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Sample records for genetic alterations affecting

  1. Genetic Alterations Affecting Cholesterol Metabolism and Human Fertility1

    PubMed Central

    DeAngelis, Anthony M.; Roy-O'Reilly, Meaghan; Rodriguez, Annabelle

    2014-01-01

    ABSTRACT Single nucleotide polymorphisms (SNPs) represent genetic variations among individuals in a population. In medicine, these small variations in the DNA sequence may significantly impact an individual's response to certain drugs or influence the risk of developing certain diseases. In the field of reproductive medicine, a significant amount of research has been devoted to identifying polymorphisms which may impact steroidogenesis and fertility. This review discusses current understanding of the effects of genetic variations in cholesterol metabolic pathways on human fertility that bridge novel linkages between cholesterol metabolism and reproductive health. For example, the role of the low-density lipoprotein receptor (LDLR) in cellular metabolism and human reproduction has been well studied, whereas there is now an emerging body of research on the role of the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI) in human lipid metabolism and female reproduction. Identifying and understanding how polymorphisms in the SCARB1 gene or other genes related to lipid metabolism impact human physiology is essential and will play a major role in the development of personalized medicine for improved diagnosis and treatment of infertility. PMID:25122065

  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. Altering milk composition through genetic selection.

    PubMed

    Gibson, J P

    1989-10-01

    The genetic relationships among carrier, fat, protein, and lactose will allow genetic alteration in any direction desired, although some changes would be much easier than others. Genetic parameters may vary somewhat between different populations, thus affecting the rates of different directions of change. In general, however, selection for an alteration in the fat:protein ratio would proceed rapidly, principally through alteration of fat concentration. Genetic alteration of composition is likely only if economic incentives for such change exist. Economic values, and therefore selection pressure, should be applied to amounts of components rather than concentrations. Recent developments in the theory of deriving economic weights for animal breeding indicate that selection indexes need to be reassessed. Although optimum breeding goals will vary somewhat, in most circumstances fat and protein yields and concentrations and the fat:protein ratio are likely to increase due to genetic selection. Only in the unlikely situation that fat has a very small or negative economic weight are other changes indicated. Lactose concentrations are unlikely to change much in any situation. Genetic variation in the composition of fat and protein, while of biological interest, is unlikely to be of more than minor importance in genetic improvement. PMID:2600237

  4. Genetic alterations in colorectal cancer.

    PubMed

    Armaghany, Tannaz; Wilson, Jon D; Chu, Quyen; Mills, Glenn

    2012-01-01

    Colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women worldwide. Both genetic and epigenetic alterations are common in CRC and are the driving force of tumorigenesis. The adenoma-carcinoma sequence was proposed in the 1980s that described transformation of normal colorectal epithelium to an adenoma and ultimately to an invasive and metastatic tumor. Initial genetic changes start in an early adenoma and accumulate as it transforms to carcinoma. Chromosomal instability, microsatellite instability and CpG island methylator phenotype pathways are responsible for genetic instability in colorectal cancer. Chromosomal instability pathway consist of activation of proto-oncogenes (KRAS) and inactivation of at least three tumor suppression genes, namely loss of APC, p53 and loss of heterozogosity (LOH) of long arm of chromosome 18. Mutations of TGFBR and PIK3CA genes have also been recently described. Herein we briefly discuss the basic concepts of genetic integrity and the consequences of defects in the DNA repair relevant to CRC. Epigenetic alterations, essential in CRC tumorigenesis, are also reviewed alongside clinical information relevant to CRC. PMID:22574233

  5. Genetic and Epigenetic Alterations in Pancreatic Carcinogenesis

    PubMed Central

    Delpu, Yannick; Hanoun, Naïma; Lulka, Hubert; Sicard, Flavie; Selves, Janick; Buscail, Louis; Torrisani, Jérôme; Cordelier, Pierre

    2011-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Despite significant progresses in the last decades, the origin of this cancer remains unclear and no efficient therapy exists. PDAC does not arise de novo: three remarkable different types of pancreatic lesions can evolve towards pancreatic cancer. These precursor lesions include: Pancreatic intraepithelial neoplasia (PanIN) that are microscopic lesions of the pancreas, Intraductal Papillary Mucinous Neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN) that are both macroscopic lesions. However, the cellular origin of these lesions is still a matter of debate. Classically, neoplasm initiation or progression is driven by several genetic and epigenetic alterations. The aim of this review is to assemble the current information on genetic mutations and epigenetic disorders that affect genes during pancreatic carcinogenesis. We will further discuss the interest of the genetic and epigenetic alterations for the diagnosis and prognosis of PDAC. Large genetic alterations (chromosomal deletion/amplification) and single point mutations are well described for carcinogenesis inducers. Mutations classically occur within key regions of the genome. Consequences are various and include activation of mitogenic pathways or silencing of apoptotic processes. Alterations of K-RAS, P16 and DPC4 genes are frequently observed in PDAC samples and have been described to arise gradually during carcinogenesis. DNA methylation is an epigenetic process involved in imprinting and X chromosome inactivation. Alteration of DNA methylation patterns leads to deregulation of gene expression, in the absence of mutation. Both genetic and epigenetic events influence genes and non-coding RNA expression, with dramatic effects on proliferation, survival and invasion. Besides improvement in our fundamental understanding of PDAC development, highlighting the molecular alterations that occur in pancreatic carcinogenesis could provide new clinical tools for early diagnosis of PDAC and the molecular basis for the development of new effective therapies. PMID:21886451

  6. Molecular genetic analysis of MSUD from India reveals mutations causing altered protein truncation affecting the C-termini of E1? and E1?.

    PubMed

    Bashyam, Murali D; Chaudhary, Ajay K; Sinha, Manjari; Nagarajaram, H A; Devi, A Radha Rama; Bashyam, Leena; Reddy, E Chandrakanth; Dalal, Ashwin

    2012-10-01

    Maple Syrup Urine Disease is a rare metabolic disorder caused by reduced/absent activity of the branched chain ?-Ketoacid dehydrogenase enzyme complex. Mutations in BCKDHA, BCKDHB, and DBT, that encode important subunits of the enzyme complex namely E1?, E1?, and E2, are the primary cause for the disease. We have performed the first molecular genetic analysis of MSUD from India on nine patients exhibiting classical MSUD symptoms. BCKDHA and BCKDHB mutations were identified in four and five patients, respectively including seven novel mutations namely the BCKDHA c.1249delC, c.1312T>C, and c.1561T>A and the BCKDHB c.401T>A, c.548G>A, c.964A>G, and c.1065delT. The BCKDHB c.970C>T (p.R324X) mutation was shown to trigger nonsense mediated decay-based degradation of the transcript. Seven of the total 11 mutations resulted in perturbations in the E1? or E1? C-termini either through altered termination or through an amino acid change; these are expected to result in disruption of E1 enzyme complex assembly. Our study has therefore revealed that BCKDHA and BCKDHB mutations might be primarily responsible for MSUD in the Indian population. PMID:22593002

  7. Molecular and genetic analyses of the Caenorhabditis elegans dpy-2 and dpy-10 collagen genes: a variety of molecular alterations affect organismal morphology.

    PubMed Central

    Levy, A D; Yang, J; Kramer, J M

    1993-01-01

    We have identified and cloned the Caenorhabditis elegans dpy-2 and dpy-10 genes and determined that they encode collagens. Genetic data suggested that these genes are important in morphogenesis and possibly other developmental events. These data include the morphologic phenotypes exhibited by mutants, unusual genetic interactions with the sqt-1 collagen gene, and suppression of mutations in the glp-1 and mup-1 genes. The proximity of the dpy-2 and dpy-10 genes (3.5 kilobase) and the structural similarity of their encoded proteins (41% amino acid identity) indicate that dpy-2 and dpy-10 are the result of a gene duplication event. The genes do not, however, appear to be functionally redundant, because a dpy-10 null mutant is not rescued by the dpy-2 gene. In addition, full complementation between dpy-2 and dpy-10 can be demonstrated with all recessive alleles tested in trans. Sequence analysis of several mutant alleles of each gene was performed to determine the nature of the molecular defects that can cause the morphologic phenotypes. Glycine substitutions within the Gly-X-Y portion of the collagens can result in dumpy (Dpy), dumpy, left roller (DLRol), or temperature-sensitive DLRol phenotypes. dpy-10(cn64), a dominant temperature-sensitive DLRol allele, creates an Arg-to-Cys substitution in the amino non-Gly-X-Y portion of the protein. Three dpy-10 alleles contain Tc1 insertions in the coding region of the gene. dpy-10(cg36) (DRLol) creates a nonsense codon near the end of the Gly-X-Y region. The nature of this mutation, combined with genetic data, indicates that DLRol is the null phenotype of dpy-10. The Dpy phenotype results from reduced function of the dpy-10 collagen gene. Our results indicate that a variety of molecular defects in these collagens can result in severe morphologic changes in C. elegans. Images PMID:8241567

  8. Molecular and genetic analyses of the Caenorhabditis elegans dpy-2 and dpy-10 collagen genes: a variety of molecular alterations affect organismal morphology.

    PubMed

    Levy, A D; Yang, J; Kramer, J M

    1993-08-01

    We have identified and cloned the Caenorhabditis elegans dpy-2 and dpy-10 genes and determined that they encode collagens. Genetic data suggested that these genes are important in morphogenesis and possibly other developmental events. These data include the morphologic phenotypes exhibited by mutants, unusual genetic interactions with the sqt-1 collagen gene, and suppression of mutations in the glp-1 and mup-1 genes. The proximity of the dpy-2 and dpy-10 genes (3.5 kilobase) and the structural similarity of their encoded proteins (41% amino acid identity) indicate that dpy-2 and dpy-10 are the result of a gene duplication event. The genes do not, however, appear to be functionally redundant, because a dpy-10 null mutant is not rescued by the dpy-2 gene. In addition, full complementation between dpy-2 and dpy-10 can be demonstrated with all recessive alleles tested in trans. Sequence analysis of several mutant alleles of each gene was performed to determine the nature of the molecular defects that can cause the morphologic phenotypes. Glycine substitutions within the Gly-X-Y portion of the collagens can result in dumpy (Dpy), dumpy, left roller (DLRol), or temperature-sensitive DLRol phenotypes. dpy-10(cn64), a dominant temperature-sensitive DLRol allele, creates an Arg-to-Cys substitution in the amino non-Gly-X-Y portion of the protein. Three dpy-10 alleles contain Tc1 insertions in the coding region of the gene. dpy-10(cg36) (DRLol) creates a nonsense codon near the end of the Gly-X-Y region. The nature of this mutation, combined with genetic data, indicates that DLRol is the null phenotype of dpy-10. The Dpy phenotype results from reduced function of the dpy-10 collagen gene. Our results indicate that a variety of molecular defects in these collagens can result in severe morphologic changes in C. elegans. PMID:8241567

  9. Insights into genetic alterations of liver metastases from uveal melanoma.

    PubMed

    McCarthy, Conni; Kalirai, Helen; Lake, Sarah L; Dodson, Andrew; Damato, Bertil E; Coupland, Sarah E

    2016-01-01

    The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy, and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently needed novel, targeted, therapeutic regimens. PMID:26523470

  10. Genetic and epigenetic alterations during renal carcinogenesis

    PubMed Central

    Arai, Eri; Kanai, Yae

    2011-01-01

    Renal cell carcinoma (RCC) is not a single entity, but comprises a group of tumors including clear cell RCC, papillary RCC and chromophobe RCC, which arise from the epithelium of renal tubules. The majority of clear cell RCCs, the major histological subtype, have genetic or epigenetic inactivation of the von Hippel-Lindau (VHL) gene. Germline mutations in the MET and fumarate hydratase (FH) genes lead to the development of type 1 and type 2 papillary RCCs, respectively, and such mutations of either the TSC1 or TSC2 gene increase the risk of RCC. Genome-wide copy number alteration analysis has suggested that loss of chromosome 3p and gain of chromosomes 5q and 7 may be copy number aberrations indispensable for the development of clear cell RCC. When chromosome 1p, 4, 9, 13q or 14q is also lost, more clinicopathologically aggressive clear cell RCC may develop. Since renal carcinogenesis is associated with neither chronic inflammation nor persistent viral infection, and hardly any histological change is evident in corresponding non-tumorous renal tissue from patients with renal tumors, precancerous conditions in the kidney have been rarely described. However, regional DNA hypermethylation on C-type CpG islands has already accumulated in such non-cancerous renal tissues, suggesting that, from the viewpoint of altered DNA methylation, the presence of precancerous conditions can be recognized even in the kidney. Genome-wide DNA methylation profiles in precancerous conditions are basically inherited by the corresponding clear cell RCCs developing in individual patients: DNA methylation alterations at the precancerous stage may further predispose renal tissue to epigenetic and genetic alterations, generate more malignant cancers, and even determine patient outcome. The list of tumor-related genes silenced by DNA hypermethylation has recently been increasing. Genetic and epigenetic profiling provides an optimal means of prognostication for patients with RCCs. Recently developed high-throughput technologies for genetic and epigenetic analyses will further accelerate the identification of key molecules for use in the prevention, diagnosis and therapy of RCCs. PMID:21228928

  11. Genetic alterations and signaling pathways in the evolution of gliomas.

    PubMed

    Ohgaki, Hiroko; Kleihues, Paul

    2009-12-01

    Gliomas are the most common primary brain tumors. They account for more than 70% of all neoplasms of the central nervous system and vary considerably in morphology, location, genetic alterations, and response to therapy. Most frequent and malignant are glioblastomas. The vast majority (>90%) develops rapidly after a short clinical history and without evidence of a less malignant precursor lesion (primary or de novo glioblastoma). Secondary glioblastomas develop more slowly through progression from low-grade or anaplastic astrocytoma. These glioblastoma subtypes constitute distinct disease entities that affect patients of different age, develop through distinct genetic pathways, show different RNA and protein expression profiles, and may differ in their response to radio- and chemotherapy. Recently, isocitrate dehydrogenase 1 (IDH1) mutations have been identified as a very early and frequent genetic alteration in the pathway to secondary glioblastomas as well as that in oligodendroglial tumors, providing the first evidence that low-grade astrocytomas and oligodendrogliomas may share common cells of origin. In contrast, primary glioblastomas very rarely contain IDH1 mutations, suggesting that primary and secondary glioblastomas may originate from different progenitor cells, despite the fact that they are histologically largely indistinguishable. In this review, we summarize the current status of genetic alterations and signaling pathways operative in the evolution of astrocytic and oligodendroglial tumors. PMID:19737147

  12. Parental Virtue and Prenatal Genetic Alteration Research.

    PubMed

    Tonkens, Ryan

    2015-12-01

    Although the philosophical literature on the ethics of human prenatal genetic alteration (PGA) purports to inform us about how to act, it rarely explicitly recognizes the perspective of those who will be making the PGA decision in practice. Here I approach the ethics of PGA from a distinctly virtue-based perspective, taking seriously what it means to be a good parent making this decision for one's child. From this perspective, I generate a sound verdict on the moral standing of human PGA (research): given the current state of the art, good parents have compelling reason not to consent to PGA (research) for their child, especially as part of the first wave(s) of PGA research participants and especially for non-medically oriented purposes. This is because doing otherwise is inconsistent with a plausible and defensible understanding of virtuous parenting and parental virtues, founded on a genuine concern for promoting the overall flourishing of the eventual child. In essence, given the current and foreseeable state of the art, parents who allow prenatal genetic alteration of their children are less-than-virtuous parents to those children, even in cases where they have a right to do so and even if PGA turns out to be beneficial to the eventual child. PMID:26160602

  13. PRODUCTION OF EXTRACELLULAR NUCLEIC ACIDS BY GENETICALLY ALTERED BACTERIA IN AQUATIC-ENVIRONMENT MICROCOSMS

    EPA Science Inventory

    Factors which affect the production of extracellular DNA by genetically altered strains of Escherichia coli, Pseudomonas aeruginosa, pseudomonas cepacia, and Bradyrhizobium japonicum in aquatic environments were investigated. he presence or absence of the ambient microbial commun...

  14. Characterization of the activity of the PI3K/mTOR inhibitor XL765 (SAR245409) in tumor models with diverse genetic alterations affecting the PI3K pathway.

    PubMed

    Yu, Peiwen; Laird, A Douglas; Du, Xiangnan; Wu, Jianming; Won, Kwang-Ai; Yamaguchi, Kyoko; Hsu, Pin Pin; Qian, Fawn; Jaeger, Christopher T; Zhang, Wentao; Buhr, Chris A; Shen, Paula; Abulafia, Wendy; Chen, Jason; Young, Jenny; Plonowski, Arthur; Yakes, F Michael; Chu, Felix; Lee, Michelle; Bentzien, Frauke; Lam, Sanh Tan; Dale, Stephanie; Matthews, David J; Lamb, Peter; Foster, Paul

    2014-05-01

    Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (?, ?, ?, and ?) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP(3) in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects. PMID:24634413

  15. Low temperature alteration processes affecting ultramafic bodies

    USGS Publications Warehouse

    Nesbitt, H.W.; Bricker, O.P.

    1978-01-01

    At low temperatures, in the presence of an aqueous solution, olivine and orthopyroxene are not stable relative to the hydrous phases brucite, serpentine and talc. Alteration of dunite and peridotite to serpentine or steatite bodies must therefore proceed via non-equilibrium processes. The compositions of natural solutions emanating from dunites and peridotites demonstrate that the dissolution of forsterite and/or enstatite is rapid compared with the precipitation of the hydrous phases; consequently, dissolution of anhydrous minerals controls the chemistry of such solutions. In the presence of an aqueous phase, precipitation of hydrous minerals is the rate-controlling step. Brucite-bearing and -deficient serpentinites alter at low temperature by non-equilibrium processes, as evidenced by the composition of natural solutions from these bodies. The solutions approach equilibrium with the least stable hydrous phase and, as a consequence, are supersaturated with other hydrous phases. Dissolution of the least stable phase is rapid compared to precipitation of other phases, so that the dissolving mineral controls the solution chemistry. Non-equilibrium alteration of anhydrous ultramafic bodies continues until at least one anhydrous phase equilibrates with brucite, chrysotile or talc. The lowest temperature (at a given pressure) at which this happens is defined by the reaction: 3H2O + 2Mg2SiO4 ??? Mg3Si2O5(OH)4 + Mg(OH)2 (Johannes, 1968, Contrib. Mineral. Petrol. 19, 309-315) so that non-equilibrium alteration may occur well into greenschist facies metamorphic conditions. ?? 1978.

  16. Molecular genetics in affective illness

    SciTech Connect

    Mendlewicz, J.; Sevy, S.; Mendelbaum, K. )

    1993-01-01

    Genetic transmission in manic depressive illness (MDI) has been explored in twins, adoption, association, and linkage studies. The X-linked transmission hypothesis has been tested by using several markers on chromosome X: Xg blood group, color blindness, glucose-6-phosphate dehydrogenase (G6PD), factor IX (hemophilia B), and DNA probes such as DXS15, DXS52, F8C, ST14. The hypothesis of autosomal transmission has been tested by association studies with the O blood group located on chromosome 9, as well as linkage studies on chromosome 6 with the Human Leucocyte Antigens (HLA) haplotypes and on Chromosome 11 with DNA markers for the following genes: D2 dopamine receptor, tyrosinase, C-Harvey-Ras-A (HRAS) oncogene, insuline (ins), and tyrosine hydroxylase (TH). Although linkage studies support the hypothesis of a major locus for the transmission of MDI in the Xq27-28 region, several factors are limiting the results, and are discussed in the present review. 105 refs., 1 fig., 2 tabs.

  17. Genetics of affective and anxiety disorders.

    PubMed

    Leonardo, E D; Hen, Ren

    2006-01-01

    The study of the genetics of complex behaviors has evolved dramatically from the days of the nature versus nurture debates that dominated much of the past century. Here we discuss advances in our understanding of the genetics of affective and anxiety disorders. In particular, we highlight our growing understanding of specific gene-environment interactions that occur during critical periods in development, setting the stage for later behavioral phenotypes. We review the recent literature in the field, focusing on recent advances in our understanding of the role of the serotonin system in establishing normal anxiety levels during development. We emphasize the importance of understanding the effect of genetic variation at the level of functional circuits and provide examples from the literature of how such an approach has been exploited to study novel genetic endpoints, including genetically based variation in response to medication, a potentially valuable phenotype that has not received much attention to date. PMID:16318591

  18. Do alterations in mesofauna community affect earthworms?

    PubMed

    Uvarov, Alexei V; Karaban, Kamil

    2015-11-01

    Interactions between the saprotrophic animal groups that strongly control soil microbial activities and the functioning of detrital food webs, such as earthworms and mesofauna, are not well understood. Earthworm trophic and engineering activities strongly affect mesofauna abundance and diversity through various direct and indirect pathways. In contrast, mesofauna effects on earthworm populations are less evident; however, their importance may be high, considering the keystone significance of earthworms for the functioning of the soil system. We studied effects of a diverse mesofauna community of a deciduous forest on two earthworm species representing epigeic (Lumbricus rubellus) and endogeic (Aporrectodea caliginosa) ecological groups. In microcosms, the density of total mesofauna or its separate groups (enchytraeids, collembolans, gamasid mites) was manipulated (increased) and responses of earthworms and soil systems were recorded. A rise in mesofauna density resulted in a decrease of biomass and an increased mortality in L. rubellus, presumably due to competition with mesofauna for litter resources. In contrast, similar mesofauna manipulations promoted reproduction of A. caliginosa, suggesting a facilitated exploitation of litter resources due to increased mesofauna activities. Changes of microcosm respiration rates, litter organic matter content and microbial activities across the manipulation treatments indicate that mesofauna modify responses of soil systems in the presence of earthworms. However, similar mesofauna manipulations could induce different responses in soil systems with either epigeic or endogeic lumbricids, which suggests that earthworm/mesofauna interactions are species-specific. Thus, mesofauna impacts should be treated as a factor affecting the engineering activities of epigeic and endogeic earthworms in the soil. PMID:26188519

  19. 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.

  20. Genetic factors affecting dental caries risk.

    PubMed

    Opal, S; Garg, S; Jain, J; Walia, I

    2015-03-01

    This article reviews the literature on genetic aspects of dental caries and provides a framework for the rapidly changing disease model of caries. The scope is genetic aspects of various dental factors affecting dental caries. The PubMed database was searched for articles with keywords 'caries', 'genetics', 'taste', 'diet' and 'twins'. This was followed by extensive handsearching using reference lists from relevant articles. The post-genomic era will present many opportunities for improvement in oral health care but will also present a multitude of challenges. We can conclude from the literature that genes have a role to play in dental caries; however, both environmental and genetic factors have been implicated in the aetiology of caries. Additional studies will have to be conducted to replicate the findings in a different population. Identification of genetic risk factors will help screen and identify susceptible patients to better understand the contribution of genes in caries aetiopathogenesis. Information derived from these diverse studies will provide new tools to target individuals and/or populations for a more efficient and effective implementation of newer preventive measures and diagnostic and novel therapeutic approaches in the management of this disease. PMID:25721273

  1. 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

  2. Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression

    PubMed Central

    Provenzano, Aldesia; Mazzinghi, Benedetta; Becherucci, Francesca; Giunti, Laura; Sansavini, Giulia; Ravaglia, Fiammetta; Roperto, Rosa Maria; Farsetti, Silvia; Benetti, Elisa; Rotondi, Mario; Murer, Luisa; Lazzeri, Elena; Lasagni, Laura; Materassi, Marco

    2015-01-01

    In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid?resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner. PMID:25060053

  3. Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression.

    PubMed

    Giglio, Sabrina; Provenzano, Aldesia; Mazzinghi, Benedetta; Becherucci, Francesca; Giunti, Laura; Sansavini, Giulia; Ravaglia, Fiammetta; Roperto, Rosa Maria; Farsetti, Silvia; Benetti, Elisa; Rotondi, Mario; Murer, Luisa; Lazzeri, Elena; Lasagni, Laura; Materassi, Marco; Romagnani, Paola

    2015-01-01

    In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner. PMID:25060053

  4. Distinct Genetic Alterations in Colorectal Cancer

    PubMed Central

    Ashktorab, Hassan; Schffer, 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

  5. Genetic Alterations in Presumptive Precursor Lesions of Breast Carcinomas

    PubMed Central

    Aubele, Michaela; Werner, Martin; Hfler, Heinz

    2002-01-01

    The hypothetical multistep model of breast carcinogenesis suggests a transition from normal epithelium to invasive carcinoma via intraductal hyperplasia (without and with atypia) and in situcarcinoma. These presumptive precursor lesions are currently defined by their histological features, and their prognosis is imprecisely estimated from indirect epidemiological evidence. Cytogenetic and molecular?genetic analysis of these lesions give evidence for an accumulation of various genetic alterations during breast tumorigenesis. Using immuno?histochemistry overexpression of the c?erbB?2 oncogene was found in ductal carcinoma in situ(DCIS), but not in atypical intraductal hyperplasia (AIDH) and intraductal hyperplasia (IDH). An expression of mutant p53 tumor suppressor gene as well as expression of cyclin D1 was identified in DCIS. In IDH lesions loss of heterozygosity (LOH) at various loci could be identified, and comparative genomic hybridization (CGH) and fluorescence in situhybridization (FISH) studies delivered evidence for DNA amplification on chromosomal region 20q13 in the early stage of IDH. However, little is currently known about genetic alterations in those premalignant lesions, and the chronology of genetic alterations and histopathological changes during carcinogenesis is mainly undiscovered. Figure 1 can be viewed in colour on http://www.esacp.org/acp/2002/24?23/aubele.htm PMID:12446956

  6. Selected genetic disorders affecting Ashkenazi Jewish families.

    PubMed

    Weinstein, Lenore B

    2007-01-01

    Ashkenazi Jews of Central and Eastern European ancestry have a disproportionately high prevalence of several autosomal recessive genetic disorders. This article describes these 9 disorders and their genetic inheritance patterns: Bloom syndrome; Canavan disease; cystic fibrosis; familial dysautonomia; Fanconi anemia; Gaucher disease; Mucolipidosis IV; Niemann-Pick disease; and Tay-Sachs disease. Genetic testing, counseling, and family planning options for the at-risk population are described. The role of the community health nurse is addressed. PMID:17149032

  7. Genetic Alterations in Poorly Differentiated and Undifferentiated Thyroid Carcinomas

    PubMed Central

    Soares, Paula; Lima, Jorge; Preto, Ana; Castro, Patricia; Vinagre, João; Celestino, Ricardo; Couto, Joana P; Prazeres, Hugo; Eloy, Catarina; Máximo, Valdemar; Sobrinho-Simões, M

    2011-01-01

    Thyroid gland presents a wide spectrum of tumours derived from follicular cells that range from well differentiated, papillary and follicular carcinoma (PTC and FTC, respectively), usually carrying a good prognosis, to the clinically aggressive, poorly differentiated (PDTC) and undifferentiated thyroid carcinoma (UTC). It is usually accepted that PDTC and UTC occur either de novo or progress from a pre-existing well differentiated carcinoma through a multistep process of genetic and epigenetic changes that lead to clonal expansion and neoplastic development. Mutations and epigenetic alterations in PDTC and UTC are far from being totally clarified. Assuming that PDTC and UTC may derive from well differentiated thyroid carcinomas (WDTC), it is expected that some PDTC and UTC would harbour genetic alterations that are typical of PTC and FTC. This is the case for some molecular markers (BRAF and NRAS) that are present in WDTC, PDTC and UTC. Other genes, namely P53, are almost exclusively detected in less differentiated and undifferentiated thyroid tumours, supporting a diagnosis of PDTC or, much more often, UTC. Thyroid-specific rearrangements RET/PTC and PAX8/PPARγ, on the other hand, are rarely found in PDTC and UTC, suggesting that these genetic alterations do not predispose cells to dedifferentiation. In the present review we have summarized the molecular changes associated with the two most aggressive types of thyroid cancer. PMID:22654560

  8. Invasion of Impatiens glandulifera affects terrestrial gastropods by altering microclimate

    NASA Astrophysics Data System (ADS)

    Ruckli, Regina; Rusterholz, Hans-Peter; Baur, Bruno

    2013-02-01

    Invasive species can have far-reaching impacts on ecosystems. Invasive plants may be able to change habitat structure and quality. We conducted a field experiment to examine whether the invasive plant Impatiens glandulifera affects native terrestrial gastropods. We also evaluated whether the invasive plant alters forest soil characteristics and microclimate which in turn may influence gastropod abundance. We sampled gastropods in plots installed in patches of I. glandulifera, in plots in which I. glandulifera was regularly removed by hand, and in control plots which were not yet colonized by the invasive plant. The three types of plots were equally distributed over three mixed deciduous forest areas that were slightly, moderately or heavily affected by a wind throw 11 years ago. A total of 33 gastropod species were recorded. Gastropod species richness was not affected by delayed effects of the wind throw, but it was significantly higher in invaded plots than in uninvaded plots. Similarly, gastropod abundance was higher in invaded plots than in the two types of control plots. Canonical correspondence analysis revealed marginally significant shifts of gastropod communities between the three types of plots and indicated that soil moisture, presence of I. glandulifera and cover of woody debris affected gastropod species composition. Field measurements showed that soil moisture was higher and daily soil temperature was more damped in patches of I. glandulifera than in the native ground vegetation. The changed microclimatic conditions may favour certain gastropod species. In particular, ubiquitous species and species with a high inundation tolerance increased in abundance in plots invaded by I. glandulifera. Our field experiment demonstrated that an invasive plant can indirectly affect native organisms by changing soil characteristics and microclimate.

  9. Molecular genetic alterations in glioblastomas with oligodendroglial component.

    PubMed

    Kraus, J A; Lamszus, K; Glesmann, N; Beck, M; Wolter, M; Sabel, M; Krex, D; Klockgether, T; Reifenberger, G; Schlegel, U

    2001-04-01

    Glioblastoma multiforme is the most malignant astrocytic glioma and usually resistant to chemotherapy. A small fraction of glioblastomas may contain areas with histological features of oligodendroglial differentiation. To determine the molecular genetic alterations in such "glioblastomas with oligodendroglial component", we investigated 13 of these tumors for genetic alterations and/or expression of the TP53, CDKN2A, PTEN, and EGFR genes. In addition, we performed microsatellite analyses for loss of heterozygosity (LOH) on chromosome arms 1p, 19q and 10q. None of tumors showed evidence for LOH on 10q. LOH on 1p was detected in 3 tumors, 1 of which additionally showed LOH on 19q. The 3 tumors with LOH on 1p showed neither TP53 mutations nor nuclear p53 accumulation. In contrast, 9 of 10 tumors without demonstrated losses on 1p showed nuclear p53 accumulation. TP53 mutations were identified in 3 of these cases. Further aberrations detected were epidermal growth factor receptor (EGFR) overexpression (3 of 13 tumors), homozygous CDKN2A deletion (2 of 11 tumors), and PTEN mutation (1 of 13 tumors). Taken together, our results indicate that "glioblastomas with oligodendroglial component" carry heterogeneous genetic alterations. LOH on 10q, PTEN mutation, and homozygous CDKN2A deletion appear to be less common in these tumors as compared to ordinary glioblastomas. Furthermore, a subset of these tumors demonstrates LOH on 1p, i.e., an alteration that has recently been linked to chemosensitivity and good prognosis in anaplastic oligodendrogliomas. PMID:11355302

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

    PubMed

    Tobis, Blint; Halszlaki, Csaba; Balla, Bernadett; Ksa, Jnos P; rvai, Kristf; Horvth, Pter; Takcs, Istvn; Nagy, Zsolt; Horvth, Evelin; Hornyi, Jnos; Jray, Balzs; Szkely, Eszter; Szkely, Tams; Gy?ri, Gabriella; Putz, Zsuzsanna; Dank, Magdolna; Valkusz, Zsuzsanna; Vasas, Bla; Ivnyi, Bla; Lakatos, Pter

    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. PMID:26259532

  11. Alteration of photosynthesis in grapevines affected by esca.

    PubMed

    Petit, A-N; Vaillant, N; Boulay, M; Clment, C; Fontaine, F

    2006-10-01

    ABSTRACT To further understand the development of esca disease in grapevine, its physiological impact on plants grown in the vineyard was characterized, focusing mainly on photosynthesis. For this purpose, the state of the photosynthetic apparatus was evaluated in symptomatic and asymptomatic leaves in esca-infected grape plants, and wood carbohydrates stored in annual canes were assayed. In symptomatic leaves, esca greatly affected grapevine physiology. Foliar symptoms were associated with both stomatal closure and alteration of the photosynthetic apparatus as revealed by (i) a decrease in CO(2) assimilation, transpiration, and a significant increase in intercellular CO(2) concentration; (ii) a strong drop in both the maximum fluorescence yield and the effective Photosystem II quantum yield; and (iii) a reduction of total chlorophyll but a stable carotenoid content. On symptomatic canes, all these variables were affected more on leaves with symptoms than without symptoms, suggesting a gradation in photosynthesis disruptions in the plant according to the degree of symptom severity. In addition, canes of symptomatic plants had reduced carbohydrate reserves during the winter rest, whether they exhibit symptoms or not. The following year, the lower pool of reserves may contribute to a significant decrease in plant development, as well as a global loss in plant vigor. PMID:18943493

  12. 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. PMID:24735114

  13. 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

  14. Targeted exome sequencing profiles genetic alterations in leiomyosarcoma.

    PubMed

    Agaram, Narasimhan P; Zhang, Lei; LeLoarer, Francois; Silk, Tarik; Sung, Yun-Shao; Scott, Sasinya N; Kuk, Deborah; Qin, Li-Xuan; Berger, Michael F; Antonescu, Cristina R; Singer, Samuel

    2016-02-01

    Leiomyosarcoma (LMS) belongs to the class of genetically complex sarcomas and shows numerous, often non-recurrent chromosomal imbalances and aberrations. We investigated a group of LMS using NGS platform to identify recurrent genetic abnormalities and possible therapeutic targets. Targeted exome sequencing of 230 cancer-associated genes was performed on 35 primary soft tissue and visceral (extra-uterine) LMS. Sequence data were analyzed to identify single nucleotide variants, small insertions/deletions (indels), and copy number alterations. Key alterations were further investigated using FISH assay. The study group included patients with median age of 64 years and median tumor size of 7 cm. The primary sites included retroperitoneal/intra-abdominal, extremity, truncal, and visceral. Thirty-one tumors were high grade LMS, while four were low grade. Losses of chromosomal regions involving key tumor suppressor genes PTEN (10q), RB1 (13q), CDH1 (16q), and TP53 (17p) were the most frequent genetic events. Gains mainly involved chromosome regions 17p11.2 (MYOCD) and 15q25-26 (IGF1R). The most frequent mutations were identified in the TP53 gene in 13 of 35 (37%) cases. FISH analysis showed amplification of the myocardin (MYOCD) gene in 5 of 25 (20%) cases analyzed. None of the four low grade LMS showed losses or mutations of PTEN or TP53 genes. Genetic complexity is the hallmark of LMS with losses of important tumor suppressor genes being a common feature. MYOCD, a key gene associated with smooth muscle differentiation, is amplified in a subset of both retroperitoneal and extremity LMS. Further studies are necessary to investigate the significance of gains/amplifications in the development of these tumors. 2015 Wiley Periodicals, Inc. PMID:26541895

  15. Genetic factors affecting susceptibility to udder pathogens.

    PubMed

    Detilleux, J C

    2009-02-16

    Many studies have identified genetic factors underlying resistance or susceptibility to mastitis in dairy cows and heifers. Some authors focused on polygenic variation while others searched for genes and/or quantitative trait loci with major effects on mastitis. Classical traits related to mastitis include somatic cell counts, electrical conductivity and clinical cases of the disease. With the development of automatic milking devices and '-omics' technologies, new traits are considered, such as acute phase proteins, immunological assays, and milk flow patterns, and new biological pathways are discovered, for example the role of mammary epithelium and the nervous system. The usefulness of these traits for the identification of resistant cows is discussed in relation to the biological mechanisms underlying the development of the disease. In addition, the utility of these traits for genetic improvement is reviewed. Finally, the problem of durability in resistance is addressed, including co-evolution and the cost of resistance. PMID:18930606

  16. Alteration of the Langerin Oligomerization State Affects Birbeck Granule Formation

    PubMed Central

    Chabrol, Eric; Thpaut, Michel; Dezutter-Dambuyant, Colette; Vivs, Corinne; Marcoux, Julien; Kahn, Richard; Valladeau-Guilemond, Jenny; Vachette, Patrice; Durand, Dominique; Fieschi, Franck

    2015-01-01

    Langerin, a trimeric C-type lectin specifically expressed in Langerhans cells, has been reported to be a pathogen receptor through the recognition of glycan motifs by its three carbohydrate recognition domains (CRD). In the context of HIV-1 (human immunodeficiency virus-1) transmission, Langerhans cells of genital mucosa play a protective role by internalizing virions in Birbeck Granules (BG) for elimination. Langerin (Lg) is directly involved in virion binding and BG formation through its CRDs. However, nothing is known regarding the mechanism of langerin assembly underlying BG formation. We investigated at the molecular level the impact of two CRD mutations, W264R and F241L, on langerin structure, function, and BG assembly using a combination of biochemical and biophysical approaches. Although the W264R mutation causes CRD global unfolding, the F241L mutation does not affect the overall structure and gp120 (surface HIV-1 glycoprotein of 120kDa) binding capacities of isolated Lg-CRD. In contrast, this mutation induces major functional and structural alterations of the whole trimeric langerin extracellular domain (Lg-ECD). As demonstrated by small-angle x-ray scattering comparative analysis of wild-type and mutant forms, the F241L mutation perturbs the oligomerization state and the global architecture of Lg-ECD. Correlatively, despite conserved intrinsic lectin activity of the CRD, avidity property of Lg-ECD is affected as shown by a marked decrease of gp120 binding. Beyond the change of residue itself, the F241L mutation induces relocation of the K200 side chain also located within the interface between protomers of trimeric Lg-ECD, thereby explaining the defective oligomerization of mutant Lg. We conclude that not only functional CRDs but also their correct spatial presentation are critical for BG formation as well as gp120 binding. PMID:25650933

  17. Alteration of the langerin oligomerization state affects Birbeck granule formation.

    PubMed

    Chabrol, Eric; Thpaut, Michel; Dezutter-Dambuyant, Colette; Vivs, Corinne; Marcoux, Julien; Kahn, Richard; Valladeau-Guilemond, Jenny; Vachette, Patrice; Durand, Dominique; Fieschi, Franck

    2015-02-01

    Langerin, a trimeric C-type lectin specifically expressed in Langerhans cells, has been reported to be a pathogen receptor through the recognition of glycan motifs by its three carbohydrate recognition domains (CRD). In the context of HIV-1 (human immunodeficiency virus-1) transmission, Langerhans cells of genital mucosa play a protective role by internalizing virions in Birbeck Granules (BG) for elimination. Langerin (Lg) is directly involved in virion binding and BG formation through its CRDs. However, nothing is known regarding the mechanism of langerin assembly underlying BG formation. We investigated at the molecular level the impact of two CRD mutations, W264R and F241L, on langerin structure, function, and BG assembly using a combination of biochemical and biophysical approaches. Although the W264R mutation causes CRD global unfolding, the F241L mutation does not affect the overall structure and gp120 (surface HIV-1 glycoprotein of 120 kDa) binding capacities of isolated Lg-CRD. In contrast, this mutation induces major functional and structural alterations of the whole trimeric langerin extracellular domain (Lg-ECD). As demonstrated by small-angle x-ray scattering comparative analysis of wild-type and mutant forms, the F241L mutation perturbs the oligomerization state and the global architecture of Lg-ECD. Correlatively, despite conserved intrinsic lectin activity of the CRD, avidity property of Lg-ECD is affected as shown by a marked decrease of gp120 binding. Beyond the change of residue itself, the F241L mutation induces relocation of the K200 side chain also located within the interface between protomers of trimeric Lg-ECD, thereby explaining the defective oligomerization of mutant Lg. We conclude that not only functional CRDs but also their correct spatial presentation are critical for BG formation as well as gp120 binding. PMID:25650933

  18. Genetic alterations defining NSCLC subtypes and their therapeutic implications.

    PubMed

    Pikor, Larissa A; Ramnarine, Varune R; Lam, Stephen; Lam, Wan L

    2013-11-01

    Lung cancer is the leading cause of cancer death worldwide, accounting for more deaths than breast, prostate and colon cancer combined. While treatment decisions are determined primarily by stage, therapeutically non small cell lung cancer (NSCLC) has traditionally been treated as a single disease. However, recent findings have led to the recognition of histology and molecular subtypes as important determinants in treatment selection. Identifying the genetic differences that define these molecular and histological subtypes has the potential to impact treatment and as such is currently the focus of much research. Microarray and genomic sequencing efforts have provided unparalleled insight into the genomes of lung cancer subtypes, specifically adenocarcinoma (AC) and squamous cell carcinoma (SqCC), revealing subtype specific genomic alterations and molecular subtypes as well as differences in cell signaling pathways. In this review, we discuss the recurrent genomic alterations characteristic of AC and SqCC (including molecular subtypes), their therapeutic implications and emerging clinical practices aimed at tailoring treatments based on a tumor's molecular alterations with the hope of improving patient response and survival. PMID:24011633

  19. Human Genetic Variation Influences Vitamin C Homeostasis by Altering Vitamin C Transport and Antioxidant Enzyme Function

    PubMed Central

    Michels, Alexander J.; Hagen, Tory M.; Frei, Balz

    2015-01-01

    New evidence for the regulation of vitamin C homeostasis has emerged from several studies of human genetic variation. Polymorphisms in the genes encoding sodium-dependent vitamin C transport proteins are strongly associated with plasma ascorbate levels and likely impact tissue cellular vitamin C status. Furthermore, genetic variants of proteins that suppress oxidative stress or detoxify oxidatively damaged biomolecules, i.e., haptoglobin, glutathione-S-transferases, and possibly manganese superoxide dismutase, affect ascorbate levels in the human body. There also is limited evidence for a role of glucose transport proteins. In this review, we examine the extent of the variation in these genes, their impact on vitamin C status, and their potential role in altering chronic disease risk. We conclude that future epidemiological studies should take into account genetic variation in order to successfully determine the role of vitamin C nutriture or supplementation in human vitamin C status and chronic disease risk. PMID:23642198

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

    PubMed

    Grnblatt, 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. PMID:25046835

  1. The Scope of Our Affective Influences: When and How Naturally Occurring Positive, Negative, and Neutral Affects Alter Judgment.

    PubMed

    Gasper, Karen; Danube, Cinnamon L

    2016-03-01

    To determine how naturally arising affect alters judgment, we examined whether (a) affective states exert a specific, rather than a general, influence on valenced-specific judgments; (b) neutral affect is associated with increased neutral judgments, independent of positive, negative, and ambivalent affects, and whether neutral judgments are associated with behavioral disengagement; and (c) the informational value of naturally arising states may be difficult to alter via salience and relevance manipulations. The results support several conclusions: (a) Affective states exerted a judgment-specific effect-positive affect was most strongly associated with positive judgments, negative affect with negative judgments, and neutral affect with neutral judgments. (b) Neutral affect influenced judgments, taking into account positive, negative, and ambivalent affects; and neutral judgments predicted behavioral disengagement. (c) With the exception of negative affect, naturally arising affective states typically influenced judgments regardless of their salience and relevance. PMID:26865292

  2. Large-scale natural disturbance alters genetic population structure of the sailfin molly, Poecilia latipinna.

    PubMed

    Apodaca, Joseph J; Trexler, Joel C; Jue, Nathaniel K; Schrader, Matthew; Travis, Joseph

    2013-02-01

    Many inferences about contemporary rates of gene flow are based on the assumption that the observed genetic structure among populations is stable. Recent studies have uncovered several cases in which this assumption is tenuous. Most of those studies have focused on the effects that regular environmental fluctuations can have on genetic structure and gene flow patterns. Occasional catastrophic disturbances could also alter either the distribution of habitat or the spatial distribution of organisms in a way that affects population structure. However, evidence of such effects is sparse in the literature because it is difficult to obtain. Hurricanes, in particular, have the potential to exert dramatic effects on population structure of organisms found on islands or coral reefs or in near shore and coastal habitats. Here we draw on a historic genetic data set and new data to suggest that the genetic structure of sailfin molly (Poecilia latipinna) populations in north Florida was altered dramatically by an unusually large and uncommon type of storm surge associated with Hurricane Dennis in 2005. We compare the spatial pattern of genetic variation in these populations after Hurricane Dennis to the patterns described in an earlier study in this same area. We use comparable genetic data from another region of Florida, collected in the same two periods, to estimate the amount of change expected from typical temporal variation in population structure. The comparative natural history of sailfin mollies in these two regions indicates that the change in population structure produced by the storm surge is not the result of many local extinctions with recolonization from a few refugia but emerged from a pattern of mixing and redistribution. PMID:23348779

  3. 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.

  4. How spatio-temporal habitat connectivity affects amphibian genetic structure

    PubMed Central

    Watts, Alexander G.; Schlichting, Peter E.; Billerman, Shawn M.; Jesmer, Brett R.; Micheletti, Steven; Fortin, Marie-Josée; Funk, W. Chris; Hapeman, Paul; Muths, Erin; Murphy, Melanie A.

    2015-01-01

    Heterogeneous landscapes and fluctuating environmental conditions can affect species dispersal, population genetics, and genetic structure, yet understanding how biotic and abiotic factors affect population dynamics in a fluctuating environment is critical for species management. We evaluated how spatio-temporal habitat connectivity influences dispersal and genetic structure in a population of boreal chorus frogs (Pseudacris maculata) using a landscape genetics approach. We developed gravity models to assess the contribution of various factors to the observed genetic distance as a measure of functional connectivity. We selected (a) wetland (within-site) and (b) landscape matrix (between-site) characteristics; and (c) wetland connectivity metrics using a unique methodology. Specifically, we developed three networks that quantify wetland connectivity based on: (i) P. maculata dispersal ability, (ii) temporal variation in wetland quality, and (iii) contribution of wetland stepping-stones to frog dispersal. We examined 18 wetlands in Colorado, and quantified 12 microsatellite loci from 322 individual frogs. We found that genetic connectivity was related to topographic complexity, within- and between-wetland differences in moisture, and wetland functional connectivity as contributed by stepping-stone wetlands. Our results highlight the role that dynamic environmental factors have on dispersal-limited species and illustrate how complex asynchronous interactions contribute to the structure of spatially-explicit metapopulations. PMID:26442094

  5. Genetic and environmental factors that affect gestation length

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic and environmental factors that might affect gestation length (GL) were investigated so that more accurate predictions of calving dates could be provided to dairy producers. Data from >8 million calvings from 1999 through 2005 for 5 dairy breeds were assembled from lactation, reproduction, an...

  6. Alterations in psychosocial health of people affected by asbestos poisoning

    PubMed Central

    Clemente, Miguel; Reig-Botella, Adela; Prados, Juan Carlos

    2015-01-01

    OBJECTIVE To analyze the state of psychosocial and mental health of professionals affected by asbestos. METHODS A cross-sectional study was conducted with 110 professionals working in the Ferrolterra region of Spain, who were affected by asbestos poisoning. This group was compared with a group of 70 shipyard workers with no manifestation of work-related diseases. All the participants were male with a mean age of 67 years. This study was conducted in 2013, between January and June, and used the SCL-90 questionnaire by Derogatis as its primary measure for research. This questionnaire consists of 9 variables that measure psychosomatic symptoms. In addition, an overall index of psychosomatic gravity was calculated. The participants were also asked two questions concerning their overall perception of feeling good. Data were analyzed by ANOVA and logistic regression. RESULTS Participants affected by asbestos poisoning showed high occurrence rates of psychological health variables such as somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism, and global severity index. CONCLUSIONS Social interaction as a differentiating factor between workers affected by work-related chronic syndromes as compared to healthy participants will possibly aid in the development of intervention programs by improving the social network of affected individuals. PMID:25902564

  7. Altered Hemodynamics in the Embryonic Heart Affects Outflow Valve Development

    PubMed Central

    Menon, Vinal; Eberth, John F.; Goodwin, Richard L.; Potts, Jay D.

    2016-01-01

    Cardiac valve structure and function are primarily determined during early development. Consequently, abnormally-formed heart valves are the most common type of congenital heart defects. Several adult valve diseases can be backtracked to abnormal valve development, making it imperative to completely understand the process and regulation of heart valve development. Epithelial-to-mesenchymal transition (EMT) plays an important role in the development of heart valves. Though hemodynamics is vital to valve development, its role in regulating EMT is still unknown. In this study, intracardiac hemodynamics were altered by constricting the outflow tract (OFT)/ventricle junction (OVJ) of HH16–17 (Hamilton and Hamburger (HH) Stage 16–17) chicken embryos, ex ovo for 24 h. The constriction created an increase in peak and time-averaged centerline velocity along the OFT without changes to volumetric flow or heart rate. Computational fluid dynamics was used to estimate the level of increased spatially-averaged wall shear stresses on the OFT cushion from AMIRA reconstructions. OFT constriction led to a significant decrease in OFT cushion volume and the number of invaded mesenchyme in the OFT cushion. qPCR analysis revealed altered mRNA expression of a representative panel of genes, vital to valve development, in the OFT cushions from banded hearts. This study indicates the importance of hemodynamics in valve development. PMID:26878022

  8. Body Weight Selection Affects Quantitative Genetic Correlated Responses in Gut Microbiota

    PubMed Central

    Zhao, Lele; Zhao, Wenjing; He, Chuan; Honaker, Christa F.; Zhai, Zhengxiao; Sun, Zikui; Siegel, Paul B.

    2014-01-01

    The abundance of gut microbiota can be viewed as a quantitative trait, which is affected by the genetics and environment of the host. To quantify the effects of host genetics, we calculated the heritability of abundance of specific microorganisms and genetic correlations among them in the gut microbiota of two lines of chickens maintained under the same husbandry and dietary regimes. The lines, which originated from a common founder population, had undergone >50 generations of selection for high (HW) or low (LW) 56-day body weight and now differ by more than 10-fold in body weight at selection age. We identified families of Paenibacillaceae, Streptococcaceae, Helicobacteraceae, and Burkholderiaceae that had moderate heritabilities. Although there were no obvious phenotypic correlations among gut microbiota, significant genetic correlations were observed. Moreover, the effects were modified by genetic selection for body weight, which altered the quantitative genetic background of the host. Heritabilities for Bacillaceae, Flavobacteriaceae, Helicobacteraceae, Comamonadaceae, Enterococcaceae, and Streptococcaceae were moderate in LW line and little to zero in the HW line. These results suggest that loci associated with these microbiota families, while exhibiting genetic variation in LW, have been fixed in HW line. Also, long term selection for body weight has altered the genetic correlations among gut microbiota. No microbiota families had significant heritabilities in both the LW and HW lines suggesting that the presence and/or absence of a particular microbiota family either has a strong growth promoting or inhibiting effect, but not both. These results demonstrate that the quantitative genetics of the host have considerable influence on the gut microbiota. PMID:24608294

  9. Body weight selection affects quantitative genetic correlated responses in gut microbiota.

    PubMed

    Meng, He; Zhang, Yan; Zhao, Lele; Zhao, Wenjing; He, Chuan; Honaker, Christa F; Zhai, Zhengxiao; Sun, Zikui; Siegel, Paul B

    2014-01-01

    The abundance of gut microbiota can be viewed as a quantitative trait, which is affected by the genetics and environment of the host. To quantify the effects of host genetics, we calculated the heritability of abundance of specific microorganisms and genetic correlations among them in the gut microbiota of two lines of chickens maintained under the same husbandry and dietary regimes. The lines, which originated from a common founder population, had undergone >50 generations of selection for high (HW) or low (LW) 56-day body weight and now differ by more than 10-fold in body weight at selection age. We identified families of Paenibacillaceae, Streptococcaceae, Helicobacteraceae, and Burkholderiaceae that had moderate heritabilities. Although there were no obvious phenotypic correlations among gut microbiota, significant genetic correlations were observed. Moreover, the effects were modified by genetic selection for body weight, which altered the quantitative genetic background of the host. Heritabilities for Bacillaceae, Flavobacteriaceae, Helicobacteraceae, Comamonadaceae, Enterococcaceae, and Streptococcaceae were moderate in LW line and little to zero in the HW line. These results suggest that loci associated with these microbiota families, while exhibiting genetic variation in LW, have been fixed in HW line. Also, long term selection for body weight has altered the genetic correlations among gut microbiota. No microbiota families had significant heritabilities in both the LW and HW lines suggesting that the presence and/or absence of a particular microbiota family either has a strong growth promoting or inhibiting effect, but not both. These results demonstrate that the quantitative genetics of the host have considerable influence on the gut microbiota. PMID:24608294

  10. Altered emotional perception in alcoholics: deficits in affective prosody comprehension.

    TOXLINE Toxicology Bibliographic Information

    Monnot M; Nixon S; Lovallo W; Ross E

    2001-03-01

    BACKGROUND: Affective prosody is a nonlinguistic aspect of language that conveys emotion and attitude during discourse. It is a dominant function of the right hemisphere. Because skills associated with the right hemisphere have been found to be impaired in alcoholics, this study explored the possibility that affective prosodic functioning may be sensitive to the effects of alcohol due to heavy persistent drinking or prenatal exposure.METHODS: Subjects were aged 25 to 58 years. Twenty-nine men and three women who met DSM-IV criteria for an alcohol use disorder with a median of 39 days of sobriety, 11 men with a probable history of fetal alcohol exposure (FAexp), and 41 age-matched control subjects of both sexes were tested by using the Aprosodia Battery. This instrument assesses affective prosodic comprehension (APC) across a range of verbal articulatory demands.RESULTS: The alcoholic group scored 2 SD below the control mean, and the FAexp group scored -5 SD regardless of whether they had ever been diagnosed with alcohol abuse. Despite their poor performance on APC, alcoholic and FAexp groups performed similarly to the control group on vocabulary, abstract reasoning, and an index of cognitive impairment that used the Shipley Institute of Living Scale. Multiple regression analyses that used nine alcohol use variables to model APC resulted in four significant contributors to the effect. These regressors were related to early exposure to ethanol and chronicity of alcohol abuse.CONCLUSIONS: Alcoholics and FAexp subjects were significantly less accurate at APC compared with controls. These alcohol-exposed subjects appear to be deficient in the ability to understand emotional valence in the speech of others, which results in errors of judgment that may impair social interactions.

  11. The Afterlife of Interspecific Indirect Genetic Effects: Genotype Interactions Alter Litter Quality with Consequences for Decomposition and Nutrient Dynamics

    PubMed Central

    Genung, Mark A.; Bailey, Joseph K.; Schweitzer, Jennifer A.

    2013-01-01

    Aboveground-belowground linkages are recognized as divers of community dynamics and ecosystem processes, but the impacts of plant-neighbor interactions on these linkages are virtually unknown. Plant-neighbor interactions are a type of interspecific indirect genetic effect (IIGE) if the focal plants phenotype is altered by the expression of genes in a neighboring heterospecific plant, and IIGEs could persist after plant senescence to affect ecosystem processes. This perspective can provide insight into how plant-neighbor interactions affect evolution, as IIGEs are capable of altering species interactions and community composition over time. Utilizing genotypes of Solidago altissima and Solidago gigantea, we experimentally tested whether IIGEs that had affected living focal plants would affect litter decomposition rate, as well as nitrogen (N) and phosphorous (P) dynamics after the focal plant senesced. We found that species interactions affected N release and genotype interactions affected P immobilization. From a previous study we knew that neighbor genotype influenced patterns of biomass allocation for focal plants. Here we extend those previous results to show that these changes in biomass allocation altered litter quality, that then altered rates of decomposition and nutrient cycling. Our results provide insights into above- and belowground linkages by showing that, through their effects on plant litter quality (e.g., litter lignin:N), IIGEs can have afterlife effects, tying plant-neighbor interactions to ecosystem processes. This holistic approach advances our understanding of decomposition and nutrient cycling by showing that evolutionary processes (i.e., IIGEs) can influence ecosystem functioning after plant senescence. Because plant traits are determined by the combined effects of genetic and environmental influences, and because these traits are known to affect decomposition and nutrient cycling, we suggest that ecosystem processes can be described as gene-less products of genetic interactions among the species comprising ecological communities. PMID:23349735

  12. Production of extracellular nucleic acids by genetically altered bacteria in aquatic-environment microcosms.

    PubMed

    Paul, J H; David, A W

    1989-08-01

    The factors which affect the production of extracellular DNA by genetically altered strains of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas cepacia, and Bradyrhizobium japonicum in aquatic environments were investigated. Cellular nucleic acids were labeled in vivo by incubation with [3H]thymidine or [3H]adenine, and production of extracellular DNA in marine waters, artificial seawater, or minimal salts media was determined by detecting radiolabeled macromolecules in incubation filtrates. The presence or absence of the ambient microbial community had little effect on the production of extracellular DNA. Three of four organisms produced the greatest amounts of extracellular nucleic acids when incubated in low-salinity media (2% artificial seawater) rather than high-salinity media (10 to 50% artificial seawater). The greatest production of extracellular nucleic acids by P. cepacia occurred at pH 7 and 37 degrees C, suggesting that extracellular-DNA production may be a normal physiologic function of the cell. Incubation of labeled P. cepacia cells in water from Bimini Harbor, Bahamas, resulted in labeling of macromolecules of the ambient microbial population. Collectively these results indicate that (i) extracellular-DNA production by genetically altered bacteria released into aquatic environments is more strongly influenced by physiochemical factors than biotic factors, (ii) extracellular-DNA production rates are usually greater for organisms released in freshwater than marine environments, and (iii) ambient microbial populations can readily utilize materials released by these organisms. PMID:2506807

  13. 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 ? (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 suggests that the molecular pathogenesis of PA-MPC may be different from that of other adenocarcinomas. PMID:26893860

  14. 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

  15. Combined genetic and imaging diagnosis for two large Chinese families affected with Pelizaeus-Merzbacher disease.

    PubMed

    Lv, Y; Cao, L H; Pang, H; Lu, L N; Li, J L; Fu, Y; Qi, S L; Luo, Y; Li-Ling, J

    2012-01-01

    Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder characterized by nystagmus, impaired motor development, ataxia, and progressive spasticity. Genetically defective or altered levels of proteolipid protein (PLP1) or gap-junction alpha protein 12 gene have been found to be a common cause. Here we report on two large Han Chinese families affected with this disease. The probands of both families had produced sons featuring cerebral palsy that had never been correctly diagnosed. PMD was suspected after careful analysis of family history and clinical features. Three rounds of molecular testing, including RT-PCR, genetics linkage and SRY sequence analyses, in combination with fetal ultrasound and magnetic resonance imaging, confirmed the diagnosis. In Family 1, in addition to two patients, three carriers were identified, including one who was not yet married. Genetic testing indicated that a fetus did not have the disease. A healthy girl was born later. In Family 2, two patients and two carriers were identified, while a fetus was genetically normal. A healthy girl was born later. We concluded that by combining genetic testing and imaging, awareness of the symptoms of PMD and understanding of its molecular biology, there is great benefit for families that are at risk for producing offspring affected with this severe disease. PMID:22911587

  16. Tooth dentin defects reflect genetic disorders affecting bone mineralization.

    PubMed

    Opsahl Vital, S; Gaucher, C; Bardet, C; Rowe, P S; George, A; Linglart, A; Chaussain, C

    2012-04-01

    Several genetic disorders affecting bone mineralization may manifest during dentin mineralization. Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix (ECM) which is secreted by well-differentiated odontoblasts and osteoblasts, respectively. However, unlike bone, dentin is not remodelled and is not involved in the regulation of calcium and phosphate metabolism. In contrast to bone, teeth are accessible tissues with the shedding of deciduous teeth and the extractions of premolars and third molars for orthodontic treatment. The feasibility of obtaining dentin makes this a good model to study biomineralization in physiological and pathological conditions. In this review, we focus on two genetic diseases that disrupt both bone and dentin mineralization. Hypophosphatemic rickets is related to abnormal secretory proteins involved in the ECM organization of both bone and dentin, as well as in the calcium and phosphate metabolism. Osteogenesis imperfecta affects proteins involved in the local organization of the ECM. In addition, dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth. In conclusion, dentin constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization. PMID:22296718

  17. Tooth dentin defects reflect genetic disorders affecting bone mineralization

    PubMed Central

    Vital, S. Opsahl; Gaucher, C.; Bardet, C.; Rowe, P.S.; George, A.; Linglart, A.; Chaussain, C.

    2012-01-01

    Several genetic disorders affecting bone mineralization may manifest during dentin mineralization. Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix (ECM) which is secreted by well-differentiated odontoblasts and osteoblasts, respectively. However, unlike bone, dentin is not remodelled and is not involved in the regulation of calcium and phosphate metabolism. In contrast to bone, teeth are accessible tissues with the shedding of deciduous teeth and the extractions of premolars and third molars for orthodontic treatment. The feasibility of obtaining dentin makes this a good model to study biomineralization in physiological and pathological conditions. In this review, we focus on two genetic diseases that disrupt both bone and dentin mineralization. Hypophosphatemic rickets is related to abnormal secretory proteins involved in the ECM organization of both bone and dentin, as well as in the calcium and phosphate metabolism. Osteogenesis imperfecta affects proteins involved in the local organization of the ECM. In addition, dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth. In conclusion, dentin constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization. PMID:22296718

  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. Gene flow in genetically altered crops helps progress transgenic turfgrass.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Numerous useful traits are being imparted into transgenic and non-transgenic plants. Gene flow as indicated in a recent publication from the Council for Agricultural Science and Technology (CAST 2007) is the successful transfer of genetic information between different individuals, populations, and g...

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

    PubMed Central

    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 (FIS 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. PMID:20216571

  2. 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 (?=0.005, 95% confidence interval (CI) -0.003 to 0.017), we found significant genetic differentiation among populations post-disease (?=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. PMID:20216571

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

    PubMed

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

    2015-12-01

    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 expected from complex environments with many obstacles. PMID:26696601

  4. Genetic alteration of Zymomonas mobilis for ethanol production

    SciTech Connect

    Skotnicki, M.L.; Lee, K.J.; Tribe, D.E.; Rogers, P.L.

    1982-01-01

    Strain improvement by mutagenesis with UV resulted in Zymomonas mobilis strains which were highly EtOH and temperature tolerant and which were able to produce more than 100 g EtOH /h at EtOH concentrations of 80-90 g/L. Genetic engineering has the potential of producing strains with the ability to ferment starch and cellulose directly to EtOH.

