments of +N1 - P (50 kg N ha(-1) year(-1)), +N2 - P (100 kg N ha(-1) year(-1)), -N + P (50 kg P ha(-1) year(-1)), +N1 + P, +N2 + P and -N - P (without N and P addition). Soil samples were analyzed for mineral N and available P concentrations. Leaves and twigs in summer and their litters in winter were classified as and sorted into young and old components to measure N and P concentrations. Soil mineral N and available P increased with N and P additions, respectively. Nitrogen addition increased leaf and twig N concentrations in the second year, but not in the first year; P addition increased leaf and twig P concentrations in both years and enhanced young but not old leaf and twig N accumulations. Nitrogen and P resorption proficiencies in litters increased in response to N and P additions, but N and P resorption efficiencies were not significantly altered. Nitrogen resorption efficiency was generally higher in leaves than in twigs and in young vs old leaves and twigs. Phosphorus resorption efficiency showed a minimal variation from 26.6 to 47.0%. Therefore, P input intensified leaf and twig N enrichment with N addition, leaf and twig nutrients were both gradually resorbed with aging, and organ and age effects depended on the extent of nutrient limitation.

  2. Origin of the genetic code: was the original mechanism lost or altered during evolution after the universal genetic code was virtually frozen?

    NASA Astrophysics Data System (ADS)

    Trevors, T. J.

    2011-10-01

    The natural mechanism that organized the corresponding coding between nucleic acids and the corresponding amino acids is still unknown. It is also not known if molecular remnants or relics of this mechanism are present in some living cells as an altered mechanism or the original mechanism was lost during evolution. Prokaryotic organisms may be a plausible location for discovering such a mechanism as they are the ancient species on the Earth. The hypothesis is proposed that the molecular mechanism that generated the universal genetic code was lost, or altered for other functions, once the genetic code was virtually frozen/fixed. By virtually freezing the code, evolution could proceed at a faster pace without generating a new genetic coding system for different species. Different combinations of the code emerged in the evolving species. This is an efficient mechanism of generating new code combinations from an existing genetic code.

  3. Genetic and Epigenetic Alterations of Brassica nigra Introgression Lines from Somatic Hybridization: A Resource for Cauliflower Improvement

    PubMed Central

    Wang, Gui-xiang; Lv, Jing; Zhang, Jie; Han, Shuo; Zong, Mei; Guo, Ning; Zeng, Xing-ying; Zhang, Yue-yun; Wang, You-ping; Liu, Fan

    2016-01-01

    Broad phenotypic variations were obtained previously in derivatives from the asymmetric somatic hybridization of cauliflower “Korso” (Brassica oleracea var. botrytis, 2n = 18, CC genome) and black mustard “G1/1” (Brassica nigra, 2n = 16, BB genome). However, the mechanisms underlying these variations were unknown. In this study, 28 putative introgression lines (ILs) were pre-selected according to a series of morphological (leaf shape and color, plant height and branching, curd features, and flower traits) and physiological (black rot/club root resistance) characters. Multi-color fluorescence in situ hybridization revealed that these plants contained 18 chromosomes derived from “Korso.” Molecular marker (65 simple sequence repeats and 77 amplified fragment length polymorphisms) analysis identified the presence of “G1/1” DNA segments (average 7.5%). Additionally, DNA profiling revealed many genetic and epigenetic differences among the ILs, including sequence alterations, deletions, and variation in patterns of cytosine methylation. The frequency of fragments lost (5.1%) was higher than presence of novel bands (1.4%), and the presence of fragments specific to Brassica carinata (BBCC 2n = 34) were common (average 15.5%). Methylation-sensitive amplified polymorphism analysis indicated that methylation changes were common and that hypermethylation (12.4%) was more frequent than hypomethylation (4.8%). Our results suggested that asymmetric somatic hybridization and alien DNA introgression induced genetic and epigenetic alterations. Thus, these ILs represent an important, novel germplasm resource for cauliflower improvement that can be mined for diverse traits of interest to breeders and researchers. PMID:27625659

  4. Genetic and Epigenetic Alterations of Brassica nigra Introgression Lines from Somatic Hybridization: A Resource for Cauliflower Improvement.

    PubMed

    Wang, Gui-Xiang; Lv, Jing; Zhang, Jie; Han, Shuo; Zong, Mei; Guo, Ning; Zeng, Xing-Ying; Zhang, Yue-Yun; Wang, You-Ping; Liu, Fan

    2016-01-01

    Broad phenotypic variations were obtained previously in derivatives from the asymmetric somatic hybridization of cauliflower "Korso" (Brassica oleracea var. botrytis, 2n = 18, CC genome) and black mustard "G1/1" (Brassica nigra, 2n = 16, BB genome). However, the mechanisms underlying these variations were unknown. In this study, 28 putative introgression lines (ILs) were pre-selected according to a series of morphological (leaf shape and color, plant height and branching, curd features, and flower traits) and physiological (black rot/club root resistance) characters. Multi-color fluorescence in situ hybridization revealed that these plants contained 18 chromosomes derived from "Korso." Molecular marker (65 simple sequence repeats and 77 amplified fragment length polymorphisms) analysis identified the presence of "G1/1" DNA segments (average 7.5%). Additionally, DNA profiling revealed many genetic and epigenetic differences among the ILs, including sequence alterations, deletions, and variation in patterns of cytosine methylation. The frequency of fragments lost (5.1%) was higher than presence of novel bands (1.4%), and the presence of fragments specific to Brassica carinata (BBCC 2n = 34) were common (average 15.5%). Methylation-sensitive amplified polymorphism analysis indicated that methylation changes were common and that hypermethylation (12.4%) was more frequent than hypomethylation (4.8%). Our results suggested that asymmetric somatic hybridization and alien DNA introgression induced genetic and epigenetic alterations. Thus, these ILs represent an important, novel germplasm resource for cauliflower improvement that can be mined for diverse traits of interest to breeders and researchers.

  5. Sulfur dioxide addition at crush alters Saccharomyces cerevisiae strain composition in spontaneous fermentations at two Canadian wineries.

    PubMed

    Morgan, Sydney C; Scholl, Chrystal M; Benson, Natasha L; Stone, Morgan L; Durall, Daniel M

    2017-03-06

    During winemaking, sulfur dioxide (SO2) is often added prior to the onset of alcoholic fermentation to prevent the growth of spoilage microorganisms and to create an environment that promotes the rapid colonization of the grape must by Saccharomyces cerevisiae. Most recent research has focused on the impacts of SO2 additions on spoilage microorganisms or on the yeast community at a species level, but less is known about the impacts that SO2 additions have on S. cerevisiae populations. We investigated whether different levels of SO2 addition at crush (0, 20, or 40mg/L SO2) have an effect upon the relative abundance and composition of S. cerevisiae strains conducting spontaneous fermentations of two grape varietals at two commercial wineries. Yeast isolates collected from fermentations were identified to the strain level using microsatellite analysis. Commercial strains made up the majority (64-98%) of the S. cerevisiae strains isolated during fermentation, and most of these commercial strains were used as inoculants by their respective wineries. Different SO2 additions were found to significantly alter S. cerevisiae strain compositions at both wineries (p≤0.002). The results of this study demonstrate that initial SO2 addition significantly alters the S. cerevisiae strain composition in spontaneous fermentations, and highlights the dominance of commercial strains in commercial winery environments. Because different yeast strains are known to produce different chemical and sensory profiles, our findings have important implications for winemakers. In addition, adding different concentrations of SO2 may be a way for winemakers to manage or control the strain composition during spontaneous fermentations.

  6. Cell type of origin as well as genetic alterations contribute to breast cancer phenotypes

    PubMed Central

    West, William W.; Qiu, Fang; Band, Hamid; Band, Vimla

    2015-01-01

    Breast cancer is classified into different subtypes that are associated with different patient survival outcomes, underscoring the importance of understanding the role of precursor cell and genetic alterations in determining tumor subtypes. In this study, we evaluated the oncogenic phenotype of two distinct mammary stem/progenitor cell types designated as K5+/K19− or K5+/K19+ upon introduction of identical combinations of oncogenes-mutant H-Ras (mRas) and mutant p53 (mp53), together with either wild-type ErbB2(wtErbB2) or wild-type EGFR (wtEGFR). We examined their tumor forming and metastasis potential, using both in-vitro and in-vivo assays. Both the combinations efficiently transformed K5+/K19− or K5+/K19+ cells. Xenograft tumors formed by these cells were histologically heterogeneous, with variable proportions of luminal, basal-like and claudin-low type components depending on the cell types and oncogene combinations. Notably, K5+/K19− cells transformed with mRas/mp53/wtEGFR combination had a significantly longer latency for primary tumor development than other cell lines but more lung metastasis incidence than same cells expressing mRas/mp53/wtErbB2. K5+/K19+ cells exhibit shorter overall tumor latency, and high metastatic potential than K5+/K19− cells, suggesting that these K19+ progenitors are more susceptible to oncogenesis and metastasis. Our results suggest that both genetic alterations and cell type of origin contribute to oncogenic phenotype of breast tumors. PMID:25940703

  7. Cell type of origin as well as genetic alterations contribute to breast cancer phenotypes.

    PubMed

    Bhagirath, Divya; Zhao, Xiangshan; West, William W; Qiu, Fang; Band, Hamid; Band, Vimla

    2015-04-20

    Breast cancer is classified into different subtypes that are associated with different patient survival outcomes, underscoring the importance of understanding the role of precursor cell and genetic alterations in determining tumor subtypes. In this study, we evaluated the oncogenic phenotype of two distinct mammary stem/progenitor cell types designated as K5+/K19- or K5+/K19+ upon introduction of identical combinations of oncogenes-mutant H-Ras (mRas) and mutant p53 (mp53), together with either wild-type ErbB2(wtErbB2) or wild-type EGFR (wtEGFR). We examined their tumor forming and metastasis potential, using both in-vitro and in-vivo assays. Both the combinations efficiently transformed K5+/K19- or K5+/K19+ cells. Xenograft tumors formed by these cells were histologically heterogeneous, with variable proportions of luminal, basal-like and claudin-low type components depending on the cell types and oncogene combinations. Notably, K5+/K19- cells transformed with mRas/mp53/wtEGFR combination had a significantly longer latency for primary tumor development than other cell lines but more lung metastasis incidence than same cells expressing mRas/mp53/wtErbB2. K5+/K19+ cells exhibit shorter overall tumor latency, and high metastatic potential than K5+/K19- cells, suggesting that these K19+ progenitors are more susceptible to oncogenesis and metastasis. Our results suggest that both genetic alterations and cell type of origin contribute to oncogenic phenotype of breast tumors.

  8. Genetic and epigenetic alteration profiles for multiple genes in salivary gland carcinomas.

    PubMed

    Kishi, Munehiro; Nakamura, Mitsutoshi; Nishimine, Masayoshi; Ikuta, Miwa; Kirita, Tadaaki; Konishi, Noboru

    2005-02-01

    As combinations of genetic and/or epigenetic alterations occurring during salivary gland carcinogenesis are largely unknown, we here analyzed 36 salivary gland carcinomas (SGCs) for changes in INK4a/ARF, RB1, p21, p27, PTEN, p53, MDM2 and O6-MGMT genes using methylation specific PCR (MSP), loss of heterozygosity (LOH) assays and mutational analysis with immunohistochemistry (IHC), as well as histone H3 and H4 acetylation status. The RB1 gene was found to be the most frequently methylated (41.7% of cases), while methylation of p27(Kip1) and O6-MGMT were less frequent 8.3% and 5.6%, respectively). Two other genes, p21(Waf1) and PTEN, were unmethylated in the SGCs examined. RB1 methylation significantly correlated with loss of expression as determined by IHC (P=0.03), and also a poor prognosis (P=0.02). p53 mutations were found in 8 cases (22.2%), coupled with p14ARF hypermethylation in two cases. LOH in INK4a/ARF and the RB1 locus was observed in 33.3% and 28.6% of the lesions, respectively. There was no correlation between 9p21 LOH and methylation of the INK4a/ARF gene. Promoter hypermethylation of RB1 coupled with LOH was evident in three samples immuno-negative for RB1. Acetylation of histone H3 and H4 was detected in 6 and 5 cases, respectively. These findings indicate that epigenetic silencing of tumour suppressor genes via promoter hypermethylation might be crucial for salivary gland carcinogenesis, particularly in the RB1 gene. Thus epigenetic events including methylation and acetylation as well as genetic alterations may have important contributions.

  9. High prevalence of p16 genetic alterations in head and neck tumours

    PubMed Central

    Miracca, E C; Kowalski, L P; Nagai, M A

    1999-01-01

    Inactivation of the p16 gene is believed to contribute to the tumorigenic process of several neoplasms, including head and neck tumours. In the present study, DNA samples from paired tumour and adjacent normal tissue from 47 patients with squamous cell carcinoma of the head and neck were investigated for the occurrence of p16 genetic alterations. Single-strand conformation polymorphism and direct DNA sequence analysis led to the identification of p16 mutations in six cases (13%). Southern blot analysis showed that homozygous deletion is a rare event in the group of tumours analysed. Loss of heterozygosity (LOH) analysis was performed by polymerase chain reaction (PCR) using two microsatellite markers (IFNA and D9S171) from the 9p21 region. Taking into account only the informative cases, 17 of 32 tumours (53%) showed LOH for at least one of the markers analysed. The methylation status of the CpG sites in the exon 1 of the p16 gene was analysed using methylation-sensitive restriction enzymes and PCR amplification. Hypermethylation was observed in 22 (47%) of the head and neck tumours analysed. In our series of head and neck tumours, evidence for inactivation of both p16 alleles was observed in 13 cases with hypermethylation and LOH, two cases with hypermethylation and mutation, four cases with mutation and LOH and one case with homozygous deletion. These findings provide further evidence that genetic alterations, especially hypermethylation and LOH, leading to the inactivation of the p16 tumour suppressor gene are common in primary head and neck tumours. © 1999 Cancer Research Campaign PMID:10574255

  10. Female and male genetic effects on offspring paternity: additive genetic (co)variances in female extra-pair reproduction and male paternity success in song sparrows (Melospiza melodia).

    PubMed

    Reid, Jane M; Arcese, Peter; Keller, Lukas F; Losdat, Sylvain

    2014-08-01

    Ongoing evolution of polyandry, and consequent extra-pair reproduction in socially monogamous systems, is hypothesized to be facilitated by indirect selection stemming from cross-sex genetic covariances with components of male fitness. Specifically, polyandry is hypothesized to create positive genetic covariance with male paternity success due to inevitable assortative reproduction, driving ongoing coevolution. However, it remains unclear whether such covariances could or do emerge within complex polyandrous systems. First, we illustrate that genetic covariances between female extra-pair reproduction and male within-pair paternity success might be constrained in socially monogamous systems where female and male additive genetic effects can have opposing impacts on the paternity of jointly reared offspring. Second, we demonstrate nonzero additive genetic variance in female liability for extra-pair reproduction and male liability for within-pair paternity success, modeled as direct and associative genetic effects on offspring paternity, respectively, in free-living song sparrows (Melospiza melodia). The posterior mean additive genetic covariance between these liabilities was slightly positive, but the credible interval was wide and overlapped zero. Therefore, although substantial total additive genetic variance exists, the hypothesis that ongoing evolution of female extra-pair reproduction is facilitated by genetic covariance with male within-pair paternity success cannot yet be definitively supported or rejected either conceptually or empirically.

  11. Additive genetic variance and developmental plasticity in growth trajectories in a wild cooperative mammal.

    PubMed

    Huchard, E; Charmantier, A; English, S; Bateman, A; Nielsen, J F; Clutton-Brock, T

    2014-09-01

    Individual variation in growth is high in cooperative breeders and may reflect plastic divergence in developmental trajectories leading to breeding vs. helping phenotypes. However, the relative importance of additive genetic variance and developmental plasticity in shaping growth trajectories is largely unknown in cooperative vertebrates. This study exploits weekly sequences of body mass from birth to adulthood to investigate sources of variance in, and covariance between, early and later growth in wild meerkats (Suricata suricatta), a cooperative mongoose. Our results indicate that (i) the correlation between early growth (prior to nutritional independence) and adult mass is positive but weak, and there are frequent changes (compensatory growth) in post-independence growth trajectories; (ii) among parameters describing growth trajectories, those describing growth rate (prior to and at nutritional independence) show undetectable heritability while associated size parameters (mass at nutritional independence and asymptotic mass) are moderately heritable (0.09 ≤ h(2) < 0.3); and (iii) additive genetic effects, rather than early environmental effects, mediate the covariance between early growth and adult mass. These results reveal that meerkat growth trajectories remain plastic throughout development, rather than showing early and irreversible divergence, and that the weak effects of early growth on adult mass, an important determinant of breeding success, are partly genetic. In contrast to most cooperative invertebrates, the acquisition of breeding status is often determined after sexual maturity and strongly impacted by chance in many cooperative vertebrates, who may therefore retain the ability to adjust their morphology to environmental changes and social opportunities arising throughout their development, rather than specializing early.

  12. An efficient system for selectively altering genetic information within mRNAs

    PubMed Central

    Montiel-González, Maria Fernanda; Vallecillo-Viejo, Isabel C.; Rosenthal, Joshua J. C.

    2016-01-01

    Site-directed RNA editing (SDRE) is a strategy to precisely alter genetic information within mRNAs. By linking the catalytic domain of the RNA editing enzyme ADAR to an antisense guide RNA, specific adenosines can be converted to inosines, biological mimics for guanosine. Previously, we showed that a genetically encoded iteration of SDRE could target adenosines expressed in human cells, but not efficiently. Here we developed a reporter assay to quantify editing, and used it to improve our strategy. By enhancing the linkage between ADAR's catalytic domain and the guide RNA, and by introducing a mutation in the catalytic domain, the efficiency of converting a UAG premature termination codon (PTC) to tryptophan (UGG) was improved from ∼11 % to ∼70 %. Other PTCs were edited, but less efficiently. Numerous off-target edits were identified in the targeted mRNA, but not in randomly selected endogenous messages. Off-target edits could be eliminated by reducing the amount of guide RNA with a reduction in on-target editing. The catalytic rate of SDRE was compared with those for human ADARs on various substrates and found to be within an order of magnitude of most. These data underscore the promise of site-directed RNA editing as a therapeutic or experimental tool. PMID:27557710

  13. Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2

    PubMed Central

    Fiori, E.; Babicola, L.; Andolina, D.; Coassin, A.; Pascucci, T.; Patella, L.; Han, Y.-C.; Ventura, A.

    2015-01-01

    Feingold syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various learning disabilities. Heterozygous deletion of the miR-17–92 cluster is responsible for a subset of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize this disorder are partially recapitulated in mice that harbor a heterozygous deletion of this cluster (miR-17–92Δ/+ mice). Although Feingold patients develop a wide array of learning disabilities, no scientific description of learning/cognitive disabilities, intellectual deficiency, and brain alterations have been described in humans and animal models of FS2. The aim of this study was to draw a behavioral profile, during development and in adulthood, of miR-17–92Δ/+ mice, a genetic mouse model of FS2. Moreover, dopamine, norepinephrine and serotonin tissue levels in the medial prefrontal cortex (mpFC), and Hippocampus (Hip) of miR-17–92Δ/+ mice were analyzed. Our data showed decreased body growth and reduced vocalization during development. Moreover, selective deficits in spatial ability, social novelty recognition and memory span were evident in adult miR-17–92Δ/+ mice compared with healthy controls (WT). Finally, we found altered dopamine as well as serotonin tissue levels, in the mpFC and Hip, respectively, of miR-17–92Δ/+ in comparison with WT mice, thus suggesting a possible link between cognitive deficits and altered brain neurotransmission. PMID:26026879

  14. Neurobehavioral Alterations in a Genetic Murine Model of Feingold Syndrome 2.

    PubMed

    Fiori, E; Babicola, L; Andolina, D; Coassin, A; Pascucci, T; Patella, L; Han, Y-C; Ventura, A; Ventura, R

    2015-09-01

    Feingold syndrome (FS) is an autosomal dominant disorder characterized by microcephaly, short stature, digital anomalies, esophageal/duodenal atresia, facial dysmorphism, and various learning disabilities. Heterozygous deletion of the miR-17-92 cluster is responsible for a subset of FS (Feingold syndrome type 2, FS2), and the developmental abnormalities that characterize this disorder are partially recapitulated in mice that harbor a heterozygous deletion of this cluster (miR-17-92∆/+ mice). Although Feingold patients develop a wide array of learning disabilities, no scientific description of learning/cognitive disabilities, intellectual deficiency, and brain alterations have been described in humans and animal models of FS2. The aim of this study was to draw a behavioral profile, during development and in adulthood, of miR-17-92∆/+ mice, a genetic mouse model of FS2. Moreover, dopamine, norepinephrine and serotonin tissue levels in the medial prefrontal cortex (mpFC), and Hippocampus (Hip) of miR-17-92∆/+ mice were analyzed.Our data showed decreased body growth and reduced vocalization during development. Moreover, selective deficits in spatial ability, social novelty recognition and memory span were evident in adult miR-17-92∆/+ mice compared with healthy controls (WT). Finally, we found altered dopamine as well as serotonin tissue levels, in the mpFC and Hip, respectively, of miR-17-92∆/+ in comparison with WT mice, thus suggesting a possible link between cognitive deficits and altered brain neurotransmission.

  15. GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings

    PubMed Central

    Caciotti, Anna; Garman, Scott C; Rivera-Colón, Yadilette; Procopio, Elena; Catarzi, Serena; Ferri, Lorenzo; Guido, Carmen; Martelli, Paola; Parini, Rossella; Antuzzi, Daniela; Battini, Roberta; Sibilio, Michela; Simonati, Alessandro; Fontana, Elena; Salviati, Alessandro; Akinci, Gulcin; Cereda, Cristina; Dionisi-Vici, Carlo; Deodato, Francesca; d’Amico, Adele; d’Azzo, Alessandra; Bertini, Enrico; Filocamo, Mirella; Scarpa, Maurizio; di Rocco, Maja; Tifft, Cynthia J; Ciani, Federica; Gasperini, Serena; Pasquini, Elisabetta; Guerrini, Renzo; Donati, Maria Alice; Morrone, Amelia

    2011-01-01

    GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000– 1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes, showed that all the amino acids replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease. PMID:21497194

  16. Widespread evidence for non-additive genetic variation in Cloninger's and Eysenck's personality dimensions using a twin plus sibling design.

    PubMed

    Keller, Matthew C; Coventry, William L; Heath, Andrew C; Martin, Nicholas G

    2005-11-01

    Studies using the classical twin design often conclude that most genetic variation underlying personality is additive in nature. However, studies analyzing only twins are very limited in their ability to detect non-additive genetic variation and are unable to detect sources of variation unique to twins, which can mask non-additive genetic variation. The current study assessed 9672 MZ and DZ twin individuals and 3241 of their siblings to investigate the environmental and genetic architecture underlying eight dimensions of personality: four from Eysenck's Personality Questionnaire and four from Cloninger's Temperament and Character Inventory. Broad-sense heritability estimates from best-fitting models were two to three times greater than the narrow-sense heritability estimates for Harm Avoidance, Novelty Seeking, Reward Dependence, Persistence, Extraversion, and Neuroticism. This genetic non-additivity could be due to dominance, additive-by-additive epistasis, or to additive genetic effects combined with higher-order epistasis. Environmental effects unique to twins were detected for both Lie and Psychoticism but accounted for little overall variation. Our results illustrate the increased sensitivity afforded by extending the classical twin design to include siblings, and may provide clues to the evolutionary origins of genetic variation underlying personality.

  17. Global change and biological soil crusts: Effects of ultraviolet augmentation under altered precipitation regimes and nitrogen additions

    USGS Publications Warehouse

    Belnap, J.; Phillips, S.L.; Flint, S.; Money, J.; Caldwell, M.

    2008-01-01

    Biological soil crusts (BSCs), a consortium of cyanobacteria, lichens, and mosses, are essential in most dryland ecosystems. As these organisms are relatively immobile and occur on the soil surface, they are exposed to high levels of ultraviolet (UV) radiation and atmospheric nitrogen (N) deposition, rising temperatures, and alterations in precipitation patterns. In this study, we applied treatments to three types of BSCs (early, medium, and late successional) over three time periods (spring, summer, and spring-fall). In the first year, we augmented UV and altered precipitation patterns, and in the second year, we augmented UV and N. In the first year, with average air temperatures, we saw little response to our treatments except quantum yield, which was reduced in dark BSCs during one of three sample times and in Collema BSCs two of three sample times. There was more response to UV augmentation the second year when air temperatures were above average. Declines were seen in 21% of the measured variables, including quantum yield, chlorophyll a, UV-protective pigments, nitrogenase activity, and extracellular polysaccharides. N additions had some negative effects on light and dark BSCs, including the reduction of quantum yield, ??-carotene, nitrogenase activity, scytonemin, and xanthophylls. N addition had no effects on the Collema BSCs. When N was added to samples that had received augmented UV, there were only limited effects relative to samples that received UV without N. These results indicate that the negative effect of UV and altered precipitation on BSCs will be heightened as global temperatures increase, and that as their ability to produce UV-protective pigments is compromised, physiological functioning will be impaired. N deposition will only ameliorate UV impacts in a limited number of cases. Overall, increases in UV will likely lead to lowered productivity and increased mortality in BSCs through time, which, in turn, will reduce their ability to contribute

  18. Association analysis of historical bread wheat germplasm using additive genetic covariance of relatives and population structure.

    PubMed

    Crossa, José; Burgueño, Juan; Dreisigacker, Susanne; Vargas, Mateo; Herrera-Foessel, Sybil A; Lillemo, Morten; Singh, Ravi P; Trethowan, Richard; Warburton, Marilyn; Franco, Jorge; Reynolds, Matthew; Crouch, Jonathan H; Ortiz, Rodomiro

    2007-11-01

    Linkage disequilibrium can be used for identifying associations between traits of interest and genetic markers. This study used mapped diversity array technology (DArT) markers to find associations with resistance to stem rust, leaf rust, yellow rust, and powdery mildew, plus grain yield in five historical wheat international multienvironment trials from the International Maize and Wheat Improvement Center (CIMMYT). Two linear mixed models were used to assess marker-trait associations incorporating information on population structure and covariance between relatives. An integrated map containing 813 DArT markers and 831 other markers was constructed. Several linkage disequilibrium clusters bearing multiple host plant resistance genes were found. Most of the associated markers were found in genomic regions where previous reports had found genes or quantitative trait loci (QTL) influencing the same traits, providing an independent validation of this approach. In addition, many new chromosome regions for disease resistance and grain yield were identified in the wheat genome. Phenotyping across up to 60 environments and years allowed modeling of genotype x environment interaction, thereby making possible the identification of markers contributing to both additive and additive x additive interaction effects of traits.

  19. Influence of disinfection with peracetic acid and hypochlorite in dimensional alterations of casts obtained from addition silicone and polyether impressions.

    PubMed

    Queiroz, Daher Antonio; Peçanha, Marcelo Massaroni; Neves, Ana Christina Claro; Frizzera, Fausto; Tonetto, Mateus Rodrigues; Silva-Concílio, Laís Regiane

    2013-11-01

    Dental impressions disinfection is important to reduce the risk of cross contamination but this process may produce dimensional distortions. Peracetic acid is a disinfectant agent with several favorable characteristics yet underutilized in Dentistry. The aim of this paper is to compare the dimensional stability of casts obtained from addition silicone and polyether impressions that were immersed for 10 minutes in a solution of 0.2% peracetic acid or 1% sodium hypochlorite. Sixty samples in type IV gypsum were produced after a master cast that simulated a full crown preparation of a maxillary premolar. Samples were divided in 6 groups (n = 10) according to the impression material and disinfection agent: Group AC--addition silicone control (without disinfectant); Group APA--addition silicone + 0.2% peracetic acid; Group AH--addition silicone + 1% sodium hypochlorite; Group PC--polyether control (without disinfectant); Group PPA--polyether + 0.2% peracetic acid; Group PH--polyether + 1% sodium hypochlorite. Cast height, base and top diameter were measured and a mean value was obtained for each sample and group all data was statistically analyzed (ANOVA, p < 0.05). There was not a significant statistical difference between addition silicone and polyether impressions regardless of the disinfectant materials. It can be concluded that disinfection with the proposed agents did not produce significant alterations of the impressions and the peracetic acid could be considered a reliable material to disinfect dental molds.

  20. Genetic possibilities for altering sunflower oil quality to obtain novel oils.

    PubMed

    Skorić, Dragan; Jocić, Sinisa; Sakac, Zvonimir; Lecić, Nada

    2008-04-01

    The sunflower is one of the four most important oilseed crops in the world, and the nutritional quality of its edible oil ranks among the best vegetable oils in cultivation. Typically up to 90% of the fatty acids in conventional sunflower oil are unsaturated, namely oleic (C 18:1, 16%-19%) and linoleic (C 18:2, 68%-72%) fatty acids. Palmitic (C 16:0, 6%), stearic (C 18:0, 5%), and minor amounts of myristic (C 14:0), myristoleic (C 14:1), palmitoleic (C 16:1), arachidic (C 20:0), behenic (C 22:0), and other fatty acids account for the remaining 10%. Advances in modern genetics, most importantly induced mutations, have altered the fatty acid composition of sunflower oil to a significant extent. Treating sunflower seeds with gamma- and X-rays has produced mutants with 25%-30% palmitic acid. Sunflower seed treatment with X-rays has also resulted in mutants having 30% palmitoleic acid, while treatments with mutagenic sodium azide have produced seeds containing 35% stearic acid. The most important mutations have been obtained by treatment with dimethyl sulfate, which produced genotypes with more than 90% oleic acid. Mutants have also been obtained that have a high linoleic acid content (>80%) by treating seeds with X-rays and ethyl methanesulfonate. Of the vitamin E family of compounds, sunflower oil is known to predominantly contain alpha-tocopherol (>90%). Spontaneous mutations controlled by recessive genes have been discovered that significantly alter tocopherol forms and levels. The genes in question are tph(1) (50% alpha- and 50% beta-tocopherol), tph(2) (0%-5% alpha- and 95%-100% gamma-tocopherol), and tph(1)tph(2) (8%-40% alpha-, 0%-25% beta-, 25%-84% gamma-, and 8%-50% delta-tocopherol). The existence of (mutant) genes for increased levels of individual fatty acids and for different forms and levels of tocopherol enables the development of sunflower hybrids with different oil quality. The greatest progress has been made in developing high-oleic hybrids (>90

  1. A blend of essential plant oils used as an additive to alter silage fermentation or used as a feed additive for lactating dairy cows.

    PubMed

    Kung, L; Williams, P; Schmidt, R J; Hu, W

    2008-12-01

    A blend of essential plant oils was evaluated for its effects on silage fermentation and animal performance. In the first experiment, the blend of essential oils was mixed with freshly chopped whole-plant corn to achieve a concentration of 0, 40, or 80 mg of active product per kilogram of fresh forage weight. Whole-plant corn was also mixed with a buffered propionic acid-based product at 0.2% of fresh forage weight. The blend of essential oils did not affect the populations of yeasts, molds, lactic acid bacteria, or enterobacteria; the fermentation end products; or the aerobic stability of the corn silage. Addition of the buffered propionic acid additive moderately reduced the production of acids during fermentation and resulted in a small reduction in the numbers of yeasts after ensiling, but did not affect aerobic stability. In a second experiment, 30 Holstein cows (4 primiparous and 26 multiparous) averaging 118 +/- 70 d in milk and producing 38 +/- 16 kg of milk/d were fed a total mixed ration, once daily, that consisted of (on a DM basis) 25% corn silage, 15% alfalfa silage, 10% alfalfa hay, and 50% concentrate. One-half of the cows were fed a blend of essential oils that was mixed directly into their total mixed ration to provide 1.2 g/cow per d for 9 wk. Cows fed the essential oils ate 1.9 kg more dry matter/d and produced 2.7 kg more 3.5% fat-corrected milk/d than did cows fed the control diet. The percentages of milk fat and protein, the somatic cell count numbers, and the concentrations of milk urea nitrogen were unaffected by treatment. Feed efficiency, change in body weight, and change in body condition scoring were also similar between treatments. After 12 h of incubation, the addition of a moderate dose and a high dose of essential oils to in vitro ruminal fermentations had no effect on the concentration of total VFA compared with the control treatment. However, they decreased the molar proportions of acetic, butyric, and valeric acids and increased

  2. Genetic alterations and oxidative metabolism in sporadic colorectal tumors from a Spanish community.

    PubMed

    Oliva, M R; Ripoll, F; Muñiz, P; Iradi, A; Trullenque, R; Valls, V; Drehmer, E; Sáez, G T

    1997-04-01

    Deletions of loci on chromosomes 5q, 17p, 18q, and 22q, together with the incidence of p53 mutations and amplification of the double minute-2 gene were investigated in the sporadic colorectal tumors of 44 patients from a Spanish community. Chromosome deletions were analyzed by means of loss of heterozygosity analysis using a restriction fragment length polymorphism assay. Allelic losses were also detected by polymerase chain reaction (PCR)-single-stranded conformation polymorphism (SSCP) analysis of a polymorphic site in intron 2 of the p53 gene. The percentages of genetic deletions on the screened chromosomes were 39.3% (5q), 58.3% (17p), 40.9% (18q), and 40% (22q). Mutations in p53 exons 2-9 were examined by PCR-SSCP analysis and direct sequencing of the mutated region. Twenty of 44 tumor samples (45.45%) showed mutations at various exons except for exons 2, 3, and 9, the most frequent changes being G-->T transversion and C-->T transition. Because oxygen-free radicals play a role in the carcinogenesis process, we evaluated the oxidative status of the colorectal tumors. Antioxidant activities, lipid peroxidation, and DNA-damaged product concentrations in colon tumors and normal mucosa were compared. In tumor tissues, superoxide dismutase and catalase decreased fourfold and twofold, respectively, whereas glutathione peroxidase and reduced glutathione increased threefold. Malondialdehyde and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were twofold higher in colorectal tumors than in normal mucosa. Seven of 10 DNA tumor samples (70%) showing higher values of 8-OHdG also had genetic alterations at different chromosomal loci. In these samples, the p53 gene was deleted or mutated in 71.4% of cases. We concluded that the observed changes in the oxidative metabolism of the tumor cells and the consecutive increase in DNA damage may potentiate the genomic instability of different chromosomal regions, leading to further cell malignancy and tumor expansion.

  3. New ideas in epilepsy genetics: novel epilepsy genes, copy number alterations, and gene regulation.

    PubMed

    Gurnett, Christina A; Hedera, Peter

    2007-03-01

    The majority of genes associated with epilepsy syndromes to date are ion channel genes. Selection bias may have allowed us to establish their role in epilepsy based on a priori knowledge of the significance of these proteins in regulating neuronal excitability. There are, however, more than 3000 genes expressed at the synapse, as well as many other genes expressed nearby in supporting cells and glia that can likewise regulate excitability. Identification of new genes involved in epilepsy may arise from studying the targets of anticonvulsant medications, ascertainment of an epileptic phenotype in mice, or as a result of positional cloning efforts. There are several loci for idiopathic focal and generalized epilepsies that lie in chromosomal regions that are devoid of known ion channels; therefore, the number of novel genes involved in epilepsy is likely to increase. Establishing the role of these novel genes in the pathogenesis of epilepsy has not been an easy task compared with the relative ease with which ion channel mutations can be studied. This review will describe several novel epilepsy genes and will then discuss other genetic causes of epilepsy, including alterations of chromosomal copy number and gene regulatory elements.

  4. Pharmacological Profiles of Alpha 2 Adrenergic Receptor Agonists Identified Using Genetically Altered Mice and Isobolographic Analysis

    PubMed Central

    Fairbanks, Carolyn A.; Stone, Laura S.; Wilcox, George L.

    2009-01-01

    Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (α2ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express α2AAR and α2CAR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal α2ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal α2AR agonists featured. PMID:19393691

  5. Genetic association and altered gene expression of osteoprotegerin in otosclerosis patients.

    PubMed

    Priyadarshi, Saurabh; Ray, Chinmay Sundar; Biswal, Narayan Chandra; Nayak, Soumya Ranjan; Panda, Khirod Chandra; Desai, Ashim; Ramchander, Puppala Venkat

    2015-07-01

    Otosclerosis (OTSC) is a late-onset hearing disorder characterized by increased bone turnover in the otic capsule. Disturbed osteoprotegerin expression has been found in the otosclerotic foci which may have an important role in the pathogenesis of OTSC. To identify the genetic risk factors, we sequenced the coding region and exon-intron boundaries of the OPG gene in 254 OTSC patients and 262 controls. Sequence analysis identified five known polymorphisms c.9C>G, c.30+15C>T, c.400+4C>T, c.768A>G, and c.817+8A>C. Testing of these SNPs revealed sex specific association with c.9C>G in males and c.30+15C>T in females after multiple correction. Furthermore, meta-analysis provided evidence of association of the c.9C>G polymorphism with OTSC. In secondary analysis, we investigated the mRNA expression of OPG and associated genes RANK and RANKL in otosclerotic tissues compared to controls. Expression analysis revealed significantly missing/reduced OPG expression only in otosclerotic tissues. However, the signal sequence polymorphism c.9C>G has shown no effect on OPG mRNA expression. In conclusion, our results suggest that the risk of OTSC is influenced by variations in the OPG gene along with other factors which might regulate its altered expression in otosclerotic tissues. Further research is warranted to elucidate the mechanisms underlying these observations.

  6. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain.

    PubMed

    Miksys, Sharon; Lerman, Caryn; Shields, Peter G; Mash, Deborah C; Tyndale, Rachel F

    2003-07-01

    CYP2B6 metabolizes drugs such as nicotine and bupropion, and many toxins and carcinogens. Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates. The aim of this study was to compare CYP2B6 expression in brains of human smokers and non-smokers and alcoholics and non-alcoholics (n=26). CYP2B6 expression was brain region-specific, and was observed in both neurons and astrocytes. CYP2B6 levels were higher in brains of smokers and alcoholics, particularly in cerebellar Purkinje cells and hippocampal pyramidal neurons, cells known to be damaged in alcoholics. Significantly more (p<0.05) CYP2B6 protein was seen in four brain regions of smoking alcoholics compared to non-smoking non-alcoholics: hippocampus (5.8-fold), caudate nucleus (3.3-fold), putamen (3.0-fold) and cerebellar hemisphere (1.6-fold). The genetic variant C1459T (R487C) has been associated with reduced hepatic enzyme levels, stability and activity. Preliminary genotyping of this small sample (n=24) suggested that individuals with the CC genotype had higher brain CYP2B6 than those with the CT or TT genotype. Higher brain CYP2B6 activity in smokers and alcoholics may cause altered sensitivity to centrally acting drugs, increased susceptibility to neurotoxins and carcinogenic xenobiotics and contribute to central tolerance to nicotine.

  7. Very low levels of direct additive genetic variance in fitness and fitness components in a red squirrel population

    PubMed Central

    McFarlane, S Eryn; Gorrell, Jamieson C; Coltman, David W; Humphries, Murray M; Boutin, Stan; McAdam, Andrew G

    2014-01-01

    A trait must genetically correlate with fitness in order to evolve in response to natural selection, but theory suggests that strong directional selection should erode additive genetic variance in fitness and limit future evolutionary potential. Balancing selection has been proposed as a mechanism that could maintain genetic variance if fitness components trade off with one another and has been invoked to account for empirical observations of higher levels of additive genetic variance in fitness components than would be expected from mutation–selection balance. Here, we used a long-term study of an individually marked population of North American red squirrels (Tamiasciurus hudsonicus) to look for evidence of (1) additive genetic variance in lifetime reproductive success and (2) fitness trade-offs between fitness components, such as male and female fitness or fitness in high- and low-resource environments. “Animal model” analyses of a multigenerational pedigree revealed modest maternal effects on fitness, but very low levels of additive genetic variance in lifetime reproductive success overall as well as fitness measures within each sex and environment. It therefore appears that there are very low levels of direct genetic variance in fitness and fitness components in red squirrels to facilitate contemporary adaptation in this population. PMID:24963372

  8. A pilot study evaluating genetic alterations that drive tobacco- and betel quid-associated oral cancer in Northeast India.

    PubMed

    Yadav, Dhirendra Singh; Chattopadhyay, Indranil; Verma, Anand; Devi, Thoudam Regina; Singh, L C; Sharma, Jagannath Dev; Kataki, Amal Ch; Saxena, Sunita; Kapur, Sujala

    2014-09-01

    The susceptibility of an individual to oral cancer is mediated by genetic factors and carcinogen-exposure behaviors such as betel quid chewing, tobacco use, and alcohol consumption. This pilot study was aimed to identify the genetic alteration in 100 bp upstream and downstream flanking regions in addition to the exonic regions of 169 cancer-associated genes by using Next Generation sequencing with aim to elucidate the molecular pathogenesis of tobacco- and betel quid-associated oral cancer of Northeast India. To understand the role of chemical compounds present in tobacco and betel quid associated with the progression of oral cancer, single nucleotide polymorphisms (SNPs) and insertion and deletion (Indels) found in this study were analyzed for their association with chemical compounds found in tobacco and betel quid using Comparative Toxogenomic Database. Genes (AR, BRCA1, IL8, and TP53) with novel SNP were found to be associated with arecoline which is the major component of areca nut. Genes (BARD1, BRCA2, CCND2, IGF1R, MSH6, and RASSF1) with novel deletion and genes (APC, BRMS1, CDK2AP1, CDKN2B, GAS1, IGF1R, and RB1) with novel insertion were found to be associated with aflatoxin B1 which is produced by fermented areca nut. Genes (ADH6, APC, AR, BARD1, BRMS1, CDKN1A, E2F1, FGFR4, FLNC, HRAS, IGF1R, IL12B, IL8, NBL1, STAT5B, and TP53) with novel SNP were found to be associated with aflatoxin B1. Genes (ATM, BRCA1, CDKN1A, EGFR, IL8, and TP53) with novel SNP were found to be associated with tobacco specific nitrosamines.

  9. Genetic and Phenotypic Analyses of a Papaver somniferum T-DNA Insertional Mutant with Altered Alkaloid Composition

    PubMed Central

    Kawano, Noriaki; Kiuchi, Fumiyuki; Kawahara, Nobuo; Yoshimatsu, Kayo

    2012-01-01

    The in vitro shoot culture of a T-DNA insertional mutant of Papaver somniferum L. established by the infection of Agrobacterium rhizogenes MAFF03-01724 accumulated thebaine instead of morphine as a major opium alkaloid. To develop a non-narcotic opium poppy and to gain insight into its genetic background, we have transplanted this mutant to soil, and analyzed its alkaloid content along with the manner of inheritance of T-DNA insertion loci among its selfed progenies. In the transplanted T0 primary mutant, the opium (latex) was found to be rich in thebaine (16.3% of dried opium) by HPLC analysis. The analyses on T-DNA insertion loci by inverse PCR, adaptor-ligation PCR, and quantitative real-time PCR revealed that as many as 18 copies of T-DNAs were integrated into a poppy genome in a highly complicated manner. The number of copies of T-DNAs was decreased to seven in the selected T3 progenies, in which the average thebaine content was 2.4-fold that of the wild type plant. This may indicate that the high thebaine phenotype was increasingly stabilized as the number of T-DNA copies was decreased. In addition, by reverse transcription PCR analysis on selected morphine biosynthetic genes, the expression of codeine 6-O-demethylase was clearly shown to be diminished in the T0 in vitro shoot culture, which can be considered as one of the key factors of altered alkaloid composition. PMID:24288085

  10. Defects in Tendon, Ligament, and Enthesis in Response to Genetic Alterations in Key Proteoglycans and Glycoproteins: A Review

    PubMed Central

    Juneja, Subhash C.

    2013-01-01

    This review summarizes the genetic alterations and knockdown approaches published in the literature to assess the role of key proteoglycans and glycoproteins in the structural development, function, and repair of tendon, ligament, and enthesis. The information was collected from (i) genetically altered mice, (ii) in vitro knockdown studies, (iii) genetic variants predisposition to injury, and (iv) human genetic diseases. The genes reviewed are for small leucine-rich proteoglycans (lumican, fibromodulin, biglycan, decorin, and asporin); dermatan sulfate epimerase (Dse) that alters structure of glycosaminoglycan and hence the function of small leucine-rich proteoglycans by converting glucuronic to iduronic acid; matricellular proteins (thrombospondin 2, secreted phosphoprotein 1 (Spp1), secreted protein acidic and rich in cysteine (Sparc), periostin, and tenascin X) including human tenascin C variants; and others, such as tenomodulin, leukocyte cell derived chemotaxin 1 (chondromodulin-I, ChM-I), CD44 antigen (Cd44), lubricin (Prg4), and aggrecan degrading gene, a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5 (Adamts5). Understanding these genes represents drug targets for disrupting pathological mechanisms that lead to tendinopathy, ligamentopathy, enthesopathy, enthesitis and tendon/ligament injury, that is, osteoarthritis and ankylosing spondylitis. PMID:24324885

  11. A large-scale genetic screen for mutants with altered salicylic acid accumulation in Arabidopsis.

    PubMed

    Ding, Yezhang; Shaholli, Danjela; Mou, Zhonglin

    2014-01-01

    Salicylic acid (SA) is a key defense signal molecule against biotrophic and hemibiotrophic pathogens in plants, but how SA is synthesized in plant cells still remains elusive. Identification of new components involved in pathogen-induced SA accumulation would help address this question. To this end, we performed a large-scale genetic screen for mutants with altered SA accumulation during pathogen infection in Arabidopsis using a bacterial biosensor Acinetobacter sp. ADPWH_lux-based SA quantification method. A total of 35,000 M2 plants in the npr1-3 mutant background have been individually analyzed for the bacterial pathogen Pseudomonas syringae pv. maculicola (Psm) ES4326-induced SA accumulation. Among the mutants isolated, 19 had SA levels lower than npr1 (sln) and two exhibited increased SA accumulation in npr1 (isn). Complementation tests revealed that seven of the sln mutants are new alleles of eds5/sid1, two are sid2/eds16 alleles, one is allelic to pad4, and the remaining seven sln and two isn mutants are new non-allelic SA accumulation mutants. Interestingly, a large group of mutants (in the npr1-3 background), in which Psm ES4326-induced SA levels were similar to those in the wild-type Columbia plants, were identified, suggesting that the signaling network fine-tuning pathogen-induced SA accumulation is complex. We further characterized the sln1 single mutant and found that Psm ES4326-induced defense responses were compromised in this mutant. These defense response defects could be rescued by exogenous SA, suggesting that SLN1 functions upstream of SA. The sln1 mutation was mapped to a region on the north arm of chromosome I, which contains no known genes regulating pathogen-induced SA accumulation, indicating that SLN1 likely encodes a new regulator of SA biosynthesis. Thus, the new sln and isn mutants identified in this genetic screen are valuable for dissecting the molecular mechanisms underlying pathogen-induced SA accumulation in plants.

  12. Toxicological safety assessment of genetically modified Bacillus thuringiensis with additional N-acyl homoserine lactonase gene.

    PubMed

    Peng, Donghai; Zhou, Chenfei; Chen, Shouwen; Ruan, Lifang; Yu, Ziniu; Sun, Ming

    2008-01-01

    The aim of the present study is to evaluate the toxicology safety to mammals of a genetically modified (GM) Bacillus thuringiensis with an additional N-acyl homoserine lactones gene (aiiA), which possesses insecticidal activity together with restraint of bacterial pathogenicity and is intended for use as a multifunctional biopesticide. Safety assessments included an acute oral toxicity test and 28-d animal feeding study in Wistar rats, primary eye and dermal irritation in Zealand White rabbits, and delayed contact hypersensitivity in guinea pigs. Tests were conducted using spray-dried powder preparation. This GM product showed toxicity neither in oral acute toxicity test nor in 28-d animal feeding test at a dose of 5,000 mg/kg body weight. During the animal feeding test, there were no significant differences in growth, food and water consumption, hematology, blood biochemical indices, organ weights, and histopathology finding between rats in controls and tested groups. Tested animals in primary eye and dermal irritation and delayed contact hypersensitivity test were also devoid of any toxicity compared to controls. All the above results demonstrated that the GM based multifunctional B. thuringiensis has low toxicity and low eye and dermal irritation and would not cause hypersensitivity to laboratory mammals and therefore could be regarded as safe for use as a pesticide.

  13. Genetic alterations related to BRAF-FGFR genes and dysregulated MAPK/ERK/mTOR signaling in adult pilocytic astrocytoma.

    PubMed

    Pathak, Pankaj; Kumar, Anupam; Jha, Prerana; Purkait, Suvendu; Faruq, Mohammed; Suri, Ashish; Suri, Vaishali; Sharma, Mehar C; Sarkar, Chitra

    2016-09-08

    Pilocytic astrocytomas occur rarely in adults and show aggressive tumor behavior. However, their underlying molecular-genetic events are largely uncharacterized. Hence, 59 adult pilocytic astrocytoma (APA) cases of classical histology were studied (MIB-1 LI: 1%-5%). Analysis of BRAF alterations using qRT-PCR, confirmed KIAA1549-BRAF fusion in 11 (19%) and BRAF-gain in 2 (3.4%) cases. BRAF-V600E mutation was noted in 1 (1.7%) case by sequencing. FGFR1-mutation and FGFR-TKD duplication were seen in 7/59 (11.9%) and 3/59 (5%) cases, respectively. Overall 36% of APAs harbored BRAF and/or FGFR genetic alterations. Notably, FGFR related genetic alterations were enriched in tumors of supratentorial region (8/25, 32%) as compared with other locations (P = 0.01). The difference in age of cases with FGFR1-mutation (Mean age ± SD: 37.2 ± 15 years) vs. KIAA1549-BRAF fusion (Mean age ± SD: 25.1 ± 4.1 years) was statistically significant (P = 0.03). Combined BRAF and FGFR alterations were identified in 3 (5%) cases. Notably, the cases with more than one genetic alteration were in higher age group (Mean age ± SD: 50 ± 12 years) as compared with cases with single genetic alteration (Mean age ± SD: 29 ± 10; P = 0.003). Immunopositivity of p-MAPK/p-MEK1 was found in all the cases examined. The pS6-immunoreactivity, a marker of mTOR activation was observed in 34/39 (87%) cases. Interestingly, cases with BRAF and/or FGFR related alteration showed significantly lower pS6-immunostatining (3/12; 25%) as compared with those with wild-type BRAF and/or FGFR (16/27; 59%) (P = 0.04). Further, analysis of seven IDH wild-type adult diffuse astrocytomas (DA) showed FGFR related genetic alterations in 43% cases. These and previous results suggest that APAs are genetically similar to IDH wild-type adult DAs. APAs harbor infrequent BRAF alterations but more frequent FGFR alterations as compared with pediatric cases. KIAA1549-BRAF fusion

  14. Impacts of genetically engineered alterations in carbon sink pathways on photosynthetic performance

    DOE PAGES

    Holland, Steven C.; Artier, Juliana; Miller, Neil T.; ...

