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Sample records for genetic factors modulating

  1. Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets.

    Science.gov (United States)

    Fazlollahi, Mina; Muroff, Ivor; Lee, Eunjee; Causton, Helen C; Bussemaker, Harmen J

    2016-03-29

    Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

  2. Splicing factors act as genetic modulators of TDP-43 production in a new autoregulatory TDP-43 Drosophila model.

    Science.gov (United States)

    Pons, Marine; Miguel, Laetitia; Miel, Camille; Avequin, Tracey; Juge, François; Frebourg, Thierry; Campion, Dominique; Lecourtois, Magalie

    2017-09-01

    TDP-43 is a critical RNA-binding factor associated with RNA metabolism. In the physiological state, maintaining normal TDP-43 protein levels is critical for proper physiological functions of the cells. As such, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. TDP-43 is a major disease-causing protein in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). Several studies argue for a pathogenic role of elevated TDP-43 levels in these disorders. Modulating the cycle of TDP-43 production might therefore provide a new therapeutic strategy. In this study, we developed a new transgenic Drosophila model mimicking the TDP-43 autoregulatory feedback loop in order to identify genetic modulators of TDP-43 protein steady-state levels in vivo. First, we showed that our TDP-43_TDPBR Drosophila model recapitulates key features of the TDP-43 autoregulatory processes previously described in mammalian and cellular models, namely alternative splicing events, differential usage of polyadenylation sites, nuclear retention of the transcript and a decrease in steady-state mRNA levels. Using this new Drosophila model, we identified several splicing factors, including SF2, Rbp1 and Sf3b1, as genetic modulators of TDP-43 production. Interestingly, our data indicate that these three RNA-binding proteins regulate TDP-43 protein production, at least in part, by controlling mRNA steady-state levels. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. Genetic factors modulate the impact of pubertal androgen excess on insulin sensitivity and fertility.

    Directory of Open Access Journals (Sweden)

    Abigail R Dowling

    Full Text Available Polycystic ovary syndrome (PCOS is the most common endocrine disorder of reproductive age women. The syndrome is caused by a combination of environmental influences and genetic predisposition. Despite extensive efforts, the heritable factors contributing to PCOS development are not fully understood. The objective of this study was to test the hypothesis that genetic background contributes to the development of a PCOS-like reproductive and metabolic phenotype in mice exposed to excess DHEA during the pubertal transition. We tested whether the PCOS phenotype would be more pronounced on the diabetes-prone C57BL/6 background than the previously used strain, BALB/cByJ. In addition, we examined strain-dependent upregulation of the expression of ovarian and extra-ovarian candidate genes implicated in human PCOS, genes containing known strain variants, and genes involved with steroidogenesis or insulin sensitivity. These studies show that there are significant strain-related differences in metabolic response to excess androgen exposure during puberty. Additionally, our results suggest the C57BL/6J strain provides a more robust and uniform experimental platform for PCOS research than the BALB/cByJ strain.

  4. Genetic modulation of the FV(Leiden)/normal FV ratio and risk of venous thrombosis in factor V Leiden heterozygotes.

    Science.gov (United States)

    Segers, O; Simioni, P; Tormene, D; Bulato, C; Gavasso, S; Rosing, J; Castoldi, Elisabetta

    2012-01-01

    The factor (F)V Leiden mutation causes activated protein C (APC) resistance by decreasing the susceptibility of FVa to APC-mediated inactivation and by impairing the APC-cofactor activity of FV in FVIIIa inactivation. However, APC resistance and the risk of venous thromboembolism (VTE) vary widely among FV Leiden heterozygotes. Common F5 genetic variation probably contributes to this variability. APC resistance was determined in 250 FV Leiden heterozygotes and 133 normal relatives using the prothrombinase-based assay, which specifically measures the susceptibility of plasma FVa to APC. The effects of 12 F5 single-nucleotide polymorphisms (SNPs) on the normalized APC sensitivity ratio (nAPCsr) and on FV levels were determined by multiple regression analysis. In FV Leiden heterozygotes,VTE risk increased with increasing nAPCsr, reaching an odds ratio (OR) of 9.9 (95% confidence interval [CI] 1.2–80.5) in the highest nAPCsr quartile. The minor alleles of several F5 SNPs, including 327 A/G (Q51Q), 409 G/C (D79H), 2663 A/G(K830R, T2 haplotype), 6533 T/C (M2120T) and 6755 A/G (D2194G, R2 haplotype), increased the nAPCsr in FV Leiden heterozygotes, but not in their normal relatives. Most of these effects could be attributed to a shift in the FV(Leiden)/normal FV ratio. Four FV Leiden heterozygotes with extremely high nAPCsr turned out to be pseudo-homozygotes, i.e. they carried a deleterious mutation on the non-Leiden allele. In FV Leiden heterozygotes, the prothrombinase-based nAPCsr is a marker of VTE risk and is modulated by common F5 SNPs that affect the FV(Leiden)/normal FV ratio in plasma.

  5. Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

    Science.gov (United States)

    Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

    2016-09-01

    Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. Landscape genetics and limiting factors

    Science.gov (United States)

    Samuel A. Cushman; Andrew J. Shirk; Erin L. Landguth

    2013-01-01

    Population connectivity is mediated by the movement of organisms or propagules through landscapes. However, little is known about how variation in the pattern of landscape mosaics affects the detectability of landscape genetic relationships. The goal of this paper is to explore the impacts of limiting factors on landscape genetic processes using simulation...

  7. Analog Module Placement Design Using Genetic Algorithm

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    This paper presents a novel genetic algorithm for analog module placement based on ageneralization of the two-dimensional bin packing problem. The genetic encoding and operators assure that allproblem constraints are always satisfied. Thus the potential problems of adding penalty terms to the costfunction are eliminated so that the search configuration space is drastically decreased. The dedicated costfunction is based on the special requirements of analog integrated circuits. A fractional factorial experimentwas conducted using an orthogonal array to study the algorithm parameters. A meta GA was applied todetermine the optimal parameter values. The algorithm was tested with several local benchmark circuits. Theexperimental results show that the algorithm has better performance than the simulated annealing approachwith satisfactory results comparable to manual placement. This study demonstrates the effectiveness of thegenetic algorithm in the analog module placement problem. The algorithm has been successfully used in alayout synthesis tool.

  8. Congenic mice provide in vivo evidence for a genetic locus that modulates intrinsic transforming growth factor β1-mediated signaling and bone acquisition.

    Science.gov (United States)

    Mukherjee, Aditi; Larson, Emily A; Carlos, Amy S; Belknap, John K; Rotwein, Peter; Klein, Robert F

    2012-06-01

    Osteoporosis, the most common skeletal disorder, is characterized by low bone mineral density (BMD) and an increased risk of fragility fractures. BMD is the best clinical predictor of future osteoporotic fracture risk, but is a complex trait controlled by multiple environmental and genetic determinants with individually modest effects. Quantitative trait locus (QTL) mapping is a powerful method for identifying chromosomal regions encompassing genes involved in shaping complex phenotypes, such as BMD. Here we have applied QTL analysis to male and female genetically-heterogeneous F(2) mice derived from a cross between C57BL/6 and DBA/2 strains, and have identified 11 loci contributing to femoral BMD. Further analysis of a QTL on mouse chromosome 7 following the generation of reciprocal congenic strains has allowed us to determine that the high BMD trait, which tracks with the DBA/2 chromosome and exerts equivalent effects on male and female mice, is manifested by enhanced osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and by increased growth of metatarsal bones in short-term primary culture. An insertion/deletion DNA polymorphism in Ltbp4 exon 12 that causes the in-frame removal of 12 codons in the DBA/2-derived gene maps within 0.6 Mb of the marker most tightly linked to the QTL. LTBP4, one of four paralogous mouse proteins that modify the bioavailability of the transforming growth factor β (TGF-β) family of growth factors, is expressed in differentiating MSC-derived osteoblasts and in long bones, and reduced responsiveness to TGF-β1 is observed in MSCs of mice homozygous for the DBA/2 chromosome 7. Taken together, our results identify a potential genetic and biochemical relationship between decreased TGF-β1-mediated signaling and enhanced femoral BMD that may be regulated by a variant LTBP4 molecule. Copyright © 2012 American Society for Bone and Mineral Research.

  9. Liver fibrogenesis and genetic factors.

    Science.gov (United States)

    Boursier, Jérôme; Louvet, Alexandre

    2011-06-01

    Chronic liver diseases lead to the accumulation of fibrosis in the liver with eventual progression to cirrhosis and its complications. However, there is a wide range of inter-individual variation in the liver fibrogenesis process, thus posing a challenge to physicians to identify patients with poor prognosis. As demographic and environmental factors only account for a small portion of fibrogenesis variability, host genetic factors have been suggested as playing an important role. Due to technical limitations, the first genetic studies were restricted to the evaluation of candidate genes having a known or supposed function in liver fibrogenesis. Recently, technological improvements have made it possible to study the whole human genome in a single scan. Genome-wide association studies have considerably heightened the interest in genetics as part of the study of liver fibrogenesis through their identification of previously unsuspected genes that are statistically associated with liver fibrosis. It is thus possible to determine new diagnostic or prognostic genetic markers for the management of patients with chronic liver diseases. Moreover, functional analyses of these genes may provide new insights into the pathophysiology of liver fibrogenesis.

  10. Genetic engineering and coagulation factors.

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    Fass, D N; Toole, J J

    1985-06-01

    It is unfortunate that we cannot report, in the area of coagulation, advances that have been seen in related fields such as thrombolytic therapy. The reported progress (Gold et al, 1984; Van de Werf et al, 1984) with human recombinant tissue plasminogen activator (Pennica et al, 1983) augers well for the application of recombinant technology to the problems faced by patients with coagulation defects. While plasminogen activator is being assessed in an acute therapeutic setting, its use signals a beginning of the application of the technology to abnormalities of the haemostatic mechanism. Chronic administration of coagulation factors for prophylaxis and replacement therapy would appear to be just one more step down the pathway illuminated by the biochemists, microbiologists and cell biologists who have preceded the clinicians in this promising area. There is no record of the use of genetically engineered materials in the treatment of coagulation defects, primarily because the body of knowledge and refined techniques have only recently been acquired. For this reason we have had to project developments in other areas onto the problems that exist for the haemostatically compromised patient. In describing the potential usefulness of these technologies, it is difficult to ascertain where the logical projection, from a fully investigated model system, diverges from flights of imaginative fancy. Cloning projects considered overly ambitious and grandiose at the beginning of this decade are already accomplished feats. The feasibility of gene therapy in the mammalian system has been demonstrated, and trade publications now discuss governmental approval for investigative use of this procedure in 1985. Panels of physicians, scientists and even politicians now seriously contemplate and promulgate views and regulations pertaining to the efficacy and ethics of the use of genetic engineering in the treatment of human disease. The haemophilias will certainly be among the first

  11. Modulation of DNA binding by gene-specific transcription factors.

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    Schleif, Robert F

    2013-10-01

    The transcription of many genes, particularly in prokaryotes, is controlled by transcription factors whose activity can be modulated by controlling their DNA binding affinity. Understanding the molecular mechanisms by which DNA binding affinity is regulated is important, but because forming definitive conclusions usually requires detailed structural information in combination with data from extensive biophysical, biochemical, and sometimes genetic experiments, little is truly understood about this topic. This review describes the biological requirements placed upon DNA binding transcription factors and their consequent properties, particularly the ways that DNA binding affinity can be modulated and methods for its study. What is known and not known about the mechanisms modulating the DNA binding affinity of a number of prokaryotic transcription factors, including CAP and lac repressor, is provided.

  12. Integrative genetic analysis of transcription modules: towards filling the gap between genetic lociand inherited traits

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hongqiang [University of Tennessee Health Science Center, Memphis; Chen, Hao [University of Tennessee Health Science Center, Memphis; Bao, Lei [University of Tennessee Health Science Center, Memphis; Manly, Kenneth [University of Tennessee Health Science Center, Memphis; Chesler, Elissa J [ORNL; Lu, Lu [University of Tennessee Health Science Center, Memphis; Wang, Jintao [University of Tennessee Health Science Center, Memphis; Zhou, Mi [University of Tennessee Health Science Center, Memphis; Williams, Robert [University of Tennessee Health Science Center, Memphis; Cui, Yan [University of Tennessee Health Science Center, Memphis

    2005-01-01

    Genetic loci that regulate inherited traits are routinely identified using quantitative trait locus (QTL) mapping methods. However, the genotype-phenotype associations do not provide information on the gene expression program through which the genetic loci regulate the traits. Transcription modules are 'selfconsistent regulatory units' and are closely related to the modular components of gene regulatory network [Ihmels, J., Friedlander, G., Bergmann, S., Sarig, O., Ziv, Y. and Barkai, N. (2002) Revealing modular organization in the yeast transcriptional network. Nat. Genet., 31, 370-377; Segal, E., Shapira, M., Regev, A., Pe'er, D., Botstein, D., Koller, D. and Friedman, N. (2003) Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat. Genet., 34, 166-176]. We used genome-wide genotype and gene expression data of a genetic reference population that consists of mice of 32 recombinant inbred strains to identify the transcription modules and the genetic loci regulating them. Twenty-nine transcription modules defined by genetic variations were identified. Statistically significant associations between the transcription modules and 18 classical physiological and behavioral traits were found. Genome-wide interval mapping showed that major QTLs regulating the transcription modules are often co-localized with the QTLs regulating the associated classical traits. The association and the possible co-regulation of the classical trait and transcription module indicate that the transcription module may be involved in the gene pathways connecting the QTL and the classical trait. Our results show that a transcription module may associate with multiple seemingly unrelated classical traits and a classical trait may associate with different modules. Literature mining results provided strong independent evidences for the relations among genes of the transcription modules, genes in the regions of the QTLs

  13. An unbiased systems genetics approach to mapping genetic loci modulating susceptibility to severe streptococcal sepsis.

    Directory of Open Access Journals (Sweden)

    Nourtan F Abdeltawab

    2008-04-01

    Full Text Available Striking individual differences in severity of group A streptococcal (GAS sepsis have been noted, even among patients infected with the same bacterial strain. We had provided evidence that HLA class II allelic variation contributes significantly to differences in systemic disease severity by modulating host responses to streptococcal superantigens. Inasmuch as the bacteria produce additional virulence factors that participate in the pathogenesis of this complex disease, we sought to identify additional gene networks modulating GAS sepsis. Accordingly, we applied a systems genetics approach using a panel of advanced recombinant inbred mice. By analyzing disease phenotypes in the context of mice genotypes we identified a highly significant quantitative trait locus (QTL on Chromosome 2 between 22 and 34 Mb that strongly predicts disease severity, accounting for 25%-30% of variance. This QTL harbors several polymorphic genes known to regulate immune responses to bacterial infections. We evaluated candidate genes within this QTL using multiple parameters that included linkage, gene ontology, variation in gene expression, cocitation networks, and biological relevance, and identified interleukin1 alpha and prostaglandin E synthases pathways as key networks involved in modulating GAS sepsis severity. The association of GAS sepsis with multiple pathways underscores the complexity of traits modulating GAS sepsis and provides a powerful approach for analyzing interactive traits affecting outcomes of other infectious diseases.

  14. Assessment of DNA damage and its modulation by dietary and genetic factors in smokers using the Comet assay: a biomarker model.

    Science.gov (United States)

    Glei, M; Habermann, N; Osswald, K; Seidel, C; Persin, C; Jahreis, G; Pool-Zobel, B L

    2005-01-01

    Methods are needed to assess exposure to genotoxins in humans and to improve understanding of dietary cancer prevention. The Comet assay was used to detect smoking-related exposures and dietary modulations in target tissues. Buccal scrapings, blood and faeces were collected from 38 healthy male volunteers (smokers and non-smokers) during a dietary intervention study with bread supplemented with prebiotics+/-antioxidants. GSTM1-genotype was determined with PCR. Buccal and peripheral lymphocytes were analysed for DNA damage using the Comet assay. Genotoxicity of faecal water (FW) was assayed in human colon HT29 clone 19A cells. 'Tail intensity' (TI) was used as a quantitative indicator of DNA damage in the Comet assay. Intervention with bread reduced DNA damage in lymphocytes of smokers (8.3+/-1.7% TI versus 10.2+/-4.1% TI, n=19), but not of non-smokers (8.6+/-2.8% TI versus 8.3+/-2.7% TI, n=15). Faecal water genotoxicity was reduced only in non-smokers (9.4+/-2.9% TI versus 18.9+/-13.1% TI, n=15) but not in smokers (15.5+/-10.7% TI versus 20.4+/-14.1% TI, n=13). The Comet assay was efficient in the detection of both smoking-related exposure (buccal cells) and efficacy of dietary intervention (faecal samples). Smokers and non-smokers profited differently from the intervention with prebiotic bread+/-antioxidants. Stratification of data by genotype enhanced specificity/sensitivity of the intervention effects and contributed important information on the role of susceptibility.

  15. Genetic Factors of Ophthalmic Importance.

    Science.gov (United States)

    Pollard, Zane F.

    Reviewed are chromosomal anomalies affecting one's eyes. Brief descriptions are given of the genetic etiology of bilateral retinoblastoma (malignant tumors), aniridia (absence of the iris), cataracts, congenital glaucoma, Reginitis Pigmentosa (progressive deterioration of the visual cells), Choroidermia (degeneration of the vascular coat of the…

  16. Genetic Factors of Ophthalmic Importance.

    Science.gov (United States)

    Pollard, Zane F.

    Reviewed are chromosomal anomalies affecting one's eyes. Brief descriptions are given of the genetic etiology of bilateral retinoblastoma (malignant tumors), aniridia (absence of the iris), cataracts, congenital glaucoma, Reginitis Pigmentosa (progressive deterioration of the visual cells), Choroidermia (degeneration of the vascular coat of the…

  17. Force Factor Modulation in Electro Dynamic Loudspeakers

    DEFF Research Database (Denmark)

    Risbo, Lars; Agerkvist, Finn T.; Tinggaard, Carsten

    2016-01-01

    The relationship between the non-linear phenomenon of ’reluctance force’ and the position dependency of the voice coil inductance was established in 1949 by Cunningham, who called it ’magnetic attraction force’. This paper revisits Cunningham’s analysis and expands it into a generalised form...... that includes the frequency dependency and applies to coils with non-inductive (lossy) blocked impedance. The paper also demonstrates that Cunningham’s force can be explained physically as a modulation of the force factor which again is directly linked to modulation of the flux of the coil. A verification based...... on both experiments and simulations is presented along discussions of the impact of force factor modulation for various motor topologies. Finally, it is shown that the popular L2R2 coil impedance model does not correctly predict the force unless the new analysis is applied....

  18. Force Factor Modulation in Electro Dynamic Loudspeakers

    DEFF Research Database (Denmark)

    Risbo, Lars; Agerkvist, Finn T.; Tinggaard, Carsten

    2016-01-01

    The relationship between the non-linear phenomenon of ’reluctance force’ and the position dependency of the voice coil inductance was established in 1949 by Cunningham, who called it ’magnetic attraction force’. This paper revisits Cunningham’s analysis and expands it into a generalised form that...... on both experiments and simulations is presented along discussions of the impact of force factor modulation for various motor topologies. Finally, it is shown that the popular L2R2 coil impedance model does not correctly predict the force unless the new analysis is applied....... that includes the frequency dependency and applies to coils with non-inductive (lossy) blocked impedance. The paper also demonstrates that Cunningham’s force can be explained physically as a modulation of the force factor which again is directly linked to modulation of the flux of the coil. A verification based...

  19. Interaction between lifestyle factors and the XRCC1, XPD, and XRCC3 genetic variations modulates the risk for sporadic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Procopciuc Lucia Maria

    2014-03-01

    , fumatul în asociere cu variația genetică Arg399Gln-XRCC1 influențează debutul timpuriu al cancerului colorectal sporadic. Tot în cazul femeilor, dieta bogată în carne roșie prăjită în asociere cu variațiile genetice Arg399Gln-XRCC1, Lys751Gln-XPD și Thr241Met- XRCC3 influențează semnificativ riscul de apariție al cancerului colorectal sporadic.

  20. Modulation of the Genome and Epigenome of Individuals Susceptible to Autism by Environmental Risk Factors

    Directory of Open Access Journals (Sweden)

    Costas Koufaris

    2015-04-01

    Full Text Available Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD. Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the incidence of ASD is not well understood. A greater understanding of the metabolic, cellular, and biochemical events involved in gene x environment interactions in ASD would have important implications for the prevention and possible treatment of the disorder. In this review we discuss various established and more alternative processes through which environmental factors implicated in ASD can modulate the genome and epigenome of genetically-susceptible individuals.

  1. Gestalt factors modulate basic spatial vision.

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    Sayim, B; Westheimer, G; Herzog, M H

    2010-05-01

    Human perception of a stimulus varies depending on the context in which the stimulus is presented. Such contextual modulation has often been explained by two basic neural mechanisms: lateral inhibition and spatial pooling. In the present study, we presented observers with a vernier stimulus flanked by single lines; observers' ability to discriminate the offset direction of the vernier stimulus deteriorated in accordance with both explanations. However, when the flanking lines were part of a geometric shape (i.e., a good Gestalt), this deterioration strongly diminished. These findings cannot be explained by lateral inhibition or spatial pooling. It seems that Gestalt factors play an important role in contextual modulation. We propose that contextual modulation can be used as a quantitative measure to investigate the rules governing the grouping of elements into meaningful wholes.

  2. Genetic risk factors for autoimmune diseases

    NARCIS (Netherlands)

    Feltkamp, T.E.W.; Aarden, L.A.; Lucas, C.J.; Verweij, C.L.; Vries, R.R.P. de

    1999-01-01

    In most autoimmune diseases multigenic factors play a significant role in pathogenesis. Progress in identifying these genetic factors, many of which are located outside the major histocompatibility complex, was the subject of a recent meeting. Chemicals/CAS: Interleukin-10, 130068-27-8; Transforming

  3. Stroke Risk Factors, Genetics, and Prevention.

    Science.gov (United States)

    Boehme, Amelia K; Esenwa, Charles; Elkind, Mitchell S V

    2017-02-03

    Stroke is a heterogeneous syndrome, and determining risk factors and treatment depends on the specific pathogenesis of stroke. Risk factors for stroke can be categorized as modifiable and nonmodifiable. Age, sex, and race/ethnicity are nonmodifiable risk factors for both ischemic and hemorrhagic stroke, while hypertension, smoking, diet, and physical inactivity are among some of the more commonly reported modifiable risk factors. More recently described risk factors and triggers of stroke include inflammatory disorders, infection, pollution, and cardiac atrial disorders independent of atrial fibrillation. Single-gene disorders may cause rare, hereditary disorders for which stroke is a primary manifestation. Recent research also suggests that common and rare genetic polymorphisms can influence risk of more common causes of stroke, due to both other risk factors and specific stroke mechanisms, such as atrial fibrillation. Genetic factors, particularly those with environmental interactions, may be more modifiable than previously recognized. Stroke prevention has generally focused on modifiable risk factors. Lifestyle and behavioral modification, such as dietary changes or smoking cessation, not only reduces stroke risk, but also reduces the risk of other cardiovascular diseases. Other prevention strategies include identifying and treating medical conditions, such as hypertension and diabetes, that increase stroke risk. Recent research into risk factors and genetics of stroke has not only identified those at risk for stroke but also identified ways to target at-risk populations for stroke prevention. © 2017 American Heart Association, Inc.

  4. Splicing modulation therapy in the treatment of genetic diseases

    Directory of Open Access Journals (Sweden)

    Arechavala-Gomeza V

    2014-12-01

    Full Text Available Virginia Arechavala-Gomeza,1 Bernard Khoo,2 Annemieke Aartsma-Rus3 1Neuromuscular Disorders Group, BioCruces Health Research Institute, Barakaldo, Bizkaia, Spain; 2Endocrinology, Division of Medicine, University College London, London, UK; 3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands All authors contributed equally to this manuscript Abstract: Antisense-mediated splicing modulation is a tool that can be exploited in several ways to provide a potential therapy for rare genetic diseases. This approach is currently being tested in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy. The present review outlines the versatility of the approach to correct cryptic splicing, modulate alternative splicing, restore the open reading frame, and induce protein knockdown, providing examples of each. Finally, we outline a possible path forward toward the clinical application of this approach for a wide variety of inherited rare diseases. Keywords: splicing, therapy, antisense oligonucleotides, cryptic splicing, alternative splicing

  5. Genetic factors affecting dental caries risk.

    Science.gov (United States)

    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.

  6. Genetic modulation of the pharmacological treatment of pain.

    Science.gov (United States)

    Lötsch, Jörn; Geisslinger, Gerd; Tegeder, Irmgard

    2009-11-01

    Inadequately treated acute and chronic pain remains a major cause of suffering and dissatisfaction in pain therapy. A cause for the variable success of pharmacologic pain therapy is the different genetic disposition of patients to develop pain or to respond to analgesics. The patient's phenotype may be regarded as the result of synergistic or antagonistic effects of several genetic variants concomitantly present in an individual. Variants modulate the risk of developing painful disease or its clinical course (e.g., migraine, fibromyalgia, low back pain). Other variants modulate the perception of pain (e.g., OPRM1 or GCH1 variants conferring modest pain protection by increasing the tone of the endogenous opioid system or decreasing nitric oxide formation). Other polymorphisms alter pharmacokinetic mechanisms controlling the local availability of active analgesic molecules at their effector sites (e.g., decreased CYP2D6 related prodrug activation of codeine to morphine). In addition, genetic variants may alter pharmacodynamic mechanisms controlling the interaction of the analgesic molecules with their target structures (e.g., opioid receptor mutations). Finally, opioid dosage requirements may be increased depending on the risk of drug addiction (e.g., DRD2 polymorphisms decreasing the functioning of the dopaminergic reward system). With the complex nature of pain involving various mechanisms of nociception, drug action, drug pharmacology, pain disease and possibly substance addiction, a multigenic or even genome wide approach to genetics could be required to base individualized pain therapy on the patient's genotype.

  7. The Genetic and Environmental Factors for Keratoconus

    Science.gov (United States)

    Gordon-Shaag, Ariela; Millodot, Michel; Shneor, Einat; Liu, Yutao

    2015-01-01

    Keratoconus (KC) is the most common cornea ectatic disorder. It is characterized by a cone-shaped thin cornea leading to myopia, irregular astigmatism, and vision impairment. It affects all ethnic groups and both genders. Both environmental and genetic factors may contribute to its pathogenesis. This review is to summarize the current research development in KC epidemiology and genetic etiology. Environmental factors include but are not limited to eye rubbing, atopy, sun exposure, and geography. Genetic discoveries have been reviewed with evidence from family-based linkage analysis and fine mapping in linkage region, genome-wide association studies, and candidate genes analyses. A number of genes have been discovered at a relatively rapid pace. The detailed molecular mechanism underlying KC pathogenesis will significantly advance our understanding of KC and promote the development of potential therapies. PMID:26075261

  8. Human genetic factors in tuberculosis: an update.

    Science.gov (United States)

    van Tong, Hoang; Velavan, Thirumalaisamy P; Thye, Thorsten; Meyer, Christian G

    2017-09-01

    Tuberculosis (TB) is a major threat to human health, especially in many developing countries. Human genetic variability has been recognised to be of great relevance in host responses to Mycobacterium tuberculosis infection and in regulating both the establishment and the progression of the disease. An increasing number of candidate gene and genome-wide association studies (GWAS) have focused on human genetic factors contributing to susceptibility or resistance to TB. To update previous reviews on human genetic factors in TB we searched the MEDLINE database and PubMed for articles from 1 January 2014 through 31 March 2017 and reviewed the role of human genetic variability in TB. Search terms applied in various combinations were 'tuberculosis', 'human genetics', 'candidate gene studies', 'genome-wide association studies' and 'Mycobacterium tuberculosis'. Articles in English retrieved and relevant references cited in these articles were reviewed. Abstracts and reports from meetings were also included. This review provides a recent summary of associations of polymorphisms of human genes with susceptibility/resistance to TB. © 2017 John Wiley & Sons Ltd.

  9. Inferring modulators of genetic interactions with epistatic nested effects models.

    Science.gov (United States)

    Pirkl, Martin; Diekmann, Madeline; van der Wees, Marlies; Beerenwinkel, Niko; Fröhlich, Holger; Markowetz, Florian

    2017-04-01

    Maps of genetic interactions can dissect functional redundancies in cellular networks. Gene expression profiles as high-dimensional molecular readouts of combinatorial perturbations provide a detailed view of genetic interactions, but can be hard to interpret if different gene sets respond in different ways (called mixed epistasis). Here we test the hypothesis that mixed epistasis between a gene pair can be explained by the action of a third gene that modulates the interaction. We have extended the framework of Nested Effects Models (NEMs), a type of graphical model specifically tailored to analyze high-dimensional gene perturbation data, to incorporate logical functions that describe interactions between regulators on downstream genes and proteins. We benchmark our approach in the controlled setting of a simulation study and show high accuracy in inferring the correct model. In an application to data from deletion mutants of kinases and phosphatases in S. cerevisiae we show that epistatic NEMs can point to modulators of genetic interactions. Our approach is implemented in the R-package 'epiNEM' available from https://github.com/cbg-ethz/epiNEM and https://bioconductor.org/packages/epiNEM/.

  10. Age-related decline in brain resources modulates genetic effects on cognitive functioning

    Directory of Open Access Journals (Sweden)

    Ulman Lindenberger

    2008-12-01

    Full Text Available Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging.Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008, who reported that the effects of the Catechol-O-Methyltransferase (COMT gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed.

  11. Age-Related Decline in Brain Resources Modulates Genetic Effects on Cognitive Functioning

    Science.gov (United States)

    Lindenberger, Ulman; Nagel, Irene E.; Chicherio, Christian; Li, Shu-Chen; Heekeren, Hauke R.; Bäckman, Lars

    2008-01-01

    Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words) PMID:19225597

  12. Shared genetic factors in migraine and depression

    Science.gov (United States)

    Stam, A H.; de Vries, B; Janssens, A C.J.W.; Vanmolkot, K R.J.; Aulchenko, Y S.; Henneman, P; Oostra, B A.; Frants, R R.; van den Maagdenberg, A M.J.M.; Ferrari, M D.; van Duijn, C M.; Terwindt, G M.

    2010-01-01

    Objective: To investigate the co-occurrence of migraine and depression and assess whether shared genetic factors may underlie both diseases. Methods: Subjects were 2,652 participants of the Erasmus Rucphen Family genetic isolate study. Migraine was diagnosed using a validated 3-stage screening method that included a telephone interview. Symptoms of depression were assessed using the Center for Epidemiologic Studies Depression scale and the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). The contribution of shared genetic factors in migraine and depression was investigated by comparing heritability estimates for migraine with and without adjustment for symptoms of depression, and by comparing the heritability scores of depression between migraineurs and controls. Results: We identified 360 migraine cases: 209 had migraine without aura (MO) and 151 had migraine with aura (MA). Odds ratios for depression in patients with migraine were 1.29 (95% confidence interval [CI] 0.98–1.70) for MO and 1.70 (95% CI 1.28–2.24) for MA. Heritability estimates were significant for all migraine (0.56), MO (0.77), and MA (0.96), and decreased after adjustment for symptoms of depression or use of antidepressant medication, in particular for MA. Comparison of the heritability scores for depression between patients with migraine and controls showed a genetic correlation between HADS-D score and MA. Conclusions: There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors. GLOSSARY CES-D = Center for Epidemiologic Studies Depression Scale; CI = confidence interval; ERF = Erasmus Rucphen Family; HADS-D = Hospital Anxiety and Depression Scale; IHS = International Headache Society; MA = migraine with aura; MO = migraine without aura; OR = odds ratio. PMID:20071666

  13. Genetic and computational identification of a conserved bacterial metabolic module.

    Directory of Open Access Journals (Sweden)

    Cara C Boutte

    2008-12-01

    Full Text Available We have experimentally and computationally defined a set of genes that form a conserved metabolic module in the alpha-proteobacterium Caulobacter crescentus and used this module to illustrate a schema for the propagation of pathway-level annotation across bacterial genera. Applying comprehensive forward and reverse genetic methods and genome-wide transcriptional analysis, we (1 confirmed the presence of genes involved in catabolism of the abundant environmental sugar myo-inositol, (2 defined an operon encoding an ABC-family myo-inositol transmembrane transporter, and (3 identified a novel myo-inositol regulator protein and cis-acting regulatory motif that control expression of genes in this metabolic module. Despite being encoded from non-contiguous loci on the C. crescentus chromosome, these myo-inositol catabolic enzymes and transporter proteins form a tightly linked functional group in a computationally inferred network of protein associations. Primary sequence comparison was not sufficient to confidently extend annotation of all components of this novel metabolic module to related bacterial genera. Consequently, we implemented the Graemlin multiple-network alignment algorithm to generate cross-species predictions of genes involved in myo-inositol transport and catabolism in other alpha-proteobacteria. Although the chromosomal organization of genes in this functional module varied between species, the upstream regions of genes in this aligned network were enriched for the same palindromic cis-regulatory motif identified experimentally in C. crescentus. Transposon disruption of the operon encoding the computationally predicted ABC myo-inositol transporter of Sinorhizobium meliloti abolished growth on myo-inositol as the sole carbon source, confirming our cross-genera functional prediction. Thus, we have defined regulatory, transport, and catabolic genes and a cis-acting regulatory sequence that form a conserved module required for myo

  14. Genetic and environmental factors of atopy

    Directory of Open Access Journals (Sweden)

    Akiko Otsu

    2002-01-01

    Full Text Available Atopy is a common immune disorder characterized by raised IgE levels, which lead to clinical disorders (i.e. primarily bronchial asthma, atopic dermatitis and allergic rhinoconjuctivitis. Interleukin (IL-4 and IL-13, derived from T-helper cell type 2 (Th2 subsets, are central in mediating IgE production and development of immediate hypersensitivity. Atopy is also characterized by Th1/Th2 skewing that derives from genetic and environmental factors. The prevalence of atopy has increased in recent decades, especially in developed countries among children and young adults. In the present review, we first discuss the relationship between the Th1/Th2 imbalance and the recent rise of allergy. Second, we present evidence that human genetic variation is also a key factor responsible for atopy.

  15. Environmental and genetic risk factors in obesity.

    Science.gov (United States)

    Hebebrand, Johannes; Hinney, Anke

    2009-01-01

    Because of its high prevalence and the associated medical and psychosocial risks, research into the causes of childhood obesity has experienced a tremendous upswing. Formal genetic data based on twin, adoption, and family studies lead to the conclusion that at least 50% of the interindividual variance of the body mass index (BMI; defined as weight in kilograms divided by height in meters squared) is due to genetic factors. As a result of the recent advent of genome-wide association studies, the first polygenes involved in body weight regulation have been detected. Each of the predisposing alleles explain a few hundred grams of body weight. More polygenes will be detected in the near future, thus for the first time allowing in-depth analyses of gene-gene and gene-environment interactions. They also will enable developmental studies to assess the effect of such alleles throughout childhood and adulthood. The recent increase in obesity prevalence rates illustrates the extreme relevance of environmental factors for body weight. Similar to polygenes, the effect sizes of most such environmental factors are likely to be small, thus rendering their detection difficult. In addition, the validation of the true causality of such factors is not a straightforward task. Important factors are socioeconomic status and television consumption. The authors conclude by briefly assessing implications for treatment and prevention of childhood obesity.

  16. Environmental and genetical factors in airway allergies

    Directory of Open Access Journals (Sweden)

    Katarzyna Idzik

    2012-12-01

    Full Text Available It is estimated that approximately 23% of the European population is clinically diagnosed with allergies. In the past three decades, an increase in the incidence of respiratory allergies was noted. At the beginning of the 20th century allergic inflammations affected only around 1% of the world population. Medical symptoms of allergic airway inflammation are variable for different patients. Airways allergy are complex phenotypes, which are determined by both genetic and environmental factors. Potential environmental factors include air pollution, tobacco smoke, diet and hygienic habits. The base of phenotypes diversity is still unknown. Genetic studies of allergic disease are complex , the disease derives from the global effect of a series of genes considered individually. What is more, there are epigenetic effects and interactions among the possible causal genes and a range of environmental factors. Single nucleotide polymorphism (SNP in genes encoding chemokines and their receptors, interleukins and their receptors, eosinophil peroxidase and leukotrienes have been found as a possible factor for a development of allergic airway inflammation. It is known that SNPs are specific for different cohort.

  17. Genetic risk factors for hypertrophic scar development.

    Science.gov (United States)

    Thompson, Callie M; Hocking, Anne M; Honari, Shari; Muffley, Lara A; Ga, Maricar; Gibran, Nicole S

    2013-01-01

    Hypertrophic scars (HTSs) occur in 30 to 72% patients after thermal injury. Risk factors include skin color, female sex, young age, burn site, and burn severity. Recent correlations between genetic variations and clinical conditions suggest that single-nucleotide polymorphisms (SNPs) may be associated with HTS formation. The authors hypothesized that an SNP in the p27 gene (rs36228499) previously associated with decreased restenosis after coronary stenting would be associated with lower Vancouver Scar Scale (VSS) measurements and decreased itching. Patient and injury characteristics were collected from adults with thermal burns. VSS scores were calculated at 4 to 9 months after injury. Genotyping was performed using real-time polymerase chain reaction. Logistic regression was used to determine risk factors for HTS as measured by a VSS score >7. Three hundred subjects had a median age of 39 years (range, 18-91); 69% were male and median burn size was 7% TBSA (range, 0.25-80). Consistent with literature, the p27 variant SNP had an allele frequency of 40%, but was not associated with reduced HTS formation or lower itch scores in any genetic model. HTS formation was associated with American Indian/Alaskan Native race (odds ratio [OR], 12.2; P = .02), facial burns (OR, 9.4; P = .04), and burn size ≥20% TBSA (OR, 1.99; P = .03). Although the p27 SNP may protect against vascular fibroproliferation, the effect cannot be generalized to cutaneous scars. This study suggests that American Indian/Alaskan Native race, facial burns, and higher %TBSA are independent risk factors for HTS. The American Indian/Alaskan Native association suggests that there are potentially yet-to-be-identified genetic variants.