  5. 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 expected from complex environments with many obstacles. PMID:26696601

  6. Environmental and genetic factors affecting cow survival of Israeli Holsteins.

    PubMed

    Weller, J I; Ezra, E

    2015-01-01

    The objectives were to investigate the effects of various environmental factors that may affect herd-life of Israeli Holsteins, including first-calving age and season, calving ease, number of progeny born, and service sire for first calving in complete and truncated records; and to estimate heritabilities and genetic correlations between herd-life and the other traits included in the Israeli breeding index. The basic data set consisted of 590,869 cows in milk recording herds with first freshening day between 1985 and at least 8 yr before the cut-off date of September 15, 2013. Herd-life was measured as days from first calving to culling. The phenotypic and genetic trends for herd-life were 5.7 and 16.8d/yr. The genetic trend was almost linear, whereas the phenotypic trend showed 4 peaks and 3 valleys. Cows born in February and March had the shortest herd-life, whereas cows born in September had the longest herd-life. Herd-life was maximal with calving age of 23mo, which is 1mo less than the mean calving age, and minimal at 19 and 31mo of calving age. Dystocia and twinning on first-parity calving reduced herd-life by approximately180 and 120d, but the interaction effect increased herd-life by 140d. Heritability for herd-life was 0.14. Despite the fact that the service sire effect was significant in the fixed model analysis, service sire effect accounted for <0.05% of the total variance. In the analysis of 1,431,938 truncated records, the effects of dystocia and twinning rate were very similar but less than 50% of the effects found in the analysis of complete records. Pregnancy at the truncation date increased expected herd-life by 432d. The correlation between actual herd-life and predicted herd-life based on truncated records was 0.44. Genetic correlations between the truncated records and actual herd-life were 0.75 for records truncated after 6mo but approached unity for records truncated after 3 yr. The genetic correlations of herd-life with first-parity milk, fat, and protein production, somatic cell score (SCS), and female fertility were all positive, except for SCS, in which negative values are economically favorable. The highest correlations with herd-life in absolute value were with female fertility and SCS. PMID:25468704

  7. Cause and Consequences of Genetic and Epigenetic Alterations in Human Cancer

    PubMed Central

    Sadikovic, B; Al-Romaih, K; Squire, J.A; Zielenska, M

    2008-01-01

    Both genetic and epigenetic changes contribute to development of human cancer. Oncogenomics has primarily focused on understanding the genetic basis of neoplasia, with less emphasis being placed on the role of epigenetics in tumourigenesis. Genomic alterations in cancer vary between the different types and stages, tissues and individuals. Moreover, genomic change ranges from single nucleotide mutations to gross chromosomal aneuploidy; which may or may not be associated with underlying genomic instability. Collectively, genomic alterations result in widespread deregulation of gene expression profiles and the disruption of signalling networks that control proliferation and cellular functions. In addition to changes in DNA and chromosomes, it has become evident that oncogenomic processes can be profoundly influenced by epigenetic mechanisms. DNA methylation is one of the key epigenetic factors involved in regulation of gene expression and genomic stability, and is biologically necessary for the maintenance of many cellular functions. While there has been considerable progress in understanding the impact of genetic and epigenetic mechanisms in tumourigenesis, there has been little consideration of the importance of the interplay between these two processes. In this review we summarize current understanding of the role of genetic and epigenetic alterations in human cancer. In addition we consider the associated interactions of genetic and epigenetic processes in tumour onset and progression. Furthermore, we provide a model of tumourigenesis that addresses the combined impact of both epigenetic and genetic alterations in cancer cells. PMID:19506729

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

    PubMed

    Caciotti, Anna; Garman, Scott C; Rivera-Coln, 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

    2011-07-01

    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 acid 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

  9. A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis.

    PubMed

    Remy, Elisabeth; Rebouissou, Sandra; Chaouiya, Claudine; Zinovyev, Andrei; Radvanyi, François; Calzone, Laurence

    2015-10-01

    Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer. PMID:26238783

  10. 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

  11. 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. PMID:25155242

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

    PubMed Central

    Domingues, Patrcia; Gonzlez-Tablas, Mara; Otero, lvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonalves, Jess Mara; Lopes, Mara Celeste; Orfao, Alberto; Tabernero, Mara 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

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

    PubMed

    Domingues, Patrcia; Gonzlez-Tablas, Mara; Otero, lvaro; Pascual, Daniel; Ruiz, Laura; Miranda, David; Sousa, Pablo; Gonalves, Jess Mara; Lopes, Mara Celeste; Orfao, Alberto; Tabernero, Mara Dolores

    2015-05-10

    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

  14. 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. PMID:26644303

  15. The Potential for Genetically Altered Microglia to Influence Glioma Treatment

    PubMed Central

    Li, W.; Holsinger, R.M.D.; Kruse, C.A.; Flügel, A.; Graeber, M.B.

    2014-01-01

    Diffuse and unstoppable infiltration of brain and spinal cord tissue by neoplastic glial cells is the single most important therapeutic problem posed by the common glioma group of tumors: astrocytoma, oligoastrocytoma, oligodendroglioma, their malignant variants and glioblastoma. These neoplasms account for more than two thirds of all malignant central nervous system tumors. However, most glioma research focuses on an examination of the tumor cells rather than on host-specific, tumor micro-environmental cells and factors. This can explain why existing diffuse glioma therapies fail and why these tumors have remained incurable. Thus, there is a great need for innovation. We describe a novel strategy for the development of a more effective treatment of diffuse glioma. Our approach centers on gaining control over the behavior of the microglia, the defense cells of the CNS, which are manipulated by malignant glioma and support its growth. Armoring microglia against the influences from glioma is one of our research goals. We further discuss how microglia precursors may be genetically enhanced to track down infiltrating glioma cells. PMID:24047526

  16. Genetic alterations in periprosthetic soft-tissue masses from patients with metal-on-metal hip replacement.

    PubMed

    Sarhadi, Virinder Kaur; Parkkinen, Jyrki; Reito, Aleksi; Nieminen, Jyrki; Porkka, Noora; Wirtanen, Tiina; Laitinen, Minna; Eskelinen, Antti; Knuutila, Sakari

    2015-11-01

    Adverse soft tissue reactions in patients with metal-on-metal (MoM) hip replacement are associated with cobalt (Co) and chromium (Cr) particles released from the implant. Exposing the patients to long periods of increased metal ions concentrations resulting from the wear of these implants poses an increased risk of genotoxicity/mutagenicity. A variable proportion of patients develop periprosthetic soft-tissue masses or pseudotumors at the site of the implant. There is a concern that exposure to increased metal ions could increase the risk of cancer. In order to investigate whether the periprosthetic soft-tissue mass harbours any cancer- related genetic alterations, we studied DNA isolated from periprosthetic tissues of 20 patients with MoM hip replacement, for copy number alterations and mutations in hotspot regions of 50 cancer genes using aCGH and amplicon-based next generation sequencing. Our results showed copy number gains at 12q14.3 and 21q21.1in tumour from patient diagnosed with liposarcoma. Copy number alterations in periprosthetic tissues were seen in three other patients, one had a region of gain at 9q24.1 affecting JAK2 and INSL6, and two patients had region of gain at 6p21.1, affecting RUNX2. Mutation analysis showed V1578del mutation in NOTCH1 in two patients. The copy number alterations and mutations seen in periprosthetic soft-tissue masses are earlier reported in either haematological malignancies or in osteoblast related bone dysplasia. The presence of genetic anomalies was associated with longer in-situ time of the implant. Our findings warrant the need of similar studies in larger patient cohorts to evaluate the risk of development of neoplastic alterations in periprosthetic tissues of patients with MoM hip replacement. PMID:26355908

  17. Neonatal handling alters the structure of maternal behavior and affects mother-pup bonding.

    PubMed

    Reis, A R; de Azevedo, M S; de Souza, M A; Lutz, M L; Alves, M B; Izquierdo, I; Cammarota, M; Silveira, P P; Lucion, A B

    2014-05-15

    During early life, a mother and her pups establish a very close relationship, and the olfactory learning of the nest odor is very important for the bond formation. The olfactory bulb (OB) is a structure that plays a fundamental role in the olfactory learning (OL) mechanism that also involves maternal behavior (licking and contact). We hypothesized that handling the pups would alter the structure of the maternal behavior, affect OL, and alter mother-pup relationships. Moreover, changes in the cyclic AMP-response element binding protein phosphorylation (CREB) and neurotrophic factors could be a part of the mechanism of these changes. This study aimed to analyze the effects of neonatal handling, 1 min per day from postpartum day 1 to 10 (PPD 1 to PPD 10), on the maternal behavior and pups' preference for the nest odor in a Y maze (PPD 11). We also tested CREB's phosphorylation and BDNF signaling in the OB of the pups (PPD 7) by Western blot analysis. The results showed that handling alters mother-pups interaction by decreasing mother-pups contact and changing the temporal pattern of all components of the maternal behavior especially the daily licking and nest-building. We found sex-dependent changes in the nest odor preference, CREB and BDNF levels in pups OB. Male pups were more affected by alterations in the licking pattern, and female pups were more affected by changes in the mother-pup contact (the time spent outside the nest and nursing). PMID:24598277

  18. Genetic variations alter production and behavioral responses following heat stress in two strains of laying hens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heat stress is a problem for both egg production and hen well-being. Given a stressor, genetic differences alter the type and degree of hens’ responses and their adaptation. This study examined heat stress responses of two strains of White Leghorns: Dekalb XL (DXL), a commercial strain individually ...

  19. Screening for GNAS genetic and epigenetic alterations in progressive osseous heteroplasia: first Italian series.

    PubMed

    Elli, F M; Barbieri, A M; Bordogna, P; Ferrari, P; Bufo, R; Ferrante, E; Giardino, E; Beck-Peccoz, P; Spada, A; Mantovani, G

    2013-10-01

    Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder. PMID:23796510

  20. Altered gene dosage confirms the genetic interaction between FIAT and αNAC.

    PubMed

    Hekmatnejad, Bahareh; Mandic, Vice; Yu, Vionnie W C; Akhouayri, Omar; Arabian, Alice; St-Arnaud, René

    2014-04-01

    Factor inhibiting ATF4-mediated transcription (FIAT) interacts with Nascent polypeptide associated complex and coregulator alpha (αNAC). In cultured osteoblastic cells, this interaction contributes to maximal FIAT-mediated inhibition of Osteocalcin (Ocn) gene transcription. We set out to demonstrate the physiological relevance of this interaction by altering gene dosage in compound Fiat and Naca (encoding αNAC) heterozygous mice. Compound Naca(+/-); Fiat(+/-) heterozygous animals were viable, developed normally, and exhibited no significant difference in body weight compared with control littermate genotypes. Animals with a single Fiat allele had reduced Fiat mRNA expression without changes in the expression of related family members. Expression of the osteocyte differentiation marker Dmp1 was elevated in compound heterozygotes. Static histomorphometry parameters were assessed at 8weeks of age using microcomputed tomography (μCT). Trabecular measurements were not different between genotypes. Cortical thickness and area were not affected by gene dosage, but we measured a significant increase in cortical porosity in compound heterozygous mice, without changes in biomechanical parameters. The bone phenotype of compound Naca(+/-); Fiat(+/-) heterozygotes confirms that FIAT and αNAC are part of a common genetic pathway and support a role for the FIAT/αNAC interaction in normal bone physiology. PMID:24440290

  1. Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases.

    PubMed

    Tuna, Musaffe; Machado, Andreia S; Calin, George A

    2016-03-01

    MicroRNAs (miRNAs) are a well-studied group of noncoding RNAs that control gene expression by interacting mainly with messenger RNA. It is known that miRNAs and their biogenesis regulatory machineries have crucial roles in multiple cell processes; thus, alterations in these genes often lead to disease, such as cancer. Disruption of these genes can occur through epigenetic and genetic alterations, resulting in aberrant expression of miRNAs and subsequently of their target genes. This review focuses on the disruption of miRNAs and their key regulatory machineries by genetic alterations, with emphasis on mutations and epigenetic changes in cancer and other diseases. 2015 Wiley Periodicals, Inc. PMID:26651018

  2. Genetic Characterization of Ten-Eleven-Translocation Methylcytosine Dioxygenase Alterations in Human Glioma

    PubMed Central

    Kraus, Theo F. J.; Greiner, Andrea; Steinmaurer, Martina; Dietinger, Vanessa; Guibourt, Virginie; Kretzschmar, Hans A.

    2015-01-01

    The molecular mechanisms leading to brain tumors still remain unclear. Nevertheless, there is increasing evidence that epigenetic effects play crucial roles in tumor development and progression. Thereby, 5-hydroxymethylcytosine (5hmC) represents a further base modification of cytosine besides 5-methylcytosine (5mC). In addition to the role of 5hmC as an intermediate in demethylation, 5hmC is of reasonable importance for cellular control. Previous studies showed that loss of 5hmC is a hallmark of human malignancies, e.g. in glioma, melanoma, and myeloid tumors. In myeloid malignancies studies showed that loss of 5hmC was due to mutations within ten-eleven-translocation (TET) genes, enzymes being responsible for conversion of 5mC to 5hmC. Nevertheless, till date there are no genetic characterization data of TET enzymes available for glioma. In this study, we genetically characterized TET2 and TET3 alterations in 50 human gliomas (WHO-Grade II-IV) and in 19 healthy brain samples. We identified 7 genetic alterations within TET2 (p.V218M, p.G355N, p.P363L, p.L1721W, p.P1723S, p.I1762V, p.H1778R). Additionally, we performed quantification of 5hmC amount and added functional prediction analysis of identified TET alterations to evaluate the biological impact of these alterations on the hydroxymethylome. An analysis of TET3 showed no non-synonymous alterations. In summary, we did not find correlations of TET alterations with 5hmC amount. Thus, our data emphasize that, in contrast to leukemia, loss of 5hmC in glioma is not caused by TET gene alterations. Moreover, other disturbances, such as disrupted gene expressions or functional inhibitions of TET proteins may be responsible for the aberrant epigenome of human glioma. PMID:26284134

  3. Do Knowledge Arrangements Affect Student Reading Comprehension of Genetics?

    ERIC Educational Resources Information Center

    Wu, Jen-Yi; Tung, Yu-Neng; Hwang, Bi-Chi; Lin, Chen-Yung; Che-Di, Lee; Chang, Yung-Ta

    2014-01-01

    Various sequences for teaching genetics have been proposed. Three seventh-grade biology textbooks in Taiwan share similar key knowledge assemblages but have different knowledge arrangements. To investigate the influence of knowledge arrangements on student understanding of genetics, we compared students' reading comprehension of the three…

  4. Do Knowledge Arrangements Affect Student Reading Comprehension of Genetics?

    ERIC Educational Resources Information Center

    Wu, Jen-Yi; Tung, Yu-Neng; Hwang, Bi-Chi; Lin, Chen-Yung; Che-Di, Lee; Chang, Yung-Ta

    2014-01-01

    Various sequences for teaching genetics have been proposed. Three seventh-grade biology textbooks in Taiwan share similar key knowledge assemblages but have different knowledge arrangements. To investigate the influence of knowledge arrangements on student understanding of genetics, we compared students' reading comprehension of the three

  5. 33 CFR 149.15 - What is the process for submitting alterations and modifications affecting the design and...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... submitting alterations and modifications affecting the design and construction of a deepwater port? 149.15...) DEEPWATER PORTS DEEPWATER PORTS: DESIGN, CONSTRUCTION, AND EQUIPMENT General § 149.15 What is the process for submitting alterations and modifications affecting the design and construction of a deepwater...

  6. 33 CFR 149.15 - What is the process for submitting alterations and modifications affecting the design and...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... submitting alterations and modifications affecting the design and construction of a deepwater port? 149.15...) DEEPWATER PORTS DEEPWATER PORTS: DESIGN, CONSTRUCTION, AND EQUIPMENT General § 149.15 What is the process for submitting alterations and modifications affecting the design and construction of a deepwater...

  7. 33 CFR 149.15 - What is the process for submitting alterations and modifications affecting the design and...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... submitting alterations and modifications affecting the design and construction of a deepwater port? 149.15...) DEEPWATER PORTS DEEPWATER PORTS: DESIGN, CONSTRUCTION, AND EQUIPMENT General § 149.15 What is the process for submitting alterations and modifications affecting the design and construction of a deepwater...

  8. 33 CFR 149.15 - What is the process for submitting alterations and modifications affecting the design and...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... submitting alterations and modifications affecting the design and construction of a deepwater port? 149.15...) DEEPWATER PORTS DEEPWATER PORTS: DESIGN, CONSTRUCTION, AND EQUIPMENT General § 149.15 What is the process for submitting alterations and modifications affecting the design and construction of a deepwater...

  9. 33 CFR 149.15 - What is the process for submitting alterations and modifications affecting the design and...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... submitting alterations and modifications affecting the design and construction of a deepwater port? 149.15...) DEEPWATER PORTS DEEPWATER PORTS: DESIGN, CONSTRUCTION, AND EQUIPMENT General § 149.15 What is the process for submitting alterations and modifications affecting the design and construction of a deepwater...

  10. Predictors of uptake of obesity genetic testing among affected adults.

    PubMed

    Segal, Mary E; Polansky, Marcia; Sankar, Pamela

    2007-01-01

    Given that a large number of candidate genes coding for a tendency toward obesity have been identified and some findings have been replicated, we explored characteristics of those who would be most likely to obtain future genetic testing for this tendency. During a series of focus groups, obese respondents rated their likelihood of obtaining testing under conditions in which either genetically-targeted drug treatment would be available, a positive test would be associated with a prognosis for developing diabetes, or neither of these. Interest in testing was greater given the first two scenarios than the third. Older age and belief that genetics were an important cause of obesity were associated with greater interest. For the first two scenarios, higher educational status was associated with greater interest, while for the third, respondents who said emotional issues caused overweight and those who crash-dieted intermittently were more likely to want genetic testing. Although further research is required to validate these findings, this study is the first published report of respondents' ratings of likelihood to obtain genetic testing for propensity to obesity, and suggests strong interest in genetic testing among some people, even in the absence of further treatment implications of the test. PMID:17024370

  11. Use of Genetically Altered Stem Cells for the Treatment of Huntington's Disease.

    PubMed

    Crane, Andrew T; Rossignol, Julien; Dunbar, Gary L

    2014-01-01

    Transplantation of stem cells for the treatment of Huntington's disease (HD) garnered much attention prior to the turn of the century. Several studies using mesenchymal stem cells (MSCs) have indicated that these cells have enormous therapeutic potential in HD and other disorders. Advantages of using MSCs for cell therapies include their ease of isolation, rapid propagation in culture, and favorable immunomodulatory profiles. However, the lack of consistent neuronal differentiation of transplanted MSCs has limited their therapeutic efficacy to slowing the progression of HD-like symptoms in animal models of HD. The use of MSCs which have been genetically altered to overexpress brain derived neurotrophic factor to enhance support of surviving cells in a rodent model of HD provides proof-of-principle that these cells may provide such prophylactic benefits. New techniques that may prove useful for cell replacement therapies in HD include the use of genetically altering fate-restricted cells to produce induced pluripotent stem cells (iPSCs). These iPSCs appear to have certain advantages over the use of embryonic stem cells, including being readily available, easy to obtain, less evidence of tumor formation, and a reduced immune response following their transplantation. Recently, transplants of iPSCs have shown to differentiate into region-specific neurons in an animal model of HD. The overall successes of using genetically altered stem cells for reducing neuropathological and behavioral deficits in rodent models of HD suggest that these approaches have considerable potential for clinical use. However, the choice of what type of genetically altered stem cell to use for transplantation is dependent on the stage of HD and whether the end-goal is preserving endogenous neurons in early-stage HD, or replacing the lost neurons in late-stage HD. This review will discuss the current state of stem cell technology for treating the different stages of HD and possible future directions for stem-cell therapy in HD. PMID:24961705

  12. Altered expression of MGMT in high-grade gliomas results from the combined effect of epigenetic and genetic aberrations.

    PubMed

    Ramalho-Carvalho, João; Pires, Malini; Lisboa, Susana; Graça, Inês; Rocha, Patrícia; Barros-Silva, João Diogo; Savva-Bordalo, Joana; Maurício, Joaquina; Resende, Mário; Teixeira, Manuel R; Honavar, Mrinalini; Henrique, Rui; Jerónimo, Carmen

    2013-01-01

    MGMT downregulation in high-grade gliomas (HGG) has been mostly attributed to aberrant promoter methylation and is associated with increased sensitivity to alkylating agent-based chemotherapy. However, HGG harboring 10q deletions also benefit from treatment with alkylating agents. Because the MGMT gene is mapped at 10q26, we hypothesized that both epigenetic and genetic alterations might affect its expression and predict response to chemotherapy. To test this hypothesis, promoter methylation and mRNA levels of MGMT were determined by quantitative methylation-specific PCR (qMSP) or methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and quantitative RT-PCR, respectively, in a retrospective series of 61 HGG. MGMT/chromosome 10 copy number variations were determined by FISH or MS-MLPA analysis. Molecular findings were correlated with clinical parameters to assess their predictive value. Overall, MGMT methylation ratios assessed by qMSP and MS-MLPA were inversely correlated with mRNA expression levels (best coefficient value obtained with MS-MLPA). By FISH analysis in 68.3% of the cases there was loss of 10q26.1 and in 15% of the cases polysomy was demonstrated; the latter displayed the highest levels of transcript. When genetic and epigenetic data were combined, cases with MGMT promoter methylation and MGMT loss depicted the lowest transcript levels, although an impact in response to alkylating agent chemotherapy was not apparent. Cooperation between epigenetic (promoter methylation) and genetic (monosomy, locus deletion) changes affecting MGMT in HGG is required for effective MGMT silencing. Hence, evaluation of copy number alterations might add relevant prognostic and predictive information concerning response to alkylating agent-based chemotherapy. PMID:23505468

  13. Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses.

    PubMed

    Aubrecht, Taryn G; Weil, Zachary M; Magalang, Ulysses J; Nelson, Randy J

    2013-07-01

    Obstructive sleep apnea (OSA) and dim light at night (dLAN) have both been independently associated with alterations in mood and cognition. We aimed to determine whether dLAN would interact with intermittent hypoxia (IH), a condition characteristic of OSA, to alter the behavioral, cognitive, and affective responses. Adult male mice were housed in either standard lighting conditions (14:10-h light-dark cycle; 150 lux:0 lux) or dLAN (150 lux:5 lux). Mice were then exposed to IH (15 cycles/h, 8 h/day, FiO2 nadir of 5%) for 3 wk, then tested in assays of affective and cognitive responses; brains were collected for dendritic morphology and PCR analysis. Exposure to dLAN and IH increased anxiety-like behaviors, as assessed in the open field, elevated plus maze, and the light/dark box. dLAN and IH increased depressive-like behaviors in the forced swim test. IH impaired learning and memory performance in the passive avoidance task; however, no differences were observed in spatial working memory, as assessed by y-maze or object recognition. IH combined with dLAN decreased cell body area in the CA1 and CA3 regions of the hippocampus. Overall, IH decreased apical spine density in the CA3, whereas dLAN decreased spine density in the CA1 of the hippocampus. TNF-? gene expression was not altered by IH or lighting condition, whereas VEGF expression was increased by dLAN. The combination of IH and dLAN provokes negative effects on hippocampal dendritic morphology, affect, and cognition, suggesting that limiting nighttime exposure to light in combination with other established treatments may be of benefit to patients with OSA. PMID:23657638

  14. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia

    PubMed Central

    Roberts, Kathryn G.; Morin, Ryan D.; Zhang, Jinghui; Hirst, Martin; Zhao, Yongjun; Su, Xiaoping; Chen, Shann-Ching; Payne-Turner, Debbie; Churchman, Michelle; Harvey, Richard C.; Chen, Xiang; Kasap, Corynn; Yan, Chunhua; Becksfort, Jared; Finney, Richard P.; Teachey, David T.; Maude, Shannon L.; Tse, Kane; Moore, Richard; Jones, Steven; Mungall, Karen; Birol, Inanc; Edmonson, Michael N.; Hu, Ying; Buetow, Kenneth E.; Chen, I-Ming; Carroll, William L.; Wei, Lei; Ma, Jing; Kleppe, Maria; Levine, Ross L.; Garcia-Manero, Guillermo; Larsen, Eric; Shah, Neil P.; Devidas, Meenakshi; Reaman, Gregory; Smith, Malcolm; Paugh, Steven W.; Evans, William E.; Grupp, Stephan A.; Jeha, Sima; Pui, Ching-Hon; Gerhard, Daniela S.; Downing, James R.; Willman, Cheryl L.; Loh, Mignon; Hunger, Stephen P.; Marra, Marco; Mullighan, Charles G.

    2012-01-01

    SUMMARY Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL, and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2 and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2 negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy. PMID:22897847

  15. Distinct responses of xenografted gliomas to different alkylating agents are related to histology and genetic alterations.

    PubMed

    Leuraud, Pascal; Taillandier, Luc; Medioni, Jacques; Aguirre-Cruz, Lucinda; Crinire, Emmanuelle; Marie, Yannick; Kujas, Michle; Golmard, Jean-Louis; Duprez, Adrien; Delattre, Jean-Yves; Sanson, Marc; Poupon, Marie-France

    2004-07-01

    A series of 12 human gliomas was established as xenografts in nude mice and used to evaluate the relationship between histology, genetic parameters, and response to alkylating agents. Eight were high-grade oligodendroglial tumors, and four were glioblastoma. They were characterized for their genetic alterations, including those considered as "early" alterations, namely loss of chromosome 1 +/- loss of chromosome 19q, TP53 mutation, and those considered as "late" alterations, namely loss of chromosome 10, loss of chromosome 9p, EGFR genomic amplification, PTEN mutation, CDKN2A homozygous deletion, and telomerase reactivation. Chemosensitivity of xenografts to four alkylating agents, temozolomide (42 mg/kg, days 1-5, p.o.), 1,3-bis(2-chloroethyl)-1-nitrosourea (5 mg/kg, day 1, i.p.), Ifosfamide (90 mg/kg, days 1-3, i.p.), and carboplatin (66 mg/kg, day 1, i.p.) was tested by administration of drugs to tumor-bearing mice. Although each tumor presented an individual response pattern, glioblastoma had a lower chemosensitivity than oligodendrogliomas, and temozolomide was the most effective drug. Deletion of 1p +/- 19q was associated with higher chemosensitivity, whereas late molecular alterations, particularly EGFR amplification, were associated with chemoresistance. These results suggest that the combined use of histology and molecular markers should eventually be helpful selecting the most appropriate agents for treatment of malignant oligodendrogliomas and astrocytomas. PMID:15231677

  16. Identification of novel genetic alterations in samples of malignant glioma patients.

    PubMed

    Milinkovic, Vedrana; Bankovic, Jasna; Rakic, Miodrag; Stankovic, Tijana; Skender-Gazibara, Milica; Ruzdijic, Sabera; Tanic, Nikola

    2013-01-01

    Glioblastoma is the most frequent and malignant human brain tumor. High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis. We investigated alterations in AP-PCR DNA profiles of 30 glioma patients, and detected specific changes in 11 genes not previously associated with this disease: LHFPL3, SGCG, HTR4, ITGB1, CPS1, PROS1, GP2, KCNG2, PDE4D, KIR3DL3, and INPP5A. Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors, while changes in GP2, KCNG2 and KIR3DL3 should be considered as passenger mutations, consequence of high level of genomic instability. Identified genes have a significant role in signal transduction or cell adhesion, which are important processes for cancer development and progression. According to our results, LHFPL3 might be characteristic of primary glioblastoma, SGCG, HTR4, ITGB1, CPS1, PROS1 and INPP5A were detected predominantly in anaplastic astrocytoma, suggesting their role in progression of secondary glioblastoma, while alterations of PDE4D seem to have important role in development of both glioblastoma subtypes. Some of the identified genes showed significant association with p53, p16, and EGFR, but there was no significant correlation between loss of PTEN and any of identified genes. In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes. PMID:24358143

  17. Population genetic dynamics of three-spined sticklebacks (Gasterosteus aculeatus) in anthropogenic altered habitats

    PubMed Central

    Scharsack, Joern P; Schweyen, Hannah; Schmidt, Alexander M; Dittmar, Janine; Reusch, Thorsten BH; Kurtz, Joachim

    2012-01-01

    In industrialized and/or agriculturally used landscapes, inhabiting species are exposed to a variety of anthropogenic changes in their environments. Genetic diversity may be reduced if populations encounter founder events, bottlenecks, or isolation. Conversely, genetic diversity may increase if populations adapt to changes in selective regimes in newly created habitats. With the present study, genetic variability of 918 sticklebacks from 43 samplings (21.3 ± 3.8 per sample) at 36 locations from cultivated landscapes in Northwest Germany was analyzed at nine neutral microsatellite loci. To test if differentiation is influenced by habitat alterations, sticklebacks were collected from ancient running waters and adjacent artificial stagnant waters, from brooks with salt water inflow of anthropogenic and natural origin and adjacent freshwater sites. Overall population structure was dominated by isolation by distance (IBD), which was significant across all populations, and analysis of molecular variance (AMOVA) revealed that 10.6% of the variation was explained by river catchment area. Populations in anthropogenic modified habitats deviated from the general IBD structure and in the AMOVA, grouping by habitat type running/stagnant water explained 4.9% of variation and 1.4% of the variation was explained by salt-/freshwater habitat. Sticklebacks in salt-polluted water systems seem to exhibit elevated migratory activity between fresh- and saltwater habitats, reducing IBD. In other situations, populations showed distinct signs of genetic isolation, which in some locations was attributed to mechanical migration barriers, but in others to potential anthropogenic induced bottleneck or founder effects. The present study shows that anthropogenic habitat alterations may have diverse effects on the population genetic structure of inhabiting species. Depending on the type of habitat change, increased genetic differentiation, diversification, or isolation are possible consequences. PMID:22833789

  18. Population genetic dynamics of three-spined sticklebacks (Gasterosteus aculeatus) in anthropogenic altered habitats.

    PubMed

    Scharsack, Joern P; Schweyen, Hannah; Schmidt, Alexander M; Dittmar, Janine; Reusch, Thorsten Bh; Kurtz, Joachim

    2012-06-01

    In industrialized and/or agriculturally used landscapes, inhabiting species are exposed to a variety of anthropogenic changes in their environments. Genetic diversity may be reduced if populations encounter founder events, bottlenecks, or isolation. Conversely, genetic diversity may increase if populations adapt to changes in selective regimes in newly created habitats. With the present study, genetic variability of 918 sticklebacks from 43 samplings (21.3 3.8 per sample) at 36 locations from cultivated landscapes in Northwest Germany was analyzed at nine neutral microsatellite loci. To test if differentiation is influenced by habitat alterations, sticklebacks were collected from ancient running waters and adjacent artificial stagnant waters, from brooks with salt water inflow of anthropogenic and natural origin and adjacent freshwater sites. Overall population structure was dominated by isolation by distance (IBD), which was significant across all populations, and analysis of molecular variance (AMOVA) revealed that 10.6% of the variation was explained by river catchment area. Populations in anthropogenic modified habitats deviated from the general IBD structure and in the AMOVA, grouping by habitat type running/stagnant water explained 4.9% of variation and 1.4% of the variation was explained by salt-/freshwater habitat. Sticklebacks in salt-polluted water systems seem to exhibit elevated migratory activity between fresh- and saltwater habitats, reducing IBD. In other situations, populations showed distinct signs of genetic isolation, which in some locations was attributed to mechanical migration barriers, but in others to potential anthropogenic induced bottleneck or founder effects. The present study shows that anthropogenic habitat alterations may have diverse effects on the population genetic structure of inhabiting species. Depending on the type of habitat change, increased genetic differentiation, diversification, or isolation are possible consequences. PMID:22833789

  19. Campylobacter jejuni pdxA Affects Flagellum-Mediated Motility to Alter Host Colonization

    PubMed Central

    Asakura, Hiroshi; Hashii, Noritaka; Uema, Masashi; Kawasaki, Nana; Sugita-Konishi, Yoshiko; Igimi, Shizunobu; Yamamoto, Shigeki

    2013-01-01

    Vitamin B6 (pyridoxal-5'-phosphate, PLP) is linked to a variety of biological functions in prokaryotes. Here, we report that the pdxA (putative 4-hydroxy-L-threonine phosphate dehydrogenase) gene plays a pivotal role in the PLP-dependent regulation of flagellar motility, thereby altering host colonization in a leading foodborne pathogen, Campylobacter jejuni. A C. jejuni pdxA mutant failed to produce PLP and exhibited a coincident loss of flagellar motility. Mass spectrometric analyses showed a 3-fold reduction in the main flagellar glycan pseudaminic acid (Pse) associated with the disruption of pdxA. The pdxA mutant also exhibited reduced growth rates compared with the WT strain. Comparative metabolomic analyses revealed differences in respiratory/energy metabolism between WT C. jejuni and the pdxA mutant, providing a possible explanation for the differential growth fitness between the two strains. Consistent with the lack of flagellar motility, the pdxA mutant showed impaired motility-mediated responses (bacterial adhesion, ERK1/2 activation, and IL-8 production) in INT407 cells and reduced colonization of chickens compared with the WT strain. Overall, this study demonstrated that the pdxA gene affects the PLP-mediated flagellar motility function, mainly through alteration of Pse modification, and the disruption of this gene also alters the respiratory/energy metabolisms to potentially affect host colonization. Our data therefore present novel implications regarding the utility of PLP and its dependent enzymes as potent target(s) for the control of this pathogen in the poultry host. PMID:23936426

  20. A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.

    PubMed

    Kim, Soo Ki; Nasu, Akihiro; Komori, Junji; Shimizu, Takahiro; Matsumoto, Yuko; Minaki, Yasuko; Kohno, Kenji; Shimizu, Kazuharu; Uemoto, Shinji; Chiba, Tsutomu; Marusawa, Hiroyuki

    2014-03-01

    Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient "toxin-receptor mediated conditional cell knockout" (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells. PMID:23959426

  1. Genetics and personality affect visual perspective in autobiographical memory.

    PubMed

    Lemogne, Cdric; Bergouignan, Loretxu; Boni, Claudette; Gorwood, Philip; Plissolo, Antoine; Fossati, Philippe

    2009-09-01

    Major depression is associated with a decrease of 1st person (versus 3rd person) visual perspective in autobiographical memory, even after full remission. This study aimed to examine visual perspective in healthy never-depressed subjects presenting with either genetic or psychological vulnerability for depression. Sixty healthy participants performed the Autobiographical Memory Test with an assessment of visual perspective. Genetic vulnerability was defined by the presence of at least one S or L(G) allele of the polymorphism of the serotonin-transporter-linked promoter region (5-HTTLPR). Psychological vulnerability was defined by high scores of harm avoidance measured by the Temperament and Character Inventory. Life stress exposure, depressive mood, rumination, and familial history of depression were assessed through standardized procedures. Visual perspective for positive memories was independently predicted by both harm avoidance and a gene by environment interaction between the 5-HTTLPR polymorphism and life stress exposure. Visual perspective and vulnerability for depression may share some biological bases. PMID:19423361

  2. Genetic Mapping of Novel Loci Affecting Canine Blood Phenotypes

    PubMed Central

    White, Michelle E.; Hayward, Jessica J.; Stokol, Tracy; Boyko, Adam R.

    2015-01-01

    Since the publication of the dog genome and the construction of high-quality genome-wide SNP arrays, thousands of dogs have been genotyped for disease studies. For many of these dogs, additional clinical phenotypes are available, such as hematological and clinical chemistry results collected during routine veterinary care. Little is known about the genetic basis of variation in blood phenotypes, but this variation may play an important role in the etiology and progression of many diseases. From a cohort of dogs that had been previously genotyped on a semi-custom Illumina CanineHD array for various genome-wide association studies (GWAS) at Cornell University Hospital for Animals, we chose 353 clinically healthy, adult dogs for our analysis of clinical pathologic test results (14 hematological tests and 25 clinical chemistry tests). After correcting for age, body weight and sex, genetic associations were identified for amylase, segmented neutrophils, urea nitrogen, glucose, and mean corpuscular hemoglobin. Additionally, a strong genetic association (P = 8.1×10−13) was evident between a region of canine chromosome 13 (CFA13) and alanine aminotransferase (ALT), explaining 23% of the variation in ALT levels. This region of CFA13 encompasses the GPT gene that encodes the transferase. Dogs homozygous for the derived allele exhibit lower ALT activity, making increased ALT activity a less useful marker of hepatic injury in these individuals. Overall, these associations provide a roadmap for identifying causal variants that could improve interpretation of clinical blood tests and understanding of genetic risk factors associated with diseases such as canine diabetes and anemia, and demonstrate the utility of holistic phenotyping of dogs genotyped for disease mapping studies. PMID:26683458

  3. Genetic diversity affects colony survivorship in commercial honey bee colonies

    NASA Astrophysics Data System (ADS)

    Tarpy, David R.; vanEngelsdorp, Dennis; Pettis, Jeffrey S.

    2013-08-01

    Honey bee ( Apis mellifera) queens mate with unusually high numbers of males (average of approximately 12 drones), although there is much variation among queens. One main consequence of such extreme polyandry is an increased diversity of worker genotypes within a colony, which has been shown empirically to confer significant adaptive advantages that result in higher colony productivity and survival. Moreover, honey bees are the primary insect pollinators used in modern commercial production agriculture, and their populations have been in decline worldwide. Here, we compare the mating frequencies of queens, and therefore, intracolony genetic diversity, in three commercial beekeeping operations to determine how they correlate with various measures of colony health and productivity, particularly the likelihood of queen supersedure and colony survival in functional, intensively managed beehives. We found the average effective paternity frequency ( m e ) of this population of honey bee queens to be 13.6 ± 6.76, which was not significantly different between colonies that superseded their queen and those that did not. However, colonies that were less genetically diverse (headed by queens with m e ≤ 7.0) were 2.86 times more likely to die by the end of the study when compared to colonies that were more genetically diverse (headed by queens with m e > 7.0). The stark contrast in colony survival based on increased genetic diversity suggests that there are important tangible benefits of increased queen mating number in managed honey bees, although the exact mechanism(s) that govern these benefits have not been fully elucidated.

  4. Genetic diversity affects colony survivorship in commercial honey bee colonies.

    PubMed

    Tarpy, David R; Vanengelsdorp, Dennis; Pettis, Jeffrey S

    2013-08-01

    Honey bee (Apis mellifera) queens mate with unusually high numbers of males (average of approximately 12 drones), although there is much variation among queens. One main consequence of such extreme polyandry is an increased diversity of worker genotypes within a colony, which has been shown empirically to confer significant adaptive advantages that result in higher colony productivity and survival. Moreover, honey bees are the primary insect pollinators used in modern commercial production agriculture, and their populations have been in decline worldwide. Here, we compare the mating frequencies of queens, and therefore, intracolony genetic diversity, in three commercial beekeeping operations to determine how they correlate with various measures of colony health and productivity, particularly the likelihood of queen supersedure and colony survival in functional, intensively managed beehives. We found the average effective paternity frequency (m e ) of this population of honey bee queens to be 13.6 ± 6.76, which was not significantly different between colonies that superseded their queen and those that did not. However, colonies that were less genetically diverse (headed by queens with m e  ≤ 7.0) were 2.86 times more likely to die by the end of the study when compared to colonies that were more genetically diverse (headed by queens with m e  > 7.0). The stark contrast in colony survival based on increased genetic diversity suggests that there are important tangible benefits of increased queen mating number in managed honey bees, although the exact mechanism(s) that govern these benefits have not been fully elucidated. PMID:23728203

  5. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.

    PubMed

    Zhang, Jinghui; Wu, Gang; Miller, Claudia P; Tatevossian, Ruth G; Dalton, James D; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S; Fulton, Lucinda L; Dooling, David J; Vadodaria, Bhavin; Mulder, Heather L; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J; Mardis, Elaine R; Wilson, Richard K; Downing, James R; Baker, Suzanne J; Ellison, David W

    2013-06-01

    The most common pediatric brain tumors are low-grade gliomas (LGGs). We used whole-genome sequencing to identify multiple new genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24 of 39 (62%) tumors. Intragenic duplications of the portion of FGFR1 encoding the tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes expressing FGFR1 with the duplication involving the TKD into the brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. FGFR1 with the duplication induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs and LGGNTs. PMID:23583981

  6. 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.

  7. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas

    PubMed Central

    Zhang, Jinghui; Wu, Gang; Miller, Claudia P.; Tatevossian, Ruth G.; Dalton, James D.; Tang, Bo; Orisme, Wilda; Punchihewa, Chandanamali; Parker, Matthew; Qaddoumi, Ibrahim; Boop, Fredrick A.; Lu, Charles; Kandoth, Cyriac; Ding, Li; Lee, Ryan; Huether, Robert; Chen, Xiang; Hedlund, Erin; Nagahawatte, Panduka; Rusch, Michael; Boggs, Kristy; Cheng, Jinjun; Becksfort, Jared; Ma, Jing; Song, Guangchun; Li, Yongjin; Wei, Lei; Wang, Jianmin; Shurtleff, Sheila; Easton, John; Zhao, David; Fulton, Robert S.; Fulton, Lucinda L.; Dooling, David J.; Vadodaria, Bhavin; Mulder, Heather L.; Tang, Chunlao; Ochoa, Kerri; Mullighan, Charles G.; Gajjar, Amar; Kriwacki, Richard; Sheer, Denise; Gilbertson, Richard J.; Mardis, Elaine R.; Wilson, Richard K.; Downing, James R.; Baker, Suzanne J.; Ellison, David W.

    2013-01-01

    The commonest pediatric brain tumors are low-grade gliomas (LGGs). We utilized whole genome sequencing to discover multiple novel genetic alterations involving BRAF, RAF1, FGFR1, MYB, MYBL1 and genes with histone-related functions, including H3F3A and ATRX, in 39 LGGs and low-grade glioneuronal tumors (LGGNTs). Only a single non-silent somatic alteration was detected in 24/39 (62%) tumors. Intragenic duplications of the FGFR1 tyrosine kinase domain (TKD) and rearrangements of MYB were recurrent and mutually exclusive in 53% of grade II diffuse LGGs. Transplantation of Trp53-null neonatal astrocytes containing TKD-duplicated FGFR1 into brains of nude mice generated high-grade astrocytomas with short latency and 100% penetrance. TKD-duplicated FGFR1 induced FGFR1 autophosphorylation and upregulation of the MAPK/ERK and PI3K pathways, which could be blocked by specific inhibitors. Focusing on the therapeutically challenging diffuse LGGs, our study of 151 tumors has discovered genetic alterations and potential therapeutic targets across the entire range of pediatric LGGs/LGGNTs. PMID:23583981

  8. Genetic alterations of histone lysine methyltransferases and their significance in breast cancer

    PubMed Central

    Liu, Hui; Holowatyj, Andreana; Yang, Zeng-Quan

    2015-01-01

    Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer. PMID:25537518

  9. Association of genetic alterations on chromosome 17 and loss of hormone receptors in breast cancer.

    PubMed Central

    Ito, I.; Yoshimoto, M.; Iwase, T.; Watanabe, S.; Katagiri, T.; Harada, Y.; Kasumi, F.; Yasuda, S.; Mitomi, T.; Emi, M.

    1995-01-01

    To investigate possible relationships between genetic alterations and hormonal deregulation during breast cancer development and/or progression, we examined 616 primary breast cancers for loss of heterozygosity (LOH) at chromosomal regions 16q24, 17p13.3 and 17q21, and for amplifications of the ERBB2 and c-MYC loci. A comparison of oestrogen receptor (ER) and progesterone receptor (PgR) status in tumour cells with data concerning these genetic alterations revealed that LOH at 17q21 was significantly correlated with absence of oestrogen receptors (ER) (P < 0.0003) or progesterone receptors (PgR) (P < 0.0001), and with the absence of both (P < 0.0001). Similarly, a significant association was observed between amplification of ERBB2 and the absence of either ER or PgR. LOH at 17p13.3 was associated with the absence of PgR (P < 0.01). These data suggest a possible relationship between specific genetic changes on chromosome 17 and hormonal deregulation in the progression of breast cancer. Images Figure 1 PMID:7880720

  10. Which Genetics Variants in DNase-Seq Footprints Are More Likely to Alter Binding?

    PubMed Central

    Moyerbrailean, Gregory A.; Kalita, Cynthia A.; Harvey, Chris T.; Wen, Xiaoquan; Luca, Francesca; Pique-Regi, Roger

    2016-01-01

    Large experimental efforts are characterizing the regulatory genome, yet we are still missing a systematic definition of functional and silent genetic variants in non-coding regions. Here, we integrated DNaseI footprinting data with sequence-based transcription factor (TF) motif models to predict the impact of a genetic variant on TF binding across 153 tissues and 1,372 TF motifs. Each annotation we derived is specific for a cell-type condition or assay and is locally motif-driven. We found 5.8 million genetic variants in footprints, 66% of which are predicted by our model to affect TF binding. Comprehensive examination using allele-specific hypersensitivity (ASH) reveals that only the latter group consistently shows evidence for ASH (3,217 SNPs at 20% FDR), suggesting that most (97%) genetic variants in footprinted regulatory regions are indeed silent. Combining this information with GWAS data reveals that our annotation helps in computationally fine-mapping 86 SNPs in GWAS hit regions with at least a 2-fold increase in the posterior odds of picking the causal SNP. The rich meta information provided by the tissue-specificity and the identity of the putative TF binding site being affected also helps in identifying the underlying mechanism supporting the association. As an example, the enrichment for LDL level-associated SNPs is 9.1-fold higher among SNPs predicted to affect HNF4 binding sites than in a background model already including tissue-specific annotation. PMID:26901046

  11. Warming and altered precipitation affect litter decomposition and nitrogen dynamics in a mixed-grass prairie

    NASA Astrophysics Data System (ADS)

    Chen, X.; Luo, Y.; Xu, X.; Li, D.; Niu, S.

    2013-12-01

    Litter decomposition and nitrogen dynamics are important processes in ecosystems and how they respond to climate changes is a global concern. In order to explore the effects of warming and altered precipitation on litter decomposition and nitrogen dynamics, we conducted a field decomposition experiment with warming (+3C) and altered precipitation (half and double) in a mixed-grass prairie in Oklahoma, USA, using litter bags with dominant C3 and C4 grasses since June, 2012. Litter bags were collected every month in the first six months and subsequently every three month thereafter. Remaining litter biomass as well as element concentration were measured in the lab. Warming significantly decreased the litter decomposition rate (k) by 25.4% for C3 grasses and 25.0% for C4 grasses. Doubled precipitation significantly increased the litter decomposition rate by 23.3% for C3 grasses and 30.1% for C4 grasses while half precipitation showed no significant effects. Soil temperature and soil moisture, controlled by warming and altered precipitation, are found to be the most important factors in regulating litter decomposition rate. Warming also decreased N concentration in C3 grasses while doubled precipitation increased N concentration in C4 grasses after one year of field decomposition. During that time, N concentration showed an average increase of 99.6% in C3 grass while only 68.1% in C4 grass. Other elements such as P and K were not much affected by these treatments although there were significant differences between C3 and C4 grasses. Our results suggest that climate change has significant impact on litter decomposition rate, which could influence the carbon balance of the ecosystem. Nutrient dynamics, especially nitrogen, were shown to be specific to plant types under altered climatic conditions. Our results show that conclusion derived from single-factor climate change experiments should be treated with caution due to interactive effects of warming with altered precipitation and differential responses of C3 and C4 plants.

  12. 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. PMID:24786699

  13. Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas.

    PubMed

    Mizoguchi, Masahiro; Nutt, Catherine L; Mohapatra, Gayatry; Louis, David N

    2004-10-01

    Genetic alterations of PI3K (phosphoinositide 3-kinase) subunits have been documented in a number of tumor types, with increased PI3K activity linked to gene amplification and mutation of catalytic subunits, as well as mutations of regulatory subunits. Among high grade gliomas, activation of the PI3K-AKT signaling pathway through loss of PTEN function is common. We therefore investigated whether genetic alteration of class IA PI3Ks might provide a mechanism for deregulation of this pathway in glioblastomas. We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR-SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits. FISH revealed frequent balanced copy number increases of both PIK3CA and PIK3CD, and one case showed an extra copy limited to PIK3CA. One glioblastoma exhibited a 9-bp deletion that encompassed the exon-intron junction of exon 12 of PIK3R1, documenting for the first time a mutation within a PI3K regulatory subunit in human glioblastoma. This deletion would be predicted to yield a truncated protein that lacks the inhibitory domain, resulting in increased PI3K activity. Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation. These results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating the PI3K-AKT signaling pathway independently of PTEN mutation. PMID:15605984

  14. 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.

  15. Alterations in Ribosomal Protein Rps28 Can Diversely Affect Translational Accuracy in Saccharomyces Cerevisiae

    PubMed Central

    Anthony, R. A.; Liebman, S. W.

    1995-01-01

    Three small-subunit ribosomal proteins shown to influence translational accuracy in Saccharomyces cerevisiae are conserved in structure and function with their procaryotic counterparts. One of these, encoded by RPS28A and RPS28B (RPS28), is comparable to bacterial S12. The others, encoded by sup44 (RPS4) or, sup46 and YS11A (RPS13), are homologues of procaryotic S5 and S4, respectively. In Escherichia coli, certain alterations in S12 cause hyperaccurate translation or antibiotic resistance that can be counteracted by other changes in S5 or S4 that reduce translational accuracy. Using site-directed and random mutagenesis, we show that different changes in RPS28 can have diametrical influences on translational accuracy or antibiotic sensitivity in yeast. Certain substitutions in the amino-terminal portion of the protein, which is diverged from the procaryotic homologues, cause varying levels of nonsense suppression or antibiotic sensitivity. Other alterations, found in the more conserved carboxyl-terminal portion, counteract SUP44- or SUP46-associated antibiotic sensitivity, mimicking E. coli results. Although mutations in these different parts of RPS28 have opposite affects on translational accuracy or antibiotic sensitivity, additive phenotypes can be observed when opposing mutations are combined in the same protein. PMID:7498767

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

    PubMed Central

    Wei, Wei; Davis, Robert Edward; Nuss, Donald L.; Zhao, Yan

    2013-01-01

    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 sequential changes in meristem fate from vegetative to inflorescence, and to floral, leading to flower formation and eventual seed production. The transition is rarely reversible once initiated. In this communication, we report that a bacterial infection can derail the genetically programmed fate of meristem cells, thereby drastically altering the growth pattern of the host plant. We identified four characteristic symptoms in tomato plants infected with a cell wall-less bacterium, phytoplasma. The symptoms are a manifestation of the pathogen-induced alterations of growth pattern, whereas each symptom corresponds to a distinct phase in the derailment of shoot apical meristem fate. The phases include premature floral meristem termination, suppressed floral meristem initiation, delayed conversion of vegetative meristem to inflorescence meristem, and repetitive initiation and outgrowth of lateral vegetative meristems. We further found that the pathogen-induced alterations of growth pattern were correlated with transcriptional reprogramming of key meristem switching genes. Our findings open an avenue toward understanding pathological alterations in patterns of plant growth and development, thus aiding identification of molecular targets for disease control and symptom alleviation. The findings also provide insights for understanding stem cell pluripotency and raise a tantalizing possibility for using phytoplasma as a tool to dissect the course of normal plant development and to modify plant morphogenesis by manipulating meristem fate. PMID:24191032

  17. Functional TLR5 genetic variants affect human colorectal cancer survival.

    PubMed

    Klimosch, Sascha N; Frsti, Asta; Eckert, Jana; Knezevic, Jelena; Bevier, Melanie; von Schnfels, Witigo; Heits, Nils; Walter, Jessica; Hinz, Sebastian; Lascorz, Jesus; Hampe, Jochen; Hartl, Dominik; Frick, Julia-Stefanie; Hemminki, Kari; Schafmayer, Clemens; Weber, Alexander N R

    2013-12-15

    Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1? mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development. PMID:24154872

  18. Genetic Factors Affecting Late-Onset Alzheimer's Disease Susceptibility.

    PubMed

    Rezazadeh, Maryam; Khorrami, Aziz; Yeghaneh, Tarlan; Talebi, Mahnaz; Kiani, Seyed Jalal; Heshmati, Yaser; Gharesouran, Jalal

    2016-03-01

    Alzheimer's disease is considered a progressive brain disease in the older population. Late-onset Alzheimer's disease (LOAD) as a multifactorial dementia has a polygenic inheritance. Age, environment, and lifestyle along with a growing number of genetic factors have been reported as risk factors for LOAD. Our aim was to present results of LOAD association studies that have been done in northwestern Iran, and we also explored possible interactions with apolipoprotein E (APOE) status. We re-evaluated the association of these markers in dominant, recessive, and additive models. In all, 160 LOAD and 163 healthy control subjects of Azeri Turkish ethnicity were studied. The Chi-square test with Yates' correction and Fisher's exact test were used for statistical analysis. A Bonferroni-corrected p value, based on the number of statistical tests, was considered significant. Our results confirmed that chemokine receptor type 2 (CCR2), estrogen receptor 1 (ESR1), toll-like receptor 2 (TLR2), tumor necrosis factor alpha (TNF ?), APOE, bridging integrator 1 (BIN1), and phosphatidylinositol-binding clathrin assembly protein (PICALM) are LOAD susceptibility loci in Azeri Turk ancestry populations. Among them, variants of CCR2, ESR1, TNF ?, and APOE revealed associations in three different genetic models. After adjusting for APOE, the association (both allelic and genotypic) with CCR2, BIN1, and ESR? (PvuII) was evident only among subjects without the APOE ?4, whereas the association with CCR5, without Bonferroni correction, was significant only among subjects carrying the APOE ?4 allele. This result is an evidence of a synergistic and antagonistic effect of APOE on variant associations with LOAD. PMID:26553058

  19. Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

    PubMed Central

    Tesson, Christelle; Nawara, Magdalena; Salih, MustafaA.M.; Rossignol, Rodrigue; Zaki, MahaS.; AlBalwi, Mohammed; Schule, Rebecca; Mignot, Cyril; Obre, Emilie; Bouhouche, Ahmed; Santorelli, FilippoM.; Durand, ChristelleM.; Oteyza, AndrsCaballero; El-Hachimi, KhalidH.; AlDrees, Abdulmajeed; Bouslam, Naima; Lamari, Foudil; Elmalik, SalahA.; Kabiraj, MohammadM.; Seidahmed, MohammedZ.; Esteves, Typhaine; Gaussen, Marion; Monin, Marie-Lorraine; Gyapay, Gabor; Lechner, Doris; Gonzalez, Michael; Depienne, Christel; Mochel, Fanny; Lavie, Julie; Schols, Ludger; Lacombe, Didier; Yahyaoui, Mohamed; AlAbdulkareem, Ibrahim; Zuchner, Stephan; Yamashita, Atsushi; Benomar, Ali; Goizet, Cyril; Durr, Alexandra; Gleeson, JosephG.; Darios, Frederic; Brice, Alexis; Stevanin, Giovanni

    2012-01-01

    Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function. PMID:23176821

  20. Genetic alteration regulated by microRNAs in biliary tract cancers.

    PubMed

    Wang, Ning; Xia, Shihai; Chen, Kai; Xiang, Xiaohui; Zhu, Aijun

    2015-11-01

    Biliary tract cancers (BTCs) constitute a relatively rare but highly malignant class of tumors with poor prognosis including gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma. Recently, accumulated evidences have demonstrated that deregulated expression of microRNAs (miRNAs) is closely associated with the development, invasion, metastasis and prognosis of different cancers including BTCs. MiRNAs comprise an endogenously expressed and highly evolutionarily conserved group of small, non-coding, single-stranded RNAs which negatively regulate target genes expression by means of combining with 3' untranslated region (UTR) of corresponding mRNAs at the post-transcriptional level with significant roles in various fundamental cellular procedures including cell proliferation, differentiation, migration, cell cycle control and apoptosis. Recent studies have indicated that miRNAs could function as novel tumor-promoting genes or tumor suppressor genes to act as potential therapeutic targets in anticancer treatment because the genetic alteration regulated by miRNAs could result in tumorigenesis and tumor inhibition. Anomalous miRNAs expression patterns, acting as phenotypic signatures of distinct cancers, are promising to be used as diagnostic, prognostic, predictive biomarkers. In this review, we summarize the current findings from the studies about potential genetic alteration regulated by miRNAs and their roles in BTCs. PMID:26095617

  1. Attitudes toward prenatal genetic testing for Treacher Collins syndrome among affected individuals and families.

    PubMed

    Wu, Rebecca L; Lawson, Cathleen S; Jabs, Ethylin Wang; Sanderson, Saskia C

    2012-07-01

    Treacher Collins syndrome (TCS) is a craniofacial syndrome that is both phenotypically variable and heterogeneous, caused by mutations in the TCOF1, POLR1C, and POLR1D genes. We examined attitudes towards TCS prenatal genetic testing among affected families using a telephone questionnaire. Participants were 31 affected adults and relatives recruited primarily through families cared for in the mid-Atlantic region. Nineteen participants (65%) reported that they would take a TCS prenatal genetic test which could not predict degree of disease severity. Interest in TCS genetic testing was associated with higher income, higher concern about having a child with TCS, lower religiosity, lower concern about genetic testing procedures, and having a sporadic rather than familial mutation. Over half reported that their decision to have TCS genetic testing would be influenced a great deal by their desire to relieve anxiety and attitudes toward abortion. Ten participants (32%) reported that they would be likely to end the pregnancy upon receiving a positive test result; this was lower amongst TCS affected individuals and higher amongst participants with children with TCS. Genetics healthcare providers need to be aware of affected individuals' and families' attitudes and interest in prenatal genetic testing for TCS, and the possible implications for other craniofacial disorders, so that patients' information needs can be met. PMID:22628272

  2. Genetic and Metabolic Signals during Acute Enteric Bacterial Infection Alter the Microbiota and Drive Progression to Chronic Inflammatory Disease.

    PubMed

    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. PMID:26764594

  3. Reconfiguring phosphorylation signaling by genetic polymorphisms affects cancer susceptibility.

    PubMed

    Wang, Yongbo; Cheng, Han; Pan, Zhicheng; Ren, Jian; Liu, Zexian; Xue, Yu

    2015-06-01

    Large-scale sequencing has characterized an enormous number of genetic variations (GVs), and the functional analysis of GVs is fundamental to understanding differences in disease susceptibility and therapeutic response among and within populations. Using a combination of a sequence-based predictor with known phosphorylation and protein-protein interaction information, we computationally detected 9606 potential phosSNPs (phosphorylation-related single nucleotide polymorphisms), including 720 known, disease-associated SNPs that dramatically modify the human phosSNP-associated kinase-substrate network. Further analyses demonstrated that the proteins in the network are heavily associated in various signaling and cancer pathways, while cancer genes and drug targets are significantly enriched. We re-constructed four population-specific kinase-substrate networks and found that several inherited disease or cancer genes, such as IRS1, RAF1, and EGFR, were differentially regulated by phosSNPs. Thus, phosSNPs may influence disease susceptibility and be involved in cancer development by reconfiguring phosphorylation networks in different populations. Moreover, by systematically characterizing potential phosphorylation-related cancer mutations (phosCMs) in 12 types of cancers, we observed that both types of GVs preferentially occur in the known cancer genes, while a considerable number of phosphorylated proteins, especially those over-representing cancer genes, contain both phosSNPs and phosCMs. Furthermore, it was observed that phosSNPs were significantly enriched in amplification genes identified from breast cancers and tyrosine kinase circuits of lung cancers. Taken together, these results should prove helpful for further elucidation of the functional impacts of disease-associated SNPs. PMID:25722345

  4. Genetic and histopathological alterations induced by cypermethrin in rat kidney and liver: Protection by sesame oil.

    PubMed

    Soliman, Mohamed Mohamed; Attia, Hossam F; El-Ella, Ghada A Abou

    2015-12-01

    Pesticides are widespread synthesized substances used for public health protection and agricultural programs. However, they cause environmental pollution and health hazards. This study aimed to examine the protective effects of sesame oil (SO) on the genetic alterations induced by cypermethrin (CYP) in the liver and kidney of Wistar rats. Male rats were divided into four groups, each containing 10 rats: the control group received vehicle, SO group (5 mL/kg b.w), CYP group (12 mg/kg b.w), and protective group received SO (5 mL/kg b.w) plus CYP (12 mg/kg b.w). Biochemical analysis showed an increase in albumin, urea, creatinine, GPT, GOT, and lipid profiles in the CYP group. Co-administration of SO with CYP normalized such biochemical changes. CYP administration decreased both the activity and mRNA expression of the examined antioxidants. SO co-administration recovered CYP, downregulating the expression of glutathione-S-transferase (GST), catalase, and superoxide dismutase. Additionally, SO co-administration with CYP counteracted the CYP- altering the expression of renal interleukins (IL-1 and IL-6), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), anigotensinogen (AGT), AGT receptors (AT1), and genes of hepatic glucose and fatty acids metabolism. CYP induced degenerative changes in the kidney and liver histology which are ameliorated by SO. In conclusion, SO has a protective effect against alterations and pathological changes induced by CYP in the liver and kidney at genetic and histological levels. PMID:25816392

  5. Process-induced extracellular matrix alterations affect the mechanisms of soft tissue repair and regeneration

    PubMed Central

    Xu, Hui; Sandor, Maryellen; Lombardi, Jared

    2013-01-01

    Extracellular matrices derived from animal tissues for human tissue repairs are processed by various methods of physical, chemical, or enzymatic decellularization, viral inactivation, and terminal sterilization. The mechanisms of action in tissue repair vary among bioscaffolds and are suggested to be associated with process-induced extracellular matrix modifications. We compared three non-cross-linked, commercially available extracellular matrix scaffolds (Strattice, Veritas, and XenMatrix), and correlated extracellular matrix alterations to in vivo biological responses upon implantation in non-human primates. Structural evaluation showed significant differences in retaining native tissue extracellular matrix histology and ultrastructural features among bioscaffolds. Tissue processing may cause both the condensation of collagen fibers and fragmentation or separation of collagen bundles. Calorimetric analysis showed significant differences in the stability of bioscaffolds. The intrinsic denaturation temperature was measured to be 51°C, 38°C, and 44°C for Strattice, Veritas, and XenMatrix, respectively, demonstrating more extracellular matrix modifications in the Veritas and XenMatrix scaffolds. Consequently, the susceptibility to collagenase degradation was increased in Veritas and XenMatrix when compared to their respective source tissues. Using a non-human primate model, three bioscaffolds were found to elicit different biological responses, have distinct mechanisms of action, and yield various outcomes of tissue repair. Strattice permitted cell repopulation and was remodeled over 6 months. Veritas was unstable at body temperature, resulting in rapid absorption with moderate inflammation. XenMatrix caused severe inflammation and sustained immune reactions. This study demonstrates that extracellular matrix alterations significantly affect biological responses in soft tissue repair and regeneration. The data offer useful insights into the rational design of extracellular matrix products and bioscaffolds of tissue engineering. PMID:24555005

  6. Altered visual experience and acute visual deprivation affect predatory targeting by infrared-imaging Boid snakes.

    PubMed

    Grace, M S; Woodward, O M

    2001-11-23

    Boid and Crotaline snakes use both their eyes and infrared-imaging facial pit organs to target homeothermic prey. These snakes can target in complete darkness, but the eyes can also effectively direct predatory strikes. We investigated the behavioral correlates of boid snakes' simultaneous use of two imaging systems by testing whether congenital unilateral visual deprivation affects targeting performance. Normally sighted Burmese pythons exhibited average targeting angle of zero (on the midline axis of the head), but three unilaterally anophthalmic Burmese pythons targeted preferentially on the sighted side. A unilaterally anophthalmic amethystine python also targeted on the sighted side, and a unilaterally anophthalmic Brazilian rainbow boa tended to target on the sighted side, though its mean targeting angle was not significantly different from zero. When unilaterally anophthalmic Burmese pythons were temporarily blinded, mean strike angle changed to that of normally sighted snakes. These results show that while infrared-imaging snakes can shift between visual and infrared information under acute experimental conditions, loss of part of the visual field during development results in abnormal predatory targeting behavior. In contrast, normally sighted snakes subjected to temporary unilateral blinding do not target preferentially on the sighted side. Therefore, while loss of part of the visual field may be compensated for by infrared input in normal snakes, partial absence of visual input during development may alter central organization of visual information. Conversely, absence of half the visual field during development does not alter targeting performance based upon infrared input alone, suggesting that organization of the central infrared map does not depend upon normal organization of visual input. PMID:11701137

  7. 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. PMID:26026879

  8. Copy Number Variation Affecting the Photoperiod-B1 and Vernalization-A1 Genes Is Associated with Altered Flowering Time in Wheat (Triticum aestivum)

    PubMed Central

    Isaac, Peter; Laurie, David A.

    2012-01-01

    The timing of flowering during the year is an important adaptive character affecting reproductive success in plants and is critical to crop yield. Flowering time has been extensively manipulated in crops such as wheat (Triticum aestivum L.) during domestication, and this enables them to grow productively in a wide range of environments. Several major genes controlling flowering time have been identified in wheat with mutant alleles having sequence changes such as insertions, deletions or point mutations. We investigated genetic variants in commercial varieties of wheat that regulate flowering by altering photoperiod response (Ppd-B1 alleles) or vernalization requirement (Vrn-A1 alleles) and for which no candidate mutation was found within the gene sequence. Genetic and genomic approaches showed that in both cases alleles conferring altered flowering time had an increased copy number of the gene and altered gene expression. Alleles with an increased copy number of Ppd-B1 confer an early flowering day neutral phenotype and have arisen independently at least twice. Plants with an increased copy number of Vrn-A1 have an increased requirement for vernalization so that longer periods of cold are required to potentiate flowering. The results suggest that copy number variation (CNV) plays a significant role in wheat adaptation. PMID:22457747

  9. 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

  10. Altering trehalose-6-phosphate content in transgenic potato tubers affects tuber growth and alters responsiveness to hormones during sprouting.