    2016-10-05

    Genetic engineering of photosynthetic organisms typically redirects native metabolism towards desirable products, which thereby represent new metabolic sinks. There is limited information on how these modifications impact the evolved mechanisms of photosynthetic energy metabolism and cellular growth. Two engineered strains of Synechocystis sp. PCC 6803 with altered carbon sink capacity were assayed for their photosynthetic and CO2 concentrating mechanism properties in conditions of high and low inorganic carbon (Ci) availability. In the ΔglgC mutant, glycogen cannot be synthesized and a carbon sink pathway has been effectively removed. The JU547 strain has been engineered by integration of the Pseudomonas syringae ethylenemore » forming enzyme and provides a new sink. When cultured under high carbon conditions, ΔglgC displayed diminished photochemical efficiency, a more reduced NADPH pool, delayed initiation of the Calvin-Benson-Bassham cycle, and impairment of linear and cyclic electron flows. It also exhibited a large decrease in photochemical quenching indicative of the accumulation of QA-, normally associated with a reduced PQ pool, but appears instead to be the result of an undefined dissipative mechanism to spill excess energy. In the case of carbon sink integration, JU547 displayed slightly more oxidized PQ and NADPH pools and increased rates of cyclic electron flow and an enhanced demand for inorganic carbon as suggested by increase in the expression of the bicarbonate transporter, SbtA. Overall, the results highlight the importance of the native regulatory network of autotrophic metabolism in governing photosynthetic performance and provide cogent examples of both predicable and difficult to predict phenotypic consequences upon installation of new pathways in autotrophs.« less

  15. Impacts of genetically engineered alterations in carbon sink pathways on photosynthetic performance

    SciTech Connect

    Holland, Steven C.; Artier, Juliana; Miller, Neil T.; Cano, Melissa; Yu, Jianping; Ghirardi, Maria L.; Burnap, Robert L.

    2016-10-05

    Genetic engineering of photosynthetic organisms typically redirects native metabolism towards desirable products, which thereby represent new metabolic sinks. There is limited information on how these modifications impact the evolved mechanisms of photosynthetic energy metabolism and cellular growth. Two engineered strains of Synechocystis sp. PCC 6803 with altered carbon sink capacity were assayed for their photosynthetic and CO2 concentrating mechanism properties in conditions of high and low inorganic carbon (Ci) availability. In the ΔglgC mutant, glycogen cannot be synthesized and a carbon sink pathway has been effectively removed. The JU547 strain has been engineered by integration of the Pseudomonas syringae ethylene forming enzyme and provides a new sink. When cultured under high carbon conditions, ΔglgC displayed diminished photochemical efficiency, a more reduced NADPH pool, delayed initiation of the Calvin-Benson-Bassham cycle, and impairment of linear and cyclic electron flows. It also exhibited a large decrease in photochemical quenching indicative of the accumulation of QA-, normally associated with a reduced PQ pool, but appears instead to be the result of an undefined dissipative mechanism to spill excess energy. In the case of carbon sink integration, JU547 displayed slightly more oxidized PQ and NADPH pools and increased rates of cyclic electron flow and an enhanced demand for inorganic carbon as suggested by increase in the expression of the bicarbonate transporter, SbtA. Overall, the results highlight the importance of the native regulatory network of autotrophic metabolism in governing photosynthetic performance and provide cogent examples of both predicable and difficult to predict phenotypic consequences upon installation of new pathways in autotrophs.

  16. Genetic alteration profiling of patients with resected squamous cell lung carcinomas

    PubMed Central

    Zhang, Ningning; Lin, Dongmei; Wu, Di; Zhu, Xinxin; Song, Wenya; Shi, Yuankai

    2016-01-01

    In this study, we analyzed the genetic profiles of squamous cell lung carcinoma (SqCLC) to identify potential therapeutic targets. Approximately 2,800 COSMIC mutations from 50 genes were determined by next-generation sequencing. Amplification/deletion of SOX2, CDKN2A, PTEN, FGFR1, EGFR, CCND1, HER2 and PDGFRA were detected by FISH and expression of VEGFR2, PD-L1 and PTEN were examined by IHC. One hundred and fifty-seven samples of SqCLC were collected. Somatic mutations was identified in 73.9% of cases, with TP53 (56.1%), CDKN2A (8.9%), PIK3CA (8.9%), KRAS (4.5%) and EGFR (3.2%). Gene copy number alterations were identified in 75.8% of cases, including SOX2 amplification (31.2%), CDKN2A deletion (21.7%), PTEN deletion (16.6%), FGFR1 amplification (15.9%), EGFR amplification (14.0%), CCND1 amplification (14.0%), HER2 amplification (9.6%) and PDGFRA amplification (7.6%). Positive expression of VEGFR2 and PD-L1 and loss of PTEN expression were observed in 80.5%, 47.2%, and 42.7% of cases, respectively. Multivariate analysis showed that positive expression of PD-L1 was an independent favorable prognostic factor for DFS (HR = 0.610; P = 0.044). In conclusion, nearly all (93.6%) SqCLC cases harbored at least one potential druggable target. The findings of this study could facilitate the identification of therapeutic target candidates for precision medicine of SqCLC. PMID:27145277

  17. Intrinsic Noise Profoundly Alters the Dynamics and Steady State of Morphogen-Controlled Bistable Genetic Switches

    PubMed Central

    Page, Karen M.

    2016-01-01

    During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules—morphogens—guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms. Here, we explore the dynamics of the toggle switch and use exact numerical simulations of the kinetic reactions, the corresponding Chemical Langevin Equation, and Minimum Action Path theory to establish a framework for studying the effect of gene expression noise on patterning time and boundary position. This provides insight into the time scale, gene expression trajectories and directionality of stochastic switching events between cell states. Taking gene expression noise into account predicts that the final boundary position of a morphogen-induced toggle switch, although robust to changes in the details of the noise, is distinct from that of the deterministic system. Moreover, the dramatic increase in patterning time close to the boundary predicted from the deterministic case is substantially reduced. The resulting stochastic switching introduces differences in patterning time along the morphogen gradient that result in a patterning wave propagating away from the morphogen source with a velocity determined by the intrinsic noise. The wave sharpens and slows as it advances and may never reach steady state in a biologically relevant time. This could explain experimentally observed dynamics of pattern formation. Together the analysis reveals the importance of dynamical transients for understanding morphogen-driven transcriptional networks and indicates that gene expression noise can qualitatively

  18. Recent and Projected Increases in Atmospheric CO2 Concentration Can Enhance Gene Flow between Wild and Genetically Altered Rice (Oryza sativa)

    PubMed Central

    Ziska, Lewis H.; Gealy, David R.; Tomecek, Martha B.; Jackson, Aaron K.; Black, Howard L.

    2012-01-01

    Although recent and projected increases in atmospheric carbon dioxide can alter plant phenological development, these changes have not been quantified in terms of floral outcrossing rates or gene transfer. Could differential phenological development in response to rising CO2 between genetically modified crops and wild, weedy relatives increase the spread of novel genes, potentially altering evolutionary fitness? Here we show that increasing CO2 from an early 20th century concentration (300 µmol mol−1) to current (400 µmol mol−1) and projected, mid-21st century (600 µmol mol−1) values, enhanced the flow of genes from wild, weedy rice to the genetically altered, herbicide resistant, cultivated population, with outcrossing increasing from 0.22% to 0.71% from 300 to 600 µmol mol−1. The increase in outcrossing and gene transfer was associated with differential increases in plant height, as well as greater tiller and panicle production in the wild, relative to the cultivated population. In addition, increasing CO2 also resulted in a greater synchronicity in flowering times between the two populations. The observed changes reported here resulted in a subsequent increase in rice dedomestication and a greater number of weedy, herbicide-resistant hybrid progeny. Overall, these data suggest that differential phenological responses to rising atmospheric CO2 could result in enhanced flow of novel genes and greater success of feral plant species in agroecosystems. PMID:22649533

  19. Touch imprint cytology with massively parallel sequencing (TIC-seq): a simple and rapid method to snapshot genetic alterations in tumors.

    PubMed

    Amemiya, Kenji; Hirotsu, Yosuke; Goto, Taichiro; Nakagomi, Hiroshi; Mochizuki, Hitoshi; Oyama, Toshio; Omata, Masao

    2016-12-01

    Identifying genetic alterations in tumors is critical for molecular targeting of therapy. In the clinical setting, formalin-fixed paraffin-embedded (FFPE) tissue is usually employed for genetic analysis. However, DNA extracted from FFPE tissue is often not suitable for analysis because of its low levels and poor quality. Additionally, FFPE sample preparation is time-consuming. To provide early treatment for cancer patients, a more rapid and robust method is required for precision medicine. We present a simple method for genetic analysis, called touch imprint cytology combined with massively paralleled sequencing (touch imprint cytology [TIC]-seq), to detect somatic mutations in tumors. We prepared FFPE tissues and TIC specimens from tumors in nine lung cancer patients and one patient with breast cancer. We found that the quality and quantity of TIC DNA was higher than that of FFPE DNA, which requires microdissection to enrich DNA from target tissues. Targeted sequencing using a next-generation sequencer obtained sufficient sequence data using TIC DNA. Most (92%) somatic mutations in lung primary tumors were found to be consistent between TIC and FFPE DNA. We also applied TIC DNA to primary and metastatic tumor tissues to analyze tumor heterogeneity in a breast cancer patient, and showed that common and distinct mutations among primary and metastatic sites could be classified into two distinct histological subtypes. TIC-seq is an alternative and feasible method to analyze genomic alterations in tumors by simply touching the cut surface of specimens to slides.

  20. [Questions safety and tendency of using genetically modified microorganisms in food, food additives and food derived].

    PubMed

    Khovaev, A A

    2008-01-01

    In this article analysis questions of using genetically modified microorganisms in manufacture food production, present new GMM used in manufacture -food ferments; results of medical biological appraisal/ microbiological and genetic expert examination/ of food, getting by use microorganisms or there producents with indication modern of control methods.

  1. Examination of Genetic Alterations in Preneoplastic and Neoplastic Lesions of the Lung From Uranium Miners. Final Technical Report

    SciTech Connect

    Anderson, Marshall

    2000-07-12

    Lung cancer is one of the leading causes of death in the United States and in Western Europe. The incidence of lung cancer in developing countries is rising as their cigarette smoking habits increase. The objectives of this proposed research are to analyze genetic alterations associated with the development and progression on non-small cell lung carcinoma (MSCLC). Endpoints that may be realized from this proposed research are: (1) detection of early genetic and/or cellular alterations which ultimately could lead to diagnostic modalities for the early detection of lung cancer; and (2) detection of novel tumor suppressor genes on chromosome 9p. This proposal will analyze both tumor specimens and sputum samples.

  2. Simple additive simulation overestimates real influence: altered nitrogen and rainfall modulate the effect of warming on soil carbon fluxes.

    PubMed

    Ni, Xiangyin; Yang, Wanqin; Qi, Zemin; Liao, Shu; Xu, Zhenfeng; Tan, Bo; Wang, Bin; Wu, Qinggui; Fu, Changkun; You, Chengming; Wu, Fuzhong

    2016-12-09

    Experiments and models have led to a consensus that there is positive feedback between carbon (C) fluxes and climate warming. However, the effect of warming may be altered by regional and global changes in nitrogen (N) and rainfall levels, but the current understanding is limited. Through synthesizing global data on soil C pool, input and loss from experiments simulating N deposition, drought and increased precipitation, we quantified the responses of soil C fluxes and equilibrium to the three single factors and their interactions with warming. We found that warming slightly increased the soil C input and loss by 5% and 9%, respectively, but had no significant effect on the soil C pool. Nitrogen deposition alone increased the soil C input (+20%), but the interaction of warming and N deposition greatly increased the soil C input by 49%. Drought alone decreased the soil C input by 17%, while the interaction of warming and drought decreased the soil C input to a greater extent (-22%). Increased precipitation stimulated the soil C input by 15%, but the interaction of warming and increased precipitation had no significant effect on the soil C input. However, the soil C loss was not significantly affected by any of the interactions, although it was constrained by drought (-18%). These results implied that the positive C fluxes-climate warming feedback was modulated by the changing N and rainfall regimes. Further, we found that the additive effects of [warming × N deposition] and [warming × drought] on the soil C input and of [warming × increased precipitation] on the soil C loss were greater than their interactions, suggesting that simple additive simulation using single-factor manipulations may overestimate the effects on soil C fluxes in the real world. Therefore, we propose that more multifactorial experiments should be considered in studying Earth systems.

  3. Planning additional drilling campaign using two-space genetic algorithm: A game theoretical approach

    NASA Astrophysics Data System (ADS)

    Kumral, Mustafa; Ozer, Umit

    2013-03-01

    Grade and tonnage are the most important technical uncertainties in mining ventures because of the use of estimations/simulations, which are mostly generated from drill data. Open pit mines are planned and designed on the basis of the blocks representing the entire orebody. Each block has different estimation/simulation variance reflecting uncertainty to some extent. The estimation/simulation realizations are submitted to mine production scheduling process. However, the use of a block model with varying estimation/simulation variances will lead to serious risk in the scheduling. In the medium of multiple simulations, the dispersion variances of blocks can be thought to regard technical uncertainties. However, the dispersion variance cannot handle uncertainty associated with varying estimation/simulation variances of blocks. This paper proposes an approach that generates the configuration of the best additional drilling campaign to generate more homogenous estimation/simulation variances of blocks. In other words, the objective is to find the best drilling configuration in such a way as to minimize grade uncertainty under budget constraint. Uncertainty measure of the optimization process in this paper is interpolation variance, which considers data locations and grades. The problem is expressed as a minmax problem, which focuses on finding the best worst-case performance i.e., minimizing interpolation variance of the block generating maximum interpolation variance. Since the optimization model requires computing the interpolation variances of blocks being simulated/estimated in each iteration, the problem cannot be solved by standard optimization tools. This motivates to use two-space genetic algorithm (GA) approach to solve the problem. The technique has two spaces: feasible drill hole configuration with minimization of interpolation variance and drill hole simulations with maximization of interpolation variance. Two-space interacts to find a minmax solution

  4. Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations

    PubMed Central

    Ganz, Ariel B.; Cohen, Vanessa V.; Swersky, Camille C.; Stover, Julie; Vitiello, Gerardo A.; Lovesky, Jessica; Chuang, Jasmine C.; Shields, Kelsey; Fomin, Vladislav G.; Lopez, Yusnier S.; Mohan, Sanjay; Ganti, Anita; Carrier, Bradley; Malysheva, Olga V.; Caudill, Marie A.

    2017-01-01

    Single nucleotide polymorphisms (SNPs) in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women (n = 75) consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9) for 10–12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N-methyltransferase (PEMT) denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term. PMID:28134761

  5. The TP53 tumour suppressor gene in colorectal carcinomas. I. Genetic alterations on chromosome 17.

    PubMed Central

    Meling, G. I.; Lothe, R. A.; Børresen, A. L.; Graue, C.; Hauge, S.; Clausen, O. P.; Rognum, T. O.

    1993-01-01

    In 231 colorectal carcinomas, allele variation at four restriction fragments length polymorphisms (RFLP) loci on chromosome 17 have been studied by Southern analysis. Heterozygous loss of the TP53 gene was found in 68% (129/189) of the carcinomas informative on both chromosome arms. In 41% (77/189) of the carcinomas the loss was found only on 17p. Two probes were used to detect alterations on 17p, pBHP53 and pYNZ22. When loss was demonstrated with pYNZ22, pBHP53 also always showed loss (n = 45), whereas when loss was demonstrated with pBHP53, only 45 of 54 (83%) showed loss with pYNZ22. Loss on 17q was found in 34% (64/189) of the carcinomas, and 6% (12/189) had loss on this chromosome arm, only. Loss on 17q was significantly associated with loss on 17p (P < 0.01). These data confirm that the TP53 gene is the target of loss on chromosome arm 17p in colorectal carcinomas, and demonstrate that loss of the TP53 gene is most frequently part of limited, subchromosomal loss. Furthermore, the results do not suggest any additional tumour suppressor gene(s) on chromosome 17 involved in colorectal carcinogenesis. Images Figure 2 PMID:8094008

  6. PIK3CA Mutation in Colorectal Cancer: Relationship with Genetic and Epigenetic Alterations1

    PubMed Central

    Nosho, Katsuhiko; Kawasaki, Takako; Ohnishi, Mutsuko; Suemoto, Yuko; Kirkner, Gregory J; Zepf, Dimity; Yan, Liying; Longtine, Janina A; Fuchs, Charles S; Ogino, Shuji

    2008-01-01

    Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and β-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level. PMID:18516290

  7. Detection of ultrastructural changes in genetically altered and exercised skeletal muscle using PS-OCT

    NASA Astrophysics Data System (ADS)

    Pasquesi, James J.; Schlachter, Simon C.; Boppart, Marni D.; Chaney, Eric; Kaufman, Stephen J.; Boppart, Stephen A.

    2006-02-01

    Birefringence of skeletal muscle has been associated with the ultrastructure of individual sarcomeres, specifically the arrangement of A-bands corresponding to the thick myosin filaments. Murine skeletal muscle (gastrocnemius) was imaged with a fiber-based PS-OCT imaging system to determine the level of birefringence present in the tissue under various conditions. In addition to muscle controls from wild-type mice, muscle from abnormal mice included: genetically-modified (mdx) mice which model human muscular dystrophy, transgenic mice exhibiting an overexpression of integrin (α7β1), and transgenic integrin (α7β1)knockout mice. Comparisons were also made between rested and exercised muscles to determine the effects of exercise on muscle birefringence for each of these normal and abnormal conditions. The PS-OCT images revealed that the presence of birefringence was similar in the rested muscle with dystrophy-like features (i.e., lacking the structural protein dystrophin - mdx) and in the integrin (α7β1)knockout muscle when compared to the normal (wild-type) control. However, exercising these abnormal muscle tissues drastically reduced the presence of birefringence detected by the PS-OCT system. The muscle exhibiting an overexpression of integrin (α7β1) remained heavily birefringent before and after exercise, similar to the normal (wild-type) muscle. These results suggest that there is a distinct relationship between the degree of birefringence detected using PS-OCT and the sarcomeric ultrastructure present within skeletal muscle.

  8. Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether t...

  9. Evidence that disease-induced population decline changes genetic structure and alters dispersal patterns in the Tasmanian devil.

    PubMed

    Lachish, S; Miller, K J; Storfer, A; Goldizen, A W; Jones, M E

    2011-01-01

    Infectious disease has been shown to be a major cause of population declines in wild animals. However, there remains little empirical evidence on the genetic consequences of disease-mediated population declines, or how such perturbations might affect demographic processes such as dispersal. Devil facial tumour disease (DFTD) has resulted in the rapid decline of the Tasmanian devil, Sarcophilus harrisii, and threatens to cause extinction. Using 10 microsatellite DNA markers, we compared genetic diversity and structure before and after DFTD outbreaks in three Tasmanian devil populations to assess the genetic consequences of disease-induced population decline. We also used both genetic and demographic data to investigate dispersal patterns in Tasmanian devils along the east coast of Tasmania. We observed a significant increase in inbreeding (F(IS) pre/post-disease -0.030/0.012, P<0.05; relatedness pre/post-disease 0.011/0.038, P=0.06) in devil populations after just 2-3 generations of disease arrival, but no detectable change in genetic diversity. Furthermore, although there was no subdivision apparent among pre-disease populations (θ=0.005, 95% confidence interval (CI) -0.003 to 0.017), we found significant genetic differentiation among populations post-disease (θ=0.020, 0.010-0.027), apparently driven by a combination of selection and altered dispersal patterns of females in disease-affected populations. We also show that dispersal is male-biased in devils and that dispersal distances follow a typical leptokurtic distribution. Our results show that disease can result in genetic and demographic changes in host populations over few generations and short time scales. Ongoing management of Tasmanian devils must now attempt to maintain genetic variability in this species through actions designed to reverse the detrimental effects of inbreeding and subdivision in disease-affected populations.

  10. Genetic and physiological alterations occurring in a yeast population continuously propagated at increasing temperatures with cell recycling.

    PubMed

    Souza, Crisla S; Thomaz, Daniel; Cides, Elaine R; Oliveira, Karen F; Tognolli, João O; Laluce, Cecilia

    2007-12-01

    This work investigated the effects of increasing temperature from 30°C to 47°C on the physiological and genetic characteristics of Saccharomyces cerevisiae strain 63M after continuous fermentation with cell recycling in a system of five reactors in series. Steady state was attained at 30°C, and then the temperature of the system was raised so it ranged from 35°C in the last reactor to 43°C in the first reactor or feeding reactor with a 2°C difference between reactors. After 15 days at steady state, the temperature was raised from 37°C to 45°C for 25 days at steady state, then from 39°C to 47°C for 20 days at steady state. Starter strain 63M was a hybrid strain constructed to have a MAT a/α, LYS/lys, URA/ura genotype. This hybrid yeast showed vigorous growth on plates at 40°C, weak growth at 41°C, positive assimilation of melibiose, positive fermentation of galactose, raffinose and sucrose. Of 156 isolates obtained from this system at the end of the fermentation process, only 17.3% showed the same characteristics as starter strain 63M. Alterations in mating type reaction and in utilization of raffinose, melibiose, and sucrose were identified. Only 1.9% of the isolates lost the ability to grow at 40°C. Isolates showing requirements for lysine and uracil were also obtained. In addition, cell survival was observed at 39-47°C, but no isolates showing growth above 41°C were obtained.

  11. Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis.

    PubMed

    Le Henaff, Carole; Faria Da Cunha, Mélanie; Hatton, Aurélie; Tondelier, Danielle; Marty, Caroline; Collet, Corinne; Zarka, Mylène; Geoffroy, Valérie; Zatloukal, Kurt; Laplantine, Emmanuel; Edelman, Aleksander; Sermet-Gaudelus, Isabelle; Marie, Pierre J

    2016-04-01

    Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti-osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at low levels. Genetic studies showed that Krt8 deletion (Krt8(-/-)) in F508del-Cftr mice increased the levels of circulating markers of bone formation, corrected the expression of osteoblast phenotypic genes, promoted trabecular bone formation and improved bone mass and microarchitecture. Mechanistically, Krt8 deletion in F508del-Cftr mice corrected overactive NF-κB signaling and decreased Wnt-β-catenin signaling induced by the F508del-Cftr mutation in osteoblasts. In vitro, treatment with compound 407, which specifically disrupts the Krt8-F508del-Cftr interaction in epithelial cells, corrected the abnormal NF-κB and Wnt-β-catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt-β-catenin signaling and bone formation in F508del-Cftr mice. Collectively, the results show that genetic or pharmacologic targeting of Krt8 leads to correction of osteoblast dysfunctions, altered bone formation and osteopenia in F508del-Cftr mice, providing a therapeutic strategy targeting the Krt8-F508del-CFTR interaction to correct the abnormal bone formation and bone loss in cystic fibrosis.

  12. Genome-Enabled Estimates of Additive and Nonadditive Genetic Variances and Prediction of Apple Phenotypes Across Environments

    PubMed Central

    Kumar, Satish; Molloy, Claire; Muñoz, Patricio; Daetwyler, Hans; Chagné, David; Volz, Richard

    2015-01-01

    The nonadditive genetic effects may have an important contribution to total genetic variation of phenotypes, so estimates of both the additive and nonadditive effects are desirable for breeding and selection purposes. Our main objectives were to: estimate additive, dominance and epistatic variances of apple (Malus × domestica Borkh.) phenotypes using relationship matrices constructed from genome-wide dense single nucleotide polymorphism (SNP) markers; and compare the accuracy of genomic predictions using genomic best linear unbiased prediction models with or without including nonadditive genetic effects. A set of 247 clonally replicated individuals was assessed for six fruit quality traits at two sites, and also genotyped using an Illumina 8K SNP array. Across several fruit quality traits, the additive, dominance, and epistatic effects contributed about 30%, 16%, and 19%, respectively, to the total phenotypic variance. Models ignoring nonadditive components yielded upwardly biased estimates of additive variance (heritability) for all traits in this study. The accuracy of genomic predicted genetic values (GEGV) varied from about 0.15 to 0.35 for various traits, and these were almost identical for models with or without including nonadditive effects. However, models including nonadditive genetic effects further reduced the bias of GEGV. Between-site genotypic correlations were high (>0.85) for all traits, and genotype-site interaction accounted for <10% of the phenotypic variability. The accuracy of prediction, when the validation set was present only at one site, was generally similar for both sites, and varied from about 0.50 to 0.85. The prediction accuracies were strongly influenced by trait heritability, and genetic relatedness between the training and validation families. PMID:26497141

  13. The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance

    PubMed Central

    Forsberg, Simon K. G.; Andreatta, Matthew E.; Huang, Xin-Yuan; Danku, John; Salt, David E.; Carlborg, Örjan

    2015-01-01

    Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or “missing heritability”. Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations. PMID:26599497

  14. Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors

    PubMed Central

    Evers, B.Mark

    2013-01-01

    Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/β-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of β-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues. By mutational analysis, the mutations of β-catenin (I35S) and APC (E1317Q, T1493T) were identified in NET cells and the tissues. Expression of representative Wnt inhibitors was absent or markedly decreased in BON, a human pancreatic carcinoid cell line; treatment with 5-aza-2′-deoxycytidine (5-aza-CdR) increased expression levels of the Wnt inhibitors. Methylation analyses demonstrated that CpG islands of SFRP-1 and Axin-2 were methylated, whereas the promoters of DKK-1, DKK-3 and WIF-1 were unmethylated in four NET cells. Aberrant methylation of SFRP-1 was particularly observed in most of clinical NET tissues. In addition, the repression of these unmethylated genes was associated with histone H3 lysine 9 dimethylation (H3K9me2) in BON cells. Together, 5-aza-CdR treatment inhibited cell proliferation and decreased the protein levels of H3K9me2 and G9a. Moreover, a novel G9a inhibitor, UNC0638, suppressed BON cell proliferation through inhibition of Wnt/β-catenin pathway. Overexpression of the inhibitory genes, particularly SFRP-1 and WIF-1 in BON cells, resulted in suppression of anchorage-independent growth and inhibition of tumor growth in mice. Our findings suggest that aberrant Wnt/β-catenin signaling, through either mutations or epigenetic silencing of Wnt antagonists, contributes to the pathogenesis and growth of NETs and have important clinical implications for the prognosis and treatment of NETs. PMID:23354304

  15. Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

    PubMed Central

    Wang, Jing; Long, Cheng; Zhang, Haijun; Zhang, Yanan; Wang, Hao; Yue, Hongyuan; Wang, Xiaocui; Wu, Shugeng; Qi, Guanghai

    2016-01-01

    Genetic variant T329S in flavin-containing monooxygenase 3 (FMO3) impairs trimethylamine (TMA) metabolism in birds. The TMA metabolism that under complex genetic and dietary regulation, closely linked to cardiovascular disease risk. We determined whether the genetic defects in TMA metabolism may change other metabolic traits in birds, determined whether the genetic effects depend on diets, and to identify genes or gene pathways that underlie the metabolic alteration induced by genetic and diet factors. We used hens genotyped as FMO3 c.984 A>T as well as those with the homozygous normal genotype. For each genotype, hens were provided with either a corn-soybean meal basal diets (SM), which contains lower levels of TMA precursor, or the basal diets supplemented with 21% of rapeseed meal (RM), which contains higher levels of TMA precursor. An integrative analysis of metabolomic and transcriptomic was used to explore the metabolic patterns of FMO3 genetic variant in hens that were fed the two defined diets. In birds that consumed SM diets, the T329S mutation increased levels of plasma TMA and lipids, FMO3 mRNA levels, and the expression of genes involved in long chain polyunsaturated fatty acid biosynthesis. In birds that consumed RM diets, the T329S mutation induced fishy odor syndrome, a repression in LXR pathway and a reciprocal change in lipid metabolism. Variations in TMA and lipid metabolism were linked to the genetic variant in FMO3 in a diet-specific manner, which suggest FMO3 functions in TMA metabolism and lipid homeostasis. LXR pathway and polyunsaturated fatty acid metabolism are two possible mechanisms of FMO3 action in response to dietary TMA precursor. PMID:27877090

  16. Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing

    PubMed Central

    Somasundaram, Kumaravel

    2015-01-01

    Cell lines derived from tumor tissues have been used as a valuable system to study gene regulation and cancer development. Comprehensive characterization of the genetic background of cell lines could provide clues on novel genes responsible for carcinogenesis and help in choosing cell lines for particular studies. Here, we have carried out whole exome and RNA sequencing of commonly used glioblastoma (GBM) cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotide variations (SNVs), indels, differential gene expression, gene fusions and RNA editing events. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) were potentially cancer-specific. The cell lines showed frequent SNVs and indels in some of the genes that are known to be altered in GBM- EGFR, TP53, PTEN, SPTA1 and NF1. Chromatin modifying genes- ATRX, MLL3, MLL4, SETD2 and SRCAP also showed alterations. While no cell line carried IDH1 mutations, five cell lines showed hTERT promoter activating mutations with a concomitant increase in hTERT transcript levels. Five significant gene fusions were found of which NUP93-CYB5B was validated. An average of 18,949 RNA editing events was also obtained. Thus we have generated a comprehensive catalogue of genetic alterations for six GBM cell lines. PMID:26496030

  17. Lung Adenocarcinoma of Never Smokers and Smokers Harbor Differential Regions of Genetic Alteration and Exhibit Different Levels of Genomic Instability

    PubMed Central

    Thu, Kelsie L.; Vucic, Emily A.; Chari, Raj; Zhang, Wei; Lockwood, William W.; English, John C.; Fu, Rong; Wang, Pei; Feng, Ziding; MacAulay, Calum E.; Gazdar, Adi F.; Lam, Stephen; Lam, Wan L.

    2012-01-01

    Recent evidence suggests that the observed clinical distinctions between lung tumors in smokers and never smokers (NS) extend beyond specific gene mutations, such as EGFR, EML4-ALK, and KRAS, some of which have been translated into targeted therapies. However, the molecular alterations identified thus far cannot explain all of the clinical and biological disparities observed in lung tumors of NS and smokers. To this end, we performed an unbiased genome-wide, comparative study to identify novel genomic aberrations that differ between smokers and NS. High resolution whole genome DNA copy number profiling of 69 lung adenocarcinomas from smokers (n = 39) and NS (n = 30) revealed both global and regional disparities in the tumor genomes of these two groups. We found that NS lung tumors had a greater proportion of their genomes altered than those of smokers. Moreover, copy number gains on chromosomes 5q, 7p, and 16p occurred more frequently in NS. We validated our findings in two independently generated public datasets. Our findings provide a novel line of evidence distinguishing genetic differences between smoker and NS lung tumors, namely, that the extent of segmental genomic alterations is greater in NS tumors. Collectively, our findings provide evidence that these lung tumors are globally and genetically different, which implies they are likely driven by distinct molecular mechanisms. PMID:22412972

  18. 29 CFR 2590.702-1 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... diabetes. A begins to experience excessive sweating, thirst, and fatigue. A's physician examines A and... adult onset diabetes mellitus (Type 2 diabetes). (ii) Conclusion. In this Example 1, A has been... involved. The diagnosis is not based principally on genetic information. Thus, Type 2 diabetes...

  19. 45 CFR 146.122 - Additional requirements prohibiting discrimination based on genetic information.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... diabetes. A begins to experience excessive sweating, thirst, and fatigue. A's physician examines A and... adult onset diabetes mellitus (Type 2 diabetes). (ii) Conclusion. In this Example 1, A has been... involved. The diagnosis is not based principally on genetic information. Thus, Type 2 diabetes...

  20. Low-temperature alteration of dredged volcanics from the Southern Chile Ridge: Additional information about early stages of seafloor weathering

    USGS Publications Warehouse

    Pichler, T.; Ridley, W.I.; Nelson, E.

    1999-01-01

    A suite of submarine volcanic rocks from the Southern Chile Ridge has been examined in order to investigate the early stages of low temperature alteration. Alteration in these samples proceeded as follows: (1) Fe-staining on sample surface and along fractures, (2) filling of vesicles with secondary material, (3) breakdown of glassy matrix, (4) breakdown of microcrystalline matrix, and (5) breakdown and replacement of olivine. Plagioclase and pyroxene were sometimes found to be slightly altered along internal fissures. Secondary or alteration phases generally showed high K (3-5 wt.%), Fe (30-70 wt.%) and low Al ( Rb > K. During initial stages of alteration the behavior of some trace elements such as rare-earth elements (REE), Ba, Zr, Hf, Ta, Nb, and Mo are solely controlled by the precipitation of Mn-rich Fe-oxyhydroxides. The preferred incorporation of Ce into Mn-rich Fe-oxyhydroxides may be a principal factor explaining the Ce depletion in seawater. We conclude that the earliest stages of submarine weathering are controlled by Eh and pH gradients between the rock and seawater. In the absence of a buffer, oxidation of ferrous iron causes a decrease in solution pH.

  1. Stepwise emergence of azole, echinocandin and amphotericin B multidrug resistance in vivo in Candida albicans orchestrated by multiple genetic alterations

    PubMed Central

    Jensen, Rasmus Hare; Astvad, Karen Marie Thyssen; Silva, Luis Vale; Sanglard, Dominique; Jørgensen, Rene; Nielsen, Kristian Fog; Mathiasen, Estella Glintborg; Doroudian, Ghazalel; Perlin, David Scott; Arendrup, Maiken Cavling

    2015-01-01

    Objectives The objective of this study was to characterize the underlying molecular mechanisms in consecutive clinical Candida albicans isolates from a single patient displaying stepwise-acquired multidrug resistance. Methods Nine clinical isolates (P-1 to P-9) were susceptibility tested by EUCAST EDef 7.2 and Etest. P-4, P-5, P-7, P-8 and P-9 were available for further studies. Relatedness was evaluated by MLST. Additional genes were analysed by sequencing (including FKS1, ERG11, ERG2 and TAC1) and gene expression by quantitative PCR (CDR1, CDR2 and ERG11). UV-spectrophotometry and GC-MS were used for sterol analyses. In vivo virulence was determined in the insect model Galleria mellonella and evaluated by log-rank Mantel–Cox tests. Results P-1 + P-2 were susceptible, P-3 + P-4 fluconazole resistant, P-5 pan-azole resistant, P-6 + P-7 pan-azole and echinocandin resistant and P-8 + P-9 MDR. MLST supported genetic relatedness among clinical isolates. P-4 harboured four changes in Erg11 (E266D, G307S, G450E and V488I), increased expression of ERG11 and CDR2 and a change in Tac1 (R688Q). P-5, P-7, P-8 and P-9 had an additional change in Erg11 (A61E), increased expression of CDR1, CDR2 and ERG11 (except for P-7) and a different amino acid change in Tac1 (R673L). Echinocandin-resistant isolates harboured the Fks1 S645P alteration. Polyene-resistant P-8 + P-9 lacked ergosterol and harboured a frameshift mutation in ERG2 (F105SfsX23). Virulence was attenuated (but equivalent) in the clinical isolates, but higher than in the azole- and echinocandin-resistant unrelated control strain. Conclusions C. albicans demonstrates a diverse capacity to adapt to antifungal exposure. Potentially novel resistance-inducing mutations in TAC1, ERG11 and ERG2 require independent validation. PMID:26017038

  2. Altered chlorplast ribosomal proteins associated with erythromycin-resistant mutants in two genetic systems of Chlamydomonas reinhardi.

    PubMed

    Mets, L; Bogorad, L

    1972-12-01

    The phenotype of several erythromycin-resistant mutants of Chlamydomonas reinhardi was further characterized in terms of the electrophoretic properties of their chloroplast ribosomal proteins. In mutant ery-M2d a single protein of the large (52 S) subunit has altered properties, which probably result from a change in its primary sequence. This mutation is inherited in a Meudelian manner. In mutant ery-U1a, which is inherited in a uniparental manner, a different single protein of the 52 S subunit is altered. This change might result from a change in either the primary sequence of the protein or in some form of secondary modification. These results indicate that these two distinct genetic systems must cooperate in the production of chloroplast ribosomes.

  3. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.

    PubMed

    Qiu, Wen; Hu, Min; Sridhar, Anita; Opeskin, Ken; Fox, Stephen; Shipitsin, Michail; Trivett, Melanie; Thompson, Ella R; Ramakrishna, Manasa; Gorringe, Kylie L; Polyak, Kornelia; Haviv, Izhak; Campbell, Ian G

    2008-05-01

    There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs.

  4. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

    PubMed Central

    Qiu, Wen; Hu, Min; Sridhar, Anita; Opeskin, Ken; Fox, Stephen; Shipitsin, Michail; Trivett, Melanie; Thompson, Ella R; Ramakrishna, Manasa; Gorringe, Kylie L; Polyak, Kornelia; Haviv, Izhak; Campbell, Ian G

    2013-01-01

    There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs. PMID:18408720

  5. Genetic alterations within the retinoblastoma locus in colorectal carcinomas. Relation to DNA ploidy pattern studied by flow cytometric analysis.

    PubMed Central

    Meling, G. I.; Lothe, R. A.; Børresen, A. L.; Hauge, S.; Graue, C.; Clausen, O. P.; Rognum, T. O.

    1991-01-01

    Alterations within the retinoblastoma (Rb) gene, as detected by the VNTR probe p68RS2.0, and flow cytometric DNA pattern have been analysed in 255 colorectal carcinomas. A total of 35.3% of the tumours had alterations within the Rb gene. Amplification of one allele was demonstrated in 29.5% of the tumours, and loss of heterozygosity was found in 11.5%. No association was found between amplification within the Rb gene and clinicopathological characteristics of the patients. The high frequency of alterations demonstrated within the Rb gene, suggests that this gene is involved in colorectal carcinogenesis with amplification as by far the most abundant genetic alteration. This may imply that the Rb gene has an oncogene-like function in colorectal carcinomas, rather than acting as a tumour suppressor gene. Sixty-three per cent of the carcinomas were DNA aneuploid, and a significant association was demonstrated between amplification within the Rb gene and DNA aneuploidy (P less than 0.01). Two other chromosome loci were analysed, on chromosome 1p (probe pYNZ2) and on chromosome 2p (probe pYNH24), respectively. On chromosome 1p, heterozygous loss was found in 22.2% of the tumours, indicating an involvement of this chromosome in a subset of colorectal carcinomas. Images Figure 1 PMID:1911187

  6. Y chromosome microdeletions and alterations of spermatogenesis, patient approach and genetic counseling.

    PubMed

    Rives, Nathalie

    2014-05-01

    Infertility affects 15% of couples at reproductive age and human male infertility appears frequently idiopathic. The main genetic causes of spermatogenesis defect responsible for non-obstructive azoospermia and severe oligozoospermia are constitutional chromosomal abnormalities and microdeletions in the azoospermia factor region of the Y chromosome. The improvement of the Yq microdeletion screening method gave new insights in the mechanism responsible for the genesis of Yq microdeletions and for the consequences of the management of male infertility and genetic counselling in case of assisted reproductive technology.

  7. Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors.

    PubMed

    Voortman, Johannes; Lee, Jih-Hsiang; Killian, Jonathan Keith; Suuriniemi, Miia; Wang, Yonghong; Lucchi, Marco; Smith, William I; Meltzer, Paul; Wang, Yisong; Giaccone, Giuseppe

    2010-07-20

    The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on array comparative genomic hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal carcinoids. In contrast to the relatively conserved karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. In SCLC tumors, as well as bronchial carcinoids and carcinoids of gastrointestinal origin, recurrent CN alterations were observed in 203 genes, including the RB1 gene and 59 microRNAs of which 51 locate in the DLK1-DIO3 domain. These findings suggest the existence of partially shared CN alterations in these tumor types. In contrast, CN alterations of the TP53 gene and the MYC family members were predominantly observed in SCLC. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resembles that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics-based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC.

  8. Phytoplasmal infection derails genetically preprogrammed meristem fate and alters plant architecture

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In the life cycle of higher plants, it is the fate of meristem cells that determines the pattern of growth and development, and therefore plant morphotype and fertility. Floral transition, the turning point from vegetative growth to reproductive development, is achieved via genetically-programmed s...

  9. Genetic variation at the TPH2 gene influences impulsivity in addition to eating disorders.

    PubMed

    Slof-Op't Landt, Margarita C T; Bartels, Meike; Middeldorp, Christel M; van Beijsterveldt, Catherina E M; Slagboom, P Eline; Boomsma, Dorret I; van Furth, Eric F; Meulenbelt, Ingrid

    2013-01-01

    Genes are involved in eating disorders (EDs) and self-induced vomiting (SV), a key symptom of different types of EDs. Perfectionism and impulsivity are potential risk factors for EDs. TPH2 (tryptophan hydroxylase 2) SNP rs1473473 was previously associated with anorexia nervosa and EDs characterized by SV. Could perfectionism or impulsivity be underlying the association between rs1473473 and EDs? Genetic association between TPH2 SNP rs1473473 and perfectionism or impulsivity was first evaluated in a random control group (N = 512). The associations obtained in this control group were subsequently tested in a group of patients with an ED (N = 267). The minor allele of rs1473473 (OR = 1.49) was more frequent in impulsive controls, but also in impulsive patients with an ED (OR = 1.83). The largest effect was found in the patients with an ED characterized by SV (OR = 2.51, p = 0.02). Genetic variation at the TPH2 gene appeared to affect impulsivity which, in turn, might predispose to the SV phenotype.

  10. Additive genetic variation for tolerance to estrogen pollution in natural populations of Alpine whitefish (Coregonus sp., Salmonidae).

    PubMed

    Brazzola, Gregory; Chèvre, Nathalie; Wedekind, Claus

    2014-11-01

    The evolutionary potential of natural populations to adapt to anthropogenic threats critically depends on whether there exists additive genetic variation for tolerance to the threat. A major problem for water-dwelling organisms is chemical pollution, and among the most common pollutants is 17α-ethinylestradiol (EE2), the synthetic estrogen that is used in oral contraceptives and that can affect fish at various developmental stages, including embryogenesis. We tested whether there is variation in the tolerance to EE2 within Alpine whitefish. We sampled spawners from two species of different lakes, bred them in vitro in a full-factorial design each, and studied growth and mortality of embryos. Exposure to EE2 turned out to be toxic in all concentrations we tested (≥1 ng/L). It reduced embryo viability and slowed down embryogenesis. We found significant additive genetic variation in EE2-induced mortality in both species, that is, genotypes differed in their tolerance to estrogen pollution. We also found maternal effects on embryo development to be influenced by EE2, that is, some maternal sib groups were more susceptible to EE2 than others. In conclusion, the toxic effects of EE2 were strong, but both species demonstrated the kind of additive genetic variation that is necessary for an evolutionary response to this type of pollution.

  11. Additive genetic variation for tolerance to estrogen pollution in natural populations of Alpine whitefish (Coregonus sp., Salmonidae)

    PubMed Central

    Brazzola, Gregory; Chèvre, Nathalie; Wedekind, Claus

    2014-01-01

    The evolutionary potential of natural populations to adapt to anthropogenic threats critically depends on whether there exists additive genetic variation for tolerance to the threat. A major problem for water-dwelling organisms is chemical pollution, and among the most common pollutants is 17α-ethinylestradiol (EE2), the synthetic estrogen that is used in oral contraceptives and that can affect fish at various developmental stages, including embryogenesis. We tested whether there is variation in the tolerance to EE2 within Alpine whitefish. We sampled spawners from two species of different lakes, bred them in vitro in a full-factorial design each, and studied growth and mortality of embryos. Exposure to EE2 turned out to be toxic in all concentrations we tested (≥1 ng/L). It reduced embryo viability and slowed down embryogenesis. We found significant additive genetic variation in EE2-induced mortality in both species, that is, genotypes differed in their tolerance to estrogen pollution. We also found maternal effects on embryo development to be influenced by EE2, that is, some maternal sib groups were more susceptible to EE2 than others. In conclusion, the toxic effects of EE2 were strong, but both species demonstrated the kind of additive genetic variation that is necessary for an evolutionary response to this type of pollution. PMID:25553069

  12. An optimized method for cryogenic storage of Xenopus sperm to maximise the effectiveness of research using genetically altered frogs.

    PubMed

    Pearl, Esther; Morrow, Sean; Noble, Anna; Lerebours, Adelaide; Horb, Marko; Guille, Matthew

    2017-04-01

    Cryogenic storage of sperm from genetically altered Xenopus improves cost effectiveness and animal welfare associated with their use in research; currently it is routine for X. tropicalis but not reliable for X. laevis. Here we compare directly the three published protocols for Xenopus sperm freeze-thaw and determine whether sperm storage temperature, method of testes maceration and delays in the freezing protocols affect successful fertilisation and embryo development in X. laevis. We conclude that the protocol is robust and that the variability observed in fertilisation rates is due to differences between individuals. We show that the embryos made from the frozen-thawed sperm are normal and that the adults they develop into are reproductively indistinguishable from others in the colony. This opens the way for using cryopreserved sperm to distribute dominant genetically altered (GA) lines, potentially saving travel-induced stress to the male frogs, reducing their numbers used and making Xenopus experiments more cost effective.

  13. Alterations in K-ras, APC and p53-multiple genetic pathway in colorectal cancer among Indians.

    PubMed

    Malhotra, Pooja; Anwar, Mumtaz; Nanda, Neha; Kochhar, Rakesh; Wig, Jai Dev; Vaiphei, Kim; Mahmood, Safrun

    2013-06-01

    The incidence of colorectal cancer (CRC) is increasing rapidly in Asian countries during the past few decades, but no comprehensive analysis has been done to find out the exact cause of this disease. In this study, we investigated the frequencies of mutations and expression pattern of K-ras, APC (adenomatosis polyposis coli) and p53 in tumor, adjoining and distant normal mucosa and to correlate these alterations with patients clinicopathological parameters as well as with the survival. Polymerase chain reaction (PCR)-restriction digestion was used to detect mutations in K-ras and PCR-SSCP (Single Strand Conformation Polymorphism) followed by DNA sequencing was used to detect mutations in APC and p53 genes. Immunohistochemistry was used to detect the expression pattern of K-ras, APC and p53 proteins. The frequencies of mutations of K-ras, APC and p53 in 30 tumor tissues samples were 26.7 %, 46.7 % and 20 %, respectively. Only 3.3 % of tumors contained mutations in all the three genes. The most common combination of mutation was APC and p53 whereas mutation in both p53 and K-ras were extremely rare. There was no association between the mutations and expression pattern of K-ras, APC and p53 (p>0.05). In Indians, the frequency of alterations of K-ras and APC is similar as in Westerns, whereas the frequency of p53 mutation is slightly lower. The lack of multiple mutations in tumor specimens suggests that these genetic alterations might have independent influences on CRC development and there could be multiple alternative genetic pathways to CRC in our present study cohort.

  14. PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

    PubMed Central

    Schmit, Fabienne; Utermark, Tamara; Zhang, Sen; Wang, Qi; Von, Thanh; Roberts, Thomas M.; Zhao, Jean J.

    2014-01-01

    There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established KrasG12D/PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α. PMID:24737887

  15. Genetic obesity alters recruitment of TANK-binding kinase 1 and AKT into hypothalamic lipid rafts domains.

    PubMed

    Delint-Ramirez, Ilse; Maldonado Ruiz, Roger; Torre-Villalvazo, Ivan; Fuentes-Mera, Lizeth; Garza Ocañas, Lourdes; Tovar, Armando; Camacho, Alberto

    2015-01-01

    Lipid rafts (LRs) are membrane subdomains enriched in cholesterol, glycosphingolipids and sphingolipids containing saturated fatty acid. Signaling proteins become concentrated in these microdomains mainly by saturated fatty acid modification, thus facilitating formation of protein complexes and activation of specific signaling pathways. High intake of saturated fatty acids promotes inflammation and insulin resistance, in part by disrupting insulin signaling pathway. Here we investigate whether lipid-induced toxicity in obesity correlates with altered composition of insulin signaling proteins in LRs in the brain. Our results showed that insulin receptor (IR) is highly concentrated in LRs fraction in comparison with soluble or postsynaptic density (PSD) fractions. Analysis of LRs domains from hippocampus of obese mouse showed a significant decrease of IR and its downstream signaling protein AKT, while in the PSD fraction we detected partial decrease of AKT and no changes in the IR concentration. No changes were shown in the soluble extract. In hypothalamus, genetic obesity also decreases interaction of AKT, but we did not detect changes in the IR distribution. However, in this structure genetic obesity increases recruitment of the IR negative regulator TANK-binding kinase 1 (TBK1) into LRs and PSD fraction. No changes of AKT, IR and TBK1 were found in soluble fractions of obese in comparison with lean mice. In vitro studies showed that incubation with saturated palmitic acid but not with unsaturated docosahexaenoic acid (DHA) or palmitoleic acid decreases association of IR and AKT and increases TBK1 recruitment into LRs and PSD domains, emulating what happens in the obese mice. TBK1 recruitment to insoluble domains correlates with decreases of IR tyrosine phosphorylation and ser473 AKT phosphorylation, markers of insulin resistance. These data support the hypothesis that hyperlipidemia associated with genetic obesity alters targeting of TBK1 and insulin signaling

  16. Genetic and Epigenetic Alterations of TERT Are Associated with Inferior Outcome in Adolescent and Young Adult Patients with Melanoma

    PubMed Central

    Seynnaeve, Brittani; Lee, Seungjae; Borah, Sumit; Park, Yongseok; Pappo, Alberto; Kirkwood, John M.; Bahrami, Armita

    2017-01-01

    Progression of melanoma to distant sites in adolescents and young adults (AYAs) is not reliably predicted by clinicopathologic criteria. TERT promoter mutations when combined with BRAF/NRAS mutations correlate with adverse outcome in adult melanoma. To determine the prognostic value of TERT alterations in AYA melanoma, we investigated the association of TERT promoter mutations, as well as promoter methylation, an epigenetic alteration also linked to TERT upregulation, with TERT mRNA expression and outcome using a well-characterized cohort of 27 patients with melanoma (ages 8–25, mean 20). TERT mRNA expression levels were significantly higher in tumors harboring TERT promoter mutation and/or hypermethylation than those without either aberration (P = 0.046). TERT promoter mutations alone did not predict adverse outcomes (P = 0.50), but the presence of TERT promoter methylation, alone or concurrent with promoter mutations, correlated with reduced recurrence-free survival (P = 0.001). These data suggest that genetic and epigenetic alterations of TERT are associated with TERT upregulation and may predict clinical outcomes in AYA melanoma. A more exhaustive understanding of the different molecular mechanisms leading to increased TERT expression may guide development of prognostic assays to stratify AYA melanoma patients according to clinical risk. PMID:28378855

  17. The role of exosomes contents on genetic and epigenetic alterations of recipient cancer cells

    PubMed Central

    Behbahani, Golnoush Dehbashi; Khani, Soghra; Hosseini, Hamideh Mahmoodzadeh; Abbaszadeh-Goudarzi, Kazem; Nazeri, Saeed

    2016-01-01

    Exosomes, as a mediator of cell-to-cell transfer of genetic information, act an important role in intercommunication between tumor cells and their niche including fibroblasts, endothelial cells, adipocytes and monocytes. Several studies have shown that tumor cells can influence their neighboring cells by releasing exosomes. These exosomes provide signaling cues for stimulation, activation, proliferation and differentiation of cells. Exosomes contain mRNAs, microRNAs (miRNA), and proteins that could be transferred to target cells inducing genetic and epigenetic changes. By facilitating the horizontal transfer of bioactive molecules such as proteins, RNAs and microRNAs, they are now thought to have vital roles in tumor invasion and metastases, inflammation, coagulation, and stem cell renewal and expansion. The aim of this review article is to discuss the significance of exosome-mediated intercellular communication within the tumor biology. PMID:27872698

  18. Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates.