  18. Developmental Patterning as a Quantitative Trait: Genetic Modulation of the Hoxb6 Mutant Skeletal Phenotype.

    Directory of Open Access Journals (Sweden)

    Claudia Kappen

    Full Text Available The process of patterning along the anterior-posterior axis in vertebrates is highly conserved. The function of Hox genes in the axis patterning process is particularly well documented for bone development in the vertebral column and the limbs. We here show that Hoxb6, in skeletal elements at the cervico-thoracic junction, controls multiple independent aspects of skeletal pattern, implicating discrete developmental pathways as substrates for this transcription factor. In addition, we demonstrate that Hoxb6 function is subject to modulation by genetic factors. These results establish Hox-controlled skeletal pattern as a quantitative trait modulated by gene-gene interactions, and provide evidence that distinct modifiers influence the function of conserved developmental genes in fundamental patterning processes.

  19. Toward automatic phenotyping of retinal images from genetically determined mono- and dizygotic twins using amplitude modulation-frequency modulation methods

    Science.gov (United States)

    Soliz, P.; Davis, B.; Murray, V.; Pattichis, M.; Barriga, S.; Russell, S.

    2010-03-01

    This paper presents an image processing technique for automatically categorize age-related macular degeneration (AMD) phenotypes from retinal images. Ultimately, an automated approach will be much more precise and consistent in phenotyping of retinal diseases, such as AMD. We have applied the automated phenotyping to retina images from a cohort of mono- and dizygotic twins. The application of this technology will allow one to perform more quantitative studies that will lead to a better understanding of the genetic and environmental factors associated with diseases such as AMD. A method for classifying retinal images based on features derived from the application of amplitude-modulation frequency-modulation (AM-FM) methods is presented. Retinal images from identical and fraternal twins who presented with AMD were processed to determine whether AM-FM could be used to differentiate between the two types of twins. Results of the automatic classifier agreed with the findings of other researchers in explaining the variation of the disease between the related twins. AM-FM features classified 72% of the twins correctly. Visual grading found that genetics could explain between 46% and 71% of the variance.

  20. Genetics Home Reference: factor X deficiency

    Science.gov (United States)

    ... deficiency occurs in approximately 1 per million individuals worldwide. Related Information What information about a genetic condition can statistics provide? Why are some genetic conditions more common ...

  1. GENETIC FACTORS ASSOCIATED WITH AMYOTROPHIC LATERAL SCLEROSIS

    Directory of Open Access Journals (Sweden)

    Katarina Vrabec

    2015-10-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a rare complex neurodegenerative disease characterized by degeneration of motor neurons in the cerebral cortex, brainstem and spinal cord. The disease mainly occurs in adults, typically between 50. and 60. years and presents with symptoms like muscular weakness, atrophy and later on paralysis which lead to death due to respiratory failure within 2-5 years from onset and remains incurable. The symptoms typically start in the muscles of arms or legs (spinal onset or bulbary (bulbar onset. Most ALS cases are sporadic although about 5% are familiar. Genetic factors contribute to the disease in sporadic form as well as in familial form. Mutations have been found in 116 genes among which SOD1, TARDBP, FUS and C9ORF72 are represented in highest frequencies. Besides those four genes we are also describing 13 other genes involved in the disease process. Oligogenic model has been proposed for ALS that considers mutations in two or more genes in one patient. We emphasize the convergence between hereditary and sporadic form, which are clinically inseparable, and other neurodegenerative diseases that share with ALS genetic and clinical characteristics. Because about 2/3 of familial cases and only about 11% of sporadic cases are explained by mutations the research have been aimed at discovering new candidate genes using  genome –wide association studies and at the epigenetic causes of the disease. We have recently completed the first representative genetic analysis of patients with ALS in Slovenia and research on methylation and microRNAs is currently in progress.

  2. Genetic factors in Threatened Species Recovery Plans on three continents

    Science.gov (United States)

    Threatened species' recovery planning is applied globally to stem the current species extinction crisis. Evidence supports a key role of genetic processes, such as inbreeding depression, in determining species viability. We examined whether genetic factors are considered in threa...

  3. Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease

    Science.gov (United States)

    Baumgaertel, Johanna; Haussmann, Robert; Gruschwitz, Antonia; Werner, Annett; Osterrath, Antje; Lange, Jan; Donix, Katharina L.; Linn, Jennifer; Donix, Markus

    2016-01-01

    Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients. PMID:27699079

  4. Improved Student Linkage of Mendelian and Molecular Genetic Concepts through a Yeast-Based Laboratory Module

    Science.gov (United States)

    Wolyniak, Michael J.

    2013-01-01

    A study of modern genetics requires students to successfully unite the principles of Mendelian genetics with the functions of DNA. Traditional means of teaching genetics are often successful in teaching Mendelian and molecular ideas but not in allowing students to see how the two subjects relate. The laboratory module presented here attempts to…

  5. Risk factors for Alzheimer's disease : a genetic-epidemiologic study

    NARCIS (Netherlands)

    C.M. van Duijn (Cock)

    1992-01-01

    textabstractThe work presented in this thesis has been motivated by the Jack of knowledge of risk factors for Alzheimer's disease. It has been long recognised that genetic factors are implicated, in particular in early-onset Alzheimer's disease.4 But to what extent are genetic factors involved? Are

  6. Plant Oils and Cardiometabolic Risk Factors: The Role of Genetics

    OpenAIRE

    Smith, Caren E.

    2012-01-01

    More than 25 years have passed since Ancel Keys and others observed that high intake of monounsaturated fatty acids, especially as supplied by plants (eg, olive oil) was associated with lower cardiovascular and overall mortality. About 15 years later, advances in genotyping technologies began to facilitate widespread study of relationships between dietary fats and genetic variants, illuminating the role of genetic variation in modulating human responses to fatty acids. More recently, microarr...

  7. Genetics Home Reference: factor V Leiden thrombophilia

    Science.gov (United States)

    ... Conditions factor V Leiden thrombophilia factor V Leiden thrombophilia Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Factor V Leiden thrombophilia is an inherited disorder of blood clotting . Factor ...

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

    Science.gov (United States)

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

    2016-01-01

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

  9. Genetic and pharmacological factors that influence reproductive aging in nematodes.

    Directory of Open Access Journals (Sweden)

    Stacie E Hughes

    2007-02-01

    Full Text Available Age-related degenerative changes in the reproductive system are an important aspect of aging, because reproductive success is the major determinant of evolutionary fitness. Caenorhabditis elegans is a prominent organism for studies of somatic aging, since many factors that extend adult lifespan have been identified. However, mechanisms that control reproductive aging in nematodes or other animals are not well characterized. To use C. elegans to measure reproductive aging, we analyzed mated hermaphrodites that do not become sperm depleted and monitored the duration and level of progeny production. Mated hermaphrodites display a decline of progeny production that culminates in reproductive cessation before the end of the lifespan, demonstrating that hermaphrodites undergo reproductive aging. To identify factors that influence reproductive aging, we analyzed genetic, environmental, and pharmacological factors that extend lifespan. Dietary restriction and reduced insulin/insulin-like growth factor signaling delayed reproductive aging, indicating that nutritional status and a signaling pathway that responds to environmental stress influence reproductive aging. Cold temperature delayed reproductive aging. The anticonvulsant medicine ethosuximide, which affects neural activity, delayed reproductive aging, indicating that neural activity can influence reproductive aging. Some of these factors decrease early progeny production, but there is no consistent relationship between early progeny production and reproductive aging in strains with an extended lifespan. To directly examine the effects of early progeny production on reproductive aging, we used sperm availability to modulate the level of early reproduction. Early progeny production neither accelerated nor delayed reproductive aging, indicating that reproductive aging is not controlled by use-dependent mechanisms. The implications of these findings for evolutionary theories of aging are discussed.

  10. Genetic sorting of subordinate species in grassland modulated by intraspecific variation in dominant species.

    Directory of Open Access Journals (Sweden)

    Danny J Gustafson

    Full Text Available Genetic variation in a single species can have predictable and heritable effects on associated communities and ecosystem processes, however little is known about how genetic variation of a dominant species affects plant community assembly. We characterized the genetic structure of a dominant grass (Sorghastrum nutans and two subordinate species (Chamaecrista fasciculata, Silphium integrifolium, during the third growing season in grassland communities established with genetically distinct (cultivated varieties or local ecotypes seed sources of the dominant grasses. There were genetic differences between subordinate species growing in the cultivar versus local ecotype communities, indicating that intraspecific genetic variation in the dominant grasses affected the genetic composition of subordinate species during community assembly. A positive association between genetic diversity of S. nutans, C. fasciculata, and S. integrifolium and species diversity established the role of an intraspecific biotic filter during community assembly. Our results show that intraspecific variation in dominant species can significantly modulate the genetic composition of subordinate species.

  11. Predictability of Genetic Interactions from Functional Gene Modules

    Directory of Open Access Journals (Sweden)

    Jonathan H. Young

    2017-02-01

    Full Text Available Characterizing genetic interactions is crucial to understanding cellular and organismal response to gene-level perturbations. Such knowledge can inform the selection of candidate disease therapy targets, yet experimentally determining whether genes interact is technically nontrivial and time-consuming. High-fidelity prediction of different classes of genetic interactions in multiple organisms would substantially alleviate this experimental burden. Under the hypothesis that functionally related genes tend to share common genetic interaction partners, we evaluate a computational approach to predict genetic interactions in Homo sapiens, Drosophila melanogaster, and Saccharomyces cerevisiae. By leveraging knowledge of functional relationships between genes, we cross-validate predictions on known genetic interactions and observe high predictive power of multiple classes of genetic interactions in all three organisms. Additionally, our method suggests high-confidence candidate interaction pairs that can be directly experimentally tested. A web application is provided for users to query genes for predicted novel genetic interaction partners. Finally, by subsampling the known yeast genetic interaction network, we found that novel genetic interactions are predictable even when knowledge of currently known interactions is minimal.

  12. Factors affecting student performance in an undergraduate genetics course.

    Science.gov (United States)

    Bormann, J Minick; Moser, D W; Bates, K E

    2013-05-01

    The objective of this study was to determine some of the factors that affect student success in a genetics course. Genetics for the Kansas State University College of Agriculture is taught in the Department of Animal Sciences and Industry and covers Mendelian inheritance, molecular genetics, and quantitative/population genetics. Data collected from 1,516 students over 7 yr included year and semester of the course; age; gender; state of residence; population of hometown; Kansas City metro resident or not; instructor of course; American College Testing Program (ACT) scores; number of transfer credits; major; college; preveterinary student or not; freshman, sophomore, junior, and senior grade point average (GPA); semester credits when taking genetics; class standing when enrolled in genetics; cumulative GPA before and after taking genetics; semester GPA in semester taking genetics, number of semesters between the biology prerequisite and genetics; grade in biology; location of biology course; and final percentage in genetics. Final percentage in genetics did not differ due to instructor, gender, state of residence, major, or college (P > 0.16). Transfer students tended to perform better than nontransfer students (P = 0.09), and students from the Kansas City metro outscored students from other areas (P = 0.03). Preveterinary option students scored higher in genetics than non-preveterinary students (P genetics (P = 0.06). Students who took biology at Kansas State University performed better in genetics than students who transferred the credit (P genetics (P genetics, students should take biology from Kansas State, perform well in biology, and wait until at least sophomore standing to enroll in genetics.

  13. Genetic modulation of energy metabolism in birds through mitochondrial function

    NARCIS (Netherlands)

    Tieleman, B. Irene; Versteegh, Maaike A.; Fries, Anthony; Helm, Barbara; Dingemanse, Niels J.; Gibbs, H. Lisle; Williams, Joseph B.

    2009-01-01

    Despite their central importance for the evolution of physiological variation, the genetic mechanisms that determine energy expenditure in animals have largely remained unstudied. We used quantitative genetics to confirm that both mass-specific and whole-organism basal metabolic rate (BMR) were heri

  14. Pathogenesis of coronary artery disease: focus on genetic risk factors and identification of genetic variants

    Directory of Open Access Journals (Sweden)

    Sayols-Baixeras S

    2014-01-01

    Full Text Available Sergi Sayols-Baixeras, Carla Lluís-Ganella, Gavin Lucas, Roberto ElosuaCardiovascular Epidemiology and Genetics Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, SpainAbstract: Coronary artery disease (CAD is the leading cause of death and disability worldwide, and its prevalence is expected to increase in the coming years. CAD events are caused by the interplay of genetic and environmental factors, the effects of which are mainly mediated through cardiovascular risk factors. The techniques used to study the genetic basis of these diseases have evolved from linkage studies to candidate gene studies and genome-wide association studies. Linkage studies have been able to identify genetic variants associated with monogenic diseases, whereas genome-wide association studies have been more successful in determining genetic variants associated with complex diseases. Currently, genome-wide association studies have identified approximately 40 loci that explain 6% of the heritability of CAD. The application of this knowledge to clinical practice is challenging, but can be achieved using various strategies, such as genetic variants to identify new therapeutic targets, personal genetic information to improve disease risk prediction, and pharmacogenomics. The main aim of this narrative review is to provide a general overview of our current understanding of the genetics of coronary artery disease and its potential clinical utility.Keywords: coronary artery disease, pathogenesis, genetic risk factors, genetic variants

  15. Genetics and behavioral medicine: Risk factors for cardiovascular disease

    NARCIS (Netherlands)

    Vogler, G.P.; McClearn, G.E.; Snieder, H.; Boomsma, D.I.; Palmer, R.; Knijff, P. de; Slagboom, P.E.

    1997-01-01

    This is the second in a series of three articles addressing the intersection of interests in behavioral genetics and behavioral medicine. In this article, we use risk factors for cardiovascular disease as a prototypical trait for which behavioral genetic approaches provide powerful tools for underst

  16. Genetics and behavioral medicine: Risk factors for cardiovascular disease

    NARCIS (Netherlands)

    Vogler, G.P.; McClearn, G.E.; Snieder, H.; Boomsma, D.I.; Palmer, R.; Knijff, P. de; Slagboom, P.E.

    1997-01-01

    This is the second in a series of three articles addressing the intersection of interests in behavioral genetics and behavioral medicine. In this article, we use risk factors for cardiovascular disease as a prototypical trait for which behavioral genetic approaches provide powerful tools for

  17. Risk factors for amyotrophic lateral sclerosis : Lifestyle, environment and genetics

    NARCIS (Netherlands)

    Seelen, M.

    2015-01-01

    In this thesis the results of studies aiming to identify risk factors for amyotrophic lateral sclerosis (ALS) are described. A population-based case-control design was used to perform (1) epidemiological risk factor studies, examining lifestyle factors and environmental exposures, and (2) genetic st

  18. Risk factors for amyotrophic lateral sclerosis : Lifestyle, environment and genetics

    NARCIS (Netherlands)

    Seelen, M.

    2015-01-01

    In this thesis the results of studies aiming to identify risk factors for amyotrophic lateral sclerosis (ALS) are described. A population-based case-control design was used to perform (1) epidemiological risk factor studies, examining lifestyle factors and environmental exposures, and (2) genetic st

  19. Obesity in childhood and adolescence, genetic factors.

    Science.gov (United States)

    Memedi, Rexhep; Tasic, Velibor; Nikolic, Erieta; Jancevska, Aleksandra; Gucev, Zoran

    2013-01-01

    Obesity and overweight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. The etiology is complex, but most often idiopathic. Hormonal, syndromic and medication-induced obesity are well investigated. Genetic causes are increasingly described. Novel technologies such as whole exome sequencing identify ever more candidate genes influencing or causing obesity. All insights into the complex problem of obesity in a team approach to treatment: diet, psychology, medications and surgery. We briefly review epidemiology, etiology, consequences and treatment approaches in childhood and adolescent obesity, with special emphasis on emerging knowledge of its genetics.

  20. Genetic, molecular and functional analyses of complement factor I deficiency

    DEFF Research Database (Denmark)

    Nilsson, S.C.; Trouw, L.A.; Renault, N.;

    2009-01-01

    Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three...

  1. Genetic factors involves in intracranial aneurysms--actualities

    National Research Council Canada - National Science Library

    Mohan, D; Munteanu, V; Coman, T; Ciurea, A V

    2015-01-01

    ...% of all IAs in the population. Cerebral aneurysm disease is related to hemodynamic and genetic factors, associated with structural weakness in the arterial wall, which was acquired by a specific, often unknown, event...

  2. Environmental and genetical factors in airway allergies

    OpenAIRE

    Katarzyna Idzik

    2012-01-01

    It is estimated that approximately 23% of the European population is clinically diagnosed with allergies. In the past three decades, an increase in the incidence of respiratory allergies was noted. At the beginning of the 20th century allergic inflammations affected only around 1% of the world population. Medical symptoms of allergic airway inflammation are variable for different patients. Airways allergy are complex phenotypes, which are determined by both genetic and...

  3. Orthodontic Treatment, Genetic Factors and Risk of Temporomandibular Disorder

    OpenAIRE

    Slade, Gary D.; Diatchenko, Luda; Ohrbach, Richard; Maixner, William

    2008-01-01

    Traditionally, four groups of factors have been identified in the etiology of temporomandibular disorder (TMD): anatomical variation in the masticatory system; psychosocial characteristics; pain in other body regions; and demographics. Orthodontic treatment has been variously cited both as a protective and harmful factor in TMD etiology. Recently, a search has begun for a genetic influence on TMD etiology. Genetic markers can be of additional value in identifying gene-environment interactions...

  4. Network statistics of genetically-driven gene co-expression modules in mouse crosses

    Directory of Open Access Journals (Sweden)

    Marie-Pier eScott-Boyer

    2013-12-01

    Full Text Available In biology, networks are used in different contexts as ways to represent relationships between entities, such as for instance interactions between genes, proteins or metabolites. Despite progress in the analysis of such networks and their potential to better understand the collective impact of genes on complex traits, one remaining challenge is to establish the biologic validity of gene co-expression networks and to determine what governs their organization. We used WGCNA to construct and analyze seven gene expression datasets from several tissues of mouse recombinant inbred strains (RIS. For six out of the 7 networks, we found that linkage to module QTLs (mQTLs could be established for 29.3% of gene co-expression modules detected in the several mouse RIS. For about 74.6% of such genetically-linked modules, the mQTL was on the same chromosome as the one contributing most genes to the module, with genes originating from that chromosome showing higher connectivity than other genes in the modules. Such modules (that we considered as genetically-driven had network statistic properties (density, centralization and heterogeneity that set them apart from other modules in the network. Altogether, a sizeable portion of gene co-expression modules detected in mouse RIS panels had genetic determinants as their main organizing principle. In addition to providing a biologic interpretation validation for these modules, these genetic determinants imparted on them particular properties that set them apart from other modules in the network, to the point that they can be predicted to a large extent on the basis of their network statistics.

  5. Genetic factors in familial aggregation of blood pressure of Portuguese nuclear families.

    Science.gov (United States)

    Fermino, Rogério César; Seabra, André; Garganta, Rui; Maia, José António Ribeiro

    2009-03-01

    Despite of the increase in the prevalence of hypertension in Portugal, the importance of genetic factors in blood pressure (BP) has not been studied extensively in our country. To verify the indirect presence of vertical transmission of genetic factors between parents and children in BP values, and to estimate the magnitude of genetic factors contributing for variation in BP values in the population. Sample size comprises 367 individuals (164 parents and 203 children) pertaining the 107 nuclear families participating in 'Familias Activas' project, proceeding from different regions of North Portugal. The BP was measured with Omron model M6 (HEM-7001-E) digital device. SPSS 15.0 was used for data analysis; PEDSTATS was used to verify the structure of each family data. Familial correlations and heritability estimates were computed in FCOR and ASSOC modules of S.A.G.E. version 5.3. For systolic BP (SBP), correlation values were low to moderate (0.21< or = r < or =0.35); for diastolic BP (DBP) values were found to be moderate (0.24< or = r < or =0. 50). Genetic factors explain 43 and 49% of the total variation in SBP and DBP, respectively. A moderate amount of the SBP and the DBP is accounted for by genetic factors.

  6. [Genetic and epigenetic factors of polycystic ovary syndrome].

    Science.gov (United States)

    Herczeg, Zita; Vanya, Melinda; Szili, Károly; Dézsi, Csilla; Nagy, Zsolt; Szabó, János

    2016-08-01

    The development of polycystic ovary syndrome and its exact pathophysiological mechanism is still unclear, but environmental and genetic factors likely play a role. Exposition to teratogenic effects during the prenatal development can lead to chronic diseases in the postnatal period. This finding confirms the common familial aggregation as well. A literature search was conducted up to January 1, 2016 for articles dealing with the genetic or epigenetic factors of polycystic ovary syndrome. This review will discuss the current understanding of the genetic basis and clinical presentation of this disease. Orv. Hetil., 2016, 157(32), 1275-1281.

  7. [Environmental and genetic risk factors for endometrial carcinoma].

    Science.gov (United States)

    Sénéchal, Claire; Cottereau, Edouard; de Pauw, Antoine; Elan, Camille; Dagousset, Isabelle; Fourchotte, Virginie; Gauthier-Villars, Marion; Lae, Marick; Stoppa-Lyonnet, Dominique; Buecher, Bruno

    2015-03-01

    In France, endometrial cancer is at the first rank of gynecological cancers for cancer incidence, before ovarian and cervical cancers. In fact, the number of incident cases has been estimated to 7275 for the year 2012; the number of death due to endometrial cancer to 2025. This cancer is hormone-dependent and endogenous (reproductive factors) or exogenous (oral combined contraceptives, hormone replacement therapy) causes of exposition to estrogens are the major environmental risk factors for both types of endometrial cancers: type I or well-differentiated endometrioid adenocarcinomas; and type II including all other histological types: papillary serous adenocarcinomas, clear cell adenocarcinomas and carcinosarcomas, also known as malignant mixed Mullerian tumor, MMMT. Obesity, diabetes mellitus and adjuvant treatment of breast cancer with tamoxifen are also associated with an increased risk of endometrial cancer. Genetic factors may also be implicated in the pathogenesis of endometrial cancer either as "minor genetic factors" (susceptibility factors), which remain largely unknown and are responsible for the increased observed risk in relatives of women affected with endometrial cancer; or as major genetic factors responsible for hereditary forms and namely for Lynch syndrome whose genetic transmission is of autosomic dominant type. The appropriate recognition of Lynch syndrome is of critical importance because affected patients and their relatives should benefit from specific care. The aims of this review is to describe major environmental and genetic risk factors for endometrial cancer with specific attention to most recent advances in this field and to describe recommendations for care of at-risk women.

  8. Class II HLA interactions modulate genetic risk for multiple sclerosis

    DEFF Research Database (Denmark)

    Moutsianas, Loukas; Jostins, Luke; Beecham, Ashley H;

    2015-01-01

    Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on ...

  9. Genetics Home Reference: factor VII deficiency

    Science.gov (United States)

    ... VII deficiency , is caused by mutations in the F7 gene, which provides instructions for making a protein ... about the gene associated with factor VII deficiency F7 Related Information What is a gene? What is ...

  10. Capsaicinoids Modulating Cardiometabolic Syndrome Risk Factors: Current Perspectives

    Directory of Open Access Journals (Sweden)

    Vijaya Juturu

    2016-01-01

    Full Text Available Capsaicinoids are bioactive nutrients present within red hot peppers reported to cut ad libitum food intake, to increase energy expenditure (thermogenesis and lipolysis, and to result in weight loss over time. In addition it has shown more benefits such as improvement in reducing oxidative stress and inflammation, improving vascular health, improving endothelial function, lowering blood pressure, reducing endothelial cytokines, cholesterol lowering effects, reducing blood glucose, improving insulin sensitivity, and reducing inflammatory risk factors. All these beneficial effects together help to modulate cardiometabolic syndrome risk factors. The early identification of cardiometabolic risk factors can help try to prevent obesity, hypertension, diabetes, and cardiovascular disease.

  11. Genetic and environmental influences on emotion-modulated startle reflex: a twin study.

    Science.gov (United States)

    Anokhin, Andrey P; Golosheykin, Simon; Heath, Andrew C

    2007-01-01

    Emotion-modulated startle reflex is an important indicator of traitlike differences in affective processing implicated in the biological basis of personality and psychopathology. This study examined heritability of startle modulation by affective pictures in 66 pairs of monozygotic and 57 pairs of dizygotic female twins. Consistent with previous studies, startle magnitude was significantly influenced by emotional valence of the picture (positive < neutral < negative). Absolute response magnitude showed high heritability in all three valence conditions (59-61%); however, there were no significant genetic influences on the amount of startle modulation. Thus, our data do not support the hypothesis that emotion-modulated startle can serve as an indicator of genetically transmitted individual differences in affective processing.

  12. Progress in the identification of genetic factors in periodontitis

    NARCIS (Netherlands)

    Laine, M.L.; Jepsen, S.; Loos, B.G.

    2014-01-01

    The susceptibility to periodontitis is determined by a complex interplay between bacteria, the immune system, and life-style factors, and is mainly regulated by genes. The genetic factors contributing to the pathogenesis of periodontitis are still not fully defined. The aim of the present review is

  13. Genetic and environmental factors affecting the coumarin anticoagulant level

    NARCIS (Netherlands)

    L.E. Visser (Loes)

    2004-01-01

    textabstractThis introductory chapter has illustrated that various factors, such as genetic factors, drugs, diet and intercurrent diseases may affect anticoagulation levels. Most of the clinical and pharmacological data related to coumarin anticoagulants have so far been obtained from studying warfa

  14. Genetic inflammatory factors predict restenosis after percutaneous coronary interventions

    NARCIS (Netherlands)

    Monraats, PS; Pires, NMM; Agema, WRP; Zwinderman, AH; Schepers, A; de Maat, MPM; Doevendans, PA; de Winter, RJ; Tio, RA; Waltenberger, J; Frants, RR; Quax, PHA; van Vlijmen, BJM; Atsma, DE; van der Laarse, A; van der Wall, EE; Jukema, JW

    2005-01-01

    Background - Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal

  15. Progress in the identification of genetic factors in periodontitis

    NARCIS (Netherlands)

    Laine, M.L.; Jepsen, S.; Loos, B.G.

    2014-01-01

    The susceptibility to periodontitis is determined by a complex interplay between bacteria, the immune system, and life-style factors, and is mainly regulated by genes. The genetic factors contributing to the pathogenesis of periodontitis are still not fully defined. The aim of the present review is

  16. Genetics Home Reference: factor XI deficiency

    Science.gov (United States)

    ... common feature of factor XI deficiency is prolonged bleeding after trauma or surgery, especially involving the inside of the mouth and ... nasal cavities ) or the urinary tract . If the bleeding is left untreated after surgery, solid swellings consisting of congealed blood (hematomas) can ...

  17. Plant Oils and Cardiometabolic Risk Factors: The Role of Genetics.

    Science.gov (United States)

    Smith, Caren E

    2012-09-01

    More than 25 years have passed since Ancel Keys and others observed that high intake of monounsaturated fatty acids, especially as supplied by plants (eg, olive oil) was associated with lower cardiovascular and overall mortality. About 15 years later, advances in genotyping technologies began to facilitate widespread study of relationships between dietary fats and genetic variants, illuminating the role of genetic variation in modulating human responses to fatty acids. More recently, microarray technologies evaluate the ways in which minor, bioactive compounds in plant oils (including olive, thyme, lemongrass, clove, eucalyptus, and others) alter gene expression to mediate anti-inflammatory and antioxidant effects. Results from a range of diverse technologies and approaches are coalescing to improve understanding of the role of the genome in shaping our responses to plant oils, and to clarify the genetic mechanisms underlying the cardioprotective benefits we derive from a wide range of plant oil constituents.

  18. Functional modules of sigma factor regulons guarantee adaptability and evolvability

    Science.gov (United States)

    Binder, Sebastian C.; Eckweiler, Denitsa; Schulz, Sebastian; Bielecka, Agata; Nicolai, Tanja; Franke, Raimo; Häussler, Susanne; Meyer-Hermann, Michael

    2016-02-01

    The focus of modern molecular biology turns from assigning functions to individual genes towards understanding the expression and regulation of complex sets of molecules. Here, we provide evidence that alternative sigma factor regulons in the pathogen Pseudomonas aeruginosa largely represent insulated functional modules which provide a critical level of biological organization involved in general adaptation and survival processes. Analysis of the operational state of the sigma factor network revealed that transcription factors functionally couple the sigma factor regulons and significantly modulate the transcription levels in the face of challenging environments. The threshold quality of newly evolved transcription factors was reached faster and more robustly in in silico testing when the structural organization of sigma factor networks was taken into account. These results indicate that the modular structures of alternative sigma factor regulons provide P. aeruginosa with a robust framework to function adequately in its environment and at the same time facilitate evolutionary change. Our data support the view that widespread modularity guarantees robustness of biological networks and is a key driver of evolvability.

  19. Analysis of genetic and non genetic risk factors for cisplatin ototoxicity in pediatric patients.

    Science.gov (United States)

    Olgun, Yüksel; Aktaş, Safiye; Altun, Zekiye; Kırkım, Günay; Kızmazoğlu, Deniz Çakır; Erçetin, Ayşe Pınar; Demir, Banu; İnce, Dilek; Mutafoğlu, Kamer; Demirağ, Bengü; Ellidokuz, Hülya; Olgun, Nur; Güneri, Enis Alpin

    2016-11-01

    The aim of this study was to analyse the genetic and non genetic risk factors for cisplatin ototoxicity. This study was conducted on 72 children who received cisplatin based chemotherapy. Brock and Muenster classifications were used to evaluate ototoxicity seen in these children. 6 single nucleotide polymorphisms (SNP); ERCC1 rs 11615, GSTP1 rs1138272, GSTP1 rs1695, LRP2 rs 2075252, TPMT rs 12201199, COMT rs 9332377, were evaluated as genetic factors by real time PCR. Non genetic factors such as cranial irradiation, cumulative doses of cisplatin, age, gender, administration of other ototoxic drugs were analysed as well. By using Chi-square test, risk factors were matched with the ototoxicity classifications. Significant risk factors were reevaluated using logistic regression modelling. According to univariate analyses, male gender, co-treatment with aminoglycosides and mutant genotype of GSTP1 rs1695 were significantly related with cisplatin ototoxicity. Logistic regression modelling analyses also showed that male gender, co-treatment with aminoglycosides were found to be significantly related with cisplatin ototoxicity. Mutant genotype of GSTP1 rs1695 was not found to be significant, but close to the level of statistical significance. Male gender, co-treatment with aminoglycosides are significant risk factors for cisplatin ototoxicity in pediatric patients. Mutant genotype of GSTP1 rs1695 seems to be a genetic risk factor in univariate analyses, although not confirmed by multivariate analyses. Therefore, GSTP1 rs1695 SNP needs to be studied in larger series. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

    Science.gov (United States)

    Bettencourt, Conceição; Hensman‐Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Panas, Marios; Yescas‐Gómez, Petra; García‐Velázquez, Lizbeth Esmeralda; Alonso‐Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan; Sweeney, Mary; Wood, Nicholas; Giunti, Paola; Durr, Alexandra; Holmans, Peter; Houlden, Henry; Tabrizi, Sarah J.

    2016-01-01

    Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990 PMID:27044000

  1. Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype

    Science.gov (United States)

    Ceccarelli, Fulvia; Perricone, Carlo; Borgiani, Paola; Ciccacci, Cinzia; Rufini, Sara; Cipriano, Enrica; Alessandri, Cristiano; Spinelli, Francesca Romana; Sili Scavalli, Antonio; Novelli, Giuseppe; Valesini, Guido; Conti, Fabrizio

    2015-01-01

    Genetic factors exert an important role in determining Systemic Lupus Erythematosus (SLE) susceptibility, interplaying with environmental factors. Several genetic studies in various SLE populations have identified numerous susceptibility loci. From a clinical point of view, SLE is characterized by a great heterogeneity in terms of clinical and laboratory manifestations. As widely demonstrated, specific laboratory features are associated with clinical disease subset, with different severity degree. Similarly, in the last years, an association between specific phenotypes and genetic variants has been identified, allowing the possibility to elucidate different mechanisms and pathways accountable for disease manifestations. However, except for Lupus Nephritis (LN), no studies have been designed to identify the genetic variants associated with the development of different phenotypes. In this review, we will report data currently known about this specific association. PMID:26798662

  2. Genetic and epigenetic factors: Role in male infertility

    Directory of Open Access Journals (Sweden)

    M B Shamsi

    2011-01-01

    Full Text Available Genetic factors contribute upto 15%-30% cases of male infertility. Formation of spermatozoa occurs in a sequential manner with mitotic, meiotic, and postmeiotic differentiation phases each of which is controlled by an intricate genetic program. Genes control a variety of physiologic processes, such as hypothalamus-pituitary-gonadal axis, germ cell development, and differentiation. In the era of assisted reproduction technology, it is important to understand the genetic basis of infertility to provide maximum adapted therapeutics and counseling to the couple.

  3. Genetic factors associated with the development of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Crohn's disease (CD) and ulcerative colitis (UC) are complex polygenic disorders, characterized by several genes together with environmental factors contributing to the development of inflammatory bowel disease (IBD). Recent advances in research on genetic susceptibility have allowed the identification of diverse genes at different levels: (1) Innate immunity; (2) Antigen presentation molecules; (3) Epithelial integrity; (4) Drug transporter; (5) Cell adhesion. The application of genetic testing into clinical practice is close and all genetic markers may have several clinical implications: prediction of disease phenotype, molecular classification, prevention of complications, and prognosis.

  4. Cognitive control and the COMT Val158Met polymorphism: genetic modulation of videogame training and transfer to task-switching efficiency

    NARCIS (Netherlands)

    Colzato, L.S.; van den Wildenberg, W.P.M.; Hommel, B.

    2014-01-01

    The study investigated whether successful transfer of game-based cognitive improvements to untrained tasks might be modulated by preexisting neuro-developmental factors, such as genetic variability related to the catechol-O-methyltransferase (COMT)—an enzyme responsible for the degradation of dopami

  5. A common genetic factor underlies hypertension and other cardiovascular disorders

    Directory of Open Access Journals (Sweden)

    Spector Tim D

    2004-11-01

    Full Text Available Abstract Background Certain conditions characterised by blood vessel occlusion or vascular spasm have been found to cluster together in epidemiological studies. However the biological causes for these associations remain controversial. This study used a classical twin design to examine whether these conditions are linked through shared environmental exposures or by a common underlying genetic propensity to vasospasm. Methods We investigated the association between hypertension, migraine, Raynaud's phenomenon and coronary artery disease in twins from a national register. Phenotype status was determined using a questionnaire and the genetic and environmental association between phenotypes was estimated through variance components analysis. Results Responses were obtained from 2,204 individuals comprising 525 monozygotic and 577 dizygotic pairs. There was a significant genetic contribution to all four traits with heritabilities ranging from 0.34 to 0.64. Multivariate model-fitting demonstrated that a single common genetic factor underlies the four conditions. Conclusions We have confirmed an association between hypertension, migraine, Raynaud's phenomenon and coronary artery disease, and shown that a single genetic factor underlies them. The demonstration of a shared genetic factor explains the association between them and adds weight to the theory of an inherited predisposition to vasospasm.

  6. Genetic and environmental modulation of neurotrophic and anabolic stress response: Counterbalancing forces.

    Science.gov (United States)

    Taylor, Marcus K; Carpenter, Jennifer; Stone, Michael; Hernandez, Lisa M; Rauh, Mitchell J; Laurent, Heidemarie K; Granger, Douglas A

    2015-11-01

    The serotonin transporter genetic variant 5HTTLPR influences activation and feedback control of the hypothalamic-pituitary-adrenal axis, and has been shown to influence the effect of stressful life events on behavioral health. We recently reported that 5HTTLPR modulates cortisol response in healthy military men exposed to intense stress. Less is known of its combined effects with environmental factors in this context, or of its effect on neuroprotective stress responses. In this follow-up study, we examined the unique and combined effects of 5HTTLPR and prior trauma exposure on neuroprotective (salivary nerve growth factor [sNGF]), anabolic (dehydroepiandrosterone sulfate [DHEAS] and testosterone), and catabolic (cortisol) stress responses. Ninety-three healthy, active-duty military men were studied before, during, and 24h after a stressful 12-day survival course. Distinct and interactive effects of 5HTTLPR long allele carriage [L] versus homozygous short allele carriage [SS]) and prior trauma exposure (low versus high) were evaluated, after which a priori group comparisons were performed between hypothesized high resilience (L/low) and low resilience (SS/high) groups. For sNGF, L/low produced the greatest sNGF throughout stress exposure while SS/high demonstrated the smallest; L/high and SS/low bisected these two extremes and were nearly identical to each other (i.e., SS/high < SS/low = L/high < L/low). Thus, 5HTTLPR and prior trauma exposure demonstrated counterbalancing (additive) forces. Similar patterns were found for DHEAS. To our knowledge, this study is the first to report counterbalancing genetic and environmental effects on novel biomarkers related to resilience in humans exposed to real-world stress. These findings have profound implications for health, performance and training in high-stress occupational settings.

  7. Intrauterine and genetic factors in early childhood sensitization

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus

    2010-01-01

    The allergy-associated (atopic) diseases; asthma, eczema and rhinoconjunctivitis, are the most common chronic diseases in childhood. A large number of environmental and genetic risk factors have been suggested, but still our understanding of the underlying disease mechanisms and etiologies...... of opportunity” for prevention. The aim of this thesis was to increase the understanding of sensitization in early life. We studied indicators of sensitization in the newborn, and early development of sensitization and disease associated with a newly discovered genetic risk factor. Such insight may increase our...... and identifying the environmental risk factors interacting with this genetic susceptibility and the age at which intervention should be initiated. We found a FLG-associated pattern of atopic disease in early childhood characterized by early onset of eczema, early onset of asthma with severe exacerbations...