    PubMed

    Debast, Stefan; Nunes-Nesi, Adriano; Hajirezaei, Mohammad R; Hofmann, Jrg; Sonnewald, Uwe; Fernie, Alisdair R; Brnke, Frederik

    2011-08-01

    Trehalose-6-phosphate (T6P) is a signaling metabolite that regulates carbon metabolism, developmental processes, and growth in plants. In Arabidopsis (Arabidopsis thaliana), T6P signaling is, at least in part, mediated through inhibition of the SNF1-related protein kinase SnRK1. To investigate the role of T6P signaling in a heterotrophic, starch-accumulating storage organ, transgenic potato (Solanum tuberosum) plants with altered T6P levels specifically in their tubers were generated. Transgenic lines with elevated T6P levels (B33-TPS, expressing Escherichia coli osmoregulatory trehalose synthesis A [OtsA], which encodes a T6P synthase) displayed reduced starch content, decreased ATP contents, and increased respiration rate diagnostic for high metabolic activity. On the other hand, lines with significantly reduced T6P (B33-TPP, expressing E. coli OtsB, which encodes a T6P phosphatase) showed accumulation of soluble carbohydrates, hexose phosphates, and ATP, no change in starch when calculated on a fresh weight basis, and a strongly reduced tuber yield. [?C]glucose feeding to transgenic tubers indicated that carbon partitioning between starch and soluble carbohydrates was not altered. Transcriptional profiling of B33-TPP tubers revealed that target genes of SnRK1 were strongly up-regulated and that T6P inhibited potato tuber SnRK1 activity in vitro. Among the SnRK1 target genes in B33-TPP tubers, those involved in the promotion of cell proliferation and growth were down-regulated, while an inhibitor of cell cycle progression was up-regulated. T6P-accumulating tubers were strongly delayed in sprouting, while those with reduced T6P sprouted earlier than the wild type. Early sprouting of B33-TPP tubers correlated with a reduced abscisic acid content. Collectively, our data indicate that T6P plays an important role for potato tuber growth. PMID:21670224

  11. The effects of altered thyroid status on lipid metabolism in the genetic hyperlipemic Zucker rat.

    PubMed

    Engelken, S F; Eaton, R P

    1981-01-01

    Exposure to thyroid hormone (T4) has been known to affect the plasma triglyceride (TG) as well as the plasma cholesterol level, but the mechanisms and degree of response in genetic hyperlipidemic states have not been defined. In the present study, we examined TG secretion and removal in vivo in genetically hyperlipemic Zucker rats maintained in hypothyroid, euthyroid, and hyperthyroid states for 6 weeks. The induction of the hypothyroid state resulted in marked weight loss with reduced food intake, and a parallel reduction in plasma TG concentration, hepatic TG production, and peripheral TG removal. In contrast, a similar degree of weight loss in the hyperthyroid state was associated with increased food intake, but no significant reduction in plasma TG concentration, production, or clearance. The changes in plasma cholesterol concentration in the hyperthyroid state were striking, with a 94% reduction in LDL cholesterol, but only a minimal reduction in the HDL cholesterol level. The hypercholesterolemic state in the Zucker rat. The results suggest that the very low density lipoprotein TG metabolism is influenced by hypothyroid but not the hyperthyroid state in this model of human genetic Type IV hyperlipemia. The primary reduction in LDL relative to HDL in response to thyroxine excess, suggests a therapeutic potential in disorders of genetic hyperlipidemia. PMID:7008806

  12. Human genetics. The genetics of Mexico recapitulates Native American substructure and affects biomedical traits.

    PubMed

    Moreno-Estrada, Andrés; Gignoux, Christopher R; Fernández-López, Juan Carlos; Zakharia, Fouad; Sikora, Martin; Contreras, Alejandra V; Acuña-Alonzo, Victor; Sandoval, Karla; Eng, Celeste; Romero-Hidalgo, Sandra; Ortiz-Tello, Patricia; Robles, Victoria; Kenny, Eimear E; Nuño-Arana, Ismael; Barquera-Lozano, Rodrigo; Macín-Pérez, Gastón; Granados-Arriola, Julio; Huntsman, Scott; Galanter, Joshua M; Via, Marc; Ford, Jean G; Chapela, Rocío; Rodriguez-Cintron, William; Rodríguez-Santana, Jose R; Romieu, Isabelle; Sienra-Monge, Juan José; del Rio Navarro, Blanca; London, Stephanie J; Ruiz-Linares, Andrés; Garcia-Herrera, Rodrigo; Estrada, Karol; Hidalgo-Miranda, Alfredo; Jimenez-Sanchez, Gerardo; Carnevale, Alessandra; Soberón, Xavier; Canizales-Quinteros, Samuel; Rangel-Villalobos, Héctor; Silva-Zolezzi, Irma; Burchard, Esteban Gonzalez; Bustamante, Carlos D

    2014-06-13

    Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between subcontinental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide. PMID:24926019

  13. Genetic and expression alterations in association with the sarcomatous change of cholangiocarcinoma cells

    PubMed Central

    Yoo, Hee-Jung; Yun, Bo-Ra; Kwon, Jung-Hee; Ahn, Hyuk-Soo; Seol, Min-A; Lee, Mi-Jin; Yu, Goung-Ran; Yu, Hee-Chul; Hong, BeeHak; Choi, KwanYong

    2009-01-01

    Cholangiocarcinoma (CC) is an intrahepatic bile duct carcinoma with a high mortality rate and a poor prognosis. Sarcomatous change/epithelial mesenchymal transition (EMT) of CC frequently leads to aggressive intrahepatic spread and metastasis. The aim of this study was to identify the genetic alterations and gene expression pattern that might be associated with the sarcomatous change in CC. Previously, we established 4 human CC cell lines (SCK, JCK1, Cho-CK, and Choi-CK). In the present study, we characterized a typical sarcomatoid phenotype of SCK, and classified the other cell lines according to tumor cell differentiation (a poorly differentiated JCK, a moderately differentiated Cho-CK, and a well differentiated Choi-CK cells), both morphologically and immunocytologically. We further analyzed the genetic alterations of two tumor suppressor genes (p53 and FHIT) and the expression of Fas/FasL gene, well known CC-related receptor and its ligand, in these four CC cell lines. The deletion mutation of p53 was found in the sarcomatoid SCK cells. These cells expressed much less Fas/FasL mRNAs than did the other ordinary CC cells. We further characterize the gene expression pattern that is involved in the sarcomatous progression of CC, using cDNA microarrays that contained 18,688 genes. Comparison of the expression patterns between the sarcomatoid SCK cells and the differentiated Choi-CK cells enabled us to identify 260 genes and 247 genes that were significantly over-expressed and under-expressed, respectively. Northern blotting of the 14 randomly selected genes verified the microarray data, including the differential expressions of the LGALS1, TGFBI, CES1, LDHB, UCHL1, ASPH, VDAC1, VIL2, CCND2, S100P, CALB1, MAL2, GPX1, and ANXA8 mRNAs. Immunohistochemistry also revealed in part the differential expressions of these gene proteins. These results suggest that those genetic and gene expression alterations may be relevant to the sarcomatous change/EMT in CC cells. PMID:19287191

  14. Alterations in welding process voltage affect the generation of ultrafine particles, fume composition, and pulmonary toxicity.

    PubMed

    Antonini, James M; Keane, Michael; Chen, Bean T; Stone, Samuel; Roberts, Jenny R; Schwegler-Berry, Diane; Andrews, Ronnee N; Frazer, David G; Sriram, Krishnan

    2011-12-01

    The goal was to determine if increasing welding voltage changes the physico-chemical properties of the fume and influences lung responses. Rats inhaled 40 mg/m (3 h/day 3 days) of stainless steel (SS) welding fume generated at a standard voltage setting of 25 V (regular SS) or at a higher voltage (high voltage SS) of 30 V. Particle morphology, size and composition were characterized. Bronchoalveolar lavage was performed at different times after exposures to assess lung injury. Fumes collected from either of the welding conditions appeared as chain-like agglomerates of nanometer-sized primary particles. High voltage SS welding produced a greater number of ultrafine-sized particles. Fume generated by high voltage SS welding was higher in manganese. Pulmonary toxicity was more substantial and persisted longer after exposure to the regular SS fume. In summary, a modest raise in welding voltage affected fume size and elemental composition and altered the temporal lung toxicity profile. PMID:21281223

  15. Chemosensory cues affect amygdaloid neurogenesis and alter behaviors in the socially monogamous prairie vole.

    PubMed

    Liu, Y; Lieberwirth, C; Jia, X; Curtis, J T; Meredith, M; Wang, Z X

    2014-05-01

    The current study examined the effects of pheromonal exposure on adult neurogenesis and revealed the role of the olfactory pathways on adult neurogenesis and behavior in the socially monogamous prairie vole (Microtus ochrogaster). Subjects were injected with a cell proliferation marker [5-bromo-2'-deoxyuridine (BrdU)] and then exposed to their own soiled bedding or bedding soiled by a same- or opposite-sex conspecific. Exposure to opposite-sex bedding increased BrdU labeling in the amygdala (AMY), but not the dentate gyrus (DG), of female, but not male, voles, indicating a sex-, stimulus-, and brain region-specific effect. The removal of the main olfactory bulbs or lesioning of the vomeronasal organ (VNOX) in females reduced BrdU labeling in the AMY and DG, and inhibited the male bedding-induced BrdU labeling in the AMY, revealing the importance of an intact olfactory pathway for amygdaloid neurogenesis. VNOX increased anxiety-like behavior and altered social preference, but it did not affect social recognition memory in female voles. VNOX also reduced the percentage of BrdU-labeled cells that co-expressed the neuronal marker TuJ1 in the AMY, but not the DG. Together, our data indicate the importance of the olfactory pathway in mediating brain plasticity in the limbic system as well as its role in behavior. PMID:24641515

  16. Altering the axial light gradient affects photomorphogenesis in emerging seedlings of Zea mays L

    NASA Technical Reports Server (NTRS)

    Parks, B. M.; Poff, K. L.

    1986-01-01

    The axial (longitudinal) red light gradient (632 nanometers) of 4 day old dark-grown maize seedlings is increased by staining the peripheral cells of the coleoptile. The magnitude of increase in the light gradient is dependent solely on the light-absorbing qualities of the stain used. Metanil yellow has no effect on the axial red-light gradient, while methylene blue causes a large increase in this light gradient. These stains did not affect growth in darkness or the sensitivity of mesocotyl elongation to red light. However, mesocotyl elongation was altered for the dark-grown seedlings stained with methylene blue when these seedlings were transplanted, covered with soil, and permitted to emerge under natural lighting conditions. These observations are consistent with the idea that there is a single perceptive site below the coleoptilar node, and suggest that this perceptive site gives the actinic light which has traveled downward through the length of the shoot from an entry point in the plant tip region.

  17. The constant region affects antigen binding of antibodies to DNA by altering secondary structure

    PubMed Central

    Xia, Yumin; Janda, Alena; Eryilmaz, Ertan; Casadevall, Arturo; Putterman, Chaim

    2013-01-01

    We previously demonstrated an important role of the constant region in the pathogenicity of anti-DNA antibodies. To determine the mechanisms by which the constant region affects autoantibody binding, a panel of isotypeswitch variants (IgG1, IgG2a, IgG2b) was generated from the murine PL9-11 IgG3 autoantibody. The affinity of the PL9-11 antibody panel for histone was measured by surface plasmon resonance (SPR). Tryptophan fluorescence was used to determine wavelength shifts of the antibody panel upon binding to DNA and histone. Finally, circular dichroism spectroscopy was used to measure changes in secondary structure. SPR analysis revealed significant differences in histone binding affinity between members of the PL9-11 panel. The wavelength shifts of tryptophan fluorescence emission were found to be dependent on the antibody isotype, while circular dichroism analysis determined that changes in antibody secondary structure content differed between isotypes upon antigen binding. Thus, the antigen binding affinity is dependent on the particular constant region expressed. Moreover, the effects of antibody binding to antigen were also constant region dependent. Alteration of secondary structures influenced by constant regions may explain differences in fine specificity of anti-DNA antibodies between antibodies with similar variable regions, as well as cross-reactivity of anti-DNA antibodies with non-DNA antigens. PMID:23665381

  18. Chemosensory cues affect amygdaloid neurogenesis and alter behaviors in the socially monogamous prairie vole

    PubMed Central

    Liu, Y; Lieberwirth, C; Jia, X; Curtis, JT; Meredith, M; Wang, ZX

    2014-01-01

    The current study examined the effects of pheromonal exposure on adult neurogenesis and revealed the role of the olfactory pathways on adult neurogenesis and behavior in the socially monogamous prairie vole (Microtus ochrogaster). Subjects were injected with a cell proliferation marker, 5-bromo-2-deoxyuridine (BrdU), and then exposed to their own soiled bedding or bedding soiled by a same- or opposite-sex conspecific. Exposure to opposite-sex bedding increased BrdU-labeling in the amygdala (AMY), but not the dentate gyrus (DG), of female, but not male, volesindicating a sex-, stimulus-, and brain region-specific effect. The removal of the main olfactory bulbs or lesioning the vomeronasal organ (VNOX) in females reduced BrdU-labeling in the AMY and DG as well as inhibited the male bedding-induced BrdU-labeling in the AMYrevealing the importance of an intact olfactory pathway on amygdaloid neurogenesis. VNOX increased anxiety-like behavior and altered social preference, but it did not affect social recognition memory in female voles. VNOX also reduced the percentage of BrdU-labeled cells that co-expressed the neuronal marker TuJ1 in the AMY, but not the DG. Together, our data indicate the importance of the olfactory pathway in mediating brain plasticity in the limbic system as well as its role in behavior. PMID:24641515

  19. Collecting Duct Carcinomas Represent a Unique Tumor Entity Based on Genetic Alterations

    PubMed Central

    Parr, Martin; Hartmann, Arndt; Füssel, Susanne; Toma, Marieta; Grobholz, Rainer; Pflugmann, Thomas; Wullich, Bernd; Strauss, Arne; Behnes, Carl Ludwig; Otto, Wolfgang; Stöckle, Michael; Jung, Volker

    2013-01-01

    Collecting duct carcinoma (CDC) is a rare renal neoplasm that is associated with poor prognosis due to its highly aggressive course and limited response to immuno- or chemotherapy. Histologically, CDC is defined as a subtype of renal cell carcinomas, but in some cases, it is difficult to differentiate from urothelial carcinomas (UC). Therefore the aim of this study was to determine genetic alterations of CDC in comparison to that of urothelial carcinomas of the upper urinary tract (UUT-UC) to clarify the histological origin of this rare tumor entity. Twenty-nine CDC samples were obtained from seven different German centers and compared with twenty-six urothelial carcinomas of the upper urinary tract. Comparative genomic hybridization (CGH) was used to investigate the genetic composition of patients’ tumors and allowed the detection of losses and gains of DNA copy numbers throughout the entire genome. The clinical data were correlated with CGH results. CGH analysis of CDC revealed DNA aberrations in many chromosomes. DNA losses were more frequently observed than gains, while high-level amplifications were not detected. The mean frequency of CDC chromosomal aberrations (4.9/case) was slightly lower than that in UUT-UC (5.4/case). Recurrent CDC DNA losses occurred at 8p (n=9/29), 16p (9/29), 1p (n=7/29) and 9p (n=7/29), and gains occurred in 13q (n=9/29). In contrast to CDC, the most frequently detected UUT-UC DNA aberration was a loss at 9q (n=13/26). DNA losses at 9q, 13q and 8q as well as gains at 8p showed significant variations in UUT-UC compared to CDC. There was no correlation between the patients’ clinical course and the presence or absence of these recurrent genetic alterations. CDCs are characterized by a different genetic pattern compared to UUT-UC. Regarding the published data on renal cell carcinoma, we conclude that CDC appears to be a unique entity among kidney carcinomas. PMID:24167600

  20. Genetic background alters dominance relationships between mat alleles in the ciliate Tetrahymena thermophila.

    PubMed

    Phadke, Sujal S; Paixo, Tiago; Pham, Tuan; Pham, Stephanie; Zufall, Rebecca A

    2014-01-01

    The pattern of inheritance and mechanism of sex determination can have important evolutionary consequences. We studied probabilistic sex determination in the ciliate Tetrahymena thermophila, which was previously shown to cause evolution of skewed sex ratios. We find that the genetic background alters the sex determination patterns of mat alleles in heterozygotes and that allelic interaction can differentially influence the expression probability of the 7 sexes. We quantify the dominance relationships between several mat alleles and find that A-type alleles, which specify sex I, are indeed recessive to B-type alleles, which are unable to specify that sex. Our results provide additional support for the presence of modifier loci and raise implications for the dynamics of sex ratios in populations of T. thermophila. PMID:24190504

  1. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics

    PubMed Central

    Haenisch, Britta; Nöthen, Markus M; Molderings, Gerhard J

    2012-01-01

    Despite increasing understanding of its pathophysiology, the aetiology of systemic mast cell activation disease (MCAD) remains largely unknown. Research has shown that somatic mutations in kinases are necessary for the establishment of a clonal mast cell population, in particular mutations in the tyrosine kinase Kit and in enzymes and receptors with crucial involvement in the regulation of mast cell activity. However, other, as yet undetermined, abnormalities are necessary for the manifestation of clinical disease. The present article reviews molecular genetic research into the identification of disease-associated genes and their mutational alterations. The authors also present novel data on familial systemic MCAD and review the associated literature. Finally, the importance of understanding the molecular basis of inherited mutations in terms of diagnostics and therapy is emphasized. PMID:22957768

  2. Comparative genomic hybridization reveals population-based genetic alterations in hepatoblastomas

    PubMed Central

    Gray, S G; Kytl, S; Matsunaga, T; Larsson, C; Ekstrm, T J

    2000-01-01

    Hepatoblastoma is a malignant paediatric liver tumour. In order to approach the genetic background of this malignancy we have screened a panel of eighteen cases from Europe and Japan for chromosomal imbalances using comparative genomic hybridization (CGH). The most frequent losses included chromosomal regions 13q21q22 (28%) and 9p22-pter (22%), while the most frequent gains occurred on 2q23q24 (33%), 20q (28%) and 1q24q25 (28%). A significant difference in CGH alterations between the tumours from patients of Caucasian and Japanese was revealed where loss of 13q was found only in the Japanese samples. In conclusion, the findings indicate several candidate regions for suppressor genes and oncogenes potentially involved in the hepatoblastomas of different ethnic origin. 2000 Cancer Research Campaign PMID:10993649

  3. Drug-induced and Genetic Alterations in Stress-Responsive Systems: Implications for Specific Addictive Diseases

    PubMed Central

    Zhou, Yan; Proudnikov, Dmitri; Yuferov, Vadim; Kreek, Mary Jeanne

    2009-01-01

    From the earliest work in our laboratory, we hypothesized, and with studies conducted in both clinical research and animal models, we have shown that drugs of abuse, administered or self-administered, on a chronic basis, profoundly alter stress-responsive systems. Alterations of expression of specific genes involved in stress responsivity, with increases or decreases in mRNA levels, receptor and neuropeptide levels, and resultant changes in hormone levels, have been documented to occur after chronic intermittent exposure to heroin, morphine, other opiates, cocaine, other stimulants and alcohol in animal models and in human molecular genetics. The best studied of the stress-responsive systems in humans and mammalian species in general is undoubtedly the HPA axis. In addition, there are stress-responsive systems in other parts in the brain itself, and some of these include components of the HPA axis, such as CRF and CRF receptors, along with POMC gene and gene products. Several other stress-responsive systems are known to influence the HPA axis, such as the vasopressin-vasopressin receptor system. Orexin-hypocretin, acting at its receptors, may effect changes which suggest that it should be properly categorized as a stress-responsive system. However, less is known about the interactions and connectivity of some of these different neuropeptide and receptor systems, and in particular, about the possible connectivity of fast-acting (e.g., glutamate and GABA) and slow-acting (including dopamine, serotonin and norepinephrine) neurotransmitters with each of these stress-responsive components and the resultant impact, especially in the setting of chronic exposure to drugs of abuse. Several of these stress-responsive systems and components, primarily based on our laboratory-based and human molecular genetics research of addictive diseases, will be briefly discussed in this review. PMID:19914222

  4. 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

  5. Unique genetic alterations and clinicopathological features of hepatocellular adenoma in Chinese population.

    PubMed

    Liu, Hai-Ping; Zhao, Qian; Jin, Guang-Zhi; Qian, You-Wen; Gu, Yi-Jin; Dong, Hui; Lu, Xin-Yuan; Cong, Wen-Ming; Wu, Meng-Chao

    2015-12-01

    Hepatocellular adenoma (HCA) is a benign hepatocyte-derived tumor commonly seen in reproductive-aged women with long-term use of oral contraceptives (OCs) in European and North American countries. Accordingly, HCA is currently classified into four molecular subtypes as adopted by the World Health Organization. The present study was firstly to characterize and determine the genetic alterations and clinicopathological features of the largest series of HCAs in China. We reviewed 189 patients with HCA who underwent hepatectomies at our liver center from January 1984 to January 2012, among which 36 HCAs were randomly selected for the sequencing of HNF1?, ?-catenin and gp130 genes, and 60 HCAs were randomly selected for detecting microsatellite instability (MSI). Compared with Western studies, our data showed distinctive findings including male (69.8%) and overweight/obese (50.3%) predominance. Only 3.5% of female patients had a documented history of OCs use for 2-4 years. All 36 sequenced HCAs showed HNF1? mutations (72% missense, 28% synonymous), 2 hotspot polymorphisms of HNF1? (I27L: rs1169288 and S487N: rs2464196) were seen in 17 (47%) and 10 (27.8%) cases, respectively, and a novel single nucleotide polymorphism site (rs1169304) in intron 9 of HNF1? was detected in 32 (88%) cases, but no ?-catenin or gp130 gene mutation was detected, and no nuclear ?-catenin staining was detected by immunohistochemistry. The frequency of MSI was 75% for D12S1398 (HNF1? inactivated pathway) and 78.5% for D6S1064 (HIPPO signaling pathway) in 34 overweight/obese patients with HCA. Our results firstly indicate that patients with HCA in China frequently occur in male overweigh and obese adult population, lack an association with OCs use and exhibit unique genetic alterations. Taken together, these observations suggest that alternative pathogenetic pathways involve in HCA tumorigenesis in Chinese patients. PMID:26608415

  6. [Biological role and prognostic significance of genetic alterations in human malignant melanomas].

    PubMed

    Vzkeleti, Laura

    2015-09-01

    Metastatic process accounts for the vast majority of melanoma associated mortality, and also results in difficulties in the effective treatment. Therefore, identification of novel biomarkers could contribute to melanoma prognosis, and may also provide new opportunities for efficient cancer treatment. Several signaling pathways have been identified as key regulators in melanoma progression, including the frequent activation of Ras/MAPK signaling pathway through the mutant BRAF or NRAS genes. Besides, alterations of CCND1 may also be of great importance. The oncogene plays a significant role in the G1/S phase transition of the cell cycle, and its transcriptional activation is primarily carried out by the Ras/MAPK cascade. One of our aims was to determine the genetic and gene expression alterations of CCND1 during melanoma progression, considering the mutation status of BRAF and NRAS genes. Analysis of CCND1 copy number alterations revealed significant association with poor clinical outcome in primary melanomas, which was influenced by the mutation status of BRAF or NRAS in the term of sun exposure. Regarding gene expression, CCND1 mRNA level decreased in lesions with multiple metastases and were correlated with both the mRNA levels and mutation status of BRAF and NRAS. CCND1 protein expression was associated with Breslow thickness, metastasis formation and shorter survival time. However, the proportion of cells expressing the protein showed a heterogeneous distribution, influencing the association with clinical-pathological parameters. Therefore melanoma cell lines with different biological behavior were also analyzed for protein expression. These experiments revealed an increasing CCND1 protein level throughout primary cancer progression, which then decreased in the metastasis. The other purpose of our study was to determine the role of 7q31 region in melanoma progression, which was found frequently altered using array comparative genomic hybridization (aCGH). 7q31 is a gene dense locus, including the FRA7G fragile site, which serves as a mutation hot spot. In its close vicinity TES (focal adhesions) and CAV1 (lipid rafts) genes are located. Using interphase FISH, significant associations were found between 7q31 copy number alterations and poor clinical outcome. Both mRNA and protein levels of CAV1 decreased in thick lesions whereas primary melanomas forming multiple metastases were featured by decreased TES mRNA level. PMID:26339916

  7. Life history influences how fire affects genetic diversity in two lizard species.

    PubMed

    Smith, Annabel L; Bull, C Michael; Gardner, Michael G; Driscoll, Don A

    2014-05-01

    'Fire mosaics' are often maintained in landscapes to promote successional diversity in vegetation with little understanding of how this will affect ecological processes in animal populations such as dispersal, social organization and re-establishment. To investigate these processes, we conducted a replicated, spatiotemporal landscape genetics study of two Australian woodland lizard species [Amphibolurus norrisi (Agamidae) and Ctenotus atlas (Scincidae)]. Agamids have a more complex social and territory structure than skinks, so fire might have a greater impact on their population structure and thus genetic diversity. Genetic diversity increased with time since fire in C. atlas and decreased with time since fire in A. norrisi. For C. atlas, this might reflect its increasing population size after fire, but we could not detect increased gene flow that would reduce the loss of genetic diversity through genetic drift. Using landscape resistance analyses, we found no evidence that postfire habitat succession or topography affected gene flow in either species and we were unable to distinguish between survival and immigration as modes of postfire re-establishment. In A. norrisi, we detected female-biased dispersal, likely reflecting its territorial social structure and polygynous mating system. The increased genetic diversity in A. norrisi in recently burnt habitat might reflect a temporary disruption of its territoriality and increased male dispersal, a hypothesis that was supported with a simulation experiment. Our results suggest that the effects of disturbance on genetic diversity will be stronger for species with territorial social organization. PMID:24750427

  8. Genetic barcode sequencing for screening altered population dynamics of hematopoietic stem cells transduced with lentivirus

    PubMed Central

    Zanatta, Daniela B; Tsujita, Maristela; Borelli, Primavera; Aguiar, Rodrigo B; Ferrari, Daniel G; Strauss, Bryan E

    2014-01-01

    Insertional mutagenesis has been associated with malignant cell transformation in gene therapy protocols, leading to discussions about vector security. Therefore, clonal analysis is important for the assessment of vector safety and its impact on patient health. Here, we report a unique approach to assess dynamic changes in clonality of lentivirus transduced cells upon Sanger sequence analysis of a specially designed genetic barcode. In our approach, changes in the electropherogram peaks are measured and compared between successive time points, revealing alteration in the cell population. After in vitro validation, barcoded lentiviral libraries carrying IL2RG or LMO2 transgenes, or empty vector were used to transduce mouse hematopoietic (ckit+) stem cells, which were subsequently transplanted in recipient mice. We found that neither the empty nor IL2RG encoding vector had an effect on cell dynamics. In sharp contrast, the LMO2 oncogene was associated with altered cell dynamics even though hematologic counts remained unchanged, suggesting that the barcode could reveal changes in cell populations not observed by the frontline clinical assay. We describe a simple and sensitive method for the analysis of clonality, which could be easily used by any laboratory for the assessment of cellular behavior upon lentiviral transduction. PMID:26052520

  9. Diet-induced and mono-genetic obesity alter volatile organic compound signature in mice.

    PubMed

    Kistler, Martin; Muntean, Andreea; Szymczak, Wilfried; Rink, Nadine; Fuchs, Helmut; Gailus-Durner, Valerie; Wurst, Wolfgang; Hoeschen, Christoph; Klingenspor, Martin; Hrabě de Angelis, Martin; Rozman, Jan

    2016-01-01

    The prevalence of obesity is still rising in many countries, resulting in an increased risk of associated metabolic diseases. In this study we aimed to describe the volatile organic compound (VOC) patterns symptomatic for obesity. We analyzed high fat diet (HFD) induced obese and mono-genetic obese mice (global knock-in mutation in melanocortin-4 receptor MC4R-ki). The source strengths of 208 VOCs were analyzed in ad libitum fed mice and after overnight food restriction. Volatiles relevant for a random forest-based separation of obese mice were detected (26 in MC4R-ki, 22 in HFD mice). Eight volatiles were found to be important in both obesity models. Interestingly, by creating a partial correlation network of the volatile metabolites, the chemical and metabolic origins of several volatiles were identified. HFD-induced obese mice showed an elevation in the ketone body acetone and acrolein, a marker of lipid peroxidation, and several unidentified volatiles. In MC4R-ki mice, several yet-unidentified VOCs were found to be altered. Remarkably, the pheromone (methylthio)methanethiol was found to be reduced, linking metabolic dysfunction and reproduction. The signature of volatile metabolites can be instrumental in identifying and monitoring metabolic disease states, as shown in the screening of the two obese mouse models in this study. Our findings show the potential of breath gas analysis to non-invasively assess metabolic alterations for personalized diagnosis. PMID:26860833

  10. Genetical and comparative genomics of Brassica under altered Ca supply identifies Arabidopsis Ca-transporter orthologs.

    PubMed

    Graham, Neil S; Hammond, John P; Lysenko, Artem; Mayes, Sean; O 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

    2014-07-01

    Although Ca transport in plants is highly complex, the overexpression of vacuolar Ca(2+) 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 Ca(2+) 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

  11. Genetic alterations and epithelial dysplasia in juvenile polyposis syndrome and sporadic juvenile polyps.

    PubMed Central

    Wu, T. T.; Rezai, B.; Rashid, A.; Luce, M. C.; Cayouette, M. C.; Kim, C.; Sani, N.; Mishra, L.; Moskaluk, C. A.; Yardley, J. H.; Hamilton, S. R.

    1997-01-01

    Juvenile polyps are regarded as hamartomatous polyps and occur in sporadic and familial syndromic settings. There is increased risk of gastrointestinal neoplasia in patients with juvenile polyposis syndrome, but the molecular mechanisms are not known. We therefore studied 78 colorectal juvenile polyposis from 12 patients with juvenile polyps syndrome and 34 sporadic juvenile polyps for epithelial dysplasia and genetic changes associated with colorectal neoplasia. Dysplasia occurred in 31% of syndromic juvenile polyps but not in sporadic juvenile polyps (P < 0.0001). Topographic control of proliferation and expression of the cyclin-dependent kinase inhibitor p21(WAFI/CIP1) seen in native colorectal epithelium was lost in 79% of dysplastic juvenile polyps and in 8% of nondysplastic juvenile polyps (P < 0.000001). Somatic mutations in the adenomatous polyposis coli (APC) gene were demonstrated in 50% of dysplastic juvenile polyps (3 of 6) but not in any of 16 juvenile polyps without dysplasia (P = 0.01). Both sporadic and syndromic juvenile polyps had K-ras mutations (14%) and there was no relationship to dysplasia. p53 gene product overexpression identified by immunohistochemical staining occurred rarely in dysplastic juvenile polyps (2 of 24, 8%). Our results indicate that the multiple genetic alterations involved in usual colorectal neoplasia also play a role in neoplastic transformation of juvenile polyps, predominantly in juvenile polyposis syndrome. Images Figure 1 Figure 2 Figure 3 PMID:9060832

  12. Genetic alterations in endometrial cancer by targeted next-generation sequencing.

    PubMed

    Chang, Ya-Sian; Huang, Hsien-Da; Yeh, Kun-Tu; Chang, Jan-Gowth

    2016-02-01

    Many genetic factors play important roles in the development of endometrial cancer. The aim of this study was to investigate genetic alterations in the Taiwanese population with endometrial cancer. DNA was extracted from 10 cases of fresh-frozen endometrial cancer tissue. The exomes of cancer-related genes were captured using the NimbleGen Comprehensive Cancer Panel (578 cancer-related genes) and sequenced using the Illumina Genomic Sequencing Platform. Our results revealed 120 variants in 99 genes, 21 of which were included in the Oncomine Cancer Research Panel used in the National Cancer Institute Match Trial. The 21 genes comprised 8 tumor suppressor candidates (ATM, MSH2, PIK3R1, PTCH1, PTEN, TET2, TP53, and TSC1) and 13 oncogene candidates (ALK, BCL9, CTNNB1, ERBB2, FGFR2, FLT3, HNF1A, KIT, MTOR, PDGFRA, PPP2R1A, PTPN11, and SF3B1). We identified a high frequency of mutations in PTEN (50%) and genes involved in the endometrial cancer-related molecular pathway, which involves the IL-7 signaling pathway (PIK3R1, n=1; AKT2, n=1; FOXO1, n=1). We report the mutational landscape of endometrial cancer in the Taiwanese population. We believe that this study will shed new light on fundamental aspects for understanding the molecular pathogenesis of endometrial cancer and may aid in the development of new targeted therapies. PMID:26626801

  13. 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. PMID:23563121

  14. Genetic alteration and misexpression of Polycomb group genes in hepatocellular carcinoma.

    PubMed

    Gao, Shu-Bin; Sun, Shi-Long; Zheng, Qi-Lin; Zhang, Li; Zhu, Yuequan; Jin, Guang-Hui; Xue, Li-Xiang

    2015-01-01

    Although the abnormal expression of Polycomb-group (PcG) proteins is closely associated with carcinogenesis and the clinicopathological features of hepatocellular carcinoma (HCC), the genetic mutation profile of PcG genes has not been well established. In this study of human HCC specimens, we firstly discovered a highly conserved mutation site, G553C, in the Polycomb Repressive Complex 2 (PRC2) gene enhancer of zeste homolog 2 (EZH2). This site also harbors a single nucleotide polymorphism (SNP), rs2302427, which plays an important antagonistic role in HCC. Kaplan-Meier survival curves showed that the tumor-free and overall survival of patients with EZH2 G553C were superior to those without the mutation. The G allele frequencies in patients and healthy subjects were 0.2% and 0.122%, respectively, with significant differences in distribution. The individuals carrying the GG and the GC genotypes at rs2302427 showed 3.083-fold and 1.827-fold higher risks of HCC, respectively, compared with individuals carrying the wild-type allele. Furthermore, Immunohistochemical staining revealed that the expression levels of CBX8 (in 53/123 samples) and BMI1 (in 60/130 samples) were markedly increased in human HCC specimens. Importantly, the overall and tumor-free survival rates were significantly reduced in the group of patients who simultaneously expressed PRC1 and PRC2. These results argue that a combination of PRC1 and PRC2 expression has a significant predictive/prognostic value for HCC patients. Taken together, our results indicate the abnormal expression and genetic mutation of PcG members are two independent events; cumulative genetic and epigenetic alterations act synergistically in liver carcinogenesis. PMID:26693053

  15. 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. PMID:23719190

  16. Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are rare or absent in pleomorphic xanthoastrocytomas.

    PubMed

    Kaulich, Kerstin; Blaschke, Britta; Nümann, Astrid; von Deimling, Andreas; Wiestler, Otmar D; Weber, Ruthild G; Reifenberger, Guido

    2002-12-01

    Pleomorphic xanthoastrocytoma (PXA) is a rare, usually well-circumscribed and superficially located neoplasm that preferentially arises in the cerebral cortex of children and young adults. The molecular aberrations that are associated with these tumors have not been studied systematically so far. We here report on a molecular genetic analysis of 62 PXAs (46 PXAs of World Health Organization [WHO] grade II and 16 PXAs with anaplastic features) for alterations of 5 candidate genes known to be frequently aberrant in diffusely infiltrating astrocytic gliomas, i.e. TP53, CDKN2A (p16(INK4a)), CDK4, MDM2, and EGFR. Only 3 PXAs (5%) carried a TP53 mutation. None of the 62 PXAs had lost both copies of the CDKN2A gene. The CDK4, MDM2, or EGFR genes were not amplified in any of the tumors. Fourteen PXAs were additionally analyzed for loss of heterozygosity (LOH) at microsatellite markers located on the chromosomes/chromosomal arms 1, gp, 9p, 10, 17, 19q, and 22q. Two PXAs (14%) had LOH at all informative markers on 9p, while 1 PXA demonstrated an interstitial area of allelic imbalance between D22S533 and D22S417 at 22q11.2-q13.3. Further analysis of 10 PXAs for inactivation of the CDKN2A. p14(ARF), and CDKN2B (p15(INK4b)) genes on 9p21 did not reveal any homozygous deletion, mutation, promoter hypermethylation, or complete loss of mRNA expression. Taken together, our results indicate that the chromosomal and genetic aberrations in PXAs are different from those typically associated with the diffusely infiltrating astrocytic and oligodendroglial gliomas. These genetic differences likely contribute to the more favorable behavior of PXAs and may be helpful for the molecular differential diagnosis of cerebral gliomas. PMID:12484572

  17. Iron-salicylate complex induces peroxidation, alters hepatic lipid profile and affects plasma lipoprotein composition.

    PubMed

    Brunet, S; Guertin, F; Thibault, L; Gavino, V; Delvin, E; Levy, E

    1997-03-21

    Iron overload, with its associated toxic effects, has serious health consequences and results in damage to the liver, heart and other organs. Salicylate may be used as the lipophilic carrier, transporting more iron into hepatocytes. In this study, we examined the effect of the combined administration of these compounds on plasma lipid profile and lipoprotein composition, as well as on hepatic lipid concentration. Male Spraque-Dawley rats were injected i.p. with Fe (15 mg/kg weight). This injection was repeated 24 h later with a gavage of sodium salicylate (700 mg/kg). Control rats received 0.9% NaCl only. The peroxidation indices TBARS (P < 0.001) and conjugated dienes (P < 0.05) significantly increased in the blood (50 and 122%, respectively) and liver (333 and 101%, respectively) of Fe salicylate-treated rats. Concomitantly, blood and liver arachidonic acid content was diminished by iron treatment. In parallel, the plasma lipid profile was markedly affected in Fe-salicylate treated-rats. Lower plasma concentrations of total cholesterol (25%, P < 0.0001) cholesteryl ester, (34%, P < 0.001) and high-density lipoprotein-cholesterol (50%, P < 0.001) were observed. Lipoprotein composition analysis revealed enrichment of free cholesterol and depletion of cholesterol ester in very low-density, intermediate-density, low-density and high-density (HDL2, HDL3) lipoproteins. Furthermore, SDS-polyacrylamide gel electrophoresis revealed several alterations in the apolipoprotein distribution of these lipoproteins. The activity of lecithin:cholesterol acyltransferase was unchanged and could not account for the reduction of cholesterol esterification. As for the plasma, the liver exhibited a significant (P < 0.001) decrease in total cholesterol (2.42 +/- 0.07 versus 1.89 +/- 0.06 mg/g liver), essentially due to a reduction in cholesteryl ester (0.93 +/- 0.07 versus 0.51 +/- 0.03 mg/g, P < 0.001). Again, the activity of ACAT (dpm/mg microsomal protein) was not lower (12,700 +/- 1250) than that of controls (9650 +/- 1080). Thus, the iron-salicylate was able to induce peroxidation and to profoundly affect the intravascular and intrahepatic lipid, and plasma lipoprotein metabolism. Additional work is needed to elucidate the mechanisms involved in the underlying lipid and lipoprotein abnormalities. PMID:9105557

  18. Genetic alterations in quadruple malignancies of a patient with multiple sclerosis: their role in malignancy development and response to therapy.

    PubMed

    Milosevic, Zorica; Tanic, Nikola; Bankovic, Jasna; Stankovic, Tijana; Buta, Marko; Lavrnic, Dragana; Milovanovic, Zorka; Pupic, Gordana; Stojkovic, Sonja; Milinkovic, Vedrana; Ito, Yasuhiro; Dzodic, Radan

    2014-01-01

    Multiple cancers represent 2.42% of all human cancers and are mainly double or triple cancers. Many possible causes of multiple malignancies have been reported such as genetic alterations, exposure to anti-cancer chemotherapy, radiotherapy, immunosuppressive therapy and reduced immunologic response. We report a female patient with multiple sclerosis and quadruple cancers of different embryological origin. Patient was diagnosed with stage III (T3, N1a, MO) medullary thyroid carcinoma (MTC), multicentric micropapillary thyroid carcinoma, scapular and lumbar melanomas (Clark II, Breslow II), and lobular invasive breast carcinoma (T1a, NO, MO). All tumors present in our patient except micropapillary thyroid carcinomas were investigated for gene alterations known to have a key role in cancer promotion and progression. Tumor samples were screened for the p16 alterations (loss of heterozygosity and homozygous deletions), loss of heterozygosity of PTEN, p53 alterations (mutational status and loss of heterozygosity) and mutational status of RET, HRAS and KRAS. Each type of tumor investigated had specific pattern of analyzed genetic alterations. The most prominent genetic changes were mutual alterations in PTEN and p53 tumor suppressors present in breast cancer and two melanomas. These co-alterations could be crucial for promoting development of multiple malignancies. Moreover the insertion in 4(th) codon of HRAS gene was common for all tumor types investigated. It represents frameshift mutation introducing stop codon at position 5 which prevents synthesis of a full-length protein. Since the inactivated RAS enhances sensitivity to tamoxifen and radiotherapy this genetic alteration could be considered as a good prognostic factor for this patient. PMID:24817989

  19. Personalized Therapy in Patients With Anaplastic Thyroid Cancer: Targeting Genetic and Epigenetic Alterations

    PubMed Central

    Smith, Neal

    2015-01-01

    Context: Anaplastic thyroid cancer (ATC) is the most lethal of all thyroid cancers and one of the most aggressive human carcinomas. In the search for effective treatment options, research toward targeted, personalized therapies is proving to be a path with great potential. As we gain a deeper understanding of the genetic (eg, BRAFV600E, PIK3CA, TP53, hTERT mutations, etc) and epigenetic (eg, histone methylation, histone de-acetylation, microRNA regulatory circuits, etc) alterations driving ATC, we are able to find targets when developing novel therapies to improve the lives of patients. Beyond development, we can look into the effectiveness of already approved targeted therapies (eg, anti-BRAFV600E selective inhibitors, tyrosine kinase inhibitors, histone deacetylase inhibitors, inhibitors of DNA methylation, etc) to potentially test in ATC after learning the molecular mechanisms that aid in tumor progression. Design: We performed a literature analysis in Medline through the PubMed web site for studies published between 2003 and 2014 using the following main keywords: anaplastic thyroid cancer, genetic and epigenetic alterations. Objective: Here, we outlined the common pathways that are altered in ATC, including the BRAFV600E/ERK1/2-MEK1/2 and PI3K-AKT pathways. We then examined the current research looking into personalized, potential targeted therapies in ATC, mentioning those that have been tentatively advanced into clinical trials and those with the potential to reach that stage. We also reviewed side effects of the current and potential targeted therapies used in patients with advanced thyroid cancer. Conclusions: DNA and RNA next-generation sequencing analysis will be fundamental to unraveling a precise medicine and therapy in patients with ATC. Indeed, given the deep biological heterogeneity/complexity and high histological grade of this malignancy and its tumor microenvironment, personalized therapeutic approaches possibly based on the use of combinatorial targeted therapy will provide a rational approach when finding the optimal way to improve treatments for patients with ATC. PMID:25347569

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

    PubMed

    Skori?, Dragan; Joci?, Sinisa; Sakac, Zvonimir; Leci?, 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% oleic acid). There has been considerable work done recently on the development of high-oleic hybrids with altered tocopherol levels, the oil of which will have 10-20 times greater oxidative stability than that of conventional sunflower oil. While sunflower breeders work on developing hybrids with altered oil quality, medical scientists in general and nutritionists in particular will determine the parameters for the use of these novel types of oil that can improve human nutrition and be used in the prevention of cardiovascular diseases. PMID:18418432

  1. A Novel Statistical Model to Estimate Host Genetic Effects Affecting Disease Transmission

    PubMed Central

    Anacleto, Osvaldo; Garcia-Cortés, Luis Alberto; Lipschutz-Powell, Debby; Woolliams, John A.; Doeschl-Wilson, Andrea B.

    2015-01-01

    There is increasing recognition that genetic diversity can affect the spread of diseases, potentially affecting plant and livestock disease control as well as the emergence of human disease outbreaks. Nevertheless, even though computational tools can guide the control of infectious diseases, few epidemiological models can simultaneously accommodate the inherent individual heterogeneity in multiple infectious disease traits influencing disease transmission, such as the frequently modeled propensity to become infected and infectivity, which describes the host ability to transmit the infection to susceptible individuals. Furthermore, current quantitative genetic models fail to fully capture the heritable variation in host infectivity, mainly because they cannot accommodate the nonlinear infection dynamics underlying epidemiological data. We present in this article a novel statistical model and an inference method to estimate genetic parameters associated with both host susceptibility and infectivity. Our methodology combines quantitative genetic models of social interactions with stochastic processes to model the random, nonlinear, and dynamic nature of infections and uses adaptive Bayesian computational techniques to estimate the model parameters. Results using simulated epidemic data show that our model can accurately estimate heritabilities and genetic risks not only of susceptibility but also of infectivity, therefore exploring a trait whose heritable variation is currently ignored in disease genetics and can greatly influence the spread of infectious diseases. Our proposed methodology offers potential impacts in areas such as livestock disease control through selective breeding and also in predicting and controlling the emergence of disease outbreaks in human populations. PMID:26405030

  2. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    ERIC Educational Resources Information Center

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

  3. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    ERIC Educational Resources Information Center

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in

  4. ENVIRONMENTAL, GENETIC AND SOCIAL FACTORS AFFECTING THE EXPRESSION OF ESTRUS IN BEEF COWS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic, social and environmental factors affecting behavioral estrus were evaluated in Angus (n = 10), Brahman (n = 10) and Senepol (n = 10) cows during a synchronized estrus and subsequent spontaneous estrus. Cows were equally stratified by breed to two groups of 15. Both groups were pre-synchro...

  5. Intracolonial genetic variation affects reproductive skew and colony productivity during colony foundation in a parthenogenetic termite

    PubMed Central

    2014-01-01

    Background In insect societies, intracolonial genetic variation is predicted to affect both colony efficiency and reproductive skew. However, because the effects of genetic variation on these two colony characteristics have been tested independently, it remains unclear whether they are affected by genetic variation independently or in a related manner. Here we test the effect of genetic variation on colony efficiency and reproductive skew in a rhinotermitid termite, Reticulitermes speratus, a species in which female-female pairs can facultatively found colonies. We established colonies using two types of female-female pairs: colonies founded by sisters (i.e., sister-pair colonies) and those founded by females from different colonies (i.e., unrelated-pair colonies). Colony growth and reproductive skew were then compared between the two types of incipient colonies. Results At 15months after colony foundation, unrelated-pair colonies were larger than sister-pair colonies, although the caste ratio between workers and nymphs, which were alternatively differentiated from young larvae, did not differ significantly. Microsatellite DNA analyses of both founders and their parthenogenetically produced offspring indicated that, in both sister-pair and unrelated-pair colonies, there was no significant skew in the production of eggs, larvae, workers and soldiers. Nymph production, however, was significantly more skewed in the sister-pair colonies than in unrelated-pair colonies. Because nymphs can develop into winged adults (alates) or nymphoid reproductives, they have a higher chance of direct reproduction than workers in this species. Conclusions Our results support the idea that higher genetic variation among colony members could provide an increase in colony productivity, as shown in hymenopteran social insects. Moreover, this study suggests that low genetic variation (high relatedness) between founding females increases reproductive skew via one female preferentially channeling her relatives along the reproductive track. This study thus demonstrated that, in social insects, intracolonial genetic variation can simultaneously affect both colony efficiency and reproductive skew. PMID:25123355

  6. 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 bottlenecks were detected in about half the populations we sampled, and effective population size estimates were well below recommended minimum thresholds to avoid inbreeding. Efforts focused on maintaining and enhancing existing wetlands to facilitate dispersal between basins and increase local effective population sizes may be critical for these otherwise isolated populations.

  7. Alteration of NH2-terminal residues of nerve growth factor affects activity and Trk binding without affecting stability or conformation.

    PubMed

    Woo, S B; Timm, D E; Neet, K E

    1995-03-17

    The role of the NH2-terminal region of nerve growth factor (NGF) was studied with an NGF delta 9/13 deletion mutant, overexpressed in a baculovirus system, and mouse NGF truncated at Met-9 by cleavage with CNBr (des-(1-9)-NGF). Structural studies have been performed on the purified proteins, in addition to biological activity assessment, in order to determine effects of such modifications on global conformation and stability. The activity of NGF delta 9/13 was reduced below detectable levels, and the activity of the des-(1-9)-NGF form was decreased by at least a 50-fold in a PC12 bioassay. Competitive binding of NGF delta 9/13 to low affinity receptors on PC12 cells was not impaired; however, the mutant was not capable of competing for the cold chase-stable, high affinity binding of NGF to the cells. The binding of NGF delta 9/13 to Sf21 cells ectopically expressing the TrkA NGF receptor was also abolished. Thus, deletion of residues 9-13 significantly altered the binding affinity for the high affinity receptors on PC12 cells and for the TrkA receptor, but not for the low affinity receptor. Neither the secondary structure, determined by circular dichroism, nor the conformational stability determined by equilibrium denaturation of NGF delta 9/13 was altered as compared with wild type NGF. Slight conformational and stability perturbations of des-(1-9)-NGF were revealed by the same analysis; however, these changes were found to reflect the influence of the formic acid treatment, not the truncation of 9 residues. Our results support the conclusion that the NH2-terminal domain encompassing residues 1-9 and 9-13 is essential for maintaining the binding capability of NGF for high affinity TrkA receptors. Moreover, conformational and stability data show that the functional results of these modifications of the NH2-terminal region are directly due to receptor binding and not to secondary effects of improper folding or other indirect structural changes. PMID:7890765

  8. 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. PMID:26546826

  9. Behavioral Studies and Genetic Alterations in Corticotropin-Releasing Hormone (CRH) Neurocircuitry: Insights into Human Psychiatric Disorders

    PubMed Central

    Laryea, Gloria; Arnett, Melinda G.; Muglia, Louis J.

    2012-01-01

    To maintain well-being, all organisms require the ability to re-establish homeostasis in the presence of adverse physiological or psychological experiences. The regulation of the hypothalamic-pituitary adrenal (HPA) axis during stress is important in preventing maladaptive responses that may increase susceptibility to affective disorders. Corticotropin-releasing hormone (CRH) is a central stress hormone in the HPA axis pathway and has been implicated in stress-induced psychiatric disorders, reproductive and cardiac function, as well as energy metabolism. In the context of psychiatric disorders, CRH dysfunction is associated with the occurrence of post-traumatic stress disorder, major depression, anorexia nervosa, and anxiety disorders. Here, we review the synthesis, molecular signaling and regulation, as well as synaptic activity of CRH. We go on to summarize studies of altered CRH signaling in mutant animal models. This assembled data demonstrate an important role for CRH in neuroendocrine, autonomic, and behavioral correlates of adaptation and maladaptation. Next, we present findings regarding human genetic polymorphisms in CRH pathway genes that are associated with stress and psychiatric disorders. Finally, we discuss a role for regulators of CRH activity as potential sites for therapeutic intervention aimed at treating maladaptive behaviors associated with stress. PMID:23077729

  10. Recognition memory is associated with altered resting-state functional connectivity in people at genetic risk for Alzheimer's disease.

    PubMed

    Matura, Silke; Prvulovic, David; Butz, Marius; Hartmann, Daniel; Sepanski, Beate; Linnemann, Katja; Oertel-Knchel, Viola; Karakaya, Tarik; Fuer, Fabian; Pantel, Johannes; van de Ven, Vincent

    2014-10-01

    The apolipoprotein E ?4 (ApoE ?4) allele not only represents the strongest single genetic risk factor for sporadic Alzheimer's disease, but also imposes independent effects on brain function in healthy individuals where it has been shown to promote subtle memory deficits and altered intrinsic functional brain network connectivity. Based on previous work showing a potential relevance of the default mode network (DMN) functional connectivity for episodic memory function, we hypothesized that the ApoE ?4 genotype would affect memory performance via modulation of the DMN. We assessed 63 healthy individuals (50-80 years old), of which 20 carried the ?4 allele. All participants underwent resting-state functional magnetic resonance imaging (fMRI), high-resolution 3D anatomical MRI imaging and neuropsychological assessment. Functional connectivity analysis of resting-state activity was performed with a predefined seed region located in the left posterior cingulate cortex (PCC), a core region of the DMN. ApoE ?4 carriers performed significantly poorer than non-carriers in wordlist recognition and cued recall. Furthermore, ?4 carriers showed increased connectivity relative to ?4 non-carriers between the PCC seed region and left-hemispheric middle temporal gyrus (MTG). There was a positive correlation between recognition memory scores and resting-state connectivity in the left MTG in ?4 carriers. These results can be interpreted as compensatory mechanisms strengthening the cross-links between DMN core areas and cortical areas involved in memory processing. PMID:24989884

  11. Constructing the toolbox: Patient-specific genetic factors of altered fracture healing

    PubMed Central

    Drissi, Hicham; Paglia, David N.; Alaee, Farhang; Yoshida, Ryu

    2014-01-01

    The multifaceted sequence of events that follow fracture repair can be further complicated when considering risk factors for impaired union, present in a large and growing percentage of the population. Risk factors such as diabetes, substance abuse, and poor nutrition affect both the young and old alike, and have been shown to dramatically impair the body’s natural healing processes. To this end, biotherapeudic interventions such as ultrasound, electrical simulation, growth factor treatment (BMP-2, BMP-7, PDGF-BB, FGF-2) have been evaluated in preclinical models and in some cases are used widely for patients with established non-union or risk/indication or impaired healing (ie. ultrasound, BMP-2, etc.). Despite the promise of these interventions, they have been shown to be reliant on patient compliance and can produce adverse side-effects such as heterotopic ossification. Gene and cell therapy approaches have attempted to apply controlled regimens of these factors and have produced promising results. However, there are safety and efficacy concerns that may limit the translation of these approaches. In addition, none of the above mentioned approaches consider genetic variation between individual patients. Several clinical and preclinical studies have demonstrated a genetic component to fracture repair and that SNPs and genetic background variation play major roles in the determination of healing outcomes. Despite this, there is a need for preclinical data to dissect the mechanism underlying the influence of specific gene loci on the processes of fracture healing, which will be paramount in the future of patient-centered interventions for fracture repair. PMID:25558470

  12. Use of Closely Related Affected Individuals for the Genetic Study of Complex Diseases in Founder Populations

    PubMed Central

    Bourgain, C.; Gnin, E.; Holopainen, P.; Mustalahti, K.; Mki, M.; Partanen, J.; Clerget-Darpoux, F.

    2001-01-01

    We propose a method, the maximum identity length contrast (MILC) statistic, to locate genetic risk factors for complex diseases in founder populations. The MILC approach compares the identity length of parental haplotypes that are transmitted to affected offspring with the identity length of those that are not transmitted to affected offspring. Initially, the statistical properties of the method were assessed using randomly selected affected individuals with unknown relationship. Because both nuclear families with multiple affected sibs and large pedigrees are often available in founder populations, we performed simulations to investigate the properties of the MILC statistic in the presence of closely related affected individuals. The simulation showed that the use of closely related affected individuals greatly enhances the power of the statistic. For a given sample size and type I error, the use of affected sib pairs, instead of affected individuals randomly selected from the population, could increase the power by a factor of two. This increase was related to an increase of kinship-coefficient contrast between haplotype groups when closely related individuals were considered. The MILC approach allows the simultaneous use of affected individuals from a founder population and affected individuals with any kind of relationship, close or remote. We used the MILC approach to analyze the role of HLA in celiac disease and showed that the effect of HLA may be detected with the MILC approach by typing only 11 affected individuals, who were part of a single large Finnish pedigree. PMID:11102286

  13. Vitamin D Related Host Genetic Variants Alter HIV Disease Progression in Children

    PubMed Central

    Moodley, Amaran; Qin, Min; Singh, Kumud K.; Spector, Stephen A.

    2013-01-01

    Background Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children. Methods The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by RT-PCR in HIV-infected children who participated in the PACTG P152 and P300 protocols which pre-dated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease end-point (?2 OI's, weight-growth failure) or death, which constituted the progression-free-survival. Analyses were performed for age >2 years and ?2 years separately adjusting for race and treatment effect. Results Of the 998 children evaluated, 139 experienced HIV disease progression. For children >2 years, rapid disease progression was associated with the DHCR7 G allele compared to the T allele (G/G vs. T/T: HR=5.0, p=0.035, G/T vs. T/T: HR=4.5, p=0.042, G/G+G/T vs. T/T: HR=4.8, p=0.036), and the Bsm-I A allele compared to the G allele (A/G vs. G/G: HR=2.2, p=0.014 and A/G+A/A vs. G/G: HR=2.0, p=0.026). In children ?2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, p=0.03; A/A vs. G/G: HR=2.8, p=0.046) and whites (A/A vs. G/G: HR=6.6, p=0.025; A/A vs. G/A+G/G: HR=3.6, p=0.038). Conclusions Vitamin D related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children, and may vary by age and race. PMID:23736144

  14. Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene ExpressionBased Proliferation Signature

    PubMed Central

    Salaverria, Itziar; Zettl, Andreas; Be, Slvia; Moreno, Victor; Valls, Joan; Hartmann, Elena; Ott, German; Wright, George; Lopez-Guillermo, Armando; Chan, Wing C.; Weisenburger, Dennis D.; Gascoyne, Randy D.; Grogan, Thomas M.; Delabie, Jan; Jaffe, Elaine S.; Montserrat, Emili; Muller-Hermelink, Hans-Konrad; Staudt, Louis M.; Rosenwald, Andreas

    2008-01-01

    Purpose To compare the genetic relationship between cyclin D1positive and cyclin D1negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs. Patients and Methods Seventy-one cyclin D1positive and six cyclin D1negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH). Results Cyclin D1negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity. Conclusion Cyclin D1positive and negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL. PMID:17296973

  15. 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. PMID:25998045

  16. Dioecy, more than monoecy, affects plant spatial genetic structure: the case study of Ficus

    PubMed Central

    Nazareno, Alison G; Alzate-Marin, Ana L; Pereira, Rodrigo Augusto S

    2013-01-01

    In this analysis, we attempt to understand how monoecy and dioecy drive spatial genetic structure (SGS) in plant populations. For this purpose, plants of the genus Ficus were used as a comparative model due to their particular characteristics, including high species diversity, variation in life histories, and sexual systems. One of the main issues we assessed is whether dioecious fig tree populations are more spatially genetically structured than monoecious populations. Using the Sp statistic, which allows for quantitative comparisons among different studies, we compared the extent of SGS between monoecious and dioecious Ficus species. To broaden our conclusions we used published data on an additional 27 monoecious and dioecious plant species. Furthermore, genetic diversity analyses were performed for two monoecious Ficus species using 12 microsatellite markers in order to strengthen our conclusions about SGS. Our results show that dioecy, more than monoecy, significantly contributes to SGS in plant populations. On average, the estimate of Sp was six times higher for dioecious Ficus species than monoecious Ficus species and it was two times higher in dioecious than monoecious plant species. Considering these results, we emphasize that the long-distance pollen dispersal mechanism in monoecious Ficus species seems to be the dominant factor in determining weak spatial genetic structure, high levels of genetic diversity, and lack of inbreeding. Although Ficus constitute a model species to study SGS, a more general comparison encompassing a wider range of plants is required in order to better understand how sexual systems affect genetic structure. PMID:24223285

  17. Genetic variation affecting host-parasite interactions: different genes affect different aspects of sigma virus replication and transmission in Drosophila melanogaster.

    PubMed

    Bangham, Jenny; Kim, Kang-Wook; Webster, Claire L; Jiggins, Francis M

    2008-04-01

    In natural populations, genetic variation affects resistance to disease. Knowing how much variation exists, and understanding the genetic architecture of this variation, is important for medicine, for agriculture, and for understanding evolutionary processes. To investigate the extent and nature of genetic variation affecting resistance to pathogens, we are studying a tractable model system: Drosophila melanogaster and its natural pathogen the vertically transmitted sigma virus. We show that considerable genetic variation affects transmission of the virus from parent to offspring. However, maternal and paternal transmission of the virus is affected by different genes. Maternal transmission is a simple Mendelian trait: most of the genetic variation is explained by a polymorphism in ref(2)P, a gene already well known to affect resistance to sigma. In contrast, there is considerable genetic variation in paternal transmission that cannot be explained by ref(2)P and is caused by other loci on chromosome 2. Furthermore, we found no genetic correlation between paternal transmission of the virus and resistance to infection by the sigma virus following injection. This suggests that different loci affect viral replication and paternal transmission. PMID:18430944

  18. The experience of altered states of consciousness in shamanic ritual: the role of pre-existing beliefs and affective factors.

    PubMed

    Polito, Vince; Langdon, Robyn; Brown, Jac

    2010-12-01

    Much attention has been paid recently to the role of anomalous experiences in the aetiology of certain types of psychopathology, e.g. in the formation of delusions. We examine, instead, the top-down influence of pre-existing beliefs and affective factors in shaping an individual's characterisation of anomalous sensory experiences. Specifically we investigated the effects of paranormal beliefs and alexithymia in determining the intensity and quality of an altered state of consciousness (ASC). Fifty five participants took part in a sweat lodge ceremony, a traditional shamanic ritual which was unfamiliar to them. Participants reported significant alterations in their state of consciousness, quantified using the 'APZ' questionnaire, a standardized measure of ASC experience. Participants endorsing paranormal beliefs compatible with shamanic mythology, and those showing difficulty identifying feelings scored higher on positive dimensions of ASC experience. Our findings demonstrate that variation in an individual's characterisation of anomalous experiences is nuanced by pre-existing beliefs and affective factors. PMID:20558090

  19. Neonatal Phytoestrogen Exposure Alters Oviduct Mucosal Immune Response to Pregnancy and Affects Preimplantation Embryo Development in the Mouse1

    PubMed Central

    Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Phelps, Jazma Y.; Cantor, Amy M.; Williams, Carmen J.

    2012-01-01

    ABSTRACT Treatment of neonatal mice with the phytoestrogen genistein (50 mg/kg/day) results in complete female infertility caused in part by preimplantation embryo loss in the oviduct between Days 2 and 3 of pregnancy. We previously demonstrated that oviducts of genistein-treated mice are posteriorized as compared to control mouse oviducts because they express numerous genes normally restricted to posterior regions of the female reproductive tract (FRT), the cervix and vagina. We report here that neonatal genistein treatment resulted in substantial changes in oviduct expression of genes important for the FRT mucosal immune response, including immunoglobulins, antimicrobials, and chemokines. Some of the altered immune response genes were chronically altered beginning at the time of neonatal genistein treatment, indicating that these alterations were a result of the posteriorization phenotype. Other alterations in oviduct gene expression were observed only in early pregnancy, immediately after the FRT was exposed to inflammatory or antigenic stimuli from ovulation and mating. The oviduct changes affected development of the surviving embryos by increasing the rate of cleavage and decreasing the trophectoderm-to-inner cell mass cell ratio at the blastocyst stage. We conclude that both altered immune responses to pregnancy and deficits in oviduct support for preimplantation embryo development in the neonatal genistein model are likely to contribute to infertility phenotype. PMID:22553218

  20. Genetic Analysis of 63 Mutations Affecting Maize Kernel Development Isolated from Mutator Stocks

    PubMed Central

    Scanlon, M. J.; Stinard, P. S.; James, M. G.; Myers, A. M.; Robertson, D. S.

    1994-01-01

    Sixty-three mutations affecting development of the maize kernel were isolated from active Robertson's Mutator (Mu) stocks. At least 14 previously undescribed maize gene loci were defined by mutations in this collection. Genetic mapping located 53 of these defective kernel (dek) mutations to particular chromosome arms, and more precise map determinations were made for 21 of the mutations. Genetic analyses identified 20 instances of allelism between one of the novel mutations and a previously described dek mutation, or between new dek mutations identified in this study; phenotypic variability was observed in three of the allelic series. Viability testing of homozygous mutant kernels identified numerous dek mutations with various pleiotropic effects on seedling and plant development. The mutations described here presumably arose by insertion of a Mu transposon within a dek gene; thus, many of the affected loci are expected to be accessible to molecular cloning via transposon-tagging. PMID:8138165

  1. Alterations in homocysteine metabolism among alcohol dependent patients--clinical, pathobiochemical and genetic aspects.