    PubMed

    Shima, James E; Komori, Takafumi; Taylor, Travis R; Stryke, Doug; Kawamoto, Michiko; Johns, Susan J; Carlson, Elaine J; Ferrin, Thomas E; Giacomini, Kathleen M

    2010-10-01

    Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 (SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney. Naturally occurring genetic variants of OAT4 were identified in public databases and by resequencing DNA samples from 272 individuals comprising 4 distinct ethnic groups. Nine total nonsynonymous variants were identified and functionally assessed using uptake of three radiolabeled substrates. A nonsense variant, R48Stop, and three other variants (R121C, V155G, and V155M) were found at frequencies of at least 2% in an ethnic group specific fashion. The L29P, R48Stop, and H469R variants displayed a complete loss of function, and kinetic analysis identified a reduced V(max) in the common nonsynonymous variants. Plasma membrane levels of OAT4 protein were absent or reduced in the nonfunctional variants, providing a mechanistic reason for the observed loss of function. Characterization of the genetic variants of reabsorptive transporters such as OAT4 is an important step in understanding variability in tubular reabsorption with important implications in innate homeostatic processes and drug disposition.

  19. Quantitative Chemical-Genetic Interaction Map Connects Gene Alterations to Drug Responses | Office of Cancer Genomics

    Cancer.gov

    In a recent Cancer Discovery report, CTD2 researchers at the University of California in San Francisco developed a new quantitative chemical-genetic interaction mapping approach to evaluate drug sensitivity or resistance in isogenic cell lines. Performing a high-throughput screen with isogenic cell lines allowed the researchers to explore the impact of a panel of emerging and established drugs on cells overexpressing a single cancer-associated gene in isolation.

  20. Genetic Alterations in Familial Breast Cancer: Mapping and Cloning Genes Other Than BRCAl

    DTIC Science & Technology

    1997-09-01

    cancer in female Cowden patients (-30%) DAMD17-94-J-4307 makes it a strong candidate for a breast cancer susceptibility gene (Hanssen and Fryns ...suppressor for these cancers as well (Jones et al. 1994; Zedenius et al. 1995). In patients with Cowden disease (CD; MIM 158350 [Hanssen and Fryns ...3660-3663 Hanssen AMN, Fryns JP (1995) Cowden syndrome. J Med Genet 32:117-119 Henle W, Henle G (1970) Evidence for a relation of Epstein- Barr

  1. Genetic variants of human organic anion transporter 4 demonstrate altered transport of endogenous substrates

    PubMed Central

    Shima, James E.; Komori, Takafumi; Taylor, Travis R.; Stryke, Doug; Kawamoto, Michiko; Johns, Susan J.; Carlson, Elaine J.; Ferrin, Thomas E.

    2010-01-01

    Apical reabsorption from the urine has been shown to be important for such processes as the maintenance of critical metabolites in the blood and the excretion of nephrotoxic compounds. The solute carrier (SLC) transporter OAT4 (SLC22A11) is expressed on the apical membrane of renal proximal tubule cells and is known to mediate the transport of a variety of xenobiotic and endogenous organic anions. Functional characterization of genetic variants of apical transporters thought to mediate reabsorption, such as OAT4, may provide insight into the genetic factors influencing the complex pathways involved in drug elimination and metabolite reclamation occurring in the kidney. Naturally occurring genetic variants of OAT4 were identified in public databases and by resequencing DNA samples from 272 individuals comprising 4 distinct ethnic groups. Nine total nonsynonymous variants were identified and functionally assessed using uptake of three radiolabeled substrates. A nonsense variant, R48Stop, and three other variants (R121C, V155G, and V155M) were found at frequencies of at least 2% in an ethnic group specific fashion. The L29P, R48Stop, and H469R variants displayed a complete loss of function, and kinetic analysis identified a reduced Vmax in the common nonsynonymous variants. Plasma membrane levels of OAT4 protein were absent or reduced in the nonfunctional variants, providing a mechanistic reason for the observed loss of function. Characterization of the genetic variants of reabsorptive transporters such as OAT4 is an important step in understanding variability in tubular reabsorption with important implications in innate homeostatic processes and drug disposition. PMID:20668102

  2. Development of a certified reference material for genetically modified potato with altered starch composition.

    PubMed

    Broothaerts, Wim; Corbisier, Philippe; Emons, Hendrik; Emteborg, Håkan; Linsinger, Thomas P J; Trapmann, Stefanie

    2007-06-13

    The presence of genetically modified organisms (GMOs) in food and feed products is subject to regulation in the European Union (EU) and elsewhere. As part of the EU authorization procedure for GMOs intended for food and feed use, reference materials must be produced for the quality control of measurements to quantify the GMOs. Certified reference materials (CRMs) are available for a range of herbicide- and insect-resistant genetically modified crops such as corn, soybean, and cotton. Here the development of the first CRM for a GMO that differs from its non-GMO counterpart in a major compositional constituent, that is, starch, is described. It is shown that the modification of the starch composition of potato (Solanum tuberosum L.) tubers, together with other characteristics of the delivered materials, have important consequences for the certification strategy. Moreover, the processing and characterization of the EH92-527-1 potato material required both new and modified procedures, different from those used routinely for CRMs produced from genetically modified seeds.

  3. Statistics of Scientific Procedures on Living Animals 2012: another increase in experimentation - genetically-altered animals dominate again.

    PubMed

    Hudson-Shore, Michelle

    2013-09-01

    The Annual Statistics of Scientific Procedures on Living Animals Great Britain 2012 reveal that the level of animal experimentation in Great Britain continues to rise, with just over 4.1 million procedures being started in that year. Despite the previous year's indication that the dominance of the production and use of genetically-altered (GA, i.e. genetically-modified animals plus animals with harmful genetic defects) animal might be abating, it returned with a vengeance in 2012. Breeding increased from 43% to 48% of all procedures, and GA animals were involved in 59% of all the procedures. Indeed, if the breeding of these animals were removed from the statistics, the total number of procedures would actually decline by 2%. In order to honour their pledge to reduce animal use in science, the Coalition Government will have to address this issue. The general trends in the species used, and the numbers and types of procedures, are also reviewed. Finally, forthcoming changes to the statistics are discussed.

  4. Additional studies of sheep haemopexin: genetic control, frequencies and postnatal development.

    PubMed

    Stratil, A; Bobák, P; Margetín, M; Glasnák, V

    1989-01-01

    This study presents evidence that sheep haemopexin phenotypes are genetically controlled by three alleles, HpxA, HpxB1 and HpxB2, of a single autosomal locus. Frequencies of two alleles, HpxA and HpxB (HpxB encompasses two isoalleles, HpxB1 and HpxB2), were studied in eight sheep breeds in Czechoslovakia. The frequency of the HpxA allele was highest (ranging from 0.81 in Merino to 1.0 in East Friesian sheep). Qualitative and quantitative changes in haemopexin during postnatal development were studied by starch gel electrophoresis and rocket immunoelectrophoresis respectively. In electrophoresis, 1- or 2-day-old lambs had two very weak zones corresponding in mobility to two slower zones of adult animals. Later, the third more anodic zone appeared and gradually increased in intensity. In 1-month-old lambs the patterns were practically identical with those of adult animals. Using rocket immunoelectrophoresis, the level of haemopexin shortly after birth was practically zero. It rose sharply till the sixth day of life; then the level continued to rise slowly till about 1 month of age. The mean haemopexin level in adult sheep was 64.5 +/- 18.26 (SD) mg/100ml serum, ranging from 30.5 to 116.5 mg/100ml.

  5. Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington’s Disease

    PubMed Central

    Cummings, Damian M.; André, Véronique M.; Uzgil, Besim O.; Gee, Steven M.; Fisher, Yvette E.; Cepeda, Carlos; Levine, Michael S.

    2009-01-01

    Previously, we identified progressive alterations in spontaneous excitatory (EPSCs) and inhibitory (IPSCs) postsynaptic currents in the striatum of the R6/2 mouse model of Huntington’s disease (HD). Medium-sized spiny neurons (MSNs) from these mice displayed a lower frequency of EPSCs and a population of cells exhibited an increased frequency of IPSCs beginning at about 40 days, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD, the R6/2, the YAC128 and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency and evoked EPSCs were larger in behaviorally phenotypic mice while spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABAA receptors induced complex discharges in slices and seizures in vivo at all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype. PMID:19692612

  6. Genetically altered fields in head and neck cancer and second field tumor

    PubMed Central

    Sabharwal, Robin; Mahendra, Ashish; Moon, Ninad J; Gupta, Parul; Jain, Ashish; Gupta, Shivangi

    2014-01-01

    The concept of field cancerization has been ever changing since its first description by Slaughter et al in 1953. Field cancerization explains the mechanisms by which second primary tumors (SPTs) develop. SPTs are the tumors, which develop in the oral cavity in succession to the primary malignant tumors, which might vary in duration ranging from few months to years. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remains in the organ, demonstrating the concept of field cancerization. This review explains the concept of field cancerization and various field theories along with molecular basis of field formation. PMID:25136520

  7. Genetically altered fields in head and neck cancer and second field tumor.

    PubMed

    Sabharwal, Robin; Mahendra, Ashish; Moon, Ninad J; Gupta, Parul; Jain, Ashish; Gupta, Shivangi

    2014-07-01

    The concept of field cancerization has been ever changing since its first description by Slaughter et al in 1953. Field cancerization explains the mechanisms by which second primary tumors (SPTs) develop. SPTs are the tumors, which develop in the oral cavity in succession to the primary malignant tumors, which might vary in duration ranging from few months to years. Conceivably, a population of daughter cells with early genetic changes (without histopathology) remains in the organ, demonstrating the concept of field cancerization. This review explains the concept of field cancerization and various field theories along with molecular basis of field formation.

  8. Region-Specific Genetic Alterations in the Aging Hippocampus: Implications For Cognitive Aging

    PubMed Central

    Burger, Corinna

    2010-01-01

    Aging is associated with cognitive decline in both humans and animals and of all brain regions, the hippocampus appears to be particularly vulnerable to senescence. Age-related spatial learning deficits result from alterations in hippocampal connectivity and plasticity. These changes are differentially expressed in each of the hippocampal fields known as cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and the dentate gyrus. Each sub-region displays varying degrees of susceptibility to aging. For example, the CA1 region is particularly susceptible in Alzheimer's disease while the CA3 region shows vulnerability to stress and glucocorticoids. Further, in animals, aging is the main factor associated with the decline in adult neurogenesis in the dentate gyrus. This review discusses the relationship between region-specific hippocampal connectivity, morphology, and gene expression alterations and the cognitive deficits associated with senescence. In particular, data are reviewed that illustrate how the molecular changes observed in the CA1, CA3, and dentate regions are associated with age-related learning deficits. This topic is of importance because increased understanding of how gene expression patterns reflect individual differences in cognitive performance is critical to the process of identifying new and clinically useful biomarkers for cognitive aging. PMID:21048902

  9. Region-specific genetic alterations in the aging hippocampus: implications for cognitive aging.

    PubMed

    Burger, Corinna

    2010-01-01

    Aging is associated with cognitive decline in both humans and animals and of all brain regions, the hippocampus appears to be particularly vulnerable to senescence. Age-related spatial learning deficits result from alterations in hippocampal connectivity and plasticity. These changes are differentially expressed in each of the hippocampal fields known as cornu ammonis 1 (CA1), cornu ammonis 3 (CA3), and the dentate gyrus. Each sub-region displays varying degrees of susceptibility to aging. For example, the CA1 region is particularly susceptible in Alzheimer's disease while the CA3 region shows vulnerability to stress and glucocorticoids. Further, in animals, aging is the main factor associated with the decline in adult neurogenesis in the dentate gyrus. This review discusses the relationship between region-specific hippocampal connectivity, morphology, and gene expression alterations and the cognitive deficits associated with senescence. In particular, data are reviewed that illustrate how the molecular changes observed in the CA1, CA3, and dentate regions are associated with age-related learning deficits. This topic is of importance because increased understanding of how gene expression patterns reflect individual differences in cognitive performance is critical to the process of identifying new and clinically useful biomarkers for cognitive aging.

  10. Selection and explosive growth alter genetic architecture and hamper the detection of causal rare variants

    PubMed Central

    Zaitlen, Noah A.; Ye, Chun Jimmie; Witte, John S.

    2016-01-01

    The role of rare alleles in complex phenotypes has been hotly debated, but most rare variant association tests (RVATs) do not account for the evolutionary forces that affect genetic architecture. Here, we use simulation and numerical algorithms to show that explosive population growth, as experienced by human populations, can dramatically increase the impact of very rare alleles on trait variance. We then assess the ability of RVATs to detect causal loci using simulations and human RNA-seq data. Surprisingly, we find that statistical performance is worst for phenotypes in which genetic variance is due mainly to rare alleles, and explosive population growth decreases power. Although many studies have attempted to identify causal rare variants, few have reported novel associations. This has sometimes been interpreted to mean that rare variants make negligible contributions to complex trait heritability. Our work shows that RVATs are not robust to realistic human evolutionary forces, so general conclusions about the impact of rare variants on complex traits may be premature. PMID:27197206

  11. Hemorheological alterations in sickle cell anemia and their clinical consequences - The role of genetic modulators.

    PubMed

    Silva, Marisa; Vargas, Sofia; Coelho, Andreia; Dias, Alexandra; Ferreira, Teresa; Morais, Anabela; Maia, Raquel; Kjöllerström, Paula; Lavinha, João; Faustino, Paula

    2016-01-01

    Sickle cell anemia (SCA) is an autosomal recessive disease caused by the HBB:c.20A>T mutation that leads to hemoglobin S synthesis. The disease presents with high clinical heterogeneity characterized by chronic hemolysis, recurrent episodes of vaso-oclusion and infection. This work aimed to characterize by in silico studies some genetic modulators of severe hemolysis and stroke risk in children with SCA, and understand their consequences at the hemorheological level.Association studies were performed between hemolysis biomarkers as well as the degree of cerebral vasculopathy and the inheritance of several polymorphic regions in genes related with vascular cell adhesion and vascular tonus in pediatric SCA patients. In silico tools (e.g. MatInspector) were applied to investigate the main variant consequences.Variants in vascular adhesion molecule-1 (VCAM1) gene promoter and endothelial nitric oxide synthase (NOS3) gene were significantly associated with higher degree of hemolysis and stroke events. They potentially modify transcription factor binding sites (e.g. VCAM1 rs1409419_T allele may lead to an EVI1 gain) or disturb the corresponding protein structure/function. Our findings emphasize the relevance of genetic variation in modulating the disease severity due to their effect on gene expression or modification of protein biological activities related with sickled erythrocyte/endothelial interactions and consequent hemorheological abnormalities.

  12. Genetic and molecular alterations in pancreatic cancer: Implications for personalized medicine

    PubMed Central

    Fang, Yantian; Yao, Qizhi; Chen, Zongyou; Xiang, Jianbin; William, Fisher E.; Gibbs, Richard A.; Chen, Changyi

    2013-01-01

    Recent advances in human genomics and biotechnologies have profound impacts on medical research and clinical practice. Individual genomic information, including DNA sequences and gene expression profiles, can be used for prediction, prevention, diagnosis, and treatment for many complex diseases. Personalized medicine attempts to tailor medical care to individual patients by incorporating their genomic information. In a case of pancreatic cancer, the fourth leading cause of cancer death in the United States, alteration in many genes as well as molecular profiles in blood, pancreas tissue, and pancreas juice has recently been discovered to be closely associated with tumorigenesis or prognosis of the cancer. This review aims to summarize recent advances of important genes, proteins, and microRNAs that play a critical role in the pathogenesis of pancreatic cancer, and to provide implications for personalized medicine in pancreatic cancer. PMID:24172537

  13. Molecular detection of altered X-inactivation patterns in the diagnosis of genetic disease.

    PubMed

    Malcolm, S

    1992-01-01

    It is widely assumed that when a female carrier of a genetic disorder exhibits clinical signs of the disorder it is due to chance non-random X-inactivation in particular tissues. Recently molecular methods have become available for the analysis of X-chromosome inactivation status. These are based either on the methylation patterns of DNA from the active and inactive chromosomes or on the rescue of active X chromosomes in somatic cell hybrids. As a consequence of the molecular studies, it has become obvious that there are some special cases of non-random X-inactivation patterns. These include females carrying X-linked immunodeficiencies and, sometimes, one of a pair of identical female twins.

  14. Alteration of Box-Jenkins methodology by implementing genetic algorithm method

    NASA Astrophysics Data System (ADS)

    Ismail, Zuhaimy; Maarof, Mohd Zulariffin Md; Fadzli, Mohammad

    2015-02-01

    A time series is a set of values sequentially observed through time. The Box-Jenkins methodology is a systematic method of identifying, fitting, checking and using integrated autoregressive moving average time series model for forecasting. Box-Jenkins method is an appropriate for a medium to a long length (at least 50) time series data observation. When modeling a medium to a long length (at least 50), the difficulty arose in choosing the accurate order of model identification level and to discover the right parameter estimation. This presents the development of Genetic Algorithm heuristic method in solving the identification and estimation models problems in Box-Jenkins. Data on International Tourist arrivals to Malaysia were used to illustrate the effectiveness of this proposed method. The forecast results that generated from this proposed model outperformed single traditional Box-Jenkins model.

  15. The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations

    PubMed Central

    Meeth, Katrina; Wang, Jake; Micevic, Goran; Damsky, William; Bosenberg, Marcus W.

    2017-01-01

    Summary The remarkable success of immune therapies emphasizes the need for immune competent cancer models. Elegant genetically engineered mouse models of a variety of cancers have been established, but their effective use is limited by cost and difficulties in rapidly generating experimental data. Some mouse cancer cell lines are transplantable to immunocompetent host mice and have been utilized extensively to study cancer immunology. Here we describe a comprehensive system of mouse melanoma cell lines that are syngeneic to C57Bl/6J, have well-defined human-relevant driver mutations, and are genomically stable. These will be a useful tool for the study of tumor immunology and genotype-specific cancer biology. PMID:27287723

  16. The YUMM lines: a series of congenic mouse melanoma cell lines with defined genetic alterations.

    PubMed

    Meeth, Katrina; Wang, Jake Xiao; Micevic, Goran; Damsky, William; Bosenberg, Marcus W

    2016-09-01

    The remarkable success of immune therapies emphasizes the need for immune-competent cancer models. Elegant genetically engineered mouse models of a variety of cancers have been established, but their effective use is limited by cost and difficulties in rapidly generating experimental data. Some mouse cancer cell lines are transplantable to immunocompetent host mice and have been utilized extensively to study cancer immunology. Here, we describe the Yale University Mouse Melanoma (YUMM) lines, a comprehensive system of mouse melanoma cell lines that are syngeneic to C57BL/6, have well-defined human-relevant driver mutations, and are genomically stable. This will be a useful tool for the study of tumor immunology and genotype-specific cancer biology.

  17. Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population.

    PubMed

    Laskar, Ruhina S; Talukdar, Fazlur R; Choudhury, Javed H; Singh, Seram Anil; Kundu, Sharbadeb; Dhar, Bishal; Mondal, Rosy; Ghosh, Sankar Kumar

    2015-06-01

    Several studies from developing countries have shown human papillomavirus to be associated with colorectal cancers, but the molecular characteristics of such cancers are poorly known. We studied the various genetic variations like microsatellite instability (MSI), oncogenic mutations and epigenetic deregulations like CpG island methylation in HPV associated and nonassociated colorectal cancer patients from Indian population. HPV DNA was detected by PCR using My09/My11 and Gp5+/Gp6+ consensus primers and typed using HPV16 and HPV18 specific primers. MSI was detected using BAT 25 and BAT 26 markers, and mutation of KRAS, TP53 and BRAF V600E were detected by direct sequencing. Methyl specific polymerase chain reaction (MSP) was used to determine promoter methylation of the classical CIMP panel markers (P16, hMLH1, MINT1, MINT2 and MINT31) and other tumour-related genes (DAPK, RASSF1, BRCA1 and GSTP1). HPV DNA was detected in 34/93 (36.5 %) colorectal tumour tissues, HPV 18 being the predominant high-risk type. MSI was detected in 7.5 % cases; KRAS codon 12, 13, BRAF V600E and TP53 mutations were detected in 36.5, 3.2 and 37.6 % of the cases, respectively. CIMP-high was observed in 44.08 % cases. HPV presence was not associated with age, stage or grade of tumours, MSI or mutations in KRAS, TP53 or BRAF genes. Higher methylation frequencies of all genes/loci under study except RASSF1, as well as significantly higher CIMP-high characteristics were observed in HPV positive tumours as compared to negative cases. HPV in association with genetic and epigenetic features might be a potent risk factor for colorectal cancer in Indian population.

  18. Genetic evidence for an additional function of phage T4 gene 32 protein: interaction with ligase.

    PubMed

    Mosig, G; Breschkin, A M

    1975-04-01

    Gene 32 of bacteriophage T4 is essential for DNA replication, recombination, and repair. In an attempt to clarify the role of the corresponding gene product, we have looked for mutations that specifically inactivate one but not all of its functions and for compensating suppressor mutations in other genes. Here we describe a gene 32 ts mutant that does not produce progeny, but in contrast to an am mutant investigated by others, is capable of some primary and secondary DNA replication and of forming "joint" recombinational intermediates after infection of Escherichia coli B at the restrictive temperature. However, parental and progeny DNA strands are not ligated to covalently linked "recombinant" molecules, and single strands of vegetative DNA do not exceed unit length. Progeny production as well as capacity for covalent linkage in this gene 32 ts mutant are partially restored by additional rII mutations. Suppression by rII depends on functioning host ligase [EC 6.5.1.2; poly(deoxyribonucleotide):poly(deoxyribonucleotide) ligase (AMP-forming, NMN-forming)]. This gene 32 ts mutation (unlike some others) in turn suppresses the characteristic plaque morphology of rII mutants. We conclude that gene 32 protein, in addition to its role in DNA replication and in the formation of "joint" recombinational intermediates, interacts with T4 ligase [EC 6.5.1.1; poly(deoxyribonucleotide):poly(deoxyribonucleotide) ligase (AMP-forming)] when recombining DNA strands are covalently linked. The protein of the mutant that we describe here is mainly defective in this interaction, thus inactivating T4 ligase in recombination. Suppressing rII mutations facilitate substitution of host ligase. There is suggestive evidence that these interactions occur at the membrane.

  19. Notch Pathway Is Activated via Genetic and Epigenetic Alterations and Is a Therapeutic Target in Clear Cell Renal Cancer.

    PubMed

    Bhagat, Tushar D; Zou, Yiyu; Huang, Shizheng; Park, Jihwan; Palmer, Matthew B; Hu, Caroline; Li, Weijuan; Shenoy, Niraj; Giricz, Orsolya; Choudhary, Gaurav; Yu, Yiting; Ko, Yi-An; Izquierdo, María C; Park, Ae Seo Deok; Vallumsetla, Nishanth; Laurence, Remi; Lopez, Robert; Suzuki, Masako; Pullman, James; Kaner, Justin; Gartrell, Benjamin; Hakimi, A Ari; Greally, John M; Patel, Bharvin; Benhadji, Karim; Pradhan, Kith; Verma, Amit; Susztak, Katalin

    2017-01-20

    Clear cell renal cell carcinoma (CCRCC) is an incurable malignancy in advanced stages and needs newer therapeutic targets. Transcriptomic analysis of CCRCCs and matched microdissected renal tubular controls revealed overexpression of NOTCH ligands and receptors in tumor tissues. Examination of the TCGA RNA-seq data set also revealed widespread activation of NOTCH pathway in a large cohort of CCRCC samples. Samples with NOTCH pathway activation were also clinically distinct and were associated with better overall survival. Parallel DNA methylation and copy number analysis demonstrated that both genetic and epigenetic alterations led to NOTCH pathway activation in CCRCC. NOTCH ligand JAGGED1 was overexpressed and associated with loss of CpG methylation of H3K4me1-associated enhancer regions. JAGGED2 was also overexpressed and associated with gene amplification in distinct CCRCC samples. Transgenic expression of intracellular NOTCH1 in mice with tubule-specific deletion of VHL led to dysplastic hyperproliferation of tubular epithelial cells, confirming the procarcinogenic role of NOTCH in vivo Alteration of cell cycle pathways was seen in murine renal tubular cells with NOTCH overexpression, and molecular similarity to human tumors was observed, demonstrating that human CCRCC recapitulates features and gene expression changes observed in mice with transgenic overexpression of the Notch intracellular domain. Treatment with the γ-secretase inhibitor LY3039478 led to inhibition of CCRCC cells in vitro and in vivo In summary, these data reveal the mechanistic basis of NOTCH pathway activation in CCRCC and demonstrate this pathway to a potential therapeutic target.

  20. Genetical and Comparative Genomics of Brassica under Altered Ca Supply Identifies Arabidopsis Ca-Transporter Orthologs[W][OPEN

    PubMed Central

    Graham, Neil S.; Hammond, John P.; Lysenko, Artem; Mayes, Sean; Ó Lochlainn, Seosamh; Blasco, Bego; Bowen, Helen C.; Rawlings, Chris J.; Rios, Juan J.; Welham, Susan; Carion, Pierre W.C.; Dupuy, Lionel X.; King, Graham J.; White, Philip J.; Broadley, Martin R.

    2014-01-01

    Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca2+ transporters in crops is a promising new technology to improve dietary Ca supplies through biofortification. Here, we sought to identify novel targets for increasing plant Ca accumulation using genetical and comparative genomics. Expression quantitative trait locus (eQTL) mapping to 1895 cis- and 8015 trans-loci were identified in shoots of an inbred mapping population of Brassica rapa (IMB211 × R500); 23 cis- and 948 trans-eQTLs responded specifically to altered Ca supply. eQTLs were screened for functional significance using a large database of shoot Ca concentration phenotypes of Arabidopsis thaliana. From 31 Arabidopsis gene identifiers tagged to robust shoot Ca concentration phenotypes, 21 mapped to 27 B. rapa eQTLs, including orthologs of the Ca2+ transporters At-CAX1 and At-ACA8. Two of three independent missense mutants of BraA.cax1a, isolated previously by targeting induced local lesions in genomes, have allele-specific shoot Ca concentration phenotypes compared with their segregating wild types. BraA.CAX1a is a promising target for altering the Ca composition of Brassica, consistent with prior knowledge from Arabidopsis. We conclude that multiple-environment eQTL analysis of complex crop genomes combined with comparative genomics is a powerful technique for novel gene identification/prioritization. PMID:25082855

  1. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers

    PubMed Central

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  2. Fourier analysis of wing beat signals: assessing the effects of genetic alterations of flight muscle structure in Diptera.

    PubMed Central

    Hyatt, C J; Maughan, D W

    1994-01-01

    A method for determining and analyzing the wing beat frequency in Diptera is presented. This method uses an optical tachometer to measure Diptera wing movement during flight. The resulting signal from the optical measurement is analyzed using a Fast Fourier Transform (FFT) technique, and the dominant frequency peak in the Fourier spectrum is selected as the wing beat frequency. Also described is a method for determining quantitatively the degree of variability of the wing beat frequency about the dominant frequency. This method is based on determination of a quantity called the Hindex, which is derived using data from the FFT analysis. Calculation of the H index allows computer-based selection of the most suitable segment of recorded data for determination of the representative wing beat frequency. Experimental data suggest that the H index can also prove useful in examining wing beat frequency variability in Diptera whose flight muscle structure has been genetically altered. Examples from Drosophila indirect flight muscle studies as well as examples of artificial data are presented to illustrate the method. This method fulfills a need for a standardized method for determining wing beat frequencies and examining wing beat frequency variability in insects whose flight muscles have been altered by protein engineering methods. PMID:7811927

  3. Modeling Parkinson's disease genetics: altered function of the dopamine system in Adh4 knockout mice.

    PubMed

    Belin, Andrea Carmine; Westerlund, Marie; Anvret, Anna; Lindqvist, Eva; Pernold, Karin; Ogren, Sven Ove; Duester, Gregg; Galter, Dagmar

    2011-03-01

    Class IV alcohol dehydrogenase (ADH4) efficiently reduces aldehydes produced during lipid peroxidation, and may thus serve to protect from toxic effects of aldehydes e.g. on neurons. We hypothesized that ADH4 dysfunction may increase risk for Parkinson's disease (PD) and previously reported association of an ADH4 allele with PD. We found that a promoter polymorphism in this allele induced a 25-30% reduction of transcriptional activity. Based on these findings, we have now investigated whether Adh4 homo- (Adh4-/-) or heterozygous (Adh4+/-) knockout mice display any dopamine system-related changes in behavior, biochemical parameters or olfaction compared to wild-type mice. The spontaneous locomotor activity was found to be similar in the three groups, whereas administration of d-amphetamine or apomorphine induced a significant increase in horizontal activity in the Adh4-/- mice compared to wild-type mice. We measured levels of monoamines and their metabolites in striatum, frontal cortex and substantia nigra and found increased levels of dopamine and DOPAC in substantia nigra of Adh4-/- mice. Investigation of olfactory function revealed a reduced sense of smell in Adh4-/- mice accompanied by alterations in dopamine metabolite levels in the olfactory bulb. Taken together, our results suggest that lack of Adh4 gene activity induces changes in the function of the dopamine system, findings which are compatible with a role of loss-of-function mutations in ADH4 as possible risk factors for PD.

  4. Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas.

    PubMed

    Lomas, Jesus; Bello, M Josefa; Arjona, Dolores; Alonso, M Eva; Martinez-Glez, Victor; Lopez-Marin, Isabel; Amiñoso, Cinthia; de Campos, Jose M; Isla, Alberto; Vaquero, Jesus; Rey, Juan A

    2005-03-01

    The role of the NF2 gene in the development of meningiomas has recently been documented; inactivating mutations plus allelic loss at 22q, the site of this gene (at 22q12), have been identified in both sporadic and neurofibromatosis type 2-associated tumors. Although epigenetic inactivation through aberrant CpG island methylation of the NF2 5' flanking region has been documented in schwannoma (another NF2-associated neoplasm), data on participation of this epigenetic modification in meningiomas are not yet widely available. Using methylation-specific PCR (MSP) plus sequencing, we assessed the presence of aberrant promoter NF2 methylation in a series of 88 meningiomas (61 grade I, 24 grade II, and 3 grade III), in which the allelic constitution at 22q and the NF2 mutational status also were determined by RFLP/microsatellite and PCR-SSCP analyses. Chromosome 22 allelic loss, NF2 gene mutation, and aberrant NF2 promoter methylation were detected in 49%, 24%, and 26% of cases, respectively. Aberrant NF2 methylation with loss of heterozygosity (LOH) at 22q was found in five cases, and aberrant methylation with NF2 mutation in another; LOH 22q and the mutation were found in 16 samples. The aberrant methylation of the NF2 gene also was the sole alteration in 15 samples, most of which were from grade I tumors. These results indicate that aberrant NF2 hypermethylation may participate in the development of a significant proportion of sporadic meningiomas, primarily those of grade I.

  5. The Addition of Medium-Chain Triglycerides to a Purified Fish Oil Based Diet Alters Inflammatory Profiles in Mice

    PubMed Central

    Carlson, SJ; Nandivada, P; Chang, MI; Mitchell, PD; O’Loughlin, A; Cowan, E; Gura, KM; Nose, V; Bistrian, B; Puder, M

    2014-01-01

    Objective Parenteral nutrition associated liver disease (PNALD) is a deadly complication of long term parenteral nutrition (PN) use in infants. Fish oil-based lipid emulsion has been shown in recent years to effectively treat PNALD. Alternative fat sources free of essential fatty acids have recently been investigated for health benefits related to decreased inflammatory response. We hypothesized that the addition of medium-chain triglycerides (MCT) to a purified fish oil-based diet would decrease the response to inflammatory challenge in mice, while allowing for sufficient growth and development. Materials/Methods Six groups of ten adult male C57/Bl6 mice were pair-fed different dietary treatments for a period of twelve weeks, varying only in fat source (percent calories by weight): 10.84% soybean oil (SOY), 10% coconut oil (HCO), 10% medium-chain triglycerides (MCT), 3% purified fish oil (PFO), 3% purified fish oil with 3% medium-chain triglycerides (50:50 MCT:PFO) and 3% purified fish oil with 7.59% medium-chain triglycerides (70:30 MCT:PFO). An endotoxin challenge was administered to half of the animals in each group at the completion of dietary treatment. Results All groups demonstrated normal growth throughout the study period. Groups fed MCT and HCO diets demonstrated biochemical essential fatty acid deficiency and decreased IL-6 and TNF-α response to endotoxin challenge. Groups containing PFO had increased inflammatory response to endotoxin challenge, and the addition of MCT to PFO mitigated this inflammatory response. Conclusion These results suggest that the addition of MCT to PFO formulations may decrease the host response to inflammatory challenge, which may pose potential for optimized PN formulations. Inclusion of MCT in lipid emulsions given with PN formulations may be of use in therapeutic interventions for disease states resulting from chronic inflammation. PMID:25458829

  6. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition.

    PubMed

    Sharpley, Mark S; Marciniak, Christine; Eckel-Mahan, Kristin; McManus, Meagan; Crimi, Marco; Waymire, Katrina; Lin, Chun Shi; Masubuchi, Satoru; Friend, Nicole; Koike, Maya; Chalkia, Dimitra; MacGregor, Grant; Sassone-Corsi, Paolo; Wallace, Douglas C

    2012-10-12

    Maternal inheritance of mtDNA is the rule in most animals, but the reasons for this pattern remain unclear. To investigate the consequence of overriding uniparental inheritance, we generated mice containing an admixture (heteroplasmy) of NZB and 129S6 mtDNAs in the presence of a congenic C57BL/6J nuclear background. Analysis of the segregation of the two mtDNAs across subsequent maternal generations revealed that proportion of NZB mtDNA was preferentially reduced. Ultimately, this segregation process produced NZB-129 heteroplasmic mice and their NZB or 129 mtDNA homoplasmic counterparts. Phenotypic comparison of these three mtDNA lines demonstrated that the NZB-129 heteroplasmic mice, but neither homoplasmic counterpart, had reduced activity, food intake, respiratory exchange ratio; accentuated stress response; and cognitive impairment. Therefore, admixture of two normal but different mouse mtDNAs can be genetically unstable and can produce adverse physiological effects, factors that may explain the advantage of uniparental inheritance of mtDNA.

  7. Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations

    PubMed Central

    Backman, Samuel; Maharjan, Rajani; Falk-Delgado, Alberto; Crona, Joakim; Cupisti, Kenko; Stålberg, Peter; Hellman, Per; Björklund, Peyman

    2017-01-01

    Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue. PMID:28327598

  8. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia

    PubMed Central

    Alshammari, T K; Alshammari, M A; Nenov, M N; Hoxha, E; Cambiaghi, M; Marcinno, A; James, T F; Singh, P; Labate, D; Li, J; Meltzer, H Y; Sacchetti, B; Tempia, F; Laezza, F

    2016-01-01

    Cognitive processing is highly dependent on the functional integrity of gamma-amino-butyric acid (GABA) interneurons in the brain. These cells regulate excitability and synaptic plasticity of principal neurons balancing the excitatory/inhibitory tone of cortical networks. Reduced function of parvalbumin (PV) interneurons and disruption of GABAergic synapses in the cortical circuitry result in desynchronized network activity associated with cognitive impairment across many psychiatric disorders, including schizophrenia. However, the mechanisms underlying these complex phenotypes are still poorly understood. Here we show that in animal models, genetic deletion of fibroblast growth factor 14 (Fgf14), a regulator of neuronal excitability and synaptic transmission, leads to loss of PV interneurons in the CA1 hippocampal region, a critical area for cognitive function. Strikingly, this cellular phenotype associates with decreased expression of glutamic acid decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) and also coincides with disrupted CA1 inhibitory circuitry, reduced in vivo gamma frequency oscillations and impaired working memory. Bioinformatics analysis of schizophrenia transcriptomics revealed functional co-clustering of FGF14 and genes enriched within the GABAergic pathway along with correlatively decreased expression of FGF14, PVALB, GAD67 and VGAT in the disease context. These results indicate that Fgf14−/− mice recapitulate salient molecular, cellular, functional and behavioral features associated with human cognitive impairment, and FGF14 loss of function might be associated with the biology of complex brain disorders such as schizophrenia. PMID:27163207

  9. Keynote lecture: The genetics and epigenetics of altered proliferative homeostasis in ageing and cancer

    PubMed Central

    Martin, George M.

    2007-01-01

    Ageing mammals are subject to an amazing array of aberrations in proliferative homeostasis. These are of two basic types: the post-maturational failure to adequately replace effete somatic cells (atrophies) and excessive proliferations of somatic cells (hyperplasias). To a surprising degree, these occur side by side within the same tissues and are features of numerous mammalian geriatric disorders. Atrophy is the likely usual initial event, the proliferative response perhaps developing as a secondary, compensatory, initially adaptive reaction. We have little understanding of why this putative compensatory reaction so often fails to be appropriately regulated in ageing mammals, leading to such pathologies as chronic inflammation, fibrosis, metaplasia and neoplasia. Advances in formal genetic analysis, mutagenesis, stem cell biology and epigenetics are likely to provide major new understanding. Stochastic epigenetic shifts in gene expression are of growing interest, particularly in explaining intra-specific variations on rates and patterns of ageing. Nature may well have evolved such random fluctuations in gene expression as a type of group-selectionist adaptive strategy to cope with diverse stochastic environmental challenges. Alternatively, such background “noise” in transcription and translation may simply reflect a type of informational entropy. PMID:17116316

  10. Genetic Association and Altered Gene Expression of Mir-155 in Multiple Sclerosis Patients

    PubMed Central

    Paraboschi, Elvezia Maria; Soldà, Giulia; Gemmati, Donato; Orioli, Elisa; Zeri, Giulia; Benedetti, Maria Donata; Salviati, Alessandro; Barizzone, Nadia; Leone, Maurizio; Duga, Stefano; Asselta, Rosanna

    2011-01-01

    Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system characterized by chronic inflammation, demyelination, and axonal damage. As microRNA (miRNA)-dependent alterations in gene expression in hematopoietic cells are critical for mounting an appropriate immune response, miRNA deregulation may result in defects in immune tolerance. In this frame, we sought to explore the possible involvement of miRNAs in MS pathogenesis by monitoring the differential expression of 22 immunity-related miRNAs in peripheral blood mononuclear cells of MS patients and healthy controls, by using a microbead-based technology. Three miRNAs resulted >2 folds up-regulated in MS vs controls, whereas none resulted down-regulated. Interestingly, the most up-regulated miRNA (mir-155; fold change = 3.30; P = 0.013) was previously reported to be up-regulated also in MS brain lesions. Mir-155 up-regulation was confirmed by qPCR experiments. The role of mir-155 in MS susceptibility was also investigated by genotyping four single nucleotide polymorphisms (SNPs) mapping in the mir-155 genomic region. A haplotype of three SNPs, corresponding to a 12-kb region encompassing the last exon of BIC (the B-cell Integration Cluster non-coding RNA, from which mir-155 is processed), resulted associated with the disease status (P = 0.035; OR = 1.36, 95% CI = 1.05–1.77), suggesting that this locus strongly deserves further investigations. PMID:22272099

  11. Ontogeny of mouse vestibulo-ocular reflex following genetic or environmental alteration of gravity sensing.

    PubMed

    Beraneck, Mathieu; Bojados, Mickael; Le Séac'h, Anne; Jamon, Marc; Vidal, Pierre-Paul

    2012-01-01

    The vestibular organs consist of complementary sensors: the semicircular canals detect rotations while the otoliths detect linear accelerations, including the constant pull of gravity. Several fundamental questions remain on how the vestibular system would develop and/or adapt to prolonged changes in gravity such as during long-term space journey. How do vestibular reflexes develop if the appropriate assembly of otoliths and semi-circular canals is perturbed? The aim of present work was to evaluate the role of gravity sensing during ontogeny of the vestibular system. In otoconia-deficient mice (ied), gravity cannot be sensed and therefore maculo-ocular reflexes (MOR) were absent. While canals-related reflexes were present, the ied deficit also led to the abnormal spatial tuning of the horizontal angular canal-related VOR. To identify putative otolith-related critical periods, normal C57Bl/6J mice were subjected to 2G hypergravity by chronic centrifugation during different periods of development or adulthood (Adult-HG) and compared to non-centrifuged (control) C57Bl/6J mice. Mice exposed to hypergravity during development had completely normal vestibulo-ocular reflexes 6 months after end of centrifugation. Adult-HG mice all displayed major abnormalities in maculo-ocular reflexe one month after return to normal gravity. During the next 5 months, adaptation to normal gravity occurred in half of the individuals. In summary, genetic suppression of gravity sensing indicated that otolith-related signals might be necessary to ensure proper functioning of canal-related vestibular reflexes. On the other hand, exposure to hypergravity during development was not sufficient to modify durably motor behaviour. Hence, 2G centrifugation during development revealed no otolith-specific critical period.

  12. Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects

    PubMed Central

    Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A.

    2016-01-01

    The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates’ offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of “half-sibling” in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure. PMID:26801647

  13. Implementation of the Realized Genomic Relationship Matrix to Open-Pollinated White Spruce Family Testing for Disentangling Additive from Nonadditive Genetic Effects.

    PubMed

    Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Porth, Ilga; Chen, Charles; El-Kassaby, Yousry A

    2016-01-22

    The open-pollinated (OP) family testing combines the simplest known progeny evaluation and quantitative genetics analyses as candidates' offspring are assumed to represent independent half-sib families. The accuracy of genetic parameter estimates is often questioned as the assumption of "half-sibling" in OP families may often be violated. We compared the pedigree- vs. marker-based genetic models by analysing 22-yr height and 30-yr wood density for 214 white spruce [Picea glauca (Moench) Voss] OP families represented by 1694 individuals growing on one site in Quebec, Canada. Assuming half-sibling, the pedigree-based model was limited to estimating the additive genetic variances which, in turn, were grossly overestimated as they were confounded by very minor dominance and major additive-by-additive epistatic genetic variances. In contrast, the implemented genomic pairwise realized relationship models allowed the disentanglement of additive from all nonadditive factors through genetic variance decomposition. The marker-based models produced more realistic narrow-sense heritability estimates and, for the first time, allowed estimating the dominance and epistatic genetic variances from OP testing. In addition, the genomic models showed better prediction accuracies compared to pedigree models and were able to predict individual breeding values for new individuals from untested families, which was not possible using the pedigree-based model. Clearly, the use of marker-based relationship approach is effective in estimating the quantitative genetic parameters of complex traits even under simple and shallow pedigree structure.

  14. Paradoxical role of C1561T glutamate carboxypeptidase II (GCPII) genetic polymorphism in altering disease susceptibility.

    PubMed

    Divyya, Shree; Naushad, Shaik Mohammad; Addlagatta, Anthony; Murthy, P V L N; Reddy, Ch Ram; Digumarti, Raghunadha Rao; Gottumukkala, Suryanarayana Raju; Kumar, Ajit; Rammurti, S; Kutala, Vijay Kumar

    2012-04-15

    Glutamate carboxypeptidase II (GCPII) is predominantly expressed in brain, intestinal mucosa and prostate cancer in the form of three splice variants i.e. N-acetylated-α-linked acidic dipeptidase (NAALADase), folyl poly-γ-glutamate carboxypeptidase (FGCP) and prostate specific membrane antigen (PSMA) respectively. Its inhibition was found to confer protection against certain neurological disorders and cancer. Despite the pivotal role of this enzyme, the most common polymorphism i.e. H475Y has not been explored comprehensively in all its splice variants. In this study, we have determined the role of this variant in different disease conditions such as breast and prostate cancers, autism, coronary artery disease (CAD) and miscarriages (N=1561). Genotyping was done by PCR-RFLP and dideoxy sequencing. Plasma folate levels were estimated by Axysm folate kit. GCPII expression was studied by semi-quantitative RT-PCR. In silico model was developed using PYMOL. We observed the protective role of H475Y variant in cancers [breast cancer; OR (95% CI): 0.81 (0.55-1.19), prostate cancer: OR (95% CI): 0.00 (0.00-0.66)], and in autism (OR (95% CI): 0.47 (0.21-1.03), whereas inflated risk was observed in CAD (OR (95% CI): 1.69 (1.20-2.37) and miscarriages [Maternal OR (95% CI): 3.26 (2.11-5.04); Paternal OR(95% CI): 1.99 (1.23-3.21)]. Further, this variant was found to impair the intestinal folate absorption in subjects with dietary folate intake in the lowest tertile (CC vs. CT in lowest tertile; 7.56±0.85ng/ml vs. 2.73±045ng/ml, p=0.005). In silico model of GCPII showed steric hindrance with H475Y resulting in stereochemical alteration of catalytic site, thus interfering with ligand binding. Statistically significant association was not observed between dietary folate levels and GCPII expression. However, a positive correlation was seen between plasma folate levels and GCPII expression (r=0.70, p<0.05). To conclude, our data suggests that GCPII H475Y variant shows inverse

  15. Motor Experience Reprograms Development of a Genetically-Altered Bilateral Corticospinal Motor Circuit

    PubMed Central

    Serradj, Najet

    2016-01-01

    Evidence suggests that motor experience plays a role in shaping development of the corticospinal system and voluntary motor control, which is a key motor function of the system. Here we used a mouse model with conditional forebrain deletion of the gene for EphA4 (Emx1-Cre:EphA4tm2Kldr), which regulates development of the laterality of corticospinal tract (CST). We combined study of Emx1-Cre:EphA4tm2Kldr with unilateral forelimb constraint during development to expand our understanding of experience-dependent CST development from both basic and translational perspectives. This mouse develops dense ipsilateral CST projections, a bilateral motor cortex motor representation, and bilateral motor phenotypes. Together these phenotypes can be used as readouts of corticospinal system organization and function and the changes brought about by experience. The Emx1-Cre:EphA4tm2Kldr mouse shares features with the common developmental disorder cerebral palsy: bilateral voluntary motor impairments and bilateral CST miswiring. Emx1-Cre:EphA4tm2Kldr mice with typical motor experiences during development display the bilateral phenotype of “mirror” reaching, because of a strongly bilateral motor cortex motor representation and a bilateral CST. By contrast, Emx1-Cre:EphA4tm2Kldr mice that experienced unilateral forelimb constraint from P1 to P30 and tested at maturity had a more contralateral motor cortex motor representation in each hemisphere; more lateralized CST projections; and substantially more lateralized/independent reaching movements. Changes in CST organization and function in this model can be explained by reduced synaptic competition of the CST from the side without developmental forelimb motor experiences. Using this model we show that unilateral constraint largely abrogated the effects of the genetic mutation on CST projections and thus demonstrates how robust and persistent experience-dependent development can be for the establishment of corticospinal system

  16. Addition of Phenylboronic Acid to Malus domestica Pollen Tubes Alters Calcium Dynamics, Disrupts Actin Filaments and Affects Cell Wall Architecture.

    PubMed

    Fang, Kefeng; Gao, Sai; Zhang, Weiwei; Xing, Yu; Cao, Qingqin; Qin, Ling

    2016-01-01

    A key role of boron in plants is to cross-link the cell wall pectic polysaccharide rhamnogalacturonan-II (RG-II) through borate diester linkages. Phenylboronic acid (PBA) can form the same reversible ester bonds but cannot cross-link two molecules, so can be used as an antagonist to study the function of boron. This study aimed to evaluate the effect of PBA on apple (Malus domestica) pollen tube growth and the underlying regulatory mechanism. We observed that PBA caused an inhibition of pollen germination, tube growth and led to pollen tube morphological abnormalities. Fluorescent labeling, coupled with a scanning ion-selective electrode technique, revealed that PBA induced an increase in extracellular Ca2+ influx, thereby elevating the cytosolic Ca2+ concentration [Ca2+]c and disrupting the [Ca2+]c gradient, which is critical for pollen tube growth. Moreover the organization of actin filaments was severely perturbed by the PBA treatment. Immunolocalization studies and fluorescent labeling, together with Fourier-transform infrared analysis (FTIR) suggested that PBA caused an increase in the abundance of callose, de-esterified pectins and arabinogalactan proteins (AGPs) at the tip. However, it had no effect on the deposition of the wall polymers cellulose. These effects are similar to those of boron deficiency in roots and other organs, indicating that PBA can induce boron deficiency symptoms. The results provide new insights into the roles of boron in pollen tube development, which likely include regulating [Ca2+]c and the formation of the actin cytoskeleton, in addition to the synthesis and assembly of cell wall components.

  17. Towards a phylogenetic generic classification of Thelypteridaceae: Additional sampling suggests alterations of neotropical taxa and further study of paleotropical genera.

    PubMed

    Almeida, Thaís Elias; Hennequin, Sabine; Schneider, Harald; Smith, Alan R; Batista, João Aguiar Nogueira; Ramalho, Aline Joseph; Proite, Karina; Salino, Alexandre

    2016-01-01

    Thelypteridaceae is one of the largest fern families, having about 950 species and a cosmopolitan distribution but with most species occurring in tropical and subtropical regions. Its generic classification remains controversial, with different authors recognizing from one up to 32 genera. Phylogenetic relationships within the family have not been exhaustively studied, but previous studies have confirmed the monophyly of the lineage. Thus far, sampling has been inadequate for establishing a robust hypothesis of infrafamilial relationships within the family. In order to understand phylogenetic relationships within Thelypteridaceae and thus to improve generic reclassification, we expand the molecular sampling, including new samples of Old World taxa and, especially, many additional neotropical representatives. We also explore the monophyly of exclusively or mostly neotropical genera Amauropelta, Goniopteris, Meniscium, and Steiropteris. Our sampling includes 68 taxa and 134 newly generated sequences from two plastid genomic regions (rps4-trnS and trnL-trnF), plus 73 rps4 and 72 trnL-trnF sequences from GenBank. These data resulted in a concatenated matrix of 1980 molecular characters for 149 taxa. The combined data set was analyzed using maximum parsimony and bayesian inference of phylogeny. Our results are consistent with the general topological structure found in previous studies, including two main lineages within the family: phegopteroid and thelypteroid. The thelypteroid lineage comprises two clades; one of these included the segregates Metathelypteris, Coryphopteris, and Amauropelta (including part of Parathelypteris), whereas the other comprises all segregates of Cyclosorus s.l., such as Goniopteris, Meniscium, and Steiropteris (including Thelypteris polypodioides, previously incertae sedis). The three mainly neotropical segregates were found to be monophyletic but nested in a broadly defined Cyclosorus. The fourth mainly neotropical segregate, Amauropelta

  18. The addition of charcoals to broiler diets did not alter the recovery of Salmonella Typhimurium during grow-out.

    PubMed

    Wilson, K M; Bourassa, D V; Davis, A J; Freeman, M E; Buhr, R J

    2016-03-01

    recovery from breast skin (charcoals 5+/60 compared to control 8+/20). While the addition of charcoals to broilers feed did not significantly affect Salmonella recovery during production (from litter or ceca samples) there was a lower Salmonella recovery from breast skin following scalding and defeathering.

  19. Selection for increased desiccation resistance in Drosophila melanogaster: Additive genetic control and correlated responses for other stresses

    SciTech Connect

    Hoffmann, A.A.; Parsons, P.A. )

    1989-08-01

    Previously we found that Drosophila melanogaster lines selected for increased desiccation resistance have lowered metabolic rate and behavioral activity levels, and show correlated responses for resistance to starvation and a toxic ethanol level. These results were consistent with a prediction that increased resistance to many environmental stresses may be genetically correlated because of a reduction in metabolic energy expenditure. Here we present experiments on the genetic basis of the selection response and extend the study of correlated responses to other stresses. The response to selection was not sex-specific and involved X-linked and autosomal genes acting additively. Activity differences contributed little to differences in desiccation resistance between selected and control lines. Selected lines had lower metabolic rates than controls in darkness when activity was inhibited. Adults from selected lines showed increased resistance to a heat shock, {sup 60}Co-gamma-radiation, and acute ethanol and acetic acid stress. The desiccation, ethanol and starvation resistance of isofemale lines set up from the F2s of a cross between one of the selected and one of the control lines were correlated. Selected and control lines did not differ in ether-extractable lipid content or in resistance to acetone, ether or a cold shock.