  8. Intrauterine and genetic factors in early childhood sensitization

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus

    2010-01-01

    predictive value of elevated cord blood IgE found in recent studies. Future studies should control for materno-fetal transfer of IgE or preferably use other markers of atopy. Variation in the gene coding for the skin barrier protein filaggrin (FLG) is the strongest known genetic risk factor for eczema. FLG......The allergy-associated (atopic) diseases; asthma, eczema and rhinoconjunctivitis, are the most common chronic diseases in childhood. A large number of environmental and genetic risk factors have been suggested, but still our understanding of the underlying disease mechanisms and etiologies...... of opportunity” for prevention. The aim of this thesis was to increase the understanding of sensitization in early life. We studied indicators of sensitization in the newborn, and early development of sensitization and disease associated with a newly discovered genetic risk factor. Such insight may increase our...

  9. Genetic update on inflammatory factors in ulcerative colitis: Review of the current literature

    Institute of Scientific and Technical Information of China (English)

    Patricia; Sarlos; Erzsebet; Kovesdi; Lili; Magyari; Zsolt; Banfai; Andras; Szabo; Andras; Javorhazy; Bela; Melegh

    2014-01-01

    Ulcerative colitis(UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammationrelated genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.

  10. Host susceptibility factors in mycobacterial infection. Genetics and body morphotype.

    Science.gov (United States)

    Guide, Shireen V; Holland, Steven M

    2002-03-01

    Through identification and evaluation of mutations and polymorphisms in components of the IFN gamma response pathways, a better understanding of the mechanisms and risk factors influencing the development of mycobacterial disease is gained. This may lead the way for development of therapeutic and preventative strategies. Although conventional science has focused on identifying discrete mutations, greater awareness of the impact of subtle changes, both at the genetic (polymorphisms) and physical levels (body morphotype), may prove critical in the investigative process. There has been extraordinary progress in the understanding of mycobacterial susceptibility factors over the last few years. The recognition of characteristic phenotypes will lead to the identification of new genetic bases for disease.

  11. Genetic and environmental factors influencing the Placental Growth Factor (PGF) variation in two populations

    DEFF Research Database (Denmark)

    Sorice, Rossella; Ruggiero, Daniela; Nutile, Teresa

    2012-01-01

    . However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have...... strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability....

  12. Genetic and non-genetic factors affecting semen production traits in Karan Fries crossbred bulls.

    Science.gov (United States)

    Chauhan, Indra Sen; Gupta, Ashok K; Khate, Keviletsu; Chauhan, Anuj; Rao, Thakur Krishna Shankar; Pathak, Shivendra; Hazra, Ritwik; Singh, Maneesh

    2010-12-01

    The objective of the study was to evaluate the effects of genetic and non-genetic factors on production of breeding bulls and semen quality parameters in Karan Fries crossbred male by fitting least squares analysis. Genetically, the animals were divided into three subclasses. The non-genetic factors were season of birth, period of birth, and age group with three subclasses each for season of birth and period of birth. Age group was classified into four subclasses. The traits generated in the study were number of males reaching semen donation stage (AFSC) and first freezing (AFSF), age at last semen collection (ALSC) and last freezing (ALSF), age at disposal (AD), and lifetime semen production traits (up to 1 year after first freezing). The effect of period of birth was significant for AFSC, AFSF, ALSC, and AD. It was also significant for total ejaculates produced in a year. The age group had significant effect on AFSF. Effect of genetic group was significant for freezable ejaculates produced in a year, for frozen semen doses produced in a year, and for number of ejaculates cryoprocessed in a year. Season had no statistically significant effect on any of the traits studied. The influence of period revealed that the most of the traits of breeding bulls improved after intermediate period, which could be due to better care, training, feeding, and other management practices in the latter years. However, no consistent trend could be established for the effects of genetic groups and other non-genetic causes on the traits considered.

  13. Genetic factors associated with cancer male breast: a literature review

    Directory of Open Access Journals (Sweden)

    Nathalia Maria Tomaz Silveira

    2016-10-01

    Full Text Available The male breast cancer is a rare neoplastic framework, covers 1% of cases of breast cancer worldwide, 1% of malignant tumors in men and has an annual incidence of 1 per 100,000 men. Information was gathered about the current studies related to genetic character in addressed condition, in which the goal was to analyze aspects of predisposition and association, using 16 original articles indexed in the period between January 2011 to February 2016, written in English and Spanish, with experimental design or observational, using male breast cancer descriptors, breast cancer and genetic factor for breast cancer, as well as their English translations male breast cancer, cancer treatment, breast cancer and genetic factors. It was mainly discussed the genetic influence on the occurrence of male breast cancer, such as changes in suppressors BRCA genes, relationships with CHECK2 checkpoint, family history and links with Klinefelter syndrome, among other factors. Environmental aspects are also suggested by the literature on the clinical neoplasic manifestation, but with less conclusive emphases. Although the literature on the subject still need growth and deepening, we observe scientific reassurances about the importance of genetic influence, especially the BRCA 1, about the Multifactorial etiology of the neoplasia.

  14. Prognostic Factors for Distress After Genetic Testing for Hereditary Cancer.

    Science.gov (United States)

    Voorwinden, Jan S; Jaspers, Jan P C

    2016-06-01

    The psychological impact of an unfavorable genetic test result for counselees at risk for hereditary cancer seems to be limited: only 10-20 % of counselees have psychological problems after testing positive for a known familial mutation. The objective of this study was to find prognostic factors that can predict which counselees are most likely to develop psychological problems after presymptomatic genetic testing. Counselees with a 50 % risk of BRCA1/2 or Lynch syndrome completed questionnaires at three time-points: after receiving a written invitation for a genetic counseling intake (T1), 2-3 days after receiving their DNA test result (T2), and 4-6 weeks later (T3). The psychological impact of the genetic test result was examined shortly and 4-6 weeks after learning their test result. Subsequently, the influence of various potentially prognostic factors on psychological impact were examined in the whole group. Data from 165 counselees were analyzed. Counselees with an unfavorable outcome did not have more emotional distress, but showed significantly more cancer worries 4-6 weeks after learning their test result. Prognostic factors for cancer worries after genetic testing were pre-existing cancer worries, being single, a high risk perception of getting cancer, and an unfavorable test result. Emotional distress was best predicted by pre-existing cancer worries and pre-existing emotional distress. The psychological impact of an unfavorable genetic test result appears considerable if it is measured as "worries about cancer." Genetic counselors should provide additional guidance to counselees with many cancer worries, emotional distress, a high risk perception or a weak social network.

  15. Genetic, Maternal, and Environmental Risk Factors for Cryptorchidism

    DEFF Research Database (Denmark)

    Barthold, Julia Spencer; Reinhardt, Susanne; Thorup, Jorgen

    2016-01-01

    Unilateral or bilateral cryptorchidism is an isolated anomaly in the majority of cases, with evidence to date suggesting that it is a complex disorder resulting from interactions between genetic and environmental factors. Population, family, and limited genome-wide association data suggest modera...

  16. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G; Ruigrok, Ynte M; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E; de Bakker, Paul I W

    2016-01-01

    BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RE

  17. The genetic factors influencing the development of trichotillomania

    Indian Academy of Sciences (India)

    Koushik Chatterjee

    2012-08-01

    Trichotillomania (TTM), an obsessive–compulsive spectrum disorder (OCSD), is a psychiatric condition characterized by repetitive hair pulling. Evidence from family and twin studies suggest a heritable link of TTM. Functional polymorphisms in genes involved in neuronal pathways might influence the susceptibility to TTM. This review is an attempt to compile the genetic factors reported to modify the development of TTM.

  18. Shared Genetic Risk Factors of Intracranial, Abdominal, and Thoracic Aneurysms

    NARCIS (Netherlands)

    van 't Hof, Femke N G|info:eu-repo/dai/nl/341753610; Ruigrok, Ynte M|info:eu-repo/dai/nl/303621222; Lee, Cue Hyunkyu; Ripke, Stephan; Anderson, Graig; de Andrade, Mariza; Baas, Annette F; Blankensteijn, Jan D; Böttinger, Erwin P; Bown, Matthew J; Broderick, Joseph; Bijlenga, Philippe; Carrell, David S; Crawford, Dana C; Crosslin, David R; Ebeling, Christian; Eriksson, Johan G; Fornage, Myriam; Foroud, Tatiana; von Und Zu Fraunberg, Mikael; Friedrich, Christoph M; Gaál, Emília I; Gottesman, Omri; Guo, Dong-Chuan; Harrison, Seamus C; Hernesniemi, Juha; Hofman, Albert; Inoue, Ituro; Jääskeläinen, Juha E; Jones, Gregory T; Kiemeney, Lambertus A L M; Kivisaari, Riku; Ko, Nerissa; Koskinen, Seppo; Kubo, Michiaki; Kullo, Iftikhar J; Kuivaniemi, Helena; Kurki, Mitja I; Laakso, Aki; Lai, Dongbing; Leal, Suzanne M; Lehto, Hanna; LeMaire, Scott A; Low, Siew-Kee; Malinowski, Jennifer; McCarty, Catherine A; Milewicz, Dianna M; Mosley, Thomas H; Nakamura, Yusuke; Nakaoka, Hirofumi; Niemelä, Mika; Pacheco, Jennifer; Peissig, Peggy L; Pera, Joanna; Rasmussen-Torvik, Laura; Ritchie, Marylyn D; Rivadeneira, Fernando; van Rij, Andre M; Santos-Cortez, Regie Lyn P; Saratzis, Athanasios; Slowik, Agnieszka; Takahashi, Atsushi; Tromp, Gerard; Uitterlinden, André G; Verma, Shefali S; Vermeulen, Sita H; Wang, Gao T; Han, Buhm; Rinkel, Gabriël J E|info:eu-repo/dai/nl/085712000; de Bakker, Paul I W|info:eu-repo/dai/nl/342957082

    2016-01-01

    BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RE

  19. A Strong Case for Viral Genetic Factors in HIV Virulence

    Directory of Open Access Journals (Sweden)

    Joshua T. Herbeck

    2011-03-01

    Full Text Available HIV infections show great variation in the rate of progression to disease, and the role of viral genetic factors in this variation had remained poorly characterized until recently. Now a series of four studies [1–4] published within a year has filled this important gap and has demonstrated a robust effect of the viral genotype on HIV virulence.

  20. Prognostic Factors for Distress After Genetic Testing for Hereditary Cancer

    NARCIS (Netherlands)

    Voorwinden, Jan S; Jaspers, Jan P C

    2015-01-01

    The psychological impact of an unfavorable genetic test result for counselees at risk for hereditary cancer seems to be limited: only 10-20 % of counselees have psychological problems after testing positive for a known familial mutation. The objective of this study was to find prognostic factors tha

  1. Resiliency to Victimization: The Role of Genetic Factors

    Science.gov (United States)

    Beaver, Kevin M.; Mancini, Christina; DeLisi, Matt; Vaughn, Michael G.

    2011-01-01

    There is a burgeoning line of criminological research examining the genetic underpinnings to a wide array of antisocial phenotypes. From this perspective, genes are typically viewed as risk factors that increase the odds of various maladaptive behaviors. However, genes can also have protective effects that insulate against the deleterious effects…

  2. Prognostic Factors for Distress After Genetic Testing for Hereditary Cancer

    NARCIS (Netherlands)

    Voorwinden, Jan S.; Jaspers, Jan P C

    2016-01-01

    The psychological impact of an unfavorable genetic test result for counselees at risk for hereditary cancer seems to be limited: only 10-20 % of counselees have psychological problems after testing positive for a known familial mutation. The objective of this study was to find prognostic factors tha

  3. The role of genetic factors in age at natural menopause

    NARCIS (Netherlands)

    Bruin, de J.P.; Bovenhuis, H.; Noord, van P.A.H.; Pearson, P.; Arendonk, van J.A.M.; Velde, ter E.R.; Kuurman, W.W.

    2001-01-01

    Background: Environmental factors explain only a small part of the age variance at which menopause commences. The variation in natural menopause is a trait predominantly determined by interaction of multiple genes, whose identity and causative genetic variation remains to be determined. Menopause is

  4. Congenital diaphragmatic hernia : the importance of genetic and environmental factors

    NARCIS (Netherlands)

    M.F. van Dooren (Marieke)

    2004-01-01

    textabstractFor the studies described in this thesis we used a study protocol 'Environmental and Genetic factors in Congenital Diaphragmatic Hernia and Esophageal Atresia', approved by the Institutional Review Board, in collaboration with the parent support groups, 'Stichting Hernia Diafragrnatica'

  5. Identification of common genetic variation that modulates alternative splicing.

    Directory of Open Access Journals (Sweden)

    Jeremy Hull

    2007-06-01

    Full Text Available Alternative splicing of genes is an efficient means of generating variation in protein function. Several disease states have been associated with rare genetic variants that affect splicing patterns. Conversely, splicing efficiency of some genes is known to vary between individuals without apparent ill effects. What is not clear is whether commonly observed phenotypic variation in splicing patterns, and hence potential variation in protein function, is to a significant extent determined by naturally occurring DNA sequence variation and in particular by single nucleotide polymorphisms (SNPs. In this study, we surveyed the splicing patterns of 250 exons in 22 individuals who had been previously genotyped by the International HapMap Project. We identified 70 simple cassette exon alternative splicing events in our experimental system; for six of these, we detected consistent differences in splicing pattern between individuals, with a highly significant association between splice phenotype and neighbouring SNPs. Remarkably, for five out of six of these events, the strongest correlation was found with the SNP closest to the intron-exon boundary, although the distance between these SNPs and the intron-exon boundary ranged from 2 bp to greater than 1,000 bp. Two of these SNPs were further investigated using a minigene splicing system, and in each case the SNPs were found to exert cis-acting effects on exon splicing efficiency in vitro. The functional consequences of these SNPs could not be predicted using bioinformatic algorithms. Our findings suggest that phenotypic variation in splicing patterns is determined by the presence of SNPs within flanking introns or exons. Effects on splicing may represent an important mechanism by which SNPs influence gene function.

  6. Genetic, metabolic and environmental factors involved in the development of liver cirrhosis in Mexico.

    Science.gov (United States)

    Ramos-Lopez, Omar; Martinez-Lopez, Erika; Roman, Sonia; Fierro, Nora A; Panduro, Arturo

    2015-11-07

    Liver cirrhosis (LC) is a chronic illness caused by inflammatory responses and progressive fibrosis. Globally, the most common causes of chronic liver disease include persistent alcohol abuse, followed by viral hepatitis infections and nonalcoholic fatty liver disease. However, regardless of the etiological factors, the susceptibility and degree of liver damage may be influenced by genetic polymorphisms that are associated with distinct ethnic and cultural backgrounds. Consequently, metabolic genes are influenced by variable environmental lifestyle factors, such as diet, physical inactivity, and emotional stress, which are associated with regional differences among populations. This Topic Highlight will focus on the genetic and environmental factors that may influence the metabolism of alcohol and nutrients in the setting of distinct etiologies of liver disease. The interaction between genes and environment in the current-day admixed population, Mestizo and Native Mexican, will be described. Additionally, genes involved in immune regulation, insulin sensitivity, oxidative stress and extracellular matrix deposition may modulate the degree of severity. In conclusion, LC is a complex disease. The onset, progression, and clinical outcome of LC among the Mexican population are influenced by specific genetic and environmental factors. Among these are an admixed genome with a heterogenic distribution of European, Amerindian and African ancestry; a high score of alcohol consumption; viral infections; a hepatopathogenic diet; and a high prevalence of obesity. The variance in risk factors among populations suggests that intervention strategies directed towards the prevention and management of LC should be tailored according to such population-based features.

  7. Coregulation of genetic programs by the transcription factors NFIB and STAT5.

    Science.gov (United States)

    Robinson, Gertraud W; Kang, Keunsoo; Yoo, Kyung Hyun; Tang, Yong; Zhu, Bing-Mei; Yamaji, Daisuke; Colditz, Vera; Jang, Seung Jian; Gronostajski, Richard M; Hennighausen, Lothar

    2014-05-01

    Mammary-specific genetic programs are activated during pregnancy by the common transcription factor signal transducer and activator of transcription (STAT) 5. More than one third of these genes carry nuclear factor I/B (NFIB) binding motifs that coincide with STAT5 in vivo binding, suggesting functional synergy between these two transcription factors. The role of NFIB in this governance was investigated in mice from which Nfib had been inactivated in mammary stem cells or in differentiating alveolar epithelium. Although NFIB was not required for alveolar expansion, the combined absence of NFIB and STAT5 prevented the formation of functional alveoli. NFIB controlled the expression of mammary-specific and STAT5-regulated genes and chromatin immunoprecipitation-sequencing established STAT5 and NFIB binding at composite regulatory elements containing histone H3 lysine dimethylation enhancer marks and progesterone receptor binding. By integrating previously published chromatin immunoprecipitation-sequencing data sets, the presence of NFIB-STAT5 modules in other cell types was investigated. Notably, genomic sites bound by NFIB in hair follicle stem cells were also occupied by STAT5 in mammary epithelium and coincided with enhancer marks. Many of these genes were under NFIB control in both hair follicle stem cells and mammary alveolar epithelium. We propose that NFIB-STAT5 modules, possibly in conjunction with other transcription factors, control cell-specific genetic programs.

  8. Psychological mechanisms in hyperactivity: II. The role of genetic factors.

    Science.gov (United States)

    Kuntsi, J; Stevenson, J

    2001-02-01

    The main aim of this study was to combine two research approaches to hyperactivity: the behaviour genetic approach and the testing of psychological theories of hyperactivity. For a sample of 268 twin pairs aged 7-11 years we obtained ratings on the Conners' scales from both teachers (CTRS-28) and parents (CPRS-48). Forty-six hyperactive twin pairs (pairs in which at least one twin was pervasively hyperactive) and 47 control twin pairs were assessed on a psychological test battery. Confirming findings from previous twin studies, a substantial proportion of the variance in hyperactivity considered as a dimension was due to genetic effects. There was significant evidence of genetic effects also on extreme hyperactivity, although the present group heritability estimates were somewhat lower than those reported in most previous studies. We investigated the possibility that the psychological mechanisms we reported to be associated with hyperactivity (Kuntsi, Oosterlaan, & Stevenson, 2001) share common genetic factors with hyperactive behaviour. The data produced significant evidence of such shared genetic effects only on hyperactivity and the variability of reaction times. Given that the high variability in speed of responding would indicate a state-regulation problem, this is the psychological mechanism that could possibly be the "link" between genetic effects and hyperactive behaviour.

  9. Genetic factors in exercise adoption, adherence and obesity.

    Science.gov (United States)

    Herring, M P; Sailors, M H; Bray, M S

    2014-01-01

    Physical activity and exercise play critical roles in energy balance. While many interventions targeted at increasing physical activity have demonstrated efficacy in promoting weight loss or maintenance in the short term, long term adherence to such programmes is not frequently observed. Numerous factors have been examined for their ability to predict and/or influence physical activity and exercise adherence. Although physical activity has been demonstrated to have a strong genetic component in both animals and humans, few studies have examined the association between genetic variation and exercise adherence. In this review, we provide a detailed overview of the non-genetic and genetic predictors of physical activity and adherence to exercise. In addition, we report the results of analysis of 26 single nucleotide polymorphisms in six candidate genes examined for association to exercise adherence, duration, intensity and total exercise dose in young adults from the Training Interventions and Genetics of Exercise Response (TIGER) Study. Based on both animal and human research, neural signalling and pleasure/reward systems in the brain may drive in large part the propensity to be physically active and to adhere to an exercise programme. Adherence/compliance research in other fields may inform future investigation of the genetics of exercise adherence. © 2013 The Authors. obesity reviews © 2013 International Association for the Study of Obesity.

  10. Factors influencing uptake of familial long QT syndrome genetic testing.

    Science.gov (United States)

    Burns, Charlotte; McGaughran, Julie; Davis, Andrew; Semsarian, Christopher; Ingles, Jodie

    2016-02-01

    Ongoing challenges of clinical assessment of long QT syndrome (LQTS) highlight the importance of genetic testing in the diagnosis of asymptomatic at-risk family members. Effective access, uptake, and communication of genetic testing are critical for comprehensive cascade family screening and prevention of disease complications such as sudden cardiac death. The aim of this study was to describe factors influencing uptake of LQTS genetic testing, including those relating to access and family communication. We show those who access genetic testing are overrepresented by the socioeconomically advantaged, and that although overall family communication is good, there are some important barriers to be addressed. There were 75 participants (aged 18 years or more, with a clinical and/or genetic diagnosis of LQTS; response rate 71%) who completed a survey including a number of validated scales; demographics; and questions about access, uptake, and communication. Mean age of participants was 46 ± 16 years, 20 (27%) were males and 60 (80%) had genetic testing with a causative gene mutation in 42 (70%). Overall uptake of cascade testing within families was 60% after 4 years from proband genetic diagnosis. All participants reported at least one first-degree relative had been informed of their risk, whereas six (10%) reported at least one first-degree relative had not been informed. Those who were anxious or depressed were more likely to perceive barriers to communicating. Genetic testing is a key aspect of care in LQTS families and intervention strategies that aim to improve equity in access and facilitate effective family communication are needed.

  11. Genetic and physiological factors affecting repair and mutagenesis in yeast

    Energy Technology Data Exchange (ETDEWEB)

    Lemontt, J F

    1979-01-01

    Current views of DNA repair and mutagenesis in the yeast Saccharomyces cerevisiae are discussed in the light of recent data and with emphasis on the isolation and characterization of genetically well-defined mutations that affect DNA metabolism in general (including replication and recombination). Various pathways of repair are described, particularly in relation to their imvolvement in mutagenic mechanisms. In addition to genetic control, certain physiological factors such as cell age, DNA replication, and the regulatory state of the mating-type locus are shown to also play a role in repair and mutagenesis.

  12. Genetic and physiological factors affecting repair and mutagenesis in yeast

    Energy Technology Data Exchange (ETDEWEB)

    Lemontt, J F

    1979-01-01

    Current views of DNA repair and mutagenesis in the yeast Saccharomyces cerevisiae are discussed in the light of recent data, and with emphasis on the isolation and characterization of genetically well-defined mutations that affect DNA metabolism in general (including replication and recombination). Various pathways of repair are described particularly in relation to their involvement in mutagenic mechanisms. In addition to genetic control, certain physiological factors such as cell age, DNA replication, and the regulatory state of the mating-type locus, are shown to also play a role in repair and mutagenesis.

  13. Mutagen sensitivity: a genetic predisposition factor for cancer.

    Science.gov (United States)

    Wu, Xifeng; Gu, Jian; Spitz, Margaret R

    2007-04-15

    Mutagen sensitivity, measured by quantifying the chromatid breaks induced by mutagens in short-term cultures of peripheral blood lymphocytes, has been used as an indirect measure of DNA repair capacity. Numerous epidemiologic studies have suggested that mutagen sensitivity is a cancer susceptibility factor for a variety of epithelial cancers. A recent classic twin study examined systematically the role of genetic and environmental factors on the mutagen sensitivity phenotype and provided compelling evidence that mutagen sensitivity is highly heritable. A new prospective analysis provides further support to the notion that mutagen sensitivity increases the risk of cancer. In this review, we briefly summarize nearly two decades of epidemiologic and genetic studies linking mutagen sensitivity and cancer risk. The evidence is becoming increasingly convincing that mutagen sensitivity is a risk factor for cancer development.

  14. Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.

    Science.gov (United States)

    Tu, Wen-Yo; Simpson, Julie E; Highley, J Robin; Heath, Paul R

    2017-02-02

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets.

  15. Bioinformatics Identification of Modules of Transcription Factor Binding Sites in Alzheimer's Disease-Related Genes by In Silico Promoter Analysis and Microarrays

    Directory of Open Access Journals (Sweden)

    Regina Augustin

    2011-01-01

    Full Text Available The molecular mechanisms and genetic risk factors underlying Alzheimer's disease (AD pathogenesis are only partly understood. To identify new factors, which may contribute to AD, different approaches are taken including proteomics, genetics, and functional genomics. Here, we used a bioinformatics approach and found that distinct AD-related genes share modules of transcription factor binding sites, suggesting a transcriptional coregulation. To detect additional coregulated genes, which may potentially contribute to AD, we established a new bioinformatics workflow with known multivariate methods like support vector machines, biclustering, and predicted transcription factor binding site modules by using in silico analysis and over 400 expression arrays from human and mouse. Two significant modules are composed of three transcription factor families: CTCF, SP1F, and EGRF/ZBPF, which are conserved between human and mouse APP promoter sequences. The specific combination of in silico promoter and multivariate analysis can identify regulation mechanisms of genes involved in multifactorial diseases.

  16. BELFAST nonagenarians: nature or nurture? Immunological, cardiovascular and genetic factors

    Directory of Open Access Journals (Sweden)

    Rea I M

    2010-05-01

    Full Text Available Abstract Nonagenarians are the fastest growing sector of populations across Western European and the developed world. They are some of the oldest members of our societies and survivors of their generation and may help us understand how to age not only longer, but better. The Belfast Longevity Group enlisted the help of 500 community-living, mobile, mentally competent, 'elite' nonagenarians, as part of an ongoing study of ageing. We assessed some immunological, cardiovascular, nutritional and genetic factors and some aspects of their interaction in this group of 'oldest old'. Here we present some of the evidence related to genetic and nutritional factors which seem to be important for good quality ageing in nonagenarians from the Belfast Elderly Longitudinal Free-living Ageing STudy (BELFAST.

  17. Genetic and environmental factors in breakfast eating patterns.

    Science.gov (United States)

    Keski-Rahkonen, Anna; Viken, Richard J; Kaprio, Jaakko; Rissanen, Aila; Rose, Richard J

    2004-09-01

    Despite many studies on the prevalence of breakfast eating, we know little about factors that determine breakfast eating patterns. Our aim was to find out to which extent breakfast eating frequency is influenced by genetic and environmental factors using twin and twin-family models in a population sample of 16-year-old twins (n = 5250) and their parents (n = 4663). In common effects sex-limitation models, additive genetic effects explained 41% (95% CI: 21-63%) of the variance in breakfast eating in girls and 66% (95% CI: 47-79%) in boys, and common environmental effects 45% (95% CI: 23-62%) in girls and 14% (95% CI: 5-29%) in boys. Of twin-family models, phenotypic assortment models fitted the data best. Heritability estimates increased somewhat (72%, 95% CI: 46-98% in girls and 63%, 95% CI: 38-89%) in boys. Common family environment remained substantial in both sexes. Cultural transmission was nonsignificant. The relative influence of genetic and family factors on adolescent breakfast eating frequency differs by sex and is generation-specific.

  18. Genetic and non-genetic factors affecting morphometry of Sirohi goats

    Directory of Open Access Journals (Sweden)

    S. D. Dudhe

    2015-11-01

    Full Text Available Aim: The aim was to estimate genetic and non-genetic factors affecting morphometric traits of Sirohi goats under field condition. Materials and Methods: The detailed information of all animals on body measurements at birth, 3, 6, 9, and 12 months of age was collected from farmer’s flock under field condition born during 2007-2013 to analyze the effect of genetic and non-genetic factors. The least squares maximum likelihood program was used to estimate genetic and non-genetic parameters affecting morphometric traits. Results and Discussion: Effect of sire, cluster, year of birth, and sex was found to be highly significant (p<0.01 on all three morphometric traits, parity was highly significant (p<0.01 for body height (BH and body girth (BG at birth. The h2 estimates for morphometric traits ranged among 0.528±0.163 to 0.709±0.144 for BH, 0.408±0.159 to 0.605±0.192 for body length (BL, and 0.503±0.197 to 0.695±0.161 for BG. Conclusion: The effect of sire was highly significant (p<0.01 and also h² estimate of all morphometric traits were medium to high; therefore, it could be concluded on the basis of present findings that animals with higher body measurements at initial phases of growth will perform better with respect to even body weight traits at later stages of growth.

  19. Modeling development and quantitative trait mapping reveal independent genetic modules for leaf size and shape.

    Science.gov (United States)

    Baker, Robert L; Leong, Wen Fung; Brock, Marcus T; Markelz, R J Cody; Covington, Michael F; Devisetty, Upendra K; Edwards, Christine E; Maloof, Julin; Welch, Stephen; Weinig, Cynthia

    2015-10-01

    Improved predictions of fitness and yield may be obtained by characterizing the genetic controls and environmental dependencies of organismal ontogeny. Elucidating the shape of growth curves may reveal novel genetic controls that single-time-point (STP) analyses do not because, in theory, infinite numbers of growth curves can result in the same final measurement. We measured leaf lengths and widths in Brassica rapa recombinant inbred lines (RILs) throughout ontogeny. We modeled leaf growth and allometry as function valued traits (FVT), and examined genetic correlations between these traits and aspects of phenology, physiology, circadian rhythms and fitness. We used RNA-seq to construct a SNP linkage map and mapped trait quantitative trait loci (QTL). We found genetic trade-offs between leaf size and growth rate FVT and uncovered differences in genotypic and QTL correlations involving FVT vs STPs. We identified leaf shape (allometry) as a genetic module independent of length and width and identified selection on FVT parameters of development. Leaf shape is associated with venation features that affect desiccation resistance. The genetic independence of leaf shape from other leaf traits may therefore enable crop optimization in leaf shape without negative effects on traits such as size, growth rate, duration or gas exchange.

  20. Shared Genetic Factors Influence Amygdala Volumes and Risk for Alcoholism

    Science.gov (United States)

    Dager, Alecia D; McKay, D Reese; Kent, Jack W; Curran, Joanne E; Knowles, Emma; Sprooten, Emma; Göring, Harald HH; Dyer, Thomas D; Pearlson, Godfrey D; Olvera, Rene L; Fox, Peter T; Lovallo, William R; Duggirala, Ravi; Almasy, Laura; Blangero, John; Glahn, David C

    2015-01-01

    Alcohol abuse and dependence (alcohol use disorders, AUDs) are associated with brain shrinkage. Subcortical structures including the amygdala, hippocampus, ventral striatum, dorsal striatum, and thalamus subserve reward functioning and may be particularly vulnerable to alcohol-related damage. These structures may also show pre-existing deficits impacting the development and maintenance of AUD. It remains unclear whether there are common genetic features underlying both subcortical volumes and AUD. In this study, structural brain images were acquired from 872 Mexican-American individuals from extended pedigrees. Subcortical volumes were obtained using FreeSurfer, and quantitative genetic analyses were performed in SOLAR. We hypothesized the following: (1) reduced subcortical volumes in individuals with lifetime AUD relative to unrelated controls; (2) reduced subcortical volumes in individuals with current relative to past AUD; (3) in non-AUD individuals, reduced subcortical volumes in those with a family history of AUD compared to those without; and (4) evidence for common genetic underpinnings (pleiotropy) between AUD risk and subcortical volumes. Results showed that individuals with lifetime AUD showed larger ventricular and smaller amygdala volumes compared to non-AUD individuals. For the amygdala, there were no differences in volume between current vs past AUD, and non-AUD individuals with a family history of AUD demonstrated reductions compared to those with no such family history. Finally, amygdala volume was genetically correlated with the risk for AUD. Together, these results suggest that reduced amygdala volume reflects a pre-existing difference rather than alcohol-induced neurotoxic damage. Our genetic correlation analysis provides evidence for a common genetic factor underlying both reduced amygdala volumes and AUD risk. PMID:25079289

  1. Shared genetic factors influence amygdala volumes and risk for alcoholism.

    Science.gov (United States)

    Dager, Alecia D; McKay, D Reese; Kent, Jack W; Curran, Joanne E; Knowles, Emma; Sprooten, Emma; Göring, Harald H H; Dyer, Thomas D; Pearlson, Godfrey D; Olvera, Rene L; Fox, Peter T; Lovallo, William R; Duggirala, Ravi; Almasy, Laura; Blangero, John; Glahn, David C

    2015-01-01

    Alcohol abuse and dependence (alcohol use disorders, AUDs) are associated with brain shrinkage. Subcortical structures including the amygdala, hippocampus, ventral striatum, dorsal striatum, and thalamus subserve reward functioning and may be particularly vulnerable to alcohol-related damage. These structures may also show pre-existing deficits impacting the development and maintenance of AUD. It remains unclear whether there are common genetic features underlying both subcortical volumes and AUD. In this study, structural brain images were acquired from 872 Mexican-American individuals from extended pedigrees. Subcortical volumes were obtained using FreeSurfer, and quantitative genetic analyses were performed in SOLAR. We hypothesized the following: (1) reduced subcortical volumes in individuals with lifetime AUD relative to unrelated controls; (2) reduced subcortical volumes in individuals with current relative to past AUD; (3) in non-AUD individuals, reduced subcortical volumes in those with a family history of AUD compared to those without; and (4) evidence for common genetic underpinnings (pleiotropy) between AUD risk and subcortical volumes. Results showed that individuals with lifetime AUD showed larger ventricular and smaller amygdala volumes compared to non-AUD individuals. For the amygdala, there were no differences in volume between current vs past AUD, and non-AUD individuals with a family history of AUD demonstrated reductions compared to those with no such family history. Finally, amygdala volume was genetically correlated with the risk for AUD. Together, these results suggest that reduced amygdala volume reflects a pre-existing difference rather than alcohol-induced neurotoxic damage. Our genetic correlation analysis provides evidence for a common genetic factor underlying both reduced amygdala volumes and AUD risk.

  2. Noninheritable Maternal Factors Useful for Genetic Manipulation in Mammals.

    Science.gov (United States)

    Sakurai, Takayuki; Shindo, Takayuki; Sato, Masahiro

    2017-01-01

    Mammalian early embryogenesis is supported by maternal factors, such as messenger RNA (mRNA) and proteins, produced and accumulated during oogenesis at least up to the stage when zygotic activation commences. These maternal factors are involved in biologically important events such as epigenetic activation, reprogramming, and mitochondrial growth. Most of these maternal mRNAs are degraded by the 2-cell to 4 ~ 8-cell stages. Maternal proteins, which are produced during oogenesis or by the maternal mRNAs, are degraded by the 4 ~ 8-cell stage. In other words, the maternal factors exist during specific stages of early embryogenesis. In this chapter, we will briefly summarize the property of these maternal factors and mention possible applications of these factors for developing new reproduction engineering-related technologies and producing genetically modified animals. More specifically, we will show the usefulness of maternally accumulated Cas9 protein as a promising tool for CRISPR-/Cas9-based simultaneous genetic modification of multiple loci in mammals.

  3. Modulation of tumor necrosis factor by microbial pathogens.

    Directory of Open Access Journals (Sweden)

    2006-02-01

    Full Text Available In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcome or deflect the host responses mediated by TNF. For example, modulatory proteins encoded by multiple families of viruses can block TNF and TNF-mediated responses at multiple levels, such as the inhibition of the TNF ligand or its receptors, or by modulating key transduction molecules of the TNF signaling pathway. Bacteria, on the other hand, tend to modify TNF-mediated responses specifically by regulating components of the TNF signaling pathway. Investigation of these diverse strategies employed by viral and bacterial pathogens has significantly advanced our understanding of both host TNF responses and microbial pathogenesis. This review summarizes the diverse microbial strategies to regulate TNF and how such insights into TNF modulation could benefit the treatment of inflammatory or autoimmune diseases.

  4. Role of DNA Methylation in Modulating Transcription Factor Occupancy

    Directory of Open Access Journals (Sweden)

    Matthew T. Maurano

    2015-08-01

    Full Text Available Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5% of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites.

  5. Analytical Assessment of the Q-Factor due to Cross-Phase Modulation (XPM)

    Institute of Scientific and Technical Information of China (English)

    Stephan; Pachnicke; Edgar; Voges

    2003-01-01

    The paper describes the impact of cross-phase modulation on NRZ modulated WDM systems. The impairments due to XPM will be related to a Q-factor and the effects of dispersion management will be covered.

  6. Genetic modulation of training and transfer in older adults:BDNF Val66Met polymorphism is associated with wider useful field of view

    Directory of Open Access Journals (Sweden)

    Lorenza S Colzato

    2011-09-01

    Full Text Available Western society has an increasing proportion of older adults. Increasing age is associated with a general decrease in the control over task-relevant mental processes. In the present study we investigated the possibility that successful transfer of game-based cognitive improvements to untrained tasks in elderly people is modulated by preexisting neuro-developmental factors as genetic variability related to levels of the brain-derived neurotrophic factor (BDNF, an important neuromodulator underlying cognitive processes. We trained participants, genotyped for the BDNF Val66Met polymorphism, on cognitive tasks developed to improve dynamic attention. Pre-training (baseline and post-training measures of attentional processes (divided and selective attention were acquired by means of the Useful Field of View (UFOV task. As expected, Val/Val homozygous individuals showed larger beneficial transfer effects than Met/-carriers. Our findings support the idea that genetic predisposition modulates transfer effects.

  7. [Influence of genetic factors on human sexual orientation. Review].

    Science.gov (United States)

    Rodríguez-Larralde, Alvaro; Paradisi, Irene

    2009-09-01

    Human sexual orientation is a complex trait, influenced by several genes, experiential and sociocultural factors. These elements interact and produce a typical pattern of sexual orientation towards the opposite sex. Some exceptions exist, like bisexuality and homosexuality, which seem to be more frequent in males than females. Traditional methods for the genetic study of behavior multifactorial characteristics consist in detecting the presence of familial aggregation. In order to identify the importance of genetic and environmental factors in this aggregation, the concordance of the trait for monozygotic and dizygotic twins and for adopted sibs, reared together and apart, is compared. These types of studies have shown that familial aggregation is stronger for male than for female homosexuality. Based on the threshold method for multifactorial traits, and varying the frequency of homosexuality in the population between 4 and 10%, heritability estimates between 0.27 and 0.76 have been obtained. In 1993, linkage between homosexuality and chromosomal region Xq28 based on molecular approaches was reported. Nevertheless, this was not confirmed in later studies. Recently, a wide search of the genome has given significant or close to significant linkage values with regions 7q36, 8p12 and 10q26, which need to be studied more closely. Deviation in the proportion of X chromosome inactivation in mothers of homosexuals seems to favor the presence of genes related with sexual orientation in this chromosome. There is still much to be known about the genetics of human homosexuality.