    PubMed

    Lutz, Ulrich C

    2008-01-01

    Addiction research focusing on homocysteine metabolism and its association with aspects of alcohol dependence has revealed important findings. Recent literature on this topic has been taken into account for the review provided. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolism. Plasma homocysteine levels are influenced by the single-nucleotide polymorphism (SNP) MTHFR C677T. Besides genetic factors, environmental factors have an impact on homocysteine plasma levels too. Thus, chronic alcohol intake is associated with elevated homocysteine plasma concentrations. Elevation of plasma homocysteine concentration is considered as a predictor for the occurrence of alcohol withdrawal seizures and--as homocysteine is a cardiovascular risk factor--might contribute to the higher risk for myocardial infarction among alcohol dependent patients. Homocysteine acts as an N-methyl-D-aspartate (NMDA) receptor agonist and has excitotoxic effects. Furthermore, it has been demonstrated that homocysteine has neurotoxic effects especially on dopaminergic neurons. As the rewarding effects of alcohol are mediated by the dopaminergic system, a homocysteine-dependent impairment of the reward system possibly leads to an altered drinking behaviour according to the deficit hypothesis of addiction. Homocysteine is involved in the metabolism of methyl groups and DNA-methylation plays a role in regulation of gene expression. Therefore it has been suggested that homocysteine is an important epigenetic factor. It remains to be determined whether alcohol dependent patients benefit from homocysteine lowering strategies, e.g., via supplementation of folate, vitamin B6 and B12. In this respect it is not clear yet, if a supplementation therapy can reduce the risk for the occurrence of alcohol withdrawal seizures. PMID:19630705

  2. Genetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity

    PubMed Central

    Salojin, Konstantin V.; Hamman, Brian D.; Chang, Wei Chun; Jhaver, Kanchan G.; Al-Shami, Amin; Crisostomo, Jeannette; Wilkins, Carrie; Digeorge-Foushee, Ann Marie; Allen, Jason; Patel, Nita; Gopinathan, Suma; Zhou, Julia; Nouraldeen, Amr; Jessop, Theodore C.; Bagdanoff, Jeffrey T.; Augeri, David J.; Read, Robert; Vogel, Peter; Swaffield, Jonathan; Wilson, Alan; Platt, Kenneth A.; Carson, Kenneth G.; Main, Alan; Zambrowicz, Brian P.; Oravecz, Tamas

    2014-01-01

    Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4+ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1−/− B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1−/− CD4+ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4+ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders. PMID:24852423

  3. Preschool-Aged Children with Iron Deficiency Anemia Show Altered Affect and Behavior1,2

    PubMed Central

    Lozoff, Betsy; Corapci, Feyza; Burden, Matthew J.; Kaciroti, Niko; Angulo-Barroso, Rosa; Sazawal, Sunil; Black, Maureen

    2012-01-01

    This study compared social looking and response to novelty in preschool-aged children (47–68 mo) with or without iron deficiency anemia (IDA). Iron status of the participants from a low-income community in New Delhi, India, was based on venous hemoglobin, mean corpuscular volume, and red cell distribution width. Children’s social looking toward adults, affect, and wary or hesitant behavior in response to novelty were assessed in a semistructured paradigm during an in-home play observation. Affect and behavior were compared as a function of iron status: IDA (n = 74) vs. nonanemic (n = 164). Compared with nonanemic preschoolers, preschoolers with IDA displayed less social looking toward their mothers, moved close to their mothers more quickly, and were slower to display positive affect and touch novel toys for the first time. These results indicate that IDA in the preschool period has affective and behavioral effects similar to those reported for IDA in infancy. PMID:17311960

  4. Altered sleep composition after traumatic brain injury does not affect declarative sleep-dependent memory consolidation

    PubMed Central

    Mantua, Janna; Mahan, Keenan M.; Henry, Owen S.; Spencer, Rebecca M. C.

    2015-01-01

    Individuals with a history of traumatic brain injury (TBI) often report sleep disturbances, which may be caused by changes in sleep architecture or reduced sleep quality (greater time awake after sleep onset, poorer sleep efficiency, and sleep stage proportion alterations). Sleep is beneficial for memory formation, and herein we examine whether altered sleep physiology following TBI has deleterious effects on sleep-dependent declarative memory consolidation. Participants learned a list of word pairs in the morning or evening, and recall was assessed 12-h later, following an interval awake or with overnight sleep. Young adult participants (1822 years) were assigned to one of four experimental groups: TBI Sleep (n = 14), TBI Wake (n = 12), non-TBI Sleep (n = 15), non-TBI Wake (n = 15). Each TBI participant was >1 year post-injury. Sleep physiology was measured with polysomnography. Memory consolidation was assessed by comparing change in word-pair recall over 12-h intersession intervals. The TBI group spent a significantly greater proportion of the night in SWS than the non-TBI group at the expense of NREM1. The TBI group also had marginally lower EEG delta power during SWS in the central region. Intersession changes in recall were greater for intervals with sleep than without sleep in both groups. However, despite abnormal sleep stage proportions for individuals with a TBI history, there was no difference in the intersession change in recall following sleep for the TBI and non-TBI groups. In both Sleep groups combined, there was a positive correlation between Intersession Change and the proportion of the night in NREM2 + SWS. Overall, sleep composition is altered following TBI but such deficits do not yield insufficiencies in sleep-dependent memory consolidation. PMID:26097451

  5. How reactive fluids alter fracture walls and affect shale-matrix accessibility

    NASA Astrophysics Data System (ADS)

    Fitts, J. P.; Deng, H.; Peters, C. A.

    2014-12-01

    Predictions of mass transfer across fracture boundaries and fluid flow in fracture networks provide fundamental inputs into risk and life cycle assessments of geologic energy technologies including oil and gas extraction, geothermal energy systems and geologic CO2 storage. However, major knowledge gaps exist due to the lack of experimental observations of how reactive fluids alter the pore structures and accessible surface area within fracture boundaries that control the mass transfer of organics, metals and salts, and influence fluid flow within the fracture. To investigate the fracture and rock matrix properties governing fracture boundary alteration, we developed a new flow-through cell that enables time-dependent 2D x-ray imaging of mineral dissolution and/or precipitation at a fracture surface. The parallel plate design provides an idealized fracture geometry to investigate the relationship between flow rate, reaction rate, and mineral spatial heterogeneity and variation. In the flow-cell, a carbonate-rich sample of Eagle Ford shale was reacted with acidified brine. The extent and rate of mineral dissolution were correlated with calcite abundance relative to less soluble silicate minerals. Three-dimensional x-ray tomography of the reacted fracture wall shows how calcite dissolution left behind a porous network of silicate minerals. And while this silicate network essentially preserved the location of the initial fracture wall, the pore network structures within the fracture boundary were dramatically altered, such that the accessible surface area of matrix components increased significantly. In a second set of experiments with a limestone specimen, however, the extent of dissolution and retreat of the fracture wall was not strictly correlated with the occurrence of calcite. Instead, the pattern and extent of dissolution suggested secondary causes such as calcite morphology, the presence of argillaceous minerals and other diagenetic features. Our experiments show that while calcite dissolution is the primary geochemical driver of fracture wall alterations, hydrodynamic properties and matrix accessibility within fracture boundaries evolve based on a complex relationship between mineral spatial heterogeneity and variation, fluid chemistry and flow rate.

  6. 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.

  7. Alterations in affective processing of attack images following September 11, 2001.

    PubMed

    Tso, Ivy F; Chiu, Pearl H; King-Casas, Brooks R; Deldin, Patricia J

    2011-10-01

    The events of September 11, 2001 created unprecedented uncertainty about safety in the United States and created an aftermath with significant psychological impact across the world. This study examined emotional information encoding in 31 healthy individuals whose stress response symptoms ranged from none to a moderate level shortly after the attacks as assessed by the Impact of Event Scale-Revised. Participants viewed attack-related, negative (but attack-irrelevant), and neutral images while their event-related brain potentials (ERPs) were recorded. Attack images elicited enhanced P300 relative to negative and neutral images, and emotional images prompted larger slow waves than neutral images did. Total symptoms were correlated with altered N2, P300, and slow wave responses during valence processing. Specifically, hyperarousal and intrusion symptoms were associated with diminished stimulus discrimination between neutral and unpleasant images; avoidance symptoms were associated with hypervigilance, as suggested by reduced P300 difference between attack and other images and reduced appraisal of attack images as indicated by attenuated slow wave. The findings in this minimally symptomatic sample are compatible with the alterations in cognition in the posttraumatic stress disorder (PTSD) literature and are consistent with a dimensional model of PTSD. PMID:21882249

  8. Altered ovarian function affects skeletal homeostasis independent of the action of follicle-stimulating hormone.

    PubMed

    Gao, Jianjun; Tiwari-Pandey, Rashmi; Samadfam, Rana; Yang, Yinzhi; Miao, Dengshun; Karaplis, Andrew C; Sairam, M Ram; Goltzman, David

    2007-06-01

    Osteoporosis is a leading public health problem. Although a major cause in women is thought to be a decline in estrogen, it has recently been proposed that FSH or follitropin is required for osteoporotic bone loss. We examined the FSH receptor null mouse (FORKO mouse) to determine whether altered ovarian function could induce bone loss independent of FSH action. By 3 months of age, FORKO mice developed age-dependent declines in bone mineral density and trabecular bone volume of the lumbar spine and femur, which could be partly reversed by ovarian transplantation. Bilateral ovariectomy reduced elevated circulating testosterone levels in FORKO mice and decreased bone mass to levels indistinguishable from those in ovariectomized wild-type controls. Androgen receptor blockade and especially aromatase inhibition each produced bone volume reductions in the FORKO mouse. The results indicate that ovarian secretory products, notably estrogen, and peripheral conversion of ovarian androgen to estrogen can alter bone homeostasis independent of any bone resorptive action of FSH. PMID:17332067

  9. Association between Oro-Facial Defects and Systemic Alterations in Children Affected by Marfan Syndrome

    PubMed Central

    Docimo, Raffaella; Maturo, Paolo; DAuria, Francesca; Grego, Susanna; Costacurta, Micaela; Perugia, Cesare; Chiariello, Luigi

    2013-01-01

    Background: It is important to establish an early diagnosis of the Marfan Syndrome (MFS) for providing an adequate pharmacological or surgical therapy. Nevertheless, this diagnosis may be complex, given the multi-organic involvement of this disease. Aims: In this work, we evaluated the oral phenotype in a group of paediatric patients with a clinical diagnosis of MFS, to quantify the association of the oro-facial defects with other systemic alterations. Settings and Design: Paediatric subjects who were aged, with a clinical diagnosis of MFS, were selected from our regional Marfan monitoring unit. Methods and Material: All the patients were subjected to Paediatric Dentistry examinations and a radiological screening with Panoramic and Cephalometric X-Rays. The aortic dilation (Aortic Z-score value), the hyperlaxity of the ligaments and scoliosis were evaluated by cardio-surgical and orthopaedics specialists. Statistical Analysis: The correlations between the oral and systemic alterations were analyzed by using the chi square test for the nominal variables. Results and Conclusions: We found a significant correlation of the Aortic Z score with multiple oral defects which included retrognathia, malar hypoplasia, cross bite, oral respiration and an ogival palate. An association of the oral defects with hyperlaxity of the ligaments and scoliosis was also found. Thus, the data suggested that dentists should be more involved in a multidisciplinary approach, to provide an early MFS diagnosis in paediatric patients. PMID:23730650

  10. Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors.

    PubMed

    Zindy, Frederique; Uziel, Tamar; Ayrault, Olivier; Calabrese, Christopher; Valentine, Marc; Rehg, Jerold E; Gilbertson, Richard J; Sherr, Charles J; Roussel, Martine F

    2007-03-15

    Mice lacking p53 and one or two alleles of the cyclin D-dependent kinase inhibitor p18(Ink4c) are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1(+/-) mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild-type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c(-/-), p53(-/-) mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These "engineered" tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation. PMID:17363588

  11. Exposure to a commercial glyphosate formulation (Roundup) alters normal gill and liver histology and affects male sexual activity of Jenynsia multidentata (Anablepidae, Cyprinodontiformes).

    PubMed

    Hued, Andrea Cecilia; Oberhofer, Sabrina; de los ngeles Bistoni, Mara

    2012-01-01

    Roundup is the most popular commercial glyphosate formulation applied in the cultivation of genetically modified glyphosate-resistant crops. The aim of this study was to evaluate the histological lesions of the neotropical native fish, Jenynsia multidentata, in response to acute and subchronic exposure to Roundup and to determine if subchronic exposure to the herbicide causes changes in male sexual activity of individuals exposed to a sublethal concentration (0.5 mg/l) for 7 and 28 days. The estimated 96-h LC50 was 19.02 mg/l for both male and female fish. Gill and liver histological lesions were evaluated through histopathological indices allowing quantification of the histological damages in fish exposed to different concentrations of the herbicide. Roundup induced different histological alterations in a concentration-dependent manner. In subchronic-exposure tests, Roundup also altered normal histology of the studied organs and caused a significant decrease in the number of copulations and mating success in male fish exposed to the herbicide. It is expected that in natural environments contaminated with Roundup, both general health condition and reproductive success of J. multidenatata could be seriously affected. PMID:21643816

  12. Early Experiences Can Alter Gene Expression and Affect Long-Term Development. Working Paper #10

    ERIC Educational Resources Information Center

    National Scientific Council on the Developing Child, 2010

    2010-01-01

    New scientific research shows that environmental influences can actually affect whether and how genes are expressed. Thus, the old ideas that genes are "set in stone" or that they alone determine development have been disproven. In fact, scientists have discovered that early experiences can determine how genes are turned on and off and even

  13. Delineation of behavioral phenotypes in genetic syndromes: characteristics of autism spectrum disorder, affect and hyperactivity.

    PubMed

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-08-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n=104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in CdLS and FXS. High levels of impulsivity were seen in SMS, AS, CdCS, FXS and adults with CdLS. Negative affect was prominent in adults with CdLS, while positive affect was prominent in adults with AS and FXS. Heightened levels of overactivity and impulsivity were identified in FXS, AS and SMS while low levels were identified in PWS. These findings confirm and extend previously reported behavioral phenotypes. PMID:21080217

  14. Maternal environment affects the genetic basis of seed dormancy in Arabidopsis thaliana.

    PubMed

    Postma, Froukje M; gren, Jon

    2015-02-01

    The genetic basis of seed dormancy, a key life history trait important for adaptive evolution in plant populations, has yet been studied only using seeds produced under controlled conditions in greenhouse environments. However, dormancy is strongly affected by maternal environmental conditions, and interactions between seed genotype and maternal environment have been reported. Consequently, the genetic basis of dormancy of seeds produced under natural field conditions remains unclear. We examined the effect of maternal environment on the genetic architecture of seed dormancy using a recombinant inbred line (RIL) population derived from a cross between two locally adapted populations of Arabidopsis thaliana from Italy and Sweden. We mapped quantitative trait loci (QTL) for dormancy of seeds produced in the greenhouse and at the native field sites of the parental genotypes. The Italian genotype produced seeds with stronger dormancy at fruit maturation than did the Swedish genotype in all three environments, and the maternal field environments induced higher dormancy levels compared to the greenhouse environment in both genotypes. Across the three maternal environments, a total of nine dormancy QTL were detected, three of which were only detected among seeds matured in the field, and six of which showed significant QTLנmaternal environment interactions. One QTL had a large effect on dormancy across all three environments and colocalized with the candidate gene DOG1. Our results demonstrate the importance of studying the genetic basis of putatively adaptive traits under relevant conditions. PMID:25640699

  15. Production of extracellular nucleic acids by genetically altered bacteria in aquatic-environment microcosms. [Escherichia coli, Pseudomonas aeroginosa, Pseudomonas cepacia, Bradyrhizobium japonicum

    SciTech Connect

    Paul, J.H.; David, A.W. )

    1989-08-01

    The factors which affect the production of extracellular DNA by genetically altered strains of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas cepacia, and Bradyrhizobium japonicum in aquatic environments were investigated. Cellular nucleic acids were labeled in vivo by incubation with ({sup 3}H)thymidine or ({sup 3}H)adenine, and production of extracellular DNA in marine waters, artificial seawater, or minimal salts media was determined by detecting radiolabeled macromolecules in incubation filtrates. The presence or absence of the ambient microbial community had little effect on the production of extracellular DNA. Three of four organisms produced the greatest amounts of extracellular nucleic acids when incubated in low-salinity media (2% artificial seawater) rather than high-salinity media (10 to 50% artificial seawater). The greatest production of extracellular nucleic acids by P. cepacia occurred at pH 7 and 37{degree}C, suggesting that extracellular-DNA production may be a normal physiologic function of the cell. Incubation of labeled P. cepacia cells in water from Bimini Harbor, Bahamas, resulted in labeling of macromolecules of the ambient microbial population. Collectively these results indicate that (i) extracellular-DNA production by genetically altered bacteria released into aquatic environments is more strongly influenced by physicochemical factors than biotic factors, (ii) extracellular-DNA production rates are usually greater for organisms released in freshwater than marine environments, and (iii) ambient microbial populations can readily utilize materials released by these organisms.

  16. Altered functional interaction hub between affective network and cognitive control network in patients with major depressive disorder.

    PubMed

    Wang, Ya-Li; Yang, Shu-Zhen; Sun, Wei-Li; Shi, Yu-Zhong; Duan, Hui-Feng

    2016-02-01

    Emotional and cognitive dysregulation in major depressive disorder (MDD) have been consistently considered to be attributed to structural and functional abnormalities in affective network (AN) and cognitive control network (CCN). This study was to investigate the functional connectivity (FC) patterns and altered functional interactions between both networks in MDD. We investigated resting-state functional connectivity magnetic resonance imaging in the AN and the CCN in 25 MDD and 35 healthy controls (HC). The seeds were from voxel-based morphometry (VBM) analysis results. Then FC within the AN was assessed from a seed placed in the left amygdala (AMG) and FC within CCN was determined by placing seeds in the right dorsolateral prefrontal cortex (DLPFC). Compared with HC, MDD showed reduced FC between left AMG and bilateral precuneus and right anterior cingulated cortex (ACC) within AN and reduced FC between right DLPFC and left cuneus, left lingual gyrus, and right ACC within CCN. An interaction hub of altered FC in MDD between AN and CCN located in the right ACC. Interestingly, the altered FC between right ACC and left AMG was negatively correlated with depressive symptom score while the altered FC between right ACC and DLPFC was positively correlated the executive function in MDD. The right ACC not only supports the cognitive and emotional processes, but also is an altered functional interaction hub between AN and CCN in MDD. It further suggest multiple sources of dysregulation in AN and CCN implicate both top-down cognitive control and bottom-up emotional expression dysfunction in MDD. PMID:26519557

  17. Direct Retino-Raphe Projection Alters Serotonergic Tone and Affective Behavior

    PubMed Central

    Ren, Chaoran; Luan, Liju; Wui-Man Lau, Benson; Huang, Xin; Yang, Jian; Zhou, Yuan; Wu, Xihong; Gao, Jie; Pickard, Gary E; So, Kwok-Fai; Pu, Mingliang

    2013-01-01

    Light is a powerful modulator of higher-order cognitive processes such as mood but it remains unclear which neural circuits mediate the impact of light on affective behavior. We found that light deprivation produces a depressive-like behavioral state that is reversed by activation of direct retinal signals to the serotonergic dorsal raphe nucleus (DRN) in a manner equivalent to treatment with the selective serotonin reuptake inhibitor fluoxetine. Surprisingly, the DRN-projecting retinal ganglion cells (RGCs) are indistinguishable from the classic alpha/Y-like RGC type that contributes to image-forming visual pathways. Silencing RGC firing or specific immunotoxin ablation of DRN-projecting RGCs increased depressive-like behavior and reduced serotonin levels in the DRN. Serotonin has a key role in the pathophysiology of depression, and these results demonstrate that retino-raphe signals modulate DRN serotonergic tone and affective behavior. PMID:23370156

  18. Hypothyroidism Affects D2 Receptor-mediated Breathing without altering D2 Receptor Expression

    PubMed Central

    Schlenker, Evelyn H.; Rio, Rodrigo Del; Schultz, Harold D.

    2015-01-01

    Bromocriptine depressed ventilation in air and D2 receptor expression in the nucleus tractus solitaries (NTS) in male hypothyroid hamsters. Here we postulated that in age- matched hypothyroid female hamsters, the pattern of D2 receptor modulation of breathing and D2 receptor expression would differ from those reported in hypothyroid males. In females hypothyroidism did not affect D2 receptor protein levels in the NTS, carotid bodies or striatum. Bromocriptine, but not carmoxirole (a peripheral D2 receptor agonist), increased oxygen consumption and body temperature in awake air-exposed hypothyroid female hamsters and stimulated their ventilation before and following exposure to hypoxia. Carmoxirole depressed frequency of breathing in euthyroid hamsters prior to, during and following hypoxia exposures and stimulated it in the hypothyroid hamsters following hypoxia. Although hypothyroidism did not affect expression of D2 receptors, it influenced central D2 modulation of breathing in a disparate manner relative to euthyroid hamsters. PMID:24434437

  19. Direct retino-raphe projection alters serotonergic tone and affective behavior.

    PubMed

    Ren, Chaoran; Luan, Liju; Wui-Man Lau, Benson; Huang, Xin; Yang, Jian; Zhou, Yuan; Wu, Xihong; Gao, Jie; Pickard, Gary E; So, Kwok-Fai; Pu, Mingliang

    2013-06-01

    Light is a powerful modulator of higher-order cognitive processes such as mood but it remains unclear which neural circuits mediate the impact of light on affective behavior. We found that light deprivation produces a depressive-like behavioral state that is reversed by activation of direct retinal signals to the serotonergic dorsal raphe nucleus (DRN) in a manner equivalent to treatment with the selective serotonin reuptake inhibitor fluoxetine. Surprisingly, the DRN-projecting retinal ganglion cells (RGCs) are indistinguishable from the classic alpha/Y-like RGC type that contributes to image-forming visual pathways. Silencing RGC firing or specific immunotoxin ablation of DRN-projecting RGCs increased depressive-like behavior and reduced serotonin levels in the DRN. Serotonin has a key role in the pathophysiology of depression, and these results demonstrate that retino-raphe signals modulate DRN serotonergic tone and affective behavior. PMID:23370156

  20. Altering the Cognitive-Affective Dysfunctions of Psychopathic and Externalizing Offender Subtypes with Cognitive Remediation

    PubMed Central

    Baskin-Sommers, Arielle R.; Curtin, John J.; Newman, Joseph P.

    2015-01-01

    Cognitive remediation is a treatment approach with the potential to translate basic science into more specific, mechanism-based interventions by targeting particular cognitive skills. The present study translated understanding of two well-defined cognitive-emotion dysfunctions into novel deficit-matched interventions and evaluated whether cognitive remediation would demonstrate specific and generalizable change. Two antisocial-subtypes, individuals with psychopathy and externalizing traits, are characterized by cognitive-affective problems that predispose them to engage in significant substance abuse and criminal behavior, culminating in incarceration. Whereas individuals with psychopathy fail to consider important contextual information, individuals with externalizing traits lack the capacity to regulate affective reactions. Training designed to remedy these subtype-specific deficits led to improvement on both trained and non-trained tasks. Such findings offer promise for changing neural and behavioral patterns, even for what many consider to be the most recalcitrant treatment population, and presage a new era of translating cognitive-affective science into increasingly specific and effective interventions. PMID:25977843

  1. Elevated CO2 affects predator-prey interactions through altered performance.

    PubMed

    Allan, Bridie J M; Domenici, Paolo; McCormick, Mark I; Watson, Sue-Ann; Munday, Philip L

    2013-01-01

    Recent research has shown that exposure to elevated carbon dioxide (CO2) affects how fishes perceive their environment, affecting behavioral and cognitive processes leading to increased prey mortality. However, it is unclear if increased mortality results from changes in the dynamics of predator-prey interactions or due to prey increasing activity levels. Here we demonstrate that ocean pCO2 projected to occur by 2100 significantly effects the interactions of a predator-prey pair of common reef fish: the planktivorous damselfish Pomacentrus amboinensis and the piscivorous dottyback Pseudochromis fuscus. Prey exposed to elevated CO2 (880 atm) or a present-day control (440 atm) interacted with similarly exposed predators in a cross-factored design. Predators had the lowest capture success when exposed to elevated CO2 and interacting with prey exposed to present-day CO2. Prey exposed to elevated CO2 had reduced escape distances and longer reaction distances compared to prey exposed to present-day CO2 conditions, but this was dependent on whether the prey was paired with a CO2 exposed predator or not. This suggests that the dynamics of predator-prey interactions under future CO2 environments will depend on the extent to which the interacting species are affected and can adapt to the adverse effects of elevated CO2. PMID:23484032

  2. Affective changes during the postpartum period: Influences of genetic and experiential factors.

    PubMed

    Agrati, Daniella; Lonstein, Joseph S

    2016-01-01

    This article is part of a Special Issue "Parental Care". The postpartum period involves some truly transformational changes in females' socioemotional behaviors. For most female laboratory rodents and women, these changes include an improvement in their affective state, which has positive consequences for their ability to sensitively care for their offspring. There is heterogeneity among females in the likelihood of this positive affective change, though, and some women experience elevated anxiety or depression (or in rodents anxiety- or depression-related behaviors) after giving birth. We aim to contribute to the understanding of this heterogeneity in maternal affectivity by reviewing selected components of the scientific literatures on laboratory rodents and humans examining how mothers' physical contact with her infants, genetics, history of anxiety and depression and early-life and recent-life experiences contribute to individual differences in postpartum affective states. These studies together indicate that multiple biological and environmental factors beyond female maternal state shape affective responses during the postpartum period, and probably do so in an interactive manner. Furthermore, the similar capacity of some of these factors to modulate anxiety and depression in human and rodent mothers suggests cross-species conservation of mechanisms regulating postpartum affectivity. PMID:26210061

  3. Altered plasma pharmacokinetics of ceftiofur hydrochloride in cows affected with severe clinical mastitis.

    PubMed

    Gorden, P J; Kleinhenz, M D; Wulf, L W; KuKanich, B; Lee, C J; Wang, C; Coetzee, J F

    2016-01-01

    Mastitis is a frequent problem among dairy cows, reducing milk yield and increasing cull rates. Systemic therapy with the cephalosporin antimicrobial ceftiofur hydrochloride (CEF) may improve therapeutic outcomes, but the incidence of CEF violative residues has increased annually since 2011. One potential explanation is that disease status may alter the pharmacokinetics (PK) of CEF. To test this hypothesis, we compared the plasma PK of CEF in healthy cows with those with severe endotoxic mastitis. Eight cows with naturally occurring mastitis and 8 clinically healthy cows were treated with 2.2 mg of CEF per kilogram of body weight once daily for 5d via the intramuscular route. Blood was collected at 0, 0.33, 0.67, 1, 1.5, 2, 3, 4, 8, 16, and 24h after the first CEF administration and every 8h thereafter until 120h after the final dose. Plasma samples were analyzed for CEF concentrations using liquid chromatography coupled with mass spectrometry. With the exception of time 0, CEF was detected at all time points. The disease group had a significantly higher plasma CEF concentration at t=3h after the first injection and a significantly lower plasma concentration from 40 to 152h following the first injection, with the exception of the t=64h time point. Data following the first injection (time 0-24 h) were fit to a single-dose, noncompartmental PK model. This model indicated that the disease group had a shorter plasma half-life. A multidose, noncompartmental model was used to determine steady-state PK. Compared with control cows, the disease group had an initially higher peak concentration and a higher volume of distribution and drug clearance rates. The disease group also had a lower area under the curve per dosing interval, steady-state concentration maximum, and dose-adjusted peak steady-state concentration. All other PK parameters were not different between the 2 groups. Altered PK, as suggested by this trial, may contribute to an increased risk for the development of a violative residue in meat. Further research is needed to more completely characterize drug distribution in diseased cattle and to study the effect of coadministration of other drugs on drug distribution. PMID:26601579

  4. Plant hybrid zones affect biodiversity: Tools for a genetic-based understanding of community structure

    SciTech Connect

    Whitham, T.G.; Martinsen, G.D.; Keim, P.; Floate, K.D.; Dungey, H.S. |; Potts, B.M.

    1999-03-01

    Plant hybrid zones are dynamic centers of ecological and evolutionary processes for plants and their associated communities. Studies in the wild and in gardens with synthetic crosses showed that hybrid eucalypts supports the greatest species richness and abundances of insect and fungal taxa. In an updated review of 152 case studies of taxa associated with diverse hybridizing systems, there were 43 (28%) cases of hybrids being more susceptible than their parent species, 7 (5%) resistant, 35 (23%) additive, 35 (23%) dominant, and 32 (21%) showed no response to hybridization. Thus, most taxa respond to hybrids in ways that result in equal or greater abundance, and hybrids tend to accumulate the taxa of their parent species. These studies suggest that genetic-based plant traits affect the distribution of many species and that the variation in hybrids can be used as tools to examine the genetic components of community structure and biodiversity.

  5. Haplotype structure strongly affects recombination in a maize genetic interval polymorphic for Helitron and retrotransposon insertions

    PubMed Central

    He, Limei; Dooner, Hugo K.

    2009-01-01

    We have asked here how the remarkable variation in maize haplotype structure affects recombination. We compared recombination across a genetic interval of 9S in 2 highly dissimilar heterozygotes that shared 1 parent. The genetic interval in the common haplotype is ≈100 kb long and contains 6 genes interspersed with gene-fragment-bearing Helitrons and retrotransposons that, together, comprise 70% of its length. In one heterozygote, most intergenic insertions are homozygous, although polymorphic, enabling us to determine whether any recombination junctions fall within them. In the other, most intergenic insertions are hemizygous and, thus, incapable of homologous recombination. Our analysis of the frequency and distribution of recombination in the interval revealed that: (i) Most junctions were circumscribed to the gene space, where they showed a highly nonuniform distribution. In both heterozygotes, more than half of the junctions fell in the stc1 gene, making it a clear recombination hotspot in the region. However, the genetic size of stc1 was 2-fold lower when flanked by a hemizygous 25-kb retrotransposon cluster. (ii) No junctions fell in the hypro1 gene in either heterozygote, making it a genic recombination coldspot. (iii) No recombination occurred within the gene fragments borne on Helitrons nor within retrotransposons, so neither insertion class contributes to the interval's genetic length. (iv) Unexpectedly, several junctions fell in an intergenic region not shared by all 3 haplotypes. (v) In general, the ability of a sequence to recombine correlated inversely with its methylation status. Our results show that haplotypic structural variability strongly affects the frequency and distribution of recombination events in maize. PMID:19416860

  6. Aniracetam Does Not Alter Cognitive and Affective Behavior in Adult C57BL/6J Mice

    PubMed Central

    Elston, Thomas W.; Pandian, Ashvini; Smith, Gregory D.; Holley, Andrew J.; Gao, Nanjing; Lugo, Joaquin N.

    2014-01-01

    There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in naïve C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs. PMID:25099639

  7. Aniracetam does not alter cognitive and affective behavior in adult C57BL/6J mice.

    PubMed

    Elston, Thomas W; Pandian, Ashvini; Smith, Gregory D; Holley, Andrew J; Gao, Nanjing; Lugo, Joaquin N

    2014-01-01

    There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in nave C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs. PMID:25099639

  8. Transcription of Interleukin-8: How Altered Regulation Can Affect Cystic Fibrosis Lung Disease.

    PubMed

    Jundi, Karim; Greene, Catherine M

    2015-01-01

    Interleukin-8 (IL-8) is a neutrophil chemokine that is encoded on the CXCL8 gene. Normally CXCL8 expression is repressed due to histone deacetylation, octamer-1 binding to the promoter and the inhibitory effect of nuclear factor-?B repressing factor (NRF). However, in response to a suitable stimulus, the human CXCL8 gene undergoes transcription due to its inducible promoter that is regulated by the transcription factors nuclear factor-?B (NF-?B), activating protein (AP-1), CAAT/enhancer-binding protein ? (C/EBP?, also known as NF-IL-6), C/EBP homologous protein (CHOP) and cAMP response element binding protein (CREB). CXCL8 mRNA is then stabilised by the activity of p38 mitogen-activated protein kinase (p38 MAPK). Cystic fibrosis (CF) lung disease is characterised by a neutrophil-dominated airway inflammatory response. A major factor contributing to the large number of neutrophils is the higher than normal levels of IL-8 that are present within the CF lung. Infection and inflammation, together with intrinsic alterations in CF airway cells are responsible for the abnormally high intrapulmonary levels of IL-8. Strategies to inhibit aberrantly high CXCL8 expression hold therapeutic potential for CF lung disease. PMID:26140537

  9. Altered expression of an RBP-associated arginine methyltransferase 7 in Leishmania major affects parasite infection.

    PubMed

    Ferreira, Tiago R; Alves-Ferreira, Eliza V C; Defina, Tania P A; Walrad, Pegine; Papadopoulou, Barbara; Cruz, Angela K

    2014-10-01

    Protein arginine methylation is a widely conserved post-translational modification performed by arginine methyltransferases (PRMTs). However, its functional role in parasitic protozoa is still under-explored. The Leishmania major genome encodes five PRMT homologs, including PRMT7. Here we show that LmjPRMT7 expression and arginine monomethylation are tightly regulated in a lifecycle stage-dependent manner. LmjPRMT7 levels are higher during the early promastigote logarithmic phase, negligible at stationary and late-stationary phases and rise once more post-differentiation to intracellular amastigotes. Immunofluorescence and co-immunoprecipitation studies demonstrate that LmjPRMT7 is a cytosolic protein associated with several RNA-binding proteins (RBPs) from which Alba20 is monomethylated only in LmjPRMT7-expressing promastigote stages. In addition, Alba20 protein levels are significantly altered in stationary promastigotes of the LmjPRMT7 knockout mutant. Considering RBPs are well-known mammalian PRMT substrates, our data suggest that arginine methylation via LmjPRMT7 may modulate RBP function during Leishmania spp. lifecycle progression. Importantly, genomic deletion of the LmjPRMT7 gene leads to an increase in parasite infectivity both in vitro and in vivo, while lesion progression is significantly reduced in LmjPRMT7-overexpressing parasites. This study is the first to describe a role of Leishmania protein arginine methylation in host-parasite interactions. PMID:25294169

  10. Alterations in affective behavior during the time course of alcohol hangover.

    PubMed

    Karadayian, Anala G; Busso, Mara J; Feleder, Carlos; Cutrera, Rodolfo A

    2013-09-15

    Alcohol hangover is a temporary state described as the unpleasant next-day effects after binge-like drinking. Hangover begins when ethanol is absent in plasma and is characterized by physical and psychological symptoms. Affective behavior is impaired during the acute phase of alcohol intoxication; however, no reports indicate if similar effects are observed during withdrawal. The aim of this work was to study the time-extension and possible fluctuations in affective behavior during a hangover episode. Male Swiss mice were injected i.p. either with saline (control group) or with ethanol (3.8g/kg BW) (hangover group). Anxiety, fear-related behavior and despair phenotype were evaluated at a basal point (ZT0) and every 2h up to 20h after blood alcohol levels were close to zero (hangover onset). Also, anhedonia signs and pain perception disabilities were studied. Mice exhibited an increase in anxiety-like behavior during 4h and 14h after hangover onset when evaluated by the elevated-plus maze and open field test respectively (p<0.05). Fear-related behavior was detected in hangover animals by the increase of freezing and decrease of line crossings and rearing frequency during 16h after hangover onset (p<0.001). Depression signs were found in hangover mice during 14h (p<0.05). Hangover mice showed a significant decrease in pain perception when tested by tail immersion test at the beginning of hangover (p<0.05). Our findings demonstrate a time-extension between 14 and 16h for hangover affective impairments. This study shows the long lasting effects of hangover over the phase of ethanol intoxication. PMID:23850352

  11. Altered xanthophyll compositions adversely affect chlorophyll accumulation and nonphotochemical quenching in Arabidopsis mutants.

    PubMed

    Pogson, B J; Niyogi, K K; Bjrkman, O; DellaPenna, D

    1998-10-27

    Collectively, the xanthophyll class of carotenoids perform a variety of critical roles in light harvesting antenna assembly and function. The xanthophyll composition of higher plant photosystems (lutein, violaxanthin, and neoxanthin) is remarkably conserved, suggesting important functional roles for each. We have taken a molecular genetic approach in Arabidopsis toward defining the respective roles of individual xanthophylls in vivo by using a series of mutant lines that selectively eliminate and substitute a range of xanthophylls. The mutations, lut1 and lut2 (lut = lutein deficient), disrupt lutein biosynthesis. In lut2, lutein is replaced mainly by a stoichiometric increase in violaxanthin and antheraxanthin. A third mutant, aba1, accumulates normal levels of lutein and substitutes zeaxanthin for violaxanthin and neoxanthin. The lut2aba1 double mutant completely lacks lutein, violaxanthin, and neoxanthin and instead accumulates zeaxanthin. All mutants were viable in soil and had chlorophyll a/b ratios ranging from 2.9 to 3.5 and near wild-type rates of photosynthesis. However, mutants accumulating zeaxanthin exhibited a delayed greening virescent phenotype, which was most severe and often lethal when zeaxanthin was the only xanthophyll present. Chlorophyll fluorescence quenching kinetics indicated that both zeaxanthin and lutein contribute to nonphotochemical quenching; specifically, lutein contributes, directly or indirectly, to the rapid rise of nonphotochemical quenching. The results suggest that the normal complement of xanthophylls, while not essential, is required for optimal assembly and function of the light harvesting antenna in higher plants. PMID:9789087

  12. 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. PMID:26769674

  13. Genetic variations alter physiological responses following heat stress in two laying hen strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heat stress (HS) is a major problem experienced by the poultry industry during high temperature conditions. The ability to manage the detrimental effects of HS can be attributed to multiple factors, including genetic background of flocks. The objective of the present study was to determine the genet...

  14. Natural selection affects multiple aspects of genetic variation at putatively neutral sites across the human genome.

    PubMed

    Lohmueller, Kirk E; Albrechtsen, Anders; Li, Yingrui; Kim, Su Yeon; Korneliussen, Thorfinn; Vinckenbosch, Nicolas; Tian, Geng; Huerta-Sanchez, Emilia; Feder, Alison F; Grarup, Niels; Jørgensen, Torben; Jiang, Tao; Witte, Daniel R; Sandbæk, Annelli; Hellmann, Ines; Lauritzen, Torsten; Hansen, Torben; Pedersen, Oluf; Wang, Jun; Nielsen, Rasmus

    2011-10-01

    A major question in evolutionary biology is how natural selection has shaped patterns of genetic variation across the human genome. Previous work has documented a reduction in genetic diversity in regions of the genome with low recombination rates. However, it is unclear whether other summaries of genetic variation, like allele frequencies, are also correlated with recombination rate and whether these correlations can be explained solely by negative selection against deleterious mutations or whether positive selection acting on favorable alleles is also required. Here we attempt to address these questions by analyzing three different genome-wide resequencing datasets from European individuals. We document several significant correlations between different genomic features. In particular, we find that average minor allele frequency and diversity are reduced in regions of low recombination and that human diversity, human-chimp divergence, and average minor allele frequency are reduced near genes. Population genetic simulations show that either positive natural selection acting on favorable mutations or negative natural selection acting against deleterious mutations can explain these correlations. However, models with strong positive selection on nonsynonymous mutations and little negative selection predict a stronger negative correlation between neutral diversity and nonsynonymous divergence than observed in the actual data, supporting the importance of negative, rather than positive, selection throughout the genome. Further, we show that the widespread presence of weakly deleterious alleles, rather than a small number of strongly positively selected mutations, is responsible for the correlation between neutral genetic diversity and recombination rate. This work suggests that natural selection has affected multiple aspects of linked neutral variation throughout the human genome and that positive selection is not required to explain these observations. PMID:22022285

  15. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome.

    PubMed

    Eyring, Kenneth R; Pedersen, Brent S; Yang, Ivana V; Schwartz, David A

    2015-01-01

    Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease. PMID:26642056

  16. Human cytomegalovirus infection alters the expression of cellular microRNA species that affect its replication.

    PubMed

    Wang, Fu-Zhang; Weber, Frank; Croce, Carlo; Liu, Chang-Gong; Liao, Xudong; Pellett, Philip E

    2008-09-01

    The human genome encodes over 500 microRNAs (miRNAs), small RNAs (19 to 26 nucleotides [nt]) that regulate the expressions of diverse cellular genes. Many cellular processes are altered through a variety of mechanisms by human cytomegalovirus (HCMV) infection. We asked whether HCMV infection leads to changes in the expression of cellular miRNAs and whether HCMV-regulated miRNAs are important for HCMV replication. Levels of most miRNAs did not change markedly during infection, but some were positively or negatively regulated. Patterns of miRNA expression were linked to the time course of infection. Some similarly reregulated miRNAs share identical or similar seed sequences, suggesting coordinated regulation of miRNA species that have shared targets. miRNAs miR-100 and miR-101 were chosen for further analyses based on their reproducible changes in expression after infection and on the basis of having predicted targets in the 3' untranslated regions (3'-UTR) of genes encoding components of the mammalian target of rapamycin (mTOR) pathway, which is important during HCMV infection. Reporter genes that contain the 3'-UTR of mTOR (predicted targets for miR-100 and miR-101) or raptor (a component of the mTOR pathway; predicted site for miR-100) were constructed. Mimics of miR-100 and miR-101 inhibited expression from the mTOR construct, while only miR-100 inhibited the raptor construct. Together, miR-100 and miR-101 reduced mTOR protein levels. While the miR-100 and miR-101 mimics individually modestly inhibited production of infectious progeny, much greater inhibition was achieved with a combination of both (33-fold). Our key finding is that HCMV selectively manipulates the expression of some cellular miRNAs to help its own replication. PMID:18596100

  17. In Utero Cigarette Smoke Affects Allergic Airway Disease But Does Not Alter the Lung Methylome

    PubMed Central

    Eyring, Kenneth R.; Pedersen, Brent S.; Yang, Ivana V.; Schwartz, David A.

    2015-01-01

    Prenatal and postnatal cigarette smoke exposure enhances the risk of developing asthma. Despite this as well as other smoking related risks, 11% of women still smoke during pregnancy. We hypothesized that cigarette smoke exposure during prenatal development generates long lasting differential methylation altering transcriptional activity that correlates with disease. In a house dust mite (HDM) model of allergic airway disease, we measured airway hyperresponsiveness (AHR) and airway inflammation between mice exposed prenatally to cigarette smoke (CS) or filtered air (FA). DNA methylation and gene expression were then measured in lung tissue. We demonstrate that HDM-treated CS mice develop a more severe allergic airway disease compared to HDM-treated FA mice including increased AHR and airway inflammation. While DNA methylation changes between the two HDM-treated groups failed to reach genome-wide significance, 99 DMRs had an uncorrected p-value < 0.001. 6 of these 99 DMRs were selected for validation, based on the immune function of adjacent genes, and only 2 of the 6 DMRs confirmed the bisulfite sequencing data. Additionally, genes near these 6 DMRs (Lif, Il27ra, Tle4, Ptk7, Nfatc2, and Runx3) are differentially expressed between HDM-treated CS mice and HDM-treated FA mice. Our findings confirm that prenatal exposure to cigarette smoke is sufficient to modify allergic airway disease; however, it is unlikely that specific methylation changes account for the exposure-response relationship. These findings highlight the important role in utero cigarette smoke exposure plays in the development of allergic airway disease. PMID:26642056

  18. Nuclear DNA content affects the productivity of conifer forests by altering hydraulic architecture

    NASA Astrophysics Data System (ADS)

    Alday, Josu; Resco de Dios, Vctor

    2014-05-01

    Predictions of future global climate rely on feedbacks between terrestrial vegetation and the global carbon cycle, but the exact mechanisms underlying this relationship are still being discussed. One of the key knowledge gaps lies on the scaling of cellular processes to the ecosystem level. Here we examine whether an under-explored plant trait, inter-specific variation in the bulk amount of DNA in unreplicated somatic cells (2C DNA content), can explain inter-specific variation in the maximum productivity of conifer forests. We expected 2C DNA content to be negatively related to conifer productivity because: 1) it is positively correlated with cell volume (which, in turn, potentially affects structural features such as leaf mass area, a strong predictor of photosynthetic capacity); 2) it is positively correlated with stomatal size (with larger stomata leading to lower overall stomatal conductance and, by extension, lower CO2 uptake); and 3) larger genome sizes may reduce P availability in RNA (which has been hypothesized to slow growth). We present the results of regression and independent contrasts in different monospecific forests encompassing a 52 latitudinal gradient, each being dominated by 1 of 35 different conifer species. Contrary to expectations, we observed a positive correlation between genome size and maximum Gross Primary Productivity (R2 = 0.47) and also between genome size maximum tree height (R2 = 0.27). This correlation was apparently driven by the effects of genome size on stem hydraulics, since 2C DNA was positively correlated with wood density (R2 = 0.40) and also with resistance to cavitation (P50, R2 = 0.28). That is, increased genome sizes have a positive effect on the productivity of conifer forests by affecting the vascular tissues to increase their capacity for water transport. Our results shed a new light on the evolution of the vascular system of conifer forests and how they affect ecosystem productivity, and indicate the potential to further explore the trait of genome size for understanding global patterns of forest productivity.

  19. Altering the primacy bias--how does a prior task affect mismatch negativity?

    PubMed

    Mullens, Daniel; Woodley, Jessica; Whitson, Lisa; Provost, Alexander; Heathcote, Andrew; Winkler, Istvn; Todd, Juanita

    2014-05-01

    The role in which two tones are first encountered in an unattended oddball sequence affects how deviance detection, reflected by mismatch negativity, treats them later when the roles reverse: a "primacy bias." We tested whether this effect is modulated by previous behavioral relevance assigned to the two tones. To this end, sequences in which the roles of the two tones alternated were preceded by a go/no-go task in which tones were presented with equal probability. Half of the participants were asked to respond to the short sounds, the other half to long sounds. Primacy bias was initially abolished but returned dependent upon the go-stimulus that the participant was assigned. Results demonstrate a long-term impact of prior learning on deviance detection, and that even when prior importance/equivalence is learned, the bias ultimately returns. Results are discussed in terms of persistent go-stimulus specific changes in responsiveness to sound. PMID:24611446

  20. A novel in-frame deletion affecting the BAR domain of OPHN1 in a family with intellectual disability and hippocampal alterations

    PubMed Central

    Santos-Rebouças, Cíntia Barros; Belet, Stefanie; Guedes de Almeida, Luciana; Ribeiro, Márcia Gonçalves; Medina-Acosta, Enrique; Bahia, Paulo Roberto Valle; Alves da Silva, Antônio Francisco; Lima dos Santos, Flávia; Borges de Lacerda, Glenda Corrêa; Pimentel, Márcia Mattos Gonçalves; Froyen, Guy

    2014-01-01

    Oligophrenin-1 (OPHN1) is one of at least seven genes located on chromosome X that take part in Rho GTPase-dependent signaling pathways involved in X-linked intellectual disability (XLID). Mutations in OPHN1 were primarily described as an exclusive cause of non-syndromic XLID, but the re-evaluation of the affected individuals using brain imaging displayed fronto-temporal atrophy and cerebellar hypoplasia as neuroanatomical marks. In this study, we describe clinical, genetic and neuroimaging data of a three generation Brazilian XLID family co-segregating a novel intragenic deletion in OPHN1. This deletion results in an in-frame loss of exon 7 at transcription level (c.781_891del; r.487_597del), which is predicted to abolish 37 amino acids from the highly conserved N-terminal BAR domain of OPHN1. cDNA expression analysis demonstrated that the mutant OPHN1 transcript is stable and no abnormal splicing was observed. Features shared by the affected males of this family include neonatal hypotonia, strabismus, prominent root of the nose, deep set eyes, hyperactivity and instability/intolerance to frustration. Cranial MRI scans showed large lateral ventricles, vermis hypoplasia and cystic dilatation of the cisterna magna in all affected males. Interestingly, hippocampal alterations that have not been reported in patients with loss-of-function OPHN1 mutations were found in three affected individuals, suggesting an important function for the BAR domain in the hippocampus. This is the first description of an in-frame deletion within the BAR domain of OPHN1 and could provide new insights into the role of this domain in relation to brain and cognitive development or function. PMID:24105372

  1. Motion and emotion: depression reduces psychomotor performance and alters affective movements in caregiving interactions

    PubMed Central

    Young, Katherine S.; Parsons, Christine E.; Stein, Alan; Kringelbach, Morten L.

    2015-01-01

    Background: Impaired social functioning is a well-established feature of depression. Evidence to date suggests that disrupted processing of emotional cues may constitute part of this impairment. Beyond processing of emotional cues, fluent social interactions require that people physically move in synchronized, contingent ways. Disruptions to physical movements are a diagnostic feature of depression (psychomotor disturbance) but have not previously been assessed in the context of social functioning. Here we investigated the impact of psychomotor disturbance in depression on physical responsive behavior in both an experimental and observational setting. Methods: In Experiment 1, we examined motor disturbance in depression in response to salient emotional sounds, using a laboratory-based effortful motor task. In Experiment 2, we explored whether psychomotor disturbance was apparent in real-life social interactions. Using mother-infant interactions as a model affective social situation, we compared physical behaviors of mothers with and without postnatal depression (PND). Results: We found impairments in precise, controlled psychomotor performance in adults with depression relative to healthy adults (Experiment 1). Despite this disruption, all adults showed enhanced performance following exposure to highly salient emotional cues (infant cries). Examining real-life interactions, we found differences in physical movements, namely reduced affective touching, in mothers with PND responding to their infants, compared to healthy mothers (Experiment 2). Conclusions: Together, these findings suggest that psychomotor disturbance may be an important feature of depression that can impair social functioning. Future work investigating whether improvements in physical movement in depression could have a positive impact on social interactions would be of much interest. PMID:25741255

  2. Historical and anthropogenic factors affecting the population genetic structure of Ontario's inland lake populations of Walleye (Sander vitreus).

    PubMed

    Walter, Ryan P; Cena, Christopher J; Morgan, George E; Heath, Daniel D

    2012-01-01

    Populations existing in formerly glaciated areas often display composite historical and contemporary patterns of genetic structure. For Canadian freshwater fishes, population genetic structure is largely reflective of dispersal from glacial refugia and isolation within drainage basins across a range of scales. Enhancement of sport fisheries via hatchery stocking programs and other means has the potential to alter signatures of natural evolutionary processes. Using 11 microsatellite loci genotyped from 2182 individuals, we analyzed the genetic structure of 46 inland lake walleye (Sander vitreus) populations spanning five major drainage basins within the province of Ontario, Canada. Population genetic analyses coupled with genotype assignment allowed us to: 1) characterize broad- and fine-scale genetic structure among Ontario walleye populations; and 2) determine if the observed population divergence is primarily due to natural or historical processes, or recent anthropogenic events. The partitioning of genetic variation revealed higher genetic divergence among lakes than among drainage basins or proposed ancestries-indicative of relatively high isolation among lakes, study-wide. Walleye genotypes were clustered into three major groups, likely reflective of Missourian, Mississippian, and Atlantic glacial refugial ancestry. Despite detectable genetic signatures indicative of anthropogenic influences, province-wide spatial genetic structure remains consistent with the hypothesis of dispersal from distinct glacial refugia and subsequent isolation of lakes within primary drainage basins. Our results provide a novel example of minimal impacts from fishery enhancement to the broad-scale genetic structure of inland fish populations. PMID:23125407

  3. Genetic Analysis of Mutations Affecting Pcka Regulation in Rhizobium (Sinorhizobium) Meliloti

    PubMed Central

    Østeras, M.; O'Brien, SAP.; Finan, T. M.

    1997-01-01

    The enzyme phosphoenolpyruvate carboxykinase (Pck) catalyzes the first step in the gluconeogenic pathway in most organisms. We are examining the genetic regulation of the gene encoding Pck, pckA, in Rhizobium (now Sinorhizobium) meliloti. This bacterium forms N(2)-fixing root nodules on alfalfa, and the major energy sources supplied to the bacteria within these nodules are C(4)-dicarboxylic acids such as malate and succinate. R. meliloti cells growing in glucose minimal medium show very low pckA expression whereas addition of succinate to this medium results in a rapid induction of pckA transcription. We identified spontaneous mutations (rpk) that alter the regulation of pckA expression such that pckA is expressed in media containing the non-inducing carbon sources lactose and glucose. Genetic and phenotypic analysis allowed us to differentiate at least four rpk mutant classes that map to different locations on the R. meliloti chromosome. The wild-type locus corresponding to one of these rpk loci was cloned by complementation, and two Tn5 insertions within the insert DNA that no longer complemented the rpk mutation were identified. The nucleotide sequence of this region revealed that both Tn5 insertions lay within a gene encoding a protein homologous to the GalR/LacI family of transcriptional regulators that are involved in metabolism. PMID:9409818

  4. 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

  5. Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis

    PubMed Central

    Caballero, Virginia; Ruiz, Roco; Sainz, Jos Antonio; Cruz, Marina; Lpez-Nevot, Miguel Angel; Galn, Jos Jorge; Real, Luis Miguel; de Castro, Francisco; Lpez-Villaverde, Vicente; Ruiz, Agustn

    2005-01-01

    Background Endometriosis is a complex disease affecting 1015% of women at reproductive age. Very few genes are known to be altered in this pathology. RIP140 protein is an important cofactor of oestrogen receptor and many other nuclear receptors. Targeting disruption experiments of nrip1 gene in mice have demonstrated that nuclear receptor interacting protein 1 gene (nrip1), the gene encoding for rip140 protein, is essential for female fertility. Specifically, mice null for nrip1 gene are viable, but females are infertile because of complete failure of mature follicles to release oocytes at ovulation stage. The ovarian phenotype observed in mice devoid of rip140 closely resembles the luteinized unruptured follicle (LUF) syndrome that is observed in a high proportion of women affected of endometriosis or idiopathic infertility. Here we present a preliminary work that analyses the role of NRIP1 gene in humans. Methods We have sequenced the complete coding region of NRIP1 gene in 20 unrelated patients affected by endometriosis. We have performed genetic association studies by using the DNA variants identified during the sequencing process. Results We identified six DNA variants within the coding sequence of NRIP1 gene, and five of them generated amino acid changes in the protein. We observed that three of twenty sequenced patients have specific combinations of amino-acid variants within the RIP140 protein that are poorly represented in the control population (p = 0.006). Moreover, we found that Arg448Gly, a common polymorphism located within NRIP1 gene, is associated with endometriosis in a case-control study (59 cases and 141 controls, pallele positivity test = 0.027). Conclusion Our results suggest that NRIP1 gene variants, separately or in combinations, might act as predisposing factors for human endometriosis. PMID:16131398

  6. Does vegetation complexity affect host plant chemistry, and thus multitrophic interactions, in a human-altered landscape?

    PubMed

    Wschke, Nicole; Hancock, Christine; Hilker, Monika; Obermaier, Elisabeth; Meiners, Torsten

    2015-09-01

    Anthropogenic land use may shape vegetation composition and affect trophic interactions by altering concentrations of host plant metabolites. Here, we investigated the hypotheses that: (1) plant N and defensive secondary metabolite contents of the herb Plantago lanceolata are affected by land use intensity (LUI) and the surrounding vegetation composition (=plant species richness and P. lanceolata density), and that (2) changes in plant chemistry affect abundances of the herbivorous weevils Mecinus pascuorum and Mecinus labilis, as well as their larval parasitoid Mesopolobus incultus, in the field. We determined plant species richness, P. lanceolata density, and abundances of the herbivores and the parasitoid in 77 grassland plots differing in LUI index in three regions across Germany. We also measured the N and secondary metabolite [the iridoid glycosides (IGs) aucubin and catalpol] contents of P. lanceolata leaves. Mixed-model analysis revealed that: (1) concentrations of leaf IGs were positively correlated with plant species richness; leaf N content was positively correlated with the LUI index. Furthermore: (2) herbivore abundance was not related to IG concentrations, but correlated negatively with leaf N content. Parasitoid abundance correlated positively only with host abundance over the three regions. Structural equation models revealed a positive impact of IG concentrations on parasitoid abundance in one region. We conclude that changes in plant chemistry due to land use and/or vegetation composition may affect higher trophic levels and that the manifestation of these effects may depend on local biotic or abiotic features of the landscape. PMID:25986560

  7. Genetic variations in peroxisome proliferator-activated receptor ? expression affect blood pressure

    PubMed Central

    Tsai, Yau-Sheng; Xu, Lonquan; Smithies, Oliver; Maeda, Nobuyo

    2009-01-01

    Metabolic syndrome, a clustering of conditions including obesity, insulin resistance, and hypertension, is a risk factor for cardiovascular morbidity and mortality. Because peroxisome proliferator-activated receptor ? (PPAR?) regulates adipocyte differentiation and lipid metabolism and is the molecular target of a class of insulin sensitizers, genetic variants that alter Pparg gene expression are potential contributors to the metabolic syndrome. To test this possibility, we generated mice having 182% of the normal steady-state level of PPAR? mRNA by replacing the 3?-UTR of the natural Pparg gene with that of the ?-globin gene, thereby stabilizing the Pparg transcripts. This increase in PPAR? mRNA level had no apparent consequences in various physiological parameters, except that the mice repeatedly showed a trend toward lower blood pressures (by about 3 mm Hg) than their WT littermates. In contrast, the opposite trend, toward increased blood pressure, was observed in mice with genetically reduced levels of PPAR? mRNA as a consequence of insertion of an allele with an mRNA-destabilizing sequence into the endogenous 3?-UTR of the Pparg gene. By combining 12 sets of blood pressure measurements in more than 350 mutant mice having PPAR? expression levels varying from 28% to 182% and more than 280 WT littermates, we show that a 2-fold genetic increase (or decrease) in PPAR? expression levels decreases (or increases) blood pressure by about 2.8 mm Hg. Thus, our experiments demonstrate that quantitative variants causing decreased Pparg expression are a potential causative risk factor for essential hypertension. PMID:19884495

  8. Genetic loci that affect aristolochic acid-induced nephrotoxicity in the mouse

    PubMed Central

    2011-01-01

    Aristolochic acids (AA) are plant-derived nephrotoxins and carcinogens found in traditional medicines and herbal remedies. AA causes aristolochic acid nephropathy (AAN) and is a suspected environmental agent in Balkan endemic nephropathy (BEN) and its associated upper urothelial cancer. Approximately 510% of individuals exposed to AA develop renal insufficiency and/or cancer; thus a genetic predisposition to AA sensitivity has been proposed. The mouse is an established animal model of AAN, and inbred murine strains vary in AA sensitivity, confirming the genetic predisposition. We mapped quantitative trait loci (QTL) correlated with proximal tubule dysfunction after exposure to AA in an F2 population of mice, derived from breeding an AA-resistant strain (C57BL/6J) and an AA-sensitive strain (DBA/2J). A single main QTL was identified on chromosome 4 (Aanq1); three other interacting QTLs, (Aanq24) also were detected. The Aanq1 region was also detected in untreated mice, raising the possibility that preexisting differences in proximal tubule function may affect the severity of AA-elicited toxicity. This study lays the groundwork for identifying the genetic pathways contributing to AA sensitivity in the mouse and will further our understanding of human susceptibility to AA found widely in traditional medicines. PMID:21429970

  9. A genetic screen for zygotic embryonic lethal mutations affecting cuticular morphology in the wasp Nasonia vitripennis.

    PubMed Central

    Pultz, M A; Zimmerman, K K; Alto, N M; Kaeberlein, M; Lange, S K; Pitt, J N; Reeves, N L; Zehrung, D L

    2000-01-01

    We have screened for zygotic embryonic lethal mutations affecting cuticular morphology in Nasonia vitripennis (Hymenoptera; Chalcidoidea). Our broad goal was to investigate the use of Nasonia for genetically surveying conservation and change in regulatory gene systems, as a means to understand the diversity of developmental strategies that have arisen during the course of evolution. Specifically, we aim to compare anteroposterior patterning gene functions in two long germ band insects, Nasonia and Drosophila. In Nasonia, unfertilized eggs develop as haploid males while fertilized eggs develop as diploid females, so the entire genome can be screened for recessive zygotic mutations by examining the progeny of F1 females. We describe 74 of >100 lines with embryonic cuticular mutant phenotypes, including representatives of coordinate, gap, pair-rule, segment polarity, homeotic, and Polycomb group functions, as well as mutants with novel phenotypes not directly comparable to those of known Drosophila genes. We conclude that Nasonia is a tractable experimental organism for comparative developmental genetic study. The mutants isolated here have begun to outline the extent of conservation and change in the genetic programs controlling embryonic patterning in Nasonia and Drosophila. PMID:10866651

  10. Early infancy microbial and metabolic alterations affect risk of childhood asthma.

    PubMed

    Arrieta, Marie-Claire; Stiemsma, Leah T; Dimitriu, Pedro A; Thorson, Lisa; Russell, Shannon; Yurist-Doutsch, Sophie; Kuzeljevic, Boris; Gold, Matthew J; Britton, Heidi M; Lefebvre, Diana L; Subbarao, Padmaja; Mandhane, Piush; Becker, Allan; McNagny, Kelly M; Sears, Malcolm R; Kollmann, Tobias; Mohn, William W; Turvey, Stuart E; Brett Finlay, B

    2015-09-30

    Asthma is the most prevalent pediatric chronic disease and affects more than 300 million people worldwide. Recent evidence in mice has identified a "critical window" early in life where gut microbial changes (dysbiosis) are most influential in experimental asthma. However, current research has yet to establish whether these changes precede or are involved in human asthma. We compared the gut microbiota of 319 subjects enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study, and show that infants at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life. The relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate and dysregulation of enterohepatic metabolites. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny, demonstrating a causal role of these bacterial taxa in averting asthma development. These results enhance the potential for future microbe-based diagnostics and therapies, potentially in the form of probiotics, to prevent the development of asthma and other related allergic diseases in children. PMID:26424567

  11. Calcium-Induced Alteration of Cellular Morphology Affecting the Resistance of Lactobacillus acidophilus to Freezing †

    PubMed Central

    Wright, C. T.; Klaenhammer, T. R.

    1981-01-01

    Examination of factors affecting the resistance of Lactobacillus acidophilus NCFM culture concentrates to freeze injury induced during frozen storage at -20°C revealed that calcium supplementation of the growth medium contributed to the storage stability of cells prepared in static culture. Culture concentrates of L. acidophilus NCFM were prepared from cells propagated in MRS broth or MRS broth supplemented with 0.1% calcium carbonate, calcium chloride, or calcium phosphate. After 28 days of frozen storage at -20°C, concentrated cells (3.2 × 109 colony-forming units per ml) prepared from MRS broth cultures showed an 84% reduction in viable cells. Of the remaining viable cells, 88% were sublethally injured and unable to form colonies on MRS agar supplemented with 0.15% bile. Cells prepared in calcium-supplemented MRS broths demonstrated more resistance to frozen storage. Viability and injury losses in the frozen concentrates were limited to 10 to 39% and 3 to 23%, respectively. It was observed that calcium supplementation of MRS medium resulted in a morphological transition of L. acidophilus NCFM from filamentous to bacilloid rods, and the bacilloid cells were more resistant to freezing and storage at conventional freezer temperatures. The results suggest that the morphology of the L. acidophilus cell may be an important consideration in the preparation of freeze-stable culture concentrates. Images PMID:16345739

  12. Altered Cerebral Perfusion in Executive, Affective, and Motor Networks During Adolescent Depression

    PubMed Central

    Ho, Tiffany C.; Wu, Jing; Shin, David D.; Liu, Thomas T.; Tapert, Susan F.; Yang, Guang; Connolly, Colm G.; Frank, Guido K.W.; Max, Jeffrey E.; Wolkowitz, Owen; Eisendrath, Stuart; Hoeft, Fumiko; Banerjee, Dipavo; Hood, Korey; Hendren, Robert L.; Paulus, Martin P.; Simmons, Alan N.; Yang, Tony T.