  20. Enduracidin analogues with altered halogenation patterns produced by genetically engineered strains of Streptomyces fungicidicus.

    PubMed

    Yin, Xihou; Chen, Ying; Zhang, Ling; Wang, Yang; Zabriskie, T Mark

    2010-04-23

    Enduracidins (1, 2) and ramoplanin (3) are structurally and functionally closely related lipodepsipeptide antibiotics. They are active against multi-drug-resistant Gram-positive pathogens, including MRSA. Each peptide contains one chlorinated non-proteinogenic amino acid residue, Cl(2)-Hpg or Cl-Hpg. To investigate the timing of halogenation and the importance of chlorination on bioactivity and bioavailability of enduracidin, and to probe the substrate specificity and portability of the ramoplanin halogenase, we constructed the mutant strain SfDelta30 in which the enduracidin halogenase gene orf30 had been deleted and complemented it with the ramoplanin counterpart orf20. We also expressed orf20 in the enduracidin wild-type producer. Metabolite analysis revealed SfDelta30 produced the novel analogues dideschloroenduracidins A (4) and B (5), while the recombinant strains SfDelta30R20 and SfR20 produced monodeschloroenduracidins A (6) and B (7) and a trichlorinated enduracidin (8), respectively. In addition, orf30 self-complementation yielded the strain SfDelta30E30, which is capable of producing six peptides including 6 and 7. MS/MS analysis positioned the single chlorine atom in 6 at Hpg(13) and localized the third chlorine atom in 8 to Hpg(11). Biological evaluation of these enduracidin analogues indicated that all retained activity against Staphylococcus aureus. Our findings lay the foundation for further utilization of enduracidin and ramoplanin halogenases in combinatorial biosynthesis.

  1. Recent and projected increases in atmospheric CO2 concentration can enhance gene flow between wild and genetically altered rice (Oryza sativa)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although recent and projected increases in atmospheric carbon dioxide can alter plant phenological development, these changes have not been quantified in terms of floral outcrossing rates or gene transfer. Could differential phenological development in response to rising CO2 between genetically mod...

  2. ALTERED SENSITIVITY OF THE MOUSE FETUS TO IMPAIRED PROSTATIC BUD FORMATION BY DIOXIN: INFLUENCE OF GENETIC BACKGROUND AND NULL EXPRESSION OF TGF-ALFA AND EGF

    EPA Science Inventory

    Altered sensitivity of the mouse fetus to impaired prostatic bud formation by dioxin: Influence of genetic background and null expression of TGF and EGF.
    Rasmussen, N.T., Lin T-M., Fenton, S.E., Abbott, B.D. and R.E. Peterson.
    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)...

  3. Aurora kinase-A overexpression in mouse mammary epithelium induces mammary adenocarcinomas harboring genetic alterations shared with human breast cancer.

    PubMed

    Treekitkarnmongkol, Warapen; Katayama, Hiroshi; Kai, Kazuharu; Sasai, Kaori; Jones, Jennifer Carter; Wang, Jing; Shen, Li; Sahin, Aysegul A; Gagea, Mihai; Ueno, Naoto T; Creighton, Chad J; Sen, Subrata

    2016-12-01

    Recent data from The Cancer Genome Atlas analysis have revealed that Aurora kinase A (AURKA) amplification and overexpression characterize a distinct subset of human tumors across multiple cancer types. Although elevated expression of AURKA has been shown to induce oncogenic phenotypes in cells in vitro, findings from transgenic mouse models of Aurora-A overexpression in mammary glands have been distinct depending on the models generated. In the present study, we report that prolonged overexpression of AURKA transgene in mammary epithelium driven by ovine β-lactoglobulin promoter, activated through multiple pregnancy and lactation cycles, results in the development of mammary adenocarcinomas with alterations in cancer-relevant genes and epithelial-to-mesenchymal transition. The tumor incidence was 38.9% (7/18) in Aurora-A transgenic mice at 16 months of age following 4-5 pregnancy cycles. Aurora-A overexpression in the tumor tissues accompanied activation of Akt, elevation of Cyclin D1, Tpx2 and Plk1 along with downregulation of ERα and p53 proteins, albeit at varying levels. Microarray comparative genomic hybridization (CGH) analyses of transgenic mouse mammary adenocarcinomas revealed copy gain of Glp1r and losses of Ercc5, Pten and Tcf7l2 loci. Review of human breast tumor transcriptomic data sets showed association of these genes at varying levels with Aurora-A gain of function alterations. Whole exome sequencing of the mouse tumors also identified gene mutations detected in Aurora-A overexpressing human breast cancers. Our findings demonstrate that prolonged overexpression of Aurora-A can be a driver somatic genetic event in mammary adenocarcinomas associated with deregulated tumor-relevant pathways in the Aurora-A subset of human breast cancer.

  4. Deregulation of MYC and TP53 through genetic and epigenetic alterations in gallbladder carcinomas.

    PubMed

    Ishak, Geraldo; Leal, Mariana Ferreira; Dos Santos, Ney Pereira Carneiro; Demachki, Samia; Nunes, Caroline Aquino Moreira; do Nascimento Borges, Barbara; Calcagno, Danielle Queiroz; Smith, Marília Cardoso; Assumpção, Paulo Pimentel; Burbano, Rommel Rodríguez

    2015-08-01

    Gallbladder cancer is a rare malignancy and presents a poor prognosis. MYC and p53 have been implicated in gallbladder carcinogenesis. However, little is known about the molecular mechanisms involved in their regulation in this neoplasia. Here, we evaluated the MYC and TP53 copy numbers in gallbladder tumors and their possible association with protein expression. We also investigated whether MYC may be controlled by mutations and DNA promoter methylation. In the present study, 15 samples of invasive gallbladder carcinomas and six control samples were analyzed. On the other hand, the expression of MYC and p53 was more frequent in gallbladder carcinomas than in control samples (p = 0.002, p = 0.046, respectively). Gain of copies of the MYC and TP53 genes was detected in 86.7 and 50 % of gallbladder carcinomas, respectively. MYC and TP53 amplifications were associated with immunoreactivity of their protein (p = 0.029, p = 0.001, respectively). MYC hypomethylation was only detected in tumoral samples and was associated with its protein expression (p = 0.029). MYC mutations were detected in 80 % of tumor samples. The G allele at rs117856857 was associated with the presence of gallbladder tumors (p = 0.019) and with MYC expression (p = 0.044). Moreover, two tumors presented a pathogenic mutation in MYC exon 2 (rs28933407). Our study highlights that the gain of MYC and TP53 copies seems to be a frequent finding in gallbladder cancer. In addition, gain of copies, hypomethylation and point mutations at MYC may contribute to overexpression of its protein in this type of cancer.

  5. An altered redox balance and increased genetic instability characterize primary fibroblasts derived from xeroderma pigmentosum group A patients.

    PubMed

    Parlanti, Eleonora; Pietraforte, Donatella; Iorio, Egidio; Visentin, Sergio; De Nuccio, Chiara; Zijno, Andrea; D'Errico, Mariarosaria; Simonelli, Valeria; Sanchez, Massimo; Fattibene, Paola; Falchi, Mario; Dogliotti, Eugenia

    2015-12-01

    Xeroderma pigmentosum (XP)-A patients are characterized by increased solar skin carcinogenesis and present also neurodegeneration. XPA deficiency is associated with defective nucleotide excision repair (NER) and increased basal levels of oxidatively induced DNA damage. In this study we search for the origin of increased levels of oxidatively generated DNA lesions in XP-A cell genome and then address the question of whether increased oxidative stress might drive genetic instability. We show that XP-A human primary fibroblasts present increased levels and different types of intracellular reactive oxygen species (ROS) as compared to normal fibroblasts, with O₂₋• and H₂O₂ being the major reactive species. Moreover, XP-A cells are characterized by decreased reduced glutathione (GSH)/oxidized glutathione (GSSG) ratios as compared to normal fibroblasts. The significant increase of ROS levels and the alteration of the glutathione redox state following silencing of XPA confirmed the causal relationship between a functional XPA and the control of redox balance. Proton nuclear magnetic resonance (¹H NMR) analysis of the metabolic profile revealed a more glycolytic metabolism and higher ATP levels in XP-A than in normal primary fibroblasts. This perturbation of bioenergetics is associated with different morphology and response of mitochondria to targeted toxicants. In line with cancer susceptibility, XP-A primary fibroblasts showed increased spontaneous micronuclei (MN) frequency, a hallmark of cancer risk. The increased MN frequency was not affected by inhibition of ROS to normal levels by N-acetyl-L-cysteine.

  6. Analysis of protein gene products in cells with altered chromosome sets for the purpose of genetic mapping

    SciTech Connect

    Shishkin, S.S.; Zakharov, S.F.; Gromov, P.S.; Shcheglova, M.V.; Kukharenko, V.I.; Shilov, A.G.; Matveeva, N.M.; Zhdanova, N.S.; Efimochkin, A.S.; Krokhina, T.B. |

    1994-12-01

    Two-dimensional electrophoresis was used for analyzing proteins in hybrid cells that contained single human chromosomes (chromosome 5, chromosome 21, or chromosomes 5 and 21) against the background of the mouse genome. By comparing the protein patterns of hybrid and parent cells (about 1000 protein fractions for each kind of cell), five fractions among proteins of hybrid cells were supposedly identified as human proteins. The genes of two of them are probably located on chromosome 5, and those of the other three on chromosome 21. Moreover, analysis of proteins in fibroblasts of patients with the cri-du-chat syndrome (5p-) revealed a decrease in the content of two proteins as compared with those in preparations of diploid fibroblasts. This fact was regarded as evidence that two corresponding genes are located on the short arm of chromosome 5. Methodological problems associated with the use of protein pattern analysis in cells with altered chromosome sets for the purposes of genetic mapping are discussed.

  7. Genetic Deletion of TREK-1 or TWIK-1/TREK-1 Potassium Channels does not Alter the Basic Electrophysiological Properties of Mature Hippocampal Astrocytes In Situ.

    PubMed

    Du, Yixing; Kiyoshi, Conrad M; Wang, Qi; Wang, Wei; Ma, Baofeng; Alford, Catherine C; Zhong, Shiying; Wan, Qi; Chen, Haijun; Lloyd, Eric E; Bryan, Robert M; Zhou, Min

    2016-01-01

    We have recently shown that a linear current-to-voltage (I-V) relationship of membrane conductance (passive conductance) reflects the intrinsic property of K(+) channels in mature astrocytes. While passive conductance is known to underpin a highly negative and stable membrane potential (V M) essential for the basic homeostatic function of astrocytes, a complete repertoire of the involved K(+) channels remains elusive. TREK-1 two-pore domain K(+) channel (K2P) is highly expressed in astrocytes, and covalent association of TREK-1 with TWIK-1, another highly expressed astrocytic K2P, has been reported as a mechanism underlying the trafficking of heterodimer TWIK-1/TREK-1 channel to the membrane and contributing to astrocyte passive conductance. To decipher the individual contribution of TREK-1 and address whether the appearance of passive conductance is conditional to the co-expression of TWIK-1/TREK-1 in astrocytes, TREK-1 single and TWIK-1/TREK-1 double gene knockout mice were used in the present study. The relative quantity of mRNA encoding other astrocyte K(+) channels, such as Kir4.1, Kir5.1, and TREK-2, was not altered in these gene knockout mice. Whole-cell recording from hippocampal astrocytes in situ revealed no detectable changes in astrocyte passive conductance, V M, or membrane input resistance (R in) in either kind of gene knockout mouse. Additionally, TREK-1 proteins were mainly located in the intracellular compartments of the hippocampus. Altogether, genetic deletion of TREK-1 alone or together with TWIK-1 produced no obvious alteration in the basic electrophysiological properties of hippocampal astrocytes. Thus, future research focusing on other K(+) channels may shed light on this long-standing and important question in astrocyte physiology.

  8. Genetic Deletion of TREK-1 or TWIK-1/TREK-1 Potassium Channels does not Alter the Basic Electrophysiological Properties of Mature Hippocampal Astrocytes In Situ

    PubMed Central

    Du, Yixing; Kiyoshi, Conrad M.; Wang, Qi; Wang, Wei; Ma, Baofeng; Alford, Catherine C.; Zhong, Shiying; Wan, Qi; Chen, Haijun; Lloyd, Eric E.; Bryan, Robert M. Jr.; Zhou, Min

    2016-01-01

    We have recently shown that a linear current-to-voltage (I-V) relationship of membrane conductance (passive conductance) reflects the intrinsic property of K+ channels in mature astrocytes. While passive conductance is known to underpin a highly negative and stable membrane potential (VM) essential for the basic homeostatic function of astrocytes, a complete repertoire of the involved K+ channels remains elusive. TREK-1 two-pore domain K+ channel (K2P) is highly expressed in astrocytes, and covalent association of TREK-1 with TWIK-1, another highly expressed astrocytic K2P, has been reported as a mechanism underlying the trafficking of heterodimer TWIK-1/TREK-1 channel to the membrane and contributing to astrocyte passive conductance. To decipher the individual contribution of TREK-1 and address whether the appearance of passive conductance is conditional to the co-expression of TWIK-1/TREK-1 in astrocytes, TREK-1 single and TWIK-1/TREK-1 double gene knockout mice were used in the present study. The relative quantity of mRNA encoding other astrocyte K+ channels, such as Kir4.1, Kir5.1, and TREK-2, was not altered in these gene knockout mice. Whole-cell recording from hippocampal astrocytes in situ revealed no detectable changes in astrocyte passive conductance, VM, or membrane input resistance (Rin) in either kind of gene knockout mouse. Additionally, TREK-1 proteins were mainly located in the intracellular compartments of the hippocampus. Altogether, genetic deletion of TREK-1 alone or together with TWIK-1 produced no obvious alteration in the basic electrophysiological properties of hippocampal astrocytes. Thus, future research focusing on other K+ channels may shed light on this long-standing and important question in astrocyte physiology. PMID:26869883

  9. Genetics

    MedlinePlus

    ... Inheritance; Heterozygous; Inheritance patterns; Heredity and disease; Heritable; Genetic markers ... The chromosomes are made up of strands of genetic information called DNA. Each chromosome contains sections of ...

  10. The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans.

    PubMed

    Marks, Wendie N; Cavanagh, Mary E; Greba, Quentin; Cain, Stuart M; Snutch, Terrance P; Howland, John G

    2016-01-01

    Behavioural, neurological, and genetic similarities exist in epilepsies, their psychiatric comorbidities, and various psychiatric illnesses, suggesting common aetiological factors. Rodent models of epilepsy are used to characterize the comorbid symptoms apparent in epilepsy and their neurobiological mechanisms. The present study was designed to assess Pavlovian fear conditioning and latent inhibition in a polygenetic rat model of absence epilepsy, i.e. Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and the non-epileptic control (NEC) strain. Electrophysiological recordings confirmed the presence of spike-wave discharges in young adult GAERS but not NEC rats. A series of behavioural tests designed to assess anxiety-like behaviour (elevated plus maze, open field, acoustic startle response) and cognition (Pavlovian conditioning and latent inhibition) was subsequently conducted on male and female offspring. Results showed that GAERS exhibited significantly higher anxiety-like behaviour, a characteristic reported previously. In addition, using two protocols that differed in shock intensity, we found that both sexes of GAERS displayed exaggerated cued and contextual Pavlovian fear conditioning and impaired fear extinction. Fear reinstatement to the conditioned stimuli following unsignalled footshocks did not differ between the strains. Male GAERS also showed impaired latent inhibition in a paradigm using Pavlovian fear conditioning, suggesting that they may have altered attention, particularly related to previously irrelevant stimuli in the environment. Neither the female GAERS nor NEC rats showed evidence of latent inhibition in our paradigm. Together, the results suggest that GAERS may be a particularly useful model for assessing therapeutics designed to improve the emotional and cognitive disturbances associated with absence epilepsy.

  11. Autosomal and X-Linked Additive Genetic Variation for Lifespan and Aging: Comparisons Within and Between the Sexes in Drosophila melanogaster.

    PubMed

    Griffin, Robert M; Schielzeth, Holger; Friberg, Urban

    2016-12-07

    Theory makes several predictions concerning differences in genetic variation between the X chromosome and the autosomes due to male X hemizygosity. The X chromosome should: (i) typically show relatively less standing genetic variation than the autosomes, (ii) exhibit more variation in males compared to females because of dosage compensation, and (iii) potentially be enriched with sex-specific genetic variation. Here, we address each of these predictions for lifespan and aging in Drosophila melanogaster To achieve unbiased estimates of X and autosomal additive genetic variance, we use 80 chromosome substitution lines; 40 for the X chromosome and 40 combining the two major autosomes, which we assay for sex-specific and cross-sex genetic (co)variation. We find significant X and autosomal additive genetic variance for both traits in both sexes (with reservation for X-linked variation of aging in females), but no conclusive evidence for depletion of X-linked variation (measured through females). Males display more X-linked variation for lifespan than females, but it is unclear if this is due to dosage compensation since also autosomal variation is larger in males. Finally, our results suggest that the X chromosome is enriched for sex-specific genetic variation in lifespan but results were less conclusive for aging overall. Collectively, these results suggest that the X chromosome has reduced capacity to respond to sexually concordant selection on lifespan from standing genetic variation, while its ability to respond to sexually antagonistic selection may be augmented.

  12. Autosomal and X-Linked Additive Genetic Variation for Lifespan and Aging: Comparisons Within and Between the Sexes in Drosophila melanogaster

    PubMed Central

    Griffin, Robert M.; Schielzeth, Holger; Friberg, Urban

    2016-01-01

    Theory makes several predictions concerning differences in genetic variation between the X chromosome and the autosomes due to male X hemizygosity. The X chromosome should: (i) typically show relatively less standing genetic variation than the autosomes, (ii) exhibit more variation in males compared to females because of dosage compensation, and (iii) potentially be enriched with sex-specific genetic variation. Here, we address each of these predictions for lifespan and aging in Drosophila melanogaster. To achieve unbiased estimates of X and autosomal additive genetic variance, we use 80 chromosome substitution lines; 40 for the X chromosome and 40 combining the two major autosomes, which we assay for sex-specific and cross-sex genetic (co)variation. We find significant X and autosomal additive genetic variance for both traits in both sexes (with reservation for X-linked variation of aging in females), but no conclusive evidence for depletion of X-linked variation (measured through females). Males display more X-linked variation for lifespan than females, but it is unclear if this is due to dosage compensation since also autosomal variation is larger in males. Finally, our results suggest that the X chromosome is enriched for sex-specific genetic variation in lifespan but results were less conclusive for aging overall. Collectively, these results suggest that the X chromosome has reduced capacity to respond to sexually concordant selection on lifespan from standing genetic variation, while its ability to respond to sexually antagonistic selection may be augmented. PMID:27678519

  13. Involvement of GABAB receptors in biochemical alterations induced by anxiety-related responses to nicotine in mice: genetic and pharmacological approaches.

    PubMed

    Varani, Andrés P; Pedrón, Valeria T; Bettler, Bernhard; Balerio, Graciela N

    2014-06-01

    Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH-saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment.

  14. Additive genetic variation in resistance of Nile tilapia (Oreochromis niloticus) to Streptococcus iniae and S. agalactiae capsular type Ib: is genetic resistance correlated?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Streptococcus (S.) iniae and S. agalactiae are both economically important Gram positive bacterial pathogens affecting the globally farmed tilapia (Oreochromis spp.). Historically control of these bacteria in tilapia culture has included biosecurity, therapeutants and vaccination strategies. Genet...

  15. Arbuscular mycorrhizal fungal community composition is altered by long-term litter removal but not litter addition in a lowland tropical forest.

    PubMed

    Sheldrake, Merlin; Rosenstock, Nicholas P; Revillini, Daniel; Olsson, Pål Axel; Mangan, Scott; Sayer, Emma J; Wallander, Håkan; Turner, Benjamin L; Tanner, Edmund V J

    2017-04-01

    Tropical forest productivity is sustained by the cycling of nutrients through decomposing organic matter. Arbuscular mycorrhizal (AM) fungi play a key role in the nutrition of tropical trees, yet there has been little experimental investigation into the role of AM fungi in nutrient cycling via decomposing organic material in tropical forests. We evaluated the responses of AM fungi in a long-term leaf litter addition and removal experiment in a tropical forest in Panama. We described AM fungal communities using 454-pyrosequencing, quantified the proportion of root length colonised by AM fungi using microscopy, and estimated AM fungal biomass using a lipid biomarker. AM fungal community composition was altered by litter removal but not litter addition. Root colonisation was substantially greater in the superficial organic layer compared with the mineral soil. Overall colonisation was lower in the litter removal treatment, which lacked an organic layer. There was no effect of litter manipulation on the concentration of the AM fungal lipid biomarker in the mineral soil. We hypothesise that reductions in organic matter brought about by litter removal may lead to AM fungi obtaining nutrients from recalcitrant organic or mineral sources in the soil, besides increasing fungal competition for progressively limited resources.

  16. Evidence of Shared Genome-Wide Additive Genetic Effects on Interpersonal Trauma Exposure and Generalized Vulnerability to Drug Dependence in a Population of Substance Users.

    PubMed

    Palmer, Rohan H C; Nugent, Nicole R; Brick, Leslie A; Bidwell, Cinnamon L; McGeary, John E; Keller, Matthew C; Knopik, Valerie S

    2016-06-01

    Exposure to traumatic experiences is associated with an increased risk for drug dependence and poorer response to substance abuse treatment (Claus & Kindleberger, 2002; Jaycox, Ebener, Damesek, & Becker, 2004). Despite this evidence, the reasons for the observed associations of trauma and the general tendency to be dependent upon drugs of abuse remain unclear. Data (N = 2,596) from the Study of Addiction: Genetics and Environment were used to analyze (a) the degree to which commonly occurring single nucleotide polymorphisms (SNPs; minor allele frequency > 1%) in the human genome explains exposure to interpersonal traumatic experiences, and (b) the extent to which additive genetic effects on trauma are shared with additive genetic effects on drug dependence. Our results suggested moderate additive genetic influences on interpersonal trauma, h(2) SNP-Interpersonal = .47, 95% confidence interval (CI) [.10, .85], that are partially shared with additive genetic effects on generalized vulnerability to drug dependence, h(2) SNP-DD = .36, 95% CI [.11, .61]; rG-SNP = .49, 95% CI [.02, .96]. Although the design/technique does not exclude the possibility that substance abuse causally increases risk for traumatic experiences (or vice versa), these findings raise the possibility that commonly occurring SNPs influence both the general tendency towards drug dependence and interpersonal trauma.

  17. A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease.

    PubMed

    Holmans, Peter; Moskvina, Valentina; Jones, Lesley; Sharma, Manu; Vedernikov, Alexey; Buchel, Finja; Saad, Mohamad; Sadd, Mohamad; Bras, Jose M; Bettella, Francesco; Nicolaou, Nayia; Simón-Sánchez, Javier; Mittag, Florian; Gibbs, J Raphael; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nicholas W; Martinez, Maria; Singleton, Andrew B; Nalls, Michael A; Hardy, John; Morris, Huw R; Williams, Nigel M

    2013-03-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.

  18. Statistics of Scientific Procedures on Living Animals 2013: Experimentation continues to rise--the reliance on genetically-altered animals must be addressed.

    PubMed

    Hudson-Shore, Michelle

    2014-09-01

    The 2013 Statistics of Scientific Procedures on Living Animals reveal that the level of animal experimentation in Great Britain continues to rise, with 4.12 million procedures being conducted. The figures indicate that this is almost exclusively a result of the breeding and use of genetically-altered (GA) animals (i.e. genetically-modified animals, plus those with harmful genetic defects). The breeding of GA animals increased to over half (51%) of all the procedures, and GA animals were involved in 61% of all the procedures. Indeed, if these animals were removed from the statistics, the number of procedures would actually have declined by 4%. It is argued that the Coalition Government has failed to address this issue, and, as a consequence, will not be able to deliver its pledge to reduce animal use in science. Recent publications supporting the need to reassess the dominance of genetic alteration are also discussed, as well as the need to move away from the use of dogs as the default second species in safety testing. The general trends in the species used, and the numbers and types of procedures, are also reviewed. Finally, forthcoming changes to the statistics are discussed.

  19. Additional in-series compliance reduces muscle force summation and alters the time course of force relaxation during fixed-end contractions.

    PubMed

    Mayfield, Dean L; Launikonis, Bradley S; Cresswell, Andrew G; Lichtwark, Glen A

    2016-11-15

    There are high mechanical demands placed on skeletal muscles in movements requiring rapid acceleration of the body or its limbs. Tendons are responsible for transmitting muscle forces, but, because of their elasticity, can manipulate the mechanics of the internal contractile apparatus. Shortening of the contractile apparatus against the stretch of tendon affects force generation according to known mechanical properties; however, the extent to which differences in tendon compliance alter force development in response to a burst of electrical impulses is unclear. To establish the influence of series compliance on force summation, we studied electrically evoked doublet contractions in the cane toad peroneus muscle in the presence and absence of a compliant artificial tendon. Additional series compliance reduced tetanic force by two-thirds, a finding predicted based on the force-length property of skeletal muscle. Doublet force and force-time integral expressed relative to the twitch were also reduced by additional series compliance. Active shortening over a larger range of the ascending limb of the force-length curve and at a higher velocity, leading to a progressive reduction in force-generating potential, could be responsible. Muscle-tendon interaction may also explain the accelerated time course of force relaxation in the presence of additional compliance. Our findings suggest that a compliant tendon limits force summation under constant-length conditions. However, high series compliance can be mechanically advantageous when a muscle-tendon unit is actively stretched, permitting muscle fibres to generate force almost isometrically, as shown during stretch-shorten cycles in locomotor activities. Restricting active shortening would likely favour rapid force development.

  20. Defining population structure and genetic signatures of decline in the giant garter snake (Thamnophis gigas): implications for conserving threatened species within highly altered landscapes

    USGS Publications Warehouse

    Wood, Dustin A.; Halstead, Brian J.; Casazza, Michael L.; Hansen, Eric C.; Wylie, Glenn D.; Vandergast, Amy

    2015-01-01

    Anthropogenic habitat fragmentation can disrupt the ability of species to disperse across landscapes, which can alter the levels and distribution of genetic diversity within populations and negatively impact long-term viability. The giant gartersnake (Thamnophis gigas) is a state and federally threatened species that historically occurred in the wetland habitats of California’s Great Central Valley. Despite the loss of 93 % of historic wetlands throughout the Central Valley, giant gartersnakes continue to persist in relatively small, isolated patches of highly modified agricultural wetlands. Gathering information regarding genetic diversity and effective population size represents an essential component for conservation management programs aimed at this species. Previous mitochondrial sequence studies have revealed historical patterns of differentiation, yet little is known about contemporary population structure and diversity. On the basis of 15 microsatellite loci, we estimate population structure and compare indices of genetic diversity among populations spanning seven drainage basins within the Central Valley. We sought to understand how habitat loss may have affected genetic differentiation, genetic diversity and effective population size, and what these patterns suggest in terms of management and restoration actions. We recovered five genetic clusters that were consistent with regional drainage basins, although three northern basins within the Sacramento Valley formed a single genetic cluster. Our results show that northern drainage basin populations have higher connectivity than among central and southern basins populations, and that greater differentiation exists among the more geographically isolated populations in the central and southern portion of the species’ range. Genetic diversity measures among basins were significantly different, and were generally lower in southern basin populations. Levels of inbreeding and evidence of population

  1. Alterations of social interaction through genetic and environmental manipulation of the 22q11.2 gene Sept5 in the mouse brain.

    PubMed

    Harper, Kathryn M; Hiramoto, Takeshi; Tanigaki, Kenji; Kang, Gina; Suzuki, Go; Trimble, William; Hiroi, Noboru

    2012-08-01

    Social behavior dysfunction is a symptomatic element of schizophrenia and autism spectrum disorder (ASD). Although altered activities in numerous brain regions are associated with defective social cognition and perception, the causative relationship between these altered activities and social cognition and perception-and their genetic underpinnings-are not known in humans. To address these issues, we took advantage of the link between hemizygous deletion of human chromosome 22q11.2 and high rates of social behavior dysfunction, schizophrenia and ASD. We genetically manipulated Sept5, a 22q11.2 gene, and evaluated its role in social interaction in mice. Sept5 deficiency, against a high degree of homogeneity in a congenic genetic background, selectively impaired active affiliative social interaction in mice. Conversely, virally guided overexpression of Sept5 in the hippocampus or, to a lesser extent, the amygdala elevated levels of active affiliative social interaction in C57BL/6J mice. Congenic knockout mice and mice overexpressing Sept5 in the hippocampus or amygdala were indistinguishable from control mice in novelty and olfactory responses, anxiety or motor activity. Moreover, post-weaning individual housing, an environmental condition designed to reduce stress in male mice, selectively raised levels of Sept5 protein in the amygdala and increased active affiliative social interaction in C57BL/6J mice. These findings identify this 22q11.2 gene in the hippocampus and amygdala as a determinant of social interaction and suggest that defective social interaction seen in 22q11.2-associated schizophrenia and ASD can be genetically and environmentally modified by altering this 22q11.2 gene.

  2. Exploring Typical and Atypical Safety Climate Perceptions of Practitioners in the Repair, Maintenance, Minor Alteration and Addition (RMAA) Sector in Hong Kong

    PubMed Central

    Hon, Carol K.H.; Liu, Yulin

    2016-01-01

    The safety of repair, maintenance, minor alteration and addition (RMAA) work is an under-explored area. This study explored the typical and atypical safety climate perceptions of practitioners in the RMAA sector in Hong Kong, based on a self-administered questionnaire survey of 662 local practitioners in the industry. Profile analysis, via multidimensional scaling of the respondents’ scores of three safety climate scales, identified one typical perception: high in management commitment to occupational health and safety (OHS) and employee involvement, low in applicability for safety rules and regulations, and low in responsibility for OHS. The respondents were clustered into typical and atypical perception groups according to their safety climate scores’ match to the typical perception. A comparison of demographics between the two groups with logistic regression found that work level and direct employer significantly affect their classification. A multivariate analysis of variance of safety performance measures between the two groups indicated that the typical group had a significantly higher level of safety compliance than the atypical group, with no significant difference in safety participation or injury. The significance of this study lies in revealing the typical safety climate perception profile pattern of RMAA works and offering a new perspective of safety climate research. PMID:27669269

  3. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations

    PubMed Central

    Taberlay, Phillippa C.; Achinger-Kawecka, Joanna; Lun, Aaron T.L.; Buske, Fabian A.; Sabir, Kenneth; Gould, Cathryn M.; Zotenko, Elena; Bert, Saul A.; Giles, Katherine A.; Bauer, Denis C.; Smyth, Gordon K.; Stirzaker, Clare; O'Donoghue, Sean I.; Clark, Susan J.

    2016-01-01

    A three-dimensional chromatin state underpins the structural and functional basis of the genome by bringing regulatory elements and genes into close spatial proximity to ensure proper, cell-type–specific gene expression profiles. Here, we performed Hi-C chromosome conformation capture sequencing to investigate how three-dimensional chromatin organization is disrupted in the context of copy-number variation, long-range epigenetic remodeling, and atypical gene expression programs in prostate cancer. We find that cancer cells retain the ability to segment their genomes into megabase-sized topologically associated domains (TADs); however, these domains are generally smaller due to establishment of additional domain boundaries. Interestingly, a large proportion of the new cancer-specific domain boundaries occur at regions that display copy-number variation. Notably, a common deletion on 17p13.1 in prostate cancer spanning the TP53 tumor suppressor locus results in bifurcation of a single TAD into two distinct smaller TADs. Change in domain structure is also accompanied by novel cancer-specific chromatin interactions within the TADs that are enriched at regulatory elements such as enhancers, promoters, and insulators, and associated with alterations in gene expression. We also show that differential chromatin interactions across regulatory regions occur within long-range epigenetically activated or silenced regions of concordant gene activation or repression in prostate cancer. Finally, we present a novel visualization tool that enables integrated exploration of Hi-C interaction data, the transcriptome, and epigenome. This study provides new insights into the relationship between long-range epigenetic and genomic dysregulation and changes in higher-order chromatin interactions in cancer. PMID:27053337

  4. Additive influence of genetic predisposition and conventional risk factors in the incidence of coronary heart disease: a population-based study in Greece

    Technology Transfer Automated Retrieval System (TEKTRAN)

    An additive genetic risk score (GRS) for coronary heart disease (CHD) has previously been associated with incident CHD in the population-based Greek European Prospective Investigation into Cancer and nutrition (EPIC) cohort. In this study, we explore GRS-‘environment’ joint actions on CHD for severa...

  5. Fluorescent Probe Study of AOT Vesicle Membranes and Their Alteration upon Addition of Aniline or the Aniline Dimer p-Aminodiphenylamine (PADPA).

    PubMed

    Iwasaki, Fumihiko; Luginbühl, Sandra; Suga, Keishi; Walde, Peter; Umakoshi, Hiroshi

    2017-02-28

    Artificial vesicles formed from sodium bis(2-ethylhexyl) sulfosuccinate (AOT) in aqueous solution are used successfully as additives for enzymatic oligomerizations or polymerizations of aniline or the aniline dimer p-aminodiphenylamine (PADPA) under slightly acidic conditions (e.g., pH 4.3 with horseradish peroxidase and hydrogen peroxide as oxidants). In these systems, the reactions occur membrane surface-confined. Therefore, (i) the physicochemical properties of the vesicle membrane and (ii) the interaction of aniline or PADPA with the AOT membrane play crucial roles in the progress and final outcome of the reactions. For this reason, the properties of AOT vesicles with and without added aniline or PADPA were investigated by using two fluorescent membrane probes: 1,6-diphenyl-1,3,5-hexatriene (DPH) and 6-lauroyl-2-dimethylaminonaphthalene (Laurdan). DPH and Laurdan were used as "sensors" of the membrane fluidity, surface polarity, and membrane phase state. Moreover, the effect of hexanol, alone or in combination with aniline or PADPA, as a possible modifier of the AOT membrane, was also studied with the aim of evaluating whether the membrane fluidity and surface polarity is altered significantly by hexanol, which, in turn, may have an influence on the mentioned types of reactions. The data obtained indicate that the AOT vesicle membrane at room temperature and pH 4.3 (0.1 M NaH2PO4) is more fluid and has a more polar surface than in the case of fluid phospholipid vesicle membranes formed from 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). Furthermore, the fluorescence measurements indicate that mixed AOT-hexanol membranes are less fluid than pure AOT membranes and that they have a lower surface polarity than pure AOT membranes. PADPA strongly binds to AOT and to mixed AOT/hexanol membranes and leads to drastic changes in the membrane properties (decrease in fluidity and surface polarity), resulting in Laurdan fluorescence spectra, which are characteristic for

  6. Genetic variation responsible for mouse strain differences in integrin {alpha}{sub 2} expression is associated with altered platelet responses to collagen

    SciTech Connect

    Li, Tong-Tong; Larrucea, Susana; Souza, Shiloe; Leal, Suzanne M.; Lopez, Jose A.; Rubin, Edward M.; Nieswandt, Bernhard; Bray, Paul F.

    2003-11-01

    exert quantitative and qualitative alterations in human platelet adhesive receptors. Polymorphisms of both integrin {alpha}{sub 2} and GPIb have been associated with quantitative differences in receptor levels in healthy individuals. The variation of integrin {alpha}{sub 2} in the normal population is 5-fold, and some portion of this variability has been associated with a C/T polymorphism at nucleotide 807. Individuals homozygous for the 807C or 807T alleles have an average 2-fold difference in platelet {alpha}{sub 2} {beta}{sub 1} levels, and this difference has been linked to increased adhesion to collagen and clinical thrombotic events. Comparable alterations in platelet adhesion receptor expression have not been assessed in different mouse strains. Assessing the functional consequences of subtle genetic variations in humans is challenged by numerous gene-gene and gene environment interactions, and studies in mice can greatly minimize these confounding variables. In addition, comparative sequence analyses between species and between nonhuman primates have proved useful for identifying sequences that affect function and expression. Thus, in the case of platelet adhesion receptors, knowing mouse strain differences in expression levels might be valuable for defining the responsible quantitative trait loci as well as affecting strain choice for particular functional experiments.

  7. The Genetics of Keratoconus

    PubMed Central

    Nowak, Dorota M.; Gajecka, Marzena

    2011-01-01

    Keratoconus (KTCN) is non-inflammatory thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive error, and decreased vision. Keratoconus is a complex condition of multifactorial etiology. Both genetic and environmental factors are associated with KTCN. Evidence of genetic etiology includes familial inheritance, discordance between dizygotic twins, and association with other known genetic disorders. Several loci responsible for a familial form of KTCN have been mapped; however, no mutations in any genes have been identified for any of these loci. This article focuses on the genetic aspects. In addition, bioinformatics methods applied in KTCN gene identification process are discussed. PMID:21572727

  8. Rapid Genetic and Epigenetic Alterations under Intergeneric Genomic Shock in Newly Synthesized Chrysanthemum morifolium × Leucanthemum paludosum Hybrids (Asteraceae)

    PubMed Central

    Wang, Haibin; Jiang, Jiafu; Chen, Sumei; Qi, Xiangyu; Fang, Weimin; Guan, Zhiyong; Teng, Nianjun; Liao, Yuan; Chen, Fadi

    2014-01-01

    The Asteraceae family is at the forefront of the evolution due to frequent hybridization. Hybridization is associated with the induction of widespread genetic and epigenetic changes and has played an important role in the evolution of many plant taxa. We attempted the intergeneric cross Chrysanthemum morifolium × Leucanthemum paludosum. To obtain the success in cross, we have to turn to ovule rescue. DNA profiling of the amphihaploid and amphidiploid was investigated using amplified fragment length polymorphism, sequence-related amplified polymorphism, start codon targeted polymorphism, and methylation-sensitive amplification polymorphism (MSAP). Hybridization induced rapid changes at the genetic and the epigenetic levels. The genetic changes mainly involved loss of parental fragments and gaining of novel fragments, and some eliminated sequences possibly from the noncoding region of L. paludosum. The MSAP analysis indicated that the level of DNA methylation was lower in the amphiploid (∼45%) than in the parental lines (51.5–50.6%), whereas it increased after amphidiploid formation. Events associated with intergeneric genomic shock were a feature of C. morifolium × L. paludosum hybrid, given that the genetic relationship between the parental species is relatively distant. Our results provide genetic and epigenetic evidence for understanding genomic shock in wide crosses between species in Asteraceae and suggest a need to expand our current evolutionary framework to encompass a genetic/epigenetic dimension when seeking to understand wide crosses. PMID:24407856

  9. Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction*

    PubMed Central

    Mancuso, David J.; Kotzbauer, Paul; Wozniak, David F.; Sims, Harold F.; Jenkins, Christopher M.; Guan, Shaoping; Han, Xianlin; Yang, Kui; Sun, Gang; Malik, Ibrahim; Conyers, Sara; Green, Karen G.; Schmidt, Robert E.; Gross, Richard W.

    2009-01-01

    Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) results in profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis resulting in enlarged and degenerating mitochondria leading to autophagy and cognitive dysfunction. Shotgun lipidomics demonstrated multiple alterations in hippocampal lipid metabolism in iPLA2γ−/− mice including: 1) a markedly elevated hippocampal cardiolipin content with an altered molecular species composition characterized by a shift to shorter chain length molecular species; 2) alterations in both choline and ethanolamine glycerophospholipids, including a decreased plasmenylethanolamine content; 3) increased oxidized phosphatidylethanolamine molecular species; and 4) an increased content of ceramides. Electron microscopic examination demonstrated the presence of enlarged heteromorphic lamellar structures undergoing degeneration accompanied by the presence of ubiquitin positive spheroid inclusion bodies. Purification of these enlarged heteromorphic lamellar structures by buoyant density centrifugation and subsequent SDS-PAGE and proteomics identified them as degenerating mitochondria. Collectively, these results identify the obligatory role of iPLA2γ in neuronal mitochondrial lipid metabolism and membrane structure demonstrating that iPLA2γ loss of function results in a mitochondrial neurodegenerative disorder characterized by degenerating mitochondria, autophagy, and cognitive dysfunction. PMID:19840936

  10. Alteration of Sexual Reproduction and Genetic Diversity in the Kelp Species Laminaria digitata at the Southern Limit of Its Range

    PubMed Central

    Oppliger, Luz Valeria; von Dassow, Peter; Bouchemousse, Sarah; Robuchon, Marine; Valero, Myriam; Correa, Juan A.; Mauger, Stéphane; Destombe, Christophe

    2014-01-01

    Adaptation to marginal habitats at species range-limits has often been associated with parthenogenetic reproduction in terrestrial animals and plants. Laboratory observations have shown that brown algae exhibit a high propensity for parthenogenesis by various mechanisms. The kelp Laminaria digitata is an important component of the ecosystem in Northern European rocky intertidal habitats. We studied four L. digitata populations for the effects of marginality on genetic diversity and sexual reproduction. Two populations were marginal: One (Locquirec, in Northern Brittany) was well within the geographic range, but was genetically isolated from other populations by large stretches of sandy beaches. Another population was at the range limits of the species (Quiberon, in Southern Brittany) and was exposed to much higher seasonal temperature changes. Microsatellite analyses confirmed that these populations showed decreased genetic and allelic diversity, consistent with marginality and genetic isolation. Sporophytes from both marginal populations showed greatly diminished spore-production compared to central populations, but only the southern-limit population (Quiberon) showed a high propensity for producing unreduced (2N) spores. Unreduced 2N spores formed phenotypically normal gametophytes with nuclear area consistent with ≥2N DNA contents, and microsatellite studies suggested these were produced at least in part by automixis. However, despite this being the dominant path of spore production in Quiberon sporophyte individuals, the genetic evidence indicated the population was maintained mostly by sexual reproduction. Thus, although spore production and development showed the expected tendency of geographical parthenogenesis in marginal populations, this appeared to be a consequence of maladaptation, rather than an adaptation to, life in a marginal habitat. PMID:25019953

  11. Use of the MLPA assay in the molecular diagnosis of gene copy number alterations in human genetic diseases.

    PubMed

    Stuppia, Liborio; Antonucci, Ivana; Palka, Giandomenico; Gatta, Valentina

    2012-01-01

    Multiplex Ligation-dependent Probe Amplification (MLPA) assay is a recently developed technique able to evidence variations in the copy number of several human genes. Due to this ability, MLPA can be used in the molecular diagnosis of several genetic diseases whose pathogenesis is related to the presence of deletions or duplications of specific genes. Moreover, MLPA assay can also be used in the molecular diagnosis of genetic diseases characterized by the presence of abnormal DNA methylation. Due to the large number of genes that can be analyzed by a single technique, MLPA assay represents the gold standard for molecular analysis of all pathologies derived from the presence of gene copy number variation. In this review, the main applications of the MLPA technique for the molecular diagnosis of human diseases are described.

  12. Genetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The genus Capsicum represents one of several well characterized Solanaceous genera. A wealth of classical and molecular genetics research is available for the genus. Information gleaned from its cultivated relatives, tomato and potato, provide further insight for basic and applied studies. Early ...

  13. Genetics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maintaining genetic variation in wild populations of Arctic organisms is fundamental to the long-term persistence of high latitude biodiversity. Variability is important because it provides options for species to respond to changing environmental conditions and novel challenges such as emerging path...

  14. Plants with genetically modified events combined by conventional breeding: an assessment of the need for additional regulatory data.

    PubMed

    Pilacinski, W; Crawford, A; Downey, R; Harvey, B; Huber, S; Hunst, P; Lahman, L K; MacIntosh, S; Pohl, M; Rickard, C; Tagliani, L; Weber, N

    2011-01-01

    Crop varieties with multiple GM events combined by conventional breeding have become important in global agriculture. The regulatory requirements in different countries for such products vary considerably, placing an additional burden on regulatory agencies in countries where the submission of additional data is required and delaying the introduction of innovative products to meet agricultural needs. The process of conventional plant breeding has predictably provided safe food and feed products both historically and in the modern era of plant breeding. Thus, previously approved GM events that have been combined by conventional plant breeding and contain GM traits that are not likely to interact in a manner affecting safety should be considered to be as safe as their conventional counterparts. Such combined GM event crop varieties should require little, if any, additional regulatory data to meet regulatory requirements.

  15. Kiss of the Mutant Mouse: How Genetically Altered Mice Advanced Our Understanding of Kisspeptin's Role in Reproductive Physiology

    PubMed Central

    Elias, Carol F.

    2012-01-01

    The kisspeptin system has emerged as one of the most important circuits within the central network governing reproduction. Although kisspeptin physiology has been examined in many species, much of our understanding of this system has come from mice. Recently, the study of several innovative strains of genetically engineered mouse models has revealed intriguing and unexpected insights into the functions of kisspeptin signaling in the hypothalamus. Here, we review the advancements in our knowledge of the central kisspeptin system through the use of mutant mice. PMID:23011921

  16. Genetic Deficiency of Complement Component 3 Does Not Alter Disease Progression in a Mouse Model of Huntington's Disease.

    PubMed

    Larkin, Paul B; Muchowski, Paul J

    2012-01-01

    Several genes and proteins of the complement cascade are present at elevated levels in brains of patients with Huntington's disease (HD). The complement cascade is well characterized as an effector arm of the immune system, and in the brain it is important for developmental synapse elimination. We hypothesized that increased levels of complement in HD brains contributes to disease progression, perhaps by contributing to synapse elimination or inflammatory signaling. We tested this hypothesis in the R6/2 mouse model of HD by crossing mice deficient in complement component 3 (C3), a crucial complement protein found at increased levels in HD brains, to R6/2 mice and monitoring behavioral and neuropathological disease progression. We found no alterations in multiple behavioral assays, weight or survival in R6/2 mice lacking C3. We also quantified the expression of several complement cascade genes in R6/2 brains and found that the large scale upregulation of complement genes observed in HD brains is not mirrored in R6/2 brains. These data show that C3 deficiency does not alter disease progression in the R6/2 mouse model of HD.

  17. Additive genetic variation in resistance traits of an exotic pine species: little evidence for constraints on evolution of resistance against native herbivores.

    PubMed

    Moreira, X; Zas, R; Sampedro, L

    2013-05-01

    The apparent failure of invasions by alien pines in Europe has been explained by the co-occurrence of native pine congeners supporting herbivores that might easily recognize the new plants as hosts. Previous studies have reported that exotic pines show reduced tolerance and capacity to induce resistance to those native herbivores. We hypothesize that limited genetic variation in resistance to native herbivores and the existence of evolutionary trade-offs between growth and resistance could represent additional potential constraints on the evolution of invasiveness of exotic pines outside their natural range. In this paper, we examined genetic variation for constitutive and induced chemical defences (measured as non-volatile resin in the stem and total phenolics in the needles) and resistance to two major native generalist herbivores of pines in cafeteria bioassays (the phloem-feeder Hylobius abietis and the defoliator Thaumetopoea pityocampa) using half-sib families drawn from a sample of the population of Pinus radiata introduced to Spain in the mid-19th century. We found (i) significant genetic variation, with moderate-to-high narrow-sense heritabilities for both the production of constitutive non-volatile resin and induced total phenolics, and for constitutive resistance against T. pityocampa in bioassays, (ii) no evolutionary trade-offs between plant resistance and growth traits or between the production of different quantitative chemical defences and (iii) a positive genetic correlation between constitutive resistance to the two studied herbivores. Overall, results of our study indicate that the exotic pine P. radiata has limited genetic constraints on the evolution of resistance against herbivores in its introduced range, suggesting that, at least in terms of interactions with these enemies, this pine species has potential to become invasive in the future.

  18. Variable numbers of tandem repeat loci in genetically homogeneous Haemophilus influenzae strains alter during persistent colonisation of cystic fibrosis patients.

    PubMed

    Renders, N; Licciardello, L; IJsseldijk, C; Sijmons, M; van Alphen, L; Verbrugh, H; van Belkum, A

    1999-04-01

    Serial sputum isolates of Haemophilus influenzae (n = 69) were obtained from eight patients suffering from cystic fibrosis. For two of these patients all strains were analysed for polymorphism in the major outer membrane protein profile. For all patients the strains were genetically characterised by random amplification of polymorphic DNA analysis. All strains were included in a survey for polymorphism in regions containing moieties of repetitive DNA as well. A single locus containing trinucleotide repeat units, three loci harbouring tetranucleotides, one region comprising pentanucleotide units and two hexanucleotide repeat unit-containing loci were analysed for repeat number variability. Most of the regions were previously shown to be directly adjacent to or even within virulence genes. All regions behaved as genuine variable number of tandem repeat loci in the sense that genetic polymorphism based on the presence of varying numbers of repeat units could be demonstrated among different strains. Interestingly, several of the repeats showed variation in the absence of the variability as assessed by major outer membrane protein or random amplification of polymorphic DNA analysis. These observations indicate that the repeat loci may vary independently from major chromosomal polymorphism. Consequently, H. influenzae appears to modify its virulence gene regions of the chromosome during persistent colonisation of the lung in cystic fibrosis patients.

  19. Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation

    PubMed Central

    Harada, T; Baril, P; Gangeswaran, R; Kelly, G; Chelala, C; Bhakta, V; Caulee, K; Mahon, P C; Lemoine, N R

    2007-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is characterised pathologically by a marked desmoplastic stromal reaction that significantly reduces the sensitivity and specificity of cytogenetic analysis. To identify genetic alterations that reflect the characteristics of the tumour in vivo, we screened a total of 23 microdissected PDAC tissue samples using array-based comparative genomic hybridisation (array CGH) with 1 Mb resolution. Highly stringent statistical analysis enabled us to define the regions of nonrandom genomic changes. We detected a total of 41 contiguous regions (>3.0 Mb) of copy number changes, such as a genetic gain at 7p22.2–p15.1 (26.0 Mb) and losses at 17p13.3–p11.2 (13.6 Mb), 18q21.2–q22.1 (12.0 Mb), 18q22.3–q23 (7.1 Mb) and 18q12.3–q21.2 (6.9 Mb). To validate our array CGH results, fluorescence in situ hybridisation was performed using four probes from those regions, showing that these genetic alterations were observed in 37–68% of a separate sample set of 19 PDAC cases. In particular, deletion of the SEC11L3 gene (18q21.32) was detected at a very high frequency (13 out of 19 cases; 68%) and in situ RNA hybridisation for this gene demonstrated a significant correlation between deletion and expression levels. It was further confirmed by reverse transcription–PCR that SEC11L3 mRNA was downregulated in 16 out of 16 PDAC tissues (100%). In conclusion, the combination of tissue microdissection and array CGH provided a valid data set that represents in vivo genetic changes in PDAC. Our results raise the possibility that the SEC11L3 gene may play a role as a tumour suppressor in this disease. PMID:17242705

  20. Altered cortical GABAA receptor composition, physiology, and endocytosis in a mouse model of a human genetic absence epilepsy syndrome.