  8. Lay responses to health messages about the genetic risk factors for salt sensitivity: do mass media genetic health messages result in genetic determinism?

    Science.gov (United States)

    Smerecnik, Chris M R

    2010-08-01

    Media coverage of genetics may lead to overestimation of the impact of genetics on disease development. In this study, we presented one student sample and one general public sample from the Netherlands with a general or a genetic health message (HM) about salt sensitivity. After reading the genetic (but not the general) HM, participants reported higher perceived impact of genetic versus lifestyle factors and a higher attributable fraction of genetics on disease development. Nevertheless, participants were able to recognise the balance between lifestyle and genetic risk factors in disease development. They also contextualised and restricted the message's implications to the specific information provided, and did not extrapolate these implications to other diseases. These results illustrate the nuanced understanding the general public may have concerning genetic risk factors.

  9. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Nico Derichs

    2013-03-01

    Full Text Available Cystic fibrosis (CF is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

  10. Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death.

    Directory of Open Access Journals (Sweden)

    Kelly N Owens

    2008-02-01

    Full Text Available Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplastic agents are significant contributors. Genetic variation contributes markedly to differences in normal disease progression during aging and in susceptibility to ototoxic agents. Using the lateral line system of larval zebrafish, we developed an in vivo drug toxicity interaction screen to uncover genetic modulators of antibiotic-induced hair cell death and to identify compounds that confer protection. We have identified 5 mutations that modulate aminoglycoside susceptibility. Further characterization and identification of one protective mutant, sentinel (snl, revealed a novel conserved vertebrate gene. A similar screen identified a new class of drug-like small molecules, benzothiophene carboxamides, that prevent aminoglycoside-induced hair cell death in zebrafish and in mammals. Testing for interaction with the sentinel mutation suggests that the gene and compounds may operate in different pathways. The combination of chemical screening with traditional genetic approaches is a new strategy for identifying drugs and drug targets to attenuate hearing and balance disorders.

  11. Genetic modulation of personality traits: a systematic review of the literature.

    Science.gov (United States)

    Balestri, Martina; Calati, Raffaella; Serretti, Alessandro; De Ronchi, Diana

    2014-01-01

    The heritability of human personality traits is by now well established. However, since the first reports on associations between specific genetic variants and personality traits, only modest progress has been made in identifying loci that robustly support these associations. The aim of this study was to provide a summary of literature data on association studies focused on the genetic modulation of personality, according to the Cloninger, Eysenck and Costa and McCrae models. PubMed was searched for papers investigating the association between any gene variant and personality traits, which were grouped into five clusters: (a) anxiety, (b) impulsivity, (c) determination-activity, (d) socialization and (e) spirituality, in healthy individuals, populations and psychiatric patients. A total of 369 studies were included. No clear consensus on the role of any individual gene variant in personality modulation emerged, although SLC6A4 haplotypes and the DRD4 rs1800955 promoter variant seemed to be more reliably related to anxiety and impulsivity-related traits, respectively. Because conflicting results emerged from the literature, plausibly as a result of the combined influence of many loci of small effects on personality, larger sample sizes and more narrow and specific phenotype will be the minimum requirements for future genetic studies on personality. Moreover, gene × gene and gene × environment interaction studies deserve further attention.

  12. Factores de riesgo de la enfermedad periodontal: factores genéticos Risks factors in periodontal diseases: genetic factors

    Directory of Open Access Journals (Sweden)

    M. Rioboo Crespo

    2005-08-01

    factor de resistencia y susceptibilidad de la enfermedad periodontal así como los polimorfismos del gen de la vitamina D, del receptor fMLP , del receptor FcIIIb de los neutrófilos, del receptor FcgRII y de la N-acetyltransferasa (NAT2.Periodontitis is nowadays accepted as a multi-factorial disease with microbial agent as the initiator ,necessary but not enough , and a wide variety of determinants and factors that influence the manifestation and progression of the disease. The potencial importance of genetics and heredity to the knowledge about the pathogenesis and the clinic dental practice of periodontal diseases has been recognized since the earliest days of dentistry and medicine, but the relative complexity resulting from the interaction among the exposure to oral bacteria and the host response promote the dificulty of the genetics factors role clarification. Even so, genetic factors influence in periodontal diseases are suggest for several forms of periodontitis. In general, it’s considered the existence of sufficient scientific basis in favour of the genetic factors presence in Aggressive Periodontitis, whereas, the evidence of the genetic participation in Chronic Periodontitis isn’t so manifest. A multitude of host factors are involved in responses to microbial challenge and in the subsequent immune responses of the periodontal diseases, so, genetics polymorphisms probably exist in many of if not most of the inflammatory and immune mediators such as demonstrated by the IL-1,IL-4, IL-10,TNF, PGE2, specific HLA antigens (Human Leukocite Antigen, Vitamine D receptor, fMLP receptor, IgG Fc receptors (FcIIIb and FcgRII and the N-acetyltransferase (NAT2 receptor. Correlation of these genetic polymorphisms with phenotypic characteristics of periodontitis patients groups may provide the frame work for identification of individual risk profiles.

  13. Building gene expression signatures indicative of transcription factor activation to predict AOP modulation

    Science.gov (United States)

    Building gene expression signatures indicative of transcription factor activation to predict AOP modulation Adverse outcome pathways (AOPs) are a framework for predicting quantitative relationships between molecular initiatin...

  14. Motivating factors for physician ordering of factor V Leiden genetic tests.

    Science.gov (United States)

    Hindorff, Lucia A; Burke, Wylie; Laberge, Anne-Marie; Rice, Kenneth M; Lumley, Thomas; Leppig, Kathleen; Rosendaal, Frits R; Larson, Eric B; Psaty, Bruce M

    2009-01-12

    The factor V Leiden (FVL) genetic test is used by many physicians despite its uncertain clinical utility. We investigate whether self-reported motivations and behaviors concerning FVL genetic testing differ between 2 groups of primary care physicians defined by frequency of previous FVL test use. In January 2007, 112 physicians (60 frequent and 52 infrequent FVL test users) at Group Health, a large health care delivery system, were surveyed. Survey content areas included primary reasons and motivating factors for ordering the FVL test, the likelihood of ordering the FVL test for hypothetical patients, potential barriers to genetic testing, and practices and skills regarding FVL test ordering. Responses between groups agreed concerning most clinical- and patient-related factors. Frequent-FVL physicians were more likely than infrequent-FVL physicians to report ordering the FVL test for hypothetical patients with mesenteric venous thrombosis (adjusted odds ratio, 4.57; 95% confidence interval, 1.55-13.53) or venous thrombosis after hospital discharge (adjusted odds ratio, 3.42; 95% confidence interval, 1.30-8.95). Frequent-FVL physicians were also less likely to identify several items on the survey as barriers to genetic testing and were more likely to report high confidence in interpreting and explaining FVL test results. Generally, both physician groups reported similar motivating factors for ordering FVL tests, and reported behaviors were consistent with existing guidelines. More striking differences were observed for measures such as barriers to and confidence in using genetic tests. Although additional research is necessary to evaluate the impact of these results, they inform several knowledge-to-practice translation issues that are important for the successful integration of genetic testing into primary care.

  15. Motivating factors for physician ordering of Factor V Leiden genetic tests

    Science.gov (United States)

    Hindorff, Lucia A.; Burke, Wylie; Laberge, Anne-Marie; Rice, Kenneth M.; Lumley, Thomas; Leppig, Kathleen; Rosendaal, Frits R.; Larson, Eric B.; Psaty, Bruce M.

    2009-01-01

    Background The Factor V Leiden (FVL) genetic test is used by many physicians despite its uncertain clinical utility. This study investigated whether self-reported motivations and behaviors concerning FVL genetic testing differed between two groups of primary care physicians defined by frequency of prior FVL test use. Methods In January 2007, 112 primary care physicians (60 frequent, 52 infrequent FVL test users) at Group Health, a large health care delivery system, were surveyed. Survey content areas included: primary reasons and motivating factors for ordering FVL; likelihood of ordering FVL for hypothetical patients; potential barriers to genetic testing, and practices and skills regarding FVL test ordering. Results Responses between groups agreed concerning most clinical- or patient-related factors. Frequent-FVL physicians were more likely than infrequent-FVL physicians to report ordering FVL for hypothetical patients with mesenteric venous thrombosis (adjusted OR 4.57, 95% CI 1.55, 13.53) or venous thrombosis following hospital discharge (adjusted OR 3.42, 95% CI 1.30, 8.95). Frequent-FVL physicians were also less likely to agree with several potential barriers to genetic testing and more likely to report high confidence in interpreting and explaining FVL test results. Conclusions Generally, both groups of physicians reported similar motivating factors for ordering FVL, and reported behaviors were consistent with existing guidelines. More striking differences were observed for measures such as barriers to and confidence in using genetic tests. Though additional research is necessary to evaluate their impact, these results inform several knowledge-to-practice translation issues that are important to the successful integration of genetic testing into primary care. PMID:19139326

  16. IMPLEMENTATION OF SPACE VECTOR PULSE WIDTH MODULATION TECHNIQUE WITH GENETIC ALGORITHM TO OPTIMIZE UNIFIED POWER QUALITY CONDITIONER

    Directory of Open Access Journals (Sweden)

    M. Shankar

    2014-01-01

    Full Text Available This study proposes a novel control design of Unified Power Quality Conditioner (UPQC. This design is enabled by a control framework that employs Genetic Algorithm which determines optimum points and angle for filtering and Space Vector Pulse Width Modulation Technique (SVPWM to offer significant flexibility to optimize waveform. In addition the same framework integrates the major functions of the UPQC with ease to unify the treatments of several power quality problems including system harmonics in the supply voltage and load current, sags/swells in the supply voltage, variations in the load demands and poor power factor at the supply side. Simulation studies on a three phase power distribution system are used to verify the performance and implementation of this control design with the UPQC.

  17. The preservation of M-injectivity in the forming of factor modules

    Directory of Open Access Journals (Sweden)

    D. Döman

    1982-03-01

    Full Text Available For a given module M the factor modules of M-injective modules are not necessarily M-injective. Necessary and sufficient conditions are derived under which it is the case if M is projective. The result is used to characterize hereditary rings.

  18. A novel bottom-left packing genetic algorithm for analog module placement

    Directory of Open Access Journals (Sweden)

    L. Zhang

    2003-01-01

    Full Text Available This paper presents a novel genetic algorithm for analog module placement. It is based on a generalization of the two-dimensional bin packing problem. The genetic encoding and operators assures that all constraints of the problem are always satisfied. Thus the potential problems of adding penalty terms to the cost function are eliminated, so that the search configuration space decreases drastically. The dedicated cost function covers the special requirements of analog integrated circuits. A fractional factorial experiment was conducted using an orthogonal array to study the algorithm parameters. A meta-GA was applied to determine the optimal parameter values. The algorithm has been tested with several local benchmark circuits. The experimental results show this promising algorithm makes the better performance than simulated annealing approach with the satisfactory results comparable to manual placement.

  19. Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite.

    Science.gov (United States)

    Byerly, Mardi S; Swanson, Roy D; Semsarzadeh, Nina N; McCulloh, Patrick S; Kwon, Kiwook; Aja, Susan; Moran, Timothy H; Wong, G William; Blackshaw, Seth

    2013-06-15

    Disruption of finely coordinated neuropeptide signals in the hypothalamus can result in altered food intake and body weight. We identified neuron-derived neurotrophic factor (NENF) as a novel secreted protein through a large-scale screen aimed at identifying novel secreted hypothalamic proteins that regulate food intake. We observed robust Nenf expression in hypothalamic nuclei known to regulate food intake, and its expression was altered under the diet-induced obese (DIO) condition relative to the fed state. Hypothalamic Nenf mRNA was regulated by brain-derived neurotrophic factor (BDNF) signaling, itself an important regulator of appetite. Delivery of purified recombinant BDNF into the lateral cerebral ventricle decreased hypothalamic Nenf expression, while pharmacological inhibition of trkB signaling increased Nenf mRNA expression. Furthermore, recombinant NENF administered via an intracerebroventricular cannula decreased food intake and body weight and increased hypothalamic Pomc and Mc4r mRNA expression. Importantly, the appetite-suppressing effect of NENF was abrogated in obese mice fed a high-fat diet, demonstrating a diet-dependent modulation of NENF function. We propose the existence of a regulatory circuit involving BDNF, NENF, and melanocortin signaling. Our study validates the power of using an integrated experimental and bioinformatic approach to identify novel CNS-derived proteins with appetite-modulating function and reveals NENF as an important central modulator of food intake.

  20. [Endemic goiter in Latium: environmental and genetic factors].

    Science.gov (United States)

    Paggi, A

    1998-01-01

    Most studies on the pathogenesis of endemic goiter focus above all on iodine deficiency. In some endemic goiter areas (i.e. Nigeria) there is no evidence of iodine deficiency; therefore, we suggest the taking into account of various factors, both environmental and non-environmental. We report the results of two studies carried out in three different areas in Latium: one of them (Cerveteri, RM) could be classified as high prevalence of goiter area, while the two others (Roccasecca dei Volsci, LT and Castel San Pietro Romano, RM) are true endemic goiter areas. The role of environmental factors, radioactivity and electromagnetism, foodstuff, the hydrogeological and chemical composition of natural water and the importance of genetics are here discussed, assuming that the endemic goiter could have a multifactorial pathogenesis.

  1. Analysis of genetics and risk factors of Alzheimer's Disease.

    Science.gov (United States)

    Panpalli Ates, M; Karaman, Y; Guntekin, S; Ergun, M A

    2016-06-14

    Alzheimer's Disease is the leading neurodegenerative cause of dementia. The pathogenesis is not clearly understood yet, is believed to be the complex interaction between genetic and environmental factors. Consequently vascular risk factors and Apolipoprotein E genotyping are increasingly gaining importance. This study aimed at assessing the relationships between Alzheimer's Disease and Apolipoprotein E phenotype and vascular risk factors. Patients diagnosed with "possible Alzheimer's Disease" in the Gazi University, Department of Neurology, were included in the study and age-matched volunteer patients who attended the polyclinic were included as a control group. In this study, the risk factors including low education level, smoking, hyperlipidemia, higher serum total cholesterol levels, and hyperhomocysteinemia were found to be statistically significantly more common in the Alzheimer's Disease group in comparison to the Control Group, while all Apolipoprotein E ε4/ε4 genotypes were found in the Alzheimer's Disease group. The presence of the Apolipoprotein E ε4 allele is believed to increase vascular risk factors as well as to affect Alzheimer's Disease directly. The biological indicators which are used in identifying the patients' genes will be probably used in the treatment plan of the patients in the future.

  2. RhoC GTPase Overexpression Modulates Induction of Angiogenic Factors in Breast Cells

    Directory of Open Access Journals (Sweden)

    Kenneth L. van Golen

    2000-09-01

    Full Text Available Inflammatory breast cancer (IBC is a distinct and aggressive form of locally advanced breast cancer. IBC is highly angiogenic, invasive, and metastatic at its inception. Previously, we identified specific genetic alterations of IBC that contribute to this highly invasive phenotype. RhoC GTPase was overexpressed in 90% of archival IBC tumor samples, but not in stage-matched, non-IBC tumors. To study the role of RhoC GTPase in contributing to an IBC-like phenotype, we generated stable transfectants of human mammary epithelial cells overexpressing the RhoC gene, and studied the effect of RhoC GTPase overexpression on the modulation of angiogenesis in IBC. Levels of vascular endothelial growth factor (VEGF, basic fibroblast growth factor (bFGF, interleukin-6 (IL-6, and interleukin-8 (IL-8 were significantly higher in the conditioned media of the HME-RhoC transfectants than in the untransfected HME and HME-β-galactosidase control media, similar to the SUM149 IBC cell line. Inhibition of RhoC function by introduction of C3 exotransferase decreased production of angiogenic factors by the HME-RhoC transfectants and the SUM149 IBC cell line, but did not affect the control cells. These data support the conclusion that overexpression of RhoC GTPase is specifically and directly implicated in the control of the production of angiogenic factors by IBC cells.

  3. Colorectal cancer and detoxification enzymes : with emphasis on enzyme modulation and genetic polymorphisms

    NARCIS (Netherlands)

    Logt, E.M.J. van der

    2005-01-01

    The aetiology of sporadic colorectal cancer (CRC) is complex and involves genetic and lifestyle factors. To deal with the daily load of carcinogens, present in food, tobacco smoke etc., humans possess an efficient system of defence against such compounds and an important role is reserved for the det

  4. Altered distribution of susceptibility phenotypes implies environmental modulation of genetic resistance

    Science.gov (United States)

    Thomas R. Gordon; Neil McRoberts

    2012-01-01

    Resistance to disease is determined by the genetic capacity of a plant to recognize and respond to a pathogen, as modified to varying degrees by the environment in which the interaction occurs. Physical factors such as temperature and moisture can limit the ability of a pathogen to infect and cause disease, and may also influence the response of the host through...

  5. Murine Gut Microbiota Is Defined by Host Genetics and Modulates Variation of Metabolic Traits

    NARCIS (Netherlands)

    McKnite, A.M.; Lu, L.; Williams, E.; Bastiaansen, J.W.M.

    2012-01-01

    The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation

  6. Is Ankyrin a genetic risk factor for psychiatric phenotypes?

    Directory of Open Access Journals (Sweden)

    Stöber Gerald

    2011-06-01

    Full Text Available Abstract Background Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336 as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482 was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression. Methods We genotyped three single nucleotide polymorphisms (SNPs in ANK3 (rs9804190, rs10994336, and rs10761482 in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes. Results We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015 but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification. Conclusion Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.

  7. Biology, Genetics, and Environment: Underlying Factors Influencing Alcohol Metabolism.

    Science.gov (United States)

    Wall, Tamara L; Luczak, Susan E; Hiller-Sturmhöfel, Susanne

    2016-01-01

    Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence. Certain genetic variants (i.e., alleles)--particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles--have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, which can result in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups; ADH1B*2 is found frequently in northeast Asians and occasionally Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in northeast Asians. Differences in the prevalence of these alleles may account at least in part for ethnic differences in alcohol consumption and alcohol use disorder (AUD). However, these alleles do not act in isolation to influence the risk of AUD. For example, the gene effects of ALDH2*2 and ADH1B*2 seem to interact. Moreover, other factors have been found to influence the extent to which these alleles affect a person's alcohol involvement, including developmental stage, individual characteristics (e.g., ethnicity, antisocial behavior, and behavioral undercontrol), and environmental factors (e.g., culture, religion, family environment, and childhood adversity).

  8. Role of DNA Methylation in Modulating Transcription Factor Occupancy.

    Science.gov (United States)

    Maurano, Matthew T; Wang, Hao; John, Sam; Shafer, Anthony; Canfield, Theresa; Lee, Kristen; Stamatoyannopoulos, John A

    2015-08-18

    Although DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5%) of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Genetic Factors Influencing Coagulation Factor XIII B-Subunit Contribute to Risk of Ischemic Stroke.

    Science.gov (United States)

    Hanscombe, Ken B; Traylor, Matthew; Hysi, Pirro G; Bevan, Stephen; Dichgans, Martin; Rothwell, Peter M; Worrall, Bradford B; Seshadri, Sudha; Sudlow, Cathie; Williams, Frances M K; Markus, Hugh S; Lewis, Cathryn M

    2015-08-01

    Abnormal coagulation has been implicated in the pathogenesis of ischemic stroke, but how this association is mediated and whether it differs between ischemic stroke subtypes is unknown. We determined the shared genetic risk between 14 coagulation factors and ischemic stroke and its subtypes. Using genome-wide association study results for 14 coagulation factors from the population-based TwinsUK sample (N≈2000 for each factor), meta-analysis results from the METASTROKE consortium ischemic stroke genome-wide association study (12 389 cases, 62 004 controls), and genotype data for 9520 individuals from the WTCCC2 ischemic stroke study (3548 cases, 5972 controls-the largest METASTROKE subsample), we explored shared genetic risk for coagulation and stroke. We performed three analyses: (1) a test for excess concordance (or discordance) in single nucleotide polymorphism effect direction across coagulation and stroke, (2) an estimation of the joint effect of multiple coagulation-associated single nucleotide polymorphisms in stroke, and (3) an evaluation of common genetic risk between coagulation and stroke. One coagulation factor, factor XIII subunit B (FXIIIB), showed consistent effects in the concordance analysis, the estimation of polygenic risk, and the validation with genotype data, with associations specific to the cardioembolic stroke subtype. Effect directions for FXIIIB-associated single nucleotide polymorphisms were significantly discordant with cardioembolic disease (smallest P=5.7×10(-04)); the joint effect of FXIIIB-associated single nucleotide polymorphisms was significantly predictive of ischemic stroke (smallest P=1.8×10(-04)) and the cardioembolic subtype (smallest P=1.7×10(-04)). We found substantial negative genetic covariation between FXIIIB and ischemic stroke (rG=-0.71, P=0.01) and the cardioembolic subtype (rG=-0.80, P=0.03). Genetic markers associated with low FXIIIB levels increase risk of ischemic stroke cardioembolic subtype. © 2015 The

  10. The ontology of genetic susceptibility factors (OGSF) and its application in modeling genetic susceptibility to vaccine adverse events.

    Science.gov (United States)

    Lin, Yu; He, Yongqun

    2014-01-01

    Due to human variations in genetic susceptibility, vaccination often triggers adverse events in a small population of vaccinees. Based on our previous work on ontological modeling of genetic susceptibility to disease, we developed an Ontology of Genetic Susceptibility Factors (OGSF), a biomedical ontology in the domain of genetic susceptibility and genetic susceptibility factors. The OGSF framework was then applied in the area of vaccine adverse events (VAEs). OGSF aligns with the Basic Formal Ontology (BFO). OGSF defines 'genetic susceptibility' as a subclass of BFO:disposition and has a material basis 'genetic susceptibility factor'. The 'genetic susceptibility to pathological bodily process' is a subclasses of 'genetic susceptibility'. A VAE is a type of pathological bodily process. OGSF represents different types of genetic susceptibility factors including various susceptibility alleles (e.g., SNP and gene). A general OGSF design pattern was developed to represent genetic susceptibility to VAE and associated genetic susceptibility factors using experimental results in genetic association studies. To test and validate the design pattern, two case studies were populated in OGSF. In the first case study, human gene allele DBR*15:01 is susceptible to influenza vaccine Pandemrix-induced Multiple Sclerosis. The second case study reports genetic susceptibility polymorphisms associated with systemic smallpox VAEs. After the data of the Case Study 2 were represented using OGSF-based axioms, SPARQL was successfully developed to retrieve the susceptibility factors stored in the populated OGSF. A network of data from the Case Study 2 was constructed by using ontology terms and individuals as nodes and ontology relations as edges. Different social network analys is (SNA) methods were then applied to verify core OGSF terms. Interestingly, a SNA hub analysis verified all susceptibility alleles of SNPs and a SNA closeness analysis verified the susceptibility genes in Case

  11. Evidence that the modulator of the glucocorticoid-receptor complex is the endogenous molybdate factor.

    OpenAIRE

    Bodine, P V; Litwack, G

    1988-01-01

    We have recently purified the modulator of the glucocorticoid-receptor complex from rat liver. Purified modulator inhibits glucocorticoid-receptor complex activation and stabilizes the steroid-binding ability of the unoccupied glucocorticoid receptor. Since these activities are shared by exogenous sodium molybdate, modulator appears to be the endogenous factor that sodium molybdate mimics. In this report, we present additional evidence for the mechanism of action of purified modulator. (i) Mo...

  12. Genetic and environmental factors influencing the Placental Growth Factor (PGF) variation in two populations

    DEFF Research Database (Denmark)

    Sorice, Rossella; Ruggiero, Daniela; Nutile, Teresa

    2012-01-01

    . However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking) on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have...... first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871) and a replication sample from the general Danish population (N=1,812). A significant difference in PGF mean levels was found...... between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused...

  13. Genetic and environmental factors influencing the Placental Growth Factor (PGF variation in two populations.

    Directory of Open Access Journals (Sweden)

    Rossella Sorice

    Full Text Available Placental Growth Factor (PGF is a key molecule in angiogenesis. Several studies have revealed an important role of PGF primarily in pathological conditions (e.g.: ischaemia, tumour formation, cardiovascular diseases and inflammatory processes suggesting its use as a potential therapeutic agent. However, to date, no information is available regarding the genetics of PGF variability. Furthermore, even though the effect of environmental factors (e.g.: cigarette smoking on angiogenesis has been explored, no data on the influence of these factors on PGF levels have been reported so far. Here we have first investigated PGF variability in two cohorts focusing on non-genetic risk factors: a study sample from two isolated villages in the Cilento region, South Italy (N=871 and a replication sample from the general Danish population (N=1,812. A significant difference in PGF mean levels was found between the two cohorts. However, in both samples, we observed a strong correlation of PGF levels with ageing and sex, men displaying PGF levels significantly higher than women. Interestingly, smoking was also found to influence the trait in the two populations, although differently. We have then focused on genetic risk factors. The association between five single nucleotide polymorphisms (SNPs located in the PGF gene and the plasma levels of the protein was investigated. Two polymorphisms (rs11850328 and rs2268614 were associated with the PGF plasma levels in the Cilento sample and these associations were strongly replicated in the Danish sample. These results, for the first time, support the hypothesis of the presence of genetic and environmental factors influencing PGF plasma variability.

  14. Intricate environment-modulated genetic networks control isoflavone accumulation in soybean seeds

    Directory of Open Access Journals (Sweden)

    Shannon Grover

    2010-06-01

    Full Text Available Abstract Background Soybean (Glycine max [L] Merr. seed isoflavones have long been considered a desirable trait to target in selection programs for their contribution to human health and plant defense systems. However, attempts to modify seed isoflavone contents have not always produced the expected results because their genetic basis is polygenic and complex. Undoubtedly, the extreme variability that seed isoflavones display over environments has obscured our understanding of the genetics involved. Results In this study, a mapping population of RILs with three replicates was analyzed in four different environments (two locations over two years. We found a total of thirty-five main-effect genomic regions and many epistatic interactions controlling genistein, daidzein, glycitein and total isoflavone accumulation in seeds. The use of distinct environments permitted detection of a great number of environment-modulated and minor-effect QTL. Our findings suggest that isoflavone seed concentration is controlled by a complex network of multiple minor-effect loci interconnected by a dense epistatic map of interactions. The magnitude and significance of the effects of many of the nodes and connections in the network varied depending on the environmental conditions. In an attempt to unravel the genetic architecture underlying the traits studied, we searched on a genome-wide scale for genomic regions homologous to the most important identified isoflavone biosynthetic genes. We identified putative candidate genes for several of the main-effect and epistatic QTL and for QTL reported by other groups. Conclusions To better understand the underlying genetics of isoflavone accumulation, we performed a large scale analysis to identify genomic regions associated with isoflavone concentrations. We not only identified a number of such regions, but also found that they can interact with one another and with the environment to form a complex adaptable network

  15. Genetic risk factors of cisplatin induced ototoxicity in adult patients.

    Science.gov (United States)

    Talach, T; Rottenberg, J; Gal, B; Kostrica, R; Jurajda, M; Kocak, I; Lakomy, R; Vogazianos, E

    2016-01-01

    Ototoxicity is an important adverse effect of using Cisplatin (cis-diamminedichloroplatinum) (CDDP) as a form of chemotherapy. The clinical picture of CDDP induced ototoxicity includes perceptive hearing impairment (reversible or permanent) and tinnitus. Ototoxicity manifests with considerable variability between patients. The objective of this prospective study was to investigate a possible genetic background to this variability. We assessed ototoxicity induced by therapeutic doses of CDDP in adult patients with germinative testicular tumors, or other tumors treated with an identical CDDP dosage scheme. Audiological examination before, during and after the treatment has shown deterioration in hearing; first in the high-frequencies and with increased CDDP cumulative doses, impairment in other frequencies as well. Occurrence of tinnitus was not dependent on the administered dose of CDDP, or the other risk factors examined in this study. The association of CDDP induced ototoxicity with genetic polymorphisms in candidate genes was examined. Our study has demonstrated an association of early onset of CDDP induced ototoxicity with the presence of two copies of GSTT1 gene (p=0,009) and with T allele of rs9332377 polymorphism in COMT gene (p=0,001).

  16. The epidemiology of eating disorders: genetic, environmental, and societal factors

    Directory of Open Access Journals (Sweden)

    Mitchison D

    2014-02-01

    Full Text Available Deborah Mitchison,1 Phillipa J Hay2,3 1School of Medicine, University of Western Sydney, Sydney, NSW, Australia; 2Centre for Health Research, School of Medicine, University of Western Sydney, Sydney, NSW, Australia; 3School of Medicine, James Cook University, Townsville City, QLD, Australia Background: The aim of this review was to summarize the literature to date regarding the sociodemographic, environmental, and genetic correlates of eating disorders (EDs in adults. Method: A keyword search was entered into Scopus (SciVerse, Elsevier to identify relevant articles published in English up until June 2013. Articles were assessed against a range of a priori inclusion and exclusion criteria. Results: A total of 149 full-text articles were found to be eligible for the review and included 86 articles with data on sociodemographic correlates, 57 on environmental correlates, and 13 on genetic correlates. Female sex, younger age, sexual and physical abuse, participation in esthetic or weight-oriented sports, and heritability were found to be most consistently associated with higher ED prevalence and incidence. Conversely, ethnicity, socioeconomic status, education, and urbanicity did not appear to have strong associations with ED epidemiology. Conclusion: More community-based research, with an equal representation of males, needs to be conducted to confirm the current findings and provide evidence for emerging factors that may be related to EDs. Keywords: demographic, environment, abuse, prevalence, socioeconomic status, heritability

  17. GoldenBraid: an iterative cloning system for standardized assembly of reusable genetic modules.

    Directory of Open Access Journals (Sweden)

    Alejandro Sarrion-Perdigones

    Full Text Available Synthetic Biology requires efficient and versatile DNA assembly systems to facilitate the building of new genetic modules/pathways from basic DNA parts in a standardized way. Here we present GoldenBraid (GB, a standardized assembly system based on type IIS restriction enzymes that allows the indefinite growth of reusable gene modules made of standardized DNA pieces. The GB system consists of a set of four destination plasmids (pDGBs designed to incorporate multipartite assemblies made of standard DNA parts and to combine them binarily to build increasingly complex multigene constructs. The relative position of type IIS restriction sites inside pDGB vectors introduces a double loop ("braid" topology in the cloning strategy that allows the indefinite growth of composite parts through the succession of iterative assembling steps, while the overall simplicity of the system is maintained. We propose the use of GoldenBraid as an assembly standard for Plant Synthetic Biology. For this purpose we have GB-adapted a set of binary plasmids for A. tumefaciens-mediated plant transformation. Fast GB-engineering of several multigene T-DNAs, including two alternative modules made of five reusable devices each, and comprising a total of 19 basic parts are also described.

  18. Identification of genetic risk factors for maxillary lateral incisor agenesis.

    Science.gov (United States)

    Alves-Ferreira, M; Pinho, T; Sousa, A; Sequeiros, J; Lemos, C; Alonso, I

    2014-05-01

    Tooth agenesis affects 20% of the world population, and maxillary lateral incisors agenesis (MLIA) is one of the most frequent subtypes, characterized by the absence of formation of deciduous or permanent lateral incisors. Odontogenesis is a complex mechanism regulated by sequential and reciprocal epithelial-mesenchymal interactions, controlled by activators and inhibitors involved in several pathways. Disturbances in these signaling cascades can lead to abnormalities in odontogenesis, resulting in alterations in the formation of the normal teeth number. Our aim was to study a large number of genes encoding either transcription factors or key components in signaling pathways shown to be involved in tooth odontogenesis. We selected 8 genes-MSX1, PAX9, AXIN2, EDA, SPRY2, TGFA, SPRY4, and WNT10A-and performed one of the largest case-control studies taking into account the number of genes and variants assessed, aiming at the identification of MLIA susceptibility factors. We show the involvement of PAX9, EDA, SPRY2, SPRY4, and WNT10A as risk factors for MLIA. Additionally, we uncovered 3 strong synergistic interactions between MLIA liability and MSX1-TGFA, AXIN2-TGFA, and SPRY2-SPRY4 gene pairs. We report the first evidence of the involvement of sprouty genes in MLIA susceptibility. This large study results in a better understanding of the genetic components and mechanisms underlying this trait.

  19. Genetic factors and asthma in aluminum smelter workers.

    Science.gov (United States)

    Arnaiz, Nilo O; Kaufman, Joel D; Daroowalla, Feroza M; Quigley, Sean; Farin, Federico; Checkoway, Harvey

    2003-04-01

    An asthma-like condition has been reported among aluminum smelter potroom workers. The pathophysiologic mechanisms and the causative agent involved are unknown. Inasmuch as gene polymorphisms are associated with asthma in the general population, the authors of this case-control study examined whether polymorphisms were associated with the development of potroom asthma. Genotyping was performed for the beta2-adrenoreceptor, high-affinity Ig (immunoglobulin) E receptor, and Tumor Necrosis Factor on potroom workers who developed a new asthma-like condition and on individuals who did not develop respiratory problems. No associations were found between potroom asthma case status and genotype. The asthma-like condition associated with potroom work remains poorly understood. Future investigations of genetic susceptibility and occupational asthma may provide pathophysiologic insights into these work-related conditions, but larger numbers of subjects will be required.

  20. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia

    NARCIS (Netherlands)

    G.R. Dohle (Gert); D.J.J. Halley (Dicky); J.O. van Hemel; A.M. van den Ouwel; M.H. Pieters; R.F.A. Weber (Robert); L.C. Govaerts (Lutgarde)

    2002-01-01

    textabstractBACKGROUND: Male infertility due to severe oligozoospermia and azoospermia has been associated with a number of genetic risk factors. METHODS: In this study 150 men from couples requesting ICSI were investigated for genetic abnormalities, such as constitutive chromosome

  1. Genetic risk factors in infertile men with severe oligozoospermia and azoospermia

    NARCIS (Netherlands)

    G.R. Dohle (Gert); D.J.J. Halley (Dicky); J.O. van Hemel; A.M. van den Ouwel; M.H. Pieters; R.F.A. Weber (Robert); L.C. Govaerts (Lutgarde)

    2002-01-01

    textabstractBACKGROUND: Male infertility due to severe oligozoospermia and azoospermia has been associated with a number of genetic risk factors. METHODS: In this study 150 men from couples requesting ICSI were investigated for genetic abnormalities, such as constitutive chromosome

  2. Relationship between genetic and environmental factors and hypercholesterolemia in children.

    Science.gov (United States)

    Robledo, Jorge A; Siccardi, Leonardo J

    2016-10-01

    Pediatric hypercholesterolemia has increased over the past decades. Knowing the environmental and genetic factors that have an impact on it would allow establishing more adequate screening guidelines. To determine if there is an association between genetic and environmental factors and hypercholesterolemia in children. To assess the predictive qualities of outcome measures associated with hypercholesterolemia. Observational, analytical, cross-sectional study. students from all schools located in Jovita. Age: > 6 and nutritional status. A survey was administered to children to identify their level of physical activity and their eating habits. The association was assessed by estimating the OR value (p students were included. Their mean cholesterol level was 168 mg/dL, and 13.4% had hypercholesterolemia. A sedentary lifestyle was observed in 22.8%, and obesity, in 10.5%. A positive FMH, a high/ middle SEL, and obesity were associated with hypercholesterolemia (OR: 2.10, 2.10 and 2.05, respectively). No association was found between physical activity and fat/cholesterol intake and hypercholesterolemia. A positive FMH and a high/middle SEL were sensitive enough (75% and 88%) to predict hypercholesterolemia. The presence of hypercholesterolemia inboth parents in relation to hypercholesterolemia in their child showed an OR of 9.59, a sensitivity of 73%, a specificity of 71%, a positive predictive value of 57%, and a negative predictive value of 83%. A positive FMH, a high/ middle SEL, and obesity were associated with hypercholesterolemia in children. The presence of hypercholesterolemia in both parents was associated with hypercholesterolemia in their child and showed itself to be a great potential predictor and screening criterion. Sociedad Argentina de Pediatría.

  3. Current evidence for a modulation of low back pain by human genetic variants.

    Science.gov (United States)

    Tegeder, Irmgard; Lötsch, Jörn

    2009-08-01

    The manifestation of chronic back pain depends on structural, psychosocial, occupational and genetic influences. Heritability estimates for back pain range from 30% to 45%. Genetic influences are caused by genes affecting intervertebral disc degeneration or the immune response and genes involved in pain perception, signalling and psychological processing. This inter-individual variability which is partly due to genetic differences would require an individualized pain management to prevent the transition from acute to chronic back pain or improve the outcome. The genetic profile may help to define patients at high risk for chronic pain. We summarize genetic factors that (i) impact on intervertebral disc stability, namely Collagen IX, COL9A3, COL11A1, COL11A2, COL1A1, aggrecan (AGAN), cartilage intermediate layer protein, vitamin D receptor, metalloproteinsase-3 (MMP3), MMP9, and thrombospondin-2, (ii) modify inflammation, namely interleukin-1 (IL-1) locus genes and IL-6 and (iii) and pain signalling namely guanine triphosphate (GTP) cyclohydrolase 1, catechol-O-methyltransferase, mu opioid receptor (OPMR1), melanocortin 1 receptor (MC1R), transient receptor potential channel A1 and fatty acid amide hydrolase and analgesic drug metabolism (cytochrome P450 [CYP]2D6, CYP2C9).