    2013-01-01

    Objective While substantial literature has reported regional cerebral blood flow (rCBF) abnormalities in adults with depression, these studies commonly necessitated the injection of radioisotopes into subjects. The recent development of arterial spin labeling (ASL), however, allows for noninvasive measurements of rCBF. Currently, no published ASL studies have examined cerebral perfusion in adolescents with depression. Thus, the aim of the present study was to examine baseline cerebral perfusion in adolescent depression using a newly developed ASL technique: pseudocontinuous arterial spin labeling (PCASL). Method 25 medication-naive adolescents (ages 13–17 years) diagnosed with major depressive disorder (MDD) and 26 well-matched controls underwent functional magnetic resonance imaging. Baseline rCBF was measured via a novel PCASL method that optimizes tagging efficiency. Results Voxel-based whole brain analyses revealed significant frontal, limbic, paralimbic, and cingulate hypoperfusion in the group with depression (p<0.05, corrected). Hyperperfusion was also observed within the subcallosal cingulate, putamen, and fusiform gyrus (p<0.05, corrected). Similarly, region-of-interest analyses revealed amygdalar and insular hypoperfusion in the group with depression, as well as hyperperfusion in the putamen and superior insula (p<0.05, corrected). Conclusions Adolescents with depression and healthy adolescents appear to differ on rCBF in executive, affective, and motor networks. Dysfunction in these regions may contribute to the cognitive, emotional, and psychomotor symptoms commonly present in adolescent depression. These findings point to possible biomarkers for adolescent depression that could inform early interventions and treatments and establishes a methodology for using PCASL to noninvasively measure rCBF in clinical and healthy adolescent populations. PMID:24074474

  13. Human neuroblastoma cell viability and growth are affected by altered culture conditions.

    PubMed

    Carlson, K; Ehrich, M

    2000-01-01

    The effects of differing culture parameters are seldomly investigated, even though they influence the way immortalized cells grow and die. In this study, the changes in total cell number, confluency, membrane permeability, and DNA content were evaluated in SH-SY5Y and IMR-32 human neuroblastoma cells following culture at different seeding densities and media consistencies. These four endpoints were determined using a hemacytometer, phase-contrast microscope, trypan blue (0.4% v/v), and propidium iodide (50 microg/mL), respectively. Both cell lines (SH-SY5Y and IMR-32) responded in a similar manner to changing culture conditions, even though baseline values for all four endpoints were different. Higher seeding densities (19,200 and 38,400 cells/cm2) significantly increased the percent confluency and total cell number over time, but decreased the initial percentage of cells with fragmented (subG1) DNA in both cell lines when compared with lower seeding densities (4800 and 9600 cells/cm2, p < 0.05). Daily media changes significantly increased the percentage of cells in S and G2/M, but decreased the percentage of cells in G0/G1 phase of the cell cycle over time in both cell lines when compared with cultures without media changes (p < 0.05). Results suggest that environmental culture conditions greatly affect cellular mitosis and death. This information may be of particular relevance in the investigation of compounds that act on specific cell-cycle stages, such as antineoplastic agents. PMID:11319276

  14. Non-conscious visual cues related to affect and action alter perception of effort and endurance performance

    PubMed Central

    Blanchfield, Anthony; Hardy, James; Marcora, Samuele

    2014-01-01

    The psychobiological model of endurance performance proposes that endurance performance is determined by a decision-making process based on perception of effort and potential motivation. Recent research has reported that effort-based decision-making during cognitive tasks can be altered by non-conscious visual cues relating to affect and action. The effects of these non-conscious visual cues on effort and performance during physical tasks are however unknown. We report two experiments investigating the effects of subliminal priming with visual cues related to affect and action on perception of effort and endurance performance. In Experiment 1 thirteen individuals were subliminally primed with happy or sad faces as they cycled to exhaustion in a counterbalanced and randomized crossover design. A paired t-test (happy vs. sad faces) revealed that individuals cycled significantly longer (178 s, p = 0.04) when subliminally primed with happy faces. A 2 × 5 (condition × iso-time) ANOVA also revealed a significant main effect of condition on rating of perceived exertion (RPE) during the time to exhaustion (TTE) test with lower RPE when subjects were subliminally primed with happy faces (p = 0.04). In Experiment 2, a single-subject randomization tests design found that subliminal priming with action words facilitated a significantly longer TTE (399 s, p = 0.04) in comparison to inaction words. Like Experiment 1, this greater TTE was accompanied by a significantly lower RPE (p = 0.03). These experiments are the first to show that subliminal visual cues relating to affect and action can alter perception of effort and endurance performance. Non-conscious visual cues may therefore influence the effort-based decision-making process that is proposed to determine endurance performance. Accordingly, the findings raise notable implications for individuals who may encounter such visual cues during endurance competitions, training, or health related exercise. PMID:25566014

  15. GENETIC FACTORS AND DIET AFFECT LONG BONE LENGTH IN THE F34 LG,SM ADVANCED INTERCROSS

    PubMed Central

    Norgard, Elizabeth A.; Lawson, Heather A.; Pletscher, L. Susan; Wang, Bing; Brooks, Victoria R.; Wolf, Jason B.; Cheverud, James M.

    2013-01-01

    Previous studies on the LG,SM advanced intercross line have identified ~40 quantitative trait loci (QTL) for long bone (humerus, ulna, femur, and tibia) lengths. In this study, long bone length QTL were fine-mapped in the F34 generation (n=1,424) of the LG,SM advanced intercross. Environmental effects were assessed by dividing the population by sex between high fat and low fat diet, producing eight sex/diet cohorts. We identified 145 individual bone length QTL comprising 45 pleiotropic QTL; 69 replicated QTL from previous studies, 35 were new traits significant at previously identified loci, and 41 were novel QTL. Many QTL affected only a subset of the population based on sex and/or diet. Eight of ten known skeletal growth genes were up-regulated in 3-week-old LG/J male proximal tibial growth plates, relative to SM/J. The sequences of parental strains LG/J and SM/J indicated the presence of over half a million polymorphisms in the confidence intervals of these 45 QTL. We examined 526 polymorphisms and found that 97 represented radical changes to amino acid composition while 40 were predicted to be deleterious to protein function. Additional experimentation is required to understand how changes in gene regulation or protein function can alter the genetic architecture and interact with the environment to produce phenotypic variation. PMID:21170743

  16. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations

    PubMed Central

    Will, Britta; Zhou, Li; Vogler, Thomas O.; Ben-Neriah, Susanna; Schinke, Carolina; Tamari, Roni; Yu, Yiting; Bhagat, Tushar D.; Bhattacharyya, Sanchari; Barreyro, Laura; Heuck, Christoph; Mo, Yonkai; Parekh, Samir; McMahon, Christine; Pellagatti, Andrea; Boultwood, Jacqueline; Montagna, Cristina; Silverman, Lewis; Maciejewski, Jaroslaw; Greally, John M.; Ye, B. Hilda; List, Alan F.; Steidl, Christian

    2012-01-01

    Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage?/CD34+/CD38?/CD90+) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations. PMID:22753872

  17. Stem and progenitor cells in myelodysplastic syndromes show aberrant stage-specific expansion and harbor genetic and epigenetic alterations.

    PubMed

    Will, Britta; Zhou, Li; Vogler, Thomas O; Ben-Neriah, Susanna; Schinke, Carolina; Tamari, Roni; Yu, Yiting; Bhagat, Tushar D; Bhattacharyya, Sanchari; Barreyro, Laura; Heuck, Christoph; Mo, Yonkai; Parekh, Samir; McMahon, Christine; Pellagatti, Andrea; Boultwood, Jacqueline; Montagna, Cristina; Silverman, Lewis; Maciejewski, Jaroslaw; Greally, John M; Ye, B Hilda; List, Alan F; Steidl, Christian; Steidl, Ulrich; Verma, Amit

    2012-09-01

    Even though hematopoietic stem cell (HSC) dysfunction is presumed in myelodysplastic syndrome (MDS), the exact nature of quantitative and qualitative alterations is unknown. We conducted a study of phenotypic and molecular alterations in highly fractionated stem and progenitor populations in a variety of MDS subtypes. We observed an expansion of the phenotypically primitive long-term HSCs (lineage(-)/CD34(+)/CD38(-)/CD90(+)) in MDS, which was most pronounced in higher-risk cases. These MDS HSCs demonstrated dysplastic clonogenic activity. Examination of progenitors revealed that lower-risk MDS is characterized by expansion of phenotypic common myeloid progenitors, whereas higher-risk cases revealed expansion of granulocyte-monocyte progenitors. Genome-wide analysis of sorted MDS HSCs revealed widespread methylomic and transcriptomic alterations. STAT3 was an aberrantly hypomethylated and overexpressed target that was validated in an independent cohort and found to be functionally relevant in MDS HSCs. FISH analysis demonstrated that a very high percentage of MDS HSC (92% 4%) carry cytogenetic abnormalities. Longitudinal analysis in a patient treated with 5-azacytidine revealed that karyotypically abnormal HSCs persist even during complete morphologic remission and that expansion of clonotypic HSCs precedes clinical relapse. This study demonstrates that stem and progenitor cells in MDS are characterized by stage-specific expansions and contain epigenetic and genetic alterations. PMID:22753872

  18. Cytoplasmic genome substitution in wheat affects the nuclear-cytoplasmic cross-talk leading to transcript and metabolite alterations

    PubMed Central

    2013-01-01

    Background Alloplasmic lines provide a unique tool to study nuclear-cytoplasmic interactions. Three alloplasmic lines, with nuclear genomes from Triticum aestivum and harboring cytoplasm from Aegilops uniaristata, Aegilops tauschii and Hordeum chilense, were investigated by transcript and metabolite profiling to identify the effects of cytoplasmic substitution on nuclear-cytoplasmic signaling mechanisms. Results In combining the wheat nuclear genome with a cytoplasm of H. chilense, 540 genes were significantly altered, whereas 11 and 28 genes were significantly changed in the alloplasmic lines carrying the cytoplasm of Ae. uniaristata or Ae. tauschii, respectively. We identified the RNA maturation-related process as one of the most sensitive to a perturbation of the nuclear-cytoplasmic interaction. Several key components of the ROS chloroplast retrograde signaling, together with the up-regulation of the ROS scavenging system, showed that changes in the chloroplast genome have a direct impact on nuclear-cytoplasmic cross-talk. Remarkably, the H. chilense alloplasmic line down-regulated some genes involved in the determination of cytoplasmic male sterility without expressing the male sterility phenotype. Metabolic profiling showed a comparable response of the central metabolism of the alloplasmic and euplasmic lines to light, while exposing larger metabolite alterations in the H. chilense alloplasmic line as compared with the Aegilops lines, in agreement with the transcriptomic data. Several stress-related metabolites, remarkably raffinose, were altered in content in the H. chilense alloplasmic line when exposed to high light, while amino acids, as well as organic acids were significantly decreased. Alterations in the levels of transcript, related to raffinose, and the photorespiration-related metabolisms were associated with changes in the level of related metabolites. Conclusion The replacement of a wheat cytoplasm with the cytoplasm of a related species affects the nuclear-cytoplasmic cross-talk leading to transcript and metabolite alterations. The extent of these modifications was limited in the alloplasmic lines with Aegilops cytoplasm, and more evident in the alloplasmic line with H. chilense cytoplasm. We consider that, this finding might be linked to the phylogenetic distance of the genomes. PMID:24320731

  19. Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy

    PubMed Central

    Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B.; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S. Vasantha; Chandak, Giriraj Ratan

    2012-01-01

    Purpose Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Methods Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Results Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. Conclusions This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3. PMID:22876130

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

    PubMed

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

    2014-09-01

    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. PMID:25102285

  1. Seismic properties of rocks affected by hydrothermal alteration: a case study from the Lalor Lake VMS mining camp

    NASA Astrophysics Data System (ADS)

    Miah, K.; Bellefleur, G.; Schetselaar, E.

    2013-12-01

    Global demand of base metals, uranium, diamonds, and precious metals has been pushing technological barrier to find and extract minerals at higher depth, which was not feasible in just a few decades ago. Seismic properties of rocks containing and surrounding ore bodies have been useful in characterizing and modeling geologic structures, and mapping high-resolution images of ore bodies. Although seismic surveys and drill hole sonic and density logs are essential for mineral exploration at depth, limited availability of seismic logs to link rock properties of different ore forming geologic structure is a hindrance to seismic interpretations. Volcanogenic Massive Sulphides (VMS) are rich in minerals and of primary interests among geologists and mining industries alike. VMS deposits occur due to focused discharge of metal-enriched fluids associated in the hydrothermal alteration process, and are rich in Zn, Cu, Pb, Ag, Au, etc. Alteration halos surrounding ore deposits can be widespread, and their locations are easier to determine than the deposits within them. Physical rock properties affected by alteration can provide clues on type and potentially size of ore deposits in the surrounding area. In this context, variations in seismic properties of rocks due to hydrothermal alteration near the deposits can help in improving modeling accuracy, and better interpretation of seismic data for economic mineral exploration. While reflection seismic techniques can resolve ore bodies at higher depths than other conventional geophysical techniques, they are relatively expensive both in terms of field data acquisition and post-processing, especially for high-resolution 3D surveys. Acoustic impedance contrasts of ore lenses with their hosting rock environment; geometry, size and spatial location relative to the surface affect their detection with seismic data. Therefore, apriori knowledge of seismic rock properties from drill hole logs and core samples in the potential survey area are essential to determine whether any 2D/3D active survey would be worth conducting. In situ density and velocity logs, and thus, acoustic impedance provide first order control on reflectivity of various lithologies. In this abstract, we analyzed well logs from 12 drill holes geographically located in the northern Manitoba, Canada, in an attempt to characterize lithologies based on their seismic properties. Velocities, density, acoustic impedance and Poisson's ratio of major lithologies were compared among each other. Massive sulphide and Diorite have higher average acoustic impedance than the others. Our quantitative analysis suggests that alteration has considerable effect on overall acoustic impedance of Argillite, Felsic Volcanic and Stringer Sulphide rocks. This can be useful in selecting values of model parameters for seismic wave propagation simulation, which can be used to compare with seismic survey data. In addition, core sample analysis from the same drill holes aided our understanding of mineralization, alteration, and overall composition of different rocks under consideration.

  2. How does altered precipitation and annual grass invasion affect plant N uptake in a native semi-arid shrub community?

    NASA Astrophysics Data System (ADS)

    Mauritz, M.; Lipson, D.; Cleland, E. E.

    2012-12-01

    Climate change is expected to alter precipitation patterns, which will change the timing and amount of plant resources. Precipitation patterns determine water and nitrogen (N) availability, because water stimulates microbial N turnover and N transport. In order for plants to utilize water and N, they must coincide with the phenology and meet physiological requirements of the plant. As resource supply shifts, differences in species' ability to acquire resources will affect plant community composition. Semiarid ecosystems, such as shrublands in Southern California, are particularly sensitive to shifts in precipitation because they are severely water limited. This study takes advantage of the altered phenology and resource demands presented by invasive annual grasses in a native semiarid shrubland. The goal is to understand how altered precipitation patterns affect plant N uptake. Rainfall levels were manipulated to 50% and 150% of ambient levels. It is expected that higher rainfall levels promote annual grass invasion because grasses have higher water and N requirements and begin to grow earlier in the season than shrubs. A 15N tracer was added with the first rain event and plant samples were collected regularly to track the movement of N into the plants. Net soil N accumulation was determined using resin bags. Invasive grasses altered the timing and amount of N uptake but amount of rainfall had less effect on N distribution. 15N was detected sooner and at higher level in grasses than shrubs. 24hours after the first rain event 15N was detectable in grasses, 15N accumulated rapidly and peaked 2 months earlier than shrubs. Shrub 15N levels remained at pre-rain event levels for the first 2 months and began to increase at the beginning of spring, peak mid-spring and decline as the shrubs entered summer dormancy. One year later 15N levels in annual grass litter remained high, while 15N levels in shrubs returned to initial background levels as a result of resorption. 15N concentrations are more variable in grasses which could indicate higher plasticity in grass N uptake compared to shrubs. Resin N supports the 15N patterns. Resin N declined more rapidly under grasses and was lower than under shrubs, presumably due to high grass N uptake. Resin N was particularly high under shrubs in wetter conditions indicating that shrubs could not take advantage of high N supply. Together the 15N and resin N patterns indicate that grasses accumulate more N and begin N uptake earlier in the season than shrubs. Although 15N did not differ in response to rainfall, invasion alters the distribution of N in the system. Rain was only manipulated for one growing season; multiple years of altered precipitation may yield significant differences. Early season N uptake by grasses, the low variability in shrub 15N and low shrub 15N in wetter conditions, despite high resin N, indicates that N competition between invasive grasses and native shrubs is weak. If N supply is sufficient for shrub demands, invasive grasses and shrubs could coexist. This study contributes to a broader understanding of how changes in resource supply, plant phenology and functional type interact and respond to climate change.

  3. A genetic study of the anesthetic response: mutants of Drosophila melanogaster altered in sensitivity to halothane.

    PubMed Central

    Krishnan, K S; Nash, H A

    1990-01-01

    In an attempt to identify genes that control or encode the targets of general anesthetics, we have chemically mutagenized fruit flies and selected four lines that show an abnormal response to the volatile anesthetic halothane. Specifically, about 2-fold higher concentrations of halothane are required to induce the loss of motor control in the mutant flies. Fine mapping of two isolates indicates that they alter a previously uncharacterized gene of Drosophila. In the absence of anesthetics, these mutants display alterations of behavior that imply changes in the adult and the larval neuromuscular system. Images PMID:2122464

  4. Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

    PubMed Central

    Grevys, Algirdas; Bern, Malin; Foss, Stian; Bratlie, Diane Bryant; Moen, Anders; Gunnarsen, Kristin Støen; Aase, Audun; Michaelsen, Terje Einar; Sandlie, Inger

    2015-01-01

    Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge–CH2 region, structurally distant from the binding site for FcRn at the CH2–CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn–IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants. PMID:25904551

  5. Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions.

    PubMed

    Grevys, Algirdas; Bern, Malin; Foss, Stian; Bratlie, Diane Bryant; Moen, Anders; Gunnarsen, Kristin Støen; Aase, Audun; Michaelsen, Terje Einar; Sandlie, Inger; Andersen, Jan Terje

    2015-06-01

    Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge-CH2 region, structurally distant from the binding site for FcRn at the CH2-CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn-IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants. PMID:25904551

  6. Altered Mucus Glycosylation in Core 1 O-Glycan-Deficient Mice Affects Microbiota Composition and Intestinal Architecture

    PubMed Central

    Sommer, Felix; Adam, Nina; Johansson, Malin E. V.; Xia, Lijun; Hansson, Gunnar C.; Bäckhed, Fredrik

    2014-01-01

    A functional mucus layer is a key requirement for gastrointestinal health as it serves as a barrier against bacterial invasion and subsequent inflammation. Recent findings suggest that mucus composition may pose an important selection pressure on the gut microbiota and that altered mucus thickness or properties such as glycosylation lead to intestinal inflammation dependent on bacteria. Here we used TM-IEC C1galt-/- mice, which carry an inducible deficiency of core 1-derived O-glycans in intestinal epithelial cells, to investigate the effects of mucus glycosylation on susceptibility to intestinal inflammation, gut microbial ecology and host physiology. We found that TM-IEC C1galt-/- mice did not develop spontaneous colitis, but they were more susceptible to dextran sodium sulphate-induced colitis. Furthermore, loss of core 1-derived O-glycans induced inverse shifts in the abundance of the phyla Bacteroidetes and Firmicutes. We also found that mucus glycosylation impacts intestinal architecture as TM-IEC C1galt-/- mice had an elongated gastrointestinal tract with deeper ileal crypts, a small increase in the number of proliferative epithelial cells and thicker circular muscle layers in both the ileum and colon. Alterations in the length of the gastrointestinal tract were partly dependent on the microbiota. Thus, the mucus layer plays a role in the regulation of gut microbiota composition, balancing intestinal inflammation, and affects gut architecture. PMID:24416370

  7. Heterogeneity of genetic alterations in prostate cancer: evidence of the complex nature of the disease.

    PubMed

    Nwosu, V; Carpten, J; Trent, J M; Sheridan, R

    2001-10-01

    Prostate cancer is a complex, multifactorial disease with genetic and environmental factors involved in its etiology. The search for genetic determinants involved in the disease has proven to be challenging, in part because such complex diseases are often not amenable to characterization by linkage analysis and positional cloning as is the case for diseases with simple Mendelian genetic inheritance. Prostate cancer susceptibility loci that have been reported so far include HPC1 (1q24-q25), PCAP (1q42-q43), HPCX (Xq27-q28), CAPB (1p36), HPC20 (20q13), HPC2/ELAC2 (17p11) and 16q23. Prostate cancer aggressiveness loci have also been reported (5q31-q33, 7q32 and 19q12). Further complicating the process is the existence of polymorphisms in several genes associated with prostate cancer including, AR, PSA, SRD5A2, VDR and CYP isoforms. These polymorphisms, however, are not thought to be highly penetrant alleles in families at high risk for prostate cancer. It is clear that prostate cancer etiology involves several genetic loci with no major gene accounting for a large proportion of susceptibility to the disease. PMID:11673416

  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. Physical characteristics of genetically-altered wheat related to technological protein separation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wheat protein is a technologically challenging substrate for food and non-food applications because of its compositional diversity and susceptibility to denaturation. Genetic modification could be used to create cultivars capable of producing more uniform or focused and novel protein compositions t...

  10. Genetic aspects of adolescent idiopathic scoliosis in a family with multiple affected members: a research article

    PubMed Central

    2010-01-01

    Background The etiology of idiopathic scoliosis remains unknown and different factors have been suggested as causal. Hereditary factors can also determine the etiology of the disease; however, the pattern of inheritance remains unknown. Autosomal dominant, X-linked and multifactorial patterns of inheritances have been reported. Other studies have suggested possible chromosome regions related to the etiology of idiopathic scoliosis. We report the genetic aspects of and investigate chromosome regions for adolescent idiopathic scoliosis in a Brazilian family. Methods Evaluation of 57 family members, distributed over 4 generations of a Brazilian family, with 9 carriers of adolescent idiopathic scoliosis. The proband presented a scoliotic curve of 75 degrees, as determined by the Cobb method. Genomic DNA from family members was genotyped. Results Locating a chromosome region linked to adolescent idiopathic scoliosis was not possible in the family studied. Conclusion While it was not possible to determine a chromosome region responsible for adolescent idiopathic scoliosis by investigation of genetic linkage using microsatellites markers during analysis of four generations of a Brazilian family with multiple affected members, analysis including other types of genomic variations, like single nucleotide polymorphisms (SNPs) could contribute to the continuity of this study. PMID:20374654

  11. Factors affecting calculation and use of conversion equations for genetic merit of dairy bulls.

    PubMed

    Powell, R L; Wiggans, G R; VanRaden, P M

    1994-09-01

    Factors affecting calculation and use of conversion equations were reviewed. Methods of expressing reliability of converted evaluations were surveyed. Of 16 countries responding, 6 did not calculate reliability for converted evaluations, 5 accepted reliability from the exporting country, and 5 assumed genetic correlations of .6 to 1.0 with the US. Genetic correlations between the US and 8 other countries were estimated and generally were > or = .9; estimated correlations between the US and Canada were 1.0. Estimated correlations averaged .93 for milk, .89 for fat, and .92 for protein yields. Correlation estimates were lowest for countries differing most from the US in management conditions (Australia, New Zealand) or trait definition (Germany), which suggests that correlation estimates < 1.0 indicate differences in trait measurement as well as differences in biological expression. Conversion equations were computed from data of US and Canadian Holstein bulls with and against the gene flow. Equations against the gene flow generally had regression coefficients and intercepts lower than those calculated with the gene flow. Lower regression coefficients were explained by selection on the dependent variable. Lower intercepts were attributed to preferential treatment of daughters from imported semen, which would lower intercepts for equations against the gene flow and inflate intercepts with the gene flow. PMID:7814739

  12. CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

    PubMed

    Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

    2016-03-01

    The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (Pmeta=5.0 × 10(-4)) and rs800292 (Pmeta=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress. PMID:26243271

  13. Genetic variation in human NPY expression affects stress response and emotion.

    PubMed

    Zhou, Zhifeng; Zhu, Guanshan; Hariri, Ahmad R; Enoch, Mary-Anne; Scott, David; Sinha, Rajita; Virkkunen, Matti; Mash, Deborah C; Lipsky, Robert H; Hu, Xian-Zhang; Hodgkinson, Colin A; Xu, Ke; Buzas, Beata; Yuan, Qiaoping; Shen, Pei-Hong; Ferrell, Robert E; Manuck, Stephen B; Brown, Sarah M; Hauger, Richard L; Stohler, Christian S; Zubieta, Jon-Kar; Goldman, David

    2008-04-24

    Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases. PMID:18385673

  14. Genetic variation in human NPY expression affects stress response and emotion

    PubMed Central

    Zhou, Zhifeng; Zhu, Guanshan; Hariri, Ahmad R.; Enoch, Mary-Anne; Scott, David; Sinha, Rajita; Virkkunen, Matti; Mash, Deborah C.; Lipsky, Robert H.; Hu, Xian-Zhang; Hodgkinson, Colin A.; Xu, Ke; Buzas, Beata; Yuan, Qiaoping; Shen, Pei-Hong; Ferrell, Robert E.; Manuck, Stephen B.; Brown, Sarah M.; Hauger, Richard L.; Stohler, Christian S.; Zubieta, Jon-Kar; Goldman, David

    2009-01-01

    Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic1,2 and its release is induced by stress3. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories4–6. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases. PMID:18385673

  15. Is the Genetic Landscape of the Deep Subsurface Biosphere Affected by Viruses?

    PubMed Central

    Anderson, Rika E.; Brazelton, William J.; Baross, John A.

    2011-01-01

    Viruses are powerful manipulators of microbial diversity, biogeochemistry, and evolution in the marine environment. Viruses can directly influence the genetic capabilities and the fitness of their hosts through the use of fitness factors and through horizontal gene transfer. However, the impact of viruses on microbial ecology and evolution is often overlooked in studies of the deep subsurface biosphere. Subsurface habitats connected to hydrothermal vent systems are characterized by constant fluid flux, dynamic environmental variability, and high microbial diversity. In such conditions, high adaptability would be an evolutionary asset, and the potential for frequent host–virus interactions would be high, increasing the likelihood that cellular hosts could acquire novel functions. Here, we review evidence supporting this hypothesis, including data indicating that microbial communities in subsurface hydrothermal fluids are exposed to a high rate of viral infection, as well as viral metagenomic data suggesting that the vent viral assemblage is particularly enriched in genes that facilitate horizontal gene transfer and host adaptability. Therefore, viruses are likely to play a crucial role in facilitating adaptability to the extreme conditions of these regions of the deep subsurface biosphere. We also discuss how these results might apply to other regions of the deep subsurface, where the nature of virus–host interactions would be altered, but possibly no less important, compared to more energetic hydrothermal systems. PMID:22084639

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

    PubMed

    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

    2015-06-01

    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

  17. 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

  18. Partial genetic deletion of neuregulin 1 and adolescent stress interact to alter NMDA receptor binding in the medial prefrontal cortex

    PubMed Central

    Chohan, Tariq W.; Nguyen, An; Todd, Stephanie M.; Bennett, Maxwell R.; Callaghan, Paul; Arnold, Jonathon C.

    2014-01-01

    Schizophrenia is thought to arise due to a complex interaction between genetic and environmental factors during early neurodevelopment. We have recently shown that partial genetic deletion of the schizophrenia susceptibility gene neuregulin 1 (Nrg1) and adolescent stress interact to disturb sensorimotor gating, neuroendocrine activity and dendritic morphology in mice. Both stress and Nrg1 may have converging effects upon N-methyl-D-aspartate receptors (NMDARs) which are implicated in the pathogenesis of schizophrenia, sensorimotor gating and dendritic spine plasticity. Using an identical repeated restraint stress paradigm to our previous study, here we determined NMDAR binding across various brain regions in adolescent Nrg1 heterozygous (HET) and wild-type (WT) mice using [3H] MK-801 autoradiography. Repeated restraint stress increased NMDAR binding in the ventral part of the lateral septum (LSV) and the dentate gyrus (DG) of the hippocampus irrespective of genotype. Partial genetic deletion of Nrg1 interacted with adolescent stress to promote an altered pattern of NMDAR binding in the infralimbic (IL) subregion of the medial prefrontal cortex. In the IL, whilst stress tended to increase NMDAR binding in WT mice, it decreased binding in Nrg1 HET mice. However, in the DG, stress selectively increased the expression of NMDAR binding in Nrg1 HET mice but not WT mice. These results demonstrate a Nrg1-stress interaction during adolescence on NMDAR binding in the medial prefrontal cortex. PMID:25324742

  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 deletion of the P2Y2 receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2 signaling.

    PubMed

    Zhang, Yue; Pop, Ioana L; Carlson, Noel G; Kishore, Bellamkonda K

    2012-01-01

    Lithium (Li)-induced polyuria is due to resistance of the medullary collecting duct (mCD) to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE(2). We previously reported that the P2Y(2) receptor (P2Y(2)-R) antagonizes the action of AVP on the mCD and may play a role in Li-induced polyuria by enhancing the production of PGE(2) in mCD. Hence, we hypothesized that genetic deletion of P2Y(2)-R should ameliorate Li-induced polyuria. Wild-type (WT) or P2Y(2)-R knockout (KO) mice were fed normal or Li-added diets for 14 days and euthanized. Li-induced polyuria, and decreases in urine osmolality and AQP2 protein abundance in the renal medulla, were significantly less compared with WT mice despite the lack of differences in Li intake or terminal serum or inner medullary tissue Li levels. Li-induced increased urinary excretion of PGE(2) was not affected in KO mice. However, prostanoid EP(3) receptor (EP3-R) protein abundance in the renal medulla of KO mice was markedly lower vs. WT mice, irrespective of the dietary regimen. The protein abundances of other EP-Rs were not altered across the groups irrespective of the dietary regimen. Ex vivo stimulation of mCD with PGE(2) generated significantly more cAMP in Li-fed KO mice (130%) vs. Li-fed WT mice (100%). Taken together, these data suggest 1) genetic deletion of P2Y(2)-R offers significant resistance to the development of Li-induced polyuria; and 2) this resistance is apparently due to altered PGE(2) signaling mediated by a marked decrease in EP3-R protein abundance in the medulla, thus attenuating the EP3-mediated decrease in cAMP levels in mCD. PMID:21975874

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

    PubMed

    Broothaerts, Wim; Corbisier, Philippe; Emons, Hendrik; Emteborg, Hkan; 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. PMID:17508757

  2. Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings.

    PubMed

    Sacchetti, Marta; Macchi, Ilaria; Tiezzi, Alessandro; La Cava, Maurizio; Massaro-Giordano, Giacomina; Lambiase, Alessandro

    2016-02-01

    Corneal dystrophies are a heterogeneous group of bilateral, inherited, rare diseases characterized by slowly progressive corneal opacities, that lead to visual impairment. Most of them have an autosomal dominant pattern of inheritance with variable expressivity, but new mutations have been described. Many corneal dystrophies have been genetically characterized and the specific gene mutations identified, such as for the epithelial-stromal TGFBI dystrophies. Current classification systems identified four main groups of corneal dystrophies based on clinical, histologic, and genetic information. Diagnosis is performed during a routine ophthalmic examination that shows typical cellular abnormalities of the corneal epithelium, stroma, or endothelium. Disease progression should be carefully monitored to decide the proper clinical management. The treatment of corneal dystrophies is variable, depending on symptoms, clinical course, severity, and type of dystrophy. Management aimed to reduce symptoms and to improve vision, includes different surgical approaches. Novel cellular and genetic therapeutic approaches are under evaluation. J. Cell. Physiol. 231: 261-269, 2016. 2015 Wiley Periodicals, Inc. PMID:26104822

  3. Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.

    PubMed

    Vylet'al, P; Kublov, M; Kalbcov, M; Hodanov, K; Baresov, V; Stib?rkov, B; Sikora, J; H?lkov, H; Zivn, J; Majewski, J; Simmonds, A; Fryns, J-P; Venkat-Raman, G; Elleder, M; Kmoch, S

    2006-09-01

    Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome. PMID:16883323

  4. Genetic variation in the serotonin receptor gene affects immune responses in rheumatoid arthritis

    PubMed Central

    Snir, O; Hesselberg, E; Amoudruz, P; Klareskog, L; Zarea-Ganji, I; Catrina, A I; Padyukov, L; Malmström, V; Seddighzadeh, M

    2013-01-01

    Many genetic variants associate with the risk of developing rheumatoid arthritis (RA); however, their functional roles are largely unknown. Here, we aimed to investigate whether the RA-associated serotonin receptor 2A (HTR2A) haplotype affects T-cell and monocyte functions. Patients with established RA (n=379) were genotyped for two single-nucleotide polymorphisms (SNPs) in the HTR2A locus, rs6314 and rs1328674, to define presence of the risk haplotype for each individual. Patients with and without the RA-associated TC haplotype were selected and T-cell and monocyte function was monitored following in vitro stimulations with staphylococcal enterotoxin B and lipopolysaccharide (LPS) using multiparameter flow cytometry. Within the cohort, 44 patients were heterozygous for the TC haplotype (11.6%) while none were homozygous. Upon stimulation, T cells from TC-carrier patients produced more proinflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin-17 (IL-17) and interferon gamma (IFN-γ)) and monocytes produced higher levels of TNF-α compared with patients carrying the non-TC haplotype (P<0.05 and 0.01, respectively). Such cytokine production could be inhibited in the presence of the selective 5-HT2 receptor agonist (2,5-Dimethoxy-4-iodoamphetamine, DOI); interestingly, this effect was more pronounced in TC carriers. Our data demonstrate that association of RA with a distinct serotonin receptor haplotype has functional impact by affecting the immunological phenotype of T cells and monocytes. PMID:23254357

  5. Genetic alterations following ionizing radiation in human ovarian cancer-derived endothelial cells.

    PubMed

    Liu, Ting; Du, Xuelian; Sheng, Xiugui

    2014-06-01

    Recent studies have focused on the role of endothelial cells during tumor radiotherapy, and the majority of studies have found that the rate of endothelial cell apoptosis determines the response of the tumor to ionizing radiation treatment. However, gene expression changes in human ovarian cancer-derived endothelial cells in response to X-ray radiation remains poorly understood. The present study was conducted to investigate the radiation-induced gene alterations in human ovarian cancer-derived endothelial cells and to provide novel potential targets for combined anti-angiogenesis and radiation therapy for the treatment of human ovarian cancer. Ovarian cancer-derived endothelial cells, which were harvested from six human ovarian epithelial carcinomas prior to and 4 h after 400 cGy X-ray irradiation, were analyzed using cDNA microarray technology. Significant genes were selected to corroborate the microarray experiments using a quantitative polymerase chain reaction (qPCR). A total of 28 genes common to all the cDNA microarray results were identified, of which 22 genes were found to be consistently upregulated or downregulated. Thirteen genes were upregulated persistently and nine genes downregulated persistently following irradiation with 400 cGy X-ray in comparison with the matched group. The majority of the significantly altered genes (?2-fold change in expression) were found to have a role in vasculogenesis, cell cycle regulation, inflammation and the immune response, cell growth and apoptosis, nicotinamide metabolism, cell signaling, chemokines and cell adhesion. Eight randomly selected genes were corroborated using qPCR technology. Radiation-induced gene alterations in ovarian cancer-derived endothelial cells and gene-related pathways were associated with vasculogenesis and the radiosensitivity of human ovarian cancer, and may provide promising biomarkers for radiation and anti-angiogenesis treatments against ovarian carcinoma. PMID:24691555

  6. 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. PMID:25136520

  7. Genetic variants in ABCA1 promoter affect transcription activity and plasma HDL level in pigs.

    PubMed

    Dang, Xiao-yong; Chu, Wei-wei; Shi, Heng-chuan; Yu, Shi-gang; Han, Hai-yin; Gu, Shu-Hua; Chen, Jie

    2015-01-25

    Excess accumulation of cholesterol in plasma may result in coronary artery disease. Numerous studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for plasma high density lipoprotein (HDL) formation. Higher plasma levels of HDL are associated with lower risk for cardiovascular disease. Studies of human disease and animal models had shown that an increased hepatic ABCA1 activity relates to an enhanced plasma HDL level. In this study, we hypothesized that functional mutations in the ABCA1 promoter in pigs may affect gene transcription activity, and consequently the HDL level in plasma. The promoter region of ABCA1 was comparatively scanned by direct sequencing with pool DNA of high- and low-HDL groups (n=30 for each group). Two polymorphisms, c. - 608A>G and c. - 418T>A, were revealed with reverse allele distribution in the two groups. The two polymorphisms were completely linked and formed only G-A or A-T haplotypes when genotyped in a larger population (n=526). Furthermore, we found that the G-A/G-A genotype was associated with higher HDL and ABCA1 mRNA level than A-T/A-T genotype. Luciferase assay also revealed that G-A haplotype promoter had higher activity than A-T haplotype. Single-nucleotide mutant assay showed that c.-418T>A was the causal mutation for ABCA1 transcription activity alteration. Conclusively, we identified two completely linked SNPs in porcine ABCA1 promoter region which have influence on the plasma HDL level by altering ABCA1 gene transcriptional activity. PMID:25445391

  8. Evaluation of molecular genetic alterations associated with tumor progression in a case of gliomatosis cerebri.

    PubMed

    Braeuninger, Stefan; Schneider-Stock, Regine; Kirches, Elmar; Powers, James M; Korones, David N; Mawrin, Christian

    2007-03-01

    Gliomatosis cerebri (GC) is a rare tumor characterized by widespread infiltration of the brain and spinal cord. Although GC usually demonstrates histomorphological features of a low-grade tumor, the formation of secondary highly malignant tumor regions may occur. In order to reveal molecular genetic changes associated with tumor progression in GC, we analyzed factors known to be associated with malignant progression in common astocytomas in an unusual GC case of an 18-year-old patient suffering from this disease for almost 7 years. We detected allelic losses in the Rb gene and in exon 4 of the TP53 gene in a tumor region corresponding to a glioblastoma multiforme. EGFR or MDM2 gene amplifications were absent, and no PTEN mutation or allelic loss on chromosome 10 could be detected. Moreover, compared to tumor-free brain tissue of this patient, tumor regions showed increased EGFR expression. These findings show that malignant progression in GC might be associated with the acquisition of molecular genetic changes also found in low-grade astrocytomas with progression to secondary glioblastoma. These data support the notion that GC can be regarded as a subtype of a common astrocytoma. PMID:16955219

  9. Altered memory-related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer's disease.

    PubMed

    Harrison, Theresa M; Burggren, Alison C; Small, Gary W; Bookheimer, Susan Y

    2016-01-01

    The hippocampal complex is affected early in Alzheimer's disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOE?4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired-associates memory task to examine differences in task-dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOE?4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOE?4-mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context-dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOE?4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOE?4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOE?4 and are consistent with the anterior-to-posterior theory of AD progression in the hippocampus. Hum Brain Mapp 37:366-380, 2016. 2015 Wiley Periodicals, Inc. PMID:26503161

  10. Does Wheat Genetically Modified for Disease Resistance Affect Root-Colonizing Pseudomonads and Arbuscular Mycorrhizal Fungi?

    PubMed Central

    Foetzki, Andrea; Luginbühl, Carolin; Winzeler, Michael; Kneubühler, Yvan; Matasci, Caterina; Mascher-Frutschi, Fabio; Kalinina, Olena; Boller, Thomas; Keel, Christoph; Maurhofer, Monika

    2013-01-01

    This study aimed to evaluate the impact of genetically modified (GM) wheat with introduced pm3b mildew resistance transgene, on two types of root-colonizing microorganisms, namely pseudomonads and arbuscular mycorrhizal fungi (AMF). Our investigations were carried out in field trials over three field seasons and at two locations. Serial dilution in selective King's B medium and microscopy were used to assess the abundance of cultivable pseudomonads and AMF, respectively. We developed a denaturing gradient gel electrophoresis (DGGE) method to characterize the diversity of the pqqC gene, which is involved in Pseudomonas phosphate solubilization. A major result was that in the first field season Pseudomonas abundances and diversity on roots of GM pm3b lines, but also on non-GM sister lines were different from those of the parental lines and conventional wheat cultivars. This indicates a strong effect of the procedures by which these plants were created, as GM and sister lines were generated via tissue cultures and propagated in the greenhouse. Moreover, Pseudomonas population sizes and DGGE profiles varied considerably between individual GM lines with different genomic locations of the pm3b transgene. At individual time points, differences in Pseudomonas and AMF accumulation between GM and control lines were detected, but they were not consistent and much less pronounced than differences detected between young and old plants, different conventional wheat cultivars or at different locations and field seasons. Thus, we conclude that impacts of GM wheat on plant-beneficial root-colonizing microorganisms are minor and not of ecological importance. The cultivation-independent pqqC-DGGE approach proved to be a useful tool for monitoring the dynamics of Pseudomonas populations in a wheat field and even sensitive enough for detecting population responses to altered plant physiology. PMID:23372672

  11. 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

  12. Detecting Somatic Genetic Alterations in Tumor Specimens by Exon Capture and Massively Parallel Sequencing

    PubMed Central

    Won, Helen H; Scott, Sasinya N; Brannon, A. Rose; Shah, Ronak H; Berger, Michael F

    2013-01-01

    Efforts to detect and investigate key oncogenic mutations have proven valuable to facilitate the appropriate treatment for cancer patients. The establishment of high-throughput, massively parallel "next-generation" sequencing has aided the discovery of many such mutations. To enhance the clinical and translational utility of this technology, platforms must be high-throughput, cost-effective, and compatible with formalin-fixed paraffin embedded (FFPE) tissue samples that may yield small amounts of degraded or damaged DNA. Here, we describe the preparation of barcoded and multiplexed DNA libraries followed by hybridization-based capture of targeted exons for the detection of cancer-associated mutations in fresh frozen and FFPE tumors by massively parallel sequencing. This method enables the identification of sequence mutations, copy number alterations, and select structural rearrangements involving all targeted genes. Targeted exon sequencing offers the benefits of high throughput, low cost, and deep sequence coverage, thus conferring high sensitivity for detecting low frequency mutations. PMID:24192750

  13. 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.

  14. The role of genetic and epigenetic alterations in neuroblastoma disease pathogenesis.

    PubMed

    Domingo-Fernandez, Raquel; Watters, Karen; Piskareva, Olga; Stallings, Raymond L; Bray, Isabella

    2013-02-01

    Neuroblastoma is a highly heterogeneous tumor accounting for 15% of all pediatric cancer deaths. Clinical behavior ranges from the spontaneous regression of localized, asymptomatic tumors, as well as metastasized tumors in infants, to rapid progression and resistance to therapy. Genomic amplification of the MYCN oncogene has been used to predict outcome in neuroblastoma for over 30years, however, recent methodological advances including miRNA and mRNA profiling, comparative genomic hybridization (array-CGH), and whole-genome sequencing have enabled the detailed analysis of the neuroblastoma genome, leading to the identification of new prognostic markers and better patient stratification. In this review, we will describe the main genetic factors responsible for these diverse clinical phenotypes in neuroblastoma, the chronology of their discovery, and the impact on patient prognosis. PMID:23274701

  15. 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. PMID:25647260

  16. Developmental, transcriptome, and genetic alterations associated with parthenocarpy in the grapevine seedless somatic variant Corinto bianco.

    PubMed

    Royo, Carolina; Carbonell-Bejerano, Pablo; Torres-Pérez, Rafael; Nebish, Anna; Martínez, Óscar; Rey, Manuel; Aroutiounian, Rouben; Ibáñez, Javier; Martínez-Zapater, José M

    2016-01-01

    Seedlessness is a relevant trait in grapevine cultivars intended for fresh consumption or raisin production. Previous DNA marker analysis indicated that Corinto bianco (CB) is a parthenocarpic somatic variant of the seeded cultivar Pedro Ximenes (PX). This study compared both variant lines to determine the basis of this parthenocarpic phenotype. At maturity, CB seedless berries were 6-fold smaller than PX berries. The macrogametophyte was absent from CB ovules, and CB was also pollen sterile. Occasionally, one seed developed in 1.6% of CB berries. Microsatellite genotyping and flow cytometry analyses of seedlings generated from these seeds showed that most CB viable seeds were formed by fertilization of unreduced gametes generated by meiotic diplospory, a process that has not been described previously in grapevine. Microarray and RNA-sequencing analyses identified 1958 genes that were differentially expressed between CB and PX developing flowers. Genes downregulated in CB were enriched in gametophyte-preferentially expressed transcripts, indicating the absence of regular post-meiotic germline development in CB. RNA-sequencing was also used for genetic variant calling and 14 single-nucleotide polymorphisms distinguishing the CB and PX variant lines were detected. Among these, CB-specific polymorphisms were considered as candidate parthenocarpy-responsible mutations, including a putative deleterious substitution in a HAL2-like protein. Collectively, these results revealed that the absence of a mature macrogametophyte, probably due to meiosis arrest, coupled with a process of fertilization-independent fruit growth, caused parthenocarpy in CB. This study provides a number of grapevine parthenocarpy-responsible candidate genes and shows how genomic approaches can shed light on the genetic origin of woody crop somatic variants. PMID:26454283

  17. The double-edged sword of genetic accounts of criminality: causal attributions from genetic ascriptions affect legal decision making.

    PubMed

    Cheung, Benjamin Y; Heine, Steven J

    2015-12-01

    Much debate exists surrounding the applicability of genetic information in the courtroom, making the psychological processes underlying how people consider this information important to explore. This article addresses how people think about different kinds of causal explanations in legal decision-making contexts. Three studies involving a total of 600 Mechanical Turk and university participants found that genetic, versus environmental, explanations of criminal behavior lead people to view the applicability of various defense claims differently, perceive the perpetrator's mental state differently, and draw different causal attributions. Moreover, mediation and path analyses highlight the double-edged nature of genetic attributions-they simultaneously reduce people's perception of the perpetrator's sense of control while increasing people's tendencies to attribute the cause to internal factors and to expect the perpetrator to reoffend. These countervailing relations, in turn, predict sentencing in opposite directions, although no overall differences in sentencing or ultimate verdicts were found. PMID:26498975

  18. Altered gravity affects ventral root activity during fictive swimming and the static vestibuloocular reflex in young tadpoles (Xenopus laevis).

    PubMed

    Böser, S; Dournon, C; Gualandris-Parisot, L; Horn, E

    2008-03-01

    During early periods of life, modifications of the gravitational environment affect the development of sensory, neuronal and motor systems. The vestibular system exerts significant effects on motor networks that control eye and body posture as well as swimming. The objective of the present study was to study whether altered gravity (AG) affects vestibuloocular and spinal motor systems in a correlated manner. During the French Soyuz taxi flight Andromède to the International Space Station ISS (launch: October 21, 2001; landing: October 31, 2001) Xenopus laevis embryos were exposed for 10 days to microgravity (microg). In addition, a similar experiment with 3g-hypergravity (3g) was performed in the laboratory. At onset of AG, embryos had reached developmental stages 24 to 27. After exposure to AG, each tadpole was tested for its roll-induced vestibuloocular reflex (rVOR) and 3 hours later it was tested for the neuronal activity recorded from the ventral roots (VR) during fictive swimming. During the post-AG recording periods tadpoles had reached developmental stages 45 to 47. It was observed that microgravity affected VR activity during fictive swimming and rVOR. In particular, VR activity changes included a significant decrease of the rostrocaudal delay and a significant increase of episode duration. The rVOR-amplitude was transiently depressed. Hypergravity was less effective on the locomotor pattern; occurring effects on fictive swimming were the opposite of microg effects. As after microgravity, the rVOR was depressed after 3g-exposure. All modifications of the rVOR and VR-activity recovered to normal levels within 4 to 7 days after termination of AG. Significant correlations between the rVOR amplitude and VR activity of respective tadpoles during the recording period have been observed in both tadpoles with or without AG experience. The data are consistent with the assumptions that during this period of life which is characterized by a progressive development of vestibuloocular and vestibulospinal projections (i) microgravity retards the development of VR activity while hypergravity weakly accelerates it; (ii) that microgravity retards the rVOR development while hypergravity caused a sensitization, and that (iii) AG-induced changes of VR activity during fictive swimming have a vestibular origin. PMID:18666444

  19. 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

  20. Transcriptome Profiling of Human Ulcerative Colitis Mucosa Reveals Altered Expression of Pathways Enriched in Genetic Susceptibility Loci

    PubMed Central

    Li, Jin; Zhu, Junfei; Gu, Mengnan; Baldassano, Robert N.; Grant, Struan F. A.; Hakonarson, Hakon

    2014-01-01

    Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P?=?1.491019). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process. PMID:24788701

  1. 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

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

    PubMed

    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

  3. 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

  4. The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice

    PubMed Central

    Niu, Haitao; Fang, Guoqiang; Tang, Yiting; Xie, Luokun; Yang, Huan; Morel, Laurence; Diamond, Betty

    2013-01-01

    Hematopoietic stem cells (HSCs) are protected in a metabolically dormant state within the bone marrow stem cell niche. Inflammation has been shown to disrupt HSC dormancy and cause multiple functional changes. Here, we investigated whether HSC functions were altered in systemic lupus erythematosus (SLE)-prone mice and whether this contributed to clinical manifestations of SLE. We found that HSCs were significantly expanded in lupus mice. The increase in HSC cellularity was caused by both genetic lupus risk factors and inflammatory cytokines in lupus mice. In addition, the inflammatory conditions of lupus led to HSC mobilization and lineage-biased hematopoiesis. Strikingly, these functionally altered HSCs possessed robust self-renewal capacity and exhibited repopulating advantages over wild-type HSCs. A single-nucleotide polymorphism in the cdkn2c gene encoding p18INK4c within a SLE susceptibility locus was found to account for reduced p18INK4c expression and the increase in HSC self-renewal capacity in lupus mice. Lupus HSCs with enhanced self-renewal capacity and resistance to stress may compete out transplanted healthy HSCs, thereby leading to relapses after HSC transplantation. PMID:23315165

  5. Genetics of mutations affecting the development of a barley floral bract.

    PubMed Central

    Pozzi, C; Faccioli, P; Terzi, V; Stanca, A M; Cerioli, S; Castiglioni, P; Fink, R; Capone, R; Müller, K J; Bossinger, G; Rohde, W; Salamini, F

    2000-01-01

    Two groups of mutants that affect the morphology of the lemma, a floral bract of barley, are described. The first comprises phenotypes associated with mutant alleles of calcaroides loci. On the lemma of these mutants, a well-organized neomorphic structure is formed, termed the sac. We provide a morphological description of wild-type (WT) and mutant lemmas, based on scanning electron microscopy (SEM), showing that both consist of similar tissues, but that the mutant is characterized by reversed growth polarity. The sac is a unique structure among grasses, and it is remarkable that recessive mutations at five different genetic loci lead to the same organ. The second group of mutants carry recessive alleles of two leafy lemma genes, both of which are necessary to cause the transformation of the lemma into a structure having all characteristics of a vegetative leaf, as shown by SEM analysis. The presence of sheath, blade, and ligule in the mutant lemma suggests that wild-type lemma development is interrupted at a leaf-like stage. The genes cal a, b, C, d, 23, lel1, and lel2 have now been mapped at precise positions on linkage groups 2, 7, 7, 3, 7, 5, and 7, respectively. The mutants considered in this article are unaffected in other floral organs. A model for lemma development is suggested. PMID:10757774

  6. Citrus Leaf Volatiles as Affected by Developmental Stage and Genetic Type

    PubMed Central

    Azam, Muhammad; Jiang, Qian; Zhang, Bo; Xu, Changjie; Chen, Kunsong

    2013-01-01

    Major volatiles from young and mature leaves of different citrus types were analyzed by headspace-solid phase microextraction (HS-SPME)-GC-MS. A total of 123 components were identified form nine citrus cultivars, including nine aldehydes, 19 monoterpene hydrocarbons, 27 oxygenated monoterpenes, 43 sesquiterpene hydrocarbons, eight oxygenated sesquiterpenes, two ketones, six esters and nine miscellaneous. Young leaves produced higher amounts of volatiles than mature leaves in most cultivars. The percentage of aldehyde and monoterpene hydrocarbons increased, whilst oxygenated monoterpenes and sesquiterpenes compounds decreased during leaf development. Linalool was the most abundant compound in young leaves, whereas limonene was the chief component in mature ones. Notably, linalool content decreased, while limonene increased, during leaf development in most cultivars. Leaf volatiles were also affected by genetic types. A most abundant volatile in one or several genotypes can be absent in another one(s), such as limonene in young leaves of lemon vs. Satsuma mandarin and ?-terpinene in mature leaves of three genotypes vs. the other four. Compositional data was subjected to multivariate statistical analysis, and variations in leaf volatiles were identified and clustered into six groups. This research determining the relationship between production of major volatiles from different citrus varieties and leaf stages could be of use for industrial and culinary purposes. PMID:23994837

  7. Abundance and Genetic Diversity of nifH Gene Sequences in Anthropogenically Affected Brazilian Mangrove Sediments

    PubMed Central

    Dias, Armando Cavalcante Franco; Pereira e Silva, Michele de Cassia; Cotta, Simone Raposo; Dini-Andreote, Francisco; Soares, Fábio Lino; Salles, Joana Falcão; Azevedo, João Lúcio; van Elsas, Jan Dirk

    2012-01-01

    Although mangroves represent ecosystems of global importance, the genetic diversity and abundance of functional genes that are key to their functioning scarcely have been explored. Here, we present a survey based on the nifH gene across transects of sediments of two mangrove systems located along the coast line of São Paulo state (Brazil) which differed by degree of disturbance, i.e., an oil-spill-affected and an unaffected mangrove. The diazotrophic communities were assessed by denaturing gradient gel electrophoresis (DGGE), quantitative PCR (qPCR), and clone libraries. The nifH gene abundance was similar across the two mangrove sediment systems, as evidenced by qPCR. However, the nifH-based PCR-DGGE profiles revealed clear differences between the mangroves. Moreover, shifts in the nifH gene diversities were noted along the land-sea transect within the previously oiled mangrove. The nifH gene diversity depicted the presence of nitrogen-fixing bacteria affiliated with a wide range of taxa, encompassing members of the Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Firmicutes, and also a group of anaerobic sulfate-reducing bacteria. We also detected a unique mangrove-specific cluster of sequences denoted Mgv-nifH. Our results indicate that nitrogen-fixing bacterial guilds can be partially endemic to mangroves, and these communities are modulated by oil contamination, which has important implications for conservation strategies. PMID:22941088

  8. DNA ALTERATIONS

    EPA Science Inventory

    The exposure of an organism to genotoxic chemicals may induce a cascade of genetic events. nitially, structural alterations to DNA are formed. ext, the DNA damage is processed and subsequently expressed in mutant gene products. inally, diseases result from the genetic damage. he ...

  9. Detection of Genetically Altered Copper Levels in Drosophila Tissues by Synchrotron X-Ray Fluorescence Microscopy

    PubMed Central

    Lye, Jessica C.; Hwang, Joab E. C.; Paterson, David; de Jonge, Martin D.; Howard, Daryl L.; Burke, Richard

    2011-01-01

    Tissue-specific manipulation of known copper transport genes in Drosophila tissues results in phenotypes that are presumably due to an alteration in copper levels in the targeted cells. However direct confirmation of this has to date been technically challenging. Measures of cellular copper content such as expression levels of copper-responsive genes or cuproenzyme activity levels, while useful, are indirect. First-generation copper-sensitive fluorophores show promise but currently lack the sensitivity required to detect subtle changes in copper levels. Moreover such techniques do not provide information regarding other relevant biometals such as zinc or iron. Traditional techniques for measuring elemental composition such as inductively coupled plasma mass spectroscopy are not sensitive enough for use with the small tissue amounts available in Drosophila research. Here we present synchrotron x-ray fluorescence microscopy analysis of two different Drosophila tissues, the larval wing imaginal disc, and sectioned adult fly heads and show that this technique can be used to detect changes in tissue copper levels caused by targeted manipulation of known copper homeostasis genes. PMID:22053217

  10. 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.

  11. Medea selfish genetic elements as tools for altering traits of wild populations: a theoretical analysis.

    PubMed

    Ward, Catherine M; Su, Jessica T; Huang, Yunxin; Lloyd, Alun L; Gould, Fred; Hay, Bruce A

    2011-04-01

    One strategy for controlling transmission of insect-borne disease involves replacing the native insect population with transgenic animals unable to transmit disease. Population replacement requires a drive mechanism to ensure the rapid spread of linked transgenes, the presence of which may result in a fitness cost to carriers. Medea selfish genetic elements have the feature that when present in a female, only offspring that inherit the element survive, a behavior that can lead to spread. Here, we derive equations that describe the conditions under which Medea elements with a fitness cost will spread, and the equilibrium allele frequencies are achieved. Of particular importance, we show that whenever Medea spreads, the non-Medea genotype is driven out of the population, and we estimate the number of generations required to achieve this goal for Medea elements with different fitness costs and male-only introduction frequencies. Finally, we characterize two contexts in which Medea elements with fitness costs drive the non-Medea allele from the population: an autosomal element in which not all Medea-bearing progeny of a Medea-bearing mother survive, and an X-linked element in species in which X/Y individuals are male. Our results suggest that Medea elements can drive population replacement under a wide range of conditions. PMID:21062278

  12. Indirect genetic effects for growth rate in domestic pigs alter aggressive and manipulative biting behaviour.

    PubMed

    Camerlink, Irene; Ursinus, Winanda W; Bijma, Piter; Kemp, Bas; Bolhuis, J Elizabeth

    2015-01-01

    Indirect genetic effects (IGEs) are heritable effects of an individual on phenotypic values of others, and may result from social interactions. We determined the behavioural consequences of selection for IGEs for growth (IGEg) in pigs in a G E treatment design. Pigs (n = 480) were selected for high versus low IGEg with a contrast of 14 g average daily gain and were housed in either barren or straw-enriched pens (n = 80). High IGEg pigs showed from 8 to 23 weeks age 40% less aggressive biting (P = 0.006), 27% less ear biting (P = 0.03), and 40% less biting on enrichment material (P = 0.005). High IGEg pigs had a lower tail damage score (high 2.0; low 2.2; P = 0.004), and consumed 30 % less jute sacks (P = 0.002). Selection on high IGEg reduced biting behaviours additive to the, generally much larger, effects of straw-bedding (P < 0.01), with no G E interactions. These results show opportunities to reduce harmful biting behaviours in pigs. PMID:25227986

  13. Altered Intrathalamic GABAA Neurotransmission in a Mouse Model of a Human Genetic Absence Epilepsy Syndrome

    PubMed Central

    Zhou, Chengwen; Ding, Li; Deel, M. Elizabeth; Ferrick, Elizabeth A.; Emeson, Ronald B.; Gallagher, Martin J.

    2014-01-01

    We previously demonstrated that heterozygous deletion of Gabra1, the mouse homolog of the human absence epilepsy gene that encodes the GABAA receptor (GABAAR) ?1 subunit, causes absence seizures. We showed that cortex partially compensates for this deletion by increasing the cell surface expression of residual ?1 subunit and by increasing ?3 subunit expression. Absence seizures also involve two thalamic nuclei: the ventrobasal (VB) nucleus, which expresses only the ?1 and ?4 subtypes of GABAAR ? subunits, and the reticular (nRT) nucleus, which expresses only the ?3 subunit subtype. Here, we found that, unlike cortex, VB exhibited significantly reduced total and synaptic ?1 subunit expression. In addition, heterozygous ?1 subunit deletion substantially reduced miniature inhibitory postsynaptic current (mIPSC) peak amplitudes and frequency in VB. However, there was no change in expression of the extrasynaptic ?4 or ? subunits in VB and, unlike other models of absence epilepsy, no change in tonic GABAAR currents. Although heterozygous ?1 subunit knockout increased ?3 subunit expression in medial thalamic nuclei, it did not alter ?3 subunit expression in nRT. However, it did enlarge the presynaptic vesicular inhibitory amino acid transporter puncta and lengthen the time constant of mIPSC decay in nRT. We conclude that increased tonic GABAA currents are not necessary for absence seizures. In addition, heterozygous loss of ?1 subunit disinhibits VB by substantially reducing phasic GABAergic currents and surprisingly, it also increases nRT inhibition by prolonging phasic currents. The increased inhibition in nRT likely represents a partial compensation that helps reduce absence seizures. PMID:25447232

  14. 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; Amioso, 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. PMID:15609345

  15. SIRT6 dependent genetic and epigenetic alterations are associated with poor clinical outcome in HCC patients

    PubMed Central

    Marquardt, Jens U.; Fischer, Kerstin; Baus, Katharina; Kashyap, Anubha; Ma, Shengyun; Krupp, Markus; Linke, Matthias; Teufel, Andreas; Zechner, Ulrich; Strand, Dennis; Thorgeirsson, Snorri S.; Galle, Peter R.; Strand, Susanne

    2013-01-01

    Sirtuin 6 (SIRT6) is a member of the sirtuin family of NAD-dependent deacetylases. Genetic deletion of Sirt6 in mice results in a severe degenerative phenotype with impaired liver function and premature death. So far the role of SIRT6 in development and progression of hepatocellular carcinoma is unknown. We first investigated SIRT6 expression in 153 primary human liver cancers, normal and cirrhotic livers using microarray analysis. SIRT6 was significantly downregulated in both cirrhotic livers and cancer. A Sirt6 knock out (KO) gene expression signature was generated from primary hepatoctyes isolated from three week old Sirt6-deficient animals. Sirt6-deficient hepatocytes showed upregulation of established HCC-biomarkers Alpha-fetoprotein (Afp), Insulin-like growth factor 2 (Igf2), H19 and Glypican-3 (Gpc3). Furthermore decreased SIRT6 expression was observed in hepatoma cell lines that are known to be apoptosis insensitive. Re-expression of SIRT6 in HepG2 cells increased apoptosis sensitivity to CD95-stimulation or chemotherapy treatment. Loss of Sirt6 was characterized by oncogenic changes including global hypomethylation as well as metabolic changes including hypoglycemia and increased fat deposition. The hepatocyte-specific Sirt6-KO signature had prognostic impact and was enriched in patients with poorly differentiated tumors with high AFP levels as well as recurrent disease. Finally, we could demonstrate that the Sirt6-KO signature possessed a predictive value for tumors other than HCC, i.e. breast and lung cancer. Conclusion Loss of SIRT6 induces epigenetic changes which may be relevant to chronic liver diseases and HCC development. Downregulation of SIRT6 and genes dysregulated by loss of SIRT6 possess oncogenic effects in hepatocarcinogenesis. Our data demonstrate that deficiency in one epigenetic regulator predisposes a tumorigenic phenotype which ultimately has relevance for outcome of HCC and other cancer patients. PMID:23526469

  16. Ontogeny of Mouse Vestibulo-Ocular Reflex Following Genetic or Environmental Alteration of Gravity Sensing

    PubMed Central

    Beraneck, Mathieu; Bojados, Mickael; Le Sach, 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. PMID:22808156

  17. The cytochrome P450 2D6*10 genetic polymorphism alters postoperative analgesia

    PubMed Central

    Wei, Xiao-Bin; Xiao, Xi; Han, Zhou-Xin; Lin, Dan-Qin; Yu, Ping

    2015-01-01

    The present study was aimed to investigate the effects of the cytochrome P450 (CYP) 2D6*10 genetic polymorphism on postoperative patient-controlled morphine usage. A total of 114 patients were selected, and 102 patients completed the study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was used to determine the CYP2D6*10 genotype, and patients were categorized into three groups according to CYP2D6 genotype: heterozygous (m/w), wild-type homozygous (w/w), and mutant homozygous (m/m). Total morphine usage and visual analogue score (VAS) were determined 72 hours after the operation and compared across the three genotype groups. Statistical methods used to analyze results were the ?2 test, analysis of variance, and multiple linear regression analysis; P<0.05 was considered to be statistically significant. The cumulative use of morphine in the m/w group was significantly higher than that in the m/m group between T0.5 and T4h (P<0.05). There were no significant differences in the loading dose of morphine or VAS among the different genotypes within 72 hours of operation. Patients carrying the CYP2D6*10 m/w genotype required higher doses of morphine at T0.5~T4h compared to the m/m group, and therefore received a higher cumulative dose of morphine post-operation. This phenomenon may be due to a decreased ability to synthesize endogenous opioid peptide. PMID:25932231

  18. Diet- and Genetically-Induced Obesity Differentially Affect the Fecal Microbiome and Metabolome in Apc1638N Mice

    PubMed Central

    Parnell, Laurence D.; Iyer, Lakshmanan K.; Liu, Zhenhua; Kane, Anne V.; Chen, C-Y. Oliver; Tai, Albert K.; Bowman, Thomas A.; Obin, Martin S.; Mason, Joel B.; Greenberg, Andrew S.; Choi, Sang-Woon; Selhub, Jacob; Paul, Ligi; Crott, Jimmy W.