    PubMed

    Zhou, Chengwen; Huang, Zhiling; Ding, Li; Deel, M Elizabeth; Arain, Fazal M; Murray, Clark R; Patel, Ronak S; Flanagan, Christopher D; Gallagher, Martin J

    2013-07-19

    Patients with generalized epilepsy exhibit cerebral cortical disinhibition. Likewise, mutations in the inhibitory ligand-gated ion channels, GABAA receptors (GABAARs), cause generalized epilepsy syndromes in humans. Recently, we demonstrated that heterozygous knock-out (Hetα1KO) of the human epilepsy gene, the GABAAR α1 subunit, produced absence epilepsy in mice. Here, we determined the effects of Hetα1KO on the expression and physiology of GABAARs in the mouse cortex. We found that Hetα1KO caused modest reductions in the total and surface expression of the β2 subunit but did not alter β1 or β3 subunit expression, results consistent with a small reduction of GABAARs. Cortices partially compensated for Hetα1KO by increasing the fraction of residual α1 subunit on the cell surface and by increasing total and surface expression of α3, but not α2, subunits. Co-immunoprecipitation experiments revealed that Hetα1KO increased the fraction of α1 subunits, and decreased the fraction of α3 subunits, that associated in hybrid α1α3βγ receptors. Patch clamp electrophysiology studies showed that Hetα1KO layer VI cortical neurons exhibited reduced inhibitory postsynaptic current peak amplitudes, prolonged current rise and decay times, and altered responses to benzodiazepine agonists. Finally, application of inhibitors of dynamin-mediated endocytosis revealed that Hetα1KO reduced base-line GABAAR endocytosis, an effect that probably contributes to the observed changes in GABAAR expression. These findings demonstrate that Hetα1KO exerts two principle disinhibitory effects on cortical GABAAR-mediated inhibitory neurotransmission: 1) a modest reduction of GABAAR number and 2) a partial compensation with GABAAR isoforms that possess physiological properties different from those of the otherwise predominant α1βγ GABAARs.

  1. Altered Cortical GABAA Receptor Composition, Physiology, and Endocytosis in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome*

    PubMed Central

    Zhou, Chengwen; Huang, Zhiling; Ding, Li; Deel, M. Elizabeth; Arain, Fazal M.; Murray, Clark R.; Patel, Ronak S.; Flanagan, Christopher D.; Gallagher, Martin J.

    2013-01-01

    Patients with generalized epilepsy exhibit cerebral cortical disinhibition. Likewise, mutations in the inhibitory ligand-gated ion channels, GABAA receptors (GABAARs), cause generalized epilepsy syndromes in humans. Recently, we demonstrated that heterozygous knock-out (Hetα1KO) of the human epilepsy gene, the GABAAR α1 subunit, produced absence epilepsy in mice. Here, we determined the effects of Hetα1KO on the expression and physiology of GABAARs in the mouse cortex. We found that Hetα1KO caused modest reductions in the total and surface expression of the β2 subunit but did not alter β1 or β3 subunit expression, results consistent with a small reduction of GABAARs. Cortices partially compensated for Hetα1KO by increasing the fraction of residual α1 subunit on the cell surface and by increasing total and surface expression of α3, but not α2, subunits. Co-immunoprecipitation experiments revealed that Hetα1KO increased the fraction of α1 subunits, and decreased the fraction of α3 subunits, that associated in hybrid α1α3βγ receptors. Patch clamp electrophysiology studies showed that Hetα1KO layer VI cortical neurons exhibited reduced inhibitory postsynaptic current peak amplitudes, prolonged current rise and decay times, and altered responses to benzodiazepine agonists. Finally, application of inhibitors of dynamin-mediated endocytosis revealed that Hetα1KO reduced base-line GABAAR endocytosis, an effect that probably contributes to the observed changes in GABAAR expression. These findings demonstrate that Hetα1KO exerts two principle disinhibitory effects on cortical GABAAR-mediated inhibitory neurotransmission: 1) a modest reduction of GABAAR number and 2) a partial compensation with GABAAR isoforms that possess physiological properties different from those of the otherwise predominant α1βγ GABAARs. PMID:23744069

  2. Reviewing the genetic alterations in high-risk cutaneous squamous cell carcinoma: A search for prognostic markers and therapeutic targets.

    PubMed

    Ashford, Bruce G; Clark, Jonathan; Gupta, Ruta; Iyer, N Gopalakrishna; Yu, Bing; Ranson, Marie

    2017-04-03

    Cutaneous squamous cell carcinoma (SCC) is second only in incidence to basal cell carcinoma (BCC), effecting up to 500 000 people in the United States annually. Metastasis to regional lymph nodes occurs in approximately 5% of cases and imparts significant morbidity. Standard treatment in this group involves a combination of surgery and adjuvant radiation. Currently, there are no clinically useful biomarkers of metastatic potential in primary cutaneous SCC and histological predictors can be unreliable. The high level of mutational burden in normal UV-exposed skin has hampered the search for novel drivers of invasive disease, and indeed metastatic potential. This review outlines the clinical problems in high-risk and metastatic cutaneous SCCs, reviews the known genetic events and molecular mechanisms in high-risk primary cutaneous SCC and metastasis, and identifies avenues for further investigation and potential therapy.

  3. Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes.

    PubMed

    Filip, Małgorzata; Spampinato, Umberto; McCreary, Andrew C; Przegaliński, Edmund

    2012-10-02

    The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT(2C) receptors on the effects of different classes of addictive drugs, illustrated by reference to data using pharmacological and genetic tools. The neurochemical mechanism of the interaction between 5-HT(2C) receptors, with focus on the mesocorticolimbic dopaminergic system, and drugs of abuse (using cocaine as an example) is discussed. Finally, we integrate recent nonclinical and clinical research and information with marketed products possessing 5-HT(2C) receptor binding affinities. Accordingly, available nonclinical data and some clinical observations targeting 5-HT(2C) receptors may offer innovative translational strategies for combating drug dependence.This article is part of a Special Issue entitled: Brain Integration.

  4. Genetic Polymorphisms in Organic Cation Transporter 1 (OCT1) in Chinese and Japanese Populations Exhibit Altered Function

    PubMed Central

    Chen, Ligong; Takizawa, Miho; Chen, Eugene; Schlessinger, Avner; Segenthelar, Julie; Choi, Ji Ha; Sali, Andej; Kubo, Michiaki; Nakamura, Shinko; Iwamoto, Yasuhiko; Iwasaki, Naoko

    2010-01-01

    Organic cation transporter 1 (OCT1; SLC22A1) seems to play a role in the efficacy and disposition of the widely used antidiabetic drug metformin. Genetic variants in OCT1 have been identified largely in European populations. Metformin is increasingly being used in Asian populations where the incidence of type 2 diabetes (T2D) is on the rise. The goal of this study is to identify genetic variants of OCT1 in Chinese and Japanese populations, which may potentially modulate response to metformin. We used recent data from the 1000 Genomes Project (Chinese and Japanese) and direct sequencing of selected amplicons of OCT1 in 66 DNA samples from Japanese patients with T2D. A total of six nonsynonymous variants were identified. Three of them (Q97K, P117L, and R206C) had not been functionally characterized previously and had allele frequencies of 0.017, 0.023 and 0.008, respectively. The uptake of metformin in cells expressing Q97K, P117L, and R206C was significantly reduced relative to the OCT1 reference (62 ± 4.3, 55 ± 6.8, and 22 ± 1.5% for Q97K, P117L, and R206C, respectively). Kinetic studies indicated that P117L and R206C exhibited a reduced Vmax, whereas Q97K showed an increased Km. The green fluorescent protein (GFP)-tagged Q97K and P117L variants localized to the plasma membrane, whereas the GFP-tagged R206C was retained mainly in the endoplasmic reticulum. Replacement of the highly conserved R206 with different amino acids modulated the subcellular localization and function of the transporter. This study suggests that nonsynonymous variants of OCT1 in Chinese and Japanese populations may affect the differential response to metformin. PMID:20639304

  5. Genetic deletion of MT1 melatonin receptors alters spontaneous behavioral rhythms in male and female C57BL/6 mice.

    PubMed

    Adamah-Biassi, E B; Hudson, R L; Dubocovich, M L

    2014-09-01

    Behaviors vary over the 24h light/dark cycle and these temporal patterns reflect in part modulation by circadian neural circuits and hormones, such as melatonin. The goal of this study was to investigate the involvement of MT1 melatonin receptors in behavioral regulation by comparing male and female C57 wild type (WT) mice with C57 mice with genetic deletion of the MT1 receptor (MT1KO). A comprehensive array of fifteen distinct spontaneous behaviors was recorded continuously in the homecage over multiple days using the HomeCageScan system. Behaviors assessed were activity-like (i.e. come down, hang, jump, walk), exploration-like (i.e. dig, groom, rear up, sniff, stretch), resting-like (i.e. awake, remain low, rest, twitch) and ingestion-like (i.e. drink, eat). Phenotypic array and temporal distribution analysis revealed distinct behavioral rhythms that differed between WT and MT1KO mice. The rhythms were consistent from day to day in males and varied with the estrous cycle in females. We also studied the role of MT1 receptors on depressive and anxiety-like behaviors. Genetic deletion of MT1 receptors increased immobility time in the forced swim test and decreased the number of marbles buried in the marble burying test in both male and female C57 mice. We conclude that MT1 melatonin receptors are involved in neural pathways modulating diurnal rhythms of spontaneous behavior in the homecage as well as pathways regulating depressive and anxiolytic-like behaviors.

  6. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension

    PubMed Central

    White, Kevin; Lu, Yu; Annis, Sofia; Hale, Andrew E; Chau, B Nelson; Dahlman, James E; Hemann, Craig; Opotowsky, Alexander R; Vargas, Sara O; Rosas, Ivan; Perrella, Mark A; Osorio, Juan C; Haley, Kathleen J; Graham, Brian B; Kumar, Rahul; Saggar, Rajan; Saggar, Rajeev; Wallace, W Dean; Ross, David J; Khan, Omar F; Bader, Andrew; Gochuico, Bernadette R; Matar, Majed; Polach, Kevin; Johannessen, Nicolai M; Prosser, Haydn M; Anderson, Daniel G; Langer, Robert; Zweier, Jay L; Bindoff, Laurence A; Systrom, David; Waxman, Aaron B; Jin, Richard C; Chan, Stephen Y

    2015-01-01

    Iron–sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings. PMID:25825391

  7. Changes in litter quality induced by nutrient addition alter litter decomposition in an alpine meadow on the Qinghai-Tibet Plateau

    PubMed Central

    Zhu, Wenyan; Wang, Jinzhou; Zhang, Zhenhua; Ren, Fei; Chen, Litong; He, Jin-Sheng

    2016-01-01

    The effects of nitrogen (N) and phosphorus (P) addition on litter decomposition are poorly understood in Tibetan alpine meadows. Leaf litter was collected from plots within a factorial N × P addition experiment and allowed to decompose over 708 days in an unfertilized plot to determine the effects of N and/or P addition on litter decomposition. Results showed that nutrient addition significantly affected initial P and P-related biochemical properties of litter from all four species. However, the responses of litter N and N-related biochemical properties to nutrient addition were quite species-specific. Litter C decomposition and N release were species-specific. However, N and P addition significantly affected litter P release. Ratios of Hemicellulose + Cellulose to N and P were significantly related to litter C decomposition; C:N ratio was a determinant of litter N release; and C:P and (Hemicellulose + Cellulose):P controlled litter P release. Overall, litter C decomposition was controlled by litter quality of different plant species, and strongly affected by P addition. Increasing N availability is likely to affect litter C decomposition more indirectly by shifting plant species composition than directly by improving litter quality, and may accelerate N and P cycles, but shift the ecosystem to P limitation. PMID:27694948

  8. Changes in litter quality induced by nutrient addition alter litter decomposition in an alpine meadow on the Qinghai-Tibet Plateau.

    PubMed

    Zhu, Wenyan; Wang, Jinzhou; Zhang, Zhenhua; Ren, Fei; Chen, Litong; He, Jin-Sheng

    2016-10-03

    The effects of nitrogen (N) and phosphorus (P) addition on litter decomposition are poorly understood in Tibetan alpine meadows. Leaf litter was collected from plots within a factorial N × P addition experiment and allowed to decompose over 708 days in an unfertilized plot to determine the effects of N and/or P addition on litter decomposition. Results showed that nutrient addition significantly affected initial P and P-related biochemical properties of litter from all four species. However, the responses of litter N and N-related biochemical properties to nutrient addition were quite species-specific. Litter C decomposition and N release were species-specific. However, N and P addition significantly affected litter P release. Ratios of Hemicellulose + Cellulose to N and P were significantly related to litter C decomposition; C:N ratio was a determinant of litter N release; and C:P and (Hemicellulose + Cellulose):P controlled litter P release. Overall, litter C decomposition was controlled by litter quality of different plant species, and strongly affected by P addition. Increasing N availability is likely to affect litter C decomposition more indirectly by shifting plant species composition than directly by improving litter quality, and may accelerate N and P cycles, but shift the ecosystem to P limitation.

  9. Genetic and chemical reductions in protein phosphatase activity alter auxin transport, gravity response, and lateral root growth

    NASA Technical Reports Server (NTRS)

    Rashotte, A. M.; DeLong, A.; Muday, G. K.; Brown, C. S. (Principal Investigator)

    2001-01-01

    Auxin transport is required for important growth and developmental processes in plants, including gravity response and lateral root growth. Several lines of evidence suggest that reversible protein phosphorylation regulates auxin transport. Arabidopsis rcn1 mutant seedlings exhibit reduced protein phosphatase 2A activity and defects in differential cell elongation. Here we report that reduced phosphatase activity alters auxin transport and dependent physiological processes in the seedling root. Root basipetal transport was increased in rcn1 or phosphatase inhibitor-treated seedlings but showed normal sensitivity to the auxin transport inhibitor naphthylphthalamic acid (NPA). Phosphatase inhibition reduced root gravity response and delayed the establishment of differential auxin-induced gene expression across a gravity-stimulated root tip. An NPA treatment that reduced basipetal transport in rcn1 and cantharidin-treated wild-type plants also restored a normal gravity response and asymmetric auxin-induced gene expression, indicating that increased basipetal auxin transport impedes gravitropism. Increased auxin transport in rcn1 or phosphatase inhibitor-treated seedlings did not require the AGR1/EIR1/PIN2/WAV6 or AUX1 gene products. In contrast to basipetal transport, root acropetal transport was normal in phosphatase-inhibited seedlings in the absence of NPA, although it showed reduced NPA sensitivity. Lateral root growth also exhibited reduced NPA sensitivity in rcn1 seedlings, consistent with acropetal transport controlling lateral root growth. These results support the role of protein phosphorylation in regulating auxin transport and suggest that the acropetal and basipetal auxin transport streams are differentially regulated.

  10. Physiological basis of tolerance to complete submergence in rice involves genetic factors in addition to the SUB1 gene

    PubMed Central

    Singh, Sudhanshu; Mackill, David J.; Ismail, Abdelbagi M.

    2014-01-01

    1 lines. This suggests the possibility of further improvements in submergence tolerance by incorporating additional traits present in FR13A or other similar landraces. PMID:25281725

  11. Physiological basis of tolerance to complete submergence in rice involves genetic factors in addition to the SUB1 gene.

    PubMed

    Singh, Sudhanshu; Mackill, David J; Ismail, Abdelbagi M

    2014-10-03

    1 lines. This suggests the possibility of further improvements in submergence tolerance by incorporating additional traits present in FR13A or other similar landraces.

  12. Replication of a gene-environment interaction Via Multimodel inference: additive-genetic variance in adolescents' general cognitive ability increases with family-of-origin socioeconomic status.

    PubMed

    Kirkpatrick, Robert M; McGue, Matt; Iacono, William G

    2015-03-01

    The present study of general cognitive ability attempts to replicate and extend previous investigations of a biometric moderator, family-of-origin socioeconomic status (SES), in a sample of 2,494 pairs of adolescent twins, non-twin biological siblings, and adoptive siblings assessed with individually administered IQ tests. We hypothesized that SES would covary positively with additive-genetic variance and negatively with shared-environmental variance. Important potential confounds unaddressed in some past studies, such as twin-specific effects, assortative mating, and differential heritability by trait level, were found to be negligible. In our main analysis, we compared models by their sample-size corrected AIC, and base our statistical inference on model-averaged point estimates and standard errors. Additive-genetic variance increased with SES-an effect that was statistically significant and robust to model specification. We found no evidence that SES moderated shared-environmental influence. We attempt to explain the inconsistent replication record of these effects, and provide suggestions for future research.

  13. Replication of a Gene-Environment Interaction via Multimodel Inference: Additive-Genetic Variance in Adolescents’ General Cognitive Ability Increases with Family-of-Origin Socioeconomic Status

    PubMed Central

    Kirkpatrick, Robert M.; McGue, Matt; Iacono, William G.

    2015-01-01

    The present study of general cognitive ability attempts to replicate and extend previous investigations of a biometric moderator, family-of-origin socioeconomic status (SES), in a sample of 2,494 pairs of adolescent twins, non-twin biological siblings, and adoptive siblings assessed with individually administered IQ tests. We hypothesized that SES would covary positively with additive-genetic variance and negatively with shared-environmental variance. Important potential confounds unaddressed in some past studies, such as twin-specific effects, assortative mating, and differential heritability by trait level, were found to be negligible. In our main analysis, we compared models by their sample-size corrected AIC, and base our statistical inference on model-averaged point estimates and standard errors. Additive-genetic variance increased with SES—an effect that was statistically significant and robust to model specification. We found no evidence that SES moderated shared-environmental influence. We attempt to explain the inconsistent replication record of these effects, and provide suggestions for future research. PMID:25539975

  14. Metabolic differences between genetically lean and fat chickens are partly attributed to the alteration of insulin signaling in liver.

    PubMed

    Dupont, J; Chen, J; Derouet, M; Simon, J; Leclercq, B; Taouis, M

    1999-11-01

    Insulin signaling [tyrosine phosphorylation of insulin receptor (IR), insulin receptor substrate-1 (IRS-1), Src homology and collagen protein (Shc) and phosphatidyl inositol 3'-kinase activity (PI 3'-kinase)] was studied in the liver and thigh muscles of fat (FL) and lean (LL) chickens. These lines result from a divergent selection on abdominal fat pad size. The divergence is of metabolic origin. Extreme nutritional states were studied (fed, 48-h starved and 30-min refed). Such conditions significantly altered insulin signaling in chicken liver, but surprisingly not in the muscle (except the phosphorylation of Shc in the refed state). No major differences that could account for this divergence were found in muscle. Liver IR number and Shc protein did not differ between genotypes. Liver IRS-1 (protein and messenger) was lower in the fed state and higher in the starved state in FL compared to that in LL chickens. In the fed state, tyrosine phosphorylation of liver IR, IRS-1 and Shc action was higher in FL than in LL chickens that in the absence of insulin resistance rely on higher plasma insulin levels. In the starved state, phosphorylation of liver IR was lower, but the phosphorylation of IR and IRS-1 were higher in LL than in FL chickens, most likely in response to higher plasma glucose and insulin in the lean genotype. In the refed state, the phosphorylation of liver IR and IRS-1 did not differ between genotypes despite significantly lower plasma insulin in FL chickens. Finally, PI 3'-kinase was not affected by the genotype. A significant activation of early steps of insulin signaling in liver of fed FL chickens may at least partly account for their increased liver lipogenesis and ultimately their fattening.

  15. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size.

    PubMed

    Devlin, Cecilia M; Kuriakose, George; Hirsch, Emmet; Tabas, Ira

    2002-04-30

    Inflammatory cytokines have been linked to atherosclerosis by using cell culture models and acute inflammation in animals. The goal of this study was to examine lipoprotein levels and early atherosclerosis in chronic animal models of altered IL-1 physiology by using mice with deficient or excess IL-1 receptor antagonist (IL-1ra). IL-1ra knockout C57BL/6J mice fed a cholesterol/cholate diet for 3 mo had a 3-fold decrease in non-high-density lipoprotein cholesterol and a trend toward increased foam-cell lesion area compared to wild-type littermate controls. IL-1ra transgenic/low-density lipoprotein receptor (LDLR) knockout mice fed a cholesterol-saturated fat diet for 10 wk showed a 40% increase in non-high-density lipoprotein cholesterol, consistent with the IL-1ra knockout data, although there was no change in lesion size. When these IL1-ra overexpressing transgenic mice on the LDLR knockout background were fed a high-cholesterol/high-fat diet containing cholate, however, a statistically significant 40% decrease in lesion area was observed compared to LDLR knockout mice lacking the transgene. By immunohistochemistry, IL-1ra was present in C57BL/6J and LDLR knockout aortae, absent in IL-1ra knockout aortae, and present at high levels in LDLR knockout/IL-1ra transgene aortae. In summary, IL-1ra tended to increase plasma lipoprotein levels and, when fed a cholate-containing diet, decrease foam-cell lesion size. These data demonstrate that in selected models of murine atherosclerosis, chronic IL-1ra depletion or overexpression has potentially important effects on lipoprotein metabolism and foam-cell lesion development.

  16. Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium

    PubMed Central

    Prechl, József; Papp, Krisztián; Hérincs, Zoltán; Péterfy, Hajna; Lóránd, Veronika; Szittner, Zoltán; Estonba, Andone; Rovero, Paolo; Paolini, Ilaria; del Amo, Jokin; Uribarri, Maria; Alcaro, Maria Claudia; Ruiz-Larrañaga, Otsanda; Migliorini, Paola; Czirják, László

    2016-01-01

    Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement

  17. Serological and Genetic Evidence for Altered Complement System Functionality in Systemic Lupus Erythematosus: Findings of the GAPAID Consortium.

    PubMed

    Prechl, József; Papp, Krisztián; Hérincs, Zoltán; Péterfy, Hajna; Lóránd, Veronika; Szittner, Zoltán; Estonba, Andone; Rovero, Paolo; Paolini, Ilaria; Del Amo, Jokin; Uribarri, Maria; Alcaro, Maria Claudia; Ruiz-Larrañaga, Otsanda; Migliorini, Paola; Czirják, László

    2016-01-01

    Systemic lupus erythematosus is a chronic autoimmune disease with multifactorial ethiopathogenesis. The complement system is involved in both the early and late stages of disease development and organ damage. To better understand autoantibody mediated complement consumption we examined ex vivo immune complex formation on autoantigen arrays. We recruited patients with SLE (n = 211), with other systemic autoimmune diseases (n = 65) and non-autoimmune control subjects (n = 149). Standard clinical and laboratory data were collected and serum complement levels were determined. The genotype of SNP rs1143679 in the ITGAM gene was also determined. Ex vivo formation of immune complexes, with respect to IgM, IgG, complement C4 and C3 binding, was examined using a functional immunoassay on autoantigen microarray comprising nucleic acids, proteins and lipids. Complement consumption of nucleic acids increased upon binding of IgM and IgG even when serum complement levels were decreased due to consumption in SLE patients. A negative correlation between serum complement levels and ex vivo complement deposition on nucleic acid autoantigens is demonstrated. On the contrary, complement deposition on tested protein and lipid autoantigens showed positive correlation with C4 levels. Genetic analysis revealed that the non-synonymous variant rs1143679 in complement receptor type 3 is associated with an increased production of anti-dsDNA IgG antibodies. Notwithstanding, homozygous carriers of the previously reported susceptible allele (AA) had lower levels of dsDNA specific IgM among SLE patients. Both the non-synonymous variant rs1143679 and the high ratio of nucleic acid specific IgG/IgM were associated with multiple organ involvement. In summary, secondary complement deficiency in SLE does not impair opsonization of nucleic-acid-containing autoantigens but does affect other antigens and potentially other complement dependent processes. Dysfunction of the receptor recognizing complement

  18. Marker-Based Estimates Reveal Significant Non-additive Effects in Clonally Propagated Cassava (Manihot esculenta): Implications for the Prediction of Total Genetic Value and the Selection of Varieties.

    PubMed

    Wolfe, Marnin D; Kulakow, Peter; Rabbi, Ismail Y; Jannink, Jean-Luc

    2016-08-31

    In clonally propagated crops, non-additive genetic effects can be effectively exploited by the identification of superior genetic individuals as varieties. Cassava (Manihot esculenta Crantz) is a clonally propagated staple food crop that feeds hundreds of millions. We quantified the amount and nature of non-additive genetic variation for three key traits in a breeding population of cassava from sub-Saharan Africa using additive and non-additive genome-wide marker-based relationship matrices. We then assessed the accuracy of genomic prediction for total (additive plus non-additive) genetic value. We confirmed previous findings based on diallel populations, that non-additive genetic variation is significant for key cassava traits. Specifically, we found that dominance is particularly important for root yield and epistasis contributes strongly to variation in CMD resistance. Further, we showed that total genetic value predicted observed phenotypes more accurately than additive only models for root yield but not for dry matter content, which is mostly additive or for CMD resistance, which has high narrow-sense heritability. We address the implication of these results for cassava breeding and put our work in the context of previous results in cassava, and other plant and animal species.

  19. [Structural alterations in pancreatic islets in streptozotocin-induced diabetic rats treated with of bioactive additive on the basis of Gymnema sylvestre].

    PubMed

    Snigur, G L; Samokhina, M P; Pisarev, V B; Spasov, A A; Bulanov, A E

    2008-01-01

    The structural alterations in pancreatic islets in streptozotocin-induced diabetic rats were studied after the administration of Gymnema sylvestre extract or its composition. Diabetes mellitus was modeled by daily injection of streptozotocin (20 mg/kg for 5 days) and single injection of 0.2 ml of complete Freund's adjuvant, Only the animals with the blood glucose level exceeding 15 mmol/l were included in the experiment. B- and A-endocrinocytes were demonstrated using immunocytochemistry. The proportions of the area of the pancreatic islets, occupied by B- and A-endocrinocytes, as well as the volume fraction of the pancreatic islets within the pancreas, were determined. In the model of streptozotocin-induced diabetes, the part of the total islet area occupied by B-endocrinocytes, was diminished in the pancreatic islets located in all the zones of the gland. Prophylactic administration of Gymnema sylvestre extract or its composition tended to restore the area occupied by B-endocrinocytes in the pancreatic islets. These results indicate the equal potency of the composition and extract of Gymnema sylvestre to induce the regeneration of B-endocrinocytes.

  20. Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats

    PubMed Central

    Howdeshell, Kembra L.; Rider, Cynthia V.; Wilson, Vickie S.; Furr, Johnathan R.; Lambright, Christy R.; Gray, L. Earl

    2015-01-01

    Challenges in cumulative risk assessment of anti-androgenic phthalate mixtures include a lack of data on all the individual phthalates and difficulty determining the biological relevance of reduction in fetal testosterone (T) on postnatal development. The objectives of the current study were 2-fold: (1) to test whether a mixture model of dose addition based on the fetal T production data of individual phthalates would predict the effects of a 5 phthalate mixture on androgen-sensitive postnatal male reproductive tract development, and (2) to determine the biological relevance of the reductions in fetal T to induce abnormal postnatal reproductive tract development using data from the mixture study. We administered a dose range of the mixture (60, 40, 20, 10, and 5% of the top dose used in the previous fetal T production study consisting of 300 mg/kg per chemical of benzyl butyl (BBP), di(n)butyl (DBP), diethyl hexyl phthalate (DEHP), di-isobutyl phthalate (DiBP), and 100 mg dipentyl (DPP) phthalate/kg; the individual phthalates were present in equipotent doses based on their ability to reduce fetal T production) via gavage to Sprague Dawley rat dams on GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on the previously published potencies of the individual phthalates to reduce fetal T production relative to a reference chemical and published postnatal data for the reference chemical (called DAref). In addition, we predicted DA (called DAall) and response addition (RA) based on logistic regression analysis of all 5 individual phthalates when complete data were available. DA ref and DA all accurately predicted the observed mixture effect for 11 of 14 endpoints. Furthermore, reproductive tract malformations were seen in 17–100% of F1 males when fetal T production was reduced by about 25–72%, respectively. PMID:26350170

  1. Using volatile additives to alter the morphology and performance of active layers in thin-film molecular photovoltaic devices incorporating bulk heterojunctions.

    PubMed

    Dang, Minh Trung; Wuest, James D

    2013-12-07

    Thin-film photovoltaic devices composed of polymers or small molecules have an exciting future as sources of renewable energy because they can be made in large sizes on flexible surfaces by inexpensive techniques of fabrication. Significant progress in developing new molecular photovoltaic materials and device architectures has been achieved in the last decade. The identity of molecular components in active layers and their individual optoelectronic properties obviously help determine the properties of devices; in addition, however, the behavior of devices depends critically on the nature of the local organization of the components. Recent studies have shown that the morphology of active layers can be tuned by adjusting various parameters, including the solvent used to cast the layer, thermal annealing, and special processing additives. In this review, we summarize the effect of volatile additives on the nanoscale morphology of molecular blends, and we show how these effects can improve the performance of devices. Although we focus on the behavior of mixtures of the type used in current molecular thin-film photovoltaic devices, the subject of our review will interest researchers in all areas of science and technology requiring materials in which separate phases must form intimate long-lived intermixtures with defined structures.

  2. Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type

    PubMed Central

    Kang, So Young; Kim, Seok Jin; Hwang, Jinha; Lee, Seungho; Kwak, Soo Heon; Park, Kyong Soo; Yoo, Hae Yong

    2015-01-01

    Extranodal NK/T-cell lymphoma nasal type (ENKL) is a rare type of non-Hodgkin lymphoma that more frequently occurs in East Asia and Latin America. Even though its molecular background has been discussed in the last few years, the current knowledge does not explain the disease pathogenesis in most cases of ENKL. Here, we performed multiple types of next-generation sequencing on 34 ENKL samples, including whole-exome sequencing (9 cancer tissues and 4 cancer cell lines), targeted sequencing (21 cancer tissues), and RNA sequencing (3 cancer tissues and 4 cancer cell lines). Mutations were found most frequently in 3 genes, STAT3, BCOR, and MLL2 (which were present in 9, 7, and 6 cancer samples, respectively), whereas there were only 2 cases of JAK3 mutation. In total, JAK/STAT pathway- and histone modification-related genes accounted for 55.9% and 38.2% of cancer samples, respectively, and their involvement in ENKL pathogenesis was also supported by gene expression analysis. In addition, we provided 177 genes upregulated only in cancer tissues, which appear to be linked with angiocentric and angiodestructive growth of ENKL. In this study, we propose several novel driver genes of ENKL, and show that these genes and their functional groups may be future therapeutic targets of this disease. PMID:25980440

  3. X-ray survival characteristics and genetic analysis for nine saccharomyces deletion mutants that show altered radiation sensitivity

    SciTech Connect

    Game, John C.; Williamson, Marsha S.; Baccari, Clelia

    2004-01-07

    The availability of a genome-wide set of Saccharomyces deletion mutants provides a chance to identify all the yeast genes involved in DNA repair. Using X-rays, we are screening these mutants to identify additional genes that show increased sensitivity to the lethal effects of ionizing radiation. For each mutant identified as sensitive, we are confirming that the sensitivity phenotype co-segregates with the deletion allele and are obtaining multipoint survival-versus-dose assays in at least two haploid and one homozygous diploid strains. We present data for deletion mutants involving the genes DOT1, MDM20, NAT3, SPT7, SPT20, GCN5, HFI1, DCC1 and VID21/EAF1, and discuss their potential roles in repair. Eight of these genes have a clear radiation-sensitive phenotype when deleted, but the ninth, GCN5, has at most a borderline phenotype. None of the deletions confer substantial sensitivity to ultra-violet radiation, although one or two may confer marginal sensitivity. The DOT1 gene is of interest because its only known function is to methylate one lysine residue in the core of the histone H3 protein. We find that histone H3 mutants (supplied by K. Struhl) in which this residue is replaced by other amino-acids are also X-ray sensitive, seeming to confirm that methylation of the lysine-79 residue is required for effective repair of radiation damage.

  4. Genetic manipulation of cardiac Hsp72 levels does not alter substrate metabolism but reveals insights into high-fat feeding-induced cardiac insulin resistance.

    PubMed

    Henstridge, Darren C; Estevez, E; Allen, T L; Heywood, S E; Gardner, T; Yang, C; Mellett, N A; Kingwell, B A; Meikle, P J; Febbraio, M A

    2015-05-01

    Heat shock protein 72 (Hsp72) protects cells against a variety of stressors, and multiple studies have suggested that Hsp72 plays a cardioprotective role. As skeletal muscle Hsp72 overexpression can protect against high-fat diet (HFD)-induced insulin resistance, alterations in substrate metabolism may be a mechanism by which Hsp72 is cardioprotective. We investigated the impact of transgenically overexpressing (Hsp72 Tg) or deleting Hsp72 (Hsp72 KO) on various aspects of cardiac metabolism. Mice were fed a normal chow (NC) or HFD for 12 weeks from 8 weeks of age to examine the impact of diet-induced obesity on metabolic parameters in the heart. The HFD resulted in an increase in cardiac fatty acid oxidation and a decrease in cardiac glucose oxidation and insulin-stimulated cardiac glucose clearance; however, there was no difference in Hsp72 Tg or Hsp72 KO mice in these rates compared with their respective wild-type control mice. Although HFD-induced cardiac insulin resistance was not rescued in the Hsp72 Tg mice, it was preserved in the skeletal muscle, suggesting tissue-specific effects of Hsp72 overexpression on substrate metabolism. Comparison of two different strains of mice (BALB/c vs. C57BL/6J) also identified strain-specific differences in regard to HFD-induced cardiac lipid accumulation and insulin resistance. These strain differences suggest that cardiac lipid accumulation can be dissociated from cardiac insulin resistance. Our study finds that genetic manipulation of Hsp72 does not lead to alterations in metabolic processes in cardiac tissue under resting conditions, but identifies mouse strain-specific differences in cardiac lipid accumulation and insulin-stimulated glucose clearance.

  5. Female mate choice predicts paternity success in the absence of additive genetic variance for other female paternity bias mechanisms in Drosophila serrata.

    PubMed

    Collet, J M; Blows, M W

    2014-11-01

    After choosing a first mate, polyandrous females have access to a range of opportunities to bias paternity, such as repeating matings with the preferred male, facilitating fertilization from the best sperm or differentially investing in offspring according to their sire. Female ability to bias paternity after a first mating has been demonstrated in a few species, but unambiguous evidence remains limited by the access to complex behaviours, sperm storage organs and fertilization processes within females. Even when found at the phenotypic level, the potential evolution of any mechanism allowing females to bias paternity other than mate choice remains little explored. Using a large population of pedigreed females, we developed a simple test to determine whether there is additive genetic variation in female ability to bias paternity after a first, chosen, mating. We applied this method in the highly polyandrous Drosophila serrata, giving females the opportunity to successively mate with two males ad libitum. We found that despite high levels of polyandry (females mated more than once per day), the first mate choice was a significant predictor of male total reproductive success. Importantly, there was no detectable genetic variance in female ability to bias paternity beyond mate choice. Therefore, whether or not females can bias paternity before or after copulation, their role on the evolution of sexual male traits is likely to be limited to their first mate choice in D. serrata.

  6. Co-infection with Mycobacterium bovis does not alter the response to bovine leukemia virus in BoLA DRB3*0902, genetically resistant cattle.

    PubMed

    Lützelschwab, Claudia M; Forletti, Agustina; Cepeda, Rosana; Esteban, Eduardo N; Confalonieri, Omar; Gutiérrez, Silvina E

    2016-12-01

    High proviral load (HPL) profile in bovine leukemia virus infected animals poses increased risk of transmission, and development of HPL or low proviral load (LPL) profile may be attributed to host genetics. Genetic resistance and susceptibility has been mapped to the Major Histocompatibility Complex class II DRB3 gene (BoLA DRB3). The aim of this work was to determine the effect of Mycobacterium bovis infection on certain virological and host immunological parameters of BLV experimental infection. Twenty-six Argentinian Holstein calves carrying the resistance-associated marker allele BoLA DRB3*0902, susceptibility-associated marker allele BoLA DRB3*1501, or neutral BoLA DRB3 alleles, exposed to M. bovis were used. Twenty calves were inoculated with BLV, three were naturally infected and other three were BLV-negative. Seven from twenty six (27%) of the animals resulted positive to the PPD test. The proviral load, absolute leukocyte and lymphocyte counts, time to seroconversion, antibody titer against BLV, and viral antigen expression in vitro at various times post inoculation were determined and compared between PPD+ and PPD- animals. From a total of 23 BLV positive animals (naturally and experimentally infected), 13 (56.5%) developed HPL, and 10 (43.5%) developed LPL. None of the investigated parameters were affected by infection with M. bovis. We concluded that the ability of cattle carrying resistance-associated marker to control BLV and to progress towards a LPL phenotype was not altered by M. bovis co-infection.

  7. Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions.

    PubMed

    Pinel, Philippe; Fauchereau, Fabien; Moreno, Antonio; Barbot, Alexis; Lathrop, Mark; Zelenika, Diana; Le Bihan, Denis; Poline, Jean-Baptiste; Bourgeron, Thomas; Dehaene, Stanislas

    2012-01-18

    Recent advances have been made in the genetics of two human communication skills: speaking and reading. Mutations of the FOXP2 gene cause a severe form of language impairment and orofacial dyspraxia, while single-nucleotide polymorphisms (SNPs) located within a KIAA0319/TTRAP/THEM2 gene cluster and affecting the KIAA0319 gene expression are associated with reading disability. Neuroimaging studies of clinical populations point to partially distinct cerebral bases for language and reading impairments. However, alteration of FOXP2 and KIAA0319/TTRAP/THEM2 polymorphisms on typically developed language networks has never been explored. Here, we genotyped and scanned 94 healthy subjects using fMRI during a reading task. We studied the correlation of genetic polymorphisms with interindividual variability in brain activation and functional asymmetry in frontal and temporal cortices. In FOXP2, SNPs rs6980093 and rs7799109 were associated with variations of activation in the left frontal cortex. In the KIAA0319/TTRAP/THEM2 locus, rs17243157 was associated with asymmetry in functional activation of the superior temporal sulcus (STS). Interestingly, healthy subjects bearing the KIAA0319/TTRAP/THEM2 variants previously identified as enhancing the risk of dyslexia showed a reduced left-hemispheric asymmetry of the STS. Our results confirm that both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. The observed cortical effects mirror previous fMRI results in developmental language and reading disorders, and suggest that a continuum may exist between these pathologies and normal interindividual variability.

  8. Long-term nutrient addition differentially alters community composition and diversity of genes that control nitrous oxide flux from salt marsh sediments

    NASA Astrophysics Data System (ADS)

    Kearns, Patrick J.; Angell, John H.; Feinman, Sarah G.; Bowen, Jennifer L.

    2015-03-01

    Enrichment of natural waters, soils, and sediments by inorganic nutrients, including nitrogen, is occurring at an increasing rate and has fundamentally altered global biogeochemical cycles. Salt marshes are critical for the removal of land-derived nitrogen before it enters coastal waters. This is accomplished via multiple microbially mediated pathways, including denitrification. Many of these pathways, however, are also a source of the greenhouse gas nitrous oxide (N2O). We used clone libraries and quantative PCR (qPCR) to examine the effect of fertilization on the diversity and abundance of two functional genes associated with denitrification and N2O production (norB and nosZ) in experimental plots at the Great Sippewissett Salt Marsh (Falmouth, MA, USA) that have been enriched with nutrients for over 40 years. Our data showed distinct nosZ and norB community structures at different nitrogen loads, especially at the highest level of fertilization. Furthermore, calculations of the Shannon Diversity Index and Chao1 Richness Estimator indicated that nosZ gene diversity and richness increased with increased nitrogen supply, however no such relationship existed with regard to richness and diversity of the norB gene. Results from qPCR demonstrated that nosZ gene abundance was an order of magnitude lower in the extra-highly fertilized plots compared to the other plots, but the abundance of norB was not affected by fertilization. The majority of sequences obtained from the marsh plots had no close cultured relatives and they were divergent from previously sequenced norB and nosZ fragments. Despite their divergence from any cultured representatives, most of the norB and nosZ sequences appeared to be from members of the Alpha- and Betaproteobacteria, suggesting that these classes are particularly important in salt marsh nitrogen cycling. Our results suggest that both norB and nosZ containing microbes are affected by fertilization and that the Great Sippewissett Marsh may

  9. Additive-dominance genetic model analyses for late-maturity alpha-amylase activity in a bread wheat factorial crossing population.

    PubMed

    Rasul, Golam; Glover, Karl D; Krishnan, Padmanaban G; Wu, Jixiang; Berzonsky, William A; Ibrahim, Amir M H

    2015-12-01

    Elevated level of late maturity α-amylase activity (LMAA) can result in low falling number scores, reduced grain quality, and downgrade of wheat (Triticum aestivum L.) class. A mating population was developed by crossing parents with different levels of LMAA. The F2 and F3 hybrids and their parents were evaluated for LMAA, and data were analyzed using the R software package 'qgtools' integrated with an additive-dominance genetic model and a mixed linear model approach. Simulated results showed high testing powers for additive and additive × environment variances, and comparatively low powers for dominance and dominance × environment variances. All variance components and their proportions to the phenotypic variance for the parents and hybrids were significant except for the dominance × environment variance. The estimated narrow-sense heritability and broad-sense heritability for LMAA were 14 and 54%, respectively. High significant negative additive effects for parents suggest that spring wheat cultivars 'Lancer' and 'Chester' can serve as good general combiners, and that 'Kinsman' and 'Seri-82' had negative specific combining ability in some hybrids despite of their own significant positive additive effects, suggesting they can be used as parents to reduce LMAA levels. Seri-82 showed very good general combining ability effect when used as a male parent, indicating the importance of reciprocal effects. High significant negative dominance effects and high-parent heterosis for hybrids demonstrated that the specific hybrid combinations; Chester × Kinsman, 'Lerma52' × Lancer, Lerma52 × 'LoSprout' and 'Janz' × Seri-82 could be generated to produce cultivars with significantly reduced LMAA level.

  10. Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates adverse effects in female mice.

    PubMed

    Rubin, Beverly S; Paranjpe, Maneesha; DaFonte, Tracey; Schaeberle, Cheryl; Soto, Ana M; Obin, Martin; Greenberg, Andrew S

    2017-03-01

    Body weight (BW) and body composition were examined in CD-1 mice exposed perinatally or perinatally and peripubertally to 0, 0.25, 2.5, 25, or 250μg BPA/kg BW/day. Our goal was to identify the BPA dose (s) and the exposure window(s) that increased BW and adiposity, and to assess potential sex differences in this response. Both perinatal exposure alone and perinatal plus peripubertal exposure to environmentally relevant levels of BPA resulted in lasting effects on body weight and body composition. The effects were dose specific and sex specific and were influenced by the precise window of BPA exposure. The addition of peripubertal BPA exposure following the initial perinatal exposure exacerbated adverse effects in the females but appeared to reduce differences in body weight and body composition between control and BPA exposed males. Some effects of BPA on body weight and body composition showed a non-linear dose response.

  11. Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

    PubMed Central

    Whitcomb, David C.; LaRusch, Jessica; Krasinskas, Alyssa M.; Klei, Lambertus; Smith, Jill P.; Brand, Randall E.; Neoptolemos, John P.; Lerch, Markus M.; Tector, Matt; Sandhu, Bimaljit S.; Guda, Nalini M.; Orlichenko, Lidiya; Alkaade, Samer; Amann, Stephen T.; Anderson, Michelle A.; Baillie, John; Banks, Peter A.; Conwell, Darwin; Coté, Gregory A.; Cotton, Peter B.; DiSario, James; Farrer, Lindsay A.; Forsmark, Chris E.; Johnstone, Marianne; Gardner, Timothy B.; Gelrud, Andres; Greenhalf, William; Haines, Jonathan L.; Hartman, Douglas J.; Hawes, Robert A.; Lawrence, Christopher; Lewis, Michele; Mayerle, Julia; Mayeux, Richard; Melhem, Nadine M.; Money, Mary E.; Muniraj, Thiruvengadam; Papachristou, Georgios I.; Pericak-Vance, Margaret A.; Romagnuolo, Joseph; Schellenberg, Gerard D.; Sherman, Stuart; Simon, Peter; Singh, Vijay K.; Slivka, Adam; Stolz, Donna; Sutton, Robert; Weiss, Frank Ulrich; Wilcox, C. Mel; Zarnescu, Narcis Octavian; Wisniewski, Stephen R.; O'Connell, Michael R.; Kienholz, Michelle L.; Roeder, Kathryn; Barmada, M. Michael; Yadav, Dhiraj; Devlin, Bernie; Albert, Marilyn S.; Albin, Roger L.; Apostolova, Liana G.; Arnold, Steven E.; Baldwin, Clinton T.; Barber, Robert; Barnes, Lisa L.; Beach, Thomas G.; Beecham, Gary W.; Beekly, Duane; Bennett, David A.; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boxer, Adam; Burke, James R.; Buxbaum, Joseph D.; Cairns, Nigel J.; Cantwell, Laura B.; Cao, Chuanhai; Carney, Regina M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Cribbs, David H.; Crocco, Elizabeth A.; Cruchaga, Carlos; DeCarli, Charles; Demirci, F. Yesim; Dick, Malcolm; Dickson, Dennis W.; Duara, Ranjan; Ertekin-Taner, Nilufer; Faber, Kelley M.; Fallon, Kenneth B.; Farlow, Martin R.; Ferris, Steven; Foroud, Tatiana M.; Frosch, Matthew P.; Galasko, Douglas R.; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John R.; Gilman, Sid; Glass, Jonathan D.; Goate, Alison M.; Graff-Radford, Neill R.; Green, Robert C.; Growdon, John H.; Hakonarson, Hakon; Hamilton-Nelson, Kara L.; Hamilton, Ronald L.; Harrell, Lindy E.; Head, Elizabeth; Honig, Lawrence S.; Hulette, Christine M.; Hyman, Bradley T.; Jicha, Gregory A.; Jin, Lee-Way; Jun, Gyungah; Kamboh, M. Ilyas; Karydas, Anna; Kaye, Jeffrey A.; Kim, Ronald; Koo, Edward H.; Kowall, Neil W.; Kramer, Joel H.; Kramer, Patricia; Kukull, Walter A.; LaFerla, Frank M.; Lah, James J.; Leverenz, James B.; Levey, Allan I.; Li, Ge; Lin, Chiao-Feng; Lieberman, Andrew P.; Lopez, Oscar L.; Lunetta, Kathryn L.; Lyketsos, Constantine G.; Mack, Wendy J.; Marson, Daniel C.; Martin, Eden R.; Martiniuk, Frank; Mash, Deborah C.; Masliah, Eliezer; McKee, Ann C.; Mesulam, Marsel; Miller, Bruce L.; Miller, Carol A.; Miller, Joshua W.; Montine, Thomas J.; Morris, John C.; Murrell, Jill R.; Naj, Adam C.; Olichney, John M.; Parisi, Joseph E.; Peskind, Elaine; Petersen, Ronald C.; Pierce, Aimee; Poon, Wayne W.; Potter, Huntington; Quinn, Joseph F.; Raj, Ashok; Raskind, Murray; Reiman, Eric M.; Reisberg, Barry; Reitz, Christiane; Ringman, John M.; Roberson, Erik D.; Rosen, Howard J.; Rosenberg, Roger N.; Sano, Mary; Saykin, Andrew J.; Schneider, Julie A.; Schneider, Lon S.; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Tsuang, Debby W.; Valladares, Otto; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vardarajan, Badri N.; Vinters, Harry V.; Vonsattel, Jean Paul; Wang, Li-San; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Williamson, Jennifer; Woltjer, Randall L.; Wright, Clinton B.; Younkin, Steven G.; Yu, Chang-En; Yu, Lei

    2012-01-01

    Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07. PMID:23143602

  12. In vivo detection of exercised-induced ultrastructural changes in genetically-altered murine skeletal muscle using polarization-sensitive optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Boppart, Stephen

    2006-02-01

    Skeletal muscle fibers are a known source of form birefringence in biological tissue. The birefringence present in skeletal muscle is associated with the ultrastructure of individual sarcomeres, specifically the arrangement of A-bands corresponding to the thick myosin filaments. Certain structural proteins that prevent damage and maintain the structural and functional health of the muscle fiber preserve the organization of the Abands in skeletal muscle. Therefore, the level of birefringence detected can estimate the health of the muscle as well as the damage incurred during exercise. Murine skeletal muscle from both genetically-altered (mdx) and normal (wild-type) specimens were imaged in vivo with a fiber-based PSOCT imaging system to quantitatively determine the level of birefringence present in the tissue before and after exercise. The mdx muscle lacks dystrophin, a structural protein that is mutated in Duchenne muscular dystrophy in humans. Muscle from these mdx mice exhibited a marked decrease in birefringence after exercise, whereas the wild-type muscle was highly birefringent before and after exercise. The quantitative results from this tissue optics study suggest for the first time that there is a distinct relationship between the degree of birefringence detected using PS-OCT and the sarcomeric ultrastructure present within skeletal muscle.

  13. Reactive biomolecular divergence in genetically altered yeast cells and isolated mitochondria as measured by biocavity laser spectroscopy: rapid diagnostic method for studying cellular responses to stress and disease.

    PubMed

    Gourley, Paul L; Hendricks, Judy K; McDonald, Anthony E; Copeland, R Guild; Yaffe, Michael P; Naviaux, Robert K

    2007-01-01

    We report an analysis of four strains of baker's yeast (Saccharomyces cerevisiae) using biocavity laser spectroscopy. The four strains are grouped in two pairs (wild type and altered), in which one strain differs genetically at a single locus, affecting mitochondrial function. In one pair, the wild-type rho+ and a rho0 strain differ by complete removal of mitochondrial DNA (mtDNA). In the second pair, the wild-type rho+ and a rho- strain differ by knock-out of the nuclear gene encoding Cox4, an essential subunit of cytochrome c oxidase. The biocavity laser is used to measure the biophysical optic parameter Deltalambda, a laser wavelength shift relating to the optical density of cell or mitochondria that uniquely reflects its size and biomolecular composition. As such, Deltalambda is a powerful parameter that rapidly interrogates the biomolecular state of single cells and mitochondria. Wild-type cells and mitochondria produce Gaussian-like distributions with a single peak. In contrast, mutant cells and mitochondria produce leptokurtotic distributions that are asymmetric and highly skewed to the right. These distribution changes could be self-consistently modeled with a single, log-normal distribution undergoing a thousand-fold increase in variance of biomolecular composition. These features reflect a new state of stressed or diseased cells that we call a reactive biomolecular divergence (RBD) that reflects the vital interdependence of mitochondria and the nucleus.

  14. Protein expression of small conductance calcium-activated potassium channels is altered in inferior colliculus neurons of the genetically epilepsy-prone rat

    PubMed Central

    N’Gouemo, Prosper; Yasuda, Robert P.; Faingold, Carl L.

    2009-01-01

    The genetically epilepsy-prone rat (GEPR) exhibits inherited predisposition to sound stimuli-induced generalized tonic-clonic seizures (audiogenic reflex seizures) and is a valid model to study the physiopathology of epilepsy. In this model, the inferior colliculus (IC) exhibits enhanced neuronal firing that is critical in the initiation of reflex audiogenic seizures. The mechanisms underlying IC neuronal hyperexcitability that leads to seizure susceptibility are not as yet fully understood. The present report shows that the levels of protein expression of SK1 and SK3 subtypes of the small conductance Ca2+-activated K+ channels were significantly decreased, while SK2 channel proteins were increased in IC neurons of seizure-naive GEPR-3s (SN-GEPR-3), as compared to control Sprague-Dawley rats. No significant change was found in the expression of BK channel proteins in IC neurons of SN-GEPR-3s. Single episode of reflex audiogenic seizures in the GEPR-3s did not significantly alter the protein expression of SK1-3 and BK channels in IC neurons compared to SN-GEPR-3s. Thus, downregulation of SK1 and SK3 channels and upregulation of SK2 channels provide direct evidence that these Ca2+-activated K+ channels play important roles in IC neuronal hyperexcitability that leads to inherited seizure susceptibility in the GEPR. PMID:19254702

  15. Additional studies on mixed uranyl oxide-hydroxide hydrate alteration products of uraninite from the palermo and ruggles granitic pegmatites, grafton county, New Hampshire

    USGS Publications Warehouse

    Foord, E.E.; Korzeb, S.L.; Lichte, F.E.; Fitzpatrick, J.J.