  4. Genetic risk factors for Parkinson’s disease in Ukraine

    Directory of Open Access Journals (Sweden)

    A. K. Koliada

    2015-03-01

    Full Text Available The paper focuses on the genetic risk factors for Parkinson’s disease (PD such as polymorphisms in genes CYP1A1, GSTM1 and APOE. A total number of 516 people were examined. 300 persons were in the control group (mean age 67,0 ± 0,4 years; 200 males and 100 females and 216 persons were patients with PD (mean age 65,0 ± 0,7 years, 116 males and 100 females. Whole blood samples collected from each person were genotyped using PCR-RFLP. Amplification and restriction results were assessed by conducting vertical agarose gel electrophoresis. The study analyzed marker с.2452C>A in the CYP1A1 gene. In the control group, allele C frequency was 0.79, and allele A frequency – 0.21. Genotype frequencies were: CC – 0.61, AC – 0.36, AA – 0.03. In the group of patients alleles C and A frequencies were 0.64 and 0.36 correspondingly. Genotype frequencies were: CC – 0.35, AC – 0.58, AA – 0.07. There was a significant difference between both groups in allele A frequency. It is considered that 0/0 genotype for the GSTM1 gene is a risk factor for PD. In the controls, +/+ and 0/0 genotypes frequencies were 0.67 and 0.33 correspondingly. In the group of patients +/+ genotype frequency was 0.55 and 0/0 genotype frequency – 0.45. The difference was statistically significant. In the control group genotype frequencies for the АРОЕ gene were 0.715 (Е3/Е3, 0.077 (Е3/Е4, 0.009 (Е4/Е4, 0.167 (Е2/Е3, 0.031 (Е2/Е4 and 0.000 (Е2/Е2. In the group of patients with PD they were 0.634 (Е3/Е3, 0.148 (Е3/Е4, 0.032 (Е4/Е4, 0.157 (Е2/Е3, 0.023 (Е2/Е4 and 0.000 (Е2/Е2. Е3/Е4 genotype frequency was significantly higher in the group of patients with PD than in the control group. Pathogenic allele с.2452C>A of the CYP1A1 gene is associated with increased risk of PD (OR = 1.72. 0/0 genotype carriers have higher risk to develop PD (OR = 1.72. Allele έ4 of the АРОЕ gene may be associated with increased risk of PD. Risk of the disease is

  5. Genetic identification of a network of factors that functionally interact with the nucleosome remodeling ATPase ISWI.

    Directory of Open Access Journals (Sweden)

    Giosalba Burgio

    2008-06-01

    Full Text Available Nucleosome remodeling and covalent modifications of histones play fundamental roles in chromatin structure and function. However, much remains to be learned about how the action of ATP-dependent chromatin remodeling factors and histone-modifying enzymes is coordinated to modulate chromatin organization and transcription. The evolutionarily conserved ATP-dependent chromatin-remodeling factor ISWI plays essential roles in chromosome organization, DNA replication, and transcription regulation. To gain insight into regulation and mechanism of action of ISWI, we conducted an unbiased genetic screen to identify factors with which it interacts in vivo. We found that ISWI interacts with a network of factors that escaped detection in previous biochemical analyses, including the Sin3A gene. The Sin3A protein and the histone deacetylase Rpd3 are part of a conserved histone deacetylase complex involved in transcriptional repression. ISWI and the Sin3A/Rpd3 complex co-localize at specific chromosome domains. Loss of ISWI activity causes a reduction in the binding of the Sin3A/Rpd3 complex to chromatin. Biochemical analysis showed that the ISWI physically interacts with the histone deacetylase activity of the Sin3A/Rpd3 complex. Consistent with these findings, the acetylation of histone H4 is altered when ISWI activity is perturbed in vivo. These findings suggest that ISWI associates with the Sin3A/Rpd3 complex to support its function in vivo.

  6. Genetics

    DEFF Research Database (Denmark)

    Christensen, Kaare; McGue, Matt

    2016-01-01

    The sequenced genomes of individuals aged ≥80 years, who were highly educated, self-referred volunteers and with no self-reported chronic diseases were compared to young controls. In these data, healthy ageing is a distinct phenotype from exceptional longevity and genetic factors that protect...

  7. Sleep bruxism - genetic factors and psychoactive substances : Studies in Finnish twins

    OpenAIRE

    Rintakoski, Katariina

    2014-01-01

    Background: Genetic and environmental factors have a varying influence on oral health-related problems. Although studies have been conducted, the contribution of genetic factors to sleep-related bruxism remains obscure. Bruxism causes several physical problems, including abnormal tooth wear, pain in the temporomandibular joint or jaw muscles, and headaches, as well as social problems. The detailed aetiology of bruxism is unknown. In addition to genetic factors, psychoactive substances are con...

  8. Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition.

    Science.gov (United States)

    Azkona, Garikoitz; Saavedra, Ana; Aira, Zigor; Aluja, David; Xifró, Xavier; Baguley, Tyler; Alberch, Jordi; Ellman, Jonathan A; Lombroso, Paul J; Azkue, Jon J; Pérez-Navarro, Esther

    2016-02-01

    The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. The activity of STEP was modulated by genetic (STEP knockout mice) and pharmacological (recently synthesized STEP inhibitor, TC-2153) approaches. STEP(61) protein levels in the lumbar spinal cord were determined in male and female mice of different ages. Inflammatory pain was induced by complete Freund's adjuvant injection. Behavioral tests, immunoblotting, and electrophysiology were used to analyze the effect of STEP on nociception. Our results show that both genetic deletion and pharmacological inhibition of STEP induced thermal hyperalgesia and mechanical allodynia, which were accompanied by increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Striatal-enriched protein tyrosine phosphatase heterozygous and knockout mice presented a similar phenotype. Furthermore, electrophysiological experiments showed that TC-2153 increased C fiber-evoked spinal field potentials. Interestingly, we found that STEP(61) protein levels in the lumbar spinal cord inversely correlated with thermal hyperalgesia associated with age and female gender in mice. Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP(61) inactivation and increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception.

  9. Frequency modulated weak signal detection based on stochastic resonance and genetic algorithm

    Institute of Scientific and Technical Information of China (English)

    XING; Hongyan; LU; Chunxia; ZHANG; Qiang

    2016-01-01

    Stochastic resonance system is subject to the restriction of small frequency parameter in weak signal detection,in order to solve this problem,a frequency modulated weak signal detection method based on stochastic resonance and genetic algorithm is presented in this paper. The frequency limit of stochastic resonance is eliminated by introducing carrier signal,which is multiplied with the measured signal to be injected in the stochastic resonance system,meanwhile,using genetic algorithm to optimize the carrier signal frequency,which determine the generated difference-frequency signal in the lowfrequency range,so as to achieve the stochastic resonance weak signal detection. Results showthat the proposed method is feasible and effective,which can significantly improve the output SNR of stochastic resonance,in addition,the system has the better self-adaptability,according to the operation result and output phenomenon,the unknown frequency of the signal to be measured can be obtained,so as to realize the weak signal detection of arbitrary frequency.

  10. Mouse models for pseudoxanthoma elasticum: genetic and dietary modulation of the ectopic mineralization phenotypes.

    Directory of Open Access Journals (Sweden)

    Qiaoli Li

    Full Text Available Pseudoxanthoma elasticum (PXE, a heritable ectopic mineralization disorder, is caused by mutations in the ABCC6 gene. Null mice (Abcc6(-/- recapitulate the genetic, histopathologic and ultrastructural features of PXE, and they demonstrate early and progressive mineralization of vibrissae dermal sheath, which serves as a biomarker of the overall mineralization process. Recently, as part of a mouse aging study at The Jackson Laboratory, 31 inbred mouse strains were necropsied, and two of them, KK/HlJ and 129S1/SvImJ, were noted to have vibrissae dermal mineralization similar to Abcc6(-/- mice. These two strains were shown to harbor a single nucleotide polymorphism (rs32756904 in the Abcc6 gene, which resulted in out-of-frame splicing and marked reduction in ABCC6 protein expression in the liver of these mice. The same polymorphism is present in two additional mouse strains, DBA/2J and C3H/HeJ, with similar reduction in Abcc6 protein levels, yet these mice did not demonstrate tissue mineralization when kept on standard rodent diet. However, all four mouse strains, when placed on experimental diet enriched in phosphate and low in magnesium, developed extensive ectopic mineralization. These results indicate that the genetic background of mice and the mineral composition of their diet can profoundly modulate the ectopic mineralization process predicated on mutations in the Abcc6 gene. These mice provide novel model systems to study the pathomechanisms and the reasons for strain background on phenotypic variability of PXE.

  11. Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases

    OpenAIRE

    Jakóbkiewicz-Banecka, Joanna; Gabig-Cimińska, Magdalena; Banecka-Majkutewicz, Zyta; Banecki, Bogdan; Węgrzyn, Alicja; Węgrzyn, Grzegorz

    2013-01-01

    Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70 %) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal stor...

  12. Numerical method for angle-of-incidence correction factors for diffuse radiation incident photovoltaic modules

    Energy Technology Data Exchange (ETDEWEB)

    Marion, Bill

    2017-05-01

    A numerical method is provided for solving the integral equation for the angle-of-incidence (AOI) correction factor for diffuse radiation incident photovoltaic (PV) modules. The types of diffuse radiation considered include sky, circumsolar, horizon, and ground-reflected. The method permits PV module AOI characteristics to be addressed when calculating AOI losses associated with diffuse radiation. Pseudo code is provided to aid users in the implementation, and results are shown for PV modules with tilt angles from 0 degrees to 90 degrees. Diffuse AOI losses are greatest for small PV module tilt angles. Including AOI losses associated with the diffuse irradiance will improve predictions of PV system performance.

  13. TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)

    Science.gov (United States)

    TITLE:TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

  14. TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF)

    Science.gov (United States)

    TITLE:TERATOGENIC RESPONSES ARE MODULATED IN MICE LACKING EXPRESSION OF EPIDERMAL GROWTH FACTOR (EGF) AND TRANSFORMING GROWTH FACTOR-ALPHA (TGF). AUTHORS (ALL): Abbott, Barbara D.1; Best, Deborah S.1; Narotsky, Michael G.1. SPONSOR NAME: None INSTITUTIONS (ALL): 1. Repro Tox ...

  15. Coeliac disease : investigation of the genetic factors underlying coeliac disease

    NARCIS (Netherlands)

    Belzen, M.J. (Martine Juliana) van

    2003-01-01

    Coeliac disease is a common food intolerance with a complex genetic aetiology. It is caused by ingestion of gluten peptides from wheat and related proteins from barley and rye in genetically susceptible individuals. The disease affects the small intestine and leads to abnormalities ranging from the

  16. Coeliac disease : investigation of the genetic factors underlying coeliac disease

    NARCIS (Netherlands)

    Belzen, M.J. (Martine Juliana) van

    2004-01-01

    Coeliac disease is a common food intolerance with a complex genetic aetiology. It is caused by ingestion of gluten peptides from wheat and related proteins from barley and rye in genetically susceptible individuals. The disease affects the small intestine and leads to abnormalities ranging from the

  17. Mapping genetic factors controlling potato/cyst nematode interactions.

    NARCIS (Netherlands)

    Rouppe van der Voort, J.N.A.M.

    1998-01-01

    The thesis describes strategies for genetic mapping of the genomes of the potato cyst nematode and potato. Mapping in cyst nematodes was achieved by AFLP genotyping of single cysts and subsequent segregation analysis in a family of sibling populations. The genetic map of Globodera rostochiensis comp

  18. Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome

    OpenAIRE

    Ussar, Siegfried; Griffin, Nicholas W.; Bezy, Olivier; Fujisaka, Shiho; Vienberg, Sara; Softic, Samir; Deng, Luxue; Bry, Lynn; Gordon, Jeffrey I.; Kahn, C. Ronald

    2015-01-01

    Obesity, diabetes and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly-used inbred strains of mice – obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ, from Jackson Laboratory and obesity-prone, but diabetes resistant 129S6/SvEvTac from Taconic - plus three derivative lines generated by breeding these strains in a new, common environm...

  19. Modulation of the NMDA Receptor Through Secreted Soluble Factors.

    Science.gov (United States)

    Cerpa, Waldo; Ramos-Fernández, Eva; Inestrosa, Nibaldo C

    2016-01-01

    Synaptic activity is a critical determinant in the formation and development of excitatory synapses in the central nervous system (CNS). The excitatory current is produced and regulated by several ionotropic receptors, including those that respond to glutamate. These channels are in turn regulated through several secreted factors that function as synaptic organizers. Specifically, Wnt, brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF), and transforming growth factor (TGF) particularly regulate the N-methyl-D-aspartate receptor (NMDAR) glutamatergic channel. These factors likely regulate early embryonic development and directly control key proteins in the function of important glutamatergic channels. Here, we review the secreted molecules that participate in synaptic organization and discuss the cell signaling behind of this fine regulation. Additionally, we discuss how these factors are dysregulated in some neuropathologies associated with glutamatergic synaptic transmission in the CNS.

  20. Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome.

    Science.gov (United States)

    Ussar, Siegfried; Griffin, Nicholas W; Bezy, Olivier; Fujisaka, Shiho; Vienberg, Sara; Softic, Samir; Deng, Luxue; Bry, Lynn; Gordon, Jeffrey I; Kahn, C Ronald

    2015-09-01

    Obesity, diabetes, and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly used inbred strains of mice-obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ from Jackson Laboratory, and obesity-prone but diabetes-resistant 129S6/SvEvTac from Taconic-plus three derivative lines generated by breeding these strains in a new, common environment. Analysis of metabolic parameters and gut microbiota in all strains and their environmentally normalized derivatives revealed strong interactions between microbiota, diet, breeding site, and metabolic phenotype. Strain-dependent and strain-independent correlations were found between specific microbiota and phenotypes, some of which could be transferred to germ-free recipient animals by fecal transplantation. Environmental reprogramming of microbiota resulted in 129S6/SvEvTac becoming obesity resistant. Thus, development of obesity/metabolic syndrome is the result of interactions between gut microbiota, host genetics, and diet. In permissive genetic backgrounds, environmental reprograming of microbiota can ameliorate development of metabolic syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Neuroblastoma: morphological pattern, molecular genetic features, and prognostic factors

    Directory of Open Access Journals (Sweden)

    A. M. Stroganova

    2016-01-01

    Full Text Available Neuroblastoma, the most common extracranial tumor of childhood, arises from the developing neurons of the sympathetic nervous system (neural cress stem cells and has various biological and clinical characteristics. The mean age at disease onset is 18 months. Neuroblastoma has a number of unique characteristics: a capacity for spontaneous regression in babies younger than 12 months even in the presence of distant metastases, for differentiation (maturation into ganglioneuroma in infants after the first year of life, and for swift aggressive development and rapid metastasis. There are 2 clinical classifications of neuroblastoma: the International neuroblastoma staging system that is based on surgical results and the International Neuroblastoma Risk Group Staging System. One of the fundamentally important problems for the clinical picture of neuroblastoma is difficulties making its prognosis. Along with clinical parameters (a patient’s age, tumor extent and site, some histological, molecular biochemical (ploidy and genetic (chromosomal aberrations, MYCN gene status, deletion of the locus 1p36 and 11q, the longer arm of chromosome 17, etc. characteristics of tumor cells are of considerable promise. MYCN gene amplification is observed in 20–30 % of primary neuroblastomas and it is one of the major indicators of disease aggressiveness, early chemotherapy resistance, and a poor prognosis. There are 2 types of MYCN gene amplification: extrachromosomal (double acentric chromosomes and intrachromosomal (homogenically painted regions. Examination of double acentric chromosomes revealed an interesting fact that it may be eliminated (removed from the nucleus through the formation of micronuclei. MYCN oncogene amplification is accompanied frequently by 1p36 locus deletion and longer 17q arm and less frequently by 11q23 deletion; these are poor prognostic factors for the disease. The paper considers in detail the specific, unique characteristics of the

  2. A propensity score approach to correction for bias due to population stratification using genetic and non-genetic factors.

    Science.gov (United States)

    Zhao, Huaqing; Rebbeck, Timothy R; Mitra, Nandita

    2009-12-01

    Confounding due to population stratification (PS) arises when differences in both allele and disease frequencies exist in a population of mixed racial/ethnic subpopulations. Genomic control, structured association, principal components analysis (PCA), and multidimensional scaling (MDS) approaches have been proposed to address this bias using genetic markers. However, confounding due to PS can also be due to non-genetic factors. Propensity scores are widely used to address confounding in observational studies but have not been adapted to deal with PS in genetic association studies. We propose a genomic propensity score (GPS) approach to correct for bias due to PS that considers both genetic and non-genetic factors. We compare the GPS method with PCA and MDS using simulation studies. Our results show that GPS can adequately adjust and consistently correct for bias due to PS. Under no/mild, moderate, and severe PS, GPS yielded estimated with bias close to 0 (mean=-0.0044, standard error=0.0087). Under moderate or severe PS, the GPS method consistently outperforms the PCA method in terms of bias, coverage probability (CP), and type I error. Under moderate PS, the GPS method consistently outperforms the MDS method in terms of CP. PCA maintains relatively high power compared to both MDS and GPS methods under the simulated situations. GPS and MDS are comparable in terms of statistical properties such as bias, type I error, and power. The GPS method provides a novel and robust tool for obtaining less-biased estimates of genetic associations that can consider both genetic and non-genetic factors.

  3. Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Lancet Jeffrey E

    2004-08-01

    Full Text Available Abstract Background Farnesyl protein transferase inhibitors (FTIs were originally developed to inhibit oncogenic ras, however it is now clear that there are several other potential targets for this drug class. The FTI tipifarnib (ZARNESTRA™, R115777 has recently demonstrated clinical responses in adults with refractory and relapsed acute leukemias. This study was conducted to identify genetic markers and pathways that are regulated by tipifarnib in acute myeloid leukemia (AML. Methods Tipifarnib-mediated gene expression changes in 3 AML cell lines and bone marrow samples from two patients with AML were analyzed on a cDNA microarray containing approximately 7000 human genes. Pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis tool. Results The expression analysis identified a common set of genes that were regulated by tipifarnib in three leukemic cell lines and in leukemic blast cells isolated from two patients who had been treated with tipifarnib. Association of modulated genes with biological functional groups identified several pathways affected by tipifarnib including cell signaling, cytoskeletal organization, immunity, and apoptosis. Gene expression changes were verified in a subset of genes using real time RT-PCR. Additionally, regulation of apoptotic genes was found to correlate with increased Annexin V staining in the THP-1 cell line but not in the HL-60 cell line. Conclusions The genetic networks derived from these studies illuminate some of the biological pathways affected by FTI treatment while providing a proof of principle for identifying candidate genes that might be used as surrogate biomarkers of drug activity.

  4. Epigenetic and genetic factors predict women's salivary cortisol following a threat to the social self.

    Directory of Open Access Journals (Sweden)

    Shany Edelman

    Full Text Available Evidence suggests that the reactivity of the Hypothalamus-Pituitary-Adrenal axis (HPAA is modulated by both genetic and environmental variables. Of special interest are the underlying molecular mechanisms driving gender differences to psychosocial stressors. Epigenetic mechanisms that sculpt the genome are ideal candidates for mediating the effects of signals on the HPAA. In the current study, we analyzed by pyrosequencing, bisulfite-treated buccal DNA from male and female university students who participated in the Trier Social Stress Test (TSST. A linear regression model was used to ascertain the effects of sex, CpG methylation and genes on stress response. Total cortisol output (area under the curve, AUC was significantly predicted by glucocorticoid receptor (NR3C1 exon 1F methylation (averaged across 39 CpG sites solely in female subjects. A single CpG site located in the exon 1F noncanonical nerve growth factor-inducible protein A (NGFI-A transcription factor was a highly significant predictor of AUC in female subjects. Additionally, variations in the estrogen receptor alpha (ESR1 and the serotonin transporter promoter (5-HTTLPR genes were independent additive predictors of AUC. The full model accounted for half of the variance (50.06% in total cortisol output. Notably, this is the first demonstration that epigenetic changes at the GR exon 1F correlate with HPAA reactivity. These findings have important implications for understanding the molecular mechanisms underlying gender differences in stress-related disorders and underscore the unique value of modeling both epigenetic and genetic information in conferring vulnerability to stress.

  5. Epigenetic and genetic factors predict women's salivary cortisol following a threat to the social self.

    Science.gov (United States)

    Edelman, Shany; Shalev, Idan; Uzefovsky, Florina; Israel, Salomon; Knafo, Ariel; Kremer, Ilana; Mankuta, David; Kaitz, Marsha; Ebstein, Richard P

    2012-01-01

    Evidence suggests that the reactivity of the Hypothalamus-Pituitary-Adrenal axis (HPAA) is modulated by both genetic and environmental variables. Of special interest are the underlying molecular mechanisms driving gender differences to psychosocial stressors. Epigenetic mechanisms that sculpt the genome are ideal candidates for mediating the effects of signals on the HPAA. In the current study, we analyzed by pyrosequencing, bisulfite-treated buccal DNA from male and female university students who participated in the Trier Social Stress Test (TSST). A linear regression model was used to ascertain the effects of sex, CpG methylation and genes on stress response. Total cortisol output (area under the curve, AUC) was significantly predicted by glucocorticoid receptor (NR3C1) exon 1F methylation (averaged across 39 CpG sites) solely in female subjects. A single CpG site located in the exon 1F noncanonical nerve growth factor-inducible protein A (NGFI-A) transcription factor was a highly significant predictor of AUC in female subjects. Additionally, variations in the estrogen receptor alpha (ESR1) and the serotonin transporter promoter (5-HTTLPR) genes were independent additive predictors of AUC. The full model accounted for half of the variance (50.06%) in total cortisol output. Notably, this is the first demonstration that epigenetic changes at the GR exon 1F correlate with HPAA reactivity. These findings have important implications for understanding the molecular mechanisms underlying gender differences in stress-related disorders and underscore the unique value of modeling both epigenetic and genetic information in conferring vulnerability to stress.

  6. Therapeutic modulation of growth factors and cytokines in regenerative medicine.

    Science.gov (United States)

    Ioannidou, Effie

    2006-01-01

    Regeneration that takes place in the human body is limited throughout life. Therefore, when organs are irreparably damaged, they are usually replaced with an artificial device or donor organ. The term "regenerative medicine" covers the restoration or replacement of cells, tissues, and organs. Stem cells play a major role in regenerative medicine by providing the way to repopulate organs damaged by disease. Stem cells have the ability to self renew and to regenerate cells of diverse lineages within the tissue in which they reside. Stem cells could originate from embryos or adult tissues. Growth factors are proteins that may act locally or systemically to affect the growth of cells in several ways. Various cell activities, including division, are influenced by growth factors. Cytokines are a family of low-molecular-weight proteins that are produced by numerous cell types and are responsible for regulating the immune response, inflammation, tissue remodeling and cellular differentiation. Target cells of growth factors and cytokines are mesenchymal, epithelial and endothelial cells. These molecules frequently have overlapping activities and can act in an autocrine or paracrine fashion. A complex network of growth factors and cytokines guides cellular differentiation and regeneration in all organs and tissues. The aim of this paper is to review the role of growth factors and cytokines in different organs or systems and explore their therapeutic application in regenerative medicine. The role of stem cells combined with growth factors and cytokines in the regeneration of vascular and hematopoietic, neural, skeletal, pancreatic, periodontal, and mucosal tissue is reviewed. There is evidence that supports the use of growth factors and cytokines in the treatment of neurological diseases, diabetes, cardiovascular disease, periodontal disease, cancer and its complication, oral mucositis. After solving the ethical issues and establishing clear and reasonable regulations

  7. Genetic Factors that Affect Tumorigenesis in NF1

    Science.gov (United States)

    2004-11-01

    Boles, R. and Korf, B. (1995) Sanitarias de la Seguridad Social (98-0992) and Institut Catali Deletion of the entire NFI gene detected by FISH: four...Washington, Medical Genetics, Seattle, WA, USA, 2Medical and Molecular Genetics Center- IRO, Hospital Duran i Reynals, Barcelona, Spain, 3Servizio di... Hospital . Western blot analysis, using an anti-NF1 antibody (NFIGRD(D)) (Santa Cruz Biotechnology Inc, Santa Cruz, NF1 mutation analysis CA) and

  8. Based on Multi-Factors Grey Prediction Control for Elevator Velocity Modulation

    OpenAIRE

    2012-01-01

    This paper uses the double-factors grey prediction and the fuzzy controller for the elevator car speed control. We introduce double-factors grey control to predict car vibration for elevator speed during the operation. Simulation results show that based on multi-factors gray prediction fuzzy PI control for elevator velocity modulation system closer than simple gray fuzzy PI control elevator speed control system to the actual operation. The control effect of double factors grey fuzzy PI contro...

  9. Non-genetic risk factors and their influence on the management of patients in the clinic.

    Science.gov (United States)

    Álvarez, Teresa; Soto, Immaculada; Astermark, Jan

    2015-02-01

    The development of inhibitors is the most serious iatrogenic complication affecting patients with haemophilia. This complication is associated with impaired vital or functional prognosis, reduced quality of life and increased cost of treatment. The reasons why some patients develop antibodies to factor replacement and others do not remain unclear. It is however clear that inhibitor development results from a complex multifactorial interaction between genetic and non-genetic risk factors. Environmental influences implicated in increasing the risk of inhibitor formation can be viewed as modifiable risk factors. Therefore, identification of the non-genetic risk factors may offer the possibility of personalising haemophilia therapy by modifying treatment strategies in high-risk patients in the critical early phase of factor VIII exposure. In this article, we review the non-genetic factors reported as well as the potential impact of danger signals and the different scores for inhibitor development risk stratification.

  10. Genetic factors explain half of all variance in serum eosinophil cationic protein

    DEFF Research Database (Denmark)

    Elmose, Camilla; Sverrild, Asger; van der Sluis, Sophie

    2014-01-01

    , exhaled nitric oxide, and skin test reactivity, measured. Linear regression analysis and variance component models were used to study factors associated with variation in ECP and the relative genetic influence on ECP levels. RESULTS: Sex (regression coefficient = -0.107, P ... to the most parsimonious variance component model, genetic factors accounted for 57% (CI: 42-72%, P variance in ECP levels, whereas the remainder (43%) was ascribable to non-shared environmental factors. The genetic correlation between ECP and airway responsiveness to methacholine...... was statistically non-significant (r = -0.11, P = 0.50). CONCLUSION: Around half of all variance in serum ECP is explained by genetic factors. Serum ECP is influenced by sex, BMI, and airway responsiveness. Serum ECP and airway responsiveness seem not to share genetic variance....

  11. Genetic Algorithm for the Design of Electro-Mechanical Sigma Delta Modulator MEMS Sensors

    Directory of Open Access Journals (Sweden)

    Michael Kraft

    2011-09-01

    Full Text Available This paper describes a novel design methodology using non-linear models for complex closed loop electro-mechanical sigma-delta modulators (EMΣΔM that is based on genetic algorithms and statistical variation analysis. The proposed methodology is capable of quickly and efficiently designing high performance, high order, closed loop, near-optimal systems that are robust to sensor fabrication tolerances and electronic component variation. The use of full non-linear system models allows significant higher order non-ideal effects to be taken into account, improving accuracy and confidence in the results. To demonstrate the effectiveness of the approach, two design examples are presented including a 5th order low-pass EMΣΔM for a MEMS accelerometer, and a 6th order band-pass EMΣΔM for the sense mode of a MEMS gyroscope. Each example was designed using the system in less than one day, with very little manual intervention. The strength of the approach is verified by SNR performances of 109.2 dB and 92.4 dB for the low-pass and band-pass system respectively, coupled with excellent immunities to fabrication tolerances and parameter mismatch.

  12. Genetic Disruption of 2-Arachidonoylglycerol Synthesis Reveals a Key Role for Endocannabinoid Signaling in Anxiety Modulation

    Directory of Open Access Journals (Sweden)

    Brian C. Shonesy

    2014-12-01

    Full Text Available Endocannabinoid (eCB signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders.

  13. Genetic algorithm for the design of electro-mechanical sigma delta modulator MEMS sensors.

    Science.gov (United States)

    Wilcock, Reuben; Kraft, Michael

    2011-01-01

    This paper describes a novel design methodology using non-linear models for complex closed loop electro-mechanical sigma-delta modulators (EMΣΔM) that is based on genetic algorithms and statistical variation analysis. The proposed methodology is capable of quickly and efficiently designing high performance, high order, closed loop, near-optimal systems that are robust to sensor fabrication tolerances and electronic component variation. The use of full non-linear system models allows significant higher order non-ideal effects to be taken into account, improving accuracy and confidence in the results. To demonstrate the effectiveness of the approach, two design examples are presented including a 5th order low-pass EMΣΔM for a MEMS accelerometer, and a 6th order band-pass EMΣΔM for the sense mode of a MEMS gyroscope. Each example was designed using the system in less than one day, with very little manual intervention. The strength of the approach is verified by SNR performances of 109.2 dB and 92.4 dB for the low-pass and band-pass system respectively, coupled with excellent immunities to fabrication tolerances and parameter mismatch.

  14. Cellular factors targeting APCs to modulate adaptive T cell immunity.

    Science.gov (United States)

    Visperas, Anabelle; Do, Jeongsu; Min, Booki

    2014-01-01

    The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.

  15. Cellular Factors Targeting APCs to Modulate Adaptive T Cell Immunity

    Directory of Open Access Journals (Sweden)

    Anabelle Visperas

    2014-01-01

    Full Text Available The fate of adaptive T cell immunity is determined by multiple cellular and molecular factors, among which the cytokine milieu plays the most important role in this process. Depending on the cytokines present during the initial T cell activation, T cells become effector cells that produce different effector molecules and execute adaptive immune functions. Studies thus far have primarily focused on defining how these factors control T cell differentiation by targeting T cells themselves. However, other non-T cells, particularly APCs, also express receptors for the factors and are capable of responding to them. In this review, we will discuss how APCs, by responding to those cytokines, influence T cell differentiation and adaptive immunity.

  16. Final Technical Report for the grant entitled "Genetic Factors Affecting Susceptibility to Low-Dose Radiation"

    Energy Technology Data Exchange (ETDEWEB)

    Morgan, William, F., Ph.D., D.Sc.

    2006-11-22

    The goal of this proposal was to test the hypothesis that mice heterozygous for the Nijmegen Breakage Syndrome (NBS1) gene are genetically susceptible to low doses of ionizing radiation. The rationale for this is that patients with NBS are radiation sensitive, because of defects in cellular responses to radiation induced genetic damage and haploinsufficiency at this genetic locus provides the potential for genetic susceptibility to low doses of ionizing radiation. Wild type and heterozygous NBS1 mice were irradiated and followed over their lifetime for radiation induced genomic instability, carcinogenesis and non-specific life shortening. No differences in cytogenetic damage, cancer induction or life span were observed between the hypomorphic mice indicating that genetic imbalance at the NBS1 loci does not modulate low dose radiation sensitivity.

  17. Factors modulating the inflammatory response in acute gouty arthritis

    NARCIS (Netherlands)

    Cleophas, M.C.P.; Crisan, T.O.; Joosten, L.A.B.

    2017-01-01

    PURPOSE OF REVIEW: Gout is a common debilitating form of arthritis and despite our extensive knowledge on the pathogenesis its prevalence is still rising quickly. In the current review, we provide a concise overview of recent discoveries in factors tuning the inflammatory response to soluble uric

  18. Modulation of gap junction channels and hemichannels by growth factors.

    Science.gov (United States)

    Schalper, Kurt A; Riquelme, Manuel A; Brañes, María C; Martínez, Agustín D; Vega, José Luis; Berthoud, Viviana M; Bennett, Michael V L; Sáez, Juan C

    2012-03-01

    Gap junction hemichannels and cell-cell channels have roles in coordinating numerous cellular processes, due to their permeability to extra and intracellular signaling molecules. Another mechanism of cellular coordination is provided by a vast array of growth factors that interact with relatively selective cell membrane receptors. These receptors can affect cellular transduction pathways, including alteration of intracellular concentration of free Ca(2+) and free radicals and activation of protein kinases or phosphatases. Connexin and pannexin based channels constitute recently described targets of growth factor signal transduction pathways, but little is known regarding the effects of growth factor signaling on pannexin based channels. The effects of growth factors on these two channel types seem to depend on the cell type, cell stage and connexin and pannexin isoform expressed. The functional state of hemichannels and gap junction channels are affected in opposite directions by FGF-1 via protein kinase-dependent mechanisms. These changes are largely explained by channels insertion in or withdrawal from the cell membrane, but changes in open probability might also occur due to changes in phosphorylation and redox state of channel subunits. The functional consequence of variation in cell-cell communication via these membrane channels is implicated in disease as well as normal cellular responses.

  19. von Willebrand factor binds to the surface of dendritic cells and modulates peptide presentation of factor VIII.

    Science.gov (United States)

    Sorvillo, Nicoletta; Hartholt, Robin B; Bloem, Esther; Sedek, Magdalena; ten Brinke, Anja; van der Zwaan, Carmen; van Alphen, Floris P; Meijer, Alexander B; Voorberg, Jan

    2016-03-01

    It has been proposed that von Willebrand factor might affect factor VIII immunogenicity by reducing factor VIII uptake by antigen presenting cells. Here we investigate the interaction of recombinant von Willebrand factor with immature monocyte-derived dendritic cells using flow cytometry and confocal microscopy. Surprisingly, von Willebrand factor was not internalized by immature dendritic cells, but remained bound to the cell surface. As von Willebrand factor reduces the uptake of factor VIII, we investigated the repertoire of factor VIII presented peptides when in complex with von Willebrand factor. Interestingly, factor VIII-derived peptides were still abundantly presented on major histocompatibility complex class II molecules, even though a reduction of factor VIII uptake by immature dendritic cells was observed. Inspection of peptide profiles from 5 different donors showed that different core factor VIII peptide sequences were presented upon incubation with factor VIII/von Willebrand factor complex when compared to factor VIII alone. No von Willebrand factor peptides were detected when immature dendritic cells were pulsed with different concentrations of von Willebrand factor, confirming lack of von Willebrand factor endocytosis. Several von Willebrand factor derived peptides were recovered when cells were pulsed with von Willebrand factor/factor VIII complex, suggesting that factor VIII promotes endocytosis of small amounts of von Willebrand factor by immature dendritic cells. Taken together, our results establish that von Willebrand factor is poorly internalized by immature dendritic cells. We also show that von Willebrand factor modulates the internalization and presentation of factor VIII-derived peptides on major histocompatibility complex class II.

  20. Identification of Post-Transcriptional Modulators of Breast Cancer Transcription Factor Activity Using MINDy

    Science.gov (United States)

    Campbell, Thomas M.; Castro, Mauro A. A.; Ponder, Bruce A. J.

    2016-01-01

    We have recently identified transcription factors (TFs) that are key drivers of breast cancer risk. To better understand the pathways or sub-networks in which these TFs mediate their function we sought to identify upstream modulators of their activity. We applied the MINDy (Modulator Inference by Network Dynamics) algorithm to four TFs (ESR1, FOXA1, GATA3 and SPDEF) that are key drivers of estrogen receptor-positive (ER+) breast cancer risk, as well as cancer progression. Our computational analysis identified over 500 potential modulators. We assayed 189 of these and identified 55 genes with functional characteristics that were consistent with a role as TF modulators. In the future, the identified modulators may be tested as potential therapeutic targets, able to alter the activity of TFs that are critical in the development of breast cancer. PMID:27997592

  1. SAP modulates B cell functions in a genetic background-dependent manner.

    Science.gov (United States)

    Detre, Cynthia; Yigit, Burcu; Keszei, Marton; Castro, Wilson; Magelky, Erica M; Terhorst, Cox

    2013-06-01

    Mutations affecting the SLAM-associated protein (SAP) are responsible for the X-linked lympho-proliferative syndrome (XLP), a severe primary immunodeficiency syndrome with disease manifestations that include fatal mononucleosis, B cell lymphoma and dysgammaglobulinemia. It is well accepted that insufficient help by SAP-/- CD4+ T cells, in particular during the germinal center reaction, is a component of dysgammaglobulinemia in XLP patients and SAP-/- animals. It is however not well understood whether in XLP patients and SAP-/- mice B cell functions are affected, even though B cells themselves do not express SAP. Here we report that B cell intrinsic responses to haptenated protein antigens are impaired in SAP-/- mice and in Rag-/- mice into which B cells derived from SAP-/- mice together with wt CD4+ T cells had been transferred. This impaired B cells functions are in part depending on the genetic background of the SAP-/- mouse, which affects B cell homeostasis. Surprisingly, stimulation with an agonistic anti-CD40 causes strong in vivo and in vitro B cell responses in SAP-/- mice. Taken together, the data demonstrate that genetic factors play an important role in the SAP-related B cell functions. The finding that anti-CD40 can in part restore impaired B cell responses in SAP-/- mice, suggests potentially novel therapeutic interventions in subsets of XLP patients. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Modulation of tumor necrosis factor by microbial pathogens.

    OpenAIRE

    Rahman, Masmudur M.; Grant McFadden

    2006-01-01

    In response to invasion by microbial pathogens, host defense mechanisms get activated by both the innate and adaptive arms of the immune responses. TNF (tumor necrosis factor) is a potent proinflammatory cytokine expressed by activated macrophages and lymphocytes that induces diverse cellular responses that can vary from apoptosis to the expression of genes involved in both early inflammatory and acquired immune responses. A wide spectrum of microbes has acquired elegant mechanisms to overcom...

  3. Pathogenesis of malignant pleural mesothelioma and the role of environmental and genetic factors

    Directory of Open Access Journals (Sweden)

    Neragi-Miandoab Siyamek

    2008-01-01

    Full Text Available Abstract Malignant pleural mesothelioma (MPM is a rare, aggressive tumor for which no effective therapy exists despite the discovery of many possible molecular and genetic targets. Many risk factors for MPM development have been recognized including environmental exposures, genetic susceptibility, viral contamination, and radiation. However, the late stage of MPM diagnosis and the long latency that exists between some exposures and diagnosis have made it difficult to comprehensively evaluate the role of risk factors and their downstream molecular effects. In this review, we discuss the current molecular and genetic contributors in MPM pathogenesis and the risk factors associated with these carcinogenic processes.

  4. Genetic modulation of lipid profiles following lifestyle modification or metformin treatment: the Diabetes Prevention Program.