    2015-01-01

    Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on the intestinal microbiome and metabolome in a mouse model of CRC. Apc1638N mice were made obese by either high fat (HF) feeding or the presence of the Leprdb/db (DbDb) mutation. Intestinal tumors were quantified and stool microbiome and metabolome were profiled. Genetic obesity, and to a lesser extent HF feeding, promoted intestinal tumorigenesis. Each induced distinct microbial patterns: taxa enriched in HF were mostly Firmicutes (6 of 8) while those enriched in DbDb were split between Firmicutes (7 of 12) and Proteobacteria (5 of 12). Parabecteroides distasonis was lower in tumor-bearing mice and its abundance was inversely associated with colonic Il1b production (p<0.05). HF and genetic obesity altered the abundance of 49 and 40 fecal metabolites respectively, with 5 in common. Of these 5, adenosine was also lower in obese and in tumor-bearing mice (p<0.05) and its concentration was inversely associated with colonic Il1b and Tnf production (p<0.05). HF and genetic obesity differentially alter the intestinal microbiome and metabolome. A depletion of adenosine and P.distasonis in tumor-bearing mice could play a mechanistic role in tumor formation. Adenosine and P. distasonis have previously been shown to be anti-inflammatory in the colon and we postulate their reduction could promote tumorigenesis by de-repressing inflammation. PMID:26284788

  19. Selective Deletion of a Cell Cycle Checkpoint Kinase (ATR) Reduces Neurogenesis and Alters Responses in Rodent Models of Behavioral Affect

    PubMed Central

    Onksen, Jennifer L; Brown, Eric J; Blendy, Julie A

    2011-01-01

    Hippocampal function has been implicated in mood and anxiety disorders, as well as in the response to antidepressant (AD) treatment. However, the significance of new neurons in the therapeutic mechanism of ADs remains unclear. In this study, the proliferation of new neurons was inhibited through conditional deletion of ataxia telangeictasia-mutated and rad-3 related (ATR), a cell cycle checkpoint kinase, and cellular and behavioral outcomes following AD exposure were evaluated. ATR was conditionally deleted by microinjecting a Cre recombinase-expressing virus into the hippocampus of floxed-ATR mice. Behavioral assessment in multiple rodent models of affective state revealed anxiolytic-like behavior in the elevated zero maze, marble burying test, and novelty-induced hypophagia (NIH) test. The efficacy of chronic desipramine (DMI) treatment was evaluated in the NIH test, as this paradigm is thought to be sensitive to increases in neurogenesis by chronic AD exposure. Chronic exposure to DMI reduced hyponeophagia in the NIH test in control mice, whereas DMI had no behavioral effect in ATR-deleted mice. Although DMI did not alter cell proliferation in either group, it did produce a robust increase in dendritic spine density in control mice, indicative of enhanced neuronal plasticity. This effect of DMI on spine density was severely attenuated following ATR deletion. These findings demonstrate that reductions in basal neurogenesis produce an anxiolytic phenotype and reduce AD efficacy in behaviors requiring chronic exposure. Furthermore, attenuated capacity for synaptic remodeling may underlie these behaviors. ATR deletion may serve as a valuable model to study the various proposed roles of newborn neurons in the hippocampus. PMID:21248719

  20. Prawn Shell Chitosan Exhibits Anti-Obesogenic Potential through Alterations to Appetite, Affecting Feeding Behaviour and Satiety Signals In Vivo

    PubMed Central

    Egan, Áine M.; O’Doherty, John V.; Vigors, Stafford; Sweeney, Torres

    2016-01-01

    The crustacean shells-derived polysaccharide chitosan has received much attention for its anti-obesity potential. Dietary supplementation of chitosan has been linked with reductions in feed intake, suggesting a potential link between chitosan and appetite control. Hence the objective of this experiment was to investigate the appetite suppressing potential of prawn shell derived chitosan in a pig model. Pigs (70 ± 0.90 kg, 125 days of age, SD 2.0) were fed either T1) basal diet or T2) basal diet plus 1000 ppm chitosan (n = 20 gilts per group) for 63 days. The parameter categories which were assessed included performance, feeding behaviour, serum leptin concentrations and expression of genes influencing feeding behaviour in the small intestine, hypothalamus and adipose tissue. Pigs offered chitosan visited the feeder less times per day (P<0.001), had lower intake per visit (P<0.001), spent less time eating per day (P<0.001), had a lower eating rate (P<0.01) and had reduced feed intake and final body weight (P< 0.001) compared to animals offered the basal diet. There was a treatment (P<0.05) and time effect (P<0.05) on serum leptin concentrations in animals offered the chitosan diet compared to animals offered the basal diet. Pigs receiving dietary chitosan had an up-regulation in gene expression of growth hormone receptor (P<0.05), Peroxisome proliferator activated receptor gamma (P<0.01), neuromedin B (P<0.05), neuropeptide Y receptor 5 (P<0.05) in hypothalamic nuclei and neuropeptide Y (P<0.05) in the jejunum. Animals consuming chitosan had increased leptin expression in adipose tissue compared to pigs offered the basal diet (P<0.05). In conclusion, these data support the hypothesis that dietary prawn shell chitosan exhibits anti-obesogenic potential through alterations to appetite, and feeding behaviour affecting satiety signals in vivo. PMID:26901760

  1. Prawn Shell Chitosan Exhibits Anti-Obesogenic Potential through Alterations to Appetite, Affecting Feeding Behaviour and Satiety Signals In Vivo.

    PubMed

    Egan, Áine M; O'Doherty, John V; Vigors, Stafford; Sweeney, Torres

    2016-01-01

    The crustacean shells-derived polysaccharide chitosan has received much attention for its anti-obesity potential. Dietary supplementation of chitosan has been linked with reductions in feed intake, suggesting a potential link between chitosan and appetite control. Hence the objective of this experiment was to investigate the appetite suppressing potential of prawn shell derived chitosan in a pig model. Pigs (70 ± 0.90 kg, 125 days of age, SD 2.0) were fed either T1) basal diet or T2) basal diet plus 1000 ppm chitosan (n = 20 gilts per group) for 63 days. The parameter categories which were assessed included performance, feeding behaviour, serum leptin concentrations and expression of genes influencing feeding behaviour in the small intestine, hypothalamus and adipose tissue. Pigs offered chitosan visited the feeder less times per day (P<0.001), had lower intake per visit (P<0.001), spent less time eating per day (P<0.001), had a lower eating rate (P<0.01) and had reduced feed intake and final body weight (P< 0.001) compared to animals offered the basal diet. There was a treatment (P<0.05) and time effect (P<0.05) on serum leptin concentrations in animals offered the chitosan diet compared to animals offered the basal diet. Pigs receiving dietary chitosan had an up-regulation in gene expression of growth hormone receptor (P<0.05), Peroxisome proliferator activated receptor gamma (P<0.01), neuromedin B (P<0.05), neuropeptide Y receptor 5 (P<0.05) in hypothalamic nuclei and neuropeptide Y (P<0.05) in the jejunum. Animals consuming chitosan had increased leptin expression in adipose tissue compared to pigs offered the basal diet (P<0.05). In conclusion, these data support the hypothesis that dietary prawn shell chitosan exhibits anti-obesogenic potential through alterations to appetite, and feeding behaviour affecting satiety signals in vivo. PMID:26901760

  2. 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-?-linked acidic dipeptidase (NAALADase), folyl poly-?-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; 7.560.85ng/ml vs. 2.73045ng/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 association with autism and cancer while showing positive association with CAD and miscarriages. PMID:22310383

  3. Genetic merit for fertility traits in Holstein cows: V. Factors affecting circulating progesterone concentrations.

    PubMed

    Moore, S G; Scully, S; Browne, J A; Fair, T; Butler, S T

    2014-09-01

    This study investigated the factors affecting circulating progesterone (P4) concentrations in cows with similar genetic merit for milk production traits, but with extremes of good (Fert+) or poor (Fert-) genetic merit for fertility traits. Study 1: 28 cows were enrolled in an ovulation synchronization protocol at 61±13 (±standard deviation) days postpartum, and data are presented for 13 Fert+ and 9 Fert- cows that remained in the study. Progesterone concentrations were determined from d 0 to 9 (d 0=estrus) and on d 7, corpus luteum (CL) volume and blood flow area (BFA) were measured by B-mode and Doppler ultrasonography, respectively. Cows were administered PGF2α on d 7 in the p.m. and d 8 in the a.m. to regress the CL, and 2 controlled internal drug release devices were inserted per vaginum on d 8 in the a.m. Liver biopsies were collected on d 9 and hepatic mRNA abundance of genes involved in P4 catabolism was determined. On d 10, the controlled internal drug release inserts were removed and frequent blood samples were collected to measure the rate of decline in circulating P4. The Fert+ cows tended to have greater dry matter intake compared with Fert- cows (+0.79kg of dry matter/d), but similar milk production (29.82kg/d). After synchronized ovulation, the rate of increase in circulating P4 concentrations was greater in Fert+ cows compared with Fert- cows. No effect of genotype on CL volume was detected, but BFA was 42% greater in Fert+ cows compared with Fert- cows. The Fert- cows had greater mRNA abundance of cytochrome P450, family 3, subfamily A (CYP3A) compared with Fert+ cows, but the mRNA abundance of aldo-keto reductase family 1, member C1 (AKR1C1), AKR1C3, AKR1C4, and cytochrome P450, family 2, subfamily C (CYP2C) were similar. The half-life and metabolic clearance rate of P4 were similar in Fert+ cows and Fert- cows. Study 2: 23 cows were enrolled in an ovulation synchronization protocol at 55±7 (±standard deviation) d postpartum, and data are presented for 13 Fert+ and 8 Fert- cows that remained in the study. On d 4, 7, 10, and 13 (d 0=estrus), CL volume and BFA were measured as in study 1. Progesterone concentrations were measured from d 1 to 13. Corpus luteum volume was 41% greater in Fert+ cows compared with Fert- cows but no effect of genotype on BFA was detected. Mean circulating P4 concentrations were 79% greater in Fert+ cows compared with Fert- cows. Milk yield was similar in both genotypes. The results indicate that greater circulating P4 concentrations were primarily due to greater CL P4 synthetic capacity rather than differences in P4 clearance in this lactating cow genetic model of fertility. PMID:24952779

  4. Genetic variation in FOXP2 alters grey matter concentrations in schizophrenia patients.

    PubMed

    Španiel, Filip; Horáček, Jiří; Tintěra, Jaroslav; Ibrahim, Ibrahim; Novák, Tomáš; Čermák, Jan; Klírová, Monika; Höschl, Cyril

    2011-04-15

    FOXP2, the first gene known to be involved in the development of speech and language, can be considered to be, a priori, a candidate gene in schizophrenia, given the mounting evidence that the underlying core deficit in this disease could be a failure of structures relevant to normal language processing. To investigate the potential link between grey matter concentration (GMC) changes in patients with schizophrenia and the FOXP2 rs2396753 polymorphism previously reported to be associated with hallucinations in schizophrenia, we analysed high-resolution anatomical magnetic resonance images of 40 genotyped patients with schizophrenia and 36 healthy controls, using optimised voxel-based morphometry (VBM). Here we show that the common SNP rs2396753 (C>A) gene variant of the FOXP2 gene has significant effects on GMC in patients with schizophrenia, within regions of the brain known to be affected by this disease. Our data suggest that GMC reductions in schizophrenia may be driven by C allele carriers of the FOXP2 gene variant. PMID:21334420

  5. Biofortification of plants with altered antioxidant content and composition: genetic engineering strategies.

    PubMed

    Zhu, Changfu; Sanahuja, Georgina; Yuan, Dawei; Farr, Gemma; Arj, Gemma; Berman, Judit; Zorrilla-Lpez, Uxue; Banakar, Raviraj; Bai, Chao; Prez-Massot, Eduard; Bassie, Ludovic; Capell, Teresa; Christou, Paul

    2013-02-01

    Antioxidants are protective molecules that neutralize reactive oxygen species and prevent oxidative damage to cellular components such as membranes, proteins and nucleic acids, therefore reducing the rate of cell death and hence the effects of ageing and ageing-related diseases. The fortification of food with antioxidants represents an overlap between two diverse environments, namely fortification of staple foods with essential nutrients that happen to have antioxidant properties (e.g. vitamins C and E) and the fortification of luxury foods with health-promoting but non-essential antioxidants such as flavonoids as part of the nutraceuticals/functional foods industry. Although processed foods can be artificially fortified with vitamins, minerals and nutraceuticals, a more sustainable approach is to introduce the traits for such health-promoting compounds at source, an approach known as biofortification. Regardless of the target compound, the same challenges arise when considering the biofortification of plants with antioxidants, that is the need to modulate endogenous metabolic pathways to increase the production of specific antioxidants without affecting plant growth and development and without collateral effects on other metabolic pathways. These challenges become even more intricate as we move from the engineering of individual pathways to several pathways simultaneously. In this review, we consider the state of the art in antioxidant biofortification and discuss the challenges that remain to be overcome in the development of nutritionally complete and health-promoting functional foods. PMID:22970850

  6. Genetic background, and not ontogenetic effects, affects avian seasonal timing of reproduction.

    PubMed

    Gienapp, P; van Noordwijk, A J; Visser, M E

    2013-10-01

    Avian seasonal timing is a life-history trait with important fitness consequences and which is currently under directional selection due to climate change. To predict micro-evolution in this trait, it is crucial to properly estimate its heritability. Heritabilities are often estimated from pedigreed wild populations. As these are observational data, it leaves the possibility that the resemblance between related individuals is not due to shared genes but to ontogenetic effects; when the environment for the offspring provided by early laying pairs differs from that by late pairs and the laying dates of these offspring when they reproduce themselves is affected by this environment, this may lead to inflated heritability estimates. Using simulation studies, we first tested whether and how much such an early environmental effect can inflate heritability estimates from animal models, and we showed that pedigree structure determines by how much early environmental effects inflate heritability estimates. We then used data from a wild population of great tits (Parus major) to compare laying dates of females born early in the season in first broods and from sisters born much later, in second broods. These birds are raised under very different environmental conditions but have the same genetic background. The laying dates of first and second brood offspring do not differ when they reproduce themselves, clearly showing that ontogenetic effects are very small and hence, family resemblance in timing is due to genes. This finding is essential for the interpretation of the heritabilities reported from wild populations and for predicting micro-evolution in response to climate change. PMID:23837446

  7. THE ESTROGENIC AND ANTIANDROGENIC PESTICIDE METHOXYCHLOR ALTERS THE REPRODUCTIVE TRACT AND BEHAVIOR WITHOUT AFFECTING PITUITARY SIZE OR LH AND PROLACTIN SECRETION IN MALE RATS

    EPA Science Inventory

    The estrogenic and antiandrogenic pesticide methoxychlor alters the reproductive tract and behavior without affecting pituitary size or LH and prolactin secretion in male rats.

    Gray LE Jr, Ostby J, Cooper RL, Kelce WR.

    Endocrinology Branch, United States Environment...

  8. 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. PMID:22262880

  9. 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)...

  10. Prenatal genetic testing: an investigation of determining factors affecting the decision-making process.

    PubMed

    Pivetti, Monica; Melotti, Giannino

    2013-02-01

    Despite the increase in popularity of prenatal genetic testing, relatively little is known about the role psychological factors play in the decision-making process. In this analogue study, a sample of Italian female university students was used to investigate determining factors that predict the intention of undergoing prenatal genetic testing. Structural Equation Modelling was used to describe the dynamic interplay between knowledge, beliefs, attitudes and health-related behaviour such as prenatal genetic testing. Following the Theory of Reasoned Action, three dimensions predicted the intention to undergo prenatal genetic testing: the need for more scientific information, a positive attitude towards genetic testing, and the inclination to terminate pregnancy after receiving a positive test result. Results showed that less religious women tended to be more in favour of prenatal tests and in undertaking such tests. This preliminary study provides genetic counsellors and policy makers with a clearer picture of their clients' motives and attitudes behind the decision-making process of prenatal genetic testing, contributing to improving both the communication process between counsellors and their clients and the organization of genetic services. PMID:22477148

  11. How do reproductive skew and founder group size affect genetic diversity in reintroduced populations?

    PubMed

    Miller, K A; Nelson, N J; Smith, H G; Moore, J A

    2009-09-01

    Reduced genetic diversity can result in short-term decreases in fitness and reduced adaptive potential, which may lead to an increased extinction risk. Therefore, maintaining genetic variation is important for the short- and long-term success of reintroduced populations. Here, we evaluate how founder group size and variance in male reproductive success influence the long-term maintenance of genetic diversity after reintroduction. We used microsatellite data to quantify the loss of heterozygosity and allelic diversity in the founder groups from three reintroductions of tuatara (Sphenodon), the sole living representatives of the reptilian order Rhynchocephalia. We then estimated the maintenance of genetic diversity over 400 years (approximately 10 generations) using population viability analyses. Reproduction of tuatara is highly skewed, with as few as 30% of males mating across years. Predicted losses of heterozygosity over 10 generations were low (1-14%), and populations founded with more animals retained a greater proportion of the heterozygosity and allelic diversity of their source populations and founder groups. Greater male reproductive skew led to greater predicted losses of genetic diversity over 10 generations, but only accelerated the loss of genetic diversity at small population size (<250 animals). A reduction in reproductive skew at low density may facilitate the maintenance of genetic diversity in small reintroduced populations. If reproductive skew is high and density-independent, larger founder groups could be released to achieve genetic goals for management. PMID:19732338

  12. Response to Dietary Phosphate Deficiency is Affected by Genetic Background in Growing Pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Concern over the environmental impact of phosphate (P) excretion from pig production has led to reduced dietary P supplementation. To examine how genetics influence P utilization, 94 gilts sired by 2 genetic lines (PIC337 and PIC280) were fed either a P adequate diet (PA) or a 20% P deficient diet ...

  13. Does population size affect genetic diversity? A test with sympatric lizard species.

    PubMed

    Hague, M T J; Routman, E J

    2016-01-01

    Genetic diversity is a fundamental requirement for evolution and adaptation. Nonetheless, the forces that maintain patterns of genetic variation in wild populations are not completely understood. Neutral theory posits that genetic diversity will increase with a larger effective population size and the decreasing effects of drift. However, the lack of compelling evidence for a relationship between genetic diversity and population size in comparative studies has generated some skepticism over the degree that neutral sequence evolution drives overall patterns of diversity. The goal of this study was to measure genetic diversity among sympatric populations of related lizard species that differ in population size and other ecological factors. By sampling related species from a single geographic location, we aimed to reduce nuisance variance in genetic diversity owing to species differences, for example, in mutation rates or historical biogeography. We compared populations of zebra-tailed lizards and western banded geckos, which are abundant and short-lived, to chuckwallas and desert iguanas, which are less common and long-lived. We assessed population genetic diversity at three protein-coding loci for each species. Our results were consistent with the predictions of neutral theory, as the abundant species almost always had higher levels of haplotype diversity than the less common species. Higher population genetic diversity in the abundant species is likely due to a combination of demographic factors, including larger local population sizes (and presumably effective population sizes), faster generation times and high rates of gene flow with other populations. PMID:26306730

  14. 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

  15. Genetic background alters the severity and onset of neuromuscular disease caused by the loss of ubiquitin-specific protease 14 (usp14).

    PubMed

    Marshall, Andrea G; Watson, Jennifer A; Hallengren, Jada J; Walters, Brandon J; Dobrunz, Lynn E; Francillon, Ludwig; Wilson, Julie A; Phillips, Scott E; Wilson, Scott M

    2013-01-01

    In this study, we identified and characterized an N-ethyl-N-nitrosourea (ENU) induced mutation in Usp14 (nmf375) that leads to adult-onset neurological disease. The nmf375 mutation causes aberrant splicing of Usp14 mRNA, resulting in a 95% reduction in USP14. We previously showed that loss of USP14 in ataxia (ax (J)) mice results in reduced ubiquitin levels, motor endplate disease, Purkinje cell axonal dystrophy and decreased hippocampal paired pulse facilitation (PPF) during the first 4-6 weeks of life, and early postnatal lethality by two months of age. Although the loss of USP14 is comparable between the nmf375 and ax (J) mice, the nmf375 mice did not exhibit these ax (J) developmental abnormalities. However, by 12 weeks of age the nmf375 mutants present with ubiquitin depletion and motor endplate disease, indicating a continual role for USP14-mediated regulation of ubiquitin pools and neuromuscular junction (NMJ) structure in adult mice. The observation that motor endplate disease was only seen after ubiquitin depletion suggests that the preservation of NMJ structure requires the stable maintenance of synaptic ubiquitin pools. Differences in genetic background were shown to affect ubiquitin expression and dramatically alter the phenotypes caused by USP14 deficiency. PMID:24358326

  16. Comparison of genetic and epigenetic alterations at 11 tumor suppressor loci in pulmonary sclerosing hemangioma and adenocarcinoma.

    PubMed

    Lee, Hee Jin; Jang, Se Jin; Chun, Sung-Min; Park, Seung-Il; Kim, Dong Kwan; Choi, Jene

    2011-08-01

    Pulmonary sclerosing hemangioma (SH) is an unusual tumor of pneumocytic origin. Morphologically, SH can mimic pulmonary adenocarcinomas. Here, the authors compared genetic and epigenetic aberrations in SH with those in pulmonary adenocarcinoma. Clinicopathologic characteristics, microsatellite alterations, and CpG island methylation were analyzed in pulmonary SHs (n = 24) and adenocarcinomas (n = 34) to compare their patterns of molecular abnormalities. SHs were also analyzed immunohistochemically to characterize the expression status of proteins involved in basic biologic processes. The clinical presentation of SH cases was generally benign. Both cell types of SH stained positive for thyroid transcription factor 1 (TTF-1), epithelial membrane antigen (EMA), ?-catenin, E-cadherin, and vascular endothelial growth factor (VEGF). Allelic imbalances in D3S1283, D3S1234, D3S1300, D3S1285, TP53, D17S938, and D9S179 were less frequent in SH than in adenocarcinoma; rates of allelic imbalances in D20S170 and D21S1446 were not significantly different. In SH, CpG island methylation frequencies of p16(INK4a) (0.0%) and RASSF1A (12.5%) were significantly lower than those in adenocarcinoma (29.4% and 38.2%, respectively); the frequencies of HOX D9, D11, and D13 gene methylation in SH were 37.5%, 33.3%, and 33.3%, respectively. The results show that pulmonary SH and adenocarcinoma share similar genetic and epigenetic aberrations, but also exhibit significant differences, especially in tumor suppressor genes. PMID:21649526

  17. Plant species diversity and composition of experimental grasslands affect genetic differentiation of Lolium perenne populations.

    PubMed

    Nestmann, S; Sretenovic Rajicic, T; Dehmer, K J; Fischer, M; Schumacher, J; Roscher, C

    2011-05-01

    Contrasting hypotheses exist about the relationship between plant species diversity and genetic diversity. However, experimental data of species diversity effects on genetic differentiation among populations are lacking. To address this, Lolium perenne was sown with an equal number of seeds in 78 experimental grasslands (Jena Experiment) varying in species richness (1, 2, 4, 8 to 16) and functional group richness and composition (1-4; grasses, legumes, small herbs, tall herbs). Population sizes were determined 4years after sowing, and single-nucleotide polymorphism (SNP) DNA markers based on bulk samples of up to 100 individuals per population were applied. Genetic distances between the field populations and the initially sown seed population increased with sown species richness. The degree of genetic differentiation from the original seed population was largely explained by actual population sizes, which suggests that genetic drift was the main driver of differentiation. Weak relationships among relative allele frequencies and species diversity or actual population sizes, and a positive correlation between actual population sizes and expected heterozygosity also supported the role of genetic drift. Functional composition had additional effects on genetic differentiation of L. perenne populations, indicating a selection because of genotype-specific interactions with other species. Our study supports that genetic diversity is likely to be lower in plant communities with a higher number of interspecific competitors. Negative effects of species richness on population sizes may increase the probability of genetic drift, and selection because of genotype-specific interactions depending on species and genotypic community composition may modulate this relationship. PMID:21352387

  18. Prozac affects stickleback nest quality without altering androgen, spiggin or aggression levels during a 21-day breeding test.

    PubMed

    Sebire, Marion; Elphinstone Davis, Jessica; Hatfield, Robert; Winberg, Svante; Katsiadaki, Ioanna

    2015-11-01

    Pharmaceuticals are increasingly being used in human and veterinary medicine, and their presence in the aquatic environment may present a threat to non-target aquatic organisms. The selective serotonin reuptake inhibitor fluoxetine (Prozac) has been reported to affect diverse behaviours (feeding, aggression, and reproduction) and also the endocrine system (steroid biosynthesis pathway) in fish. To investigate these claims further, and in particular effects on androgen synthesis, male three-spined sticklebacks (Gasterosteus aculeatus) were exposed to fluoxetine at 0, 3.2, 10 and 32μg/L in a flow-through system for 21 days. Their sex was determined prior to exposure using a non-invasive method to collect DNA for determining the genetic sex, reported here for the first time. This was necessary as the exposure required males of a non-breeding status which had not developed secondary characteristics. Post exposure a number of biochemical (serotonin, steroid and spiggin levels) and apical (aggressive behaviour) endpoints were measured. No effects were detected on morphometric parameters, spiggin or androgen (11-ketotestosterone) levels. However, all fluoxetine-exposed male fish had higher cortisol levels in comparison to the control fish, although this effect only persisted throughout the whole exposure duration at the highest concentration (32μg/L). In addition, the ratio of 5-HIAA/5-HT (serotonin metabolite/serotonin) was significantly lower in the brains of males exposed to fluoxetine at all concentrations tested. Although we found no differences in the number of nests built by the males, the quality of the nests produced by the fluoxetine-exposed males was generally inferior consisting only of a basic, rudimentary structure. Males exposed to 32μg/L of fluoxetine displayed a delayed response to a simulated threat (rival male via own mirror image) and were less aggressive (number of bites and attacks) toward their mirror image, but these differences were not statistically significant. In summary, fluoxetine exposure resulted in reduced serotonergic activity in the male three-spined stickleback brain suggesting that the mechanism of action between humans and fish is at least partially conserved. Furthermore, this study provided additional evidence of cross-talk between the serotonergic and stress axes as demonstrated by the perturbations in cortisol levels. This potentially complex interaction at brain level may be responsible for the effects observed on nest quality, an endpoint with serious ecological consequences for this species. Finally, despite our hypothesis (an effect on steroid biosynthesis, based on limited literature evidence), we observed no effects of fluoxetine exposure (at the concentrations and duration employed) on male stickleback androgen levels. PMID:26453812

  19. Conservation of Forest Biodiversity: how sample size affects the estimation of genetic parameters.

    PubMed

    Costa, Leonardo S da; Corneleo, Nathana S; Stefenon, Valdir M

    2015-01-01

    Efficient designs are crucial for population genetic studies on forest species. In this study we employed individual based simulations aiming to evaluate what fraction of a population should be sampled to obtain confident estimations of allelic richness and of inbreeding coefficient in population genetic surveys. The simulations suggest that at least 10% of the total population has to be sampled to ensure reliable estimations of allelic richness and inbreeding coefficient. This approach will allow the confidence of the genetic parameters estimations of a larger number of populations, based on a minimal sample within each one. PMID:26062111

  20. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive–compulsive disorder as an example of overlapping clinical and genetic heterogeneity

    PubMed Central

    Murphy, Dennis L.; Moya, Pablo R.; Fox, Meredith A.; Rubenstein, Liza M.; Wendland, Jens R.; Timpano, Kiara R.

    2013-01-01

    Individuals with obsessive–compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders. PMID:23440468

  1. A Surface Biotinylation Strategy for Reproducible Plasma Membrane Protein Purification and Tracking of Genetic and Drug-Induced Alterations.

    PubMed

    Hrmann, Katrin; Stukalov, Alexey; Mller, Andr C; Heinz, Leonhard X; Superti-Furga, Giulio; Colinge, Jacques; Bennett, Keiryn L

    2016-02-01

    Plasma membrane (PM) proteins contribute to the identity of a cell, mediate contact and communication, and account for more than two-thirds of known drug targets.1-8 In the past years, several protocols for the proteomic profiling of PM proteins have been described. Nevertheless, comparative analyses have mainly focused on different variations of one approach.9-11 We compared sulfo-NHS-SS-biotinylation, aminooxy-biotinylation, and surface coating with silica beads to isolate PM proteins for subsequent analysis by one-dimensional gel-free liquid chromatography mass spectrometry. Absolute and relative numbers of PM proteins and reproducibility parameters on a qualitative and quantitative level were assessed. Sulfo-NHS-SS-biotinylation outperformed aminooxy-biotinylation and surface coating using silica beads for most of the monitored criteria. We further simplified this procedure by a competitive biotin elution strategy achieving an average PM annotated protein fraction of 54% (347 proteins). Computational analysis using additional databases and prediction tools revealed that in total over 90% of the purified proteins were associated with the PM, mostly as interactors. The modified sulfo-NHS-SS-biotinylation protocol was validated by tracking changes in the plasma membrane proteome composition induced by genetic alteration and drug treatment. Glycosylphosphatidylinositol (GPI)-anchored proteins were depleted in PM purifications from cells deficient in the GPI transamidase component PIGS, and treatment of cells with tunicamycin significantly reduced the abundance of N-glycoproteins in surface purifications. PMID:26699813

  2. 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.

  3. Genetic deletion of Rheb1 in the brain reduces food intake and causes hypoglycemia with altered peripheral metabolism.

    PubMed

    Yang, Wanchun; Jiang, Wanxiang; Luo, Liping; Bu, Jicheng; Pang, Dejiang; Wei, Jing; Du, Chongyangzi; Xia, Xiaoqiang; Cui, Yiyuan; Liu, Shuang; Mao, Qing; Chen, Mina

    2014-01-01

    Excessive food/energy intake is linked to obesity and metabolic disorders, such as diabetes. The hypothalamus in the brain plays a critical role in the control of food intake and peripheral metabolism. The signaling pathways in hypothalamic neurons that regulate food intake and peripheral metabolism need to be better understood for developing pharmacological interventions to manage eating behavior and obesity. Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a master regulator of cellular metabolism in different cell types. Pharmacological manipulations of mTOR complex 1 (mTORC1) activity in hypothalamic neurons alter food intake and body weight. Our previous study identified Rheb1 (Ras homolog enriched in brain 1) as an essential activator of mTORC1 activity in the brain. Here we examine whether central Rheb1 regulates food intake and peripheral metabolism through mTORC1 signaling. We find that genetic deletion of Rheb1 in the brain causes a reduction in mTORC1 activity and impairs normal food intake. As a result, Rheb1 knockout mice exhibit hypoglycemia and increased lipid mobilization in adipose tissue and ketogenesis in the liver. Our work highlights the importance of central Rheb1 signaling in euglycemia and energy homeostasis in animals. PMID:24451134

  4. Genetic and epigenetic alterations of bone marrow stromal cells in myelodysplastic syndrome and acute myeloid leukemia patients.

    PubMed

    Kim, Yonggoo; Jekarl, Dong Wook; Kim, Jiyeon; Kwon, Ahlm; Choi, Hayoung; Lee, Seungok; Kim, Yoo-Jin; Kim, Hee-Je; Kim, Yonghwan; Oh, Il-Hoan; Kim, Myungshin

    2015-03-01

    We evaluated the characteristics of bone marrow stromal cells (BMSCs) and hematopoietic cells (HCs) from patients of myelodysplastic syndrome (MDS, n=21) and acute myeloid leukemia (AML, n=58), and compared the results with control BMSCs derived from healthy donors (n=8). The patient BMSCs had lower proliferative activity than that of the controls due to increased senescence. This retarded proliferation induced failure to obtain enough metaphase cells for karyotyping in patient BMSCs (10%). Patient BMSCs were genetically altered which was demonstrated by chromosome abnormalities in 5% of the patients (one MDS and three AML), whereas no clonal abnormalities were detected in the controls. The most common abnormality of the BMSCs was an extra chromosome 5, followed by an extra chromosome 7 and balanced translocations. The proportion of the abnormal metaphase cells was low (17.8%). We also analyzed the epigenetic changes of long interspersed nucleotide element 1 (LINE-1) repetitive element and CDKN2B using pyrosequencing. The quantitative measurement of global LINE-1 methylation demonstrated that patient BMSCs revealed global hypomethylation (68.23.8) compared with controls (72.93.4, P<0.001) and that the global hypomethylation of BMSCs were more significant in AML than in MDS patients (67.93.8, 69.44.2, respectively). These findings seem worthy of further evaluation of their association with ineffective hematopoiesis and leukemogenesis. PMID:25665922

  5. Genetic structure of a phytophagous mite species affected by crop practices: the case of Tetranychus urticae in clementine mandarins.

    PubMed

    Pascual-Ruiz, S; Gmez-Martinez, M A; Ansaloni, T; Segarra-Moragues, J G; Sabater-Muoz, B; Jacas, J A; Hurtado-Ruiz, M A

    2014-04-01

    Tetranychus urticae Koch is a cosmopolitan mite considered as the most polyphagous species among spider mites. This mite is a key pest of clementine mandarins in Eastern Spain, where Spanish clementine production concentrates. Crop management practices can affect the population dynamics of this mite and, consequently, its impact on the orchard. Microsatellite markers were used to study mite population genetics from two commercial orchards which had been managed differently following Integrated Pest Management (IPM) or Organic Pest Management (OPM) schemes during four consecutive years. A multiplex system including 20 microsatellite loci was designed specifically and allowed an efficient and inexpensive genotyping of individual mites. We found that the IPM population had a stronger fluctuation of population structure and higher genetic diversity compared to OPM population. Thus, our study concludes that crop management has an impact on the population genetics of T. urticae which may be related to the alternation of some acaricides under IPM. PMID:24233157

  6. Genetic factors affecting gene transcription and catalytic activity of UDP-glucuronosyltransferases in human liver

    PubMed Central

    Liu, Wanqing; Ramrez, Jacqueline; Gamazon, Eric R.; Mirkov, Snezana; Chen, Peixian; Wu, Kehua; Sun, Chang; Cox, Nancy J.; Cook, Edwin; Das, Soma; Ratain, Mark J.

    2014-01-01

    The aim of this study was to discover cis- and trans-acting factors significantly affecting mRNA expression and catalytic activity of human hepatic UDP-glucuronosyltransferases (UGTs). Transcription levels of five major hepatic UGT1A (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) and five UGT2B (UGT2B4, UGT2B7, UGT2B10, UGT2B15 and UGT2B17) genes were quantified in human liver tissue samples (n = 125) using real-time PCR. Glucuronidation activities of 14 substrates were measured in 47 livers. We genotyped 167 tagSNPs (single-nucleotide polymorphisms) in UGT1A (n = 43) and UGT2B (n = 124), as well as the known functional UGT1A1*28 and UGT2B17 CNV (copy number variation) polymorphisms. Transcription levels of 15 transcription factors (TFs) known to regulate these UGTs were quantified. We found that UGT expression and activity were highly variable among the livers (median and range of coefficient of variations: 135%, 74217% and 52%, 39105%, respectively). CAR, PXR and ESR1 were found to be the most important trans-regulators of UGT transcription (median and range of correlation coefficients: 46%, 658%; 47%, 958%; and 52%, 2475%, respectively). Hepatic UGT activities were mainly determined by UGT gene transcription levels. Twenty-one polymorphisms were significantly (FDR-adjusted P < 0.05) associated with mRNA expression and/or activities of UGT1A1, UGT1A3 and UGT2B17. We found novel SNPs in the UGT2B17 CNV region accounting for variability in UGT2B17 gene transcription and testosterone glucuronidation rate, in addition to that attributable to the UGT2B17 CNV. Our study discovered novel pharmacogenetic markers and provided detailed insight into the genetic network regulating hepatic UGTs. PMID:24879639

  7. Carcinogenicity of dimethylarsinic acid in male F344 rats and genetic alterations in induced urinary bladder tumors.

    PubMed

    Wei, Min; Wanibuchi, Hideki; Morimura, Keiichirou; Iwai, Shuji; Yoshida, Kaoru; Endo, Ginji; Nakae, Dai; Fukushima, Shoji

    2002-08-01

    Arsenic is a well-documented human carcinogen, and contamination with this heavy metal is of global concern, presenting a major issue in environmental health. However, the mechanism by which arsenic induces cancer is unknown, in large part due to the lack of an appropriate animal model. In the present set of experiments, we focused on dimethylarsinic acid (DMA), a major metabolite of arsenic in most mammals including humans. We provide, for the first time, the full data, including detailed pathology, of the carcinogenicity of DMA in male F344 rats in a 2-year bioassay, along with the first assessment of the genetic alteration patterns in the induced rat urinary bladder tumors. Additionally, to test the hypothesis that reactive oxygen species (ROS) may play a role in DMA carcinogenesis, 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in urinary bladder was examined. In experiment 1, a total of 144 male F344 rats at 10 weeks of age were randomly divided into four groups that received DMA at concentrations of 0, 12.5, 50 and 200 p.p.m. in the drinking water, respectively, for 104 weeks. From weeks 97-104, urinary bladder tumors were observed in 8 of 31 and 12 of 31 rats in groups treated with 50 and 200 p.p.m. DMA, respectively, and the preneoplastic lesion, papillary or nodular hyperplasias (PN hyperplasia), was noted in 12 and 14 rats, respectively. DMA treatment did not cause tumors in other organs and no urinary bladder tumors or preneoplastic lesions were evident in the 0 and 12.5 p.p.m.-treated groups. Urinary levels of arsenicals increased significantly in a dose-responsive manner except for arsenobetaine (AsBe). DMA and trimethylarsine oxide (TMAO) were the major compounds detected in the urine, with small amounts of monomethylarsonic acid (MMA) and tetramethylarsonium (TeMa) also detected. Significantly increased 5-bromo-2'-deoxyuridine (BrdU) labeling indices were observed in the morphologically normal epithelium of the groups treated with 50 and 200 p.p.m. DMA. Mutation analysis showed that DMA-induced rat urinary bladder tumors had a low rate of H-ras mutations (2 of 20, 10%). No alterations of the p53, K-ras or beta-catenin genes were detected. Only one TCC (6%) demonstrated nuclear accumulation of p53 protein by immunohistochemistry. In 16 of 18 (89%) of the TTCs and 3 of 4 (75%) of the papillomas, decreased p27(kip1) expression could be demonstrated. Cyclin D1 overexpression was observed in 26 of 47 (55%) PN hyperplasias, 3 of 4 (75%) papillomas, and 10 of 18 (56%) TCCs. As a molecular marker of oxidative stress, increased COX-2 expression was noted in 17 of 18 (94%) TCCs, 4 of 4 (100%) papillomas, and 39 of 47 (83%) PN hyperplasias. In experiment 2, 8-OHdG formation in urinary bladder was significantly increased after treatment with 200 p.p.m. DMA in the drinking water for 2 weeks compared with the controls. The studies demonstrated DMA to be a carcinogen for the rat urinary bladder and suggested that DMA exposure may be relevant to the carcinogenic risk of inorganic arsenic in humans. Diverse genetic alterations observed in DMA-induced urinary bladder tumors imply that multiple genes are involved in stages of DMA-induced tumor development. Furthermore, generation of ROS is likely to play an important role in the early stages of DMA carcinogenesis. PMID:12151359

  8. Titanium Mass-balance Analysis of Paso Robles Soils: Elemental Gains and Losses as Affected by Acid Alteration Fluids

    NASA Technical Reports Server (NTRS)

    Sutter, Brad; Ming, Douglas W.

    2010-01-01

    The Columbia Hills soils have been exposed to aqueous alteration in alkaline [1] as well as acid conditions [2,3]. The Paso Robles class soils are bright soils that possess the highest S concentration of any soil measured on Mars [2]. Ferric-sulfate detection by Moessbauer analysis indicated that acid solutions were involved in forming these soils [4]. These soils are proposed to have formed by alteration of nearby rock by volcanic hydrothermal or fumarolic activity. The Paso Robles soils consist of the original Paso Robles-disturbed-Pasadena (PR-dist), Paso Robles- PasoLight (PR-PL), Arad-Samra, Arad-Hula, Tyrone- Berker Island1 and Tyrone-MountDarwin [2 ,3. ]Chemical characteristics indicate that the PR-dist and PR-PL soils could be derived from acid weathering of local Wishstone rocks while the Samra and Hula soils are likely derived from local Algonquin-Iroquet rock [3]. The Paso Robles soils were exposed to acidic sulfur bearing fluids; however, little else is known about the chemistry of the alteration fluid and its effects on the alteration of the proposed parent materials. The objectives of this work are to conduct titanium normalized mass-balance analysis to1) assess elemental gains and losses from the parent materials in the formation of the Paso Robles soils and 2) utilize this information to indicate the chemical nature of the alteration fluids.

  9. Genetics

    MedlinePLUS

    Homozygous; 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. Computational and genetic evidence that different structural conformations of a non-catalytic region affect the function of plant cellulose synthase

    PubMed Central

    Slabaugh, Erin; Sethaphong, Latsavongsakda; Xiao, Chaowen; Amick, Joshua; Anderson, Charles T.; Haigler, Candace H.; Yingling, Yaroslava G.

    2014-01-01

    The β-1,4-glucan chains comprising cellulose are synthesized by cellulose synthases in the plasma membranes of diverse organisms including bacteria and plants. Understanding structure–function relationships in the plant enzymes involved in cellulose synthesis (CESAs) is important because cellulose is the most abundant component in the plant cell wall, a key renewable biomaterial. Here, we explored the structure and function of the region encompassing transmembrane helices (TMHs) 5 and 6 in CESA using computational and genetic tools. Ab initio computational structure prediction revealed novel bi-modal structural conformations of the region between TMH5 and 6 that may affect CESA function. Here we present our computational findings on this region in three CESAs of Arabidopsis thaliana (AtCESA1, 3, and 6), the Atcesa3 ixr1-2 mutant, and a novel missense mutation in AtCESA1. A newly engineered point mutation in AtCESA1 (Atcesa1 F954L) that altered the structural conformation in silico resulted in a protein that was not fully functional in the temperature-sensitive Atcesa1 rsw1-1 mutant at the restrictive temperature. The combination of computational and genetic results provides evidence that the ability of the TMH5–6 region to adopt specific structural conformations is important for CESA function. PMID:25262226

  11. Computational and genetic evidence that different structural conformations of a non-catalytic region affect the function of plant cellulose synthase.

    PubMed

    Slabaugh, Erin; Sethaphong, Latsavongsakda; Xiao, Chaowen; Amick, Joshua; Anderson, Charles T; Haigler, Candace H; Yingling, Yaroslava G

    2014-12-01

    The ?-1,4-glucan chains comprising cellulose are synthesized by cellulose synthases in the plasma membranes of diverse organisms including bacteria and plants. Understanding structure-function relationships in the plant enzymes involved in cellulose synthesis (CESAs) is important because cellulose is the most abundant component in the plant cell wall, a key renewable biomaterial. Here, we explored the structure and function of the region encompassing transmembrane helices (TMHs) 5 and 6 in CESA using computational and genetic tools. Ab initio computational structure prediction revealed novel bi-modal structural conformations of the region between TMH5 and 6 that may affect CESA function. Here we present our computational findings on this region in three CESAs of Arabidopsis thaliana (AtCESA1, 3, and 6), the Atcesa3(ixr1-2) mutant, and a novel missense mutation in AtCESA1. A newly engineered point mutation in AtCESA1 (Atcesa1(F954L) ) that altered the structural conformation in silico resulted in a protein that was not fully functional in the temperature-sensitive Atcesa1(rsw1-1) mutant at the restrictive temperature. The combination of computational and genetic results provides evidence that the ability of the TMH5-6 region to adopt specific structural conformations is important for CESA function. PMID:25262226

  12. Autism spectrum disorders: a qualitative study of attitudes toward prenatal genetic testing and termination decisions of affected pregnancies.

    PubMed

    Chen, L S; Xu, L; Dhar, S U; Li, M; Talwar, D; Jung, E

    2015-08-01

    In the United States, prenatal genetic testing (PGT) for Autism Spectrum Disorders (ASD) is currently available via clinical genetic services. Such testing may inform parents about their unborn child's risk for ASD, prepare parents for the birth of an affected infant, and allow them to arrange for early interventions. Although PGT for autism has potential benefits, the associated ethical, legal, and social implications (ELSI) should be considered. This first qualitative study employed a hypothetical scenario to explore the attitudes toward PGT and termination decisions of 42 parents of children with ASD. Over half of the participants expressed willingness to undergo PGT for autism. Reasons included better preparation for birth, early and better treatment, termination of affected pregnancy, contribution to research, and curiosity. Of the 31 parents who were either willing or unsure about undergoing the PGT, approximately three-fourths would continue their hypothetical affected pregnancies. Explanations included preparation for birth of the child, bonding or acceptance of existing ASD-affected children, apprehensions about test limitations, and religious concerns. Parents who reported they would terminate the affected pregnancy in this hypothetical situation were primarily Asians. This study contributes to the growing understanding of the ELSI aspects of PGT in clinical practice. PMID:25251361

  13. Spinocerebellar Ataxia: Patient and Health Professional Perspectives on Whether and How Patents Affect Access to Clinical Genetic Testing

    PubMed Central

    Powell, Ashton; Chandrasekharan, Subhashini; Cook-Deegan, Robert

    2011-01-01

    Genetic testing for spinocerebellar ataxia (SCA) is used in diagnosis of rare movement disorders. Such testing generally does not affect treatment, but confirmation of mutations in a known gene can confirm diagnosis and end an often years-long quest for the cause of distressing and disabling symptoms. Through interviews and a web forum hosted by the National Ataxia Foundation, patients and health professionals related their experiences with patents impact on access to genetic testing for SCA. In the United States, Athena Diagnostics holds either a patent or an exclusive license to a patent in the case of 6 SCA variants (SCA1-3 & 6-8) and two other hereditary ataxias (Friedreichs Ataxia and Early Onset Ataxia). Athena has enforced its exclusive rights to SCA-related patents by sending cease and desist letters to multiple laboratories offering genetic testing for inherited neurological conditions, including SCA. Roughly half of web forum respondents had decided not to get genetic tests. Price, coverage and reimbursement by insurers and health plans, and fear of genetic discrimination were the main reasons cited for deciding not to get tested. Price was cited as an access concern by the physicians, and as sole US provider, coverage and reimbursement depend on having payment agreements between Athena and payers. In cases where payers do not reimburse, the patient is responsible for payment, although some patients can apply to the voluntary Athena Access and Patient Protection Programs offered by the company. PMID:20393313

  14. Spinocerebellar ataxia: patient and health professional perspectives on whether and how patents affect access to clinical genetic testing.

    PubMed

    Powell, Ashton; Chandrasekharan, Subhashini; Cook-Deegan, Robert

    2010-04-01

    Genetic testing for spinocerebellar ataxia is used in diagnosis of rare movement disorders. Such testing generally does not affect treatment, but confirmation of mutations in a known gene can confirm diagnosis and end an often years-long quest for the cause of distressing and disabling symptoms. Through interviews and a web forum hosted by the National Ataxia Foundation, patients and health professionals related their experiences with the effect of patents on access to genetic testing for spinocerebellar ataxia. In the United States, Athena Diagnostics holds either a patent or an exclusive license to a patent in the case of six spinocerebellar ataxia variants (spinocerebellar ataxia 1-3 and 6-8) and two other hereditary ataxias (Friedreich's Ataxia and Early Onset Ataxia). Athena has enforced its exclusive rights to spinocerebellar ataxia-related patents by sending notification letters to multiple laboratories offering genetic testing for inherited neurological conditions, including spinocerebellar ataxia. Roughly half of web forum respondents had decided not to get genetic tests. Price, coverage and reimbursement by insurers and health plans, and fear of genetic discrimination were the main reasons cited for deciding not to get tested. Price was cited as an access concern by the physicians, and as sole US provider, coverage and reimbursement depend on having payment agreements between Athena and payers. In cases in which payers do not reimburse, the patient is responsible for payment, although some patients can apply to the voluntary Athena Access and Patient Protection Plan offered by the company. PMID:20393313

  15. How do population genetic parameters affect germination of the heterocarpic species Atriplex tatarica (Amaranthaceae)?

    PubMed Central

    Kochnkov, Jana; Mandk, Bohumil

    2009-01-01

    Background and Aims The heterocarpic species Atriplex tatarica produces two types of seeds. In this study, how basic population genetic parameters correlate with seed germinability under various experimental conditions was tested. Methods Population genetic diversity was ascertained in eight populations of A. tatarica by assessing patterns of variation at nine allozyme loci. Germinability of both seed types from all sampled populations was determined by a common laboratory experiment under different salinity levels. Basic population genetic parameters, i.e. percentage of polymorphic loci, average number of alleles per locus and observed heterozygosity were correlated with observed population germination characteristics. Key Results Atriplex tatarica possesses a remarkable heterocarpy, i.e. one type of seed is non-dormant and the other shows different dormancy levels in relation to experimental conditions. Significant negative correlations have been detected between germination of both seed types and the coefficient of inbreeding, and a significant negative correlation between germination of dormant seeds and other population genetic parameters, i.e. percentage of polymorphic loci and average number of alleles per polymorphic locus. Moreover, populations from the region characterized by a shorter growing season manifested higher germinability, i.e. had lower dormancy, than those from the lower-latitude one. Conclusions In general, germination of non-dormant seeds is probably not under strong genetic control. Hence, they germinate as soon as conditions are favourable, thus ensuring survival in the short term, but populations risk local extinction if conditions become adverse (i.e. a high-risk strategy). In contrast, germination of the dormant type of seeds is under stronger genetic control and is significantly correlated with basic population genetic parameters. These seeds ensure long-term reproduction and survival in the field by protracted germination, albeit in low quantities (i.e. A. tatarica also adopts a low-risk strategy). PMID:19339299

  16. Pubertal Onset in Girls is Strongly Influenced by Genetic Variation Affecting FSH Action

    PubMed Central

    Hagen, Casper P.; Srensen, Kaspar; Aksglaede, Lise; Mouritsen, Annette; Mieritz, Mikkel G.; Tinggaard, Jeanette; Wohlfart-Veje, Christine; Petersen, Jrgen Holm; Main, Katharina M.; Meyts, Ewa Rajpert-De; Almstrup, Kristian; Juul, Anders

    2014-01-01

    Age at pubertal onset varies substantially in healthy girls. Although genetic factors are responsible for more than half of the phenotypic variation, only a small part has been attributed to specific genetic polymorphisms identified so far. Follicle-stimulating hormone (FSH) stimulates ovarian follicle maturation and estradiol synthesis which is responsible for breast development. We assessed the effect of three polymorphisms influencing FSH action on age at breast deveopment in a population-based cohort of 964 healthy girls. Girls homozygous for FSHR -29AA (reduced FSH receptor expression) entered puberty 7.4 (2.512.4) months later than carriers of the common variants FSHR -29GG+GA, p = 0.003. To our knowledge, this is the strongest genetic effect on age at pubertal onset in girls published to date. PMID:25231187

  17. The Genetics of Mexico Recapitulates Native American Substructure and Affects Biomedical Traits

    PubMed Central

    Moreno-Estrada, Andrés; Gignoux, Christopher R.; Fernández-López, Juan Carlos; Zakharia, Fouad; Sikora, Martin; Contreras, Alejandra V.; Acuña-Alonzo, Victor; Sandoval, Karla; Eng, Celeste; Romero-Hidalgo, Sandra; Ortiz-Tello, Patricia; Robles, Victoria; Kenny, Eimear E.; Nuño-Arana, Ismael; Barquera-Lozano, Rodrigo; Macín-Pérez, Gastón; Granados-Arriola, Julio; Huntsman, Scott; Galanter, Joshua M.; Via, Marc; Ford, Jean G.; Chapela, Rocío; Rodriguez-Cintron, William; Rodríguez-Santana, Jose R.; Romieu, Isabelle; Sienra-Monge, Juan José; Navarro, Blanca del Rio; London, Stephanie J.; Ruiz-Linares, Andrés; Garcia-Herrera, Rodrigo; Estrada, Karol; Hidalgo-Miranda, Alfredo; Jimenez-Sanchez, Gerardo; Carnevale, Alessandra; Soberón, Xavier; Canizales-Quinteros, Samuel; Rangel-Villalobos, Héctor; Silva-Zolezzi, Irma; Burchard, Esteban Gonzalez; Bustamante, Carlos D.

    2014-01-01

    Mexico harbors great cultural and ethnic diversity, yet fine-scale patterns of human genome-wide variation from this region remain largely uncharacterized. We studied genomic variation within Mexico from over 1,000 individuals representing 20 indigenous and 11 mestizo populations. We found striking genetic stratification among indigenous populations within Mexico at varying degrees of geographic isolation. Some groups were as differentiated as Europeans are from East Asians. Pre-Columbian genetic substructure is recapitulated in the indigenous ancestry of admixed mestizo individuals across the country. Furthermore, two independently phenotyped cohorts of Mexicans and Mexican Americans showed a significant association between sub-continental ancestry and lung function. Thus, accounting for fine-scale ancestry patterns is critical for medical and population genetic studies within Mexico, in Mexican-descent populations, and likely in many other populations worldwide. PMID:24926019

  18. Vocal production and playback of altered song do not affect ZENK expression in black-capped chickadees (Poecile atricapillus).

    PubMed

    Roach, Sean P; Lockyer, Ashley C; Yousef, Tareq; Mennill, Daniel J; Phillmore, Leslie S

    2016-02-01

    The two-note fee bee song of the black-capped chickadee (Poecile atricapillus) is sung at many different absolute frequencies, but the relative frequencies between the start and end of the fee note (the glissando) and between the fee and the bee notes (the inter-note ratio) are preserved regardless of absolute frequency. If these relative frequencies are experimentally manipulated, birds exhibit reduced behavioural responses to playback of altered songs both in field studies and laboratory studies. Interestingly, males appear to be sensitive to alterations in the glissando, while females appear to be sensitive to alterations in both the glissando and the inter-note ratio. In this study, we sought to determine whether the behaviour of male and female chickadees corresponds to differences in zenk protein immunoreactivity (ZENK-ir) in auditory perceptual regions following playback of fee bee songs with typical and altered pitch ratios. Overall, there was a small but significant sex difference in ZENK-ir (females>males), but altering relative frequencies did not reduce ZENK-ir compared to typical song. Birds did vocalize less in response to playback of songs that lacked an inter-note interval, but amount of singing fee bee song, chick-a-dee calls, or gargles was not correlated with ZENK-ir in perceptual regions (caudomedial nidopallium, NCM and caudomedial mesopallium, CMM) or in HVC, which is part of the song system. Our results confirm that ZENK-ir in NCM and CMM is not involved in fine-grain perceptual discrimination, however it did not support the idea that increased vocalizing increases ZENK-ir in HVC. PMID:26523856

  19. Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study.

    PubMed

    Friedrich, Juliane; Brand, Bodo; Ponsuksili, Siriluck; Graunke, Katharina L; Langbein, Jan; Knaust, Jacqueline; Khn, Christa; Schwerin, Manfred

    2016-02-01

    Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 CharolaisנGerman Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. PMID:26515756

  20. Can the Genetic Origin Affect Rabbit Seminal Plasma Protein Profile along the Year?

    PubMed

    Casares-Crespo, L; Talaván, A M; Viudes-de-Castro, M P

    2016-04-01

    The study was designed to evaluate the influence of genetic origin on rabbit seminal plasma protein profile variation along the year. Seminal plasma of rabbits from line A (maternal line) and R (paternal line) collected during a natural year was subjected to polyacrylamide gel electrophoresis (SDS-PAGE). The electrophoretic profile of rabbit seminal plasma resulted in multiple protein bands of different intensity ranging from 9 to 240 kDa. Results showed that seven protein bands were significantly different between genetic lines, and among these, three protein bands were significantly different between seasons. The differentially expressed proteins were identified by MALDI-TOF/TOF or LC-MS/MS analysis and were the following ones: FAM115E-like (220, 113 and 59 kDa), ectonucleoside triphosphate diphosphohydrolase 3 isoform X2 (72 kDa), annexin A5 (32 kDa), lipocalin allergen Ory c 4 precursor (19 kDa), and haemoglobin subunit zetalike (13 kDa) between genetic lines and FAM115E-like (113 kDa), haemoglobin subunit zetalike (13 kDa) and β-nerve growth factor (12 kDa) between seasons. These results indicate that proteins from rabbit seminal plasma are under both seasonal control and genetic control. Furthermore, the differential presence of these proteins could be one of the causes explaining the differences observed in fertility and seminal parameters between these two lines in earlier studies. PMID:26936775

  1. Genetic markers that influence feed efficiency phenotypes also affect cattle temperament as measured by flight speed

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The measure of flight speed for cattle has been shown to be a predictive indicator of temperament and has also been associated with feed efficiency phenotypes, thus, genetic markers associated with both traits may assist with the selection of animals with calmer disposition and economic value. Chrom...

  2. Alterations in lignin content and phenylpropanoids pathway in date palm (Phoenix dactylifera L.) tissues affected by brittle leaf disease.

    PubMed

    Saidi, Mohammed Najib; Bouaziz, Donia; Hammami, Ines; Namsi, Ahmed; Drira, Noureddine; Gargouri-Bouzid, Radhia

    2013-10-01

    Brittle leaf disease or Maladie de la Feuille Cassante (MFC) is a lethal disorder of date palm that has assumed epidemic proportions in the oases of Tunisia and Algeria. No pathogen could ever be associated with the disease, while leaflets of affected palms have been previously shown to be deficient in manganese. The work reported here aims to understand the biochemical basis of the date palm response to this disorder. Since the typical disease symptom is the leaf fragility, we have investigated lignin content in leaves and roots. Strong decrease in total lignin content was observed in affected leaves, while lignin content increased in affected roots. Histochemical analyses showed hyperlignification thicker suberin layer in roots cortical cells. The phenylpropanoids pathway was also disrupted in leaves and roots, cinnamoyl-CoA reductase and cinnamyl-alcohol dehydrogenase gene expression was affected by the disease which severely affects the cell wall integrity. PMID:23987806

  3. Ischemic Preconditioning Affects Long-Term Cell Fate through DNA DamageRelated Molecular Signaling and Altered Proliferation

    PubMed Central

    Kapoor, Sorabh; Berishvili, Ekaterine; Bandi, Sriram; Gupta, Sanjeev

    2015-01-01

    Despite the potential of ischemic preconditioning for organ protection, long-term effects in terms of molecular processes and cell fates are ill defined. We determined consequences of hepatic ischemic preconditioning in rats, including cell transplantation assays. Ischemic preconditioning induced persistent alterations; for example, after 5 days liver histology was normal, but ?-glutamyl transpeptidase expression was observed, with altered antioxidant enzyme content, lipid peroxidation, and oxidative DNA adducts. Nonetheless, ischemic preconditioning partially protected from toxic liver injury. Similarly, primary hepatocytes from donor livers preconditioned with ischemia exhibited undesirably altered antioxidant enzyme content and lipid peroxidation, but better withstood insults. However, donor hepatocytes from livers preconditioned with ischemia did not engraft better than hepatocytes from control livers. Moreover, proliferation of hepatocytes from donor livers preconditioned with ischemia decreased under liver repopulation conditions. Hepatocytes from donor livers preconditioned with ischemia showed oxidative DNA damage with expression of genes involved in MAPK signaling that impose G1/S and G2/M checkpoint restrictions, including p38 MAPKregulated or ERK-1/2regulated cell-cycle genes such as FOS, MAPK8, MYC, various cyclins, CDKN2A, CDKN2B, TP53, and RB1. Thus, although ischemic preconditioning allowed hepatocytes to better withstand secondary insults, accompanying DNA damage and molecular events simultaneously impaired their proliferation capacity over the long term. Mitigation of ischemic preconditioninginduced DNA damage and deleterious molecular perturbations holds promise for advancing clinical applications. PMID:25128377

  4. Negative Affect Shares Genetic and Environmental Influences with Symptoms of Childhood Internalizing and Externalizing Disorders

    ERIC Educational Resources Information Center

    Mikolajewski, Amy J.; Allan, Nicholas P.; Hart, Sara A.; Lonigan, Christopher J.; Taylor, Jeanette

    2013-01-01

    The co-occurrence of internalizing and externalizing disorders suggests that they may have common underlying vulnerability factors. Research has shown that negative affect is moderately positively correlated with both internalizing and externalizing disorders in children. The present study is the first to provide an examination of negative affect

  5. 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

    Formation of a thrombus at the site of an injured vessel requires the coordinated action of critical platelet plasma membrane adhesion molecules. The most important initial contact of platelets with the exposed endothelial collagen and von Willebrand factor (VWF) involves the binding of glycoprotein (GP) Ib{alpha} to immobilized VWF. The VWF-GPIb{alpha} interaction is ''fast-on'' and relatively ''fast-off,'' and results in a rolling of platelets along the exposed subendothelium. This slowing of the platelets allows binding of the activating collagen-receptor, GPVI, to its ligand, resulting in activation of platelet integrins and subsequent firm adhesion, where the reactions between receptor and ligand are relatively ''slow-on'' but irreversible. The binding of integrin {alpha}{sub 2} {beta}{sub 1} underlying firm adhesion. Intracellular signaling between and through these adhesive receptors plays a crucial role in platelet adhesion and aggregation. The importance of the GPIb-IX-V and {alpha}{sub IIb} {beta}{sub 3} in normal hemostasis is under scored by the bleeding diatheses that have been reported in patients with quantitative or qualitative deficiencies of the genes that encode them. Mouse models are now commonplace for studying hemostasis and thrombosis, and important insights pertaining to the major platelet adhesive receptors have been gleaned from mouse studies involving targeted disruptions of the genes for GPIb{alpha}, GPVI, and integrin chains 2,9,10 1,4 IIb 11 and 3.12 A variety of different mouse strains have been used to assess hemostasis. For example, the FVB strain is typically used for transgenic experiments, the 129/Sv strain is used to derive embryonic stem (ES) cells, and the C57 strain is used for uniform background breeding studies. Different strains may exhibit different levels of gene expression, a feature that has been used to elucidate crucial gene regions regulating transcription. We and others have previously studied how genetic changes 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.

  6. NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Maternal-effect mutations in NLRP7 cause rare biparentally inherited hydatidiform moles (BiHMs), abnormal pregnancies containing hypertrophic vesicular trophoblast but no embryo. BiHM trophoblasts display abnormal DNA methylation patterns affecting maternally methylated germline differentially methy...