    1997-01-01

    Additional studies on an incompletely characterized secondary uranium "mineral" from the Ruggles and Palermo granitic pegmatites, New Hampshire, referred to as mineral "A" by Frondel (1956), reveal a mixture of schoepite-group minerals and related uranyl oxide-hydroxide hydrated compounds. A composite chemical analysis yielded (in wt.%): PbO 4.85 (EMP), UO3 83.5 (EMP), BaO 0.675 (av. of EMP and ICP), CaO 0.167 (av. of EMP and ICP), K2O 2.455 (av. of EMP and ICP), SrO 0.21 (ICP), ThO2 0.85 (ICP), H2O 6.9, ??99.61. Powder-diffraction X-ray studies indicate a close resemblance in patterns between mineral "A" and several uranyl oxide-hydroxide hydrated minerals, including the schoepite family of minerals and UO2(OH)2. The powder-diffraction data for mineral "A" are most similar to those for synthetic UO2.86??1.5H2O and UO2(OH)2, but other phases are likely present as well. TGA analysis of both mineral "A" and metaschoepite show similar weight-loss and first derivative curves. The dominant losses are at 100??C, with secondary events at 400?? and 600??C. IR spectra show the presence of (OH) and H2O. Uraninite from both pegmatites, analyzed by LAM-ICP-MS, shows the presence of Th, Pb, K and Ca.

  16. How protonation and deprotonation of 9-methylguanine alter its singlet O2 addition path: about the initial stage of guanine nucleoside oxidation.

    PubMed

    Lu, Wenchao; Teng, Huayu; Liu, Jianbo

    2016-06-01

    Mutagenicity of singlet O2 is due to its oxidatively generated damage to the guanine nucleobases of DNA. Oxidation of neutral guanosine has been assumed to be initiated by the formation of a transient 4,8-endoperoxide via a Diels-Alder cycloaddition of singlet O2. Protonation and deprotonation of guanosine represent another factor related to DNA damage and repair. Herein, 9-methylguanine was utilized as a model substrate to mimic the correlation between singlet O2 oxidation of the nucleoside and its ionization states, both in the absence and in the presence of water ligands. We used guided-ion-beam scattering tandem mass spectrometry to detect and quantify transient intermediates at room temperature. To provide a reliable description of reaction potential surfaces, different levels of theory including restricted and unrestricted density functional theory, CCSD(T), MP2, and multi-reference CASSCF and CASMP2 were applied. By means of molecular potential, kinetic and direct dynamics simulations, two reaction pathways were identified and neither follows the mechanism for neutral guanosine. Singlet O2 oxidation of protonated 9-methylguanine begins by a concerted cycloaddition; but it is mediated by a 5,8-endoperoxide. By contrast, a concerted cycloaddition does not occur for deprotonated 9-methylguanine. The latter involves a stepwise addition starting with the formation of an 8-peroxide, which subsequently evolves to a 4,8-endoperoxide. This dichotomy implies that acidic and basic media may lead to different chemistries for guanosine oxidation in aqueous solutions, starting from initial stage. The comparison with oxidation of protonated/deprotonated guanine illustrates the different mechanisms and products and particularly the suppressed oxidizability of 9-methylguanine vs. free guanine.

  17. Monitoring Impact of a Pesticide Treatment on Bacterial Soil Communities by Metabolic and Genetic Fingerprinting in Addition to Conventional Testing Procedures

    PubMed Central

    Engelen, Bert; Meinken, Kristin; von Wintzingerode, Friedrich; Heuer, Holger; Malkomes, Hans-Peter; Backhaus, Horst

    1998-01-01

    Herbogil (dinoterb), a reference herbicide, the mineral oil Oleo (paraffin oil used as an additive to herbicides), and Goltix (metamitron) were taken as model compounds for the study of impacts on microbial soil communities. After the treatment of soil samples, effects on metabolic sum parameters were determined by monitoring substrate-induced respiration (SIR) and dehydrogenase activity, as well as carbon and nitrogen mineralization. These conventional ecotoxicological testing procedures are used in pesticide registration. Inhibition of biomass-related activities and stimulation of nitrogen mineralization were the most significant effects caused by the application of Herbogil. Even though Goltix and Oleo were used at a higher dosage (10 times higher), the application of Goltix resulted in smaller effects and the additive Oleo was the least-active compound, with minor stimulation of test parameters at later observation times. The results served as a background for investigation of the power of “fingerprinting” methods in microbial ecology. Changes in catabolic activities induced by treatments were analyzed by using the 95 carbon sources provided by the BIOLOG system. Variations in the complex metabolic fingerprints demonstrated inhibition of many catabolic pathways after the application of Herbogil. Again, the effects of the other compounds were expressed at much lower levels and comprised stimulations as well as inhibitions. Testing for significance by a multivariate t test indicated that the sensitivity of this method was similar to the sensitivities of the conventional testing procedures. The variation of sensitive carbon sources, as determined by factor weights at different observation times, indicated the dynamics of the community shift induced by the Herbogil treatment in more detail. DNA extractions from soil resulted in a collection of molecules representing the genetic composition of total bacterial communities. Distinct and highly reproducible

  18. Increasing addition of autochthonous to allochthonous carbon in nutrient-rich aquatic systems stimulates carbon consumption but does not alter bacterial community composition

    NASA Astrophysics Data System (ADS)

    Attermeyer, K.; Hornick, T.; Kayler, Z. E.; Bahr, A.; Zwirnmann, E.; Grossart, H.-P.; Premke, K.

    2013-08-01

    Dissolved organic carbon (DOC) concentrations - mainly of terrestrial origin - are increasing worldwide in inland waters. The biodegradability of the DOC varies depending on quantity and chemical quality. Heterotrophic bacteria are the main consumers of DOC and thus determine DOC temporal dynamics and availability for higher trophic levels. It is therefore crucial to understand the processes controlling the bacterial turnover of additional allochthonous and autochthonous DOC in aquatic systems. Our aim was to study bacterial carbon (C) turnover with respect to DOC quantity and chemical quality using both allochthonous and autochthonous DOC sources. We incubated a natural bacterial community with allochthonous C (13C-labeled beech leachate) and increased concentrations and pulses (intermittent occurrence of organic matter input) of autochthonous C (algae lysate). We then determined bacterial carbon consumption, activities, and community composition together with the carbon flow through bacteria using stable C isotopes. The chemical analysis of single sources revealed differences in aromaticity and fractions of low and high molecular weight substances (LMWS and HMWS, respectively) between allochthonous and autochthonous C sources. In parallel to these differences in chemical composition, we observed a higher availability of allochthonous C as evidenced by increased DOC consumption and bacterial growth efficiencies (BGE) when solely allochthonous C was provided. In treatments with mixed sources, rising concentrations of added autochthonous DOC resulted in a further, significant increase in bacterial DOC consumption from 52 to 68% when nutrients were not limiting. This rise was accompanied by a decrease in the humic substances (HS) fraction and an increase in bacterial biomass. Stable C isotope analyses of phospholipid fatty acids (PLFA) and respired dissolved inorganic carbon (DIC) supported a preferential assimilation of autochthonous C and respiration of the

  19. Rate of evolutionary change in cranial morphology of the marsupial genus Monodelphis is constrained by the availability of additive genetic variation.

    PubMed

    Porto, A; Sebastião, H; Pavan, S E; VandeBerg, J L; Marroig, G; Cheverud, J M

    2015-04-01

    We tested the hypothesis that the rate of marsupial cranial evolution is dependent on the distribution of genetic variation in multivariate space. To do so, we carried out a genetic analysis of cranial morphological variation in laboratory strains of Monodelphis domestica and used estimates of genetic covariation to analyse the morphological diversification of the Monodelphis brevicaudata species group. We found that within-species genetic variation is concentrated in only a few axes of the morphospace and that this strong genetic covariation influenced the rate of morphological diversification of the brevicaudata group, with between-species divergence occurring fastest when occurring along the genetic line of least resistance. Accounting for the geometric distribution of genetic variation also increased our ability to detect the selective regimen underlying species diversification, with several instances of selection only being detected when genetic covariances were taken into account. Therefore, this work directly links patterns of genetic covariation among traits to macroevolutionary patterns of morphological divergence. Our findings also suggest that the limited distribution of Monodelphis species in morphospace is the result of a complex interplay between the limited dimensionality of available genetic variation and strong stabilizing selection along two major axes of genetic variation.

  20. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma.

    PubMed

    Ryall, Scott; Krishnatry, Rahul; Arnoldo, Anthony; Buczkowicz, Pawel; Mistry, Matthew; Siddaway, Robert; Ling, Cino; Pajovic, Sanja; Yu, Man; Rubin, Joshua B; Hukin, Juliette; Steinbok, Paul; Bartels, Ute; Bouffet, Eric; Tabori, Uri; Hawkins, Cynthia

    2016-08-31

    Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63-17.55) and median survival was 6.43 (range, 0.01-27.63) years. Our cohort contained 42 and 22 tumours reviewed as low and high grade gliomas, respectively. Five (12 %) low grade and 11 (50 %) high grade gliomas were positive for the H3F3A/HIST1H3B K27M (H3K27M) mutation. Kaplan-Meier survival analysis revealed significantly worse overall survival for patients harbouring the H3K27M mutation versus H3F3A/HIST1H3B wild type (H3WT) samples (log-rank p < 0.0001) with a median survival of 1.02 vs. 9.12 years. Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations or fusion events were detected in 44 % of patients, and was associated with long-term survival in the absence of H3K27M (log-rank p < 0.0001). Multivariate analysis demonstrated H3K27M status and high grade histology to be the most significant independent predictors of poor overall survival with hazard ratios of 6.945 and 7.721 (p < 0.0001), respectively. In contrast, MAPK pathway activation is a predictor of favourable patient outcome, although not independent of other clinical factors. Importantly, we show that low grade malignancies may harbour H3K27M mutations and that these tumours show a dismal survival compared to low grade H3WT cases. Our data strongly supports the inclusion of targeted genetic testing in childhood thalamic tumours to most accurately stratify patients into appropriate risk groups.

  1. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine in Guinea-Bissau between 2003 and 2012.

    PubMed

    Jovel, Irina Tatiana; Kofoed, Poul-Erik; Rombo, Lars; Rodrigues, Amabelia; Ursing, Johan

    2015-02-01

    In 2008, artemether-lumefantrine was introduced in Guinea-Bissau, West Africa, but quinine has also been commonly prescribed for the treatment of uncomplicated Plasmodium falciparum malaria. An efficacious high-dose chloroquine treatment regimen was used previously. Temporal and seasonal changes of genetic polymorphisms associated with altered drug susceptibility to chloroquine, lumefantrine, and quinine have been described. P. falciparum chloroquine resistance transporter (pfcrt) K76T, pfmdr1 gene copy numbers, pfmdr1 polymorphisms N86Y and Y184F, and pfmdr1 sequences 1034 to 1246 were determined using PCR-based methods. Blood samples came from virtually all (n=1,806) children<15 years of age who had uncomplicated P. falciparum monoinfection and presented at a health center in suburban Bissau (from 2003 to 2012). The pfcrt K76T and pfmdr1 N86Y frequencies were stable, and seasonal changes were not seen from 2003 to 2007. Since 2007, the mean annual frequencies increased (P<0.001) for pfcrt 76T (24% to 57%), pfmdr1 N86 (72% to 83%), and pfcrt 76+pfmdr1 86 TN (10% to 27%), and pfcrt 76T accumulated during the high transmission season (P=0.001). The pfmdr1 86+184 NF frequency increased from 39% to 66% (from 2003 to 2011; P=0.004). One sample had two pfmdr1 gene copies. pfcrt 76T was associated with a lower parasite density (P<0.001). Following the discontinuation of an effective chloroquine regimen, probably highly artemether-lumefantrine-susceptible P. falciparum (with pfcrt 76T) accumulated, possibly due to suboptimal use of quinine and despite a fitness cost linked to pfcrt 76T. (The studies reported here were registered at ClinicalTrials.gov under registration no. NCT00137514 [PSB-2001-chl-amo], NCT00137566 [PSB-2004-paracetamol], NCT00426439 [PSB-2006-coartem], NCT01157689 [AL-eff 2010], and NCT01704508 [Eurartesim 2012].).

  2. Genetic selection for body weight in chickens has altered responses of the brain's AMPK system to food intake regulation effect of ghrelin, but not obestatin.

    PubMed

    Xu, Pingwen; Siegel, Paul B; Denbow, D Michael

    2011-08-01

    The effects of ghrelin and obestatin regulation of food intake are different in mammals and chickens. We investigated central effects of ghrelin and obestatin in lines of chickens selected 50 generations for high (HWS) or low (LWS) body weight. We hypothesized that the effect of ghrelin and obestatin on food intake in 5-day-old chicks is mediated by the AMP-activated protein kinase (AMPK) system and selection for body weight alters the brain's response to ghrelin and obestatin by changing the neuronal AMPK system. Although intracerebroventricular (ICV) ghrelin injection decreased food intake in both lines, the threshold for the anorexigenic effect of central ghrelin was lower in LWS than HWS chicks. Obestatin caused a linear dose-dependent increase in food intake in HWS but not LWS chicks. ICV injection of 0.4 nmol ghrelin inhibited hypothalamic AMPK related gene expression and phosphorylation of AMPK α and acetyl-CoA carboxylase (ACC) with the magnitude of inhibition different in the two lines. In contrast, ICV injection of 4 nmol obestatin did not affect mRNA expression of AMPK system or phosphorylation of AMPK and ACC in either line. These data support the premise of a lower threshold for anorexigenic effect of central ghrelin in LWS than HWS chicks, and this difference may be associated with differential hypothalamic AMPK signaling. Additionally, the hypothalamic mRNA level of ghrelin was significantly higher in LWS than HWS, which may have also contributed to the different threshold response to ghrelin in these two lines. The expression of the ghrelin receptor was also higher in the LWS line, but not until 56 days of age. In summary, selection for body weight has resulted in differences in the central ghrelin and obestatin system, and an altered brain AMPK system may contribute to the different neuronal response to ghrelin, but not obestatin.

  3. Genetic and environmental factors impact age-related impairment of negative geotaxis in Drosophila by altering age-dependent climbing speed.

    PubMed

    Rhodenizer, Devin; Martin, Ian; Bhandari, Poonam; Pletcher, Scott D; Grotewiel, Mike

    2008-08-01

    Age-related locomotor impairment in humans is important clinically because it is associated with several co-morbidities and increased risk of death. One of the hallmarks of age-related locomotor impairment in humans is a decrease in walking speed with age. Genetically tractable model organisms such as Drosophila are essential for delineating mechanisms underlying age-related locomotor impairment and age-related decreases in locomotor speed. Negative geotaxis, the ability of flies to move vertically when startled, is a common measure of locomotor behavior that declines with age in Drosophila. Toward further developing Drosophila as a model for age-related locomotor impairment, we investigated whether negative geotaxis reflects climbing or a combination of climbing and other behaviors such as flying and jumping. Additionally, we investigated whether locomotor speed in negative geotaxis assays declines with age in flies as found for walking speed in humans. We find that the vast majority of flies climb during negative geotaxis assays and that removal of hind legs, but not wings, impairs the behavior. We also find that climbing speed decreases with age in four wild type genetic backgrounds, in flies housed at different temperatures, and in control and long-lived flies harboring a mutation in OR83b. The decreases in climbing speed correlate with the age-related impairments in the distance climbed. These studies establish negative geotaxis in Drosophila as a climbing behavior that declines with age due to a decrease in climbing speed. Age-related decreases in locomotor speed are common attributes of locomotor senescence in flies and humans.

  4. Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer

    PubMed Central

    Carethers, John M.; Jung, Barbara H.

    2015-01-01

    Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient’s genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations, and has classified new alterations. Each patient’s CRC is genetically unique, propelled by 2 to 8 driver gene alterations that have accumulated within the CRC since initiation. Commonly observed alterations across sporadic CRCs have allowed classification into a: (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability (MSI) and POLE mutations in ~15%, containing multiple frameshifted genes and BRAFV600E; (2) non-hypermutated group with multiple somatic copy number alterations and aneuploidy in ~85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes such as APC and TP53; (3) CpG Island Methylator Phenotype CRCs in ~20% that overlap greatly with MSI CRCs and some non-hypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in ~60% that associates with metastatic behavior in both hypermutated and non-hypermutated groups. Components from these classifications are now used as diagnostic, prognostic and treatment biomarkers. Additional common biomarkers may come from genome-wide association studies and microRNAs among other sources, as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care. PMID:26216840

  5. Genetic polymorphism of human cytochrome P-450 (S)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered cytochrome P-450 isozyme as cause of the genetic deficiency

    SciTech Connect

    Meier, U.T.; Meyer, U.A.

    1987-12-15

    The metabolism of the anticonvulsant mephenytoin is subject to a genetic polymorphism. In 2-5% of Caucasians and 18-23% of Japanese subjects a specific cytochrome P-450 isozyme, P-450 meph, is functionally deficient or missing. The authors have accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid induced hepatitis (anti-liver kidney microsome 2 or anti-LKM2 antibodies) specifically recognize the cytochrome P-450 involved in the mephrenytoin hydroxylation polymorphism. This is demonstrated by immunoinhibition and immunoprecipitation of microsomal (S)-mephenytoin 4-hydroxylation activity and by the recognition by anti-LKM2 antibodies of a single (/sup 125/I)-protein band on immunoblots of human liver microsomes after sodium dodecyl sulfate-polyacrylamide gel electrophoresis or isoelectric focusing. The cytochrome P-450 recognized by anti-LKM2 antibodies was immunopurified from microsomes derived from livers of extensive (EM) or poor metabolizers (PM) of (S)-mephenytoin. Comparison of the EM-type cytochrome P-450 to that isolated from PM livers revealed no difference in regard to immuno-cross-reactivity, molecular weight, isoelectric point, relative content in microsomes, two-dimensional tryptic peptide maps, one-dimensional peptide maps with three proteases, amino acid composition, and amino-terminal protein sequence. Finally, the same protein was precipitated from microsomes prepared from the liver biopsy of a subject phenotyped in vivo as a poor metabolizer of mephenytoin. These data strongly suggest that the mephenytoin hydroxylation deficiency is caused by a minor structural change leading to a functionally altered cytochrome P-450 isozyme.

  6. Molecular genetic analysis of factor XI deficiency: identification of five novel gene alterations and the origin of type II mutation in Portuguese families.

    PubMed

    Ventura, C; Santos, A I; Tavares, A; Gago, T; Lavinha, J; McVey, J H; David, D

    2000-11-01

    Coagulation factor XI (FXI) deficiency is an inherited autosomal recessive mild bleeding disorder. In this study, we report the molecular genetic analysis of FXI deficiency in six unrelated families of Portuguese origin. The Jewish type II mutation was found in two families, of seemingly Portuguese origin. Haplotype analysis in these families demonstrated that this mutation is of Jewish origin. In the remaining families, five novel FXI mutations have been identified. Two of these mutations (FXI IVS K -10T-->A and FXI 1026G-->T, cd 324) affect the FXI pre-mRNA splicing. A further two (FXI 307 ins AAGCAAT, cd 85 and FXI 1072 del A, cd 340) introduce frameshifts leading to premature termination codons. The FXI splicing mutation, 1026G-->T cd 324, was found in compound heterozygosity with missense mutation FXI K518N. Analysis of the FXI mRNA from the latter genotype demonstrated new donor splice site usage. All reported mutations most likely result in functional null-alleles. In addition, three novel polymorphisms have been identified: at nt -138 in intron A, at codon D125 in exon 5 and at codon T249 in exon 8.

  7. Feeding value of corn silage estimated with sheep and dairy cows is not altered by genetic incorporation of Bt1376 resistance to Ostrinia nubilalis.

    PubMed

    Barrière, Y; Vérité, R; Brunschwig, P; Surault, F; Emile, J C

    2001-08-01

    A genetically modified Bt176 corn hybrid (Rh208Bt)--providing control of European corn borer damage--and the conventional isogenic hybrid (Rh208)--harvested as whole plant silage--were evaluated in three separate feeding trials to verify that the in vivo feeding value was substantially equivalent among modified and conventional hybrids. In the first trial, after a week of preexperiment, two sets of six Texel sheep, housed in digestibility crates, were fed silage sources of Rh208 and Rh208Bt hybrids, and silage of three additional control varieties of low, intermediate, and high feeding value (Rh289, Adonis, and Adonis bm3) for 1 wk. Feed offered to sheep was adjusted to maintenance requirements based on metabolic body weight. Agronomic and biochemical traits were similar among the Rh208 and Rh208Bt hybrids. Organic matter digestibility (67.1 and 67.6%), crude fiber digestibility (52.9 and 54.2%), and neutral detergent fiber digestibility (50.2 and 49.0%) were not significantly different among Rh208 and Rh208Bt hybrids. In the second trial, two sets of 24 Holstein cows were fed silage from Rh208 and Rh208Bt corn hybrids for 13 wk, 9 wk after calving, and including 2 wk of preexperiment. Fat-corrected milk yield (31.3 and 31.4 kg/d), protein content (31.7 and 31.6 g/kg) and fat content (36.7 and 37.0 g/kg) in milk of dairy cows were unaffected by hybrid source. Body weight gains of cattle were not different. However, intake was significantly higher in cows fed Rh208Bt silage. In the third trial, five midlactation multiparous Holstein cows were successively fed the silage from Rh208 and Rh208Bt corn hybrids 2 or 3 wk. Data were considered only for the last week of each period. There were no significant effects on protein fractions, fatty acid composition, or coagulation properties of milk between Rh208 and Rh208Bt fed cattle. Cattle and sheep can perform equally well with a conventional or a genetically modified Bt176 corn silage.

  8. Genetic factors conferring metastasis in osteosarcoma.

    PubMed

    Maximov, Vadim V; Aqeilan, Rami I

    2016-07-01

    Osteosarcoma (OS) is a deadly bone malignancy affecting mostly children and adolescents. OS has outstandingly complex genetic alterations likely due to p53-independent genomic instability. Based on analysis of recent published research we claim existence of various genetic mechanisms of osteosarcomagenesis conferring great variability to different OS properties including metastatic potential. We also propose a model explaining how diverse genetic mechanisms occur and providing a framework for future research. P53-independent preexisting genomic instability, which precedes and frequently causes TP53 genetic alterations, is central in our model. In addition, our analyses reveal a possible cooperation between aberrantly activated HIF-1α and AP-1 genetic pathways in OS metastasis. We also review the involvement of noncoding RNA genes in OS metastasis.

  9. Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

    PubMed Central

    2010-01-01

    Background Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including LPL, APOA5 and APOE. The combined analysis of these polymorphisms could produce clinically meaningful complementary information. Methods A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the LPL-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the APOA5-S19W (rs3135506) and -1131T/C (rs662799) variants, and the APOE polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption. Results We found a significant lowering effect of the LPL-HindIII and S447X polymorphisms (p < 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the APOE-ε4 allele were significantly associated with an independent additive TG-raising effect (p < 0.05, p < 0.01, p < 0.001, p < 0.0001 and p < 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (p < 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; p = 0.042) and having one single raising polymorphism (OR

  10. Tricholoma matsutake in a natural Pinus densiflora forest: correspondence between above- and below-ground genets, association with multiple host trees and alteration of existing ectomycorrhizal communities.

    PubMed

    Lian, Chunlan; Narimatsu, Maki; Nara, Kazuhide; Hogetsu, Taizo

    2006-01-01

    Tricholoma matsutake (matsutake) is an ectomycorrhizal (ECM) fungus that produces economically important mushrooms in Japan. Here, we use microsatellite markers to identify genets of matsutake sporocarps and below-ground ECM tips, as well as associated host genotypes of Pinus densiflora. We also studied ECM fungal community structure inside, beneath and outside the matsutake fairy rings, using morphological and internal transcribed spacer (ITS) polymorphism analysis. Based on sporocarp samples, one to four genets were found within each fairy ring, and no genetic differentiation among six sites was detected. Matsutake ECM tips were only found beneath fairy rings and corresponded with the genotypes of the above-ground sporocarps. We detected nine below-ground matsutake genets, all of which colonized multiple pine trees (three to seven trees per genet). The ECM fungal community beneath fairy rings was species-poor and significantly differed from those inside and outside the fairy rings. We conclude that matsutake genets occasionally establish from basidiospores and expand on the root systems of multiple host trees. Although matsutake mycelia suppress other ECM fungi during expansion, most of them may recover after the passage of the fairy rings.

  11. Habitat Choice and Temporal Variation Alter the Balance between Adaptation by Genetic Differentiation, a Jack-of-All-Trades Strategy, and Phenotypic Plasticity.

    PubMed

    Scheiner, Samuel M

    2016-05-01

    Confronted with variable environments, species adapt in several ways, including genetic differentiation, a jack-of-all-trades strategy, or phenotypic plasticity. Adaptive habitat choice favors genetic differentiation and local adaptation over a generalist, jack-of-all-trades strategy. Models predict that, absent plasticity costs, variable environments generally favor phenotypic plasticity over genetic differentiation and being a jack-of-all-trades generalist. It is unknown how habitat choice might affect the evolution of plasticity. Using an individual-based simulation model, I explored the interaction of choice and plasticity. With only spatial variation, habitat choice promotes genetic differentiation over a jack-of-all-trades strategy or phenotypic plasticity. In the absence of plasticity, temporal variation favors a jack-of-all-trades strategy over choice-mediated genetic differentiation; when plasticity is an option, it is favored. This occurs because habitat choice creates a feedback between genetic differentiation and dispersal rates. As demes become better adapted to their local environments, the effective dispersal rate decreases, because more individuals have very high fitness and so choose not to disperse, reinforcing local stabilizing selection and negating selection for plasticity. Temporal variation breaks that feedback. These results point to a potential data paradox: systems with habitat choice may have the lowest actual movement rates. The potential for adaptive habitat choice may be very common, but its existence may reduce observed dispersal rates enough that we do not recognize systems where it may be present, warranting further exploration of likely systems.

  12. Addition of four-hundred fifty-five microsatellite marker loci to the high density Gossypium hirsutum TM-1 x G. barbadense 3-79 genetic map

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A high density genetic linkage map plays important roles in understanding genome structure of tetraploid cotton, dissecting economically important traits, identifying molecular markers associated with a trait, and cloning a gene of interest through map-based cloning strategy. Four hundred fifty f...

  13. In vitro short-term exposure to air pollution PM2.5-0.3 induced cell cycle alterations and genetic instability in a human lung cell coculture model.

    PubMed

    Abbas, Imane; Verdin, Anthony; Escande, Fabienne; Saint-Georges, Françoise; Cazier, Fabrice; Mulliez, Philippe; Courcot, Dominique; Shirali, Pirouz; Gosset, Pierre; Garçon, Guillaume

    2016-05-01

    Although its adverse health effects of air pollution particulate matter (PM2.5) are well-documented and often related to oxidative stress and pro-inflammatory response, recent evidence support the role of the remodeling of the airway epithelium involving the regulation of cell death processes. Hence, the overarching goals of the present study were to use an in vitro coculture model, based on human AM and L132 cells to study the possible alteration of TP53-RB gene signaling pathways (i.e. cell cycle phases, gene expression of TP53, BCL2, BAX, P21, CCND1, and RB, and protein concentrations of their active forms), and genetic instability (i.e. LOH and/or MSI) in the PM2.5-0.3-exposed coculture model. PM2.5-0.3 exposure of human AM from the coculture model induced marked cell cycle alterations after 24h, as shown by increased numbers of L132 cells in subG1 and S+G2 cell cycle phases, indicating apoptosis and proliferation. Accordingly, activation of the TP53-RB gene signaling pathways after the coculture model exposure to PM2.5-0.3 was reported in the L132 cells. Exposure of human AM from the coculture model to PM2.5-0.3 resulted in MS alterations in 3p chromosome multiple critical regions in L132 cell population. Hence, in vitro short-term exposure of the coculture model to PM2.5-0.3 induced cell cycle alterations relying on the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation and genetic instability.

  14. Multiple genetic imaging study of the association between cholesterol metabolism and brain functional alterations in individuals with risk factors for Alzheimer's disease

    PubMed Central

    Bai, Feng; Yuan, Yonggui; Shi, Yongmei; Zhang, Zhijun

    2016-01-01

    Alzheimer's disease (AD) is a clinically and genetically heterogeneous neurodegenerative disease. Genes involved in cholesterol metabolism may play a role in the pathological changes of AD. However, the imaging genetics-based endophenotypes derived from polymorphisms in multiple functionally related genes are unclear in individuals with risk factors for AD. Forty-three amnestic mild cognitive impairment (aMCI) subjects and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) measurements of brain topological organization. Thirty-three previously suggested tagging single nucleotide polymorphisms (SNPs) from 12 candidate genes in the cholesterol metabolism pathway were further investigated. A cholesterol metabolism pathway gene-based imaging genetics approach was then utilized to investigate disease-related differences between the groups based on genotype-by-aMCI interactions. The cholesterol metabolism pathway genes exerted widespread effects on the cortico-subcortical-cerebellar spontaneous brain activity. Meanwhile, left lateralization of global brain connectivity was associated with cholesterol metabolism pathway genes. The APOE rs429358 variation significantly influenced the brain network characteristics, affecting the activation of nodes as well as the connectivity of edges in aMCI subjects. The cholesterol metabolism pathway gene-based imaging genetics approach may provide new opportunities to understand the mechanisms underlying AD and suggested that APOE rs429358 is a core genetic variation that is associated with disease-related differences in brain function. PMID:26985771

  15. Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course.

    PubMed

    Graff, Mariaelisa; Ngwa, Julius S; Workalemahu, Tsegaselassie; Homuth, Georg; Schipf, Sabine; Teumer, Alexander; Völzke, Henry; Wallaschofski, Henri; Abecasis, Goncalo R; Edward, Lakatta; Francesco, Cucca; Sanna, Serena; Scheet, Paul; Schlessinger, David; Sidore, Carlo; Xiao, Xiangjun; Wang, Zhaoming; Chanock, Stephen J; Jacobs, Kevin B; Hayes, Richard B; Hu, Frank; Van Dam, Rob M; Crout, Richard J; Marazita, Mary L; Shaffer, John R; Atwood, Larry D; Fox, Caroline S; Heard-Costa, Nancy L; White, Charles; Choh, Audrey C; Czerwinski, Stefan A; Demerath, Ellen W; Dyer, Thomas D; Towne, Bradford; Amin, Najaf; Oostra, Ben A; Van Duijn, Cornelia M; Zillikens, M Carola; Esko, Tõnu; Nelis, Mari; Nikopensius, Tit; Metspalu, Andres; Strachan, David P; Monda, Keri; Qi, Lu; North, Kari E; Cupples, L Adrienne; Gordon-Larsen, Penny; Berndt, Sonja I

    2013-09-01

    Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10⁻⁸) near FTO (P = 3.72 × 10⁻²³), TMEM18 (P = 3.24 × 10⁻¹⁷), MC4R (P = 4.41 × 10⁻¹⁷), TNNI3K (P = 4.32 × 10⁻¹¹), SEC16B (P = 6.24 × 10⁻⁹), GNPDA2 (P = 1.11 × 10⁻⁸) and POMC (P = 4.94 × 10⁻⁸) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10⁻⁵ after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages.

  16. Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course

    PubMed Central

    Graff, Mariaelisa; Ngwa, Julius S.; Workalemahu, Tsegaselassie; Homuth, Georg; Schipf, Sabine; Teumer, Alexander; Völzke, Henry; Wallaschofski, Henri; Abecasis, Goncalo R.; Edward, Lakatta; Francesco, Cucca; Sanna, Serena; Scheet, Paul; Schlessinger, David; Sidore, Carlo; Xiao, Xiangjun; Wang, Zhaoming; Chanock, Stephen J.; Jacobs, Kevin B.; Hayes, Richard B.; Hu, Frank; Van Dam, Rob M.; Crout, Richard J.; Marazita, Mary L.; Shaffer, John R; Atwood, Larry D.; Fox, Caroline S.; Heard-Costa, Nancy L.; White, Charles; Choh, Audrey C.; Czerwinski, Stefan A.; Demerath, Ellen W.; Dyer, Thomas D.; Towne, Bradford; Amin, Najaf; Oostra, Ben A.; Van Duijn, Cornelia M.; Zillikens, M. Carola; Esko, Tõnu; Nelis, Mari; Nikopensius, Tit; Metspalu, Andres; Strachan, David P.; Monda, Keri; Qi, Lu; North, Kari E.; Cupples, L. Adrienne; Gordon-Larsen, Penny; Berndt, Sonja I.

    2013-01-01

    Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 × 10−8) near FTO (P = 3.72 × 10−23), TMEM18 (P = 3.24 × 10−17), MC4R (P = 4.41 × 10−17), TNNI3K (P = 4.32 × 10−11), SEC16B (P = 6.24 × 10−9), GNPDA2 (P = 1.11 × 10−8) and POMC (P = 4.94 × 10−8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 × 10−5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18–90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. PMID:23669352

  17. Antioxidant value addition in human diets: genetic transformation of Brassica juncea with gamma-TMT gene for increased alpha-tocopherol content.

    PubMed

    Yusuf, Mohd Aslam; Sarin, Neera Bhalla

    2007-02-01

    Alpha-tocopherol, the most biologically active form of vitamin E, is implicated in decreasing the risk of several types of cancers, coronary heart disease and a number of degenerative human conditions, when taken in excess of the recommended daily allowance. Natural alpha-tocopherol has twice the bioavailability of the synthetic isomer. This study describes a successful attempt at fortifying human diets with natural alpha-tocopherol by taking recourse to genetic engineering of an important oilseed crop, Brassica juncea. Gamma-tocopherol methyl transferase cDNA from Arabidopsis thaliana, coding for the enzyme catalysing the conversion of the large gamma-tocopherol pool to alpha-tocopherol, was overexpressed in B. juncea plants. The successful integration of the transgene was confirmed by PCR and Southern blot analysis, while the enhanced transcript level was evident in the northern blot analysis. HPLC analysis of the seeds of the T1 transgenic lines showed a shift in tocopherol profile with the highest over-expressors having alpha-tocopherol levels as high as sixfold over the non-transgenic controls. This study discusses the production of a transgenic oilseed crop with high alpha-tocopherol levels, which can provide a feasible, innocuous, and inexpensive way of taking the beneficial effects of high alpha-tocopherol intake to the masses.

  18. Genetic ablation of calcium-independent phospholipase A2gamma leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype.

    PubMed

    Mancuso, David J; Sims, Harold F; Han, Xianlin; Jenkins, Christopher M; Guan, Shao Ping; Yang, Kui; Moon, Sung Ho; Pietka, Terri; Abumrad, Nada A; Schlesinger, Paul H; Gross, Richard W

    2007-11-30

    Previously, we identified a novel calcium-independent phospholipase, designated calcium-independent phospholipase A(2) gamma (iPLA(2)gamma), which possesses dual mitochondrial and peroxisomal subcellular localization signals. To identify the roles of iPLA(2)gamma in cellular bioenergetics, we generated mice null for the iPLA(2)gamma gene by eliminating the active site of the enzyme through homologous recombination. Mice null for iPLA(2)gamma display multiple bioenergetic dysfunctional phenotypes, including 1) growth retardation, 2) cold intolerance, 3) reduced exercise endurance, 4) greatly increased mortality from cardiac stress after transverse aortic constriction, 5) abnormal mitochondrial function with a 65% decrease in ascorbate-induced Complex IV-mediated oxygen consumption, and 6) a reduction in myocardial cardiolipin content accompanied by an altered cardiolipin molecular species composition. We conclude that iPLA(2)gamma is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.

  19. Genetic alteration and mutation profiling of circulating cell-free tumor DNA (cfDNA) for diagnosis and targeted therapy of gastrointestinal stromal tumors.

    PubMed

    Yan, Weixin; Zhang, Aiguo; Powell, Michael J

    2016-07-21

    Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive type of tumor, different from smooth muscle and neural tumors of the gastrointestinal tract. The identification of genetic aberrations in proto-oncogenes that drive the growth of GISTs is critical for improving the efficacy of cancer therapy by matching targeted drugs to specific mutations. Research into the oncogenic mechanisms of GISTs has found that these tumors frequently contain activating gene mutations in either platelet-derived growth factor receptor A (PDGFRA) or a receptor tyrosine protein associated with a mast cell growth factor receptor encoded by the KIT gene. Mutant cancer subpopulations have the potential to disrupt durable patient responses to molecularly targeted therapy for GISTs, yet the prevalence and size of subpopulations remain largely unexplored. Detection of the cancer subpopulations that harbor low-frequency mutant alleles of target proto-oncogenes through the use of molecular genetic methods, such as polymerase chain reaction (PCR) target amplification technology, is hampered by the high abundance of wild-type alleles, which limit the sensitivity of detection of these minor mutant alleles. This is especially true in the case of mutant tumor DNA derived "driver" and "drug-resistant" alleles that are present in the circulating cell-free tumor DNA (cfDNA) in the peripheral blood circulation of GIST patients. So-called "liquid biopsy" allows for the dynamic monitoring of the patients' tumor status during treatment using minimally invasive sampling. New methodologies, such as a technology that employs a xenonucleic acid (XNA) clamping probe to block the PCR amplification of wild-type templates, have allowed improved molecular detection of these low-frequency alleles both in tissue biopsy samples and in cfDNA. These new methodologies could be widely applied for minimally invasive molecular testing in the therapeutic management of GISTs.

  20. Food additives

    PubMed Central

    Spencer, Michael

    1974-01-01

    Food additives are discussed from the food technology point of view. The reasons for their use are summarized: (1) to protect food from chemical and microbiological attack; (2) to even out seasonal supplies; (3) to improve their eating quality; (4) to improve their nutritional value. The various types of food additives are considered, e.g. colours, flavours, emulsifiers, bread and flour additives, preservatives, and nutritional additives. The paper concludes with consideration of those circumstances in which the use of additives is (a) justified and (b) unjustified. PMID:4467857

  1. Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

    SciTech Connect

    Langland, Gregory T.; Yannone, Steven M.; Langland, Rachel A.; Nakao, Aki; Guan, Yinghui; Long, Sydney B.T.; Vonguyen, Lien; Chen, David J.; Gray, Joe W; Chen, Fanqing

    2009-09-07

    The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNAPK in ovarian cancer.

  2. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease.

    PubMed

    Bečanović, Kristina; Nørremølle, Anne; Neal, Scott J; Kay, Chris; Collins, Jennifer A; Arenillas, David; Lilja, Tobias; Gaudenzi, Giulia; Manoharan, Shiana; Doty, Crystal N; Beck, Jessalyn; Lahiri, Nayana; Portales-Casamar, Elodie; Warby, Simon C; Connolly, Colúm; De Souza, Rebecca A G; Tabrizi, Sarah J; Hermanson, Ola; Langbehn, Douglas R; Hayden, Michael R; Wasserman, Wyeth W; Leavitt, Blair R

    2015-06-01

    Cis-regulatory variants that alter gene expression can modify disease expressivity, but none have previously been identified in Huntington disease (HD). Here we provide in vivo evidence in HD patients that cis-regulatory variants in the HTT promoter are bidirectional modifiers of HD age of onset. HTT promoter analysis identified a NF-κB binding site that regulates HTT promoter transcriptional activity. A non-coding SNP, rs13102260:G > A, in this binding site impaired NF-κB binding and reduced HTT transcriptional activity and HTT protein expression. The presence of the rs13102260 minor (A) variant on the HD disease allele was associated with delayed age of onset in familial cases, whereas the presence of the rs13102260 (A) variant on the wild-type HTT allele was associated with earlier age of onset in HD patients in an extreme case-based cohort. Our findings suggest a previously unknown mechanism linking allele-specific effects of rs13102260 on HTT expression to HD age of onset and have implications for HTT silencing treatments that are currently in development.

  3. Real-time, label-free isothermal solid-phase amplification/detection (ISAD) device for rapid detection of genetic alteration in cancers.

    PubMed

    Shin, Yong; Perera, Agampodi Promoda; Kim, Kyung Woo; Park, Mi Kyoung

    2013-06-07

    Here, we first present an isothermal solid-phase amplification/detection (ISAD) technique for the detection of single-point mutations that can be performed without labelling in real-time by utilizing both silicon microring-based solid-phase amplification and isothermal recombinase polymerase amplification (RPA). The ISAD technique was performed on a silicon microring device with a plastic chamber containing 10 μL of the reaction mixture, and characterized with an assay for the detection of the HRAS (Harvey RAS) gene single-point mutation. For the solid-phase amplification, the primer of the gene was directly attached to the surface of the device via an amine modification reaction. The amplified DNA was detected, without a label, by measuring the optical wavelength shift of the silicon microring resonator during the reaction. We demonstrated that the sensitivity of the ISAD technique was 100-times higher than that of RPA and conventional PCR methods. Moreover, this technique can be used to distinguish a single-point mutation of the HRAS gene via target amplification. This novel DNA amplification/detection technique will be useful for the detection of sequence alterations such as mutations and single-nucleotide polymorphisms as DNA biomarkers in human diseases.

  4. Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

    PubMed Central

    Langland, Gregory T.; Yannone, Steven M.; Langland, Rachel A.; Nakao, Aki; Guan, Yinghui; Long, Sydney B.T.; Vonguyen, Lien; Chen, David J.; Gray, Joe W.; Chen, Fanqing

    2010-01-01

    The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNA-PK in ovarian cancer. PMID:20204287

  5. Functional MRI to assess alterations of functional networks in response to pharmacological or genetic manipulations of the serotonergic system in mice.

    PubMed

    Razoux, Florence; Baltes, Christof; Mueggler, Thomas; Seuwen, Aline; Russig, Holger; Mansuy, Isabelle; Rudin, Markus

    2013-07-01

    Imaging methods that enable the investigation of functional networks both in human and animal brain provide important insights into mechanisms underlying pathologies including psychiatric disorders. Since the serotonergic receptor 1A (5-HT(1A)-R) has been strongly implicated in the pathophysiology of depressive and anxiety disorders, as well as in the action of antidepressant drugs, we investigated brain connectivity related to the 5-HT(1A)-R system by use of pharmacological functional magnetic resonance imaging in mice. We characterized functional connectivity elicited by activation of 5-HT(1A)-R and investigated how pharmacological and genetic manipulations of its function may modulate the evoked connectivity. Functional connectivity elicited by administration of the 5-HT(1A)-R agonist 8-OH-DPAT can be described by networks characterized by small-world attributes with nodes displaying highly concerted response patterns. Circuits identified comprised the brain structures known to be involved in stress-related disorders (e.g. prefrontal cortex, amygdala and hippocampus). The results also highlight the dorsomedial thalamus, a structure associated with fear processing, as a hub of the 5-HT(1A)-R functional network. Administration of a specific 5-HT(1A)-R antagonist or use of heterozygous 5-HT(1A)-R knockout mice significantly reduced functional connectivity elicited by 8-OH-DPAT. Whole brain functional connectivity analysis constitutes an attractive tool to characterize impairments in neurotransmission and the efficacy of pharmacological treatment in a comprehensive manner.

  6. Epigenetic alterations underlying autoimmune diseases.

    PubMed

    Aslani, Saeed; Mahmoudi, Mahdi; Karami, Jafar; Jamshidi, Ahmad Reza; Malekshahi, Zahra; Nicknam, Mohammad Hossein

    2016-01-01

    Recent breakthroughs in genetic explorations have extended our understanding through discovery of genetic patterns subjected to autoimmune diseases (AID). Genetics, on the contrary, has not answered all the conundrums to describe a comprehensive explanation of causal mechanisms of disease etiopathology with regard to the function of environment, sex, or aging. The other side of the coin, epigenetics which is defined by gene manifestation modification without DNA sequence alteration, reportedly has come in to provide new insights towards disease apprehension through bridging the genetics and environmental factors. New investigations in genetic and environmental contributing factors for autoimmunity provide new explanation whereby the interactions between genetic elements and epigenetic modifications signed by environmental agents may be responsible for autoimmune disease initiation and perpetuation. It is aimed through this article to review recent progress attempting to reveal how epigenetics associates with the pathogenesis of autoimmune diseases.

  7. Analysis of DNA Copy Number Alterations in Ovarian Serous Tumors Identifies New Molecular Genetic Changes in Low-grade and High-grade Carcinomas

    PubMed Central

    Kuo, Kuan-Ting; Guan, Bin; Feng, Yuanjian; Mao, Tsui-Lien; Chen, Xu; Jinawath, Natini; Wang, Yue; Kurman, Robert J.; Shih, Ie-Ming; Wang, Tian-Li

    2009-01-01

    Ovarian serous carcinoma, the most common and lethal type of ovarian cancer, was thought to develop from two distinct molecular pathways. High-grade (HG) serous carcinomas contain frequent TP53 mutations while low-grade (LG) carcinomas arise from serous borderline tumors (SBT) and harbor mutations in KRAS/BRAF/ERBB2 pathway. However, the molecular alterations involved in the progression from SBT to LG carcinoma remain largely unknown. As well, the extent of deletion of tumor suppressors in ovarian serous carcinomas has not been well-studied. To further address these two issues, we assessed DNA copy number changes among affinity-purified tumor cells from 37 ovarian serous neoplasms including SBT, LG and HG tumors using high density 250K SNP arrays. Chromosomal instability index as measured by changes in DNA copy number was significantly higher in HG than in LG serous carcinomas. Hemizygous ch1p36 deletion was common in LG serous carcinomas but was rarely seen in SBT. This region contains several candidate tumor suppressors including miR-34a. In contrast, in HG serous carcinomas, significant numbers of amplifications and deletions including homozygous deletions were identified. Among homozygous deletions, loci containing Rb1, CDKN2A/B, CSMD1, and DOCK4 were most common, being present in 10.6%, 6.4%, 6.4% and 4.3%, respectively, in independent 47 affinity-purified HG serous carcinomas. Except the CDKN2A/B region, these homozygous deletions were not present in either SBT or LG tumors. Our study provides a genome-wide homozygous deletion profiles in HG serous carcinomas, serving as a molecular foundation to study tumor suppressors in ovarian cancer. PMID:19383911

  8. Application of two-dimensional gel electrophoresis to interrogate alterations in the proteome of genetically modified crops. 1. Assessing analytical validation.

    PubMed

    Ruebelt, Martin C; Leimgruber, Nancy K; Lipp, Markus; Reynolds, Tracey L; Nemeth, Margaret A; Astwood, James D; Engel, Karl-Heinz; Jany, Klaus-Dieter

    2006-03-22

    Current tools used to assess the safety of food and feed derived from modern biotechnology emphasize the investigation of possible unintended effects caused directly by the expression of transgenes or indirectly by pleiotropy. These tools include extensive multisite and multiyear agronomic evaluations, compositional analyses, animal nutrition, and classical toxicology evaluations. Because analytical technologies are rapidly developing, proteome analysis based on two-dimensional gel electrophoresis (2DE) was investigated as a complementary tool to the existing technologies. A 2DE method was established for the qualitative and quantitative analysis of the seed proteome of Arabidopsis thaliana with the following validation parameters examined: (1) source and scope of variation; (2) repeatability; (3) sensitivity; and (4) linearity of the method. The 2DE method resolves proteins with isoelectric points between 4 and 9 and molecular masses (MM) of 6-120 kDa and is sensitive enough to detect protein levels in the low nanogram range. The separation of the proteins was demonstrated to be very reliable with relative position variations of 1.7 and 1.1% for the pI and MM directions, respectively. The mean coefficient of variation of 254 matched spot qualities was found to be 24.8% for the gel-to-gel and 26% for the overall variability. A linear relationship (R2 > 0.9) between protein amount and spot volume was demonstrated over a 100-fold range for the majority of selected proteins. Therefore, this method could be used to interrogate proteome alterations such as a novel protein, fusion protein, or any other change that affects molecular mass, isoelectric point, and/or quantity of a protein.

  9. Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations.

    PubMed

    Bacher, Ulrike; Haferlach, Torsten; Alpermann, Tamara; Zenger, Melanie; Hochhaus, Andreas; Beelen, Dietrich W; Uppenkamp, Michael; Rummel, Mathias; Kern, Wolfgang; Schnittger, Susanne; Haferlach, Claudia

    2011-03-01

    In AML, cooperation of mutations suppressing differentiation ('class-II-mutations') with 'class-I-mutations' increasing cell proliferation is frequent. In rare cases of myeloid malignancies, the BCR-ABL1 fusion was reported to cooperate as class-I-mutation with class-II-mutations, but most cases had to be classified as blast phase of chronic myeloid leukaemia (CML). We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions: 1:220 patients with inv(16)/CBFB-MYH11 (0·5%), 2:272 AML cases with t(8;21)/RUNX1-RUNX1T1 (0·7%), 1:1029 NPM1-mutated AML (0·1%), and one patient with s-AML following MDS with a 5q-deletion. Four patients had m-BCR (e1a2) BCR-ABL1 transcripts; one case only had an M-BCR (b3a2) breakpoint. These cases allow some interesting conclusions: The BCR-ABL1 rearrangement apparently can cooperate with the NPM1 mutation similar to other class-I-mutations. The identification of Philadelphia positive subclones in <1% of patients with CBF-leukaemias fits well with previous observations that most CBF-AML are accompanied by activating mutations in genes enhancing proliferation. Since we observed the occurrence of the Philadelphia positive subclones at diagnosis, at relapse, or throughout the disease, the time point of the emergence of Philadelphia subclones seems variable in AML. Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact.

  10. The feeding value of soybeans fed to rats, chickens, catfish and dairy cattle is not altered by genetic incorporation of glyphosate tolerance.

    PubMed

    Hammond, B G; Vicini, J L; Hartnell, G F; Naylor, M W; Knight, C D; Robinson, E H; Fuchs, R L; Padgette, S R

    1996-03-01

    Animal feeding studies were conducted with rats, broiler chickens, catfish and dairy cows as part of a safety assessment program for a soybean variety genetically modified to tolerate in-season application of glyphosate. These studies were designed to compare the feeding value (wholesomeness) of two lines of glyphosate-tolerant soybeans (GTS) to the feeding value of the parental cultivar from which they were derived. Processed GTS meal was incorporated into the diets at the same concentrations as used commercially; diary cows were fed 10 g/100 g cracked soybeans in the diet, a level that is on the high end of what is normally fed commercially. In a separate study, laboratory rats were fed 5 and 10 g unprocessed soybean meal 100 g diet. The study durations were 4 wk (rats and dairy cows), 6 wk (broilers) and 10 wk (catfish). Growth, feed conversion (rats, catfish, broilers), fillet composition (catfish), and breast muscle and fat pad weights (broilers) were compared for animals fed the parental and GTS lines. Milk production, milk composition, rumen fermentation and nitrogen digestibility were also compared for dairy cows. In all studies, measured variables were similar for animals fed both GTS lines and the parental line, indicating that the feeding value of the two GTS lines is comparable to that of the parental line. These studies support detailed compositional analysis of the GTS seeds, which showed no meaningful differences between the parental and GTS lines in the concentrations of important nutrients and antinutrients. They also confirmed the results of other studies that demonstrated the safety of the introduced protein, a bacterial 5-enolpyruvyl-shikimate-3-phosphate synthase from Agrobacterium sp. strain CP4.