    Directory of Open Access Journals (Sweden)

    Toni I Pollin

    Full Text Available Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04-1 × 10(-17. Except for total HDL particles (r = -0.03, P = 0.26, all components of the lipid profile correlated with the GRS (partial |r| = 0.07-0.17, P = 5 × 10(-5-1 10(-19. The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE ± 0.22 mg/dl/allele, P = 8 × 10(-5, P(interaction = 0.02 in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE ± 0.22 mg/dl/allele, P = 0.35 or metformin (β = -0.03, SEE ± 0.22 mg/dl/allele, P = 0.90; P(interaction = 0.64 groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE ± 0.012 ln nmol/L/allele, P = 0.01, P(interaction = 0.01 but not in the placebo (β = -0.002, SEE ± 0.008 ln nmol/L/allele, P = 0.74 or metformin (β = +0.013, SEE ± 0.008 nmol/L/allele, P = 0.12; P(interaction = 0.24 groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.

  5. Genetic modulation of lipid profiles following lifestyle modification or metformin treatment: the Diabetes Prevention Program.

    Science.gov (United States)

    Pollin, Toni I; Isakova, Tamara; Jablonski, Kathleen A; de Bakker, Paul I W; Taylor, Andrew; McAteer, Jarred; Pan, Qing; Horton, Edward S; Delahanty, Linda M; Altshuler, David; Shuldiner, Alan R; Goldberg, Ronald B; Florez, Jose C; Franks, Paul W

    2012-01-01

    Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04-1 × 10(-17)). Except for total HDL particles (r = -0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07-0.17, P = 5 × 10(-5)-1 10(-19)). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE ± 0.22 mg/dl/allele, P = 8 × 10(-5), P(interaction) = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE ± 0.22 mg/dl/allele, P = 0.35) or metformin (β = -0.03, SEE ± 0.22 mg/dl/allele, P = 0.90; P(interaction) = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE ± 0.012 ln nmol/L/allele, P = 0.01, P(interaction) = 0.01) but not in the placebo (β = -0.002, SEE ± 0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE ± 0.008 nmol/L/allele, P = 0.12; P(interaction) = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss.

  6. Genetic Modulation of Lipid Profiles following Lifestyle Modification or Metformin Treatment: The Diabetes Prevention Program

    Science.gov (United States)

    Jablonski, Kathleen A.; de Bakker, Paul I. W.; Taylor, Andrew; McAteer, Jarred; Pan, Qing; Horton, Edward S.; Delahanty, Linda M.; Altshuler, David; Shuldiner, Alan R.; Goldberg, Ronald B.; Florez, Jose C.; Bray, George A.; Culbert, Iris W.; Champagne, Catherine M.; Eberhardt, Barbara; Greenway, Frank; Guillory, Fonda G.; Herbert, April A.; Jeffirs, Michael L.; Kennedy, Betty M.; Lovejoy, Jennifer C.; Morris, Laura H.; Melancon, Lee E.; Ryan, Donna; Sanford, Deborah A.; Smith, Kenneth G.; Smith, Lisa L.; Amant, Julia A. St.; Tulley, Richard T.; Vicknair, Paula C.; Williamson, Donald; Zachwieja, Jeffery J.; Polonsky, Kenneth S.; Tobian, Janet; Ehrmann, David; Matulik, Margaret J.; Clark, Bart; Czech, Kirsten; DeSandre, Catherine; Hilbrich, Ruthanne; McNabb, Wylie; Semenske, Ann R.; Caro, Jose F.; Watson, Pamela G.; Goldstein, Barry J.; Smith, Kellie A.; Mendoza, Jewel; Liberoni, Renee; Pepe, Constance; Spandorfer, John; Donahue, Richard P.; Goldberg, Ronald B.; Prineas, Ronald; Rowe, Patricia; Calles, Jeanette; Cassanova-Romero, Paul; Florez, Hermes J.; Giannella, Anna; Kirby, Lascelles; Larreal, Carmen; McLymont, Valerie; Mendez, Jadell; Ojito, Juliet; Perry, Arlette; Saab, Patrice; Haffner, Steven M.; Montez, Maria G.; Lorenzo, Carlos; Martinez, Arlene; Hamman, Richard F.; Nash, Patricia V.; Testaverde, Lisa; Anderson, Denise R.; Ballonoff, Larry B.; Bouffard, Alexis; Calonge, B. Ned; Delve, Lynne; Farago, Martha; Hill, James O.; Hoyer, Shelley R.; Jortberg, Bonnie T.; Lenz, Dione; Miller, Marsha; Price, David W.; Regensteiner, Judith G.; Seagle, Helen; Smith, Carissa M.; Steinke, Sheila C.; VanDorsten, Brent; Horton, Edward S.; Lawton, Kathleen E.; Arky, Ronald A.; Bryant, Marybeth; Burke, Jacqueline P.; Caballero, Enrique; Callaphan, Karen M.; Ganda, Om P.; Franklin, Therese; Jackson, Sharon D.; Jacobsen, Alan M.; Jacobsen, Alan M.; Kula, Lyn M.; Kocal, Margaret; Malloy, Maureen A.; Nicosia, Maryanne; Oldmixon, Cathryn F.; Pan, Jocelyn; Quitingon, Marizel; Rubtchinsky, Stacy; Seely, Ellen W.; Schweizer, Dana; Simonson, Donald; Smith, Fannie; Solomon, Caren G.; Warram, James; Kahn, Steven E.; Montgomery, Brenda K.; Fujimoto, Wilfred; Knopp, Robert H.; Lipkin, Edward W.; Marr, Michelle; Trence, Dace; Kitabchi, Abbas E.; Murphy, Mary E.; Applegate, William B.; Bryer-Ash, Michael; Frieson, Sandra L.; Imseis, Raed; Lambeth, Helen; Lichtermann, Lynne C.; Oktaei, Hooman; Rutledge, Lily M.K.; Sherman, Amy R.; Smith, Clara M.; Soberman, Judith E.; Williams-Cleaves, Beverly; Metzger, Boyd E.; Johnson, Mariana K.; Behrends, Catherine; Cook, Michelle; Fitzgibbon, Marian; Giles, Mimi M.; Heard, Deloris; Johnson, Cheryl K.H.; Larsen, Diane; Lowe, Anne; Lyman, Megan; McPherson, David; Molitch, Mark E.; Pitts, Thomas; Reinhart, Renee; Roston, Susan; Schinleber, Pamela A.; Nathan, David M.; McKitrick, Charles; Turgeon, Heather; Abbott, Kathy; Anderson, Ellen; Bissett, Laurie; Cagliero, Enrico; Florez, Jose C.; Delahanty, Linda; Goldman, Valerie; Poulos, Alexandra; Olefsky, Jerrold M.; Carrion-Petersen, Mary Lou; Barrett-Connor, Elizabeth; Edelman, Steven V.; Henry, Robert R.; Horne, Javiva; Janesch, Simona Szerdi; Leos, Diana; Mudaliar, Sundar; Polonsky, William; Smith, Jean; Vejvoda, Karen; Pi-Sunyer, F. Xavier; Lee, Jane E.; Allison, David B.; Aronoff, Nancy J.; Crandall, Jill P.; Foo, Sandra T.; Pal, Carmen; Parkes, Kathy; Pena, Mary Beth; Rooney, Ellen S.; Wye, Gretchen E.H. Van; Viscovich, Kristine A.; Marrero, David G.; Prince, Melvin J.; Kelly, Susie M.; Dotson, Yolanda F.; Fineberg, Edwin S.; Guare, John C; Hadden, Angela M.; Ignaut, James M.; Jackson, Marcia L.; Kirkman, Marion S.; Mather, Kieren J.; Porter, Beverly D.; Roach, Paris J.; Rowland, Nancy D.; Wheeler, Madelyn L.; Ratner, Robert E.; Youssef, Gretchen; Shapiro, Sue; Bavido-Arrage, Catherine; Boggs, Geraldine; Bronsord, Marjorie; Brown, Ernestine; Cheatham, Wayman W.; Cola, Susan; Evans, Cindy; Gibbs, Peggy; Kellum, Tracy; Levatan, Claresa; Nair, Asha K.; Passaro, Maureen; Uwaifo, Gabriel; Saad, Mohammed F.; Budget, Maria; Jinagouda, Sujata; Akbar, Khan; Conzues, Claudia; Magpuri, Perpetua; Ngo, Kathy; Rassam, Amer; Waters, Debra; Xapthalamous, Kathy; Santiago, Julio V.; Dagogo-Jack, Samuel; White, Neil H.; Das, Samia; Santiago, Ana; Brown, Angela; Fisher, Edwin; Hurt, Emma; Jones, Tracy; Kerr, Michelle; Ryder, Lucy; Wernimont, Cormarie; Saudek, Christopher D.; Bradley, Vanessa; Sullivan, Emily; Whittington, Tracy; Abbas, Caroline; Brancati, Frederick L.; Clark, Jeanne M.; Charleston, Jeanne B.; Freel, Janice; Horak, Katherine; Jiggetts, Dawn; Johnson, Deloris; Joseph, Hope; Loman, Kimberly; Mosley, Henry; Rubin, Richard R.; Samuels, Alafia; Stewart, Kerry J.; Williamson, Paula; Schade, David S.; Adams, Karwyn S.; Johannes, Carolyn; Atler, Leslie F.; Boyle, Patrick J.; Burge, Mark R.; Canady, Janene L.; Chai, Lisa; Gonzales, Ysela; Hernandez-McGinnis, Doris A.; Katz, Patricia; King, Carolyn; Rassam, Amer; Rubinchik, Sofya; Senter, Willette; Waters, Debra; Shamoon, Harry; Brown, Janet O.; Adorno, Elsie; Cox, Liane; Crandall, Jill; Duffy, Helena; Engel, Samuel; Friedler, Allison; Howard-Century, Crystal J.; Kloiber, Stacey; Longchamp, Nadege; Martinez, Helen; Pompi, Dorothy; Scheindlin, Jonathan; Violino, Elissa; Walker, Elizabeth; Wylie-Rosett, Judith; Zimmerman, Elise; Zonszein, Joel; Orchard, Trevor; Wing, Rena R.; Koenning, Gaye; Kramer, M. Kaye; Barr, Susan; Boraz, Miriam; Clifford, Lisa; Culyba, Rebecca; Frazier, Marlene; Gilligan, Ryan; Harrier, Susan; Harris, Louann; Jeffries, Susan; Kriska, Andrea; Manjoo, Qurashia; Mullen, Monica; Noel, Alicia; Otto, Amy; Semler, Linda; Smith, Cheryl F.; Smith, Marie; Venditti, Elizabeth; Weinzierl, Valarie; Williams, Katherine V.; Wilson, Tara; Arakaki, Richard F.; Latimer, Renee W.; Baker-Ladao, Narleen K.; Beddow, Ralph; Dias, Lorna; Inouye, Jillian; Mau, Marjorie K.; Mikami, Kathy; Mohideen, Pharis; Odom, Sharon K.; Perry, Raynette U.; Knowler, William C.; Cooeyate, Norman; Hoskin, Mary A.; Percy, Carol A.; Acton, Kelly J.; Andre, Vickie L.; Barber, Rosalyn; Begay, Shandiin; Bennett, Peter H.; Benson, Mary Beth; Bird, Evelyn C.; Broussard, Brenda A.; Chavez, Marcella; Dacawyma, Tara; Doughty, Matthew S.; Duncan, Roberta; Edgerton, Cyndy; Ghahate, Jacqueline M.; Glass, Justin; Glass, Martia; Gohdes, Dorothy; Grant, Wendy; Hanson, Robert L.; Horse, Ellie; Ingraham, Louise E.; Jackson, Merry; Jay, Priscilla; Kaskalla, Roylen S.; Kessler, David; Kobus, Kathleen M.; Krakoff, Jonathan; Manus, Catherine; Michaels, Sara; Morgan, Tina; Nashboo, Yolanda; Nelson, Julie A.; Poirier, Steven; Polczynski, Evette; Reidy, Mike; Roumain, Jeanine; Rowse, Debra; Sangster, Sandra; Sewenemewa, Janet; Tonemah, Darryl; Wilson, Charlton; Yazzie, Michelle; Bain, Raymond; Fowler, Sarah; Brenneman, Tina; Abebe, Solome; Bamdad, Julie; Callaghan, Jackie; Edelstein, Sharon L.; Gao, Yuping; Grimes, Kristina L.; Grover, Nisha; Haffner, Lori; Jones, Steve; Jones, Tara L.; Katz, Richard; Lachin, John M.; Mucik, Pamela; Orlosky, Robert; Rochon, James; Sapozhnikova, Alla; Sherif, Hanna; Stimpson, Charlotte; Temprosa, Marinella; Walker-Murray, Fredricka; Marcovina, Santica; Strylewicz, Greg; Aldrich, F. Alan; O'Leary, Dan; Stamm, Elizabeth; Rautaharju, Pentti; Prineas, Ronald J.; Alexander, Teresa; Campbell, Charles; Hall, Sharon; Li, Yabing; Mills, Margaret; Pemberton, Nancy; Rautaharju, Farida; Zhang, Zhuming; Mayer-Davis, Elizabeth; Moran, Robert R.; Ganiats, Ted; David, Kristin; Sarkin, Andrew J.; Eastman, R.; Fradkin, Judith; Garfield, Sanford; Gregg, Edward; Zhang, Ping; Herman, William; Florez, Jose C.; Altshuler, David; de Bakker, Paul I.W.; Franks, Paul W.; Hanson, Robert L.; Jablonski, Kathleen; Knowler, William C.; McAteer, Jarred B.; Pollin, Toni I.; Shuldiner, Alan R.

    2012-01-01

    Weight-loss interventions generally improve lipid profiles and reduce cardiovascular disease risk, but effects are variable and may depend on genetic factors. We performed a genetic association analysis of data from 2,993 participants in the Diabetes Prevention Program to test the hypotheses that a genetic risk score (GRS) based on deleterious alleles at 32 lipid-associated single-nucleotide polymorphisms modifies the effects of lifestyle and/or metformin interventions on lipid levels and nuclear magnetic resonance (NMR) lipoprotein subfraction size and number. Twenty-three loci previously associated with fasting LDL-C, HDL-C, or triglycerides replicated (P = 0.04–1×10−17). Except for total HDL particles (r = −0.03, P = 0.26), all components of the lipid profile correlated with the GRS (partial |r| = 0.07–0.17, P = 5×10−5–1×10−19). The GRS was associated with higher baseline-adjusted 1-year LDL cholesterol levels (β = +0.87, SEE±0.22 mg/dl/allele, P = 8×10−5, P interaction = 0.02) in the lifestyle intervention group, but not in the placebo (β = +0.20, SEE±0.22 mg/dl/allele, P = 0.35) or metformin (β = −0.03, SEE±0.22 mg/dl/allele, P = 0.90; P interaction = 0.64) groups. Similarly, a higher GRS predicted a greater number of baseline-adjusted small LDL particles at 1 year in the lifestyle intervention arm (β = +0.30, SEE±0.012 ln nmol/L/allele, P = 0.01, P interaction = 0.01) but not in the placebo (β = −0.002, SEE±0.008 ln nmol/L/allele, P = 0.74) or metformin (β = +0.013, SEE±0.008 nmol/L/allele, P = 0.12; P interaction = 0.24) groups. Our findings suggest that a high genetic burden confers an adverse lipid profile and predicts attenuated response in LDL-C levels and small LDL particle number to dietary and physical activity interventions aimed at weight loss. PMID:22951888

  7. Identification of new genetic risk factors for prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Michelle Guy; Helen I.Field; Melissa C.Southey; Gianluca Severi; Jenny L.Donovan; Freddie C.Hamdy; David P.Dearnaley; Kenneth R.Muir; Charmaine Smith; Melisa Bagnato; Audrey T.Ardern-Jones; Zsofia Kote-Jarai; Amanda L.Hall; Lynne T.O'Brien; Beatrice N.Gehr-Swain; Rosemary A.Wilkinson; Angela Cox; Sarah Lewis; Paul M.Brown; Sameer G.Jhavar; Malgorzata Tymrakiewicz; Artitaya Lophatananon; Graham G.Giles; Sarah L.Bryant; The UK Genetic Prostate Cancer Study Collaborators; British Association of Urological Surgeons' Sectio; Alan Horwich; Robert A.Huddart; Vincent S.Khoo; Christopher C.Parker; Christopher J.Woodhouse; Alan Thompson; Tim Christmas; Ali Amin Al Olama; Chris Ogden; Cyril Fisher; Charles Jameson; Colin S.Cooper; Dallas R.English; John L.Hopper; David E.Neal; Douglas E Easton; Rosalind A.Eeles; Sarah K.Jugurnauth; Shani Mulholland; Daniel A.Leongamomlert; Stephen M.Edwards; Jonathan Morrison

    2009-01-01

    There is evidence that a substantial part of genetic predisposition to prostate cancer (PCa) may be due to lower penetrance genes which are found by genome-wide association studies.We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified.Three of these loci contain candidate susceptibility genes:MSMB,LMTK2 and KLK2/3.The MSMB and KLK2/3 genes may he useful for PCa screening,and the LMTK2 gene might provide a potential therapeutic target.Together with results from other groups,there are now 23 germline genetic variants which have been reported.These results have the potential to be developed into a genetic test.However,we consider that marketing of tests to the public is premature,as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed.Follow-up validation studies,as well as studies to explore the psychological implications of genetic profile testing,will be vital prior to roll out into healthcare.

  8. The Contribution of Epigenetics to Understanding Genetic Factors in Autism

    Science.gov (United States)

    Hall, Layla; Kelley, Elizabeth

    2014-01-01

    Autism spectrum disorder is a grouping of neurodevelopmental disorders characterized by deficits in social communication and language, as well as by repetitive and stereotyped behaviors. While the environment is believed to play a role in the development of autism spectrum disorder, there is now strong evidence for a genetic link to autism.…

  9. Exploring Genetic Factors Involved in Huntington Disease Age of Onset

    DEFF Research Database (Denmark)

    Valcárcel-Ocete, Leire; Alkorta-Aranburu, Gorka; Iriondo, Mikel;

    2015-01-01

    Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of ...

  10. The Contribution of Epigenetics to Understanding Genetic Factors in Autism

    Science.gov (United States)

    Hall, Layla; Kelley, Elizabeth

    2014-01-01

    Autism spectrum disorder is a grouping of neurodevelopmental disorders characterized by deficits in social communication and language, as well as by repetitive and stereotyped behaviors. While the environment is believed to play a role in the development of autism spectrum disorder, there is now strong evidence for a genetic link to autism.…

  11. Identifying Common Genetic Risk Factors of Diabetic Neuropathies

    Science.gov (United States)

    Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

  12. Environmental and genetic factors affecting faecal worm egg counts ...

    African Journals Online (AJOL)

    2015-12-09

    Dec 9, 2015 ... The basic principle of animal breeding and genetics is to improve ..... that FWEC can be influenced by seasonal variation, management practice .... Molento, M.B., Fortes, F.S., Pondelek, D.A.S., Borges, F.A., Chagas, A.C.S., ...

  13. A versatile, non genetically modified organism (GMO)-based strategy for controlling low-producer mutants in Bordetella pertussis cultures using antigenic modulation.

    Science.gov (United States)

    Goffin, Philippe; Slock, Thomas; Smessaert, Vincent; De Rop, Philippe; Dehottay, Philippe

    2015-08-01

    The uncontrolled presence of non-producer mutants negatively affects bioprocesses. In Bordetella pertussis cultures, avirulent mutants emerge spontaneously and accumulate. We characterized the dynamics of accumulation using high-throughput growth assays and competition experiments between virulent and avirulent (bvg(-) ) isolates. A fitness advantage of bvg(-) cells was identified as the main driver for bvg(-) accumulation under conditions of high virulence factor production. Conversely, under conditions that reduce their expression (antigenic modulation), bvg(-) takeover could be avoided. A control strategy was derived, which consists in applying modulating conditions whenever virulence factor production is not required. It has a wide range of applications, from routine laboratory operations to vaccine manufacturing, where pertussis toxin yields were increased 1.4-fold by performing early pre-culture steps in modulating conditions. Because it only requires subtle modifications of the culture medium and does not involve genetic modifications, this strategy is applicable to any B. pertussis isolate, and should facilitate regulatory acceptance of process changes for vaccine production. Strategies based on the same concept, could be derived for other industrially relevant micro-organisms. This study illustrates how a sound scientific understanding of physiological principles can be turned into a practical application for the bioprocess industry, in alignment with Quality by Design principles. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. The structure of genetic and environmental risk factors for fears and phobias.

    Science.gov (United States)

    Loken, E K; Hettema, J M; Aggen, S H; Kendler, K S

    2014-08-01

    Although prior genetic studies of interview-assessed fears and phobias have shown that genetic factors predispose individuals to fears and phobias, they have been restricted to the DSM-III to DSM-IV aggregated subtypes of phobias rather than to individual fearful and phobic stimuli. We examined the lifetime history of fears and/or phobias in response to 21 individual phobic stimuli in 4067 personally interviewed twins from same-sex pairs from the Virginia Adult Twin Study of Psychiatric and Substance Abuse Disorders (VATSPSUD). We performed multivariate statistical analyses using Mx and Mplus. The best-fitting model for the 21 phobic stimuli included four genetic factors (agora-social-acrophobia, animal phobia, blood-injection-illness phobia and claustrophobia) and three environmental factors (agora-social-hospital phobia, animal phobia, and situational phobia). This study provides the first view of the architecture of genetic and environmental risk factors for phobic disorders and their subtypes. The genetic factors of the phobias support the DSM-IV and DSM-5 constructs of animal and blood-injection-injury phobias but do not support the separation of agoraphobia from social phobia. The results also do not show a coherent genetic factor for the DSM-IV and DSM-5 situational phobia. Finally, the patterns of co-morbidity across individual fears and phobias produced by genetic and environmental influences differ appreciably.

  15. Genetic factors explain half of all variance in serum eosinophil cationic protein.

    Science.gov (United States)

    Elmose, C; Sverrild, A; van der Sluis, S; Kyvik, K O; Backer, V; Thomsen, S F

    2014-12-01

    Eosinophil cationic protein (ECP) is one of four basic proteins of the secretory granules of eosinophils. It has a variety of functions associated with inflammatory responses. Little is known about the causes for variation in serum ECP levels. To identify factors associated with variation in serum ECP and to determine the relative proportion of the variation in ECP due to genetic and non-genetic factors, in an adult twin sample. A sample of 575 twins, selected through a proband with self-reported asthma, had serum ECP, lung function, airway responsiveness to methacholine, exhaled nitric oxide, and skin test reactivity, measured. Linear regression analysis and variance component models were used to study factors associated with variation in ECP and the relative genetic influence on ECP levels. Sex (regression coefficient = -0.107, P variance component model, genetic factors accounted for 57% (CI: 42-72%, P variance in ECP levels, whereas the remainder (43%) was ascribable to non-shared environmental factors. The genetic correlation between ECP and airway responsiveness to methacholine was statistically non-significant (r = -0.11, P = 0.50). Around half of all variance in serum ECP is explained by genetic factors. Serum ECP is influenced by sex, BMI, and airway responsiveness. Serum ECP and airway responsiveness seem not to share genetic variance. © 2014 John Wiley & Sons Ltd.

  16. Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments.

    Science.gov (United States)

    Della-Morte, David; Guadagni, Fiorella; Palmirotta, Raffaele; Testa, Gianluca; Caso, Valeria; Paciaroni, Maurizio; Abete, Pasquale; Rengo, Franco; Ferroni, Patrizia; Sacco, Ralph L; Rundek, Tatjana

    2012-04-01

    Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. Investigations of the genetics of atherosclerosis and IS has greatly enhanced our knowledge of this complex multifactorial disease. In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.

  17. Environmental factors influence both abundance and genetic diversity in a widespread bird species.

    Science.gov (United States)

    Liu, Yang; Webber, Simone; Bowgen, Katharine; Schmaltz, Lucie; Bradley, Katharine; Halvarsson, Peter; Abdelgadir, Mohanad; Griesser, Michael

    2013-11-01

    Genetic diversity is one of the key evolutionary variables that correlate with population size, being of critical importance for population viability and the persistence of species. Genetic diversity can also have important ecological consequences within populations, and in turn, ecological factors may drive patterns of genetic diversity. However, the relationship between the genetic diversity of a population and how this interacts with ecological processes has so far only been investigated in a few studies. Here, we investigate the link between ecological factors, local population size, and allelic diversity, using a field study of a common bird species, the house sparrow (Passer domesticus). We studied sparrows outside the breeding season in a confined small valley dominated by dispersed farms and small-scale agriculture in southern France. Population surveys at 36 locations revealed that sparrows were more abundant in locations with high food availability. We then captured and genotyped 891 house sparrows at 10 microsatellite loci from a subset of these locations (N = 12). Population genetic analyses revealed weak genetic structure, where each locality represented a distinct substructure within the study area. We found that food availability was the main factor among others tested to influence the genetic structure between locations. These results suggest that ecological factors can have strong impacts on both population size per se and intrapopulation genetic variation even at a small scale. On a more general level, our data indicate that a patchy environment and low dispersal rate can result in fine-scale patterns of genetic diversity. Given the importance of genetic diversity for population viability, combining ecological and genetic data can help to identify factors limiting population size and determine the conservation potential of populations.

  18. Thrombosis and inflammatory bowel disease-the role of genetic risk factors

    Institute of Scientific and Technical Information of China (English)

    Georgia Tsiolakidou; Ioannis E Koutroubakis

    2008-01-01

    Thromboembolism is a significant cause of morbidity and mortality in patients with inflammatory bowel dis-ease (IBD). Recent data suggest thromboembolism as a disease-specific extraintestinal manifestation of IBD,which is developed as the result of multiple interac-tions between acquired and genetic risk factors. There is evidence indicating an imbalance of procoagulant,anticoagulant and fibrinolitic factors predisposing in thrombosis in patients with IBD. The genetic factors that have been suggested to interfere in the thrombotic manifestations of IBD include factor V Leiden, factor Ⅱ (prothrombin, G20210A), methylenetetrahydrofolate reductase gene mutation (MTHFR, 6777T), plasminogen activator inhibitor type 1 (PAI-1) gene mutation and fac-tor ⅩⅢ (va1341eu). In this article we review the current data and future prospects on the role of genetic risk factors in the development of thromboembolism in IBD.

  19. Cultural and biological factors modulate spatial biases over development.

    Science.gov (United States)

    Girelli, Luisa; Marinelli, Chiara Valeria; Grossi, Giuseppe; Arduino, Lisa S

    2017-11-01

    Increasing evidence supports the contribution of both biological and cultural factors to visuospatial processing. The present study adds to the literature by exploring the interplay of perceptual and linguistic mechanisms in determining visuospatial asymmetries in adults (Experiment 1) and children (Experiment 2). In particular, pre-schoolers (3 and 5 year-olds), school-aged children (8 year-old), and adult participants were required to bisect different types of stimuli, that is, lines, words, and figure strings. In accordance with the literature, results yielded a leftward bias for lines and words and a rightward bias for figure strings, in adult participants. More critically, different biases were found for lines, words, and figure strings in children as a function of age, reflecting the impact of both cultural and biological factors on the processing of different visuospatial materials. Specifically, an adult-like pattern of results emerged only in the older group of children (8 year-old), but not in pre-schoolers. Results are discussed in terms of literacy, reading habits exposure, and biological maturation.

  20. Novel factors modulating human β-cell proliferation.

    Science.gov (United States)

    Shirakawa, J; Kulkarni, R N

    2016-09-01

    β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human β-cell proliferation including WS6, an IkB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3β and DYRK1A inhibitors; osteoprotegrin and Denosmab, receptor activator of NF-kB (RANK) inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of human diabetes.

  1. Environmental factors influence both abundance and genetic diversity in a widespread bird species

    NARCIS (Netherlands)

    Liu, Yang; Webber, Simone; Bowgen, Katharine; Schmaltz, Lucie; Bradley, Katharine; Halvarsson, Peter; Abdelgadir, Mohanad; Griesser, Michael

    2013-01-01

    Genetic diversity is one of the key evolutionary variables that correlate with population size, being of critical importance for population viability and the persistence of species. Genetic diversity can also have important ecological consequences within populations, and in turn, ecological factors

  2. Environmental factors influence both abundance and genetic diversity in a widespread bird species

    NARCIS (Netherlands)

    Liu, Yang; Webber, Simone; Bowgen, Katharine; Schmaltz, Lucie; Bradley, Katharine; Halvarsson, Peter; Abdelgadir, Mohanad; Griesser, Michael

    2013-01-01

    Genetic diversity is one of the key evolutionary variables that correlate with population size, being of critical importance for population viability and the persistence of species. Genetic diversity can also have important ecological consequences within populations, and in turn, ecological factors

  3. Common Genetic and Nonshared Environmental Factors Contribute to the Association between Socioemotional Dispositions and the Externalizing Factor in Children

    Science.gov (United States)

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

    2013-01-01

    Background: Childhood behavioral disorders including conduct disorder (CD), oppositional defiant disorder (ODD), and attention-deficit/hyperactivity disorder (ADHD) often co-occur. Prior twin research shows that common sets of genetic and environmental factors are associated with these various disorders and they form a latent factor called…

  4. Genetically-encoded tools for cAMP probing and modulation in living systems.

    Directory of Open Access Journals (Sweden)

    Valeriy M Paramonov

    2015-09-01

    Full Text Available Intracellular 3'-5'-cyclic adenosine monophosphate (cAMP is one of the principal second messengers downstream of a manifold of signal transduction pathways, including the ones triggered by G protein-coupled receptors. Not surprisingly, biochemical assays for cAMP have been instrumental for basic research and drug discovery for decades, providing insights into cellular physiology and guiding pharmaceutical industry. However, despite impressive track record, the majority of conventional biochemical tools for cAMP probing share the same fundamental shortcoming - all the measurements require sample disruption for cAMP liberation. This common bottleneck, together with inherently low spatial resolution of measurements (as cAMP is typically analyzed in lysates of thousands of cells, underpin the ensuing limitations of the conventional cAMP assays: 1 genuine kinetic measurements of cAMP levels over time in a single given sample are unfeasible; 2 inability to obtain precise information on cAMP spatial distribution and transfer at subcellular levels, let alone the attempts to pinpoint dynamic interactions of cAMP and its effectors. At the same time, tremendous progress in synthetic biology over the recent years culminated in drastic refinement of our toolbox, allowing us not only to bypass the limitations of conventional assays, but to put intracellular cAMP life-span under tight control – something, that seemed scarcely attainable before. In this review article we discuss the main classes of modern genetically-encoded tools tailored for cAMP probing and modulation in living systems. We examine the capabilities and weaknesses of these different tools in the context of their operational characteristics and applicability to various experimental set-ups involving living cells, providing the guidance for rational selection of the best tools for particular needs.

  5. Modulation of genetic associations with serum urate levels by body-mass-index in humans.

    Science.gov (United States)

    Huffman, Jennifer E; Albrecht, Eva; Teumer, Alexander; Mangino, Massimo; Kapur, Karen; Johnson, Toby; Kutalik, Zoltán; Pirastu, Nicola; Pistis, Giorgio; Lopez, Lorna M; Haller, Toomas; Salo, Perttu; Goel, Anuj; Li, Man; Tanaka, Toshiko; Dehghan, Abbas; Ruggiero, Daniela; Malerba, Giovanni; Smith, Albert V; Nolte, Ilja M; Portas, Laura; Phipps-Green, Amanda; Boteva, Lora; Navarro, Pau; Johansson, Asa; Hicks, Andrew A; Polasek, Ozren; Esko, Tõnu; Peden, John F; Harris, Sarah E; Murgia, Federico; Wild, Sarah H; Tenesa, Albert; Tin, Adrienne; Mihailov, Evelin; Grotevendt, Anne; Gislason, Gauti K; Coresh, Josef; D'Adamo, Pio; Ulivi, Sheila; Vollenweider, Peter; Waeber, Gerard; Campbell, Susan; Kolcic, Ivana; Fisher, Krista; Viigimaa, Margus; Metter, Jeffrey E; Masciullo, Corrado; Trabetti, Elisabetta; Bombieri, Cristina; Sorice, Rossella; Döring, Angela; Reischl, Eva; Strauch, Konstantin; Hofman, Albert; Uitterlinden, Andre G; Waldenberger, Melanie; Wichmann, H-Erich; Davies, Gail; Gow, Alan J; Dalbeth, Nicola; Stamp, Lisa; Smit, Johannes H; Kirin, Mirna; Nagaraja, Ramaiah; Nauck, Matthias; Schurmann, Claudia; Budde, Kathrin; Farrington, Susan M; Theodoratou, Evropi; Jula, Antti; Salomaa, Veikko; Sala, Cinzia; Hengstenberg, Christian; Burnier, Michel; Mägi, Reedik; Klopp, Norman; Kloiber, Stefan; Schipf, Sabine; Ripatti, Samuli; Cabras, Stefano; Soranzo, Nicole; Homuth, Georg; Nutile, Teresa; Munroe, Patricia B; Hastie, Nicholas; Campbell, Harry; Rudan, Igor; Cabrera, Claudia; Haley, Chris; Franco, Oscar H; Merriman, Tony R; Gudnason, Vilmundur; Pirastu, Mario; Penninx, Brenda W; Snieder, Harold; Metspalu, Andres; Ciullo, Marina; Pramstaller, Peter P; van Duijn, Cornelia M; Ferrucci, Luigi; Gambaro, Giovanni; Deary, Ian J; Dunlop, Malcolm G; Wilson, James F; Gasparini, Paolo; Gyllensten, Ulf; Spector, Tim D; Wright, Alan F; Hayward, Caroline; Watkins, Hugh; Perola, Markus; Bochud, Murielle; Kao, W H Linda; Caulfield, Mark; Toniolo, Daniela; Völzke, Henry; Gieger, Christian; Köttgen, Anna; Vitart, Veronique

    2015-01-01

    We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

  6. Modulation of genetic associations with serum urate levels by body-mass-index in humans.

    Directory of Open Access Journals (Sweden)

    Jennifer E Huffman

    Full Text Available We tested for interactions between body mass index (BMI and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8. Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8, a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8, regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4. Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

  7. Quantifying effects of environmental and geographical factors on patterns of genetic differentiation.

    Science.gov (United States)

    Lee, Cheng-Ruei; Mitchell-Olds, Thomas

    2011-11-01

    Elucidating the factors influencing genetic differentiation is an important task in biology, and the relative contribution from natural selection and genetic drift has long been debated. In this study, we used a regression-based approach to simultaneously estimate the quantitative contributions of environmental adaptation and isolation by distance on genetic variation in Boechera stricta, a wild relative of Arabidopsis. Patterns of discrete and continuous genetic differentiation coexist within this species. For the discrete differentiation between two major genetic groups, environment has larger contribution than geography, and we also identified a significant environment-by-geography interaction effect. Elsewhere in the species range, we found a latitudinal cline of genetic variation reflecting only isolation by distance. To further confirm the effect of environmental selection on genetic divergence, we identified the specific environmental variables predicting local genotypes in allopatric and sympatric regions. Water availability was identified as the possible cause of differential local adaptation in both geographical regions, confirming the role of environmental adaptation in driving and maintaining genetic differentiation between the two major genetic groups. In addition, the environment-by-geography interaction is further confirmed by the finding that water availability is represented by different environmental factors in the allopatric and sympatric regions. In conclusion, this study shows that geographical and environmental factors together created stronger and more discrete genetic differentiation than isolation by distance alone, which only produced a gradual, clinal pattern of genetic variation. These findings emphasize the importance of environmental selection in shaping patterns of species-wide genetic variation in the natural environment.

  8. Genetic factors affecting patient responses to pancreatic cancer treatment

    Science.gov (United States)

    Fotopoulos, George; Syrigos, Konstantinos; Saif, Muhammad Wasif

    2016-01-01

    Cancer of the exocrine pancreas is a malignancy with a high lethal rate. Surgical resection is the only possible curative mode of treatment. Metastatic pancreatic cancer is incurable with modest results from the current treatment options. New genomic information could prove treatment efficacy. An independent review of PubMed and ScienceDirect databases was performed up to March 2016, using combinations of terms such pancreatic exocrine cancer, chemotherapy, genomic profile, pancreatic cancer pharmacogenomics, genomics, molecular pancreatic pathogenesis, and targeted therapy. Recent genetic studies have identified new markers and therapeutic targets. Our current knowledge of pancreatic cancer genetics must be further advanced to elucidate the molecular basis and pathogenesis of the disease, improve the accuracy of diagnosis, and guide tailor-made therapies. PMID:27708512

  9. Men's values-based factors on prostate cancer risk genetic testing: A telephone survey

    Directory of Open Access Journals (Sweden)

    Li Yuelin

    2004-12-01

    Full Text Available Abstract Background While a definitive genetic test for Hereditary Prostate Cancer (HPC is not yet available, future HPC risk testing may become available. Past survey data have shown high interest in HPC testing, but without an in-depth analysis of its underlying rationale to those considering it. Methods Telephone computer-assisted interviews of 400 men were conducted in a large metropolitan East-coast city, with subsequent development of psychometric scales and their correlation with intention to receive testing. Results Approximately 82% of men interviewed expressed that they "probably" or "definitely" would get genetic testing for prostate cancer risk if offered now. Factor analysis revealed four distinct, meaningful factors for intention to receive genetic testing for prostate cancer risk. These factors reflected attitudes toward testing and were labeled "motivation to get testing," "consequences and actions after knowing the test result," "psychological distress," and "beliefs of favorable outcomes if tested" (α = 0.89, 0.73, 0.73, and 0.60, respectively. These factors accounted for 70% of the total variability. The domains of motivation (directly, consequences (inversely, distress (inversely, and positive expectations (directly all correlated with intention to receive genetic testing (p Conclusions Men have strong attitudes favoring genetic testing for prostate cancer risk. The factors most associated with testing intention include those noted in past cancer genetics studies, and also highlights the relevance in considering one's motivation and perception of positive outcomes in genetic decision-making.