  7. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

    PubMed

    Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J; Telenti, Amalio; de Bakker, Paul I W; Walker, Bruce D; Ripke, Stephan; Brumme, Chanson J; Pulit, Sara L; Carrington, Mary; Kadie, Carl M; Carlson, Jonathan M; Heckerman, David; Graham, Robert R; Plenge, Robert M; Deeks, Steven G; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Nol P; Guiducci, Candace; Gupta, Namrata; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L; Lemay, Paul; O'Leary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L; Vine, Seanna; Addo, Marylyn M; Allen, Todd M; Altfeld, Marcus; Henn, Matthew R; Le Gall, Sylvie; Streeck, Hendrik; Haas, David W; Kuritzkes, Daniel R; Robbins, Gregory K; Shafer, Robert W; Gulick, Roy M; Shikuma, Cecilia M; Haubrich, Richard; Riddler, Sharon; Sax, Paul E; Daar, Eric S; Ribaudo, Heather J; Agan, Brian; Agarwal, Shanu; Ahern, Richard L; Allen, Brady L; Altidor, Sherly; Altschuler, Eric L; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C; Benson, Anne M; Berger, Judith; Bernard, Nicole F; Bernard, Annette M; Birch, Christopher; Bodner, Stanley J; Bolan, Robert K; Boudreaux, Emilie T; Bradley, Meg; Braun, James F; Brndjar, Jon E; Brown, Stephen J; Brown, Katherine; Brown, Sheldon T; Burack, Jedidiah; Bush, Larry M; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H; Carmichael, J Kevin; Casey, Kathleen K; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T; Chez, Nancy; Chirch, Lisa M; Cimoch, Paul J; Cohen, Daniel; Cohn, Lillian E; Conway, Brian; Cooper, David A; Cornelson, Brian; Cox, David T; Cristofano, Michael V; Cuchural, George; Czartoski, Julie L; Dahman, Joseph M; Daly, Jennifer S; Davis, Benjamin T; Davis, Kristine; Davod, Sheila M; DeJesus, Edwin; Dietz, Craig A; Dunham, Eleanor; Dunn, Michael E; Ellerin, Todd B; Eron, Joseph J; Fangman, John J W; Farel, Claire E; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A; French, Neel K; Fuchs, Jonathan D; Fuller, Jon D; Gaberman, Jonna; Gallant, Joel E; Gandhi, Rajesh T; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C; Gaultier, Cyril R; Gebre, Wondwoosen; Gilman, Frank D; Gilson, Ian; Goepfert, Paul A; Gottlieb, Michael S; Goulston, Claudia; Groger, Richard K; Gurley, T Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W David; Harrigan, P Richard; Hawkins, Trevor N; Heath, Sonya; Hecht, Frederick M; Henry, W Keith; Hladek, Melissa; Hoffman, Robert P; Horton, James M; Hsu, Ricky K; Huhn, Gregory D; Hunt, Peter; Hupert, Mark J; Illeman, Mark L; Jaeger, Hans; Jellinger, Robert M; John, Mina; Johnson, Jennifer A; Johnson, Kristin L; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C; Kauffman, Carol A; Khanlou, Homayoon; Killian, Robert K; Kim, Arthur Y; Kim, David D; Kinder, Clifford A; Kirchner, Jeffrey T; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P Todd; Kurisu, Wayne; Kwon, Douglas S; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M; Lee, David M; Lee, Jean M L; Lee, Marah J; Lee, Edward T Y; Lemoine, Janice; Levy, Jay A; Llibre, Josep M; Liguori, Michael A; Little, Susan J; Liu, Anne Y; Lopez, Alvaro J; Loutfy, Mono R; Loy, Dawn; Mohammed, Debbie Y; Man, Alan; Mansour, Michael K; Marconi, Vincent C; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N; Martin, Harold L; Mayer, Kenneth Hugh; McElrath, M Juliana; McGhee, Theresa A; McGovern, Barbara H; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X; Menezes, Prema; Mesa, Greg; Metroka, Craig E; Meyer-Olson, Dirk; Miller, Andy O; Montgomery, Kate; Mounzer, Karam C; Nagami, Ellen H; Nagin, Iris; Nahass, Ronald G; Nelson, Margret O; Nielsen, Craig; Norene, David L; O'Connor, David H; Ojikutu, Bisola O; Okulicz, Jason; Oladehin, Olakunle O; Oldfield, Edward C; Olender, Susan A; Ostrowski, Mario; Owen, William F; Pae, Eunice; Parsonnet, Jeffrey; Pavlatos, Andrew M; Perlmutter, Aaron M; Pierce, Michael N; Pincus, Jonathan M; Pisani, Leandro; Price, Lawrence Jay; Proia, Laurie; Prokesch, Richard C; Pujet, Heather Calderon; Ramgopal, Moti; Rathod, Almas; Rausch, Michael; Ravishankar, J; Rhame, Frank S

    2010-12-10

    Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

  8. Genetic changes from artificial propagation of Pacific salmon affect the productivity and viability of supplemented populations

    USGS Publications Warehouse

    Reisenbichler, R.R.; Rubin, S.P.

    1999-01-01

    Although several studies have shown genetic differences between hatchery and wild anadromous Pacific salmon (Oncorhynchus spp.), none has provided compelling evidence that artificial propagation poses a genetic threat to conservation of naturally spawning populations. When the published studies and three studies in progress are considered collectively, however, they provide strong evidence that the fitness for natural spawning and rearing can be rapidly and substantially reduced by artificial propagation. This issue takes on great importance in the Pacific Northwest where supplementation of wild salmon populations with hatchery fish has been identified as an important tool for restoring these populations. Recognition of negative aspects may lead to restricted use of supplementation, and better conservation, better evaluation, and greater benefits when supplementation is used.

  9. The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation

    PubMed Central

    Pereyra, Florencia; Jia, Xiaoming; McLaren, Paul J.; Telenti, Amalio; de Bakker, Paul I.W.; Walker, Bruce D.; Jia, Xiaoming; McLaren, Paul J.; Ripke, Stephan; Brumme, Chanson J.; Pulit, Sara L.; Telenti, Amalio; Carrington, Mary; Kadie, Carl M.; Carlson, Jonathan M.; Heckerman, David; de Bakker, Paul I.W.; Pereyra, Florencia; de Bakker, Paul I.W.; Graham, Robert R.; Plenge, Robert M.; Deeks, Steven G.; Walker, Bruce D.; Gianniny, Lauren; Crawford, Gabriel; Sullivan, Jordan; Gonzalez, Elena; Davies, Leela; Camargo, Amy; Moore, Jamie M.; Beattie, Nicole; Gupta, Supriya; Crenshaw, Andrew; Burtt, Nol P.; Guiducci, Candace; Gupta, Namrata; Carrington, Mary; Gao, Xiaojiang; Qi, Ying; Yuki, Yuko; Pereyra, Florencia; Piechocka-Trocha, Alicja; Cutrell, Emily; Rosenberg, Rachel; Moss, Kristin L.; Lemay, Paul; OLeary, Jessica; Schaefer, Todd; Verma, Pranshu; Toth, Ildiko; Block, Brian; Baker, Brett; Rothchild, Alissa; Lian, Jeffrey; Proudfoot, Jacqueline; Alvino, Donna Marie L.; Vine, Seanna; Addo, Marylyn M.; Allen, Todd M.; Altfeld, Marcus; Henn, Matthew R.; Le Gall, Sylvie; Streeck, Hendrik; Walker, Bruce D.; Haas, David W.; Kuritzkes, Daniel R.; Robbins, Gregory K.; Shafer, Robert W.; Gulick, Roy M.; Shikuma, Cecilia M.; Haubrich, Richard; Riddler, Sharon; Sax, Paul E.; Daar, Eric S.; Ribaudo, Heather J.; Agan, Brian; Agarwal, Shanu; Ahern, Richard L.; Allen, Brady L.; Altidor, Sherly; Altschuler, Eric L.; Ambardar, Sujata; Anastos, Kathryn; Anderson, Ben; Anderson, Val; Andrady, Ushan; Antoniskis, Diana; Bangsberg, David; Barbaro, Daniel; Barrie, William; Bartczak, J.; Barton, Simon; Basden, Patricia; Basgoz, Nesli; Bazner, Suzane; Bellos, Nicholaos C.; Benson, Anne M.; Berger, Judith; Bernard, Nicole F.; Bernard, Annette M.; Birch, Christopher; Bodner, Stanley J.; Bolan, Robert K.; Boudreaux, Emilie T.; Bradley, Meg; Braun, James F.; Brndjar, Jon E.; Brown, Stephen J.; Brown, Katherine; Brown, Sheldon T.; Burack, Jedidiah; Bush, Larry M.; Cafaro, Virginia; Campbell, Omobolaji; Campbell, John; Carlson, Robert H.; Carmichael, J. Kevin; Casey, Kathleen K.; Cavacuiti, Chris; Celestin, Gregory; Chambers, Steven T.; Chez, Nancy; Chirch, Lisa M.; Cimoch, Paul J.; Cohen, Daniel; Cohn, Lillian E.; Conway, Brian; Cooper, David A.; Cornelson, Brian; Cox, David T.; Cristofano, Michael V.; Cuchural, George; Czartoski, Julie L.; Dahman, Joseph M.; Daly, Jennifer S.; Davis, Benjamin T.; Davis, Kristine; Davod, Sheila M.; Deeks, Steven G.; DeJesus, Edwin; Dietz, Craig A.; Dunham, Eleanor; Dunn, Michael E.; Ellerin, Todd B.; Eron, Joseph J.; Fangman, John J.W.; Farel, Claire E.; Ferlazzo, Helen; Fidler, Sarah; Fleenor-Ford, Anita; Frankel, Renee; Freedberg, Kenneth A.; French, Neel K.; Fuchs, Jonathan D.; Fuller, Jon D.; Gaberman, Jonna; Gallant, Joel E.; Gandhi, Rajesh T.; Garcia, Efrain; Garmon, Donald; Gathe, Joseph C.; Gaultier, Cyril R.; Gebre, Wondwoosen; Gilman, Frank D.; Gilson, Ian; Goepfert, Paul A.; Gottlieb, Michael S.; Goulston, Claudia; Groger, Richard K.; Gurley, T. Douglas; Haber, Stuart; Hardwicke, Robin; Hardy, W. David; Harrigan, P. Richard; Hawkins, Trevor N.; Heath, Sonya; Hecht, Frederick M.; Henry, W. Keith; Hladek, Melissa; Hoffman, Robert P.; Horton, James M.; Hsu, Ricky K.; Huhn, Gregory D.; Hunt, Peter; Hupert, Mark J.; Illeman, Mark L.; Jaeger, Hans; Jellinger, Robert M.; John, Mina; Johnson, Jennifer A.; Johnson, Kristin L.; Johnson, Heather; Johnson, Kay; Joly, Jennifer; Jordan, Wilbert C.; Kauffman, Carol A.; Khanlou, Homayoon; Killian, Robert K.; Kim, Arthur Y.; Kim, David D.; Kinder, Clifford A.; Kirchner, Jeffrey T.; Kogelman, Laura; Kojic, Erna Milunka; Korthuis, P. Todd; Kurisu, Wayne; Kwon, Douglas S.; LaMar, Melissa; Lampiris, Harry; Lanzafame, Massimiliano; Lederman, Michael M.; Lee, David M.; Lee, Jean M.L.; Lee, Marah J.; Lee, Edward T.Y.; Lemoine, Janice; Levy, Jay A.; Llibre, Josep M.; Liguori, Michael A.; Little, Susan J.; Liu, Anne Y.; Lopez, Alvaro J.; Loutfy, Mono R.; Loy, Dawn; Mohammed, Debbie Y.; Man, Alan; Mansour, Michael K.; Marconi, Vincent C.; Markowitz, Martin; Marques, Rui; Martin, Jeffrey N.; Martin, Harold L.; Mayer, Kenneth Hugh; McElrath, M. Juliana; McGhee, Theresa A.; McGovern, Barbara H.; McGowan, Katherine; McIntyre, Dawn; Mcleod, Gavin X.; Menezes, Prema; Mesa, Greg; Metroka, Craig E.; Meyer-Olson, Dirk; Miller, Andy O.; Montgomery, Kate; Mounzer, Karam C.; Nagami, Ellen H.; Nagin, Iris; Nahass, Ronald G.; Nelson, Margret O.; Nielsen, Craig; Norene, David L.; OConnor, David H.; Ojikutu, Bisola O.; Okulicz, Jason; Oladehin, Olakunle O.; Oldfield, Edward C.

    2011-01-01

    Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLAviral peptide interaction as the major factor modulating durable control of HIV infection. PMID:21051598

  10. Indirect genetic effects and inbreeding: consequences of BLUP selection for socially affected traits on rate of inbreeding

    PubMed Central

    2014-01-01

    Background Social interactions often occur among living organisms, including aquatic animals. There is empirical evidence showing that social interactions may genetically affect phenotypes of individuals and their group mates. In this context, the heritable effect of an individual on the phenotype of another individual is known as an Indirect Genetic Effect (IGE). Selection for socially affected traits may increase response to artificial selection, but also affect rate of inbreeding. Methods A simulation study was conducted to examine the effect of Best Linear Unbiased Prediction (BLUP) selection for socially affected traits on the rate of inbreeding. A base scenario without IGE and three alternative scenarios with different magnitudes of IGE were simulated. In each generation, 25 sires and 50 dams were mated, producing eight progeny per dam. The population was selected for 20 generations using BLUP. Individuals were randomly assigned to groups of eight members in each generation, with two families per group, each contributing four individuals. Heritabilities (for both direct and indirect genetic effects) were equal to 0.1, 0.3 or 0.5, and directindirect genetic correlations were ?0.8, ?0.4, 0, 0.4, or 0.8. The rate of inbreeding was calculated from generation 10 to 20. Results For the base scenario, the rates of inbreeding were 4.09, 2.80 and 1.95% for heritabilities of 0.1, 0.3 and 0.5, respectively. Overall, rates of inbreeding for the three scenarios with IGE ranged from 2.21 to 5.76% and were greater than for the base scenarios. The results show that social interaction within groups of two families increases the resemblance between estimated breeding values of relatives, which, in turn, increases the rate of inbreeding. Conclusion BLUP selection for socially affected traits increased the rate of inbreeding. To maintain inbreeding at an acceptable rate, a selection algorithm that restricts the increase in mean kinship, such as optimum contribution selection, is required. PMID:24961990

  11. Genetic modulation of BDNF signaling affects the outcome of axonal competition in vivo

    PubMed Central

    Cao, Luxiang; Dhilla, Alefiya; Mukai, Jun; Blazeski, Richard; Lodovichi, Claudia; Mason, Carol A.; Gogos, Joseph A.

    2007-01-01

    Summary Background Activity-dependent competition that operates on branch stability or formation, plays a critical role in shaping the pattern and complexity of axonal terminal arbors. In the mammalian central nervous system (CNS), the effect of activity-dependent competition on axon arborization and the assembly of sensory maps is well established. However, the molecular pathways that modulate axonal branch stability or formation in competitive environments remain unknown. Results We establish an in vivo axonal competition paradigm in the mouse olfactory system, by employing a genetic strategy that permits suppression of neurosecretory activity in random subsets of olfactory sensory neurons (OSNs). Long-term follow up confirmed that this genetic manipulation triggers competition by revealing a bias towards selective stabilization of active arbors and local degeneration of synaptically silent ones. Using a battery of genetically modified mouse models we demonstrate that a decrease either in the total levels or the levels of activity-dependent secreted BDNF (due to a val66met substitution), rescues silent arbors from withering. We show that this effect may be mediated, at least in part, by p75(NTR). Conclusions We establish and experimentally validate a genetic in vivo axonal competition paradigm in the mammalian CNS. Using this paradigm we provide evidence for a specific effect of BDNF signaling on terminal arbor pruning under competition in vivo. Our results have implications for the formation and refinement of the olfactory and other sensory maps, as well as for neuropsychiatric diseases and traits modulated by the BDNF val66met variant. PMID:17493809

  12. Why Control Activity? Evolutionary Selection Pressures Affecting the Development of Physical Activity Genetic and Biological Regulation

    PubMed Central

    2013-01-01

    The literature strongly suggests that daily physical activity is genetically and biologically regulated. Potential identities of the responsible mechanisms are unclear, but little has been written concerning the possible evolutionary selection pressures leading to the development of genetic/biological controls of physical activity. Given the weak relationship between exercise endurance and activity levels and the differential genomic locations associated with the regulation of endurance and activity, it is probable that regulation of endurance and activity evolved separately. This hypothesis paper considers energy expenditures and duration of activity in hunter/gatherers, pretechnology farmers, and modern Western societies and considers the potential of each to selectively influence the development of activity regulation. Food availability is also considered given the known linkage of caloric restriction on physical activity as well as early data relating food oversupply to physical inactivity. Elucidating the selection pressures responsible for the genetic/biological control of activity will allow further consideration of these pressures on activity in today's society, especially the linkages between food and activity. Further, current food abundance is removing the cues for activity that were present for the first 40,000 years of human evolution, and thus future research should investigate the effects of this abundance upon the mechanisms regulating activity. PMID:24455728

  13. Twins and virtual twins: Do genetic (as well as experiential) factors affect developmental risks?

    PubMed

    Segal, Nancy L; Tan, Tony Xing; Graham, Jamie L

    2015-08-01

    Factors underlying developmental delays and psychosocial risks are of interest to international adoption communities. The current study administered a Pre-Adoption Adversity (PAA) Questionnaire to mostly American parents raising (a) adopted Chinese twins or (b) same-age unrelated adopted siblings. A goal was to replicate earlier analyses of pre-adoption adversity/adjustment among adopted preschool-age Chinese girls. A second goal was to conduct genetic analyses of four content areas (Developmental Delays at Adoption, Initial Adaptation to Adoption, Crying/Clinging, and Refusal/Avoidance) derived from the PAA Questionnaire. A key finding was that age at adoption added less than other predictors to adoptees' externalizing and internalizing behaviors. Family factors (e.g., parental education) contributed significantly to behavioral outcomes among the adopted Chinese twins. Genetic effects were indicated for all four content areas, with shared environmental effects evident for Developmental Delays at Adoption and Crying/Clinging. Future investigators should consider incorporating genetically sensitive designs into developmental research programs. PMID:25900540

  14. Source population characteristics affect heterosis following genetic rescue of fragmented plant populations

    PubMed Central

    Pickup, M.; Field, D. L.; Rowell, D. M.; Young, A. G.

    2013-01-01

    Understanding the relative importance of heterosis and outbreeding depression over multiple generations is a key question in evolutionary biology and is essential for identifying appropriate genetic sources for population and ecosystem restoration. Here we use 2455 experimental crosses between 12 population pairs of the rare perennial plant Rutidosis leptorrhynchoides (Asteraceae) to investigate the multi-generational (F1, F2, F3) fitness outcomes of inter-population hybridization. We detected no evidence of outbreeding depression, with inter-population hybrids and backcrosses showing either similar fitness or significant heterosis for fitness components across the three generations. Variation in heterosis among population pairs was best explained by characteristics of the foreign source or home population, and was greatest when the source population was large, with high genetic diversity and low inbreeding, and the home population was small and inbred. Our results indicate that the primary consideration for maximizing progeny fitness following population augmentation or restoration is the use of seed from large, genetically diverse populations. PMID:23173202

  15. How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1

    PubMed Central

    Serra, Laura; Petrucci, Antonio; Span, Barbara; Torso, Mario; Olivito, Giusy; Lispi, Ludovico; Costanzi-Porrini, Sandro; Giulietti, Giovanni; Koch, Giacomo; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

    2015-01-01

    Summary Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tract-based spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1 mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1. PMID:26214024

  16. 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. PMID:25290946

  17. GENETIC POLYMORPHISMS AFFECTING SUSCEPTIBILITY TO MERCURY NEUROTOXICITY IN CHILDREN: SUMMARY FINDINGS FROM THE CASA PIA CHILDREN's AMALGAM CLINICAL TRIAL

    PubMed Central

    Woods, James S.; Heyer, Nicholas J.; Russo, Joan E.; Martin, Michael D.; Farin, Federico M.

    2014-01-01

    Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic predisposition. We examined the possibility that common genetic variants that are known to affect neurologic functions or Hg handling in adults would modify the adverse neurobehavioral effects of Hg exposure in children. Three hundred thirty subjects who participated as children in the recently completed Casa Pia Clinical Trial of Dental Amalgams in Children were genotyped for 27 variants of 13 genes that are reported to affect neurologic functions and/or Hg disposition in adults. Urinary Hg concentrations, reflecting Hg exposure from any source, served as the Hg exposure index. Regression modeling strategies were employed to evaluate potential associations between allelic status for individual genes or combinations of genes, Hg exposure, and neurobehavioral test outcomes assessed at baseline and for 7 subsequent years during the clinical trial. Among boys, significant modification of Hg effects on neurobehavioral outcomes over a broad range of neurologic domains was observed with variant genotypes for 4 of 13 genes evaluated. Modification of Hg effects on a more limited number of neurobehavioral outcomes was also observed for variants of another 8 genes. Cluster analyses suggested some genes interacting in common processes to affect Hg neurotoxicity. In contrast, significant modification of Hg effects on neurobehavioral functions among girls with the same genotypes was substantially more limited. These observations suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children, particularly boys, with genetic variants that are relatively common to the general human population. These findings advance public health goals to identify factors underlying susceptibility to Hg toxicity and may contribute to strategies for preventing adverse health risks associated with Hg exposure. PMID:25109824

  18. Synergistic ablation does not affect atrophy or altered myosin heavy chain expression in the non-weight bearing soleus muscle

    NASA Technical Reports Server (NTRS)

    Linderman, J. K.; Talmadge, R. J.; Gosselink, K. L.; Tri, P. N.; Roy, R. R.; Grindeland, R. E.

    1996-01-01

    The purpose of this study was to investigate whether the soleus muscle undergoes atrophy and alterations in myosin heavy chain (MHC) composition during non-weight bearing in the absence of synergists. Thirty-two female rats were randomly assigned to four groups: control (C), synergistic ablation (ABL) of the gastrocnemius and plantaris muscles to overload the soleus muscle, hindlimb suspension (HLS), or a combination of synergistic ablation and hindlimb suspension (HLS-ABL). After 28 days of hindlimb suspension, soleus atrophy was more pronounced in HLS (58%) than in HLS-ABL (43%) rats. Compared to C rats, non-weight bearing decreased mixed and myofibrillar protein contents and Type I MHC 49%, 45%, and 7%, respectively, in HLS animals. In addition, de novo expression of fast Type IIx and Type IIb MHC (5% and 2%, respectively) was observed in HLS animals. Similarly, when compared to C rats, mixed and myofibrillar protein contents and Type I MHC decreased 43%, 46%, and 4%, respectively, in HLS-ABL animals. Also, de novo expression of Type IIx (4%) and IIb (1%) MHC was observed. Collectively, these data indicate that the loss of muscle protein and Type I MHC, and the de novo expression of Type IIx and Type IIb MHC in the rat soleus occur independently of the presence of synergists during non-weight bearing. Furthermore, these results confirm the contention that soleus mass and MHC expression are highly sensitive to alterations in mechanical load.

  19. Altered Sleep Regulation in a Mouse Model of SCN1A-Derived Genetic Epilepsy with Febrile Seizures Plus (GEFS+)

    PubMed Central

    Papale, Ligia A.; Makinson, Christopher D.; Ehlen, J. Christopher; Tufik, Sergio; Decker, Michael J.; Paul, Ketema N.; Escayg, Andrew

    2013-01-01

    Summary Purpose Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. Methods Using immunohistochemistry we first examined the expression of Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalographic (EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants). We also characterized the sleep-wake pattern following 6 hours of sleep deprivation. Key Findings Immunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to WT littermates during the recovery period following 6-hours of sleep deprivation. Significance These results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression of Scn1a in specific cells types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations. PMID:23311867

  20. The Role of Genetic Sex in Affect Regulation and Expression of GABA-Related Genes Across Species

    PubMed Central

    Seney, Marianne L.; Chang, Lun-Ching; Oh, Hyunjung; Wang, Xingbin; Tseng, George C.; Lewis, David A.; Sibille, Etienne

    2013-01-01

    Although circulating hormones and inhibitory gamma-aminobutyric acid (GABA)-related factors are known to affect mood, considerable knowledge gaps persist for biological mechanisms underlying the female bias in mood disorders. Here, we combine human and mouse studies to investigate sexual dimorphism in the GABA system in the context of major depressive disorder (MDD) and then use a genetic model to dissect the role of sex-related factors in GABA-related gene expression and anxiety-/depressive-like behaviors in mice. First, using meta-analysis of gene array data in human postmortem brain (N?=?51 MDD subjects, 50 controls), we show that the previously reported down-regulation in MDD of somatostatin (SST), a marker of a GABA neuron subtype, is significantly greater in women with MDD. Second, using gene co-expression network analysis in control human subjects (N?=?214; two frontal cortex regions) and expression quantitative trait loci mapping (N?=?170 subjects), we show that expression of SST and the GABA-synthesizing enzymes glutamate decarboxylase 67 (GAD67) and GAD65 are tightly co-regulated and influenced by X-chromosome genetic polymorphisms. Third, using a rodent genetic model [Four Core Genotypes (FCG) mice], in which genetic and gonadal sex are artificially dissociated (N???12/group), we show that genetic sex (i.e., X/Y-chromosome) influences both gene expression (lower Sst, Gad67, Gad65 in XY mice) and anxiety-like behaviors (higher in XY mice). This suggests that in an intact male animal, the observed behavior represents the outcomes of male genetic sex increasing and male-like testosterone decreasing anxiety-like behaviors. Gonadal sex was the only factor influencing depressive-like behavior (gonadal males?genetic sex) on GABA-related genes and anxiety-like behaviors. PMID:24062698

  1. Epidermal growth factor receptor signaling pathway is frequently altered in ampullary carcinoma at protein and genetic levels.

    PubMed

    Mikhitarian, Kaidi; Pollen, Maressa; Zhao, Zhiguo; Shyr, Yu; Merchant, Nipun B; Parikh, Alexander; Revetta, Frank; Washington, M Kay; Vnencak-Jones, Cindy; Shi, Chanjuan

    2014-05-01

    Our objective was to explore alteration of the epidermal growth factor receptor (EGFR) signaling pathway in ampullary carcinoma. Immunohistochemical studies were employed to evaluate expression of amphiregulin as well as expression and activation of EGFR. A lab-developed assay was used to identify mutations in the EGFR pathway genes, including KRAS, BRAF, PIK3CA, PTEN, and AKT1. A total of 52 ampullary carcinomas were identified, including 25 intestinal-type and 24 pancreatobiliary-type tumors, with the intestinal type being associated with a younger age at diagnosis (P=0.03) and a better prognosis (P<0.01). Expression of amphiregulin correlated with better differentiation (P<0.01), but no difference was observed between two major histologic types. Expression and activation of EGFR was more commonly seen in the pancreatobiliary type (P<0.01). Mutations were detected in 50% of the pancreatobiliary type and 60% of the intestinal type. KRAS was the most common gene mutated in the pancreatobiliary type (42%) as well as the intestinal type (52%). Other mutations detected included PIK3CA, SMAD4 and BRAF. KRAS mutations at codons 12 and 13 did not adversely affect overall survival. In conclusion, EGFR expression and activation were different between intestinal- and pancreatobiliary-type ampullary carcinoma. KRAS mutation was common in both histologic types; however, the incidence appeared to be lower in the pancreatobiliary type compared with its pancreatic counterpart, pancreatic ductal adenocarcinoma. Mutational analysis of the EGFR pathway genes may provide important insights into personalized treatment for patients with ampullary carcinoma. PMID:24186143

  2. Classroom Norms of Bullying Alter the Degree to Which Children Defend in Response to Their Affective Empathy and Power

    ERIC Educational Resources Information Center

    Peets, Kätlin; Pöyhönen, Virpi; Juvonen, Jaana; Salmivalli, Christina

    2015-01-01

    This study examined whether the degree to which bullying is normative in the classroom would moderate associations between "intra"- (cognitive and affective empathy, self-efficacy beliefs) and "inter"personal (popularity) factors and defending behavior. Participants were 6,708 third- to fifth-grade children (49% boys;…

  3. Specific Alterations in Complement Protein Activity of Little Brown Myotis (Myotis lucifugus) Hibernating in White-Nose Syndrome Affected Sites

    PubMed Central

    Moore, Marianne S.; Reichard, Jonathan D.; Murtha, Timothy D.; Zahedi, Bita; Fallier, Renee M.; Kunz, Thomas H.

    2011-01-01

    White-nose syndrome (WNS) is the most devastating condition ever reported for hibernating bats, causing widespread mortality in the northeastern United States. The syndrome is characterized by cutaneous lesions caused by a recently identified psychrophilic and keratinophylic fungus (Geomyces destructans), depleted fat reserves, atypical behavior, and damage to wings; however, the proximate cause of mortality is still uncertain. To assess relative levels of immunocompetence in bats hibernating in WNS-affected sites compared with levels in unaffected bats, we describe blood plasma complement protein activity in hibernating little brown myotis (Myotis lucifugus) based on microbicidal competence assays using Escherichia coli, Staphylococcus aureus and Candida albicans. Blood plasma from bats collected during mid-hibernation at WNS-affected sites had higher bactericidal ability against E. coli and S. aureus, but lower fungicidal ability against C. albicans when compared with blood plasma from bats collected at unaffected sites. Within affected sites during mid-hibernation, we observed no difference in microbicidal ability between bats displaying obvious fungal infections compared to those without. Bactericidal ability against E. coli decreased significantly as hibernation progressed in bats collected from an affected site. Bactericidal ability against E. coli and fungicidal ability against C. albicans were positively correlated with body mass index (BMI) during late hibernation. We also compared complement activity against the three microbes within individuals and found that the ability of blood plasma from hibernating M. lucifugus to lyse microbial cells differed as follows: E. coli>S. aureus>C. albicans. Overall, bats affected by WNS experience both relatively elevated and reduced innate immune responses depending on the microbe tested, although the cause of observed immunological changes remains unknown. Additionally, considerable trade-offs may exist between energy conservation and immunological responses. Relationships between immune activity and torpor, including associated energy expenditure, are likely critical components in the development of WNS. PMID:22140440

  4. Genetics of a Pheromonal Difference Affecting Sexual Isolation between Drosophila Mauritiana and D. Sechellia

    PubMed Central

    Coyne, J. A.; Charlesworth, B.

    1997-01-01

    Females of the sibling species Drosophila sechellia and D. mauritiana differ in their cuticular hydrocarbons: the predominant compound in D. sechellia is 7,11-heptacosadiene (7,11-HD), while that in D. mauritiana is 7-tricosene (7-T). We investigate the genetic basis of this difference and its involvement in reproductive isolation between the species. Behavioral studies involving hydrocarbon transfer suggest that these compounds play a large role in the sexual isolation between D. mauritiana males and D. sechellia females, while sexual isolation in the reciprocal hybridization results more from differences in female behavior than hydrocarbons. This interspecific difference in hydrocarbon profile is due to evolutionary change at a minimum of six loci, all on the third chromosome. The localization of evolutionary change to the third chromosome has been seen in every other genetic analysis of female hydrocarbon differences in the D. melanogaster group. We suggest that the high 7,11-HD phenotype seen in two species evolved twice independently from ancestors having the high 7-T phenotype, and that the recurrent third-chromosome effects are evolutionary convergences that may be due to a concentration of ``hydrocarbon genes'' on that chromosome. PMID:9093854

  5. Sampling issues affecting accuracy of likelihood-based classification using genetical data

    USGS Publications Warehouse

    Guinand, B.; Scribner, K.T.; Topchy, A.; Page, K.S.; Punch, W.; Burnham-Curtis, M. K.

    2004-01-01

    We demonstrate the effectiveness of a genetic algorithm for discovering multi-locus combinations that provide accurate individual assignment decisions and estimates of mixture composition based on likelihood classification. Using simulated data representing different levels of inter-population differentiation (Fst ~ 0.01 and 0.10), genetic diversities (four or eight alleles per locus), and population sizes (20, 40, 100 individuals in baseline populations), we show that subsets of loci can be identified that provide comparable levels of accuracy in classification decisions relative to entire multi-locus data sets, where 5, 10, or 20 loci were considered. Microsatellite data sets from hatchery strains of lake trout, Salvelinus namaycush, representing a comparable range of inter-population levels of differentiation in allele frequencies confirmed simulation results. For both simulated and empirical data sets, assignment accuracy was achieved using fewer loci (e.g., three or four loci out of eight for empirical lake trout studies). Simulation results were used to investigate properties of the 'leave-one-out' (L1O) method for estimating assignment error rates. Accuracy of population assignments based on L1O methods should be viewed with caution under certain conditions, particularly when baseline population sample sizes are low (<50).

  6. 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 opsonized immune complexes promotes the development of class-switched autoantibodies targeting nucleic acids. PMID:26950932

  7. Altered HBK3 expression affects glutathione and ascorbate metabolism during the early phases of Norway spruce (Picea abies) somatic embryogenesis.

    PubMed

    Belmonte, Mark F; Stasolla, Claudio

    2009-10-01

    Plant homeobox genes play an important role in plant development, including embryogenesis. Recently, the function of a class I homeobox of knox 3 gene, HBK3, has been characterized in the conifer Picea abies (L.) Karst (Norway spruce) [8]. During somatic embryogenesis, expression of HBK3 is required for the proper differentiation of proembryogenic masses into somatic embryos. This transition, fundamental for the overall embryogenic process, is accelerated in sense lines over-expressing HBK3 (HBK3-S) but precluded in antisense lines (HBK3-AS) where the expression of this gene is experimentally reduced. Altered HBK3 expression resulted in major changes of ascorbate and glutathione metabolism. During the initial phases of embryogeny the level of reduced GSH was higher in the HBK3-S lines compared to their control counterpart. An opposite profile was observed for the HBK3-AS lines where the glutathione redox state, i.e. GSH/GSH + GSSG, switched towards its oxidized form, i.e. GSSG. Very similar metabolic fluctuations were also measured for ascorbate, especially during the transition of proembryogenic masses into somatic embryos (7 days into hormone-free medium). At this stage the level of reduced ascorbate (ASC) in the HBK3-AS lines was about 75% lower compare to the untransformed line causing a switch of the ascorbate redox state, i.e. ASC/ASC + DHA + AFR, towards its oxidized forms, i.e. DHA + AFR. Changes in activities of several ascorbate and glutathione redox enzymes, including dehydroascorbate reductase (EC 1.8.5.1), ascorbate free radical reductase (EC 1.6.5.4) and glutathione reductase (GR; EC 1.6.4.2) were responsible for these metabolic differences. Data presented here suggest that HBK3 expression might regulate somatic embryo yield through alterations in glutathione and ascorbate metabolism, which have been previously implicated in controlling embryo development and maturation both in vivo and in vitro. PMID:19570687

  8. Cell shape normalization, dendrite orientation, and melanin production of normal and genetically altered (haploinsufficient NF1)-melanocytes by microstructured substrate interactions.

    PubMed

    Jungbauer, Simon; Kemkemer, Ralf; Gruler, Hans; Kaufmann, Dieter; Spatz, Joachim P

    2004-01-23

    Little is known about how functional regulation failure in genetically altered cells is influenced by topographical confinement of cells, a situation often present in tissues in vivo. We used cultured melanocytes derived from human skin samples as a model system for such investigations. Normal melanocytes have a very well defined shape consisting of a cell body and two dendrites arranged 180 degrees relative to each other. In contrast, neurofibromin 1-melanocytes (NF1-melanocytes) have up to a 50% reduction of neurofibromin 1, which results in an altered morphology that can be easily measured. NF1-melanocytes deviate from the defined structure of normal melanocytes by forming more than two dendrites per cell. We show that morphology consequences of genetically altered melanocytes can be canceled if cells interact with substrates microstructured by stripes that apply mechanophysical signals in the form of physical topography. The strength of the mechanophysical signal was varied systematically by increasing the height of the microstructures. Melanocytes respond to surface topographical features that are larger than 50 nm and have lateral confinements smaller 4 microns. The response of normal and NF1-melanocytes to different topographies was analyzed quantitatively by determining density distributions for the number of dendrites per cell, the angles between dendrites, and the orientation imprinted in the substrate. The synthesis of melanin, a pigment produced by melanocytes, differs in the case of genetically altered NF1- and normal melanocytes. In both cases, the interaction with microstripes enhanced melanin production significantly. This enhanced melanin production is speculated to be caused by the mechanical stabilization of the dendrites by substrate guidance. PMID:14999847

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

    PubMed Central

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

    2012-01-01

    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 perceptionand their genetic underpinningsare 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. PMID:22589251

  10. Negative Affect Shares Genetic and Environmental Influences with Symptoms of Childhood Internalizing and Externalizing Disorders

    ERIC Educational Resources Information Center

    Mikolajewski, Amy J.; Allan, Nicholas P.; Hart, Sara A.; Lonigan, Christopher J.; Taylor, Jeanette

    2013-01-01

    The co-occurrence of internalizing and externalizing disorders suggests that they may have common underlying vulnerability factors. Research has shown that negative affect is moderately positively correlated with both internalizing and externalizing disorders in children. The present study is the first to provide an examination of negative affect…

  11. Classroom norms of bullying alter the degree to which children defend in response to their affective empathy and power.

    PubMed

    Peets, Kätlin; Pöyhönen, Virpi; Juvonen, Jaana; Salmivalli, Christina

    2015-07-01

    This study examined whether the degree to which bullying is normative in the classroom would moderate associations between intra- (cognitive and affective empathy, self-efficacy beliefs) and interpersonal (popularity) factors and defending behavior. Participants were 6,708 third- to fifth-grade children (49% boys; Mage = 11 years) from 383 classrooms. Multilevel modeling analyses revealed that children were more likely to defend in response to their affective empathy in classrooms with high levels of bullying. In addition, popular students were more likely to support victims in classrooms where bullying was associated with social costs. These findings highlight the importance of considering interactions among individual and contextual influences when trying to understand which factors facilitate versus inhibit children's inclinations to defend others. PMID:25961871

  12. Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.

    PubMed

    Lu, Wensheng; Cheng, Yu-Ching; Chen, Keping; Wang, Hong; Gerhard, Glenn S; Still, Christopher D; Chu, Xin; Yang, Rongze; Parihar, Ankita; O'Connell, Jeffrey R; Pollin, Toni I; Angles-Cano, Eduardo; Quon, Michael J; Mitchell, Braxton D; Shuldiner, Alan R; Fu, Mao

    2015-04-15

    Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 10(-8) to 3.91 10(-19)) spanning a ?5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 10(-14)) and rs10455872 (P = 1.85 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation. PMID:25575512

  13. Fronto-temporal alterations and affect regulation in methamphetamine dependence with and without a history of psychosis.

    PubMed

    Uhlmann, Anne; Fouche, Jean-Paul; Koen, Nastassja; Meintjes, Ernesta M; Wilson, Don; Stein, Dan J

    2016-02-28

    Methamphetamine (MA) has been shown to have neurotoxic effects associated with brain structure changes and schizophrenia-like psychotic symptoms. Although these abnormalities may in turn be related to cognitive impairment and increased aggression, their association with affect dysregulation is less well studied. We investigated cortical thickness and subcortical volumes in 21 participants with MA dependence, 19 patients with MA-associated psychosis (MAP), and 19 healthy controls. Participants' affect regulation abilities were assessed through self-report scales on emotion reactivity (ERS) and difficulties in emotion regulation (DERS) and correlated with differences in cortical thickness. MAP patients showed thinner cortices in the fusiform and inferior temporal gyrus (ITG), orbitofrontal (OFC) and inferior frontal gyrus (IFG), and insula, compared to the MA group. MAP also showed significantly lower hippocampal volumes relative to MA and CTRL. Both clinical groups showed impairment in affect regulation, but only in MAP was this dysfunction associated with thinner cortices in ITG, OFC and IFG. Our findings suggest significant differences in cortical thickness in MA dependence with and without psychosis. Lower fronto-temporal cortical thickness and smaller hippocampal volumes in MAP are consistent with neuroimaging findings in other psychotic disorders, supporting the notion of MAP being a useful model of psychosis. PMID:26792587

  14. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A.

    PubMed

    Chen, Fang; Zhou, Libin; Bai, Yinyang; Zhou, Rong; Chen, Ling

    2014-07-01

    Bisphenol A (BPA), an estrogen-mimicking endocrine disrupter, when administered perinatally can affect affective behaviors in adult rodents, however the underlying mechanisms remain largely unclear. Postnatal day (PND) 80 vehicle-injected control female rats showed more obvious depression- and anxiety-like behaviors than males, indicative of sexually dimorphic affective behaviors. When female breeders were subcutaneously injected with BPA (2g/kg) from gestation day 10 to lactation day 7, sex difference of affective behaviors was impaired in their offspring (PND80 BPA-rats), as results that female BPA-rats showed a visible "antianxiety-like" behavior, and male BPA-rats increased depression-like behavior compared to vehicle-injected controls. Notably, basal levels of serum corticosterone and adrenocorticotropin (ACTH), and corticotropin-releasing hormone mRNA were increased in male BPA-rats, but not in female BPA-rats, in comparison with vehicle-injected controls. Following mild-stressor the elevation of corticosterone or ACTH levels was higher in male BPA-rats, whereas it was lower in female BPA-rats than vehicle-injected controls. In comparison with vehicle-injected controls, the level of glucocorticoid receptor (GR) mRNA in hippocampus or hypothalamic paraventricular nucleus was increased in female BPA-rats, while decreased in male BPA-rats. In addition, the levels of hippocampal mineralocorticoid receptor (MR) mRNA, neuronal nitric oxide synthase (nNOS) and phospho-cAMP response element binding protein (p-CREB) were increased in female BPA-rats, but were decreased in male BPA-rats. Furthermore, the testosterone level was reduced in male BPA-rats. The results indicate that the perinatal exposure to BPA through altering the GR and MR expression disrupts the GR-mediated feedback of hypothalamic-pituitary-adrenal (HPA) axis and MR-induced nNOS-CREB signaling, which alters sex difference in affective behaviors. PMID:24857958

  15. Genetic Diversity Affects the Daily Transcriptional Oscillations of Marine Microbial Populations

    PubMed Central

    Shilova, Irina N.; Robidart, Julie C.; DeLong, Edward F.; Zehr, Jonathan P.

    2016-01-01

    Marine microbial communities are genetically diverse but have robust synchronized daily transcriptional patterns at the genus level that are similar across a wide variety of oceanic regions. We developed a microarray-inspired gene-centric approach to resolve transcription of closely-related but distinct strains/ecotypes in high-throughput sequence data. Applying this approach to the existing metatranscriptomics datasets collected from two different oceanic regions, we found unique and variable patterns of transcription by individual taxa within the abundant picocyanobacteria Prochlorococcus and Synechococcus, the alpha Proteobacterium Pelagibacter and the eukaryotic picophytoplankton Ostreococcus. The results demonstrate that marine microbial taxa respond differentially to variability in space and time in the ocean. These intra-genus individual transcriptional patterns underlie whole microbial community responses, and the approach developed here facilitates deeper insights into microbial population dynamics. PMID:26751368

  16. Characterization of Soybean Storage and Allergen Proteins Affected by Environmental and Genetic Factors.

    PubMed

    Natarajan, Savithiry; Khan, Farooq; Song, Qijian; Lakshman, Sukla; Cregan, Perry; Scott, Roy; Shipe, Emerson; Garrett, Wesley

    2016-02-17

    There is limited information on the influence of genetic and environmental variability on soybean protein composition. This study aimed to determine the role of genotype (G), environments (E), and the interrelationship of genotype and environment (G×E) on soybean seed protein. Three sets of nine soybean genotypes were grown in replicated trials at Maryland, South Carolina, and South Dakota. At each location, the nine genotypes were grown with two planting/sowing dates. We applied two-dimensional gel electrophoresis and mass spectrometry to study the variability of soybean storage and allergen proteins. Statistical analysis of 47 storage and 8 allergen proteins, in terms of differentially expressed protein spots significant at the p<0.005 level, was performed. We found more spots that showed statistically significant differences in expression among E compared to G and G×E interaction. PMID:26807503

  17. Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder

    SciTech Connect

    Lim, L.C.C.; Sham, P.; Castle, D.

    1995-08-14

    We present evidence of a genetic association between bipolar disorder and alleles at 3 monoamine oxidase A (MAOA) markers, but not with alleles of a monoamine oxidase B (MAOB) polymorphism. The 3 MAOA markers, including one associated with low MAOA activity, show strong allelic association with each other but surprisingly not with MAOB. Our results are significantly only for females, though the number of males in our sample is too small to draw any definite conclusions. Our data is consistent with recent reports of reduced MAOA activity in patients with abnormal behavioral phenotypes. The strength of the association is weak, but significant, which suggests that alleles at the MAOA locus contribute to susceptibility to bipolar disorder rather than being a major determinant. 58 refs., 1 fig., 3 tabs.

  18. A Genetic Variant in the Distal Enhancer Region of the Human Renin Gene Affects Renin Expression

    PubMed Central

    Makino, Yasukazu; Konoshita, Tadashi; Omori, Atsuhito; Maegawa, Nobuhiro; Nakaya, Takahiro; Ichikawa, Mai; Yamamoto, Katsushi; Wakahara, Shigeyuki; Ishizuka, Tamotsu; Onoe, Tamehito; Nakamura, Hiroyuki

    2015-01-01

    Background The high heritability of plasma renin activity was confirmed in recent investigations. A variation located near the strong enhancer of the human renin gene (REN), C-5312T, has been shown to have different transcription activity levels depending on its allele: the 5312T allele shows transcription levels that are 45% greater than those of the 5312C allele. The purpose of this study was to confirm the hypothesis that variations in the enhancer region of the REN gene are involved in regulating renal expression of renin. Methods Sixty-four subjects with biopsy-proven renal diseases were included in this study (male/female: 35/29, age 41.9 ± 20.9 years, SBP/DBP 123.1 ± 23.7/73.4 ± 14.8 mmHg, s-Cr 0.93 ± 0.63 mg/dl). A genetic variant of REN, C-5312T, was assayed by PCR-RFLP and the TaqMan method. Total RNAs from a small part of the renal cortex were reverse-transcribed and amplified for REN and GAPDH with a real-time PCR system. Results Logarithmically transformed expression values of the relative ratio of REN to GAPDH (10−3) were as follows (mean ± SE): CC (26 cases), 0.016 ± 0.005; CT (33 cases), 0.047 ± 0.021 (p = 0.41 vs. CC); TT (5 cases), 0.198 ± 0.194 (p = 0.011 vs. CC, p < 0.031 vs. CT). Thus, significant differences in REN expression were observed among the genetic variants. Conclusion The results suggest that variants in the enhancer region of the human renin gene have an effect on the expression levels of renin in renal tissue; this observation is in good accordance with the results of the transcriptional assay. PMID:26366736

  19. Genetics, Synergists, and Age Affect Insecticide Sensitivity of the Honey Bee, Apis mellifera

    PubMed Central

    Rinkevich, Frank D.; Margotta, Joseph W.; Pittman, Jean M.; Danka, Robert G.; Tarver, Matthew R.; Ottea, James A.; Healy, Kristen B.

    2015-01-01

    The number of honey bee colonies in the United States has declined to half of its peak level in the 1940s, and colonies lost over the winter have reached levels that are becoming economically unstable. While the causes of these losses are numerous and the interaction between them is very complex, the role of insecticides has garnered much attention. As a result, there is a need to better understand the risk of insecticides to bees, leading to more studies on both toxicity and exposure. While much research has been conducted on insecticides and bees, there have been very limited studies to elucidate the role that bee genotype and age has on the toxicity of these insecticides. The goal of this study was to determine if there are differences in insecticide sensitivity between honey bees of different genetic backgrounds (Carniolan, Italian, and Russian stocks) and assess if insecticide sensitivity varies with age. We found that Italian bees were the most sensitive of these stocks to insecticides, but variation was largely dependent on the class of insecticide tested. There were almost no differences in organophosphate bioassays between honey bee stocks (<1-fold), moderate differences in pyrethroid bioassays (1.5 to 3-fold), and dramatic differences in neonicotinoid bioassays (3.4 to 33.3-fold). Synergism bioassays with piperonyl butoxide, amitraz, and coumaphos showed increased phenothrin sensitivity in all stocks and also demonstrated further physiological differences between stocks. In addition, as bees aged, the sensitivity to phenothrin significantly decreased, but the sensitivity to naled significantly increased. These results demonstrate the variation arising from the genetic background and physiological transitions in honey bees as they age. This information can be used to determine risk assessment, as well as establishing baseline data for future comparisons to explain the variation in toxicity differences for honey bees reported in the literature. PMID:26431171

  20. Genetics, Synergists, and Age Affect Insecticide Sensitivity of the Honey Bee, Apis mellifera.

    PubMed

    Rinkevich, Frank D; Margotta, Joseph W; Pittman, Jean M; Danka, Robert G; Tarver, Matthew R; Ottea, James A; Healy, Kristen B

    2015-01-01

    The number of honey bee colonies in the United States has declined to half of its peak level in the 1940s, and colonies lost over the winter have reached levels that are becoming economically unstable. While the causes of these losses are numerous and the interaction between them is very complex, the role of insecticides has garnered much attention. As a result, there is a need to better understand the risk of insecticides to bees, leading to more studies on both toxicity and exposure. While much research has been conducted on insecticides and bees, there have been very limited studies to elucidate the role that bee genotype and age has on the toxicity of these insecticides. The goal of this study was to determine if there are differences in insecticide sensitivity between honey bees of different genetic backgrounds (Carniolan, Italian, and Russian stocks) and assess if insecticide sensitivity varies with age. We found that Italian bees were the most sensitive of these stocks to insecticides, but variation was largely dependent on the class of insecticide tested. There were almost no differences in organophosphate bioassays between honey bee stocks (<1-fold), moderate differences in pyrethroid bioassays (1.5 to 3-fold), and dramatic differences in neonicotinoid bioassays (3.4 to 33.3-fold). Synergism bioassays with piperonyl butoxide, amitraz, and coumaphos showed increased phenothrin sensitivity in all stocks and also demonstrated further physiological differences between stocks. In addition, as bees aged, the sensitivity to phenothrin significantly decreased, but the sensitivity to naled significantly increased. These results demonstrate the variation arising from the genetic background and physiological transitions in honey bees as they age. This information can be used to determine risk assessment, as well as establishing baseline data for future comparisons to explain the variation in toxicity differences for honey bees reported in the literature. PMID:26431171

  1. Oxytocin and Vasopressin Are Dysregulated in Williams Syndrome, a Genetic Disorder Affecting Social Behavior

    PubMed Central

    Dai, Li; Carter, C. Sue; Ying, Jian; Bellugi, Ursula; Pournajafi-Nazarloo, Hossein; Korenberg, Julie R.

    2012-01-01

    The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ∼28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior. PMID:22719898

  2. Genetic Variability in Nodulation and Root Growth Affects Nitrogen Fixation and Accumulation in Pea

    PubMed Central

    Bourion, Virginie; Laguerre, Gisele; Depret, Geraldine; Voisin, Anne-Sophie; Salon, Christophe; Duc, Gerard

    2007-01-01

    Background and Aims Legume nitrogen is derived from two different sources, symbiotically fixed atmospheric N2 and soil N. The effect of genetic variability of root and nodule establishment on N acquisition and seed protein yield was investigated under field conditions in pea (Pisum sativum). In addition, these parameters were related to the variability in preference for rhizobial genotypes. Methods Five different spring pea lines (two hypernodulating mutants and three cultivars), previously identified in artificial conditions as contrasted for both root and nodule development, were characterized under field conditions. Root and nodule establishment was examined from the four-leaf stage up to the beginning of seed filling and was related to the patterns of shoot dry matter and nitrogen accumulation. The genetic structure of rhizobial populations associated with the pea lines was obtained by analysis of nodule samples. The fraction of nitrogen derived from symbiotic fixation was estimated at the beginning of seed filling and at physiological maturity, when seed protein content and yield were determined. Key Results The hypernodulating mutants established nodules earlier and maintained them longer than was the case for the three cultivars, whereas their root development and nitrogen accumulation were lower. The seed protein yield was higher in ‘Athos’ and ‘Austin’, the two cultivars with increased root development, consistent with their higher N absorption during seed filling. Conclusion The hypernodulating mutants did not accumulate more nitrogen, probably due to the C cost for nodulation being higher than for root development. Enhancing exogenous nitrogen supply at the end of the growth cycle, by increasing the potential for root N uptake from soil, seems a good option for improving pea seed filling. PMID:17670753

  3. Affected sib-pair interval mapping and exclusion for complex genetic traits: Inferring identity by descent status from relatives

    SciTech Connect

    Hauser, E.R.; Boehnke, M.; Guo, S.W.

    1994-09-01

    Affected sib-pair (ASP) methods provide a useful approach for the initial genetic mapping of complex diseases for which mode of inheritance is uncertain. Risch described a method for interval mapping and exclusion based on the ratio lambda comparing disease risk in the first degree relatives of affected individuals to disease risk in the general population. He assumed marker identity by descent (IBD) status for the ASP could be deduced from parental genotypes. For late onset diseases such as type 2 diabetes, parents may be dead or otherwise unavailable, so that marker IBD status generally cannot be inferred with certainty. Guo has developed efficient methods for probabilistic determination of marker IBD sharing for two or more loci. We have combined and extended the methods of Risch and Guo to carry out interval mapping and exclusion when parents are missing but other relatives such as additional siblings are available. Our method is based on calculating the likelihood of marker data of the ASP and their relatives conditional on the disease status of the ASP, as a function of lambda and the position of the disease locus within the genetic map. We currently are using this method to compare the information to detect or exclude linkage provided by various types of ASP nuclear families -- zero, one, or two typed parents and zero, one, two, or more additional siblings -- as a function of sample size, marker density and informativity, and risk ratio lambda.

  4. Genetic mapping of quantitative trait loci affecting susceptibility to Marek's disease virus induced tumors in F2 intercross chickens.

    PubMed Central

    Vallejo, R L; Bacon, L D; Liu, H C; Witter, R L; Groenen, M A; Hillel, J; Cheng, H H

    1998-01-01

    Marek's disease (MD) is a lymphoproliferative disease caused by the MD virus (MDV), which costs the poultry industry nearly $1 billion annually. To identify quantitative trait loci (QTL) affecting MD susceptibility, the inbred lines 6(3) (MD resistant) and 7(2) (MD susceptible) were mated to create more than 300 F2 chickens. The F2 chickens were challenged with MDV JM strain, moderately virulent) at 1 wk of age and assessed for MD susceptibility. The QTL analysis was divided into three stages. In stage 1, 65 DNA markers selected from the chicken genetic maps were typed on the 40 most MD-susceptible and the 40 most MD-resistant F2 chickens, and 21 markers residing near suggestive QTL were revealed by analysis of variance (ANOVA). In stage 2, the suggestive markers plus available flanking markers were typed on 272 F2 chickens, and three suggestive QTL were identified by ANOVA. In stage 3, using the interval mapping program Map Manager and permutation tests, two significant and two suggestive MD QTL were identified on four chromosomal subregions. Three to five loci collected explained between 11 and 23% of the phenotypic MD variation, or 32-68% of the genetic variance. This study constitutes the first report in the domestic chicken on the mapping of non-major histocompatibility complex QTL affecting MD susceptibility. PMID:9475745

  5. Analysis of genetic polymorphisms affecting the four phospholipase C (plc) genes in Mycobacterium tuberculosis complex clinical isolates.

    PubMed

    Viana-Niero, C; de Haas, P E; van Soolingen, D; Leo, S C

    2004-04-01

    The Mycobacterium tuberculosis genome contains four highly related genes which present significant similarity to Pseudomonas aeruginosa genes encoding phospholipase C enzymes. Three of these genes, plcA, plcB and plcC, are organized in tandem (locus plcABC). The fourth gene, plcD, is located in a different region. This study investigates variations in plcABC and plcD genes in clinical isolates of M. tuberculosis, Mycobacterium africanum and 'Mycobacterium canettii'. Genetic polymorphisms were examined by PCR, Southern blot hybridization, sequence analysis and RT-PCR. Seven M. tuberculosis isolates contain insertions of IS6110 elements within plcA, plcC or plcD. In 19 of 25 M. tuberculosis isolates examined, genomic deletions were identified, resulting in loss of parts of genes or complete genes from the plcABC and/or plcD loci. Partial plcD deletion was observed in one M. africanum isolate. In each case, deletions were associated with the presence of a copy of the IS6110 element and in all occurrences IS6110 was transposed in the same orientation. A mechanism of deletion resulting from homologous recombination of two copies of IS6110 was recognized in a group of genetically related M. tuberculosis isolates. Five M. tuberculosis isolates presented major polymorphisms in the plcABC and plcD regions, along with loss of expression competence that affected all four plc genes. Phospholipase C is a well-known bacterial virulence factor. The precise role of phospholipase C in the pathogenicity of M. tuberculosis is unknown, but considering the potential importance that the plc genes may have in the virulence of the tubercle bacillus, the study of isolates cultured from patients with active tuberculosis bearing genetic variations affecting these genes may provide insights into the significance of phospholipase C enzymes for tuberculosis pathogenicity. PMID:15073306

  6. Quantifying how fine-grained environmental heterogeneity and genetic variation affect demography in an annual plant population.

    PubMed

    Latimer, Andrew M; Jacobs, Brooke S

    2012-11-01

    The ability of plant species to colonize new habitats and persist in changing environments depends on their ability to respond plastically to environmental variation and on the presence of genetic variation, thus allowing adaptation to new conditions. For invasive species in particular, the relationship between phenotypic trait expression, demography, and the quantitative genetic variation that is available to respond to selection are likely to be important determinants of the successful establishment and persistence of populations. However, the magnitude and sources of individual demographic variation in exotic plant populations remain poorly understood. How important is plasticity versus adaptability in populations of invasive species? Among environmental factors, is temperature, soil nutrients, or competition most influential, and at what scales and life stages do they affect the plants? To investigate these questions we planted seeds of the exotic annual plant Erodium brachycarpum into typical pasture habitat in a spatially nested design. Seeds were drawn from 30 inbred lines to enable quantification of genetic effects. Despite a positive population growth rate, a few plants (0.1 %) produced >50 % of the seeds, suggesting a low effective population size. Emergence and early growth varied by genotype, but as in previous studies on native plants, environmental effects greatly exceeded genetic effects, and survival was unrelated to genotype. Environmental influences shifted from microscale soil compaction and litter depth at emergence through to larger-scale soil nutrient gradients during growth and to competition during later survival and seed production. Temperature had no effect. Most demographic rates were positively correlated, but emergence was negatively correlated with other rates. PMID:22707035

  7. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau

    PubMed Central

    Leng, Shuguang; Picchi, Maria A.; Liu, Yushi; Thomas, Cynthia L.; Willis, Derall G.; Bernauer, Amanda M.; Carr, Teara G.; Mabel, Padilla T.; Han, Younghun; Amos, Christopher I.; Lin, Yong; Stidley, Christine A.; Gilliland, Frank D.; Jacobson, Marty R.; Belinsky, Steven A.

    2013-01-01

    Epidemiological studies of underground miners suggested that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P = 0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (odds ratio = 1.69, P = 8.210?5) and greater survival in SCC cases (hazard ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggest that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. PMID:23354305

  8. Mutations Affecting Starch Synthase III in Arabidopsis Alter Leaf Starch Structure and Increase the Rate of Starch Synthesis1

    PubMed Central

    Zhang, Xiaoli; Myers, Alan M.; James, Martha G.

    2005-01-01

    The role of starch synthase (SS) III (SSIII) in the synthesis of transient starch in Arabidopsis (Arabidopsis thaliana) was investigated by characterizing the effects of two insertion mutations at the AtSS3 gene locus. Both mutations, termed Atss3-1 and Atss3-2, condition complete loss of SSIII activity and prevent normal gene expression at both the mRNA and protein levels. The mutations cause a starch excess phenotype in leaves during the light period of the growth cycle due to an apparent increase in the rate of starch synthesis. In addition, both mutations alter the physical structure of leaf starch. Significant increases were noted in the mutants in the frequency of linear chains in amylopectin with a degree of polymerization greater than approximately 60, and relatively small changes were observed in chains of degree of polymerization 4 to 50. Furthermore, starch in the Atss3-1 and Atss3-2 mutants has a higher phosphate content, approximately two times that of wild-type leaf starch. Total SS activity is increased in both Atss3 mutants and a specific SS activity appears to be up-regulated. The data indicate that, in addition to its expected direct role in starch assembly, SSIII also has a negative regulatory function in the biosynthesis of transient starch in Arabidopsis. PMID:15908598

  9. Water deficit alters differentially metabolic pathways affecting important flavor and quality traits in grape berries of Cabernet Sauvignon and Chardonnay

    PubMed Central

    Deluc, Laurent G; Quilici, David R; Decendit, Alain; Grimplet, Jérôme; Wheatley, Matthew D; Schlauch, Karen A; Mérillon, Jean-Michel; Cushman, John C; Cramer, Grant R

    2009-01-01

    Background Water deficit has significant effects on grape berry composition resulting in improved wine quality by the enhancement of color, flavors, or aromas. While some pathways or enzymes affected by water deficit have been identified, little is known about the global effects of water deficit on grape berry metabolism. Results The effects of long-term, seasonal water deficit on berries of Cabernet Sauvignon, a red-wine grape, and Chardonnay, a white-wine grape were analyzed by integrated transcript and metabolite profiling. Over the course of berry development, the steady-state transcript abundance of approximately 6,000 Unigenes differed significantly between the cultivars and the irrigation treatments. Water deficit most affected the phenylpropanoid, ABA, isoprenoid, carotenoid, amino acid and fatty acid metabolic pathways. Targeted metabolites were profiled to confirm putative changes in specific metabolic pathways. Water deficit activated the expression of numerous transcripts associated with glutamate and proline biosynthesis and some committed steps of the phenylpropanoid pathway that increased anthocyanin concentrations in Cabernet Sauvignon. In Chardonnay, water deficit activated parts of the phenylpropanoid, energy, carotenoid and isoprenoid metabolic pathways that contribute to increased concentrations of antheraxanthin, flavonols and aroma volatiles. Water deficit affected the ABA metabolic pathway in both cultivars. Berry ABA concentrations were highly correlated with 9-cis-epoxycarotenoid dioxygenase (NCED1) transcript abundance, whereas the mRNA expression of other NCED genes and ABA catabolic and glycosylation processes were largely unaffected. Water deficit nearly doubled ABA concentrations within berries of Cabernet Sauvignon, whereas it decreased ABA in Chardonnay at véraison and shortly thereafter. Conclusion The metabolic responses of grapes to water deficit varied with the cultivar and fruit pigmentation. Chardonnay berries, which lack any significant anthocyanin content, exhibited increased photoprotection mechanisms under water deficit conditions. Water deficit increased ABA, proline, sugar and anthocyanin concentrations in Cabernet Sauvignon, but not Chardonnay berries, consistent with the hypothesis that ABA enhanced accumulation of these compounds. Water deficit increased the transcript abundance of lipoxygenase and hydroperoxide lyase in fatty metabolism, a pathway known to affect berry and wine aromas. These changes in metabolism have important impacts on berry flavor and quality characteristics. Several of these metabolites are known to contribute to increased human-health benefits. PMID:19426499

  10. A mutation affecting expression of a major outer membrane protein of Moraxella catarrhalis alters serum resistance and survival in vivo.

    PubMed

    Helminen, M E; Maciver, I; Paris, M; Latimer, J L; Lumbley, S L; Cope, L D; McCracken, G H; Hansen, E J

    1993-11-01

    A major outer membrane protein (CopB) of Moraxella catarrhalis is a target for antibodies that enhance clearance of this organism from the lungs of mice. A mini-Tn10kan transposon was inserted into the cloned copB gene from M. catarrhalis O35E, and an isogenic mutant unable to express the CopB protein was constructed by transforming this mutated gene into the wild-type strain. The mutant grew at the same rate as the wild-type parent strain in broth. Unlike the serum-resistant parent strain, this mutant was sensitive to killing by normal human serum, and its ability to survive and grow in the lungs of animals was impaired. Genetic restoration of CopB protein expression resulted in the simultaneous acquisition of wild-type levels of serum resistance and the ability to resist pulmonary clearance in vivo. Thus, the CopB protein of M. catarrhalis may be important in the interaction between this organism and the defense mechanisms of the respiratory tract. PMID:8228353

  11. Diet-Induced Alterations of Host Cholesterol Metabolism Are Likely To Affect the Gut Microbiota Composition in Hamsters

    PubMed Central

    Martínez, Inés; Perdicaro, Diahann J.; Brown, Andrew W.; Hammons, Susan; Carden, Trevor J.; Carr, Timothy P.; Eskridge, Kent M.