  11. Cocaine Alters Cytokine Profiles in HIV-1-Infected African American Individuals in the DrexelMed HIV/AIDS Genetic Analysis Cohort

    PubMed Central

    Parikh, Nirzari; Dampier, Will; Feng, Rui; Passic, Shendra R.; Zhong, Wen; Frantz, Brian; Blakey, Brandon; Aiamkitsumrit, Benjamas; Pirrone, Vanessa; Nonnemacher, Michael R.; Jacobson, Jeffrey M.; Wigdahl, Brian

    2014-01-01

    Background This study evaluated the relationship between illicit drug use and HIV-1 disease severity in HIV-1-infected patients enrolled in the DrexelMed HIV/AIDS Genetic Analysis Cohort. Since, cocaine is known to have immunomodulatory effects, the cytokine profiles of preferential nonusers, cocaine users, and multidrug users were analyzed to understand the effects of cocaine on cytokine modulation and HIV-1 disease severity. Methods Patients within the cohort were assessed approximately every 6 months for HIV-1 clinical markers and for history of illicit drug, alcohol, and tobacco use. The Luminex human cytokine 30-plex panel was used for cytokine quantitation. Analysis was performed using a newly developed biostatistical model. Results Substance abuse was common within the cohort. Utilizing the drug screens at the time of each visit, the subjects in the cohort were categorized as preferential nonusers, cocaine users, or multidrug users. The overall health of the nonuser population was better than that of the cocaine users, with peak and current viral loads in nonusers substantially lower than those in cocaine and multidrug users. Among the 30 cytokines investigated, differential levels were established within the 3 populations. The T-helper 2 cytokines, interleukin-4 and -10, known to play a critical role during HIV-1 infection, were positively associated with increasing cocaine use. Clinical parameters such as latest viral load, CD4+ T-cell counts, and CD4:CD8 ratio were also significantly associated with cocaine use, depending on the statistical model used. Conclusions Based on these assessments, cocaine use appears to be associated with more severe HIV-1 disease. PMID:24732878

  12. Genetically Altered Mutant Mouse Models of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Exhibit the Cardiac Expression of Proinflammatory Mediators in a Gene-Dose-Dependent Manner

    PubMed Central

    Vellaichamy, Elangovan; Das, Subhankar; Subramanian, Umadevi; Maeda, Nobuyo

    2014-01-01

    The objective of this study was to examine whether genetically determined differences in the guanylyl cyclase/natriuretic peptide receptor-A gene (Npr1) affect cardiac expression of proinflammatory cytokines, hypertrophic markers, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1) in am Npr1 gene-dose–dependent manner. In the present studies, adult male Npr1 gene-disrupted (Npr1−/−), wild-type (Npr1+/+), and gene-duplicated (Npr1++/++) mice were used. The Npr1−/− mice showed 41 mm Hg higher systolic blood pressure and 60% greater heart weight to body weight (HW/BW) ratio; however, Npr1++/++ mice exhibited 15 mm Hg lower systolic blood pressure and 12% reduced HW/BW ratio compared with Npr1+/+ mice. Significant upregulation of gene expression of proinflammatory cytokines and hypertrophic markers along with enhanced NF-κB/AP-1 binding activities were observed in the Npr1−/− mouse hearts. Conversely, hypertrophic markers and proinflammatory cytokines gene expression as well as NF-κB/AP-1 binding activities were markedly decreased in Npr1++/++ mouse hearts compared with wild-type mice. The ventricular guanylyl cyclase activity and cGMP levels were reduced by 96% and 87%, respectively, in Npr1−/− mice; however, these parameters were amplified by 2.8-fold and 3.8-fold, respectively, in Npr1++/++ mice. Echocardiographic analysis revealed significantly increased fractional shortening in Npr1++/++ mice (P < .05) but greatly decreased in Npr1−/− mice (P < .01) hearts compared with Npr1+/+ mice. The present findings suggest that Npr1 represses the expression of cardiac proinflammatory mediators, hypertrophic markers, and NF-κB/AP-1–mediated mechanisms, which seem to be associated in an Npr1 gene-dose–dependent manner. PMID:24424043

  13. Neuropeptide S alters anxiety, but not depression-like behaviour in Flinders Sensitive Line rats: a genetic animal model of depression.

    PubMed

    Wegener, Gregers; Finger, Beate C; Elfving, Betina; Keller, Kirsten; Liebenberg, Nico; Fischer, Christina W; Singewald, Nicolas; Slattery, David A; Neumann, Inga D; Mathé, Aleksander A

    2012-04-01

    Neuropeptide S (NPS) and its receptor (NPSR) have been implicated in the mediation of anxiolytic-like behaviour in rodents. However, little knowledge is available regarding the NPS system in depression-related behaviours, and whether NPS also exerts anxiolytic effects in an animal model of psychopathology. Therefore, the aim of this work was to characterize the effects of NPS on depression- and anxiety-related parameters, using male and female rats in a well-validated animal model of depression: the Flinders Sensitive Line (FSL), their controls, the Flinders Resistant Line (FRL), and Sprague-Dawley (SD) rats. We found that FSL showed greater immobility in the forced swim test (FST) than FRL, confirming their phenotype. However, NPS did not affect depression-related behaviour in any rat line. No significant differences in baseline anxiety levels between the FSL and FRL strains were observed, but FSL and FRL rats displayed less anxiety-like behaviour compared to SD rats. NPS decreased anxiety-like behaviour on the elevated plus-maze in all strains. The expression of the NPSR in the amygdala, periventricular hypothalamic nucleus, and hippocampus was equal in all male strains, although a trend towards reduced expression within the amygdala was observed in FSL rats compared to SD rats. In conclusion, NPS had a marked anxiolytic effect in FSL, FRL and SD rats, but did not modify the depression-related behaviour in any strain, in spite of the significant differences in innate level between the strains. These findings suggest that NPS specifically modifies anxiety behaviour but cannot overcome/reverse a genetically mediated depression phenotype.

  14. Hypergravity-induced altered behavior in Drosophila

    NASA Astrophysics Data System (ADS)

    Hosamani, Ravikumar; Wan, Judy; Marcu, Oana; Bhattacharya, Sharmila

    2012-07-01

    Microgravity and mechanical stress are important factors of the spaceflight environment, and affect astronaut health and behavior. Structural, functional, and behavioral mechanisms of all cells and organisms are adapted to Earth's gravitational force, 1G, while altered gravity can pose challenges to their adaptability to this new environment. On ground, hypergravity paradigms have been used to predict and complement studies on microgravity. Even small changes that take place at a molecular and genetic level during altered gravity may result in changes in phenotypic behavior. Drosophila provides a robust and simple, yet very reliable model system to understand the complexity of hypergravity-induced altered behavior, due to availability of a plethora of genetic tools. Locomotor behavior is a sensitive parameter that reflects the array of molecular adaptive mechanisms recruited during exposure to altered gravity. Thus, understanding the genetic basis of this behavior in a hypergravity environment could potentially extend our understanding of mechanisms of adaptation in microgravity. In our laboratory we are trying to dissect out the cellular and molecular mechanisms underlying hypergravity-induced oxidative stress, and its potential consequences on behavioral alterations by using Drosophila as a model system. In the present study, we employed pan-neuronal and mushroom body specific knock-down adult flies by using Gal4/UAS system to express inverted repeat transgenes (RNAi) to monitor and quantify the hypergravity-induced behavior in Drosophila. We established that acute hypergravity (3G for 60 min) causes a significant and robust decrease in the locomotor behavior in adult Drosophila, and that this change is dependent on genes related to Parkinson's disease, such as DJ-1α , DJ-1β , and parkin. In addition, we also showed that anatomically the control of this behavior is significantly processed in the mushroom body region of the fly brain. This work links a molecular

  15. Genetic risk for Alzheimer’s disease alters the five-year trajectory of semantic memory activation in cognitively intact elders

    PubMed Central

    Rao, Stephen M.; Bonner-Jackson, Aaron; Nielson, Kristy A.; Seidenberg, Michael; Smith, J. Carson; Woodard, John L.; Durgerian, Sally

    2015-01-01

    Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer’s disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N=24) and non-carriers (N=21). All participants, ages 65–85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the

  16. The ability of genetically lean or fat slow-growing chickens to synthesize and store lipids is not altered by the dietary energy source.

    PubMed

    Baéza, E; Gondret, F; Chartrin, P; Le Bihan-Duval, E; Berri, C; Gabriel, I; Narcy, A; Lessire, M; Métayer-Coustard, S; Collin, A; Jégou, M; Lagarrigue, S; Duclos, M J

    2015-10-01

    The increasing use of unconventional feedstuffs in chicken's diets results in the substitution of starch by lipids as the main dietary energy source. To evaluate the responses of genetically fat or lean chickens to these diets, males of two experimental lines divergently selected for abdominal fat content were fed isocaloric, isonitrogenous diets with either high lipid (80 g/kg), high fiber (64 g/kg) contents (HL), or low lipid (20 g/kg), low fiber (21 g/kg) contents (LL) from 22 to 63 days of age. The diet had no effect on growth performance and did not affect body composition evaluated at 63 days of age. Glycolytic and oxidative energy metabolisms in the liver and glycogen storage in liver and Sartorius muscle at 63 days of age were greater in chicken fed LL diet compared with chicken fed HL diet. In Pectoralis major (PM) muscle, energy metabolisms and glycogen content were not different between diets. There were no dietary-associated differences in lipid contents of the liver, muscles and abdominal fat. However, the percentages of saturated (SFA) and monounsaturated fatty acids (MUFA) in tissue lipids were generally higher, whereas percentages of polyunsaturated fatty acids (PUFA) were lower for diet LL than for diet HL. The fat line had a greater feed intake and average daily gain, but gain to feed ratio was lower in that line compared with the lean line. Fat chickens were heavier than lean chickens at 63 days of age. Their carcass fatness was higher and their muscle yield was lower than those of lean chickens. The oxidative enzyme activities in the liver were lower in the fat line than in the lean line, but line did not affect energy metabolism in muscles. The hepatic glycogen content was not different between lines, whereas glycogen content and glycolytic potential were higher in the PM muscle of fat chickens compared with lean chickens. Lipid contents in the liver, muscles and abdominal fat did not differ between lines, but fat chickens stored less MUFA and

  17. Food additives

    MedlinePlus

    ... or natural. Natural food additives include: Herbs or spices to add flavor to foods Vinegar for pickling ... Certain colors improve the appearance of foods. Many spices, as well as natural and man-made flavors, ...

  18. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers.

    PubMed

    Okugawa, Yoshinaga; Grady, William M; Goel, Ajay

    2015-10-01

    Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.

  19. Genetic and Pharmacological Intervention of the p75NTR Pathway Alters Morphological and Behavioural Recovery Following Traumatic Brain Injury in Mice

    PubMed Central

    Alder, Janet; Fujioka, Wendy; Giarratana, Anna; Wissocki, Jenna; Thakkar, Keya; Vuong, Phung; Patel, Bijal; Chakraborty, Trisha; Elsabeh, Rami; Parikh, Ankit; Girn, Hartaj S.; Crockett, David; Thakker-Varia, Smita

    2016-01-01

    Primary objective Neurotrophin levels are elevated after TBI yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signaling improves recovery following TBI. Research design Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function. Main outcomes and results p75 was upregulated and TrkB is downregulated 1 day post LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist. Conclusions Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI. PMID:24747217

  20. Potlining Additives

    SciTech Connect

    Rudolf Keller

    2004-08-10

    In this project, a concept to improve the performance of aluminum production cells by introducing potlining additives was examined and tested. Boron oxide was added to cathode blocks, and titanium was dissolved in the metal pool; this resulted in the formation of titanium diboride and caused the molten aluminum to wet the carbonaceous cathode surface. Such wetting reportedly leads to operational improvements and extended cell life. In addition, boron oxide suppresses cyanide formation. This final report presents and discusses the results of this project. Substantial economic benefits for the practical implementation of the technology are projected, especially for modern cells with graphitized blocks. For example, with an energy savings of about 5% and an increase in pot life from 1500 to 2500 days, a cost savings of $ 0.023 per pound of aluminum produced is projected for a 200 kA pot.

  1. Phosphazene additives

    DOEpatents

    Harrup, Mason K; Rollins, Harry W

    2013-11-26

    An additive comprising a phosphazene compound that has at least two reactive functional groups and at least one capping functional group bonded to phosphorus atoms of the phosphazene compound. One of the at least two reactive functional groups is configured to react with cellulose and the other of the at least two reactive functional groups is configured to react with a resin, such as an amine resin of a polycarboxylic acid resin. The at least one capping functional group is selected from the group consisting of a short chain ether group, an alkoxy group, or an aryloxy group. Also disclosed are an additive-resin admixture, a method of treating a wood product, and a wood product.

  2. Reactive biomolecular divergence in genetically altered yeast cells and isolated mitochondria as measured by biocavity laser spectroscopy : a rapid diagnostic method for studying cellular responses to stress and disease.

    SciTech Connect

    Yaffe, Michael P.; Gourley, Paul Lee; Copeland, Robert Guild; McDonald, Anthony Eugene; Hendricks, Judy K.; Naviaux, Robert K.

    2006-12-01

    We report an analysis of four strains of baker's yeast (Saccharomyces cerevisiae) using biocavity laser spectroscopy. The four strains are grouped in two pairs (wild type and altered), in which one strain differs genetically at a single locus, affecting mitochondrial function. In one pair, the wild-type rho+ and a rho0 strain differ by complete removal of mitochondrial DNA (mtDNA). In the second pair, the wild-type rho+ and a rho- strain differ by knock-out of the nuclear gene encoding Cox4, an essential subunit of cytochrome c oxidase. The biocavity laser is used to measure the biophysical optic parameter Deltalambda, a laser wavelength shift relating to the optical density of cell or mitochondria that uniquely reflects its size and biomolecular composition. As such, Deltalambda is a powerful parameter that rapidly interrogates the biomolecular state of single cells and mitochondria. Wild-type cells and mitochondria produce Gaussian-like distributions with a single peak. In contrast, mutant cells and mitochondria produce leptokurtotic distributions that are asymmetric and highly skewed to the right. These distribution changes could be self-consistently modeled with a single, log-normal distribution undergoing a thousand-fold increase in variance of biomolecular composition. These features reflect a new state of stressed or diseased cells that we call a reactive biomolecular divergence (RBD) that reflects the vital interdependence of mitochondria and the nucleus.

  3. Altered nuclear dynamics in MDX myofibers.

    PubMed

    Iyer, Shama R; Shah, Sameer B; Valencia, Ana P; Schneider, Martin F; Hernández-Ochoa, Erick O; Stains, Joseph P; Blemker, Silvia S; Lovering, Richard M

    2017-03-01

    Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to progressive muscle degeneration and weakness. Although the genetic basis is known, the pathophysiology of dystrophic skeletal muscle remains unclear. We examined nuclear movement in wild-type (WT) and muscular dystrophy mouse model for DMD (MDX) (dystrophin-null) mouse myofibers. We also examined expression of proteins in the linkers of nucleoskeleton and cytoskeleton (LINC) complex, as well as nuclear transcriptional activity via histone H3 acetylation and polyadenylate-binding nuclear protein-1. Because movement of nuclei is not only LINC dependent but also microtubule dependent, we analyzed microtubule density and organization in WT and MDX myofibers, including the application of a unique 3D tool to assess microtubule core structure. Nuclei in MDX myofibers were more mobile than in WT myofibers for both distance traveled and velocity. MDX muscle shows reduced expression and labeling intensity of nesprin-1, a LINC protein that attaches the nucleus to the microtubule and actin cytoskeleton. MDX nuclei also showed altered transcriptional activity. Previous studies established that microtubule structure at the cortex is disrupted in MDX myofibers; our analyses extend these findings by showing that microtubule structure in the core is also disrupted. In addition, we studied malformed MDX myofibers to better understand the role of altered myofiber morphology vs. microtubule architecture in the underlying susceptibility to injury seen in dystrophic muscles. We incorporated morphological and microtubule architectural concepts into a simplified finite element mathematical model of myofiber mechanics, which suggests a greater contribution of myofiber morphology than microtubule structure to muscle biomechanical performance.NEW & NOTEWORTHY Microtubules provide the means for nuclear movement but show altered organization in the muscular dystrophy mouse model (MDX

  4. Elephant behaviour and conservation: social relationships, the effects of poaching, and genetic tools for management.

    PubMed

    Archie, Elizabeth A; Chiyo, Patrick I

    2012-02-01

    Genetic tools are increasingly valuable for understanding the behaviour, evolution, and conservation of social species. In African elephants, for instance, genetic data provide basic information on the population genetic causes and consequences of social behaviour, and how human activities alter elephants' social and genetic structures. As such, African elephants provide a useful case study to understand the relationships between social behaviour and population genetic structure in a conservation framework. Here, we review three areas where genetic methods have made important contributions to elephant behavioural ecology and conservation: (1) understanding kin-based relationships in females and the effects of poaching on the adaptive value of elephant relationships, (2) understanding patterns of paternity in elephants and how poaching can alter these patterns, and (3) conservation genetic tools to census elusive populations, track ivory, and understand the behavioural ecology of crop-raiding. By comparing studies from populations that have experienced a range of poaching intensities, we find that human activities have a large effect on elephant behaviour and genetic structure. Poaching disrupts kin-based association patterns, decreases the quality of elephant social relationships, and increases male reproductive skew, with important consequences for population health and the maintenance of genetic diversity. In addition, we find that genetic tools to census populations or gather forensic information are almost always more accurate than non-genetic alternatives. These results contribute to a growing understanding of poaching on animal behaviour, and how genetic tools can be used to understand and conserve social species.

  5. Genetic alterations by human papillomaviruses in oncogenesis.

    PubMed

    Lazo, P A; Gallego, M I; Ballester, S; Feduchi, E

    1992-03-30

    The integration sites in the cellular genome of human papillomavirus are located in chromosomal regions always associated with oncogenes or other known tumor phenotypes. Two regions, 8q24 and 12q13, are common to several cases of cervical carcinoma and can have integrated more than one type of papillomavirus DNA. These two chromosomal regions contain several genes implicated in oncogenesis. These observations strongly imply that viral integration sites of DNA tumor viruses can be used as the access point to chromosomal regions where genes implicated in the tumor phenotype are located, a situation similar to that of non-transforming retroviruses.

  6. Genetics of Melanocytic Nevi

    PubMed Central

    Roh, Mi Ryung; Eliades, Philip; Gupta, Sameer; Tsao, Hensin

    2015-01-01

    Melanocytic nevi are a benign clonal proliferation of cells expressing the melanocytic phenotype, with heterogeneous clinical and molecular characteristics. In this review, we discuss the genetics of nevi by salient nevi subtypes: congenital melanocytic nevi, acquired melanocytic nevi, blue nevi, and Spitz nevi. While the molecular etiology of nevi has been less thoroughly studied than melanoma, it is clear that nevi and melanoma share common driver mutations. Acquired melanocytic nevi harbor oncogenic mutations in BRAF, which is the predominant oncogene associated with melanoma. Congenital melanocytic nevi and blue nevi frequently harbor NRAS mutations and GNAQ mutations, respectively, while Spitz and atypical Spitz tumors often exhibit HRAS and kinase rearrangements. These initial “driver” mutations are thought to trigger the establishment of benign nevi. After this initial phase of cell proliferation, a senescence program is executed, causing termination of nevi growth. Only upon the emergence of additional tumorigenic alterations, which may provide an escape from oncogene-induced senescence, can malignant progression occur. Here, we review the current literature on the pathobiology and genetics of nevi in the hope that additional studies of nevi promise to inform our understanding of the transition from benign neoplasm to malignancy. PMID:26300491

  7. Genetic Analyses of Integrin Signaling

    PubMed Central

    Wickström, Sara A.; Radovanac, Korana; Fässler, Reinhard

    2011-01-01

    The development of multicellular organisms, as well as maintenance of organ architecture and function, requires robust regulation of cell fates. This is in part achieved by conserved signaling pathways through which cells process extracellular information and translate this information into changes in proliferation, differentiation, migration, and cell shape. Gene deletion studies in higher eukaryotes have assigned critical roles for components of the extracellular matrix (ECM) and their cellular receptors in a vast number of developmental processes, indicating that a large proportion of this signaling is regulated by cell-ECM interactions. In addition, genetic alterations in components of this signaling axis play causative roles in several human diseases. This review will discuss what genetic analyses in mice and lower organisms have taught us about adhesion signaling in development and disease. PMID:21421914

  8. Moral issues arising from genetics.

    PubMed

    Zucker, A; Patriquin, D

    1987-01-01

    Gene therapy, pre-natal diagnosis, genetically altered bacteria, patenting new life forms: these are all outgrowths from the development of genetics. Our focus will be on the moral issues engendered by some of the genetic techniques which are now so well integrated into clinical medicine. The section on genetic counseling is meant to show the most frequent moral problems encountered as they might really occur. Genetic screening is presented as a mix of preventive medicine and aid for genetic counseling. Genetic engineering is discussed in the context of evolution and human needs and desires.

  9. Molecular alterations in hepatocellular carcinoma associated with hepatitis B and hepatitis C infections

    PubMed Central

    Izzo, Francesco; Buonaguro, Franco M.

    2016-01-01

    Chronic infections with hepatitis B (HBV) and hepatitis C viruses (HCV) are the leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Both viruses encode multifunctional regulatory proteins activating several oncogenic pathways, which induce accumulation of multiple genetic alterations in the infected hepatocytes. Gene mutations in HBV- and HCV-induced HCCs frequently impair the TP53, Wnt/b-catenin, RAS/RAF/MAPK kinase and AKT/mTOR pathways, which represent important anti-cancer targets. In this review, we highlight the molecular mechanisms underlying the pathogenesis of primary liver cancer, with particular emphasis on the host genetic variations identified by high-throughput technologies. In addition, we discuss the importance of genetic alterations, such as mutations in the telomerase reverse transcriptase (TERT) promoter, for the diagnosis, prognosis, and tumor stratification for development of more effective treatment approaches. PMID:26943571

  10. Molecular and Genomic Alterations in Glioblastoma Multiforme.

    PubMed

    Crespo, Ines; Vital, Ana Louisa; Gonzalez-Tablas, María; Patino, María del Carmen; Otero, Alvaro; Lopes, María Celeste; de Oliveira, Catarina; Domingues, Patricia; Orfao, Alberto; Tabernero, Maria Dolores

    2015-07-01

    In recent years, important advances have been achieved in the understanding of the molecular biology of glioblastoma multiforme (GBM); thus, complex genetic alterations and genomic profiles, which recurrently involve multiple signaling pathways, have been defined, leading to the first molecular/genetic classification of the disease. In this regard, different genetic alterations and genetic pathways appear to distinguish primary (eg, EGFR amplification) versus secondary (eg, IDH1/2 or TP53 mutation) GBM. Such genetic alterations target distinct combinations of the growth factor receptor-ras signaling pathways, as well as the phosphatidylinositol 3-kinase/phosphatase and tensin homolog/AKT, retinoblastoma/cyclin-dependent kinase (CDK) N2A-p16(INK4A), and TP53/mouse double minute (MDM) 2/MDM4/CDKN2A-p14(ARF) pathways, in cells that present features associated with key stages of normal neurogenesis and (normal) central nervous system cell types. This translates into well-defined genomic profiles that have been recently classified by The Cancer Genome Atlas Consortium into four subtypes: classic, mesenchymal, proneural, and neural GBM. Herein, we review the most relevant genetic alterations of primary versus secondary GBM, the specific signaling pathways involved, and the overall genomic profile of this genetically heterogeneous group of malignant tumors.

  11. Behavioral phenotypes in genetic syndromes: genetic clues to human behavior.

    PubMed

    Cassidy, Suzanne B; Morris, Colleen A

    2002-01-01

    A behavioral phenotype is the characteristic cognitive, personality, behavioral, and psychiatric pattern that typifies a disorder. A number of genetic syndromes have been identified as having this type of distinctive and consistent behavior pattern. It may act as an important diagnostic sign, like a malformation or characteristic facial appearance. Such patterns are also useful for the physician's anticipatory guidance from an educational, rehabilitative, and parenting perspective. In addition, because they are the consequences of known genetic alterations, behavioral phenotypes can be potentially highly valuable clues to the identification of genes in the population that are important to determination of cognitive skills or deficits, personality determinants, behavioral abnormalities, or psychiatric disorders. The nature of a behavioral phenotype and its potential for genetic insight can be appreciated through the examples of Williams syndrome, Prader-Willi syndrome, and Angelman syndrome. The cognitive and behavioral characteristics of these disorders are distinctive. Williams syndrome is known for its association with remarkable conversational verbal abilities and excessive empathy, whereas Prader-Willi syndrome is known for temper tantrums and obsessive-compulsive features, and Angelman syndrome is associated with a constantly happy affect and hyperactivity. The genetic basis for each of these disorders is known, and the pathophysiology and genotype-phenotype correlations are beginning to provide insight into genes responsible for personality characteristics and behavioral abnormalities.

  12. Genetically modified pigs for medicine and agriculture.

    PubMed

    Prather, Randall S; Shen, Miaoda; Dai, Yifan

    2008-01-01

    The ability to genetically modify pigs has enabled scientists to create pigs that are beneficial to humans in ways that were previously unimaginable. Improvements in the methods to make genetic modifications have opened up the possibilities of introducing transgenes, knock-outs and knock-ins with precision. The benefits to medicine include the production of pharmaceuticals, the provision of organs for xenotransplantation into humans, and the development of models of human diseases. The benefits to agriculture include resistance to disease, altering the carcass composition such that it is healthier to consume, improving the pig's resistance to heat stress, and protecting the environment. Additional types of genetic modifications will likely provide animals with characteristics that will benefit humans in currently unimagined ways.

  13. A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene.

    PubMed Central

    Markowitz, S D; Myeroff, L; Cooper, M J; Traicoff, J; Kochera, M; Lutterbaugh, J; Swiriduk, M; Willson, J K

    1994-01-01

    We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation. Images PMID:8132740

  14. Distinct Transcript Isoforms of the Atypical Chemokine Receptor 1 (ACKR1) / Duffy Antigen Receptor for Chemokines (DARC) Gene Are Expressed in Lymphoblasts and Altered Isoform Levels Are Associated with Genetic Ancestry and the Duffy-Null Allele

    PubMed Central

    Davis, Melissa B.; Walens, Andrea; Hire, Rupali; Mumin, Kauthar; Brown, Andrea M.; Ford, DeJuana; Howerth, Elizabeth W.; Monteil, Michele

    2015-01-01

    The Atypical ChemoKine Receptor 1 (ACKR1) gene, better known as Duffy Antigen Receptor for Chemokines (DARC or Duffy), is responsible for the Duffy Blood Group and plays a major role in regulating the circulating homeostatic levels of pro-inflammatory chemokines. Previous studies have shown that one common variant, the Duffy Null (Fy-) allele that is specific to African Ancestry groups, completely removes expression of the gene on erythrocytes; however, these individuals retain endothelial expression. Additional alleles are associated with a myriad of clinical outcomes related to immune responses and inflammation. In addition to allele variants, there are two distinct transcript isoforms of DARC which are expressed from separate promoters, and very little is known about the distinct transcriptional regulation or the distinct functionality of these protein isoforms. Our objective was to determine if the African specific Fy- allele alters the expression pattern of DARC isoforms and therefore could potentially result in a unique signature of the gene products, commonly referred to as antigens. Our work is the first to establish that there is expression of DARC on lymphoblasts. Our data indicates that people of African ancestry have distinct relative levels of DARC isoforms expressed in these cells. We conclude that the expression of both isoforms in combination with alternate alleles yields multiple Duffy antigens in ancestry groups, depending upon the haplotypes across the gene. Importantly, we hypothesize that DARC isoform expression patterns will translate into ancestry-specific inflammatory responses that are correlated with the axis of pro-inflammatory chemokine levels and distinct isoform-specific interactions with these chemokines. Ultimately, this work will increase knowledge of biological mechanisms underlying disparate clinical outcomes of inflammatory-related diseases among ethnic and geographic ancestry groups. PMID:26473357

  15. Genetic Mapping

    MedlinePlus

    ... Fact Sheets Fact Sheets En Español: Mapeo Genético Genetic Mapping What is genetic mapping? How do researchers ... genetic map? What are genetic markers? What is genetic mapping? Among the main goals of the Human ...

  16. Genetic Counseling

    MedlinePlus

    ... Home > Pregnancy > Before or between pregnancies > Genetic counseling Genetic counseling E-mail to a friend Please fill ... a genetic counselor in your area. What is genetic counseling? Genetic counseling helps you understand how genes , ...

  17. Frequently Asked Questions about Genetic and Genomic Science

    MedlinePlus

    ... used on this page Frequently Asked Questions About Genetic and Genomic Science What are genetics and genomics? ... genetic and genomic technologies? Additional Resources What are genetics and genomics? Genetics is a term that refers ...

  18. Alterations of lead speciation by sulfate from addition of flue ...

    EPA Pesticide Factsheets

    This is the first study to evaluate the potential application of FGDG as an in situ Pb stabilizer in contaminated soils with two different compositions and to explain the underlying mechanisms. A smelter Pb contaminated soil (SM-soil), rich in ferrihydrite bound Pb (FH-Pb), cerussite and litharge with a total Pb content of 65,123 mg/kg and an organic matter rich orchard soil (BO-soil), rich in FH-Pb and humic acid bound Pb with a total Pb content of 1532 mg/kg were amended with 5% FGDG (w/w). We subjected the two soils to three leaching tests; toxicity characteristic leaching protocol (TCLP), synthetic precipitation leaching protocol (SPLP), kinetic batch leaching test (KBLT) and in-vitro bioaccessibility assay (IVBA) in order to evaluate the FGDG amendment on Pb stabilization. Solid residues of original and FGDG amended soil were analyzed using X-ray absorption spectroscopy (XAS) to identify changes in Pb speciation after each leaching test. The leachate Pb concentrations of FGDG amended soil were lowered compared to those of in non-amended soil. The linear combination fitting analysis of XAS confirmed the formation of anglesite and leadhillite in FGDG amended in soil. FGDG reduced the Pb desorption from ferrihydrite (FH), by forming FH-Pb-SO4 ternary complexes. FGDG decreased the Pb adsorption onto humic acid (HA) possibly due to the release of divalent cations such as Ca and Mg, which can compete with Pb to get adsorbed onto HA. The FGDG can successful

  19. Altered chromosome 6 in immortal human fibroblasts.

    PubMed

    Hubbard-Smith, K; Patsalis, P; Pardinas, J R; Jha, K K; Henderson, A S; Ozer, H L

    1992-05-01

    Human diploid fibroblasts have a limited life span in vitro, and spontaneous immortalization is an extremely rare event. We have used transformation of human diploid fibroblasts by an origin-defective simian virus 40 genome to develop series of genetically matched immortal cell lines to analyze immortalization. Comparison of a preimmortal transformant (SVtsA/HF-A) with its uncloned and cloned immortalized derivatives (AR5 and HAL) has failed to reveal any major alteration involving the simian virus 40 genome. Karyotypic analysis, however, demonstrated that all of the immortal cell lines in this series have alterations of chromosome 6 involving loss of the portion distal to 6q21. The karyotypic analysis was corroborated by DNA analyses. Southern analysis demonstrated that only one copy of three proto-oncogene loci (ros1, c-myb, and mas1) on 6q was retained in immortal cells. Polymerase chain reaction analysis of the microsatellite polymorphism at 6q22 (D6S87) showed loss of heterozygosity. In addition, elevated expression of c-myb (6q22-23) was observed. We hypothesize that the region at and/or distal to 6q21 plays a role in immortalization, consistent with the presence of a growth suppressor gene.

  20. Altered chromosome 6 in immortal human fibroblasts.

    PubMed Central

    Hubbard-Smith, K; Patsalis, P; Pardinas, J R; Jha, K K; Henderson, A S; Ozer, H L

    1992-01-01

    Human diploid fibroblasts have a limited life span in vitro, and spontaneous immortalization is an extremely rare event. We have used transformation of human diploid fibroblasts by an origin-defective simian virus 40 genome to develop series of genetically matched immortal cell lines to analyze immortalization. Comparison of a preimmortal transformant (SVtsA/HF-A) with its uncloned and cloned immortalized derivatives (AR5 and HAL) has failed to reveal any major alteration involving the simian virus 40 genome. Karyotypic analysis, however, demonstrated that all of the immortal cell lines in this series have alterations of chromosome 6 involving loss of the portion distal to 6q21. The karyotypic analysis was corroborated by DNA analyses. Southern analysis demonstrated that only one copy of three proto-oncogene loci (ros1, c-myb, and mas1) on 6q was retained in immortal cells. Polymerase chain reaction analysis of the microsatellite polymorphism at 6q22 (D6S87) showed loss of heterozygosity. In addition, elevated expression of c-myb (6q22-23) was observed. We hypothesize that the region at and/or distal to 6q21 plays a role in immortalization, consistent with the presence of a growth suppressor gene. Images PMID:1373811

  1. Targeting aggression in severe mental illness: The predictive role of genetic, epigenetic, and metabolomic markers.

    PubMed

    Manchia, Mirko; Fanos, Vassilios

    2017-04-02

    Human aggression is a complex and widespread social behavior that is overrepresented in individuals affected by severe mental illness (SMI), such as schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). A substantial proportion of the liability threshold for aggressive behavior is determined by genetic factors, and environmental moderators might precipitate the manifestation of this behavioral phenotype through modification of gene expression via the epigenetic machinery. These specific alterations in the genetic and epigenetic make-up of aggressive individuals might determine distinct biochemical signatures detectable through metabolomics. An additional pathophysiological component playing a role in aggressive behavior might be determined by alterations of gut microbiota. Here, we present a selective review of human data on genetic, epigenetic, and metabolomic markers of aggressive behavior in SMI, discussing also the available evidence on the role of microbiome alterations. Clinical implication of these evidences, as well as future perspectives, will be discussed.

  2. [Genetics and genetic counseling].

    PubMed

    Izzi, Claudia; Liut, Francesca; Dallera, Nadia; Mazza, Cinzia; Magistroni, Riccardo; Savoldi, Gianfranco; Scolari, Francesco

    2016-01-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic disease, characterized by progressive development of bilateral renal cysts. Two causative genes have been identified: PKD1 and PKD2. ADPKD phenotype is highly variable. Typically, ADPKD is an adult onset disease. However, occasionally, ADPKD manifests as very early onset disease. The phenotypic variability of ADPKD can be explained at three genetic levels: genic, allelic and gene modifier effects. Recent advances in molecular screening for PKD gene mutations and the introduction of the new next generation sequencing (NGS)- based genotyping approach have generated considerable improvement regarding the knowledge of genetic basis of ADPKD. The purpose of this article is to provide a comprehensive review of the genetics of ADPKD, focusing on new insights in genotype-phenotype correlation and exploring novel clinical approach to genetic testing. Evaluation of these new genetic information requires a multidisciplinary approach involving a nephrologist and a clinical geneticist.

  3. Genetic engineering compared to natural genetic variations.

    PubMed

    Arber, Werner

    2010-11-30

    By comparing strategies of genetic alterations introduced in genetic engineering with spontaneously occurring genetic variation, we have come to conclude that both processes depend on several distinct and specific molecular mechanisms. These mechanisms can be attributed, with regard to their evolutionary impact, to three different strategies of genetic variation. These are local nucleotide sequence changes, intragenomic rearrangement of DNA segments and the acquisition of a foreign DNA segment by horizontal gene transfer. Both the strategies followed in genetic engineering and the amounts of DNA sequences thereby involved are identical to, or at least very comparable with, those involved in natural genetic variation. Therefore, conjectural risks of genetic engineering must be of the same order as those for natural biological evolution and for conventional breeding methods. These risks are known to be quite low. There is no scientific reason to assume special long-term risks for GM crops. For future agricultural developments, a road map is designed that can be expected to lead, by a combination of genetic engineering and conventional plant breeding, to crops that can insure food security and eliminate malnutrition and hunger for the entire human population on our planet. Public-private partnerships should be formed with the mission to reach the set goals in the coming decades.

  4. Genetics Home Reference: steatocystoma multiplex

    MedlinePlus

    ... Genetic Changes Steatocystoma multiplex can be caused by mutations in the KRT17 gene. This gene provides instructions ... skin, nails, and other tissues. The KRT17 gene mutations that cause steatocystoma multiplex alter the structure of ...

  5. Genomic and transcriptomic alterations following hybridisation and genome doubling in trigenomic allohexaploid Brassica carinata × Brassica rapa.

    PubMed

    Xu, Y; Zhao, Q; Mei, S; Wang, J

    2012-09-01

    Allopolyploidisation is a prominent evolutionary force that involves two major events: interspecific hybridisation and genome doubling. Both events have important functional consequences in shaping the genomic architecture of the neo-allopolyploids. The respective effects of hybridisation and genome doubling upon genomic and transcriptomic changes in Brassica allopolyploids are unresolved. In this study, amplified fragment length polymorphism (AFLP), methylation-sensitive amplification polymorphism (MSAP) and cDNA-AFLP approaches were used to track genetic, epigenetic and transcriptional changes in both allohexaploid Brassica (ArArBcBcCcCc genome) and triploid hybrids (ArBcCc genome). Results from these groups were compared with each other and also to their parents Brassica carinata (BBCC genome) and Brassica rapa (AA genome). Rapid and dramatic genetic, DNA methylation and gene expression changes were detected in the triploid hybrids. During the shift from triploidy to allohexaploidy, some of the hybridisation-induced alterations underwent reversion. Additionally, novel genetic, epigenetic and transcriptional alterations were also detected. The proportions of A-genome-specific DNA methylation and gene expression alterations were significantly greater than those of BC-genome-specific alterations in the triploid hybrids. However, the two parental genomes were equally affected during the ploidy shift. Hemi-CCG methylation changes induced by hybridisation were recovered after genome doubling. Full-CG methylation changes were a more general process initiated in the hybrid and continued after genome doubling. These results indicate that genome doubling could ameliorate genomic and transcriptomic alterations induced by hybridisation and instigate additional alterations in trigenomic Brassica allohexaploids. Moreover, genome doubling also modified hybridisation-induced progenitor genome-biased alterations and epigenetic alteration characteristics.

  6. Lung cancer biology: a genetic and genomic perspective.

    PubMed

    Sánchez-Céspedes, M

    2009-05-01

    Lung cancer is the leading cause of death due to cancer in most western countries and, as tobacco consumption is not significantly decreasing worldwide, will remain so in the coming decades. Thus, in addition to preventing uptake and encouraging cessation of the smoking habit, it is important to invest in understanding the biology of this type of cancer. Of particular interest are the recent efforts directed towards characterising the entire set of gene alterations in lung cancer. The present review describes the catalogue of known genetic alterations in lung cancer, their biological role and their use in clinical management.

  7. Analysis of spatial heterogeneity in normal epithelium and preneoplastic alterations in mouse prostate tumor models

    PubMed Central

    Valkonen, Mira; Ruusuvuori, Pekka; Kartasalo, Kimmo; Nykter, Matti; Visakorpi, Tapio; Latonen, Leena

    2017-01-01

    Cancer involves histological changes in tissue, which is of primary importance in pathological diagnosis and research. Automated histological analysis requires ability to computationally separate pathological alterations from normal tissue with all its variables. On the other hand, understanding connections between genetic alterations and histological attributes requires development of enhanced analysis methods suitable also for small sample sizes. Here, we set out to develop computational methods for early detection and distinction of prostate cancer-related pathological alterations. We use analysis of features from HE stained histological images of normal mouse prostate epithelium, distinguishing the descriptors for variability between ventral, lateral, and dorsal lobes. In addition, we use two common prostate cancer models, Hi-Myc and Pten+/− mice, to build a feature-based machine learning model separating the early pathological lesions provoked by these genetic alterations. This work offers a set of computational methods for separation of early neoplastic lesions in the prostates of model mice, and provides proof-of-principle for linking specific tumor genotypes to quantitative histological characteristics. The results obtained show that separation between different spatial locations within the organ, as well as classification between histologies linked to different genetic backgrounds, can be performed with very high specificity and sensitivity. PMID:28317907

  8. Epigenetic Alterations in Alzheimer’s Disease

    PubMed Central

    Sanchez-Mut, Jose V.; Gräff, Johannes

    2015-01-01

    Alzheimer’s disease (AD) is the major cause of dementia in Western societies. It progresses asymptomatically during decades before being belatedly diagnosed when therapeutic strategies have become unviable. Although several genetic alterations have been associated with AD, the vast majority of AD cases do not show strong genetic underpinnings and are thus considered a consequence of non-genetic factors. Epigenetic mechanisms allow for the integration of long-lasting non-genetic inputs on specific genetic backgrounds, and recently, a growing number of epigenetic alterations in AD have been described. For instance, an accumulation of dysregulated epigenetic mechanisms in aging, the predominant risk factor of AD, might facilitate the onset of the disease. Likewise, mutations in several enzymes of the epigenetic machinery have been associated with neurodegenerative processes that are altered in AD such as impaired learning and memory formation. Genome-wide and locus-specific epigenetic alterations have also been reported, and several epigenetically dysregulated genes validated by independent groups. From these studies, a picture emerges of AD as being associated with DNA hypermethylation and histone deacetylation, suggesting a general repressed chromatin state and epigenetically reduced plasticity in AD. Here we review these recent findings and discuss several technical and methodological considerations that are imperative for their correct interpretation. We also pay particular focus on potential implementations and theoretical frameworks that we expect will help to better direct future studies aimed to unravel the epigenetic participation in AD. PMID:26734709

  9. New Genetics

    MedlinePlus

    ... Home > Science Education > The New Genetics The New Genetics Living Laboratories Classroom Poster Order a Free Copy ... Piece to a Century-Old Evolutionary Puzzle Computing Genetics Model Organisms RNA Interference The New Genetics is ...

  10. Genetic Disorders

    MedlinePlus

    ... Management Education & Events Advocacy For Patients About ACOG Genetic Disorders Home For Patients Search FAQs Genetic Disorders ... Spanish Genetic Disorders FAQ094, April 2014 PDF Format Genetic Disorders Pregnancy What are genes? What are chromosomes? ...

  11. Medical genetics

    SciTech Connect

    Nora, J.J.; Fraser, F.C.

    1989-01-01

    This book presents a discussion of medical genetics for the practitioner treating or counseling patients with genetic disease. It includes a discussion of the relationship of heredity and diseases, the chromosomal basis for heredity, gene frequencies, and genetics of development and maldevelopment. The authors also focus on teratology, somatic cell genetics, genetics and cancer, genetics of behavior.

  12. Biochemical And Genetic Modification Of Polysaccharides

    NASA Technical Reports Server (NTRS)

    Kern, Roger G.; Petersen, Gene R.; Richards, Gil F.

    1993-01-01

    Bacteriophages producing endopolysaccharase-type enzymes used to produce, isolate, and purify high yields of modified polysaccharides from polysaccharides produced by, and incorporated into capsules of, certain bacteria. Bacteriophages used in conversion of native polysaccharide materials into polymers of nearly uniform high molecular weight or, alternatively, into highly pure oligosaccharides. Also used in genetic selection of families of polysaccharides structurally related to native polysaccharide materials, but having altered properties. Resulting new polysaccharides and oligosaccharides prove useful in variety of products, including pharmaceutical chemicals, coating materials, biologically active carbohydrates, and drag-reducing additives for fluids.

  13. The etiology and molecular genetics of human pigmentation disorders

    PubMed Central

    Baxter, Laura L.; Pavan, William J.

    2012-01-01

    Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically normal human pigmentation encompasses a variety of skin and hair color as well as with punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while clinically abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions, often in different cell types. Thus unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, revealing a common cellular origin and/or common genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities is instructive for understanding normal pathways governing development and function of melanocytes. PMID:23799582

  14. Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis.

    PubMed

    Jafari, Abbas; Qanie, Diyako; Andersen, Thomas L; Zhang, Yuxi; Chen, Li; Postert, Benno; Parsons, Stuart; Ditzel, Nicholas; Khosla, Sundeep; Johansen, Harald Thidemann; Kjærsgaard-Andersen, Per; Delaisse, Jean-Marie; Abdallah, Basem M; Hesselson, Daniel; Solberg, Rigmor; Kassem, Moustapha

    2017-02-14

    Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB) differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis.

  15. Feline Genetics: Clinical Applications and Genetic Testing

    PubMed Central

    Lyons, Leslie A.

    2010-01-01

    DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately thirty-three genes contain fifty mutations that cause feline health problems or alterations in the cat’s appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab using a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat’s internal genome. PMID:21147473

  16. Feline genetics: clinical applications and genetic testing.

    PubMed

    Lyons, Leslie A

    2010-11-01

    DNA testing for domestic cat diseases and appearance traits is a rapidly growing asset for veterinary medicine. Approximately 33 genes contain 50 mutations that cause feline health problems or alterations in the cat's appearance. A variety of commercial laboratories can now perform cat genetic diagnostics, allowing both the veterinary clinician and the private owner to obtain DNA test results. DNA is easily obtained from a cat via a buccal swab with a standard cotton bud or cytological brush, allowing DNA samples to be easily sent to any laboratory in the world. The DNA test results identify carriers of the traits, predict the incidence of traits from breeding programs, and influence medical prognoses and treatments. An overall goal of identifying these genetic mutations is the correction of the defect via gene therapies and designer drug therapies. Thus, genetic testing is an effective preventative medicine and a potential ultimate cure. However, genetic diagnostic tests may still be novel for many veterinary practitioners and their application in the clinical setting needs to have the same scrutiny as any other diagnostic procedure. This article will review the genetic tests for the domestic cat, potential sources of error for genetic testing, and the pros and cons of DNA results in veterinary medicine. Highlighted are genetic tests specific to the individual cat, which are a part of the cat's internal genome.

  17. Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.

    PubMed

    Robinson, C L; Jouni, H; Kruisselbrink, T M; Austin, E E; Christensen, K D; Green, R C; Kullo, I J

    2016-02-01

    We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation.

  18. Genetics Home Reference: Meckel syndrome

    MedlinePlus

    ... MKS Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (3 links) Health Topic: Brain Malformations Health Topic: Kidney Cysts Health Topic: Neural Tube Defects Genetic and Rare Diseases Information Center (1 link) ...

  19. Genetics in Osteoarthritis

    PubMed Central

    Fernández-Moreno, Mercedes; Rego, Ignacio; Carreira-Garcia, Vanessa; Blanco, Francisco J

    2008-01-01

    Osteoarthritis is a degenerative articular disease with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. Despite the multifactorial nature of this pathology, from the 50’s it´s known that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidate genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this disease are not known, however, which seems clear is that expression levels of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthritis. PMID:19516961

  20. Genetic Architectures of Quantitative Variation in RNA Editing Pathways.

    PubMed

    Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj; Snyder, Elizabeth M; Raghupathy, Narayanan; Simecek, Petr; Svenson, Karen L; Dotu, Ivan; Chuang, Jeffrey H; Keller, Mark P; Attie, Alan D; Braun, Robert E; Churchill, Gary A

    2016-02-01

    RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing.

  1. Genetic interest assessment

    NASA Astrophysics Data System (ADS)

    Doughney, Erin

    Genetics is becoming increasingly integrated into peoples' lives. Different measures have been taken to try and better genetics education. This thesis examined undergraduate students at the University of North Texas not majoring in the life sciences interest in genetic concepts through the means of a Likert style survey. ANOVA analysis showed there was variation amongst the interest level in different genetic concepts. In addition age and lecture were also analyzed as contributing factors to students' interest. Both age and lecture were evaluated to see if they contributed to the interest of students in genetic concepts and neither showed statistical significance. The Genetic Interest Assessment (GIA) serves to help mediate the gap between genetic curriculum and students' interest.

  2. Mitochondrial genetics

    PubMed Central

    Chinnery, Patrick Francis; Hudson, Gavin

    2013-01-01

    Introduction In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. PMID:23704099

  3. Medical genetics

    SciTech Connect

    Jorde, L.B.; Carey, J.C.; White, R.L.

    1995-10-01

    This book on the subject of medical genetics is a textbook aimed at a very broad audience: principally, medical students, nursing students, graduate, and undergraduate students. The book is actually a primer of general genetics as applied to humans and provides a well-balanced introduction to the scientific and clinical basis of human genetics. The twelve chapters include: Introduction, Basic Cell Biology, Genetic Variation, Autosomal Dominant and Recessive Inheritance, Sex-linked and Mitochondrial Inheritance, Clinical Cytogenetics, Gene Mapping, Immunogenetics, Cancer Genetics, Multifactorial Inheritance and Common Disease, Genetic Screening, Genetic Diagnosis and Gene Therapy, and Clinical Genetics and Genetic Counseling.

  4. Genetic algorithms

    NASA Technical Reports Server (NTRS)

    Wang, Lui; Bayer, Steven E.

    1991-01-01

    Genetic algorithms are mathematical, highly parallel, adaptive search procedures (i.e., problem solving methods) based loosely on the processes of natural genetics and Darwinian survival of the fittest. Basic genetic algorithms concepts are introduced, genetic algorithm applications are introduced, and results are presented from a project to develop a software tool that will enable the widespread use of genetic algorithm technology.

  5. Genetic selection and conservation of genetic diversity*.

    PubMed

    Blackburn, H D

    2012-08-01

    For 100s of years, livestock producers have employed various types of selection to alter livestock populations. Current selection strategies are little different, except our technologies for selection have become more powerful. Genetic resources at the breed level have been in and out of favour over time. These resources are the raw materials used to manipulate populations, and therefore, they are critical to the past and future success of the livestock sector. With increasing ability to rapidly change genetic composition of livestock populations, the conservation of these genetic resources becomes more critical. Globally, awareness of the need to steward genetic resources has increased. A growing number of countries have embarked on large scale conservation efforts by using in situ, ex situ (gene banking), or both approaches. Gene banking efforts have substantially increased and data suggest that gene banks are successfully capturing genetic diversity for research or industry use. It is also noteworthy that both industry and the research community are utilizing gene bank holdings. As pressures grow to meet consumer demands and potential changes in production systems, the linkage between selection goals and genetic conservation will increase as a mechanism to facilitate continued livestock sector development.

  6. [Neurocutaneous syndrome with hair alterations].

    PubMed

    Camacho-Martínez, F

    1997-09-01

    There are multiple neurocutaneous syndromes that may show hair alterations such as the interglabellar peak or 'widow's peak', which is an alteration of the hair implantation, in addition to the genohypotrichosis, hypertrichosis and hair shaft dysplasias. In this chapter we will focus on the latter. Out of the unspecific hair shaft dysplasias the only ones showing neurological alterations are trichorrhexis invaginata, observed in the syndrome of Netherton. Among the specific dysplasias we would like to point out monilethrix, and very especially the moniliform hair syndrome, the trichorrhexis nodosa, the pili torti and trichotiodystrophy. The latter is actually a group of syndromes which associates a series of diverse symptoms that have in common hair brittleness, fertility problems and physical and mental retardation, and they constitute the basic syndrome know as 'BIDS syndrome.