  10. Genetic Factors Explain the Association Between Pain Catastrophizing and Chronic Widespread Pain.

    Science.gov (United States)

    Ogata, Soshiro; Williams, Frances; Burri, Andrea

    2017-09-01

    This study aimed to clarify whether there are shared genetic and/or environmental factors explaining the strong link between pain catastrophizing (PC) and chronic widespread pain (CWP). Data were available for N = 1,109 female twins from TwinsUK. Information on self-reported CWP and PC was subject to variance component twin analysis. Heritabilities were 40% for PC and 77% for CWP. The genetic correlation between PC and CWP was .40%, whereas no evidence of an environmental correlation could be detected (.0). According to the best-fitting additive genetic, non-shared environmental (AE) Cholesky model, an additive genetic factor loading on PC as well as CWP, as well as an additive genetic factor loading on CWP alone was found. In terms of environmental influences, 2 individual environmental factors could be identified, loading separately on PC and CWP. Overall, the results add to the knowledge on the nature of CWP and the basis of its close relationship with PC by suggesting a shared genetic etiological structure. The findings highlight a potential avenue for future research and may provide useful insight for the clinical management of pain and pain coping. Results suggest a shared genetic etiological structure between CWP and PC with no shared influence of environmental factors. Clinicians should be aware of this biological link within the context of clinical management of pain and pain coping. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

  11. The epidemiology of eating disorders: genetic, environmental, and societal factors

    OpenAIRE

    Mitchison D; Hay PJ

    2014-01-01

    Deborah Mitchison,1 Phillipa J Hay2,3 1School of Medicine, University of Western Sydney, Sydney, NSW, Australia; 2Centre for Health Research, School of Medicine, University of Western Sydney, Sydney, NSW, Australia; 3School of Medicine, James Cook University, Townsville City, QLD, Australia Background: The aim of this review was to summarize the literature to date regarding the sociodemographic, environmental, and genetic correlates of eating disorders (EDs) in adults. Method: A keyword sear...

  12. Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk

    Science.gov (United States)

    Fischer, Annegret; Ellinghaus, David; Nutsua, Marcel; Hofmann, Sylvia; Montgomery, Courtney G.; Iannuzzi, Michael C.; Rybicki, Benjamin A.; Petrek, Martin; Mrazek, Frantisek; Pabst, Stefan; Grohé, Christian; Grunewald, Johan; Ronninger, Marcus; Eklund, Anders; Padyukov, Leonid; Mihailovic-Vucinic, Violeta; Jovanovic, Dragana; Sterclova, Martina; Homolka, Jiri; Nöthen, Markus M.; Herms, Stefan; Gieger, Christian; Strauch, Konstantin; Winkelmann, Juliane; Boehm, Bernhard O.; Brand, Stephan; Büning, Carsten; Schürmann, Manfred; Ellinghaus, Eva; Baurecht, Hansjörg; Lieb, Wolfgang; Nebel, Almut; Müller-Quernheim, Joachim; Franke, Andre

    2015-01-01

    Rationale: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. Objectives: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. Methods: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms. Measurements and Main Results: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. Conclusions: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics PMID:26051272

  13. Genetic Factors Affecting Performance Traits of Sahiwal Cattle in Pakistan

    Directory of Open Access Journals (Sweden)

    Z. Rehman*§ and M. S. Khan1

    2012-06-01

    Full Text Available Data on 23925 lactations of 5897 Sahiwal cows in five Government herds of Punjab province were collected to estimate the genetic control and genetic correlations among performance traits. A repeatability animal model having herd-year-season and parity was used for this purpose. The repeatability estimates for 305-d milk yield, total milk yield, lactation length, dry period, calving interval and service period were 0.40±0.015, 0.40±0.016, 0.33±0.013, 0.14±0.005, 0.15±0.004, and 0.14±0.005 respectively. The heritability estimates for these traits were 0.10±0.016, 0.09±0.016, 0.06±0.013, 0.14±0.009, 0.15±0.010, and 0.14±0.010, respectively. The phenotypic, genetic and environmental correlation of 305-d milk yield with lactation length was 0.71, 0.48 and 0.70, respectively, with dry period was -0.31, -0.43 and -0.22, respectively while with calving interval and service period exhibited similar pattern (0.08, 0.25 and 0.08, respectively. The estimated breeding values ranged from -447 to 1254 kg, -442 to 1265 kg, -24 to 38, -78 to 116, -84 to 107 and -81 to 91, days for 305-day milk yield, total milk yield, lactation length, dry period, calving interval and service period, respectively. No specific genetic trend was observed for performance traits during the period under study. Cows have not improved in their ability to perform in various economic traits. Accurate recording of pedigree and performance is necessary for improving the performance traits of Sahiwal. Due to high repeatability estimates of yield traits selection or culling may be practised from first few records.

  14. Nephrolithiasis and Nephrocalcinosis in Children - Metabolic and Genetic Factors.

    Science.gov (United States)

    Tasic, Velibor; Gucev, Zoran

    2015-09-01

    Diagnosis and management of pediatric nephrolithiasis/nephrocalcinosis is a very complex and challenging task for every pediatrician. It is based on correct. disease history taking, which may guide to the mode of inheritance (dominant, recessive, x-linked). Ethnicity and consanguinity should also be investigated since they predispose to high prevalence of certain disorders. One should always begin with cheap and available screening tests. Herein we will review clinical, biochemical, metabolic and genetic characteristics of the inherited diseases which lead to nephrolithiasis/nephrocalcinosis, such as: idiopathic hypercalciuria, renal hypophosphatemia, renal tubular acidosis, idiopathic infantile hypercalcemia, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, hypocitraturia, cystinuria, primary hyperoxaluria and renal hypouricemia. Modern genetic techniques such as next generation sequencing enable nowadays diagnosis of rare disease using only a blood sample, trough massive parallel resequencing of many genes. This is very helpful for anuric patients or on dialysis where blood and urine biochemistry are not informative. Genetic testing also replaces invasive liver biopsy or unpleasant acidification tests and enables prenatal or early postnatal diagnosis.

  15. Modulation of topoisomerase activities by tumor necrosis factor.

    Science.gov (United States)

    Baloch, Z; Cohen, S; Fresa, K; Coffman, F D

    1995-01-01

    A number of chemotherapeutic agents which inhibit the DNA topoisomerases markedly potentiate cell death mediated by tumor necrosis factor, suggesting a role for these enzymes in the TNF cytotoxic mechanism. To investigate this possibility, topoisomerase I and II activities were assayed following TNF addition to murine L929 cells. Topoisomerase I and II activities increased within 15 min of TNF addition and returned to baseline levels within 1 and 2 hr, respectively. The increases in both topoisomerase activities were blocked by H-7 (but not H-8) and similar increases were seen following PMA addition. However, concentrations of H-7 which blocked the increased topoisomerase activities had no effect on TNF cytotoxicity nor on the enhancement of TNF cytotoxicity by topoisomerase inhibitors. Thus, in these cells topoisomerase activities are directly modified by TNF during the initial phases of a cytotoxic response. However, neither TNF cytotoxicity nor the enhancement of TNF cytotoxicity by topoisomerase inhibitors appears to require the TNF-mediated increases in topoisomerase activities.

  16. Genetic and environmental factors affecting peak bone mass in premenopausal Japanese women

    OpenAIRE

    Hayakawa, Yoshika; Yanagi, Hisako; Hara, Shuichi; Amagai, Hitoshi; Endo, Kazue; Hamaguchi, Hideo; Tomura, Shigeo

    2001-01-01

    The purpose of this study was to examine the relationships between peak bone mass and genetic and environmental factors. We measured whole-body bone mineral density (BMD), lumbar spine BMD, and radius BMD with dual-energy X-ray absorptiometry (DXA) and analyzed eight genetic factors: vitamin D receptor (VDR)-3′, VDR-5′, estrogen receptor (ER), calcitonin receptor (CTR), parathyroid hormone (PTH), osteocalcin (OC), apolipoprotein E (ApoE), and fatty acid binding protein 2 (FABP2) allelic polym...

  17. Influence Factors on Consumers’ Cognition Level to Genetically Modified Food-taking Huangshi as an Example

    OpenAIRE

    Ruishan Chen; Yazhou Xiong; Jing Mo

    2015-01-01

    This study aims to analyze the influence factors on consumers’ cognition level to genetically modified food and improve the consumers’ cognition level. In recent years, genetically modified foods in people’s daily life are becoming more and more common, but there is a lot of controversy about them. Based on the analysis of influence factors on consumers’ cognition level to GMF, a comprehensive system is established from four aspects, including the consumers’ personal characteristics, social-e...

  18. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

    DEFF Research Database (Denmark)

    Benyamin, B.; Sørensen, T.I.A.; Schousboe, K.

    2007-01-01

    AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic...... and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All......, the endophenotypes associated with the metabolic syndrome apparently do not share a substantial common genetic or familial environmental background....

  19. Genetics

    Science.gov (United States)

    ... 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 ...

  20. The influence of the genetic and non-genetic factors on bone mineral density and osteoporotic fractures in Chinese women.

    Science.gov (United States)

    Deng, Yan-Hua; Zhao, Lin; Zhang, Min-Jia; Pan, Chun-Ming; Zhao, Shuang-Xia; Zhao, Hong-Yan; Sun, Li-Hao; Tao, Bei; Song, Huai-Dong; Wang, Wei-Qing; Ning, Guang; Liu, Jian-Min

    2013-02-01

    To investigate the effects of genetic and non-genetic factors on bone mineral densities (BMDs) and osteoporotic fractures. This was a cross-sectional study to investigate the relationships between 18 SNPs and non-genetic factors with BMDs and osteoporotic fractures in 1012 Chinese Han women. Five SNPs in genes GPR177, CTNNB1, MEF2C, SOX6, and TNFRSF11B were associated with L1-4 or total hip BMDs. rs11898505 in SPTBN1 gene was associated with osteoporotic fractures. Subjects carrying the largest number of risk alleles (highest 10 %) not only had lower BMD values as compared to those carrying the least number of risk alleles (lowest 10 %), they also had a higher risk of fracture [P = 0.002, OR = 2.252, 95 %CI (1.136, 4.463)]. Results from multivariate stepwise regression analysis revealed that age [P < 0.001, OR = 1.038, 95 % CI (1.018, 1.058)], number of falls in a year [P < 0.001, OR = 2.347, 95 % CI (1.459, 3.774)], the G risk allele in rs11898505 [P = 0.023, OR = 1.559, 95 % CI (1.062, 2.290)], and the L1-4 BMD [P = 0.017, OR = 0.286, 95 % CI (0.102, 0.798)] were associated with the occurrence of osteoporotic fractures. Genetic (rs11898505) and non-genetic factors (age, number of falls in a year and L1-4 BMD) could work in concert to contribute to the risk of osteoporotic fractures.

  1. Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFβ1 signaling pathway modulation.

    Directory of Open Access Journals (Sweden)

    Ana L Teixeira

    Full Text Available Prostate cancer (PC is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT. TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT =1.5, P=0.016. GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019 and increased risk of an early relapse after ADT (HR=1.47, P=0.024. The concordance (c index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759. The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.

  2. Maternal and genetic factors in stress-resilient and -vulnerable rats: a cross-fostering study.

    Science.gov (United States)

    Uchida, Shusaku; Hara, Kumiko; Kobayashi, Ayumi; Otsuki, Koji; Hobara, Teruyuki; Yamagata, Hirotaka; Watanabe, Yoshifumi

    2010-02-26

    Early environmental factors can modulate the development of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, together with subsequent brain functions and emotional behaviors. Two rat strains, Sprague-Dawley (SD) and Fischer 344 (F344), are known to exhibit differences in HPA axis reactivity and anxiety behavior in response to restraint stress in adulthood. To investigate the contribution of maternal influences in determining HPA axis and behavioral responses to stress, a cross-fostering study was performed using stress-resilient (SD) or stress-susceptible (F344) strains. We found that SD rats adopted by either an SD (in-fostered) or an F344 (cross-fostered) dam and F344 rats adopted by an SD dam (cross-fostered) showed a suppression of the HPA axis response following 14 days of repeated restraint stress. In contrast, F344 rats adopted by an F344 dam (in-fostered) did not show such HPA axis habituation. We also found that F344 rats adopted by an F344 dam showed increased anxiety-related behaviors in social interaction and novelty-suppressed feeding tests as a result of the 14 days of restraint stress, while SD rats adopted by either an SD or an F344 dam and F344 rats adopted by an SD dam showed normal anxiety-related behaviors under the same experimental conditions. These results suggest that while genetic differences between SD and F344 strains account for some of the variations in stress vulnerability, maternal factors also contribute. (c) 2009 Elsevier B.V. All rights reserved.

  3. Dissection of genetic factors associated with amyotrophic lateral sclerosis.

    Science.gov (United States)

    Leblond, Claire S; Kaneb, Hannah M; Dion, Patrick A; Rouleau, Guy A

    2014-12-01

    Amyotrophic lateral sclerosis (ALS) is a fatal late onset neurological disorder characterized by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. The majority of cases are sporadic (SALS) and only 5-10% have a family history (FALS). FALS cases show a high heritability and this has enabled the identification of several genetic triggers, of which mutations in SOD1, FUS, TARDBP and C9ORF72 are the most frequent. While such advances have contributed to our current understanding of the causes of most cases of FALS and their underlying pathophysiological consequences, they only explain a small fraction of SALS with the etiology of most SALS cases remaining unexplained. Here, we review past and current methods used for the identification of FALS and SALS associated genes and propose a risk-based classification for these. We also discuss how the growing number of whole exome/genome sequencing datasets prepared from SALS cases, and control individuals, may reveal novel insights into the genetic etiology of SALS; for instance through revealing increased mutation burden rates across genes or genomic regions that were not previously associated with ALS or through allowing the examination of a potential "oligogenic" mechanism of the disease. Finally we summarize the three most recently discovered 'high risk' genes in ALS.

  4. Disentangling genetic and environmental risk factors for individual diseases from multiplex comorbidity networks

    CERN Document Server

    Klimek, Peter; Thurner, Stefan

    2016-01-01

    Most disorders are caused by a combination of multiple genetic and/or environmental factors. If two diseases are caused by the same molecular mechanism, they tend to co-occur in patients. Here we provide a quantitative method to disentangle how much genetic or environmental risk factors contribute to the pathogenesis of 358 individual diseases, respectively. We pool data on genetic, pathway-based, and toxicogenomic disease-causing mechanisms with disease co-occurrence data obtained from almost two million patients. From this data we construct a multilayer network where nodes represent disorders that are connected by links that either represent phenotypic comorbidity of the patients or the involvement of a certain molecular mechanism. From the similarity of phenotypic and mechanism-based networks for each disorder we derive measure that allows us to quantify the relative importance of various molecular mechanisms for a given disease. We find that most diseases are dominated by genetic risk factors, while envir...

  5. Pharmacological and Genetic Modulation of REV-ERB Activity and Expression Affects Orexigenic Gene Expression.

    Directory of Open Access Journals (Sweden)

    Ariadna Amador

    Full Text Available 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.

  6. Genetic mapping of resistance factors to Phytophthora palmivora in cocoa.

    Science.gov (United States)

    Flament, M H; Kebe, I; Clément, D; Pieretti, I; Risterucci, A M; N'Goran, J A; Cilas, C; Despréaux, D; Lanaud, C

    2001-02-01

    Phytophthora palmivora causes pod rot, a serious disease on cocoa widespread throughout the producing regions. In order to ascertain the genetic determination of cocoa resistance to P. palmivora, a study was carried out on two progenies derived from crosses between a heterozygous, moderately resistant Forastero clone, T60/887, and two closely related and highly susceptible Forastero clones, one completely homozygous, IFC2, and one partially heterozygous, IFC5. The cumulative size of both progenies was 112 individuals. Plants were subjected to natural and artificial inoculation of P. palmivora in C te d'Ivoire. The genetic maps of T60/887 and of IFC5 were constructed using amplified fragment length polymorphism (AFLP) markers and microsatellites. The map of T60/887 comprised 198 markers assembled in 11 linkage groups and representing a total length of 793 cM. The map of IFC5 comprised 55 AFLP markers that were assembled into six linkage groups for a total length of 244 cM. Ratio of rotten over total number of fruit under natural infection was measured for each tree over two harvests. Artificial inoculations were performed on leaves and pods. These tests were weakly correlated with the pod rot rate in the field. Five quantitative trait loci (QTLs) of resistance were detected for T60/887 but none were common between the three traits measured. Stability and reliability of the experimental procedures are discussed and revealed the difficult use of these artificial tests on adult trees for a good prediction of field resistance.

  7. Sex differences in genetic and environmental risk factors for irrational fears and phobias.

    Science.gov (United States)

    Kendler, K S; Jacobson, K C; Myers, J; Prescott, C A

    2002-02-01

    For irrational fears and their associated phobias, epidemiological studies suggest sex differences in prevalence and twin studies report significant genetic effects. How does sex impact on the familial transmission of liability to fears and phobias? In personal interviews with over 3000 complete pairs (of whom 1058 were opposite-sex dizygotic pairs), ascertained from a population-based registry, we assessed the lifetime prevalence of five phobias and their associated irrational fears analysed using a multiple threshold model. Twin resemblance was assessed by polychoric correlations and biometrical model-fitting incorporating sex-specific effects. For agoraphobia, situational and blood/injury fear/phobia, the best fit model suggested equal heritability in males and females and genetic correlations between the sexes of less than +0.50. For animal fear/phobias by contrast, the best fit model suggested equal heritability in males and females and a genetic correlation of unity. No evidence was found for an impact of family environment on liability to these fears or phobias. For social phobias, twin resemblance in males was explained by genetic factors and in females by familial-environmental factors. The impact of sex on genetic risk may differ meaningfully across phobia subtypes. Sex-specific genetic risk factors may exist for agoraphobia, social, situational and blood-injury phobias but not for animal fear/phobia. These results should be interpreted in the context of the limited power of twin studies, even with large sample sizes, to resolve sex-specific genetic effects.

  8. Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.

    Science.gov (United States)

    Hollenstein, U; Homoncik, M; Stohlawetz, P J; Marsik, C; Sieder, A; Eichler, H G; Jilma, B

    2000-07-01

    During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.

  9. Factores de riesgo de la enfermedad periodontal: factores genéticos Risks factors in periodontal diseases: genetic factors

    OpenAIRE

    2005-01-01

    Hoy en día y tras numerosos estudios epidemiológicos, se acepta el concepto de la existencia de determinados factores de riesgo que van a modular la susceptibilidad o resistencia del hospedador a padecer enfermedad periodontal, por lo tanto, en el desarrollo van a intervenir varias causas considerándose dicha patología de etiología multifactorial. De este modo, las enfermedades periodontales son producidas por una interacción de un agente microbiano único o múltiple considerado como el factor...

  10. Moderation of genetic factors by parental divorce in adolescents' evaluations of family functioning and subjective wellbeing.

    Science.gov (United States)

    van der Aa, Niels; Boomsma, Dorret I; Rebollo-Mesa, Irene; Hudziak, James J; Bartels, Meike

    2010-04-01

    Adolescents' evaluations of family functioning may have a significant impact on their subjective well-being and adjustment. The aim of the study was to investigate the degree to which genetic and environmental influences affect variation in evaluations of general family functioning, family conflict, and quality of life and the overlap between them. We assessed whether genetic and environmental influences are moderated by parental divorce by analyzing self-report data from 6,773 adolescent twins and their non-twin siblings. Genetic, shared, and nonshared environmental influences accounted for variation in general family functioning and family conflict, with genetic influences being relatively more important in girls than boys in general family functioning. Genetic and nonshared environmental influences accounted for variation in quality of life, with genetic influences being relatively more important in girls. Evidence was found for interaction between genetic factors and parental divorce: genetic influence on general family functioning was larger in participants from divorced families. The overlap between general family functioning and quality of life, and family conflict and quality of life was accounted for the largest part by genetic effects, with nonshared environmental effects accounting for the remaining part. By examining the data from monozygotic twins, we found evidence for interaction between genotype and nonshared, non-measured, environmental influences on evaluations of general family functioning, family conflict, and quality of life.

  11. Frequent respiratory tract infections in children. The role of environmental and genetic factors.

    NARCIS (Netherlands)

    Ruskamp, J.M.

    2009-01-01

    Respiratory tract infections (RTI), presenting as common cold, pharyngitis, tonsillitis, acute otitis media, bronchitis or pneumonia are a major health problem in children. In this thesis common environmental and host factors, as well as plausible genetic factors were evaluated in a large birth coho

  12. A guide to murine coagulation factor structure, function, assays, and genetic alterations

    NARCIS (Netherlands)

    Emeis, J.J.; Jirouskova, M.; Muchitsch, E.-M.; Shet, A.S.; Smyth, S.S.; Johnson, G.J.

    2007-01-01

    Murine blood coagulation factors and function are quite similar to those of humans. Because of this similarity and the adaptability of mice to genetic manipulation, murine coagulation factors and inhibitors have been extensively studied. These studies have provided significant insights into human

  13. Human genetic variation in VAC14 regulates Salmonella invasion and typhoid fever through modulation of cholesterol.

    Science.gov (United States)

    Alvarez, Monica I; Glover, Luke C; Luo, Peter; Wang, Liuyang; Theusch, Elizabeth; Oehlers, Stefan H; Walton, Eric M; Tram, Trinh Thi Bich; Kuang, Yu-Lin; Rotter, Jerome I; McClean, Colleen M; Chinh, Nguyen Tran; Medina, Marisa W; Tobin, David M; Dunstan, Sarah J; Ko, Dennis C

    2017-09-12

    Risk, severity, and outcome of infection depend on the interplay of pathogen virulence and host susceptibility. Systematic identification of genetic susceptibility to infection is being undertaken through genome-wide association studies, but how to expeditiously move from genetic differences to functional mechanisms is unclear. Here, we use genetic association of molecular, cellular, and human disease traits and experimental validation to demonstrate that genetic variation affects expression of VAC14, a phosphoinositide-regulating protein, to influence susceptibility to Salmonella enterica serovar Typhi (S Typhi) infection. Decreased VAC14 expression increased plasma membrane cholesterol, facilitating Salmonella docking and invasion. This increased susceptibility at the cellular level manifests as increased susceptibility to typhoid fever in a Vietnamese population. Furthermore, treating zebrafish with a cholesterol-lowering agent, ezetimibe, reduced susceptibility to S Typhi. Thus, coupling multiple genetic association studies with mechanistic dissection revealed how VAC14 regulates Salmonella invasion and typhoid fever susceptibility and may open doors to new prophylactic/therapeutic approaches.

  14. Genetic factors that increase male facial masculinity decrease facial attractiveness of female relatives.

    Science.gov (United States)

    Lee, Anthony J; Mitchem, Dorian G; Wright, Margaret J; Martin, Nicholas G; Keller, Matthew C; Zietsch, Brendan P

    2014-02-01

    For women, choosing a facially masculine man as a mate is thought to confer genetic benefits to offspring. Crucial assumptions of this hypothesis have not been adequately tested. It has been assumed that variation in facial masculinity is due to genetic variation and that genetic factors that increase male facial masculinity do not increase facial masculinity in female relatives. We objectively quantified the facial masculinity in photos of identical (n = 411) and nonidentical (n = 782) twins and their siblings (n = 106). Using biometrical modeling, we found that much of the variation in male and female facial masculinity is genetic. However, we also found that masculinity of male faces is unrelated to their attractiveness and that facially masculine men tend to have facially masculine, less-attractive sisters. These findings challenge the idea that facially masculine men provide net genetic benefits to offspring and call into question this popular theoretical framework.

  15. Rule-based models of the interplay between genetic and environmental factors in childhood allergy.

    Directory of Open Access Journals (Sweden)

    Susanne Bornelöv

    Full Text Available Both genetic and environmental factors are important for the development of allergic diseases. However, a detailed understanding of how such factors act together is lacking. To elucidate the interplay between genetic and environmental factors in allergic diseases, we used a novel bioinformatics approach that combines feature selection and machine learning. In two materials, PARSIFAL (a European cross-sectional study of 3113 children and BAMSE (a Swedish birth-cohort including 2033 children, genetic variants as well as environmental and lifestyle factors were evaluated for their contribution to allergic phenotypes. Monte Carlo feature selection and rule based models were used to identify and rank rules describing how combinations of genetic and environmental factors affect the risk of allergic diseases. Novel interactions between genes were suggested and replicated, such as between ORMDL3 and RORA, where certain genotype combinations gave odds ratios for current asthma of 2.1 (95% CI 1.2-3.6 and 3.2 (95% CI 2.0-5.0 in the BAMSE and PARSIFAL children, respectively. Several combinations of environmental factors appeared to be important for the development of allergic disease in children. For example, use of baby formula and antibiotics early in life was associated with an odds ratio of 7.4 (95% CI 4.5-12.0 of developing asthma. Furthermore, genetic variants together with environmental factors seemed to play a role for allergic diseases, such as the use of antibiotics early in life and COL29A1 variants for asthma, and farm living and NPSR1 variants for allergic eczema. Overall, combinations of environmental and life style factors appeared more frequently in the models than combinations solely involving genes. In conclusion, a new bioinformatics approach is described for analyzing complex data, including extensive genetic and environmental information. Interactions identified with this approach could provide useful hints for further in-depth studies

  16. Alcoholism and liver disease in Mexico: genetic and environmental factors.

    Science.gov (United States)

    Roman, Sonia; Zepeda-Carrillo, Eloy Alfonso; Moreno-Luna, Laura Eugenia; Panduro, Arturo

    2013-11-28

    Alcoholism and cirrhosis, which are two of the most serious health problems worldwide, have a broad spectrum of clinical outcomes. Both diseases are influenced by genetic susceptibility and cultural traits that differ globally but are specific for each population. In contrast to other regions around the world, Mexicans present the highest drinking score and a high mortality rate for alcoholic liver disease with an intermediate category level of per capita alcohol consumption. Mexico has a unique history of alcohol consumption that is linked to profound anthropological and social aspects. The Mexican population has an admixture genome inherited from different races, Caucasian, Amerindian and African, with a heterogeneous distribution within the country. Thus, genes related to alcohol addiction, such as dopamine receptor D2 in the brain, or liver alcohol-metabolizing enzymes, such as alcohol dehydrogenase class I polypeptide B, cytochrome P450 2E1 and aldehyde dehydrogenase class 2, may vary from one individual to another. Furthermore, they may be inherited as risk or non-risk haplogroups that confer susceptibility or resistance either to alcohol addiction or abusive alcohol consumption and possibly liver disease. Thus, in this era of genomics, personalized medicine will benefit patients if it is directed according to individual or population-based data. Additional association studies will be required to establish novel strategies for the prevention, care and treatment of liver disease in Mexico and worldwide.

  17. Japanese quail's genetic background modulates effects of chronic stress on emotional reactivity but not spatial learning.

    Directory of Open Access Journals (Sweden)

    Agathe Laurence

    Full Text Available Chronic stress is known to enhance mammals' emotional reactivity and alters several of their cognitive functions, especially spatial learning. Few studies have investigated such effects in birds. We investigated the impact of a two-week stress on Japanese quail's emotional reactivity and spatial learning. Quail is an avian model widely used in laboratory studies and for extrapolation of data to other poultry species. As sensitivity to chronic stress can be modulated by intrinsic factors, we tested juvenile female Japanese quail from three lines, two of them divergently selected on tonic immobility duration, an indicator of general fearfulness. The different emotional reactivity levels of quail belonging to these lines can be revealed by a large variety of tests. Half of the birds were submitted to repeated unpredictable aversive events for two weeks, whereas the other half were left undisturbed. After this procedure, two tests (open field and emergence tests evaluated the emotional reactivity of treated and control quails. They were then trained in a T-maze for seven days and their spatial learning was tested. The chronic stress protocol had an impact on resting, preening and foraging in the home cage. As predicted, the emotional reactivity of treated quails, especially those selected for long tonic immobility duration, was higher. Our spatial learning data showed that the treatment enhanced acquisition but not memorization. However, intrinsic fearfulness did not seem to interact with the treatment in this test. According to an inverted U-shaped relationship between stress and cognition, chronic stress can improve the adaptability of birds to a stressful environment. We discussed the mechanisms possibly implied in the increase of emotional reactivity and spatial abilities.

  18. Factor analysis models for structuring covariance matrices of additive genetic effects: a Bayesian implementation

    Directory of Open Access Journals (Sweden)

    Gianola Daniel

    2007-09-01

    Full Text Available Abstract Multivariate linear models are increasingly important in quantitative genetics. In high dimensional specifications, factor analysis (FA may provide an avenue for structuring (covariance matrices, thus reducing the number of parameters needed for describing (codispersion. We describe how FA can be used to model genetic effects in the context of a multivariate linear mixed model. An orthogonal common factor structure is used to model genetic effects under Gaussian assumption, so that the marginal likelihood is multivariate normal with a structured genetic (covariance matrix. Under standard prior assumptions, all fully conditional distributions have closed form, and samples from the joint posterior distribution can be obtained via Gibbs sampling. The model and the algorithm developed for its Bayesian implementation were used to describe five repeated records of milk yield in dairy cattle, and a one common FA model was compared with a standard multiple trait model. The Bayesian Information Criterion favored the FA model.

  19. Host factors and genetic susceptibility to infections due to intracellular bacteria and fastidious organisms.

    Science.gov (United States)

    Asner, S A; Morré, S A; Bochud, P-Y; Greub, G

    2014-12-01

    While genetic polymorphisms play a paramount role in tuberculosis (TB), less is known about their contribution to the severity of diseases caused by other intracellular bacteria and fastidious microorganisms. We searched electronic databases for observational studies reporting on host factors and genetic predisposition to infections caused by intracellular fastidious bacteria published up to 30 May 2014. The contribution of genetic polymorphisms was documented for TB. This includes genetic defects in the mononuclear phagocyte/T helper cell type 1 (Th1) pathway contributing to disseminated TB disease in children and genome-wide linkage analysis (GWAS) in reactivated pulmonary TB in adults. Similarly, experimental studies supported the role of host genetic factors in the clinical presentation of illnesses resulting from other fastidious intracellular bacteria. These include IL-6 -174G/C or low mannose-binding (MBL) polymorphisms, which are incriminated in chronic pulmonary conditions triggered by C. pneumoniae, type 2-like cytokine secretion polymorphisms, which are correlated with various clinical patterns of M. pneumoniae infections, and genetic variation in the NOD2 gene, which is an indicator of tubal pathology resulting from Chamydia trachomatis infections. Monocyte/macrophage migration and T lymphocyte recruitment defects are corroborated to ineffective granuloma formation observed among patients with chronic Q fever. Similar genetic polymorphisms have also been suggested for infections caused by T. whipplei although not confirmed yet. In conclusion, this review supports the paramount role of genetic factors in clinical presentations and severity of infections caused by intracellular fastidious bacteria. Genetic predisposition should be further explored through such as exome sequencing.

  20. Identification of PV solar cells and modules parameters using the genetic algorithms: Application to maximum power extraction

    Energy Technology Data Exchange (ETDEWEB)

    Zagrouba, M.; Sellami, A.; Bouaicha, M. [Laboratoire de Photovoltaique, des Semi-conducteurs et des Nanostructures, Centre de Recherches et des Technologies de l' Energie, Technopole de Borj-Cedria, Tunis, B.P. 95, 2050 Hammam-Lif (Tunisia); Ksouri, M. [Unite de Recherche RME-Groupe AIA, Institut National des Sciences Appliquees et de Technologie (Tunisia)

    2010-05-15

    In this paper, we propose to perform a numerical technique based on genetic algorithms (GAs) to identify the electrical parameters (I{sub s}, I{sub ph}, R{sub s}, R{sub sh}, and n) of photovoltaic (PV) solar cells and modules. These parameters were used to determine the corresponding maximum power point (MPP) from the illuminated current-voltage (I-V) characteristic. The one diode type approach is used to model the AM1.5 I-V characteristic of the solar cell. To extract electrical parameters, the approach is formulated as a non convex optimization problem. The GAs approach was used as a numerical technique in order to overcome problems involved in the local minima in the case of non convex optimization criteria. Compared to other methods, we find that the GAs is a very efficient technique to estimate the electrical parameters of PV solar cells and modules. Indeed, the race of the algorithm stopped after five generations in the case of PV solar cells and seven generations in the case of PV modules. The identified parameters are then used to extract the maximum power working points for both cell and module. (author)

  1. Analytical Investigation on the Power Factor of a Flux-Modulated Permanent-Magnet Synchronous Machine

    DEFF Research Database (Denmark)

    Zhang, Xiaoxu; Liu, Xiao; Liu, Jinglin;

    2015-01-01

    Flux-modulated permanent-magnet synchronous machine (FM-PMSM) is characterized as a high-torque direct-drive electrical machine, but may suffer from the low power factor. This paper aims to investigate the issue of the low power factor in theory and explore the possibilities for improvement....... An analytical model for the FM-PMSM is developed to obtain the magnetic field distribution, and its accuracy is verified by the finite-element method. On the basis of the developed analytical model, a fast approach is developed to predict the power factor of the FM-PMSM. The analytical results indicate...

  2. Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Dennis Sandris; Krych, Lukasz; Buschard, Karsten

    2014-01-01

    purely genetic are involved in disease development. Here we review the influence of dietary and environmental factors on T1D development in humans as well as animal models. Even though data are still inconclusive, there are strong indications that gut microbiota dysbiosis plays an important role in T1D...... development and evidence from animal models suggests that gut microbiota manipulation might prove valuable in future prevention of T1D in genetically susceptible individuals....

  3. Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children

    Institute of Scientific and Technical Information of China (English)

    Theresa A Mikhailov; Sylvia E Furner

    2009-01-01

    Inflammatory bowel disease is a chronic, debilitating disorder of the gastrointestinal tract. The etiology of inflammatory bowel disease has not been elucidated, but is thought to be multifactorial with both environmental and genetic influences. A large body of research has been conducted to elucidate the etiology of inflammatory bowel disease. This article reviews this literature, emphasizing the studies of breastfeeding and the studies of genetic factors, particularly NOD2 polymorphisms.

  4. Genetic increase in brain-derived neurotrophic factor levels enhances learning and memory.

    Science.gov (United States)

    Nakajo, Yukako; Miyamoto, Susumu; Nakano, Yoshikazu; Xue, Jing-Hui; Hori, Takuya; Yanamoto, Hiroji

    2008-11-19

    Brain-derived neurotrophic factor (BDNF), a neurotrophin, is known to promote neuronal differentiation stimulating neurite outgrowth in the developing CNS, and is also known to modulate synaptic plasticity, thereby contributing to learning and memory in the mature brain. Here, we investigated the role of increased levels of intracerebral BDNF in learning and memory function. Using genetically engineered transgenic BDNF overexpressing mice (RTG-BDNF), young adult, homozygous (+/+), heterozygous (+/-), or wild-type (-/-) littermates, we analyzed escape latency to a hidden-platform and swimming velocity in the Morris Water Maze test (MWM) with modifications for the mice. The MWM comprised 4 trials per day over 5 consecutive days (sessions) without prior or subsequent training. In a separate set of animals, BDNF protein levels in the cortex, thalamostriatum and the hippocampus were measured quantitatively using ELISA. In the BDNF (+/-) mice, the BDNF levels in the cortex, the thalamostriatum and the hippocampus were significantly high, compared to the wild-type littermates; 238%, 158%, and 171%, respectively (PBDNF levels in the BDNF (+/+) mice were not elevated. The BDNF (+/-), but not the (+/+) mice, demonstrated significantly shorter escape latency, shorter total path length in the MWM, and more frequent arrivals at the location where the platform had been placed previously in the probe trial, compared with the wild-type littermates (PBDNF-transgenic mice, increased BDNF levels in the brain were found to enhance spatial learning and memory function. Although it has been postulated that excessive BDNF is deteriorating for neuronal survival or neurite outgrowth, further investigations are needed to clarify the mechanism of paradoxical lack of increase in BDNF levels in the (+/+) mouse brain.

  5. Shared Genetic Factors Influence Risk for Bipolar Disorder and Alcohol Use Disorders

    Science.gov (United States)

    Carmiol, Nasdia; Peralta, Juan M; Almasy, Laura; Contreras, Javier; Pacheco, Adriana; Escamilla, Michael A; Knowles, Emma E; Raventós, Henriette; Glahn, David C

    2014-01-01

    Bipolar disorder and alcohol use disorder (AUD) have a high rate of comorbidity, more than 50% of individuals with bipolar disorder also receive a diagnosis of AUD in their lifetimes. Although both disorders are heritable, it is unclear if the same genetic factors mediate risk for bipolar disorder and AUD. We examined 733 Costa Rican individuals from 61 bipolar pedigrees. Based on a best-estimate process, 32% of the sample met criteria for bipolar disorder, 17% had a lifetime AUD diagnosis, 32% met criteria for lifetime nicotine dependence, and 21% had an anxiety disorder. AUD, nicotine dependence and anxiety disorders were relatively more common among individuals with bipolar disorder than in their non-bipolar relatives. All illnesses were shown to be heritable and bipolar disorder was genetically correlated with AUD, nicotine dependence and anxiety disorders. The genetic correlation between bipolar and AUD remained when controlling for anxiety, suggesting that unique genetic factors influence risk for comorbid bipolar and AUD independent of anxiety. Our findings provide evidence for shared genetic effects on bipolar disorder and AUD risk. Demonstrating that common genetic factors influence these independent diagnostic constructs could help to refine our diagnostic nosology. PMID:24321773

  6. Identification of genetic bases of vibrio fluvialis species-specific biochemical pathways and potential virulence factors by comparative genomic analysis.

    Science.gov (United States)

    Lu, Xin; Liang, Weili; Wang, Yunduan; Xu, Jialiang; Zhu, Jun; Kan, Biao

    2014-03-01

    Vibrio fluvialis is an important food-borne pathogen that causes diarrheal illness and sometimes extraintestinal infections in humans. In this study, we sequenced the genome of a clinical V. fluvialis strain and determined its phylogenetic relationships with other Vibrio species by comparative genomic analysis. We found that the closest relationship was between V. fluvialis and V. furnissii, followed by those with V. cholerae and V. mimicus. Moreover, based on genome comparisons and gene complementation experiments, we revealed genetic mechanisms of the biochemical tests that differentiate V. fluvialis from closely related species. Importantly, we identified a variety of genes encoding potential virulence factors, including multiple hemolysins, transcriptional regulators, and environmental survival and adaptation apparatuses, and the type VI secretion system, which is indicative of complex regulatory pathways modulating pathogenesis in this organism. The availability of V. fluvialis genome sequences may promote our understanding of pathogenic mechanisms for this emerging pathogen.