    2013-01-01

    The gastrointestinal microbiota affects the metabolism of the mammalian host and has consequences for health. However, the complexity of gut microbial communities and host metabolic pathways make functional connections difficult to unravel, especially in terms of causation. In this study, we have characterized the fecal microbiota of hamsters whose cholesterol metabolism was extensively modulated by the dietary addition of plant sterol esters (PSE). PSE intake induced dramatic shifts in the fecal microbiota, reducing several bacterial taxa within the families Coriobacteriaceae and Erysipelotrichaceae. The abundance of these taxa displayed remarkably high correlations with host cholesterol metabolites. Most importantly, the associations between several bacterial taxa with fecal and biliary cholesterol excretion showed an almost perfect fit to a sigmoidal nonlinear model of bacterial inhibition, suggesting that host cholesterol excretion can shape microbiota structure through the antibacterial action of cholesterol. In vitro experiments suggested a modest antibacterial effect of cholesterol, and especially of cholesteryl-linoleate, but not plant sterols when included in model bile micelles. The findings obtained in this study are relevant to our understanding of gut microbiota-host lipid metabolism interactions, as they provide the first evidence for a role of cholesterol excreted with the bile as a relevant host factor that modulates the gut microbiota. The findings further suggest that the connections between Coriobacteriaceae and Erysipelotrichaceae and host lipid metabolism, which have been observed in several studies, could be caused by a metabolic phenotype of the host (cholesterol excretion) affecting the gut microbiota. PMID:23124234

  12. Altered Subcellular Localization of Tumor-Specific Cyclin E Isoforms Affects Cyclin-Dependent Kinase 2 Complex Formation and Proteasomal Regulation

    PubMed Central

    Delk, Nikki A.; Hunt, Kelly K.; Keyomarsi, Khandan

    2009-01-01

    In tumors, alternative translation and posttranslational proteolytic cleavage of full-length cyclin E (EL) produces tumorigenic low molecular weight cyclin E (LMW-E) isoforms that lack a portion of the EL amino-terminus containing a nuclear localization sequence. Therefore, we hypothesized that LMW-E isoforms have altered subcellular localization. To explore our hypothesis, we compared EL versus LMW-E localization in cell lysates and in vivo using fractionation and protein complementation assays. Our results reveal that LMW-E isoforms preferentially accumulate in the cytoplasm where they bind the cyclin E kinase partner, cyclin-dependent kinase 2 (Cdk2), and have associated kinase activity. The nuclear ubiquitin ligase Fbw7 targets Cdk2-bound cyclin E for degradation; thus, we examined if altered subcellular localization affected LMW-E degradation. We found that cytoplasmic LMW-E/Cdk2 was less susceptible to Fbw7-mediated degradation. One implication of our findings is that altered LMW-E and LMW-E/Cdk2 subcellular localization may lead to aberrant LMW-E protein interactions, regulation, and activity, ultimately contributing to LMW-E tumorigenicity. PMID:19318554

  13. Genetic markers that influence feed efficiency phenotypes also affect cattle temperament as measured by flight speed.

    PubMed

    Lindholm-Perry, A K; Kuehn, L A; Freetly, H C; Snelling, W M

    2015-02-01

    Flight speed is a predictive indicator of cattle temperament and is associated with feed efficiency phenotypes. Genetic markers associated with both traits may assist with selection of calmer animals with improved economic value. A preliminary genome-wide association study determined chromosomal regions on BTA9, and 17 were associated with flight speed. The genes quaking (QKI), glutamate receptor, ionotropic, AMPA 2 (GRIA2) and glycine receptor ? (GLRB) were identified in these regions as potential functional candidates. Beef steers (n=1057) were genotyped with SNPs located within and flanking these genes. One SNP located near QKI and one near GRIA2 were nominally associated with flight speed (P?0.05) although neither was significant after Bonferroni correction. Several studies have shown a correlation between flight speed and feed intake or gain; therefore, we also analyzed SNPs on BTA6:38-39Mb known to be associated with average daily gain (ADG) and average daily feed intake (ADFI) for association with flight speed. Several SNPs on BTA6 were associated with flight speed (P?0.005), and three were significant after Bonferroni correction. These results suggest that the genes tested are unlikely to contribute to flight speed variation for our cattle population, but SNPs on BTA6 associated with ADG and ADFI may influence temperament. Use of these markers to select for economically important feed efficiency phenotypes may produce cattle with more desirable temperaments. PMID:25515066

  14. Strain-specific nuclear genetic background differentially affects mitochondria-related phenotypes in Saccharomyces cerevisiae.

    PubMed

    Montanari, Arianna; Francisci, Silvia; Fazzi D'Orsi, Mario; Bianchi, Michele Maria

    2014-06-01

    In the course of our studies on mitochondrial defects, we have observed important phenotypic variations in Saccharomyces cerevisiae strains suggesting that a better characterization of the genetic variability will be essential to define the relationship between the mitochondrial efficiency and the presence of different nuclear backgrounds. In this manuscript, we have extended the study of such relations by comparing phenotypic assays related to mitochondrial functions of three wild-type laboratory strains. In addition to the phenotypic variability among the wild-type strains, important differences have been observed among strains bearing identical mitochondrial tRNA mutations that could be related only to the different nuclear background of the cells. Results showed that strains exhibited an intrinsic variability in the severity of the effects of the mitochondrial mutations and that specific strains might be used preferentially to evaluate the phenotypic effect of mitochondrial mutations on carbon metabolism, stress responses, and mitochondrial DNA stability. In particular, while W303-1B and MCC123 strains should be used to study the effect of severe mitochondrial tRNA mutations, D273-10B/A1 strain is rather suitable for studying the effects of milder mutations. PMID:24700775

  15. Genetic and Environmental Factors Affecting the De Novo Appearance of the [Psi(+)] Prion in Saccharomyces Cerevisiae

    PubMed Central

    Derkatch, I. L.; Bradley, M. E.; Zhou, P.; Chernoff, Y. O.; Liebman, S. W.

    1997-01-01

    It has previously been shown that yeast prion [PSI(+)] is cured by GuHCl, although reports on reversibility of curing were contradictory. Here we show that GuHCl treatment of both [PSI(+)] and [psi(-)] yeast strains results in two classes of [psi(-)] derivatives: Pin(+), in which [PSI(+)] can be reinduced by Sup35p overproduction, and Pin(-), in which overexpression of the complete SUP35 gene does not lead to the [PSI(+)] appearance. However, in both Pin(+) and Pin(-) derivatives [PSI(+)] is reinduced by overproduction of a short Sup35p N-terminal fragment, thus, in principle, [PSI(+)] curing remains reversible in both cases. Neither suppression nor growth inhibition caused by SUP35 overexpression in Pin(+) [psi(-)] derivatives are observed in Pin(-) [psi(-)] derivatives. Genetic analyses show that the Pin(+) phenotype is determined by a non-Mendelian factor, which, unlike the [PSI(+)] prion, is independent of the Sup35p N-terminal domain. A Pin(-) [psi(-)] derivative was also generated by transient inactivation of the heat shock protein, Hsp104, while [PSI(+)] curing by Hsp104 overproduction resulted exclusively in Pin(+) [psi(-)] derivatives. We hypothesize that in addition to the [PSI(+)] prion-determining domain in the Sup35p N-terminus, there is another self-propagating conformational determinant in the C-proximal part of Sup35p and that this second prion is responsible for the Pin(+) phenotype. PMID:9335589

  16. Altered membrane lipid composition and functional parameters of circulating cells in cockles (Cerastoderma edule) affected by disseminated neoplasia.

    PubMed

    Le Grand, Fabienne; Soudant, Philippe; Marty, Yanic; Le Goc, Nelly; Kraffe, Edouard

    2013-01-01

    Membrane lipid composition and morpho-functional parameters were investigated in circulating cells of the edible cockle (Cerastoderma edule) affected by disseminated neoplasia (neoplastic cells) and compared to those from healthy cockles (hemocytes). Membrane sterol levels, phospholipid (PL) class and subclass proportions and their respective fatty acid (FA) compositions were determined. Morpho-functional parameters were evaluated through total hemocyte count (THC), mortality rate, phagocytosis ability and reactive oxygen species (ROS) production. Both morpho-functional parameters and lipid composition were profoundly affected in neoplastic cells. These dedifferentiated cells displayed higher THC (5), mortality rate (3) and ROS production with addition of carbonyl cyanide m-chloro phenylhydrazone (1.7) but lower phagocytosis ability (), than unaffected hemocytes. Total PL amounts were higher in neoplastic cells than in hemocytes (12.3 and 5.1 nmol10(-6) cells, respectively). However, sterols and a particular subclass of PL (plasmalogens; 1-alkenyl-2-acyl PL) were present in similar amounts in both cell type membranes. This led to a two times lower proportion of these membrane lipid constituents in neoplastic cells when compared to hemocytes (20.5% vs. 42.1% of sterols in total membrane lipids and 21.7% vs. 44.2% of plasmalogens among total PL, respectively). Proportions of non-methylene interrupted FA- and 20:1n-11-plasmalogen molecular species were the most impacted in neoplastic cells when compared to hemocytes (? and , respectively). These changes in response to this leukemia-like disease in bivalves highlight the specific imbalance of plasmalogens and sterols in neoplastic cells, in comparison to the greater stability of other membrane lipid components. PMID:23333874

  17. Your emotion or mine: labeling feelings alters emotional face perceptionan ERP study on automatic and intentional affect labeling

    PubMed Central

    Herbert, Cornelia; Sfrlea, Anca; Blumenthal, Terry

    2013-01-01

    Empirical evidence suggests that words are powerful regulators of emotion processing. Although a number of studies have used words as contextual cues for emotion processing, the role of what is being labeled by the words (i.e., one's own emotion as compared to the emotion expressed by the sender) is poorly understood. The present study reports results from two experiments which used ERP methodology to evaluate the impact of emotional faces and self- vs. sender-related emotional pronoun-noun pairs (e.g., my fear vs. his fear) as cues for emotional face processing. The influence of self- and sender-related cues on the processing of fearful, angry and happy faces was investigated in two contexts: an automatic (experiment 1) and intentional affect labeling task (experiment 2), along with control conditions of passive face processing. ERP patterns varied as a function of the label's reference (self vs. sender) and the intentionality of the labeling task (experiment 1 vs. experiment 2). In experiment 1, self-related labels increased the motivational relevance of the emotional faces in the time-window of the EPN component. Processing of sender-related labels improved emotion recognition specifically for fearful faces in the N170 time-window. Spontaneous processing of affective labels modulated later stages of face processing as well. Amplitudes of the late positive potential (LPP) were reduced for fearful, happy, and angry faces relative to the control condition of passive viewing. During intentional regulation (experiment 2) amplitudes of the LPP were enhanced for emotional faces when subjects used the self-related emotion labels to label their own emotion during face processing, and they rated the faces as higher in arousal than the emotional faces that had been presented in the label sender's emotion condition or the passive viewing condition. The present results argue in favor of a differentiated view of language-as-context for emotion processing. PMID:23888134

  18. Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression.

    PubMed

    Amador, Ariadna; Wang, Yongjun; Banerjee, Subhashis; Kameneka, Theodore M; Solt, Laura A; Burris, Thomas P

    2016-01-01

    The nuclear receptors REV-ERB? and REV-ERB? are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERB?-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression. PMID:26963516

  19. Genetic and environmental factors affecting mating type frequency in natural isolates of Tetrahymena thermophila.

    PubMed

    Arslanyolu, M; Doerder, F P

    2000-01-01

    In Tetrahymena thermophila mating type alleles specify temperature sensitive frequency distributions of multiple mating types. A-like alleles specify mating types I, II, III, V and VI, whereas B-like alleles specify mating types II through VII. We have characterized the mating type distributions specified by several A- and B-like genotypes segregated by genomic exclusion from cells isolated from a pond in northwestern Pennsylvania. The B-like genotypes are alike in specifying very low frequencies of mating type III, but differ with respect to the frequencies of other mating types, particularly II and VII. An A-like genotype specifies a high frequency of mating type III and is unstable in successive generations for the expression of mating type II, suggesting a possible modifier. Inter se crosses performed at 18 degrees C, 28 degrees C and 34 degrees C showed that each genotype specifies a frequency distribution that is uniquely affected by temperature. No mating type was affected the same way by temperature in all genotypes. In A/B heterozygotes, the B-like genotype exhibited partial dominance. The genotypes described here differ significantly from previously described genotypes from the same pond, indicating that there are numerous mating type alleles. For frequency-dependent selection to equalize mating type frequencies, it must act not only on complex multiple alleles but also on the response of mating type alleles to temperature. PMID:11140456

  20. Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression

    PubMed Central

    Amador, Ariadna; Wang, Yongjun; Banerjee, Subhashis; Kameneka, Theodore M.; Solt, Laura A.; Burris, Thomas P.

    2016-01-01

    The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression. PMID:26963516

  1. 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 (51.550.6%), 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

  2. The inhibition of aromatase alters the mechanical and rheological properties of non-small-cell lung cancer cell lines affecting cell migration.

    PubMed

    Giannopoulou, E; Siatis, K E; Metsiou, D; Kritikou, I; Papachristou, D J; Kalofonou, M; Koutras, A; Athanassiou, G; Kalofonos, H P

    2015-02-01

    Tumor invasion and metastasis are key aspects of non-small cell lung cancer (NSCLC). During migration, cells undergo mechanical alterations. The mechanical phenotype of breast cancer cells is correlated with aromatase gene expression. We have previously shown that targeting aromatase is a promising strategy for NSCLC. The aim of this study was to examine morphological and mechanical changes of NSCLC cells, upon treatment with aromatase inhibitor and correlate their ability to migrate and invade. In vitro experiments were performed using H23 and A549 NSCLC cell lines and exemestane was used for aromatase inhibition. We demonstrated that exemestane reduced H23 cell migration and invasion and caused changes in cell morphology including increased vacuolar structures and greater pleomorphism. In addition, exemestane changed the distribution of ?-tubulin in H23 and A549 cells in a way that might destabilize microtubules polymerization. These effects were associated with increased cell viscosity and decreased elastic shear modulus. Although exemestane caused similar effects in A549 cells regarding viscosity and elastic shear modulus, it did not affect A549 cell migration and caused an increase in invasion. The increased invasion was in line with vimentin perinuclear localization. Our data show that the treatment of NSCLC cells with an aromatase inhibitor not only affects cell migration and invasion but also alters the mechanical properties of the cells. It suggests that the different origin of cancer cells is associated with different morphological characteristics and mechanical behavior. PMID:25450981

  3. Early maternal separation affects ethanol-induced conditioning in a nor-BNI insensitive manner, but does not alter ethanol-induced locomotor activity.

    PubMed

    Pautassi, Ricardo Marcos; Nizhnikov, Michael E; Fabio, Ma Carolina; Spear, Norman E

    2012-01-01

    Early environmental stress significantly affects the development of offspring. This stress has been modeled in rats through the maternal separation (MS) paradigm, which alters the functioning of the HPA axis and can enhance ethanol intake at adulthood. Infant rats are sensitive to ethanol's reinforcing effects, which modulate ethanol seeking and intake. Little is known about the impact of MS on sensitivity to ethanol's appetitive and aversive effects during infancy. The present study assessed ethanol-induced conditioned place preference established through second-order conditioning (SOC), spontaneous or ethanol-induced locomotor activity and ethanol intake in preweanling rats that experienced normal animal facility rearing (AFR) or daily episodes of maternal separation (MS) during postnatal days 1-13 (PDs 1-13). Low-ethanol dose (0.5 g/kg) induced appetitive conditioned place preference (via SOC) in control rats given conventional rearing but not in rats given maternal separation in early infancy, whereas 2.0 g/kg ethanol induced aversive conditioned place preference in the former but not the latter. The administration of a kappa antagonist at PD 1 or immediately before testing did not alter ethanol-induced reinforcement. High (i.e., 2.5 and 2.0 g/kg) but not low (i.e., 0.5 g/kg) ethanol dose induced reliable motor stimulation, which was independent of early maternal separation. Ethanol intake and blood alcohol levels during conditioning were unaffected by rearing conditions. Pups given early maternal separation had lower body weights than controls and showed an altered pattern of exploration when placed in an open field. These results indicate that, when assessed in infant rats, earlier maternal separation alters the balance between the appetitive and aversive motivational effects of ethanol but has no effect on the motor activating effects of the drug. PMID:22108648

  4. Genetic and Phenotypic Selection Affect Natural (Auto-) Antibody Reactivity of Chickens

    PubMed Central

    de Jong, Britt G.; Lammers, Aart; Oberendorf, Leonora A. A.; Nieuwland, Mike G. B.; Savelkoul, Huub F. J.; Parmentier, Henk K.

    2013-01-01

    Specificity, antibody isotype distribution and levels of natural antibodies (NAb) may be potential informative parameters for immune mediated natural disease resistance, immune modulation, and maintenance of physiological homeostasis. A large proportion of mammalian NAb have affinity for or are directed against self-antigens; so called natural auto antibodies (N(A)Ab). In the present study we showed the presence and typed levels and isotypes (total immunoglobulins, IgG and IgM) of N(A)Ab in plasma binding the auto-antigen complex chicken liver cell lysate (CLL) of one-year old chickens from different genotype and phenotype backgrounds by ELISA and quantitative Western blotting. Higher levels of N(A)Ab binding CLL were found in plasma from chickens genetically selected for high specific antibody responses. In all birds, extensive staining patterns of plasma antibodies binding CLL were found for all isotypes, with IgG binding the highest number of CLL antigens and also showing the highest variation in staining patterns between individuals. Patterns of IgM antibodies binding CLL appeared to be more similar in all lines. Significant differences of binding patterns of N(A)Ab (antigen fragments of CLL and staining intensity) were detected between the different chicken lines, and lines could be clustered on the basis of their auto-antibody profile. In addition, also individual differences within lines were found. The present results indicate that analysis of the levels and the N(A)Ab repertoire of poultry like in mammals could provide a new way of distinguishing differences of immune competence and immune maturation between individuals, and could provide tools to select birds for health traits, or optimize hygiene and husbandry procedures. PMID:24039748

  5. How Different Genetically Manipulated Brassica Genotypes Affect Life Table Parameters of Plutella xylostella (Lepidoptera: Plutellidae).

    PubMed

    Nikooei, Mehrnoosh; Fathipour, Yaghoub; Jalali Javaran, Mokhtar; Soufbaf, Mahmoud

    2015-04-01

    The fitness of Plutella xylostella L. on different genetically manipulated Brassica plants, including canola's progenitor (Brassica rapa L.), two cultivated canola cultivars (Opera and RGS003), one hybrid (Hyula401), one gamma-ray mutant-RGS003, and one transgenic (PF) genotype was compared using two-sex and female-based life table parameters. All experiments were conducted in a growth chamber at 251C, 655% relative humidity, and a photoperiod of 16:8 (L:D) h. There were significant differences in duration of different life stages of P. xylostella on different plant genotypes. The shortest (13.92?d) and longest (24.61?d) total developmental time were on Opera and PF, respectively. The intrinsic rate of increase of P. xylostella ranged between 0.236 (Opera) and 0.071 day(-1) (PF). The highest (60.79 offspring) and lowest (7.88 offspring) net reproductive rates were observed on Opera and PF, respectively. Comparison of intrinsic rate of increase, net reproductive rates, finite rate of increase, mean generation time, fecundity, and survivorship of P. xylostella on the plant genotypes suggested that this pest performed well on cultivars (RGS003 and Opera) and performed poorly on the other manipulated genotypes especially on mutant-RGS003 and PF. Glucosinolate levels were significantly higher in damaged plants than undamaged ones and the lowest and highest concentrations of glucosinolates were found in transgenic genotype and canola's progenitor, respectively. Interestingly, our results showed that performance and fitness of this pest was better on canola's progenitor and cultivated plants, which had high levels of glucosinolate. PMID:26470162

  6. Genetic variation of the RASGRF1 regulatory region affects human hippocampus-dependent memory.

    PubMed

    Barman, Adriana; Assmann, Anne; Richter, Sylvia; Soch, Joram; Schütze, Hartmut; Wüstenberg, Torsten; Deibele, Anna; Klein, Marieke; Richter, Anni; Behnisch, Gusalija; Düzel, Emrah; Zenker, Martin; Seidenbecher, Constanze I; Schott, Björn H

    2014-01-01

    The guanine nucleotide exchange factor RASGRF1 is an important regulator of intracellular signaling and neural plasticity in the brain. RASGRF1-deficient mice exhibit a complex phenotype with learning deficits and ocular abnormalities. Also in humans, a genome-wide association study has identified the single nucleotide polymorphism (SNP) rs8027411 in the putative transcription regulatory region of RASGRF1 as a risk variant of myopia. Here we aimed to assess whether, in line with the RASGRF1 knockout mouse phenotype, rs8027411 might also be associated with human memory function. We performed computer-based neuropsychological learning experiments in two independent cohorts of young, healthy participants. Tests included the Verbal Learning and Memory Test (VLMT) and the logical memory section of the Wechsler Memory Scale (WMS). Two sub-cohorts additionally participated in functional magnetic resonance imaging (fMRI) studies of hippocampus function. 119 participants performed a novelty encoding task that had previously been shown to engage the hippocampus, and 63 subjects participated in a reward-related memory encoding study. RASGRF1 rs8027411 genotype was indeed associated with memory performance in an allele dosage-dependent manner, with carriers of the T allele (i.e., the myopia risk allele) showing better memory performance in the early encoding phase of the VLMT and in the recall phase of the WMS logical memory section. In fMRI, T allele carriers exhibited increased hippocampal activation during presentation of novel images and during encoding of pictures associated with monetary reward. Taken together, our results provide evidence for a role of the RASGRF1 gene locus in hippocampus-dependent memory and, along with the previous association with myopia, point toward pleitropic effects of RASGRF1 genetic variations on complex neural function in humans. PMID:24808846

  7. Germline genetics of the p53 pathway affect longevity in a gender specific manner.

    PubMed

    Gro, Sebastian; Immel, Uta-Dorothee; Klintschar, Michael; Bartel, Frank

    2014-01-01

    Aging is thought to occur through the accumulation of molecular and cellular damage. A key regulator of the cell's stress response is p53. In mice, the activity of p53 associates with lifespan. We were therefore interested whether SNPs in members of the p53-pathway are associated with longevity in humans. We genotyped the following SNPs: p53 - rs1042522 (Arg72Pro), MDM2 - rs2279744 (SNP309), MDM4 - rs4245739 (SNP34091), rs1563828 (SNP31826), PPP2R2B (rs319217) in 155 long-lived individuals (LLIs) who died at the age of 91 and over and in 171 ethnically-matched control subjects. Kaplan-Meier survival curves and log-Rank-test were used to determine the mean and median survival times. In female LLIs, the Pro-allele of rs1042522 (Arg72Pro) and the G-allele of rs2279744 (SNP309) were significantly associated with an increased survival time (P=0.026, P<0.001, respectively, log-Rank-test). In contrast, there was no difference regarding the survival time in male LLIs (rs1042522: P=0.58, rs2279744: P=0.503, log-Rank-test). There was no difference regarding the average age of death for the genotypes of the respective SNPs in the MDM4 gene (rs1563828: P=0.99; rs4245739: P=0.179, respectively). Here we show for the first time that the G-allele of rs2279744 (SNP309) is associated with increased lifespan. Importantly, this effect is gender-specific. Our data support the hypothesis that genetic variants that are associated with lower activity of p53--and therefore increased tumor risk--are associated with prolonged lifespan in a gender-specific manner. PMID:24654968

  8. The infrequent simultaneous genetic alterations in glioblastoma multiforme (LOH 10, 17, 19q, TP53 mutation and EGFR amplification) with short clinical course.

    PubMed

    Jesionek-Kupnicka, D; Kulczycka, D; Rieske, P; Szybka, M; Jab?o?ska, J; Potemski, P; Kolasa, P; Liberski, P P; Kordek, R

    2007-01-01

    We described the case of an unusual, complex genetic alteration in 57 year-old male patient with glioblastoma multiforme (GBM) with short survival (6 and half months). Alterations consisted of p53 mutation, LOH 10, LOH 17, LOH 19q and EGFR amplification. LOH1p, LOH 9 and LOH 13 were negative. Immunohistochemical study did not correlate with molecular results. The overexpression of TP53 protein and RB protein was detected only in small percentage of cells and interestingly the overexpression of EGFR was present only focally. Immnunostainings for PTEN, P16, PI3-K were negative. Additionally, we observed an overexpression of IGFB2 protein. This case indicates the accumulation of molecular changes in glioblastoma multiforme in patient with short survival. PMID:17715673

  9. Altered environment and risk of malaria outbreak in South Andaman, Andaman & Nicobar Islands, India affected by tsunami disaster

    PubMed Central

    Krishnamoorthy, Kaliannagoun; Jambulingam, Purushothaman; Natarajan, R; Shriram, AN; Das, Pradeep K; Sehgal, SC

    2005-01-01

    Background Pools of salt water and puddles created by giant waves from the sea due to the tsunami that occurred on 26th December 2004 would facilitate increased breeding of brackish water malaria vector, Anopheles sundaicus. Land uplifts in North Andaman and subsidence in South Andaman have been reported and subsidence may lead to environmental disturbances and vector proliferation. This warrants a situation analysis and vector surveillance in the tsunami hit areas endemic for malaria transmitted by brackish water mosquito, An. sundaicus to predict the risk of outbreak. Methods An extensive survey was carried out in the tsunami-affected areas in Andaman district of the Andaman and Nicobar Islands, India to assess the extent of breeding of malaria vectors in the habitats created by seawater flooding. Types of habitats in relation to source of seawater inundation and frequency were identified. The salinity of the water samples and the mosquito species present in the larval samples collected from these habitats were recorded. The malaria situation in the area was also analysed. Results South Andaman, covering Port Blair and Ferrargunj sub districts, is still under the recurring phenomenon of seawater intrusion either directly from the sea or through a network of creeks. Both daily cycles of high tides and periodical spring tides continue to cause flooding. Low-lying paddy fields and fallow land, with a salinity ranging from 3,000 to 42,505 ppm, were found to support profuse breeding of An. sundaicus, the local malaria vector, and Anopheles subpictus, a vector implicated elsewhere. This area is endemic for both vivax and falciparum malaria. Malaria slide positivity rate has started increasing during post-tsunami period, which can be considered as an indication of risk of malaria outbreak. Conclusion Paddy fields and fallow land with freshwater, hitherto not considered as potential sites for An. sundaicus, are now major breeding sites due to saline water. Consequently, there is a risk of vector abundance with enhanced malaria transmission potential, due to the vastness of these tsunami-created breeding grounds and likelihood of them becoming permanent due to continued flooding in view of land subsidence. The close proximity of the houses and paucity of cattle may lead to a higher degree of man/vector contact causing a threat of malaria outbreak in this densely populated area. Measures to prevent the possible outbreak of malaria in this tsunami-affected area are discussed. PMID:16029514

  10. Genetic disruption of the On visual pathway affects cortical orientation selectivity and contrast sensitivity in mice

    PubMed Central

    Sarnaik, Rashmi; Chen, Hui; Liu, Xiaorong

    2014-01-01

    The retina signals stimulus contrast via parallel On and Off pathways and sends the information to higher visual centers. Here we study the role of the On pathway using mice that have null mutations in the On-specific GRM6 receptor in the retina (Pinto LH, Vitaterna MH, Shimomura K, Siepka SM, Balannik V, McDearmon EL, Omura C, Lumayag S, Invergo BM, Brandon M, Glawe B, Cantrell DR, Donald R, Inayat S, Olvera MA, Vessey KA, Kirstan A, McCall MA, Maddox D, Morgans CW, Young B, Pletcher MT, Mullins RF, Troy JB, Takahashi JS. Vis Neurosci 24: 111–123, 2007; Maddox DM, Vessey KA, Yarbrough GL, Invergo BM, Cantrell DR, Inayat S, Balannik V, Hicks WL, Hawes NL, Byers S, Smith RS, Hurd R, Howell D, Gregg RG, Chang B, Naggert JK, Troy JB, Pinto LH, Nishina PM, McCall MA. J Physiol 586: 4409–4424, 2008). In these “nob” mice, single unit recordings in the primary visual cortex (V1) reveal degraded selectivity for orientations due to an increased response at nonpreferred orientations. Contrast sensitivity in the nob mice is reduced with severe deficits at low contrast, consistent with the phenotype of night blindness in human patients with mutations in Grm6. These cortical deficits can be largely explained by reduced input drive and increased response variability seen in nob V1. Interestingly, increased variability is also observed in the superior colliculus of these mice but does not affect its tuning properties. Further, the increased response variability in the nob mice is traced to the retina, a result phenocopied by acute pharmacological blockade of the On pathway in wild-type retina. Together, our results suggest that the On and Off pathways normally interact to increase response reliability in the retina, which in turn propagates to various central visual targets and affects their functional properties. PMID:24598523

  11. Fetal Exposure to Maternal Inflammation Does Not Affect Postnatal Development of Genetically-Driven Ileitis and Colitis

    PubMed Central

    Hemmerling, Jana; Heller, Katharina; Hrmannsperger, Gabriele; Bazanella, Monika; Clavel, Thomas; Kollias, George; Haller, Dirk

    2014-01-01

    Background: Chronic inflammatory disorders have been increasing in incidence over the past decades following geographical patterns of industrialization. Fetal exposure to maternal inflammation may alter organ functions and the offspring's disease risk. We studied the development of genetically-driven ileitis and colitis in response to maternal inflammation using mouse models. Methods: Disease susceptible (Tnf?ARE/+ and IL10?/?) and disease-free (Tnf+/+ and IL10?/+) offspring were raised in inflamed and non-inflamed dams. Ileal, caecal and colonic pathology was evaluated in the offspring at 8 or 12 weeks of age. Ly6G-positive cells in inflamed sections from the distal ileum and distal colon were analysed by immunofluorescence microscopy. Gene expression of pro-inflammatory cytokines was measured in whole tissue specimens by quantitative PCR. Microarray analyses were performed on laser microdissected intestinal epithelium. Caecal bacterial communities were assessed by Illumina sequencing of 16S rRNA amplicons. Results: Disease severity, the number of infiltrated neutrophils as well as Tnf and Il12p40 mRNA expression were independent of maternal inflammation in the offspring of mouse models for ileitis (Tnf?ARE/+) and colitis (IL10?/?). Although TNF-driven maternal inflammation regulated 2,174 (wild type) and 3,345 (Tnf?ARE/+) genes in the fetal epithelium, prenatal gene expression patterns were completely overwritten after birth. In addition, co-housing experiments revealed no change in phylogenetic diversity of the offspring's caecal microbiota in response to maternal inflammation. This is independent of the offspring's genotype before and after the onset of tissue pathology. Conclusions: Disease risk and activity in mouse models of chronic ileitis and colitis was independent of the fetal exposure to maternal inflammation. Likewise, maternal inflammation did not alter the diversity and composition of offspring's caecal microbiota, clearly demonstrating that changes of the gene expression program in the fetal gut epithelium were not relevant for the development of chronic inflammatory disorders in the gut. PMID:24849654

  12. Nonsynonymous natural genetic polymorphisms in the bovine leptin gene affect biochemical and biological characteristics of the mature hormone.

    PubMed

    Reicher, S; Ramos-Nieves, J M; Hileman, S M; Boisclair, Y R; Gootwine, E; Gertler, A

    2012-02-01

    Leptin (LEP) is a cytokine-like hormone proven to be involved in diverse biological processes. In livestock, it regulates feed intake, BW homeostasis, and energy balance, among other traits. Natural nonsynonymous genetic polymorphisms in the ovine leptin (oLEP) alter the biochemical and physiological characteristics of its gene products. Here we studied in vitro and in vivo the biochemical and physiological characteristics of recombinant hormones representing the oLEP and bovine leptin (bLEP) reference sequences of wild-type (WT) leptins (GenBank accession No. U84247 and U50365, respectively), oLEP and bLEP recombinant muteins carrying the R4C mutation, and oLEP recombinant hormones carrying the A59V and Q62R mutations, which were detected in bLEP. All proteins were purified to homogeneity as monomers and formed 1:1 molar ratio complexes with the chicken leptin-binding domain (LBD). Surface plasmon resonance experiments revealed that all protein variants exhibit reduced (P < 0.05) affinity to chicken (ch) and human (h) LBD compared with the WT oLEP and bLEP recombinant proteins. The ovine and bovine R4C muteins exhibited significantly (P < 0.05) greater induction of cell proliferation in a Baf/3 cell line bioassay, despite lower affinity toward both hLBD and chLBD. Intra-third cerebral ventricle infusion of oLEP and its 3 muteins in sheep resulted in reduced feed intake. However, the 3 tested muteins had a decreased (P < 0.05) inhibitory effect than the WT LEP. It was concluded that natural genetic polymorphisms in the bLEP are associated with variation in the biochemical and physiological properties of the protein. PMID:21926317

  13. Human CLP1 mutations alter tRNA biogenesis affecting both peripheral and central nervous system function

    PubMed Central

    Karaca, Ender; Weitzer, Stefan; Pehlivan, Davut; Shiraishi, Hiroshi; Gogakos, Tasos; Hanada, Toshikatsu; Jhangiani, Shalini N.; Wiszniewski, Wojciech; Withers, Marjorie; Campbell, Ian M.; Erdin, Serkan; Isikay, Sedat; Franco, Luis M.; Gonzaga-Jauregui, Claudia; Gambin, Tomasz; Gelowani, Violet; Hunter, Jill V.; Yesil, Gozde; Koparir, Erkan; Yilmaz, Sarenur; Brown, Miguel; Briskin, Daniel; Hafner, Markus; Morozov, Pavel; Farazi, Thalia A.; Bernreuther, Christian; Glatzel, Markus; Trattnig, Siegfried; Friske, Joachim; Kronnerwetter, Claudia; Bainbridge, Matthew N.; Gezdirici, Alper; Seven, Mehmet; Muzny, Donna M.; Boerwinkle, Eric; Ozen, Mustafa; Clausen, Tim; Tuschl, Thomas; Yuksel, Adnan; Hess, Andreas; Gibbs, Richard A.; Martinez, Javier; Penninger, Josef M.; Lupski, James R.

    2014-01-01

    CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a novel neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis. PMID:24766809

  14. Glucose concentration alters dissolved oxygen levels in liquid cultures of Beauveria bassiana and affects formation and bioefficacy of blastospores.

    PubMed

    Mascarin, Gabriel Moura; Jackson, Mark A; Kobori, Nilce Naomi; Behle, Robert W; Dunlap, Christopher A; Delalibera Jnior, talo

    2015-08-01

    The filamentous fungus Beauveria bassiana is an economically important pathogen of numerous arthropod pests and is able to grow in submerged culture as filaments (mycelia) or as budding yeast-like blastospores. In this study, we evaluated the effect of dissolved oxygen and high glucose concentrations on blastospore production by submerged cultures of two isolates of B. bassiana, ESALQ1432 and GHA. Results showed that maintaining adequate dissolved oxygen levels coupled with high glucose concentrations enhanced blastospore yields by both isolates. High glucose concentrations increased the osmotic pressure of the media and coincided with higher dissolved oxygen levels and increased production of significantly smaller blastospores compared with blastospores produced in media with lower concentrations of glucose. The desiccation tolerance of blastospores dried to less than 2.6 % moisture was not affected by the glucose concentration of the medium but was isolate dependent. Blastospores of isolate ESALQ1432 produced in media containing 140 g glucose L(-1) showed greater virulence toward whitefly nymphs (Bemisia tabaci) as compared with blastospores produced in media containing 40 g glucose L(-1). These results suggest a synergistic effect between glucose concentration and oxygen availability on changing morphology and enhancing the yield and efficacy of blastospores of B. bassiana, thereby facilitating the development of a cost-effective production method for this blastospore-based bioinsecticide. PMID:25947245

  15. Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder.

    PubMed

    Mnsson, Kristoffer N T; Carlbring, Per; Frick, Andreas; Engman, Jonas; Olsson, Carl-Johan; Bodlund, Owe; Furmark, Tomas; Andersson, Gerhard

    2013-12-30

    Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general. PMID:24064198

  16. Mutations altering the gammaretrovirus endoproteolytic motif affect glycosylation of the envelope glycoprotein and early events of the virus life cycle

    SciTech Connect

    Argaw, Takele; Wilson, Carolyn A.

    2015-01-15

    Previously, we found that mutation of glutamine to proline in the endoproteolytic cleavage signal of the PERV-C envelope (RQKK to RPKK) resulted in non-infectious vectors. Here, we show that RPKK results in a non-infectious vector when placed in not only a PERV envelope, but also the envelope of a related gammaretrovirus, FeLV-B. The amino acid substitutions do not prevent envelope precursor cleavage, viral core and genome assembly, or receptor binding. Rather, the mutations result in the formation of hyperglycosylated glycoprotein and a reduction in the reverse transcribed minus strand synthesis and undetectable 2-LTR circular DNA in cells exposed to vectors with these mutated envelopes. Our findings suggest novel functions associated with the cleavage signal sequence that may affect trafficking through the glycosylation machinery of the cell. Further, the glycosylation status of the envelope appears to impact post-binding events of the viral life cycle, either membrane fusion, internalization, or reverse transcription. - Highlights: • Env cleavage signal impacts infectivity of gammaretroviruses. • Non-infectious mutants have hyper-glycosylated envelope that bind target cells. • Non-infectious mutants have defects in the formation of the double-stranded DNA. • Env cleavage motif has functions beyond cleavage of the env precursor.

  17. DNMT1 genetic polymorphisms affect breast cancer risk in the central European Caucasian population

    PubMed Central

    2013-01-01

    Introduction DNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs). In cancer cells, global hypomethylation of the genome as a whole and regional hypermethylation of CpG islands have been reported. Four groups of DNMTs have been identified: DNMT1, DNMT2 (TRDMT1), DNMT3A and DNMT3B. DNMT2 uses the catalytic mechanism of DNMTs, but does in fact methylate RNA. Little is known about the significance of these genes in human breast cancer. In the study presented herein, we analyzed five distinct DNMT single SNPs with regard to potential associations with breast cancer risk. Case description In this study, we genotyped 221 female Caucasian breast cancer patients and 221 female Caucasian healthy controls, and we used five allele-specific real-time polymerase chain reaction (qPCR) assays. We selected one locus within the DNMT1 gene and two loci within the DNMT3A and DNMT3B genes, respectively. Statistics were calculated using the chi-squared and Fishers exact tests, and correlated with clinical parameters such as age, diagnosis, histology, TNM stage, hormonal receptor status, human epidermal growth factor receptor 2 (HER2) status, response to treatment and survival. Statistically significant results were obtained for correlations with the DNMT1 gene. Discussion and Evaluation Five genomic loci within the DNMT1, DNMT3A and DNMT3B genes were assessed. Statistical significance (P = 0.030) was identified for DNMT1 SNP (A201G, rs2228612): six women within the control group were GG homozygous (variant), while this mutation was absent in the breast cancer group. Conclusions We conclude that women with the DNMT1 SNP (A201G, rs2228612) GG homozygous genotype (variant) have a lower risk of developing breast cancer compared to heterozygous or wildtype genotypes. To date, alterations within the DNMT1 gene have not been reported to be associated with cancer in the Caucasian population. PMID:23638630

  18. Hybridization among divergent stocks of largemouth bass (Micropterus salmoides) results in altered cardiovascular performance: the influence of genetic and geographic distance.

    PubMed

    Cooke, S J; Philipp, D P

    2006-01-01

    Animal populations exhibit wide ranges of divergence associated with both geographic and genetic distances. Here, we examined the role of crossing distance on the cardiovascular response to exhaustive exercise among differentiated stocks of largemouth bass Micropterus salmoides at 10 degrees C and 20 degrees C. Stocks of 2+ fish were produced using adults from three regions in the midwestern United States (southeastern Wisconsin, northwestern Wisconsin, and west central Minnesota) and were crossed with fish from central Illinois. Doppler flow probes were used to quantify cardiac output, heart rate, and stroke volume. Cardiac variables (both resting and maximal) were consistently lowest in pure Illinois fish relative to the F(1) interstock hybrids. Additionally, when exposed to exercise, cardiac variables for F(1) interstock hybrids required approximately 40% longer to return to resting levels compared with the pure Illinois stock. However, the time required to exhaust fish was similar across stocks. Interestingly, all of the stocks (including the interstock hybrids and pure Illinois) maintained cardiac scope. In general, the patterns observed in cardiovascular performance were consistent for both water temperatures. Multiple regression analysis was used to determine which of the divergence metrics contributed to variation in cardiovascular performance in interstock hybrids. Mitochondrial DNA data (genetic distance) were infrequently identified as a significant source of variation in cardiovascular performance. However, genetic distance data for the neutral allozyme markers revealed that these stocks have experienced significant divergence. Latitude (geographic distance) accounted for between 31% and 45% of variation observed in the recovery parameters. This study suggests that the magnitude of stock divergence is an important determinant in the degree to which cardiovascular performance of bass is altered from interstock hybridization and associated breakdown of coadapted gene complexes. Furthermore, these data suggest that translocating bass among even geographically discrete regions or among stocks with reasonable genetic similarity can result in substantial performance alterations at the F(1) generation. PMID:16555198

  19. Host Genetic Factors Affect Susceptibility to Norovirus Infections in Burkina Faso

    PubMed Central

    Nordgren, Johan; Nitiema, Léon W.; Ouermi, Djeneba; Simpore, Jacques; Svensson, Lennart

    2013-01-01

    Norovirus (NoV) constitutes the second most common viral pathogen causing pediatric diarrhea after rotavirus. In Africa, diarrhea is a major health problem in children, and yet few studies have been performed regarding NoV. The association of histo-blood group antigens (HBGA) and susceptibility to NoV infection is well established in Caucasian populations with non-secretors being resistant to many common NoV strains. No study regarding HBGA and NoV susceptibility has yet been performed in Africa. We collected 309 stool and 208 saliva samples from diarrheal children in Ouagadougou, Burkina Faso; May 2009 to March 2010. NoV was detected using real-time PCR, and genotyped by sequencing. Saliva samples were ABO, Lewis and secretor phenotyped using in house ELISA assays. NoV was detected in 12% (n = 37) of the samples. The genotype diversity was unusually large; overall the 37 positive samples belonged to 14 genotypes. Only children <2 years of age were NoV positive and the GII.4 NoVs were more frequent in the late dry season (Jan-May). NoV infections were observed less in children with the secretor-negative phenotype or blood group A (OR 0.18; p = 0.012 and OR 0.31; p = 0.054; respectively), with two non-secretors infected with genotypes GII.7 and GII.4 respectively. Lewis-negative (Lea−b−) children, representing 32% of the study population, were susceptible to GII, but were not infected with any NoV GI. GII.4 strains preferentially infected children with blood group B whereas secretor-positive children with blood group O were infected with the largest variety of genotypes. This is the first study identifying host genetic factors associated with susceptibility to NoV in an African population, and suggests that while the non-secretor phenotype provides protection; the Lewis b antigen is not necessary for GII infection. PMID:23894502

  20. Genetic and dietary factors affecting human metabolism of 1,3-butadiene.

    PubMed

    Smith, T J; Lin, Y S; Mezzetti, M; Bois, F Y; Kelsey, K; Ibrahim, J

    2001-06-01

    The objective of this project was to determine the factors associated with differences in butadiene (BD) inhalation uptake and the rate of metabolism for BD to epoxy butene by monitoring exhaled breath during and after a brief exposure to BD in human volunteers. A total of 133 subjects (equal males and females; four racial groups) provided final data. Volunteers gave informed consent and completed a questionnaire including diet and alcohol use. A venous blood sample was collected for genotyping CYP2E1. Subjects received a 20 min exposure to 2.0 ppm of BD, followed by a 40 min washout period. The total administered dose was 0.6 ppm*h, which is in the range of everyday exposures. Ten, 1 or 2 min exhaled breath samples (five during and five after exposure) were collected using an optimized strategy. BD was determined by GC-FID analysis. Breathing activity (minute ventilation, breath frequency and tidal volume) was measured to estimate alveolar ventilation. After the washout period, 250 mg of chlorzoxazone were administered and urine samples collected for 6 h to measure 2E1 phenotype. The total BD uptake during exposure (inhaled BD minus exhaled) was estimated. A three-compartment PBPK model was fitted to each subject's breath measurements to estimate personal and population model parameters, including in-vivo BD metabolic rate. A hierarchical Bayesian PBPK model was fit by Monte Carlo simulations to estimate model parameters. Regression and ANOVA analyses were performed. Earlier data analysis showed wide ranges for both total uptake BD and metabolic rate. Both varied significantly by sex and age, and showed suggestive differences by race, with Asians having the highest rates. The analyses reported here found no correlation between total BD uptake and metabolic rate. No significant differences were found for oxidation rates by 2E1 genotype or phenotype, but the rates showed trends consistent with reported differences by genotype and phenotype for chlorzoxazone metabolism. No effects on metabolic rate were observed for long-term alcohol consumption, or consumption in the past 24 h. Overall, neither dietary factors nor genetic differences explained much of the wide variability in metabolic rates. Population characteristics, age, sex, and race, were the most important explanatory variables, but a large fraction of the total variability in metabolism remains to be explained. PMID:11397404

  1. Genetic Factors Affecting Susceptibility to Low Dose & Low Dose-Rate Radiation

    SciTech Connect

    Bedford, Joel

    2014-04-18

    Our laboratory has, among other things, developed and used the gamma H2AX focus assay and other chromosomal and cell killing assays to show that differences in this DNA double strand break (dsb) related response can be clearly and distinctly demonstrated for cells which are mildly hyper-radiosensitive such as those associated with A-T heterozygosity. We have found this level of mild hypersensitivity for cells from some 20 to 30 % of apparently normal individuals and from apparently normal parents of Retinoblastoma patients. We found significant differences in gene expression in somatic cells from unaffected parents of Rb patients as compared with normal controls, suggesting that these parents may harbor some as yet unidentified genetic abnormality. In other experiments we sought to determine the extent of differences in normal human cellular reaponses to radiation depending on their irradiation in 2D monolayer vs 3D organized acinar growth conditions. We exmined cell reproductive death, chromosomal aberration induction, and the levels of γ-H2AX foci in cells after single acute gamma-ray doses and immediately after 20 hours of irradiation at a dose rate of 0.0017 Gy/min. We found no significant differences in the dose-responses of these cells under the 2D or 3D growth conditions. While this does not mean such differences cannot occur in other situations, it does mean that they do not generally or necessarily occur. In another series of studies in collaboration with Dr Chuan Li, with supprt from this current grant. We reported a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. In yet another collaboration with Dr, B. Chen with funds from this grant, the relative radiosensitivity to cell killing as well as chromosomal instability of 13 DNA-PKcs site-directed mutant cell lines (defective at phosphorylation sites or kinase activity) were examined after exposure of synchronized G1 cells to 137Cs c rays. DNA-PKcs mutant cells defective in phosphorylation at multiple sites withinthe T2609 cluster or within the PI3K domain displayed extreme radiosensitivity. Cells defective at the S2056 cluster or T2609 single site alone were only mildly radiosensitive, but cells defective at even one site in both the S2056 and T2609 clusters were maximally radiosensitive. Thus a synergism between the capacity for phosphorylation at the S2056 and T2609 clusterswas found to be critical for induction of radiosensitivity.

  2. Alterations in the Cerebral White Matter of Genetic High Risk Offspring of Patients with Schizophrenia Spectrum Disorder

    PubMed Central

    Francis, Alan N; Bhojraj, Tejas S; Prasad, Konasale M.; Montrose, Debra; Eack, Shaun M; Rajarethinam, Rajaprabhakaran; van Elst, Ludger T; Keshavan, Matcheri S

    2012-01-01

    Alterations in White Matter (WM) may be seen in young relatives at risk and may underlie vulnerability to Schizophrenia. We were interested in exploring which of the WM regions were altered in adolescent offspring at familial risk for Schizophrenia. We examined structural alterations in the offspring of subjects with Schizophrenia or Schizoaffective disorder (HR; n=65; 36 males) and healthy controls (HC; n=80: 37 males) matched for age and education. MRI images were collected using a GE 1.5T scanner at the University of Pittsburgh Medical Center. Image processing was done using FreeSurfer (MGH) by an experienced rater blind to clinical data. We used multivariate analysis of covariance, with intracranial volume (p> 0.05) and age as covariates. High Risk offspring had significant reductions in total WM, hemispheric WM and WM within left parietal and left cingulate cortices. Male offspring had more pronounced right hemisphere WM reductions than females. PMID:22910323

  3. Genetic diversity affects testicular morphology in free-ranging lions (Panthera leo) of the Serengeti Plains and Ngorongoro Crater.

    PubMed

    Munson, L; Brown, J L; Bush, M; Packer, C; Janssen, D; Reiziss, S M; Wildt, D E

    1996-09-01

    Reduced genetic variability is known to adversely affect ejaculate quality in inbred lions (Panthera leo) physically isolated in the Ngorongoro Crater compared with outbred lions inhabiting the adjacent Serengeti Plains in East Africa. This study compared the histomorphology of testicular biopsies from these two lion populations. Ngorongoro Crater lions had fewer (P < 0.05) seminiferous tubules with spermiogenesis and fewer (P < 0.05) spermatids per seminiferous tubular cross-section than Serengeti Plains lions, although seminiferous tubular diameter did not differ (P > 0.05) between populations. Interstitial areas were greater (P < 0.05) in Crater than in Plains lions, but no qualitative differences were evident, suggesting that proportionately less testicular area was occupied by seminiferous tubules in Crater lions. None of the lions in either population had evidence of testicular degeneration. Overall results suggest that inbred Crater lions have reduced spermiogenesis and less total seminiferous tubular area per testis. These data further support the premise that genetic homogeneity compromises reproductive traits in free-living, male African lions. PMID:8958822

  4. Low frequency genetic variants in the mu-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine

    PubMed Central

    Clarke, Toni-Kim; Crist, Richard C.; Kampman, Kyle M.; Dackis, Charles A.; Pettinati, Helen M.; OBrien, Charles P.; Oslin, David W.; Ferraro, Thomas N.; Lohoff, Falk W.; Berrettini, Wade H.

    2013-01-01

    The ?-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.240.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. PMID:23454283

  5. FADS2 Genetic Variance in Combination with Fatty Acid Intake Might Alter Composition of the Fatty Acids in Brain

    PubMed Central

    Rizzi, Thais S.; van der Sluis, Sophie; Derom, Catherine; Thiery, Evert; van Kesteren, Ronald E.; Jacobs, Nele; Van Gestel, Sofie; Vlietinck, Robert; Verhage, Matthijs; Heutink, Peter; Posthuma, Danielle

    2013-01-01

    Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition. PMID:23826354

  6. FADS2 Genetic Variance in Combination with Fatty Acid Intake Might Alter Composition of the Fatty Acids in Brain.

    PubMed

    Rizzi, Thais S; van der Sluis, Sophie; Derom, Catherine; Thiery, Evert; van Kesteren, Ronald E; Jacobs, Nele; Van Gestel, Sofie; Vlietinck, Robert; Verhage, Matthijs; Heutink, Peter; Posthuma, Danielle

    2013-01-01

    Multiple lines of evidence suggest that fatty acids (FA) play an important role in cognitive function. However, little is known about the functional genetic pathways involved in cognition. The main goals of this study were to replicate previously reported interaction effects between breast feeding (BF) and FA desaturase (FADS) genetic variation on IQ and to investigate the possible mechanisms by which these variants might moderate BF effect, focusing on brain expression. Using a sample of 534 twins, we observed a trend in the moderation of BF effects on IQ by FADS2 variation. In addition, we made use of publicly available gene expression databases from both humans (193) and mice (93) and showed that FADS2 variants also correlate with FADS1 brain expression (P-value<1.1E-03). Our results provide novel clues for the understanding of the genetic mechanisms regulating FA brain expression and improve the current knowledge of the FADS moderation effect on cognition. PMID:23826354

  7. Phenotypic and genetic diversity in Sinorhizobium meliloti and S. medicae from drought and salt affected regions of Morocco

    PubMed Central

    2010-01-01

    Background Sinorhizobium meliloti and S. medicae are symbiotic nitrogen fixing bacteria in root nodules of forage legume alfalfa (Medicago sativa L.). In Morocco, alfalfa is usually grown in marginal soils of arid and semi-arid regions frequently affected by drought, extremes of temperature and soil pH, soil salinity and heavy metals, which affect biological nitrogen fixing ability of rhizobia and productivity of the host. This study examines phenotypic diversity for tolerance to the above stresses and genotypic diversity at Repetitive Extragenic Pallindromic DNA regions of Sinorhizobium nodulating alfalfa, sampled from marginal soils of arid and semi-arid regions of Morocco. Results RsaI digestion of PCR amplified 16S rDNA of the 157 sampled isolates, assigned 136 isolates as S. meliloti and the rest as S. medicae. Further phenotyping of these alfalfa rhizobia for tolerance to the environmental stresses revealed a large degree of variation: 55.41%, 82.16%, 57.96% and 3.18% of the total isolates were tolerant to NaCl (>513 mM), water stress (-1.5 MPa), high temperature (40°C) and low pH (3.5), respectively. Sixty-seven isolates of S. meliloti and thirteen isolates of S. medicae that were tolerant to salinity were also tolerant to water stress. Most of the isolates of the two species showed tolerance to heavy metals (Cd, Mn and Zn) and antibiotics (chloramphenicol, spectinomycin, streptomycin and tetracycline). The phenotypic clusters observed by the cluster analysis clearly showed adaptations of the S. meliloti and S. medicae strains to the multiple stresses. Genotyping with rep-PCR revealed higher genetic diversity within these phenotypic clusters and classified all the 157 isolates into 148 genotypes. No relationship between genotypic profiles and the phenotypes was observed. The Analysis of Molecular Variance revealed that largest proportion of significant (P < 0.01) genetic variation was distributed within regions (89%) than among regions (11%). Conclusion High degree of phenotypic and genotypic diversity is present in S. meliloti and S. medicae populations from marginal soils affected by salt and drought, in arid and semi-arid regions of Morocco. Some of the tolerant strains have a potential for exploitation in salt and drought affected areas for biological nitrogen fixation in alfalfa. PMID:20089174

  8. Expression profiling of the RPE in zebrafish smarca4 mutant revealed altered signals that potentially affect RPE and retinal differentiation

    PubMed Central

    Ma, Ping; Collery, Ross; Trowbridge, Sara; Zhong, Wenxuan; Leung, Yuk Fai

    2014-01-01

    Purpose The purpose of this study was to develop a framework for analyzing retinal pigment epithelium (RPE) expression profiles from zebrafish eye mutants. Methods The fish model we used was SWI/SNF-related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (smarca4), a retinal dystrophic mutant with a previously described retinal phenotype and expression profiles. Histological and Affymetrix GeneChip analyses were conducted to characterize the RPE defects and underlying differential expression, respectively. Results Histological analysis revealed that smarca4 RPE was formed, but its differentiation was abnormal. In particular, ultrastructural analysis of smarca4 RPE by transmission electron microscopy demonstrated several defects in melanogenesis. The nature of these defects also suggests that the cytoskeletal dynamics, which are tightly linked with melanogenesis, were impaired in smarca4 RPE. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, the gene expression profiles of microdissected retinas and RPE-attached retinas were measured with Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples by subtracting the retinal expression values from the expression values of the RPE-attached retinas. A factorial analysis was conducted using the expression values of the RPE, retinal, and whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted models to select for three groups of genes: 1) smarca4-regulated RPE genes, 2) smarca4-regulated retinal genes, and 3) smarca4-regulated RPE genes that are not differentially expressed in the retina. Interestingly, the third group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, and paracrine and intracellular signal transduction. Conclusions Our analytical framework provides an experimental approach to identify differentially-regulated genes in the retina and the RPE of zebrafish mutants in which both of these tissues are affected by the underlying mutation. Specifically, we have used the method to identify a group of 39 genes that can potentially explain the melanogenesis defect in the smarca4 RPE. In addition, several genes in this group are secreted signaling molecules. Thus, this observation further implicates that the smarca4 RPE might play a role in the retinal dystrophic phenotype in smarca4. PMID:24426776

  9. Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adult members of affected families.

    PubMed Central

    McKenna, W. J.; Spirito, P.; Desnos, M.; Dubourg, O.; Komajda, M.

    1997-01-01

    The diagnosis of hypertrophic cardiomyopathy has relied on echocardiographic demonstration of unexplained left ventricular hypertrophy. The prevalence of hypertrophic cardiomyopathy defined in this way has been estimated to be 1:500 and experience indicates that these criteria are relatively specific when other causes of left ventricular hypertrophy are absent. In recent years, however, the systematic evaluation of pedigrees performed in the context of molecular genetic studies revealed that in some families with hypertrophic cardiomyopathy up to 20% of adults who carry a disease causing gene defect do not fulfil conventional echocardiographic criteria. None the less, most of these individuals show symptoms, electrocardiographic alterations, and/or minor echocardiographic abnormalities. Revised diagnostic criteria in members of families with hypertrophic cardiomyopathy are proposed, including major and minor criteria based on symptoms, and electrocardiographic and echocardiographic abnormalities. Given that the chance of inheriting the gene defect is 1:2, the likelihood that symptoms plus electrocardiographic or echocardiographic abnormalities are the expression of a disease causing gene is high. PMID:9068395

  10. Housing systems interacting with sex and genetic line affect broiler growth and carcass traits.

    PubMed

    Zhao, Xiaoling; Ren, Wenshi; Siegel, Paul B; Li, Juan; Yin, Huadong; Liu, Yiping; Wang, Yan; Zhang, Yao; Honaker, Christa F; Zhu, Qing

    2015-07-01

    Housing systems used in the production of poultry meat vary worldwide dependent on climate, land availability, and other resources essential for production. Reported here are comparisons between pen and cage rearing (the housing system, denoted HS: ), line crosses LC: ), two native Chinese lines (EM males were mated to Y1 and Y2 and their offspring denoted as EMY1 and EMY2), and sex in determining broiler traits. At hatch, 320 males and 320 females from each LC (giving a total of 1,280 chicks) were randomly assigned within each subgroup to 16 battery pens. There were 4 replicates for each combination of LC by sex. On d 28, half of the chicks were transferred to indoor floor pens, and the others were raised in single cages from d 29 to 91. Weekly body weights, livability, and feed conversion ratios ( FCR: ) were obtained to d 91, the age at which the broilers were slaughtered for carcass measurements. The caged males and females were heavier (P < 0.05) than their penned counterparts (2,292 vs 2,219 g). Except for females from line EMY1 (94.9%), the livability for each unit from 1 to 28 d, and 29 to 91 d was greater than 95%. Penned EMY2 broilers had the highest FCR (3.02), whereas penned EMY1 broilers had the lowest FCR (2.96) among the housing systems by LC combinations (P < 0.05). Caged chickens had thicker subcutaneous fat (7.24 mm), a higher percentages of abdominal fat (5.01%) and liver mass (3.13%) , but lower eviscerated carcass (60.63%) and breast muscle weights (pectoralis major and minor, 17.10%). Males were heavier and had higher percentages of leg muscle (boneless drum plus thigh, 24.22%) and heart muscle (1.08%) than the females (P < 0.05). However, the females had thicker subcutaneous fat (7.19 mm) and higher percentages of carcass weight (87.28%), breast muscle (18.11%), abdominal fat (6.54%), and liver mass (3.15%) than males. Penned females had the highest percentage of breast muscle (18.94%), and caged females had the highest percentage of liver mass (3.72%). Females of EMY1 had the highest percentage of breast muscle (18.40%). Generally, the housing system employed and the sex of the broilers greatly affect the carcass traits. PMID:26009754

  11. The new CRISPR-Cas system: RNA-guided genome engineering to efficiently produce any desired genetic alteration in animals.

    PubMed

    Seruggia, Davide; Montoliu, Lluis

    2014-10-01

    The CRISPR-Cas system is the newest targeted nuclease for genome engineering. In less than 1year, the ease, robustness and efficiency of this method have facilitated an immense range of genetic modifications in most model organisms. Full and conditional gene knock-outs, knock-ins, large chromosomal deletions and subtle mutations can be obtained using combinations of clustered regularly interspaced short palindromic repeats (CRISPRs) and DNA donors. In addition, with CRISPR-Cas compounds, multiple genetic modifications can be introduced seamlessly in a single step. CRISPR-Cas not only brings genome engineering capacities to species such as rodents and livestock in which the existing toolbox was already large, but has also enabled precise genetic engineering of organisms with difficult-to-edit genomes such as zebrafish, and of technically challenging species such as non-human primates. The CRISPR-Cas system allows generation of targeted mutations in mice, even in laboratories with limited or no access to the complex, time-consuming standard technology using mouse embryonic stem cells. Here we summarize the distinct applications of CRISPR-Cas technology for obtaining a variety of genetic modifications in different model organisms, underlining their advantages and limitations relative to other genome editing nucleases. We will guide the reader through the many publications that have seen the light in the first year of CRISPR-Cas technology. PMID:25092533

  12. Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas.

    PubMed

    Knobbe, C B; Trampe-Kieslich, A; Reifenberger, G

    2005-10-01

    Glioblastomas frequently carry genetic alterations resulting in an aberrant activation of the phosphoinositol-3-kinase (Pi3k)/protein kinase B (Akt) signalling pathway, including most notably phosphatase and tensin homolog (PTEN) mutation, epidermal growth factor receptor (EGFR) amplification and rearrangement, as well as carboxyl-terminal modulator protein (CTMP) hypermethylation [Knobbe et al., (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Institute, 96, 483-486]. Here, we investigated two further Pi3k/Akt pathway genes, namely PIK3CA (3q26.3) and phosphatidylinositol-3-kinase enhancer (PIKE) (CENTG1, 12q14), for genetic alteration and aberrant expression in a series of 97 primary glioblastomas. Single strand conformation polymorphism (SSCP) analysis of PIK3CA revealed somatic mutations in five tumours (5%). Twelve glioblastomas (12%) showed amplification of PIKE with invariable co-amplification of the adjacent CDK4 gene. All tumours with PIKE amplification as well as the vast majority of glioblastomas without amplification demonstrated increased expression of PIKE-A but not PIKE-S/L transcripts as compared with non-neoplastic brain tissue. Taken together, our data support an important role of PIK3CA and PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas. PMID:16150119

  13. Alteration of sexual reproduction and genetic diversity in the kelp species Laminaria digitata at the southern limit of its range.

    PubMed

    Oppliger, Luz Valeria; von Dassow, Peter; Bouchemousse, Sarah; Robuchon, Marine; Valero, Myriam; Correa, Juan A; Mauger, Stphane; 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

  14. 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

  15. Genetic and biochemical characterization of mutations affecting the ability of the yeast Pachysolen tannophilus to metabolize D-xylose

    SciTech Connect

    James, A.P.; Zahab, D.M.; Mahmourides, G.; Maleszka, R.; Schneider, H. )

    1989-11-01

    Induced mutants, selected for their defective growth on D-xylose while retaining the ability to grow normally on D-glucose, were studied in Pachysolen tannophilus, a yeast capable of converting D-xylose to ethanol. Fourteen of the mutations were found to occur at nine distinct loci, and data indicated that many more loci remain to be detected. Most of the mutations were pleiotropic in character, and the expression of some of them was much affected by nutritional conditions and by genetic background. Mutations at several loci resulted in poor growth on at least one compound that was either an intermediate of the tricarboxylic acid cycle, succinate or {alpha}-ketoglutarate, or on compounds metabolizable via this cycle, ethanol or glycerol. An initial biochemical characterization of the mutants was undertaken. Analysis for xylose reductase, xylitol dehydrogenase, and xylulose kinase activity showed that one or more of these activities was affected in 12 of 13 mutants. However, drastic reduction in activity of a single enzyme was confined to that of xylitol dehydrogenase by mutations at three different loci and to that of D-xylose reductase by mutation at another locus. Growth of these latter four mutants was normal on all carbon sources tested that were not five-carbon sugars.

  16. Lessons Learned from Whole Exome Sequencing in Multiplex Families Affected by a Complex Genetic Disorder, Intracranial Aneurysm

    PubMed Central

    Farlow, Janice L.; Lin, Hai; Sauerbeck, Laura; Lai, Dongbing; Koller, Daniel L.; Pugh, Elizabeth; Hetrick, Kurt; Ling, Hua; Kleinloog, Rachel; van der Vlies, Pieter; Deelen, Patrick; Swertz, Morris A.; Verweij, Bon H.; Regli, Luca; Rinkel, Gabriel J. E.; Ruigrok, Ynte M.; Doheny, Kimberly; Liu, Yunlong; Broderick, Joseph; Foroud, Tatiana

    2015-01-01

    Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study. PMID:25803036

  17. Multiple Genetic Alterations within the PI3K Pathway Are Responsible for AKT Activation in Patients with Ovarian Carcinoma

    PubMed Central

    De Marco, Carmela; Rinaldo, Nicola; Bruni, Paola; Malzoni, Carmine; Zullo, Fulvio; Fabiani, Fernanda; Losito, Simona; Scrima, Marianna; Marino, Federica Zito; Franco, Renato; Quintiero, Alfina; Agosti, Valter; Viglietto, Giuseppe