  7. Genetics of pancreatitis: an update for clinicians and genetic counselors.

    PubMed

    Solomon, Sheila; Whitcomb, David C

    2012-04-01

    With novel genetic technologies available, there is a paradigm shift in the way that risk assessments, diagnoses,and therapies for genetic susceptibility syndromes are addressed. Hereditary pancreatitis is among these conditions, for which genetic counseling and next generation sequencing, help families better understand, cope with and live healthier lives. Identifying a genetic etiology to a condition formally believed to be solely environmentally induced can alter the path for treatment for many patients. This finding introduces the concept of gene-environment interactions in human disease and the relationship between genetic predisposition and exposure risk in disease development. The genetic counseling process is complex with medical explanations, psychosocial issues relating to coping with diagnosis, potential future health problems, recurrence risks and family planning. These sometimes difficult conversations can be facilitated by a genetic counselor as a member of the multidisciplinary team. This chapter addresses the intricate medical and psychosocial issues that can arise in the setting of treating patients with hereditary pancreatitis.

  8. Direct and indirect genetic and fine-scale location effects on breeding date in song sparrows.

    PubMed

    Germain, Ryan R; Wolak, Matthew E; Arcese, Peter; Losdat, Sylvain; Reid, Jane M

    2016-11-01

    depression. All three spatial animal models estimated small location variance in breeding date, but because relatedness and breeding location were virtually uncorrelated, modelling location variance did not alter the estimated additive genetic variances. Our results show that sex-specific additive genetic effects on breeding date can be strongly positively correlated, which would affect any predicted rates of microevolutionary change in response to sexually antagonistic or congruent selection. Further, we show that inbreeding effects on breeding date can also be sex specific and that genetic effects can exceed phenotypic variation stemming from fine-scale location-based variation within a wild population.

  9. 76 FR 60447 - Florigene Pty., Ltd.; Determination of Nonregulated Status for Altered Color Roses

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-29

    ..., ``Introduction of Organisms and Products Altered or Produced Through Genetic Engineering Which Are Plant Pests or... produced through genetic engineering that are plant pests or that there is reason to believe are...

  10. Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis

    PubMed Central

    Buysschaert, Ian; Schmidt, Thomas; Roncal, Carmen; Carmeliet, Peter; Lambrechts, Diether

    2008-01-01

    Angiogenesis is controlled by a balance between pro- and anti-angiogenic factors. Studies in mice and human beings have shown that this balance, as well as the general sensitivity of the endothelium to these factors, is genetically pre-determined. In an effort to dissect this genetic basis, different types of genetic variability have emerged: mutations and translocations in angiogenic factors have been linked to several vascular malformations and haemangiomas, whereas SNPs have been associated with complex genetic disorders, such as cancer, neurodegeneration and diabetes. In addition, copy number alterations of angiogenic factors have been reported in several tumours. More recently, epigenetic changes caused by aberrant DNA methylation or histone acetylation of anti-angiogenic molecules have been shown to determine angiogenesis as well. Initial studies also revealed a crucial role for microRNAs in stimulating or reducing angiogenesis. So far, most of these genetic studies have focused on tumour angiogenesis, but future research is expected to improve our understanding of how genetic variants determine angiogenesis in other diseases. Importantly, these genetic insights might also be of important clinical relevance for the use of anti-angiogenic strategies in cancer or macular degeneration. PMID:19210754

  11. Clopidogrel and genetic testing: is it necessary for everyone?

    PubMed

    Goswami, Sweta; Cheng-Lai, Angela; Nawarskas, James

    2012-01-01

    Clopidogrel is a widely used antiplatelet agent to treat and prevent a variety of atherothrombotic diseases. More than a decade after its initial Food and Drug Administration approval, studies have emerged raising concerns regarding its possible reduced efficacy in patients who have impaired conversion of clopidogrel to its active metabolite (ie, poor metabolizers). Research has implicated genetic variations in the CYP2C19 isozyme as at least partly responsible for the variable antiplatelet response seen with clopidogrel. Studies have shown that patients possessing genetic variants of the CYP2C19 isozyme may be at increased risk of adverse cardiovascular events due to impaired clopidogrel efficacy, although this has not been definitively demonstrated. The Food and Drug Administration has issued a boxed warning regarding this concern. However, specific recommendations on genetic testing and alternative therapeutic strategies are not currently available. Genetic testing is commercially available to test patients for variability in the CYP2C19 isozyme, but altering antiplatelet therapy based on the results of this testing has not been adequately studied, and it is therefore not clear how to adjust therapy based on the results of this genetic testing. In addition, there are many other factors that may contribute to the variability in antiplatelet effect seen with clopidogrel besides CYP2C19 genetic polymorphisms. Ongoing trials dealing with adjusting antiplatelet therapy based on genetic testing will hopefully provide more useful information on how to appropriately integrate pharmacogenomics with the care of patients with atherothrombotic disease.

  12. The genetic structure of a relict population of wood frogs

    USGS Publications Warehouse

    Scherer, Rick; Muths, Erin; Noon, Barry; Oyler-McCance, Sara

    2012-01-01

    Habitat fragmentation and the associated reduction in connectivity between habitat patches are commonly cited causes of genetic differentiation and reduced genetic variation in animal populations. We used eight microsatellite markers to investigate genetic structure and levels of genetic diversity in a relict population of wood frogs (Lithobates sylvatica) in Rocky Mountain National Park, Colorado, where recent disturbances have altered hydrologic processes and fragmented amphibian habitat. We also estimated migration rates among subpopulations, tested for a pattern of isolation-by-distance, and looked for evidence of a recent population bottleneck. The results from the clustering algorithm in Program STRUCTURE indicated the population is partitioned into two genetic clusters (subpopulations), and this result was further supported by factorial component analysis. In addition, an estimate of FST (FST = 0.0675, P value \\0.0001) supported the genetic differentiation of the two clusters. Estimates of migration rates among the two subpopulations were low, as were estimates of genetic variability. Conservation of the population of wood frogs may be improved by increasing the spatial distribution of the population and improving gene flow between the subpopulations. Construction or restoration of wetlands in the landscape between the clusters has the potential to address each of these objectives.

  13. Genetics Home Reference: histidinemia

    MedlinePlus

    ... condition characterized by elevated blood levels of the amino acid histidine, a building block of most proteins. Histidinemia ... Additional Information & Resources MedlinePlus (2 links) Health Topic: Amino Acid Metabolism Disorders Health Topic: Newborn Screening Genetic and ...

  14. Genetics Home Reference: hyperlysinemia

    MedlinePlus

    ... condition characterized by elevated blood levels of the amino acid lysine, a building block of most proteins. Hyperlysinemia ... Additional Information & Resources MedlinePlus (2 links) Health Topic: Amino Acid Metabolism Disorders Health Topic: Newborn Screening Genetic and ...

  15. Genetics Home Reference: phenylketonuria

    MedlinePlus

    ... Information & Resources MedlinePlus (4 links) Encyclopedia: Phenylketonuria Encyclopedia: Serum Phenylalanine Screening Health Topic: Newborn Screening Health Topic: Phenylketonuria Genetic and Rare Diseases Information Center (1 link) Phenylketonuria Additional NIH Resources ( ...

  16. Genetics of Alzheimer's Disease

    PubMed Central

    Ridge, Perry G.; Ebbert, Mark T. W.; Kauwe, John S. K.

    2013-01-01

    Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease. PMID:23984328

  17. Genetics, society, and decisions

    SciTech Connect

    Kowles, R.V.

    1985-01-01

    This book provides a conceptual understanding of the biology of genes and also gives current events and controversies in the field. Basic transmission genetics, molecular genetics, and population genetics are covered, with additional discussions relating to such topics as agriculture, aging, forensic science, genetic counseling, gene splicing, and recombinant DNA. Low level radiation and its effects, drugs and heredity, IQ, heredity and racial variation, and creationism versus evolution are also described. ''Billboard'' style diagrams visually explain important concepts. Boldfaced key terms are defined within the text and in a comprehensive glossary. Selected readings, discussion questions and problems, and excellent chapter summaries further aid study.

  18. Produced water exposure alters bacterial response to biocides.

    PubMed

    Vikram, Amit; Lipus, Daniel; Bibby, Kyle

    2014-11-04

    Microbial activity during the holding and reuse of wastewater from hydraulic fracturing operations, termed produced water, may lead to issues with corrosion, sulfide release, and fouling. Biocides are applied to control biological activity, often with limited efficacy, which is typically attributed to chemical interactions with the produced water. However, it is unknown whether there is a biologically driven mechanism to biocide tolerance in produced water. Here, we demonstrate that produced water exposure results in an enhanced tolerance against the typically used biocide glutaraldehyde and increased susceptibility to the oxidative biocide hypochlorite in a native and a model bacteria and that this altered resistance is due to the salinity of the produced water. In addition, we elucidate the genetic response of the model organism Pseudomonas fluorescens to produced water exposure to provide a mechanistic interpretation of the altered biocide resistance. The RNA-seq data demonstrated the induction of genes involved in osmotic stress, energy production and conversion, membrane integrity, and protein transport following produced water exposure, which facilitates bacterial survival and alters biocide tolerance. Efforts to fundamentally understand biocide resistance mechanisms, which enable the optimization of biocide application, hold significant implications for greening of the fracturing process through encouraging produced water recycling. Specifically, these results suggest the necessity of optimizing biocide application at the level of individual shale plays, rather than historical experience, based upon produced water characteristics and salinity.

  19. Alterations of Phosphodiesterases in Adrenocortical Tumors

    PubMed Central

    Hannah-Shmouni, Fady; Faucz, Fabio R.; Stratakis, Constantine A.

    2016-01-01

    Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, primarily, their action on cAMP levels, but other actions might be possible. In this report, we review what is known to date about PDE11A and PDE8B and their involvement in the predisposition to ACTs. PMID:27625633

  20. Species interactions differ in their genetic robustness

    DOE PAGES

    Chubiz, Lon M.; Granger, Brian R.; Segre, Daniel; ...

    2015-04-14

    Conflict and cooperation between bacterial species drive the composition and function of microbial communities. Stability of these emergent properties will be influenced by the degree to which species' interactions are robust to genetic perturbations. We use genome-scale metabolic modeling to computationally analyze the impact of genetic changes when Escherichia coli and Salmonella enterica compete, or cooperate. We systematically knocked out in silico each reaction in the metabolic network of E. coli to construct all 2583 mutant stoichiometric models. Then, using a recently developed multi-scale computational framework, we simulated the growth of each mutant E. coli in the presence of S.more » enterica. The type of interaction between species was set by modulating the initial metabolites present in the environment. We found that the community was most robust to genetic perturbations when the organisms were cooperating. Species ratios were more stable in the cooperative community, and community biomass had equal variance in the two contexts. Additionally, the number of mutations that have a substantial effect is lower when the species cooperate than when they are competing. In contrast, when mutations were added to the S. enterica network the system was more robust when the bacteria were competing. These results highlight the utility of connecting metabolic mechanisms and studies of ecological stability. Cooperation and conflict alter the connection between genetic changes and properties that emerge at higher levels of biological organization.« less

  1. 14 CFR 43.15 - Additional performance rules for inspections.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... TRANSPORTATION AIRCRAFT MAINTENANCE, PREVENTIVE MAINTENANCE, REBUILDING, AND ALTERATION § 43.15 Additional... inspect the following systems in accordance with the maintenance manual or Instructions for...

  2. 14 CFR 43.15 - Additional performance rules for inspections.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... TRANSPORTATION AIRCRAFT MAINTENANCE, PREVENTIVE MAINTENANCE, REBUILDING, AND ALTERATION § 43.15 Additional... inspect the following systems in accordance with the maintenance manual or Instructions for...

  3. 14 CFR 43.15 - Additional performance rules for inspections.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... TRANSPORTATION AIRCRAFT MAINTENANCE, PREVENTIVE MAINTENANCE, REBUILDING, AND ALTERATION § 43.15 Additional... inspect the following systems in accordance with the maintenance manual or Instructions for...

  4. 14 CFR 43.15 - Additional performance rules for inspections.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... TRANSPORTATION AIRCRAFT MAINTENANCE, PREVENTIVE MAINTENANCE, REBUILDING, AND ALTERATION § 43.15 Additional... inspect the following systems in accordance with the maintenance manual or Instructions for...

  5. 14 CFR 43.15 - Additional performance rules for inspections.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... TRANSPORTATION AIRCRAFT MAINTENANCE, PREVENTIVE MAINTENANCE, REBUILDING, AND ALTERATION § 43.15 Additional... inspect the following systems in accordance with the maintenance manual or Instructions for...

  6. REGION-WIDE GENETIC STRUCTURE OF THE CENTRAL STONEROLLER (CAMPOSTOMA ANOMALUM) AND THE RELATIONSHIP OF GENETIC DIVERSITY TO ENVIRONMENTAL QUALITY

    EPA Science Inventory

    Anthropogenic stressors that reduce population size, alter migration corridors or modify mutational and selective forces on populations are expected to leave a lasting genetic footprint on the distribution of intraspecific genetic variation. Thus, the pattern of intraspecific gen...

  7. Translocation t(8;14)(q24;q11) with concurrent PTEN alterations and deletions of STIL/TAL1 and CDKN2A/B in a pediatric case of acute T-lymphoblastic leukemia: A genetic profile associated with adverse prognosis.

    PubMed

    Skalska-Sadowska, Jolanta; Dawidowska, Małgorzata; Szarzyńska-Zawadzka, Bronisława; Jarmuż-Szymczak, Małgorzata; Czerwińska-Rybak, Joanna; Machowska, Ludomiła; Derwich, Katarzyna

    2017-04-01

    We report a pediatric case of acute T-lymphoblastic leukemia (T-ALL) with NOTCH1(wt) , FBXW7(wt) , STIL/TAL1, and PTEN (exons 2, 3, 4, 5) monoallelic deletions, biallelic CDKN2A/B deletion, and a minor t(8;14)(q24;q11)-positive subclone. Undetectable by a flow cytometric minimal residual disease assay, the t(8;14)(q24;q11) subclone expanded as detected by fluorescence in situ hybridization from 5% at diagnosis to 26% before consolidation and 100% at relapse bearing a monoallelic deletion (exons 2, 3) with a new frameshift mutation of PTEN and the same set of remaining molecular alterations. This case documents an unfavorable prognostic potential of a co-occurrence of this set of molecular genetic events and addresses risk stratification in T-ALL.

  8. Genetic variant rs3750625 in the 3'UTR of ADRA2A affects stress-dependent acute pain severity after trauma and alters a microRNA-34a regulatory site.

    PubMed

    Linnstaedt, Sarah D; Walker, Margaret G; Riker, Kyle D; Nyland, Jennifer E; Hu, JunMei; Rossi, Catherine; Swor, Robert A; Jones, Jeffrey S; Diatchenko, Luda; Bortsov, Andrey V; Peak, David A; McLean, Samuel A

    2017-02-01

    α2A adrenergic receptor (α2A-AR) activation has been shown in animal models to play an important role in regulating the balance of acute pain inhibition vs facilitation after both physical and psychological stress. To our knowledge, the influence of genetic variants in the gene encoding α2A-AR, ADRA2A, on acute pain outcomes in humans experiencing traumatic stress has not been assessed. In this study, we tested whether a genetic variant in the 3'UTR of ADRA2A, rs3750625, is associated with acute musculoskeletal pain (MSP) severity following motor vehicle collision (MVC, n = 948) and sexual assault (n = 84), and whether this influence was affected by stress severity. We evaluated rs3750625 because it is located in the seed binding region of miR-34a, a microRNA (miRNA) known to regulate pain and stress responses. In both cohorts, the minor allele at rs3750625 was associated with increased musculoskeletal pain in distressed individuals (stress*rs3750625 P = 0.043 for MVC cohort and P = 0.007 for sexual assault cohort). We further found that (1) miR-34a binds the 3'UTR of ADRA2A, (2) the amount of repression is greater when the minor (risk) allele is present, (3) miR-34a in the IMR-32 adrenergic neuroblastoma cell line affects ADRA2A expression, (4) miR-34a and ADRA2A are expressed in tissues known to play a role in pain and stress, (5) following forced swim stress exposure, rat peripheral nerve tissue expression changes are consistent with miR-34a regulation of ADRA2A. Together, these results suggest that ADRA2A rs3750625 contributes to poststress musculoskeletal pain severity by modulating miR-34a regulation.

  9. Monitoring cytosolic and ER Zn2+ in stimulated breast cancer cells using genetically encoded FRET sensors† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c5mt00257e Click here for additional data file.

    PubMed Central

    Hessels, Anne M.; Taylor, Kathryn M.

    2016-01-01

    The Zn2+-specific ion channel ZIP7 has been implicated to play an important role in releasing Zn2+ from the ER. External stimulation of breast cancer cells has been proposed to induce phosphorylation of ZIP7 by CK2α, resulting in ZIP7-mediated Zn2+ release from the ER into the cytosol. Here, we examined whether changes in cytosolic and ER Zn2+ concentrations can be detected upon such external stimuli. Two previously developed FRET sensors for Zn2+, eZinCh-2 (K d = 1 nM at pH 7.1) and eCALWY-4 (K d = 0.63 nM at pH 7.1), were expressed in both the cytosol and the ER of wild-type MCF-7 and TamR cells. Treatment of MCF-7 and TamR cells with external Zn2+ and pyrithione, one of the previously used triggers, resulted in an immediate increase in free Zn2+ in both cytosol and ER, suggesting that Zn2+ was directly transferred across the cellular membranes by pyrithione. Cells treated with a second trigger, EGF/ionomycin, showed no changes in intracellular Zn2+ levels, neither in multicolor imaging experiments that allowed simultaneous imaging of cytosolic and ER Zn2+, nor in experiments in which cytosolic and ER Zn2+ were monitored separately. In contrast to previous work using small-molecule fluorescent dyes, these results indicate that EGF–ionomycin treatment does not result in significant changes in cytosolic Zn2+ levels as a result from Zn2+ release from the ER. These results underline the importance of using genetically encoded fluorescent sensors to complement and verify intracellular imaging experiments with synthetic fluorescent Zn2+ dyes. PMID:26739447

  10. Interactions of chemical carcinogens and genetic variation in hepatocellular carcinoma

    PubMed Central

    Zhang, Yu-Jing

    2010-01-01

    In the etiology of hepatocellular carcinoma (HCC), in addition to hepatitis B virus and hepatitis C virus infections, chemical carcinogens also play important roles. For example, aflatoxin B1 (AFB1) epoxide reacts with guanine in DNA and can lead to genetic changes. In HCC, the tumor suppressor gene p53 codon 249 mutation is associated with AFB1 exposure and mutations in the K-ras oncogene are related to vinyl chloride exposure. Numerous genetic alterations accumulate during the process of hepatocarcinogenesis. Chemical carcinogen DNA-adduct formation is the basis for these genetic changes and also a molecular marker which reflects exposure level and biological effects. Metabolism of chemical carcinogens, including their activation and detoxification, also plays a key role in chemical hepatocarcinogenesis. Cytochrome p450 enzymes, N-acetyltransferases and glutathione S-transferases are involved in activating and detoxifying chemical carcinogens. These enzymes are polymorphic and genetic variation influences biological response to chemical carcinogens. This genetic variation has been postulated to influence the variability in risk for HCC observed both within and across populations. Ongoing studies seek to fully understand the mechanisms by which genetic variation in response to chemical carcinogens impacts on HCC risk. PMID:21160980

  11. Nitrogen as a friendly addition to steel

    SciTech Connect

    Rawers, J.C.

    2006-01-01

    Interstitial alloying with nitrogen or carbon is a common means of enhancing properties of iron-based alloys. Interstitial nitrogen addition to fcc-phase Fe-Cr-Mn/Ni alloys results in improved mechanical properties, whereas addition of carbon can result in the formation of unwanted carbides. Carbon addition to low alloy, bcc-phase iron alloys significantly improves strength through the formation of carbides, whereas addition of nitrogen in bcc-phase iron alloys can result in porous casting and reduced mechanical properties. This study will show that alloying iron-based alloys with both nitrogen and carbon can produce positive results. Nitrogen addition to Fe-C and Fe-Cr-C alloys, and both nitrogen and nitrogen-carbon additions to Fe-Cr-Mn/Ni alloys altered the microstructure, improved mechanical properties, increased hardness, and reduced wear by stabilizing the fcc-phase and altering (possibly eliminating) precipitate formation.

  12. Parkinson’s Disease in Saudi Patients: A Genetic Study

    PubMed Central

    Al-Mubarak, Bashayer R.; Bohlega, Saeed A.; Alkhairallah, Thamer S.; Magrashi, Amna I.; AlTurki, Maha I.; Khalil, Dania S.; AlAbdulaziz, Basma S.; Abou Al-Shaar, Hussam; Mustafa, Abeer E.; Alyemni, Eman A.; Alsaffar, Bashayer A.; Tahir, Asma I.; Al Tassan, Nada A.

    2015-01-01

    Parkinson’s disease (PD) is one of the major causes of parkinsonism syndrome. Its characteristic motor symptoms are attributable to dopaminergic neurons loss in the midbrain. Genetic advances have highlighted underlying molecular mechanisms and provided clues to potential therapies. However, most of the studies focusing on the genetic component of PD have been performed on American, European and Asian populations, whereas Arab populations (excluding North African Arabs), particularly Saudis remain to be explored. Here we investigated the genetic causes of PD in Saudis by recruiting 98 PD-cases (sporadic and familial) and screening them for potential pathogenic mutations in PD-established genes; SNCA, PARKIN, PINK1, PARK7/DJ1, LRRK2 and other PD-associated genes using direct sequencing. To our surprise, the screening revealed only three pathogenic point mutations; two in PINK1 and one in PARKIN. In addition to mutational analysis, CNV and cDNA analysis was performed on a subset of patients. Exon/intron dosage alterations in PARKIN were detected and confirmed in 2 cases. Our study suggests that mutations in the ORF of the screened genes are not a common cause of PD in Saudi population; however, these findings by no means exclude the possibility that other genetic events such as gene expression/dosage alteration may be more common nor does it eliminate the possibility of the involvement of novel genes. PMID:26274610

  13. Amazing Altered Books

    ERIC Educational Resources Information Center

    Kieling, Linda W.

    2006-01-01

    Linda Kieling, an art teacher at Rosemont Ridge Middle school in West Linn, Oregon, describes an altered book art project she introduced to her students. Alteration of books is a form of recycling that started in the eleventh century when Italian monks recycled old manuscripts written on vellum by scraping off the ink and adding new text and…

  14. 77 FR 42693 - Monsanto Company and KWS SAAT AG; Determination of Nonregulated Status of Sugar Beet Genetically...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-20

    ... 340, ``Introduction of Organisms and Products Altered or Produced Through Genetic Engineering Which... products altered or produced through genetic engineering that are plant pests or that there is reason...

  15. Genetic engineering of rotaviruses by reverse genetics.

    PubMed

    Komoto, Satoshi; Taniguchi, Koki

    2013-07-01

    The rotavirus genome is composed of 11 gene segments of dsRNA. A recent breakthrough in the field of rotaviruses is the development of a reverse genetics system for generating recombinant rotaviruses possessing a gene segment derived from cloned cDNA. Although this approach is a helper virus-driven system that is technically limited and gives low levels of recombinant viruses, it allows alteration of the rotavirus genome, thus contributing to our understanding of these medically important viruses. So far, this approach has successfully been applied to three of the 11 viral segments in our laboratory and others, and the efficiency of recovery of recombinant viruses has been improved. However, we are still waiting for the development of a helper virus-free reverse genetics system for generating an infectious rotavirus entirely from cDNAs, as has been achieved for other members of the Reoviridae family.

  16. Judaism, genetic screening and genetic therapy.

    PubMed

    Rosner, F

    1998-01-01

    Genetic screening, gene therapy and other applications of genetic engineering are permissible in Judaism when used for the treatment, cure, or prevention of disease. Such genetic manipulation is not considered to be a violation of God's natural law, but a legitimate implementation of the biblical mandate to heal. If Tay-Sachs disease, diabetes, hemophilia, cystic fibrosis, Huntington's disease or other genetic diseases can be cured or prevented by "gene surgery," then it is certainly permitted in Jewish law. Genetic premarital screening is encouraged in Judaism for the purpose of discouraging at-risk marriages for a fatal illness such as Tay-Sachs disease. Neonatal screening for treatable conditions such as phenylketonuria is certainly desirable and perhaps required in Jewish law. Preimplantation screening and the implantation of only "healthy" zygotes into the mother's womb to prevent the birth of an affected child are probably sanctioned in Jewish law. Whether or not these assisted reproduction techniques may be used to choose the sex of one's offspring, to prevent the birth of a child with a sex-linked disease such as hemophilia, has not yet been ruled on by modern rabbinic decisions. Prenatal screening with the specific intent of aborting an affected fetus is not allowed according to most rabbinic authorities, although a minority view permits it "for great need." Not to have children if both parents are carriers of genetic diseases such as Tay-Sachs is not a Jewish option. Preimplantation screening is preferable. All screening test results must remain confidential. Judaism does not permit the alteration or manipulation of physical traits and characteristics such as height, eye and hair color, facial features and the like, when such change provides no useful benefit to mankind. On the other hand, it is permissible to clone organisms and microorganisms to facilitate the production of insulin, growth hormone, and other agents intended to benefit mankind and to

  17. Genetic counseling

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000510.htm Genetic counseling To use the sharing features on this ... cystic fibrosis or Down syndrome. Who May Want Genetic Counseling? It is up to you whether or ...

  18. Genetic Disorders

    MedlinePlus

    ... This can cause a medical condition called a genetic disorder. You can inherit a gene mutation from ... during your lifetime. There are three types of genetic disorders: Single-gene disorders, where a mutation affects ...

  19. Genetic modification and genetic determinism.

    PubMed

    Resnik, David B; Vorhaus, Daniel B

    2006-06-26

    In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions.

  20. Genetic modification and genetic determinism

    PubMed Central

    Resnik, David B; Vorhaus, Daniel B

    2006-01-01

    In this article we examine four objections to the genetic modification of human beings: the freedom argument, the giftedness argument, the authenticity argument, and the uniqueness argument. We then demonstrate that each of these arguments against genetic modification assumes a strong version of genetic determinism. Since these strong deterministic assumptions are false, the arguments against genetic modification, which assume and depend upon these assumptions, are therefore unsound. Serious discussion of the morality of genetic modification, and the development of sound science policy, should be driven by arguments that address the actual consequences of genetic modification for individuals and society, not by ones propped up by false or misleading biological assumptions. PMID:16800884

  1. Imaging Genetics

    ERIC Educational Resources Information Center

    Munoz, Karen E.; Hyde, Luke W.; Hariri, Ahmad R.

    2009-01-01

    Imaging genetics is an experimental strategy that integrates molecular genetics and neuroimaging technology to examine biological mechanisms that mediate differences in behavior and the risks for psychiatric disorder. The basic principles in imaging genetics and the development of the field are discussed.

  2. Genetics and antisocial behavior.

    PubMed

    Joseph, Jay

    2003-01-01

    This commentary article reviews a recent meta-analysis of genetic influences on antisocial behavior by Rhee and Waldman (2002). The authors combined the results of 51 twin and adoption studies and concluded that antisocial behavior has an important genetic component. However, twin and adoption studies contain several methodological flaws and are subject to the confounding influence of environmental factors. Therefore, Rhee and Waldman's conclusions in favor of genetic influences are not supported by the evidence. Two additional topics are Rhee and Waldman's incorrect description of the heritability concept and their failure to discuss several German criminal twin studies published during the Nazi era.

  3. Inactivation of the Carney complex gene 1 (PRKAR1A) alters spatiotemporal regulation of cAMP and cAMP-dependent protein kinase: a study using genetically encoded FRET-based reporters.

    PubMed

    Cazabat, Laure; Ragazzon, Bruno; Varin, Audrey; Potier-Cartereau, Marie; Vandier, Christophe; Vezzosi, Delphine; Risk-Rabin, Marthe; Guellich, Aziz; Schittl, Julia; Lechêne, Patrick; Richter, Wito; Nikolaev, Viacheslav O; Zhang, Jin; Bertherat, Jérôme; Vandecasteele, Grégoire

    2014-03-01

    Carney complex (CNC) is a hereditary disease associating cardiac myxoma, spotty skin pigmentation and endocrine overactivity. CNC is caused by inactivating mutations in the PRKAR1A gene encoding PKA type I alpha regulatory subunit (RIα). Although PKA activity is enhanced in CNC, the mechanisms linking PKA dysregulation to endocrine tumorigenesis are poorly understood. In this study, we used Förster resonance energy transfer (FRET)-based sensors for cAMP and PKA activity to define the role of RIα in the spatiotemporal organization of the cAMP/PKA pathway. RIα knockdown in HEK293 cells increased basal as well as forskolin or prostaglandin E1 (PGE1)-stimulated total cellular PKA activity as reported by western blots of endogenous PKA targets and the FRET-based global PKA activity reporter, AKAR3. Using variants of AKAR3 targeted to subcellular compartments, we identified similar increases in the response to PGE1 in the cytoplasm and at the outer mitochondrial membrane. In contrast, at the plasma membrane, the response to PGE1 was decreased along with an increase in basal FRET ratio. These results were confirmed by western blot analysis of basal and PGE1-induced phosphorylation of membrane-associated vasodilator-stimulated phosphoprotein. Similar differences were observed between the cytoplasm and the plasma membrane in human adrenal cells carrying a RIα inactivating mutation. RIα inactivation also increased cAMP in the cytoplasm, at the outer mitochondrial membrane and at the plasma membrane, as reported by targeted versions of the cAMP indicator Epac1-camps. These results show that RIα inactivation leads to multiple, compartment-specific alterations of the cAMP/PKA pathway revealing new aspects of signaling dysregulation in tumorigenesis.

  4. When three traits make a line: evolution of phenotypic plasticity and genetic assimilation through linear reaction norms in stochastic environments.

    PubMed

    Ergon, T; Ergon, R

    2017-03-01

    Genetic assimilation emerges from selection on phenotypic plasticity. Yet, commonly used quantitative genetics models of linear reaction norms considering intercept and slope as traits do not mimic the full process of genetic assimilation. We argue that intercept-slope reaction norm models are insufficient representations of genetic effects on linear reaction norms and that considering reaction norm intercept as a trait is unfortunate because the definition of this trait relates to a specific environmental value (zero) and confounds genetic effects on reaction norm elevation with genetic effects on environmental perception. Instead, we suggest a model with three traits representing genetic effects that, respectively, (i) are independent of the environment, (ii) alter the sensitivity of the phenotype to the environment and (iii) determine how the organism perceives the environment. The model predicts that, given sufficient additive genetic variation in environmental perception, the environmental value at which reaction norms tend to cross will respond rapidly to selection after an abrupt environmental change, and eventually becomes equal to the new mean environment. This readjustment of the zone of canalization becomes completed without changes in genetic correlations, genetic drift or imposing any fitness costs of maintaining plasticity. The asymptotic evolutionary outcome of this three-trait linear reaction norm generally entails a lower degree of phenotypic plasticity than the two-trait model, and maximum expected fitness does not occur at the mean trait values in the population.

  5. [Epigenetic alterations in cervical cancer progression].

    PubMed

    Ríos-Romero, Magdalena; Soto-Valladares, Ana Guadalupe; Piña-Sánchez, Patricia

    2015-01-01

    Despite the use of the screening test, such as Papanicolaou, and the detection of human papillomavirus (HPV), cervical cancer remains as a public health problem in México and it is the second leading cause of death for malignant neoplasias among women. High-risk HPV infection is the main risk factor for the development of premalignant lesions and cervical cancer; however, HPV infection is not the only factor; there are various genetic and epigenetic alterations required for the development of neoplasias; some of them have been described and even in some cases they have been suggested as biomarkers for prognosis. However, in contrast with other cancer types, such as breast cancer, in cervical cancer the use of biomarkers has not been established for clinical applications. Unlike genetic alterations, epigenetic alterations are potentially reversible; in this sense, their characterization is important, since they have not only a potential use as biomarkers, but they also could represent new therapeutic targets for treatment of cervical cancer. This review describes some of the more common epigenetic alterations in cervical cancer and its potential use in routine clinical practice.

  6. A Glycine max homolog of NON-RACE SPECIFIC DISEASE RESISTANCE 1 (NDR1) alters defense gene expression while functioning during a resistance response to different root pathogens in different genetic backgrounds.

    PubMed

    McNeece, Brant T; Pant, Shankar R; Sharma, Keshav; Niruala, Prakash; Lawrence, Gary W; Klink, Vincent P

    2017-05-01

    A Glycine max homolog of the Arabidopsis thaliana NON-RACE SPECIFIC DISEASE RESISTANCE 1 (NDR1) coiled-coil nucleotide binding leucine rich repeat (CC-NB-LRR) defense signaling gene (Gm-NDR1-1) is expressed in root cells undergoing a defense response to the root pathogenic nematode, Heterodera glycines. Gm-NDR1-1 overexpression in the H. glycines-susceptible genotype G. max[Williams 82/PI 518671] impairs parasitism. In contrast, Gm-NDR1-1 RNA interference (RNAi) in the H. glycines-resistant genotype G. max[Peking/PI 548402] facilitates parasitism. The broad effectiveness of Gm-NDR1-1 in impairing parasitism has then been examined by engineering its heterologous expression in Gossypium hirsutum which is susceptible to the root pathogenic nematode Meloidogyne incognita. The heterologous expression of Gm-NDR1-1 in G. hirsutum effectively impairs M. incognita parasitism, reducing gall, egg mass, egg and juvenile numbers. In contrast to our prior experiments examining the effectiveness of the heterologous expression of a G. max homolog of the A. thaliana salicyclic acid signaling (SA) gene NONEXPRESSOR OF PR1 (Gm-NPR1-2), no cumulative negative effect on M. incognita parasitism has been observed in G. hirsutum expressing Gm-NDR1-1. The results indicate a common genetic basis exists for plant resistance to parasitic nematodes that involves Gm-NDR1. However, the Gm-NDR1-1 functions in ways that are measurably dissimilar to Gm-NPR1-2. Notably, Gm-NDR1-1 overexpression leads to increased relative transcript levels of its homologs of A. thaliana genes functioning in SA signaling, including NPR1-2, TGA2-1 and LESION SIMULATING DISEASE1 (LSD1-2) that is lost in Gm-NDR1-1 RNAi lines. Similar observations have been made regarding the expression of other defense genes.

  7. Population genetics of the diamondback terrapin (Malaclemys terrapin).

    PubMed

    Hauswaldt, J Susanne; Glenn, Travis C

    2005-03-01

    We examined the population genetic structure of the diamondback terrapins (Malaclemys terrapin), within and among estuaries. Based on mark-recapture studies, these estuarine turtles have high site fidelity that is likely to make them vulnerable to local extinctions. We tested if observed site fidelity of adults would be reflected in intraestuarine population genetic structure of six highly polymorphic microsatellite loci (five tetranucleotide and one dinucleotide). No evidence was found for population structuring within the Charleston estuary nor among three different estuaries in South Carolina. We then examined four other terrapin populations from North Carolina to New York, as well as from the Florida Keys and from Texas. With increasing geographical distance, genetic differentiation increased from South Carolina through New York, but overall values were low. The dinucleotide locus contributed significantly more to the genetic differentiation of some population comparisons than any of the other loci. Interestingly, terrapins from South Carolina to New York were much more genetically similar to those from Texas (rho = 0.154) than to those from Florida (rho = 0.357). We attribute this pattern to extensive translocations of terrapins during the early 20th century to replenish diminished populations and to provide turtle farms with stocks. Terrapins collected in Texas were especially sought for shipment to the northeastern US because of their larger size. Our study indicates no population structure within or among adjacent estuaries. Thus, the mark-recapture information from adult and subadult feeding locations is a poor predictor of population genetic structure. Additionally, it appears that past human activities may have drastically altered the genetics of current populations. Finally, our data suggest that translocation of eggs or head starting of terrapins within estuaries or among adjacent estuaries is acceptable from a genetic standpoint.

  8. Additive Similarity Trees

    ERIC Educational Resources Information Center

    Sattath, Shmuel; Tversky, Amos

    1977-01-01

    Tree representations of similarity data are investigated. Hierarchical clustering is critically examined, and a more general procedure, called the additive tree, is presented. The additive tree representation is then compared to multidimensional scaling. (Author/JKS)

  9. Genetic Architecture of Colorectal Cancer

    PubMed Central

    Peters, Ulrike; Bien, Stephanie; Zubair, Niha

    2015-01-01

    Colorectal cancer (CRC) is a complex disease that develops as a consequence of both genetic and environmental risk factors. A small proportion (3–5%) of cases arises from hereditary syndromes predisposing to early onset CRC as a result of mutations in over a dozen well-defined genes. In contrast, CRC is predominantly a late-onset “sporadic” disease, developing in individuals with no obvious hereditary syndrome. In recent years genome-wide association studies have discovered over 40 genetic regions to be associated with weak effects on sporadic CRC and it has been estimated that increasingly large genome-wide scans will identify many additional novel genetic regions. Subsequent experimental validations have identified the causally related variant(s) in a limited number of these genetic regions. Further biological insight could be obtained through ethnically diverse study populations, larger genetic sequencing studies, and development of higher-throughput functional experiments. Along with inherited variation, integration of the tumour genome may shed light on the carcinogenic processes in CRC. In addition to summarizing the genetic architecture of CRC, this review discusses genetic factors that modify environmental predictors of CRC, as well as examples of how genetic insight has improved clinical surveillance, prevention, and treatment strategies. In summary, substantial progress has been made in uncovering the genetic architecture of CRC and continued research efforts are expected to identify additional genetic risk factors that further our biological understanding of this disease. PMID:26187503

  10. Tourette Syndrome: Bridging the Gap between Genetics and Biology

    PubMed Central

    Richer, Petra; Fernandez, Thomas V.

    2015-01-01

    Tourette syndrome is a childhood neuropsychiatric disorder, which presents with disruptive motor and vocal tics. The disease also has a high comorbidity with obsessive-compulsive disorder and attention deficit hyperactivity disorder, which may further increase the distress experienced by patients. Current treatments act with varying efficacies in alleviating symptoms, as the underlying biology of the disease is not fully understood to provide precise therapeutic targets. Moreover, the genetic complexity of the disorder presents a substantial challenge to the identification of genetic alterations that contribute to the Tourette phenotype. Nevertheless, genetic studies have suggested involvement of dopaminergic, serotonergic, glutamatergic, and histaminergic pathways in the pathophysiology of at least some cases. In addition, genetic overlaps with other neuropsychiatric disorders may point toward a shared biology. The findings that are emerging from genetic studies will allow researchers to piece together the underlying components of the disease in the hopes that a deeper understanding of Tourette syndrome can lead to improved treatments for those affected by it. PMID:26509143

  11. Genetic variation in the natriuretic peptide system and heart failure.

    PubMed

    Lanfear, David E

    2010-05-01

    Heart failure (HF) is a modern epidemic and is one of the few cardiovascular diseases which is increasing in prevalence. The growing importance of the Natriuretic Peptide (NP) system in HF is well recognized. Laboratory tests for B-type Natriuretic Peptide (BNP) have proven value as diagnostic and prognostic tools in HF and are now part of routine clinical care. Furthermore, recombinant atrial natriuretic peptide (ANP) (carperitide) and BNP (nesiritide) and are approved HF therapies in Japan and the US, respectively and additional natriuretic peptides (e.g., CNP, urodilatin, and designer NPs) are under investigation for use in HF. Common genetic sequence variants are increasingly being recognized as determinants of disease risk or drug response and may help explain a portion of the inter-individual variation in the human NP system. This review describes current knowledge of NP system genetic variation as it pertains to HF as well as ongoing studies and where the field is expected to progress in the near future. To briefly summarize, NP system genetic variants have been associated with alterations in gene expression, NP levels, and cardiovascular disease. The next step forward will include specific investigations into how this genetic variation can advance 'Personalized Medicine', such as whether they impact the utility of diagnostic BNP testing or effectiveness of therapeutic NP infusion. This is already in progress, with pharmacogenetic studies of nesiritide currently underway. We expect that within 5 years there should be a reasonable idea of whether NP system genetic variation will have important clinical implications.

  12. Development and application of biological technologies in fish genetic breeding.

    PubMed

    Xu, Kang; Duan, Wei; Xiao, Jun; Tao, Min; Zhang, Chun; Liu, Yun; Liu, ShaoJun

    2015-02-01

    Fish genetic breeding is a process that remolds heritable traits to obtain neotype and improved varieties. For the purpose of genetic improvement, researchers can select for desirable genetic traits, integrate a suite of traits from different donors, or alter the innate genetic traits of a species. These improved varieties have, in many cases, facilitated the development of the aquaculture industry by lowering costs and increasing both quality and yield. In this review, we present the pertinent literatures and summarize the biological bases and application of selection breeding technologies (containing traditional selective breeding, molecular marker-assisted breeding, genome-wide selective breeding and breeding by controlling single-sex groups), integration breeding technologies (containing cross breeding, nuclear transplantation, germline stem cells and germ cells transplantation, artificial gynogenesis, artificial androgenesis and polyploid breeding) and modification breeding technologies (represented by transgenic breeding) in fish genetic breeding. Additionally, we discuss the progress our laboratory has made in the field of chromosomal ploidy breeding of fish, including distant hybridization, gynogenesis, and androgenesis. Finally, we systematically summarize the research status and known problems associated with each technology.

  13. Polyimide processing additives

    NASA Technical Reports Server (NTRS)

    Pratt, J. R.; St. Clair, T. L.; Burks, H. D.; Stoakley, D. M.

    1987-01-01

    A method has been found for enhancing the melt flow of thermoplastic polyimides during processing. A high molecular weight 422 copoly(amic acid) or copolyimide was fused with approximately 0.05 to 5 pct by weight of a low molecular weight amic acid or imide additive, and this melt was studied by capillary rheometry. Excellent flow and improved composite properties on graphite resulted from the addition of a PMDA-aniline additive to LARC-TPI. Solution viscosity studies imply that amic acid additives temporarily lower molecular weight and, hence, enlarge the processing window. Thus, compositions containing the additive have a lower melt viscosity for a longer time than those unmodified.

  14. [Food additives and healthiness].

    PubMed

    Heinonen, Marina

    2014-01-01

    Additives are used for improving food structure or preventing its spoilage, for example. Many substances used as additives are also naturally present in food. The safety of additives is evaluated according to commonly agreed principles. If high concentrations of an additive cause adverse health effects for humans, a limit of acceptable daily intake (ADI) is set for it. An additive is a risk only when ADI is exceeded. The healthiness of food is measured on the basis of nutrient density and scientifically proven effects.

  15. Genetic secrets: Protecting privacy and confidentiality in the genetic era

    SciTech Connect

    Rothstein, M.A.

    1998-07-01

    Few developments are likely to affect human beings more profoundly in the long run than the discoveries resulting from advances in modern genetics. Although the developments in genetic technology promise to provide many additional benefits, their application to genetic screening poses ethical, social, and legal questions, many of which are rooted in issues of privacy and confidentiality. The ethical, practical, and legal ramifications of these and related questions are explored in depth. The broad range of topics includes: the privacy and confidentiality of genetic information; the challenges to privacy and confidentiality that may be projected to result from the emerging genetic technologies; the role of informed consent in protecting the confidentiality of genetic information in the clinical setting; the potential uses of genetic information by third parties; the implications of changes in the health care delivery system for privacy and confidentiality; relevant national and international developments in public policies, professional standards, and laws; recommendations; and the identification of research needs.

  16. Referring patients for a medical genetics consultation and genetic counseling.

    PubMed

    Sutton, Reid

    2011-01-01

    Clinical geneticists and genetic counselors provide diagnosis and counseling for genetic disorders affecting every organ system and every age group. Genetic counselors are more focused on informing patients and families about the inheritance of a genetic disorder and providing recurrence risk counseling, support and information about a diagnosis and reproductive options. Medical geneticists may also share some of these roles in addition to establishing a diagnosis and providing medical management. Medical Geneticists receive training in ACGME-accredited residency programs and are certified by the American Board of Medical Genetics. Genetic counseling is a masters degree program and certification is granted by the American Board of Genetic Counseling. When a patient/family is referred to a Clinical Geneticist, they may expect a thorough evaluation in an effort to establish a diagnosis that may provide information about etiology, prognosis, therapy and recurrence risk.

  17. Genetic barcodes

    DOEpatents

    Weier, Heinz -Ulrich G

    2015-08-04

    Herein are described multicolor FISH probe sets termed "genetic barcodes" targeting several cancer or disease-related loci to assess gene rearrangements and copy number changes in tumor cells. Two, three or more different fluorophores are used to detect the genetic barcode sections thus permitting unique labeling and multilocus analysis in individual cell nuclei. Gene specific barcodes can be generated and combined to provide both numerical and structural genetic information for these and other pertinent disease associated genes.

  18. The role of genetics in the establishment and maintenance of the epigenome.

    PubMed

    Huidobro, Covadonga; Fernandez, Agustin F; Fraga, Mario F

    2013-05-01

    Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine-N-methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein-Taybi syndrome, Coffin-Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease.

  19. Aqueous Alteration of Enstatite Chondrites

    NASA Technical Reports Server (NTRS)

    Zolensky, M. E.; Ziegler, K.; Weisberg, M. K.; Gounelle, M.; Berger, E. L.; Le, L.; Ivanov, A.

    2014-01-01

    The Kaidun meteorite is different from all other meteorites [1], consisting largely of a mixture of “incompatible” types of meteoritic material – carbonaceous and enstatite chondrites, i.e. corre-sponding to the most oxidized and the most reduced samples of meteorite materials, including CI1, CM1-2, CV3, EH3-5, and EL3. In addition to these, minor amounts of ordinary and R chondrites are present. In addition, approximately half of the Kaidun lithologies are new materials not known as separate meteorites. Among these are aqueously altered enstatite chondrites [1], which are of considerable interest because they testify that not all reduced asteroids escaped late-stage oxidation, and hydrolysis, and also because hydrated poorly crystalline Si-Fe phase, which in turn is re-placed by serpentine (Figs 3-5). In the end the only indication of the original presence of metal is the re-sidual carbides. In other enstatite chondrite lithogies (of uncertain type) original silicates and metal have been thoroughly replaced by an assemblage of authi-genic plagioclase laths, calcite boxwork, and occasion-al residual grains of silica, Cr-rich troilite, ilmenite, and rare sulfides including heideite (Fig. 6). Fe and S have been largely leached from the rock (Fig. 4). Again the accessory phases are the first clue to the original character of the rock, which can be verified by O isotopes. It is fortunate that Kaidun displays every step of the alteration process.

  20. Attention Alters Perceived Attractiveness.

    PubMed

    Störmer, Viola S; Alvarez, George A

    2016-04-01

    Can attention alter the impression of a face? Previous studies showed that attention modulates the appearance of lower-level visual features. For instance, attention can make a simple stimulus appear to have higher contrast than it actually does. We tested whether attention can also alter the perception of a higher-order property-namely, facial attractiveness. We asked participants to judge the relative attractiveness of two faces after summoning their attention to one of the faces using a briefly presented visual cue. Across trials, participants judged the attended face to be more attractive than the same face when it was unattended. This effect was not due to decision or response biases, but rather was due to changes in perceptual processing of the faces. These results show that attention alters perceived facial attractiveness, and broadly demonstrate that attention can influence higher-level perception and may affect people's initial impressions of one another.

  1. Recombineering: genetic engineering in bacteria using homologous recombination.

    PubMed

    Thomason, Lynn C; Sawitzke, James A; Li, Xintian; Costantino, Nina; Court, Donald L

    2014-04-14

    The bacterial chromosome and bacterial plasmids can be engineered in vivo by homologous recombination using PCR products and synthetic oligonucleotides as substrates. This is possible because bacteriophage-encoded recombination proteins efficiently recombine sequences with homologies as short as 35 to 50 bases. Recombineering allows DNA sequences to be inserted or deleted without regard to location of restriction sites. This unit first describes preparation of electrocompetent cells expressing the recombineering functions and their transformation with dsDNA or ssDNA. It then presents support protocols that describe several two-step selection/counter-selection methods of making genetic alterations without leaving any unwanted changes in the targeted DNA, and a method for retrieving onto a plasmid a genetic marker (cloning by retrieval) from the Escherichia coli chromosome or a co-electroporated DNA fragment. Additional protocols describe methods to screen for unselected mutations, removal of the defective prophage from recombineering strains, and other useful techniques.

  2. Biochemical and genetic aspects of nystatin resistance in saccharomyces cerevisiae.

    PubMed

    Bard, M

    1972-09-01

    Two phenotypically distinct sets of nystatin-resistant mutants were investigated. One set is resistant, respiratory competent, and requires no lipid for growth. The other set is more resistant, respiratory deficient, and lipid requiring (unsaturated fatty acid or sterol). Both sets show altered sterol composition as demonstrated by the Liebermann-Burchard colorimetric reaction, ultraviolet spectrophotometry, and gas-liquid chromatography. Genetic analysis indicates that all nystatin-resistant mutants can be placed into one of six distinct genetic groups. The phenotype's nystatin resistance, lipid requirement, and respiratory deficiency are recessive. There was one case of allelism for mutants from different sets. Revertants of mutants which have the tripartite phenotype retain a residual level of nystatin resistance, but they are no longer lipid requiring or respiratory deficient. Growth studies in mutants which have the tripartite phenotype reveal that the addition of ergosterol to the growth medium results in decreased resistance to nystatin.

  3. Genetic Engineering

    ERIC Educational Resources Information Center

    Phillips, John

    1973-01-01

    Presents a review of genetic engineering, in which the genotypes of plants and animals (including human genotypes) may be manipulated for the benefit of the human species. Discusses associated problems and solutions and provides an extensive bibliography of literature relating to genetic engineering. (JR)

  4. Network-based inference of protein activity helps functionalize the genetic landscape of cancer

    PubMed Central

    Alvarez, Mariano J.; Shen, Yao; Giorgi, Federico M.; Lachmann, Alexander; Ding, B. Belinda; Ye, B. Hilda; Califano, Andrea

    2016-01-01

    Identifying the multiple dysregulated oncoproteins that contribute to tumorigenesis in a given patient is crucial for developing personalized treatment plans. However, accurate inference of aberrant protein activity in biological samples is still challenging as genetic alterations are only partially predictive and direct measurements of protein activity are generally not feasible. To address this problem we introduce and experimentally validate a new algorithm, VIPER (Virtual Inference of Protein-activity by Enriched Regulon analysis), for the accurate assessment of protein activity from gene expression data. We use VIPER to evaluate the functional relevance of genetic alterations in regulatory proteins across all TCGA samples. In addition to accurately inferring aberrant protein activity induced by established mutations, we also identify a significant fraction of tumors with aberrant activity of druggable oncoproteins—despite a lack of mutations, and vice-versa. In vitro assays confirmed that VIPER-inferred protein activity outperforms mutational analysis in predicting sensitivity to targeted inhibitors. PMID:27322546

  5. Genetics of Bladder Malignant Tumors in Childhood

    PubMed Central

    Zangari, Andrea; Zaini, Johan; Gulìa, Caterina

    2016-01-01

    Bladder masses are represented by either benign or malignant entities. Malignant bladder tumors are frequent causes of disease and death in western countries. However, in children they are less common. Additionally, different features are found in childhood, in which non epithelial tumors are more common than epithelial ones. Rhabdomyosarcoma is the most common pediatric bladder tumor, but many other types of lesions may be found, such as malignant rhabdoid tumor (MRT), inflammatory myofibroblastic tumor and neuroblastoma. Other rarer tumors described in literature include urothelial carcinoma and other epithelial neoplasms. Rhabdomyosarcoma is associated to a variety of genetic syndromes and many genes are involved in tumor development. PAX3-FKHR and PAX7-FKHR (P-F) fusion state has important implications in the pathogenesis and biolo