  7. Genetic vs Environmental Factors That Correlate With Rosacea: A Cohort-Based Survey of Twins.

    Science.gov (United States)

    Aldrich, Nely; Gerstenblith, Meg; Fu, Pingfu; Tuttle, Marie S; Varma, Priya; Gotow, Erica; Cooper, Kevin D; Mann, Margaret; Popkin, Daniel L

    2015-11-01

    To our knowledge, this is the first study on rosacea to formally define genetic and environmental contributions. To study a cohort of identical and fraternal twins to determine whether genetic factors contribute to rosacea development and, if genetic factors are present, quantitatively estimate the genetic contribution, as well as to identify environmental factors that correlate with rosacea by controlling for genetic susceptibility. Identical and fraternal twins were surveyed regarding risk factors implicated in rosacea. Faculty dermatologists determined a rosacea score for each twin participant according to the National Rosacea Society (NRS) grading system. Data were collected at the annual Twins Days Festival in Twinsburg, Ohio, on August 4-5, 2012, and August 2-3, 2013. Analysis was conducted for several months after each meeting. A cohort of 550 twin individuals, with most from Ohio, Pennsylvania, and the northeastern United States, participated. The NRS score and rosacea subtype were assessed using the NRS grading system and physical examination by board-certified dermatologists. Among the 275 twin pairs (550 individuals), there were 233 identical twin pairs with a mean rosacea score of 2.46 and 42 fraternal twin pairs with a mean rosacea score of 0.75. We observed a higher association of NRS scores between identical vs fraternal twins (r = 0.69 vs r = 0.46; P = .04), demonstrating a genetic contribution. Using the ACE model (proportion of variance in a trait heritable secondary to additive genetics [A] vs the proportions due to a common environment [C] and unique environment [E]), we calculated this genetic contribution to be 46%. A higher NRS score was also significantly associated with the following factors: age (r = 0.38; P twins allows us to separate genetic susceptibility and the influence of environmental factors affecting rosacea. We found that approximately half of the contribution to the NRS score could be accounted for by genetics

  8. Time transfer capability of standard small form factor pluggable laser modules based on photon counting approach

    Science.gov (United States)

    Trojanek, Pavel; Prochazka, Ivan; Blazej, Josef

    2017-05-01

    We are reporting on timing parameters of commonly used standard Small Form Factor Pluggable (SFP) laser modules using single photon counting method. Photon counting is a promising approach for laser time transfer via optical fiber communication hardware. The sub-picosecond precision and stability may be achieved. We have performed several experiments with the aim to measure main parameters of the modules, such as time delay precision, time stability and temperature stability, all being critical for optical time transfer applications. Two standard 16 and 10 Gbit/s at 850 nm SFP modules were examined. The ultimate precision of possible time transfer of 800 fs for averaging times of hours was achieved. The modules together with their driving circuits exhibited very good temperature stability. The temperature drift as low as 300+/-200 fs/K was measured. The achieved timing parameters will enable to use the standard SFP modules for a new method of two way time transfer where the time differences between two distant time scales are measured in parallel to data transfer on existing optical data links without any communication interference.

  9. How Genetic and Other Biological Factors Interact with Smoking Decisions.

    Science.gov (United States)

    Bierut, Laura; Cesarini, David

    2015-09-01

    Despite clear links between genes and smoking, effective public policy requires far richer measurement of the feedback between biological, behavioral, and environmental factors. The Kavli HUMAN Project (KHP) plans to exploit the plummeting costs of data gathering and to make creative use of new technologies to construct a longitudinal panel data set that would compare favorably to existing longitudinal surveys, both in terms of the richness of the behavioral measures and the cost-effectiveness of the data collection. By developing a more comprehensive approach to characterizing behavior than traditional methods, KHP will allow researchers to paint a much richer picture of an individual's life-cycle trajectory of smoking, alcohol, and drug use, and interactions with other choices and environmental factors. The longitudinal nature of KHP will be particularly valuable in light of the increasing evidence for how smoking behavior affects physiology and health. The KHP could have a transformative impact on the understanding of the biology of addictive behaviors such as smoking, and of a rich range of prevention and amelioration policies.

  10. Neuropathology and Animal Models of Autism: Genetic and Environmental Factors

    Directory of Open Access Journals (Sweden)

    Bharathi S. Gadad

    2013-01-01

    Full Text Available Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology.

  11. Non-genetic risk factors in haemophilia A inhibitor management

    DEFF Research Database (Denmark)

    Löfgren, Karin Maria; Søndergaard, H.; Skov, Søren;

    2016-01-01

    In haemophilia A (HA) management, antidrug antibodies, or inhibitors, are a serious complication that renders factor VIII (FVIII) replacement therapy ineffective, increases morbidity and reduces quality of life for affected patients. Inhibitor development aetiology is multifactorial and covers bo...... with a suspected danger signal aetiology; on-demand treatment, treatment during major bleeds or surgery, and treatment during infection or vaccination. Clinical studies as well as animal experiments addressing these factors will be reviewed......., and explanations for this association are being investigated. A potential explanation is the danger signal effect, where the immune response is activated by endogenous or exogenous danger or damage signals present at the time and site of FVIII administration. The danger theory explains how alarm signals from...... stressed, injured or dying cells can activate an immune reaction, without the involvement of foreign antigens. Bleeds, trauma, surgery or concomitant infection could be events initiating danger signalling in HA patients, resulting in an immune reaction towards administered FVIII that otherwise would pass...

  12. Genetic Schizophrenia Risk Variants Jointly Modulate Total Brain and White Matter Volume

    DEFF Research Database (Denmark)

    Terwisscha van Scheltinga, Afke F; Bakker, Steven C; van Haren, Neeltje E M

    2013-01-01

    BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modu...

  13. Influence of genetic and environmental factors on oral diseases and function in aged twins.

    Science.gov (United States)

    Kurushima, Y; Ikebe, K; Matsuda, K; Enoki, K; Ogata, S; Yamashita, M; Murakami, S; Hayakawa, K; Maeda, Y

    2015-01-01

    This study was conducted to quantify the genetic and environmental contributions to oral disease and function in twins. Participants were middle-aged and old twins, 116 monozygotic and 16 dizygotic pairs whose mean age was 66·1 ± 10·3 (SD) years. Number of teeth, percentage of decayed, filled and missing teeth and periodontal status were recorded as indicators of oral disease. The widths of upper and lower dental arch served as indicators of morphological figures. Furthermore, stimulated salivary flow rate, occlusal force and masticatory performance were measured as indicators of oral function. Univariate genetic analysis with monozygotic and dizygotic twin pairs was conducted to detect the fittest structural equation model of each outcome. Both number of teeth and periodontal status fitted the model composed of common environmental factor and unique environmental factor. Decayed, filled and missing teeth, morphological figures and measurements of oral function fitted the model composed of additive genetic factor and unique environmental factor. The model fitting of each measurement suggested that periodontal disease was mainly affected by environmental factors, while morphological figures and oral functions were influenced by both genetic and environmental factors.

  14. [Genetic and environmental factors of asthma and allergy: Results of the EGEA study].

    Science.gov (United States)

    Bouzigon, E; Nadif, R; Le Moual, N; Dizier, M-H; Aschard, H; Boudier, A; Bousquet, J; Chanoine, S; Donnay, C; Dumas, O; Gormand, F; Jacquemin, B; Just, J; Margaritte-Jeannin, P; Matran, R; Pison, C; Rage, E; Rava, M; Sarnowski, C; Smit, L A M; Temam, S; Varraso, R; Vignoud, L; Lathrop, M; Pin, I; Demenais, F; Kauffmann, F; Siroux, V

    2015-10-01

    The EGEA study (epidemiological study on the genetics and environment of asthma, bronchial hyperresponsiveness and atopy), which combines a case-control and a family-based study of asthma case (n=2120 subjects) with three surveys over 20 years, aims to identify environmental and genetic factors associated with asthma and asthma-related phenotypes. We summarize the results of the phenotypic characterization and the investigation of environmental and genetic factors of asthma and asthma-related phenotypes obtained since 2007 in the EGEA study (42 articles). Both epidemiological and genetic results confirm the heterogeneity of asthma. These results strengthen the role of the age of disease onset, the allergic status and the level of disease activity in the identification of the different phenotypes of asthma. The deleterious role of active smoking, exposure to air pollution, occupational asthmogenic agents and cleaning products on the prevalence and/or activity of asthma has been confirmed. Accounting for gene-environment interactions allowed the identification of new genetic factors underlying asthma and asthma-related traits and better understanding of their mode of action. The EGEA study is contributing to the advances in respiratory research at the international level. The new phenotypic, environmental and biological data available in EGEA study will help characterizing the long-term evolution of asthma and the factors associated to this evolution. Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.

  15. Systematic genetic analysis of transcription factors to map the fission yeast transcription-regulatory network.

    Science.gov (United States)

    Chua, Gordon

    2013-12-01

    Mapping transcriptional-regulatory networks requires the identification of target genes, binding specificities and signalling pathways of transcription factors. However, the characterization of each transcription factor sufficiently for deciphering such networks remains laborious. The recent availability of overexpression and deletion strains for almost all of the transcription factor genes in the fission yeast Schizosaccharomyces pombe provides a valuable resource to better investigate transcription factors using systematic genetics. In the present paper, I review and discuss the utility of these strain collections combined with transcriptome profiling and genome-wide chromatin immunoprecipitation to identify the target genes of transcription factors.

  16. Are there common genetic and environmental factors behind the endophenotypes associated with the metabolic syndrome?

    DEFF Research Database (Denmark)

    Benyamin, B; Sørensen, T I A; Schousboe, K

    2007-01-01

    AIMS/HYPOTHESIS: The cluster of obesity, insulin resistance, dyslipidaemia and hypertension, called the metabolic syndrome, has been suggested as a risk factor for cardiovascular disease and type 2 diabetes. The aim of the present study was to evaluate whether there are common genetic...... and environmental factors influencing this cluster in a general population of twin pairs. MATERIALS AND METHODS: A multivariate genetic analysis was performed on nine endophenotypes associated with the metabolic syndrome from 625 adult twin pairs of the GEMINAKAR study of the Danish Twin Registry. RESULTS: All...

  17. Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes

    DEFF Research Database (Denmark)

    Nielsen, Dennis Sandris; Krych, Lukasz; Buschard, Karsten;

    2014-01-01

    Type 1 diabetes (T1D) is an autoimmune disease ultimately leading to destruction of insulin secreting β-cells in the pancreas. Genetic susceptibility plays an important role in T1D etiology, but even mono-zygotic twins only have a concordance rate of around 50%, underlining that other factors than...... purely genetic are involved in disease development. Here we review the influence of dietary and environmental factors on T1D development in humans as well as animal models. Even though data are still inconclusive, there are strong indications that gut microbiota dysbiosis plays an important role in T1D...

  18. Is there a genetic correlation between general factors of intelligence and personality?

    Science.gov (United States)

    Loehlin, John C; Bartels, Meike; Boomsma, Dorret I; Bratko, Denis; Martin, Nicholas G; Nichols, Robert C; Wright, Margaret J

    2015-06-01

    We tested a hypothesis that there is no genetic correlation between general factors of intelligence and personality, despite both having been selected for in human evolution. This was done using twin samples from Australia, the United States, the Netherlands, Great Britain, and Croatia, comprising altogether 1,748 monozygotic and 1,329 same-sex dizygotic twin pairs. Although parameters in the model-fitting differed among the twin samples, the genetic correlation between the two general factors could be set to zero, with a better fit if the U.S. sample was excepted.

  19. Genetic factors for nerve susceptibility to injuries-lessons from PMP22 deifciency

    Institute of Scientific and Technical Information of China (English)

    Jun Li

    2014-01-01

    Genetic factors may be learnt from families with gene mutations that render nerve-injury sus-ceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies (HNPP). HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions (such as tight junction and adherens junctions), leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This ifnding should motivate investigators to identify additional genetic factors contribut-ing to nerve vulnerability of injury.

  20. Genetic factors for individual administration of immunosuppressants in organ transplantation

    Institute of Scientific and Technical Information of China (English)

    Song-Feng Yu; Li-Hua Wu; Shu-Sen Zheng

    2006-01-01

    BACKGROUND: The immunosuppressive drugs used worldwide have a narrow therapeutic index, which results in a need to individualize the dose regimen for different recipients. The oxidative enzymes cytochrome P450 (CYP)3A and the drug eflfux pump P-glycoprotein (P-gp) are two potential factors in the processes of metabolism. Pharmacogenetic study of immunosuppressive drugs has focused on these two enzymes. This review was undertaken to assess the role of single nuclear polymorphisms (SNPs) of these two enzymes in the individual administration of immunosuppressive drugs. DATA SOURCES: An English-language literature search was made using MEDLINE for articles on CYP3A and P-gp in organ transplantation. RESULTS: The SNPs of CYP3A and P-gp are closely correlated to the large variations of cyclosporine and tacrolimus dosage between different patients, although conlficting results were obtained by some authors. CONCLUSIONS: More studies should be conducted to elucidate further the pharmacogenetics of immuno-suppressive drugs in organ transplantation, a deep understanding of which would provide an important step toward drug regimen individualization in the posttransplant therapy.

  1. Genetic, morphometric, and behavioral factors linked to the midsagittal area of the corpus callosum

    Directory of Open Access Journals (Sweden)

    Alex J Newbury

    2012-05-01

    Full Text Available TThe corpus callosum is the main commissure connecting left and right cerebral hemispheres, and varies widely in size. Differences in the midsagittal area of the corpus callosum (MSACC have been associated with a number of cognitive and behavioral phenotypes, including obsessive-compulsive disorders, psychopathy, suicidal tendencies, bipolar disorder, schizophrenia, autism, and attention deficit hyperactivity disorder. Although there is evidence to suggest that MSACC is heritable in normal human populations, there is surprisingly little evidence concerning the genetic modulation of this variation. Mice provide a potentially ideal tool to dissect the genetic modulation of MSACC. Here, we use a large genetic reference panel—the BXD recombinant inbred (RI line—to dissect the natural variation of the MSACC. We estimated the MSACC in over 300 individuals from nearly 80 strains. We found a 4-fold difference in MSACC between individual mice, and a 2.5 fold difference between strains. MSACC is a highly heritable trait (h2 = 0.60, and we mapped a suggestive QTL to the distal portion of Chr 14. Using sequence data and neocortical expression databases, we were able to identify eight positional and plausible biological candidate genes within this interval. Finally, we found that MSACC correlated with behavioral traits associated with anxiety and attention.

  2. Phenomenological analysis of near threshold periodic modulations of the proton timelike form factor

    CERN Document Server

    Bianconi, A

    2015-01-01

    We have recently highlighted the presence of a periodically oscillating 10 \\% modulation in the BABAR data on the proton timelike form factors, in the reaction $e^++e^-$ $\\rightarrow$ $\\bar{p}+p$. Here we deepen our previous data analysis, and confirm that in the case of several standard parametrizations it is possible to write the form factor in the form $F_0$ $+$ $F_{osc}$, where $F_0$ is a parametrization expressing the long-range trend of the form factor (for $q^2$ ranging from the $\\bar{p}p$ threshold to 36 GeV$^2$), and $F_{osc}$ is a function of the form $\\exp(-Bp)\\cos(Cp)$, where $p$ is the relative momentum of the final $\\bar{p}p$ pair. Error bars allow for a clean identification of the main features of this modulation for $q^2$ $<$ 10 GeV$^2$. Assuming this oscillatory modulation to be an effect of final state interactions between the forming proton and the antiproton, we propose a phenomenological model based on a double-layer imaginary optical potential. This potential is flux-absorbing when th...

  3. Diabetes-Role of epigenetics, genetics,and physiological factors

    Institute of Scientific and Technical Information of China (English)

    Sreerama Krupanidhi; Saikiran K.Sedimbi; Ganesan Vaishnav; Sreerama Sai Madhukar; Carani B.Sanjeevi

    2009-01-01

    Cells of organ systems are endowed with a relatively similar genome while epigenome niches keep varying chronologically and defined explicitly in the respective tissues. The genome of an individual is always influenced by parental, embryonic, tissue-specific, and environmental epigenomes and the same must have been the possible reason for invariable inquiries relating to familial, environmental and life style patterns in the preliminary investigations of diabetic complications. Unprecedented methylation of lysine residues of histones and cytosines of CpG islands of promoter DNA impede the transcription of genes and homocysteine is the metabolic key player of methyl groups. Gck and COX7A1 are the 2 examples in the present review to elucidate the epigenetic influence on the onset of diabetes. miRNAs are additional promising cellular components influencing both at transcriptional and translational levels and promoting either in favour or against (i.e., feed back) TFs, signaling factors and proteins through their pliotropic effects and thus are reported to regulate cellular physiology. miR-124a and miR-9 are primarily endemic to nervous tissue and they are now being exploited in islets for their function in executing exocytosis of insulin, which of course is one of the fundamental canons of diabetes. miR-375 persuades beta cells for glucose-induced insulin gene expression. The current approach to evaluate the constellation of genes and their products involved in diabetes in huge number of samples through GWA studies may unravel intricacies involved in the management of diabetes and its associated consequences.

  4. Alternative sigma factor RpoN and its modulation protein YhbH are indispensable for Erwinia amylovora virulence.

    Science.gov (United States)

    Ancona, Veronica; Li, Wenting; Zhao, Youfu

    2014-01-01

    In Erwinia amylovora, ECF (extracytoplasmic functions) alternative sigma factor HrpL regulates the transcription of hrp (hypersensitive response and pathogenicity)-type III secretion system (T3SS) genes by binding to a consensus sequence known as the hrp box in hrp gene promoters. In turn, the expression of hrpL has been proposed to be positively controlled by alternative sigma factor 54 (σ(54)) (RpoN) and HrpS, a member of the σ(54) enhancer-binding proteins (EBPs). However, the function of RpoN has not been characterized genetically in E. amylovora. In this study, we investigated the role of RpoN, a nitrogen limitation sigma factor, and its modulation protein YhbH, a novel ribosome-associated protein, in E. amylovora virulence. Our results showed that mutations in hrpS, hrpL, rpoN and yhbH, but not yfiA and rmf3, resulted in a nonpathogenic phenotype on immature pear fruits and apple shoots. Consistently, the expression of T3SS genes, including hrpL, dspE, hrpN and hrpA, was barely detected in hrpS, hrpL, rpoN and yhbH mutants. These mutants were also not capable of eliciting a hypersensitive response (HR) on tobacco; however, the overexpression of hrpL using an inducible promoter rescued the HR-eliciting abilities of these mutants. These results suggest that a sigma factor cascade exists in the regulatory networks of E. amylovora and regulates important virulence factors. On the basis of this study and previously reported data, a model is proposed for the regulation of T3SS in E. amylovora.

  5. SCALE FACTOR DETERMINATION METHOD OF ELECTRO-OPTICAL MODULATOR IN FIBER-OPTIC GYROSCOPE

    Directory of Open Access Journals (Sweden)

    A. S. Aleynik

    2016-05-01

    Full Text Available Subject of Research. We propose a method for dynamic measurement of half-wave voltage of electro-optic modulator as part of a fiber optic gyroscope. Excluding the impact of the angular acceleration o​n measurement of the electro-optical coefficient is achieved through the use of homodyne demodulation method that allows a division of the Sagnac phase shift signal and an auxiliary signal for measuring the electro-optical coefficient in the frequency domain. Method. The method essence reduces to decomposition of step of digital serrodyne modulation in two parts with equal duration. The first part is used for quadrature modulation signals. The second part comprises samples of the auxiliary signal used to determine the value of the scale factor of the modulator. Modeling is done in standalone model, and as part of a general model of the gyroscope. The applicability of the proposed method is investigated as well as its qualitative and quantitative characteristics: absolute and relative accuracy of the electro-optic coefficient, the stability of the method to the effects of angular velocities and accelerations, method resistance to noise in actual devices. Main Results. The simulation has showed the ability to measure angular velocity changing under the influence of angular acceleration, acting on the device, and simultaneous measurement of electro-optical coefficient of the phase modulator without interference between these processes. Practical Relevance. Featured in the paper the ability to eliminate the influence of the angular acceleration on the measurement accuracy of the electro-optical coefficient of the phase modulator will allow implementing accurate measurement algorithms for fiber optic gyroscopes resistant to a significant acceleration in real devices.

  6. Genetic factors contributing to human primary ciliary dyskinesia and male infertility.

    Science.gov (United States)

    Ji, Zhi-Yong; Sha, Yan-Wei; Ding, Lu; Li, Ping

    2016-06-07

    Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from the loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. However, only 15 PCD-associated genes have been identified to cause male infertility to date. Owing to the genetic heterogeneity of PCD, comprehensive molecular genetic testing is not considered the standard of care. Here, we provide an update of the progress on the identification of genetic factors related to PCD associated with male infertility, summarizing the underlying molecular mechanisms, and discuss the clinical implications of these findings. Further research in this field will impact the diagnostic strategy for male infertility, enabling clinicians to provide patients with informed genetic counseling, and help to adopt the best course of treatment for developing directly targeted personalized medicine.

  7. Genetic interaction motif finding by expectation maximization – a novel statistical model for inferring gene modules from synthetic lethality

    Directory of Open Access Journals (Sweden)

    Ye Ping

    2005-12-01

    Full Text Available Abstract Background Synthetic lethality experiments identify pairs of genes with complementary function. More direct functional associations (for example greater probability of membership in a single protein complex may be inferred between genes that share synthetic lethal interaction partners than genes that are directly synthetic lethal. Probabilistic algorithms that identify gene modules based on motif discovery are highly appropriate for the analysis of synthetic lethal genetic interaction data and have great potential in integrative analysis of heterogeneous datasets. Results We have developed Genetic Interaction Motif Finding (GIMF, an algorithm for unsupervised motif discovery from synthetic lethal interaction data. Interaction motifs are characterized by position weight matrices and optimized through expectation maximization. Given a seed gene, GIMF performs a nonlinear transform on the input genetic interaction data and automatically assigns genes to the motif or non-motif category. We demonstrate the capacity to extract known and novel pathways for Saccharomyces cerevisiae (budding yeast. Annotations suggested for several uncharacterized genes are supported by recent experimental evidence. GIMF is efficient in computation, requires no training and automatically down-weights promiscuous genes with high degrees. Conclusion GIMF effectively identifies pathways from synthetic lethality data with several unique features. It is mostly suitable for building gene modules around seed genes. Optimal choice of one single model parameter allows construction of gene networks with different levels of confidence. The impact of hub genes the generic probabilistic framework of GIMF may be used to group other types of biological entities such as proteins based on stochastic motifs. Analysis of the strongest motifs discovered by the algorithm indicates that synthetic lethal interactions are depleted between genes within a motif, suggesting that synthetic

  8. Dietary Modulation of Gut Microbiota Contributes to Alleviation of Both Genetic and Simple Obesity in Children

    Directory of Open Access Journals (Sweden)

    Chenhong Zhang

    2015-08-01

    Research in context: Poorly managed diet and genetic mutations are the two primary driving forces behind the devastating epidemic of obesity-related diseases. Lack of understanding of the molecular chain of causation between the driving forces and the disease endpoints retards progress in prevention and treatment of the diseases. We found that children genetically obese with Prader–Willi syndrome shared a similar dysbiosis in their gut microbiota with those having diet-related obesity. A diet rich in non-digestible but fermentable carbohydrates significantly promoted beneficial groups of bacteria and reduced toxin-producers, which contributes to the alleviation of metabolic deteriorations in obesity regardless of the primary driving forces.

  9. The role of genetics in stroke risk factors; the discussion of two rare genetic syndroms associated with stroke and review of the literature

    Directory of Open Access Journals (Sweden)

    Eda Kılıç Çoban

    2015-09-01

    Full Text Available Stroke is defined as a focal or at times global neurological impairment of sudden onset, that lasts more than 24 hours or that leads to death. The nonmodifiable risk factors for stroke include age, race, gender and acquired risk factors include smoking, hypertension, diabetes and obesity. Previous studies have shown that these mentioned risk factors might be responsible for approximately 50% of patients presenting stroke. However for the remaining half of the stroke patients no risk factors could be detected and genetics might be responsible for this group. In this manuscript we would like to present 2 cases who were being followed-up with the rare genetic syndromes as Marfan syndrome and Robinow syndrome respectively. These patients presented to our clinic with stroke and no identifiable risk factors other than these genetic syndromes could be detected. By this case-series we would like to further discuss the relationship between genetic syndromes and stroke.

  10. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

    Science.gov (United States)

    Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

    2017-05-01

    Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

  11. Molecular genetic analysis of activation-tagged transcription factors thought to be involved in photomorphogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Neff, Michael M.

    2011-06-23

    This is a final report for Department of Energy Grant No. DE-FG02-08ER15927 entitled “Molecular Genetic Analysis of Activation-Tagged Transcription Factors Thought to be Involved in Photomorphogenesis”. Based on our preliminary photobiological and genetic analysis of the sob1-D mutant, we hypothesized that OBP3 is a transcription factor involved in both phytochrome and cryptochrome-mediated signal transduction. In addition, we hypothesized that OBP3 is involved in auxin signaling and root development. Based on our preliminary photobiological and genetic analysis of the sob2-D mutant, we also hypothesized that a related gene, LEP, is involved in hormone signaling and seedling development.

  12. Importance of genetic factors in the etiology of atopic dermatitis: a twin study

    DEFF Research Database (Denmark)

    Thomsen, Simon F; Ulrik, Charlotte S; Kyvik, Kirsten O;

    2007-01-01

    ?" Latent factor models of genetic and environmental influences were fitted to the observed data using maximum likelihood methods. The overall lifetime prevalence of atopic dermatitis was 7.3%. A cotwin of an affected identical twin had a sevenfold increased risk of atopic dermatitis compared......The susceptibility to develop atopic dermatitis can be attributed both to genetic and environmental causes. We estimated the relative impact of genetic and environmental factors in the etiology of atopic dermatitis in a population-based sample of twins. From the birth cohorts of 1953-1982 who were...... enrolled in The Danish Twin Registry, a total of 11,515 twin pairs were identified in a nationwide questionnaire survey. Subjects were classified as atopic dermatitis cases when responding affirmatively to the question, "Do you have, or have you ever had, eczema in the folds of your elbows or knees...

  13. Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes.

    Science.gov (United States)

    Nielsen, Dennis S; Krych, Łukasz; Buschard, Karsten; Hansen, Camilla H F; Hansen, Axel K

    2014-11-17

    Type 1 diabetes (T1D) is an autoimmune disease ultimately leading to destruction of insulin secreting β-cells in the pancreas. Genetic susceptibility plays an important role in T1D etiology, but even mono-zygotic twins only have a concordance rate of around 50%, underlining that other factors than purely genetic are involved in disease development. Here we review the influence of dietary and environmental factors on T1D development in humans as well as animal models. Even though data are still inconclusive, there are strong indications that gut microbiota dysbiosis plays an important role in T1D development and evidence from animal models suggests that gut microbiota manipulation might prove valuable in future prevention of T1D in genetically susceptible individuals.

  14. Crew Factors in Flight Operations XIV: Alertness Management in Regional Flight Operations Education Module

    Science.gov (United States)

    Rosekind, Mark R.; Co, Elizabeth L.; Neri, David F.; Oyung, Raymond L.; Mallis, Melissa M.

    2002-01-01

    Regional operations encompass a broad range of pilots and equipment. This module is intended to help all those involved in regional aviation, including pilots, schedulers, dispatchers, maintenance technicians, policy makers, and others, to understand the physiological factors underlying fatigue, how flight operations affect fatigue, and what can be done to counteract fatigue and maximize alertness and performance in their operations. The overall purpose of this module is to promote aviation safety, performance, and productivity. It is intended to meet three specific objectives: (1) to explain the current state of knowledge about the physiological mechanisms underlying fatigue; (2) to demonstrate how this knowledge can be applied to improving flight crew sleep, performance, and alertness; and (3) to offer strategies for alertness management. Aviation Safety Reporting System (ASRS) and National Transportation Safety Board (NISH) reports are used throughout this module to demonstrate that fatigue is a safety issue in the regional operations community. The appendices at the end of this module include the ASRS reports used for the examples contained in this publication, brief introductions to sleep disorders and relaxation techniques, summaries of relevant NASA publications, and a list of general readings on sleep, sleep disorders, and circadian rhythms.

  15. Crew Factors in Flight Operations XV: Alertness Management in General Aviation Education Module

    Science.gov (United States)

    Rosekind, Mark R.; Co, Elizabeth L.; Neri, David F.; Oyung, Raymond L.; Mallis, Melissa M.; Cannon, Mary M. (Technical Monitor)

    2002-01-01

    Regional operations encompass a broad range of pilots and equipment. This module is intended to help all those involved in regional aviation, including pilots, schedulers, dispatchers, maintenance technicians, policy makers, and others, to understand the physiological factors underlying fatigue, how flight operations affect fatigue, and what can be done to counteract fatigue and maximize alertness and performance in their operations. The overall purpose of this module is to promote aviation safety, performance, and productivity. It is intended to meet three specific objectives: (1) to explain the current state of knowledge about the physiological mechanisms underlying fatigue; (2) to demonstrate how this knowledge can be applied to improving flight crew sleep, performance, and alertness; and (3) to offer strategies for alertness management. Aviation Safety Reporting System (ASRS) and National Transportation Safety Board (NISH) reports are used throughout this module to demonstrate that fatigue is a safety issue in the regional operations community. The appendices at the end of this module include the ASRS reports used for the examples contained in this publication, brief introductions to sleep disorders and relaxation techniques, summaries of relevant NASA publications, and a list of general readings on sleep, sleep disorders, and circadian rhythms.

  16. [Transcription Factors in Developmental Genetics and the Evolution of Higher Plants].

    Science.gov (United States)

    Lutova, L A; Dodueva, I E; Lebedeva, M A; Tvorogova, V E

    2015-05-01

    Transcription factors play an essential role in controlling various developmental programs in plants, coordinating the action of any genetic network. Among the most important groups of plant transcription factors are the homeodomain-containing transcription factors, in particular, those belonging to the KNOX and WOX families, the functions of which are associated with regulation of the meristem activity, development of the aboveground and underground parts of plants, and control of embryogenesis. This review examines the role of KNOX and WOX transcription factors in various developmental programs, as well as in the evolutionary complication of the body plan in terrestrial plants.

  17. Rapid engineering of versatile molecular logic gates using heterologous genetic transcriptional modules.

    Science.gov (United States)

    Wang, Baojun; Buck, Martin

    2014-10-11

    We designed and constructed versatile modular genetic logic gates in bacterial cells. These function as digital logic 1-input Buffer gate, 2-input and 3-input AND gates with one inverted input and integrate multiple chemical input signals in customised logic manners. Such rapidly engineered devices serve to achieve increased sensing signal selectivity.

  18. Modulation of genetic associations with serum urate levels by body-mass-index in humans

    NARCIS (Netherlands)

    J.E. Huffman (Jennifer); E. Albrecht (Eva); A. Teumer (Alexander); M. Mangino (Massimo); K. Kapur (Karen); T. Johnson (Toby); Z. Kutalik (Zoltán); N. Pirastu (Nicola); G. Pistis (Giorgio); L.M. Lopez (Lorna); T. Haller (Toomas); P. Salo (Perttu); A. Goel (Anuj); M. Li (Man); T. Tanaka (Toshiko); A. Dehghan (Abbas); D. Ruggiero; G. Malerba (Giovanni); A.V. Smith (Albert Vernon); Nolte, I.M. (Ilja M.); L. Portas (Laura); Phipps-Green, A. (Amanda); Boteva, L. (Lora); P. Navarro (Pau); A. Johansson (Åsa); A.A. Hicks (Andrew); O. Polasek (Ozren); T. Esko (Tõnu); J. Peden (John); S.E. Harris (Sarah); D. Murgia (Daniela); Wild, S.H. (Sarah H.); A. Tenesa (Albert); A. Tin (Adrienne); E. Mihailov (Evelin); A. Grotevendt (Anne); G.K. Gislason; J. Coresh (Josef); P. d' Adamo (Pio); S. Ulivi (Shelia); P. Vollenweider (Peter); G. Waeber (Gérard); Campbell, S. (Susan); I. Kolcic (Ivana); Fisher, K. (Krista); M. Viigimaa (Margus); Metter, J.E. (Jeffrey E.); C. Masciullo (Corrado); Trabetti, E. (Elisabetta); Bombieri, C. (Cristina); R. Sorice; A. Döring (Angela); G. Reischl (Gunilla); K. Strauch (Konstantin); A. Hofman (Albert); A.G. Uitterlinden (André); M. Waldenberger (Melanie); H.E. Wichmann (Heinz Erich); G. Davies (Gail); A.J. Gow (Alan J.); Dalbeth, N. (Nicola); Stamp, L. (Lisa); Smit, J.H. (Johannes H.); M. Kirin (Mirna); R. Nagaraja (Ramaiah); M. Nauck (Matthias); C. Schurmann (Claudia); K. Budde (Klemens); S.M. Farrington (Susan); E. Theodoratou (Evropi); A. Jula (Antti); V. Salomaa (Veikko); C. Sala (Cinzia); C. Hengstenberg (Christian); M. Burnier (Michel); Mägi, R. (Reedik); N. Klopp (Norman); S. Kloiber (Stefan); S. Schipf (Sabine); S. Ripatti (Samuli); Cabras, S. (Stefano); N. Soranzo (Nicole); G. Homuth (Georg); T. Nutile; P. Munroe (Patricia); N. Hastie (Nick); H. Campbell (H.); I. Rudan (Igor); Cabrera, C. (Claudia); Haley, C. (Chris); O.H. Franco (Oscar); Merriman, T.R. (Tony R.); V. Gudnason (Vilmundur); M. Pirastu (Mario); B.W.J.H. Penninx (Brenda); H. Snieder (Harold); A. Metspalu (Andres); M. Ciullo; P.P. Pramstaller (Peter Paul); C.M. van Duijn (Cock); L. Ferrucci (Luigi); G. Gambaro (Giovanni); Deary, I.J. (Ian J.); M.G. Dunlop (Malcolm); J.F. Wilson (James F); P. Gasparini (Paolo); U. Gyllensten (Ulf); T.D. Spector (Timothy); A.F. Wright (Alan); C. Hayward (Caroline); H. Watkins (Hugh); M. Perola (Markus); M. Bochud (Murielle); W.H.L. Kao (Wen); M. Caulfield (Mark); D. Toniolo (Daniela); H. Völzke (Henry); C. Gieger (Christian); A. Köttgen (Anna); V. Vitart (Veronique)

    2015-01-01

    textabstractWe tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in

  19. Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

    NARCIS (Netherlands)

    Huffman, Jennifer E.; Albrecht, Eva; Teumer, Alexander; Mangino, Massimo; Kapur, Karen; Johnson, Toby; Kutalik, Zoltn; Pirastu, Nicola; Pistis, Giorgio; Lopez, Lorna M.; Haller, Toomas; Salo, Perttu; Goel, Anuj; Li, Man; Tanaka, Toshiko; Dehghan, Abbas; Ruggiero, Daniela; Malerba, Giovanni; Smith, Albert V.; Nolte, Ilja M.; Portas, Laura; Phipps-Green, Amanda; Boteva, Lora; Navarro, Pau; Johansson, Asa; Hicks, Andrew A.; Polasek, Ozren; Esko, Tonu; Peden, John F.; Harris, Sarah E.; Murgia, Federico; Wild, Sarah H.; Tenesa, Albert; Tin, Adrienne; Mihailov, Evelin; Grotevendt, Anne; Gislason, Gauti K.; Coresh, Josef; D'Adamo, Pio; Ulivi, Sheila; Vollenweider, Peter; Waeber, Gerard; Campbell, Susan; Kolcic, Ivana; Fisher, Krista; Viigimaa, Margus; Metter, Jeffrey E.; Masciullo, Corrado; Trabetti, Elisabetta; Bombieri, Cristina; Sorice, Rossella; Doering, Angela; Reischl, Eva; Strauch, Konstantin; Hofman, Albert; Uitterlinden, Andre G.; Waldenberger, Melanie; Wichmann, H-Erich; Davies, Gail; Gow, Alan J.; Dalbeth, Nicola; Stamp, Lisa; Smit, Johannes H.; Kirin, Mirna; Nagaraja, Ramaiah; Nauck, Matthias; Schurmann, Claudia; Budde, Kathrin; Farrington, Susan M.; Theodoratou, Evropi; Jula, Antti; Salomaa, Veikko; Sala, Cinzia; Hengstenberg, Christian; Burnier, Michel; Maegi, Reedik; Klopp, Norman; Kloiber, Stefan; Schipf, Sabine; Ripatti, Samuli; Cabras, Stefano; Soranzo, Nicole; Homuth, Georg; Nutile, Teresa; Munroe, Patricia B.; Hastie, Nicholas; Campbell, Harry; Rudan, Igor; Cabrera, Claudia; Haley, Chris; Franco, Oscar H.; Merriman, Tony R.; Gudnason, Vilmundur; Pirastu, Mario; Penninx, Brenda W.; Snieder, Harold; Metspalu, Andres; Ciullo, Marina; Pramstaller, Peter P.; van Duijn, Cornelia M.; Ferrucci, Luigi; Gambaro, Giovanni; Deary, Ian J.; Dunlop, Malcolm G.; Wilson, James F.; Gasparini, Paolo; Gyllensten, Ulf; Spector, Tim D.; Wright, Alan F.; Hayward, Caroline; Watkins, Hugh; Perola, Markus; Bochud, Murielle; Kao, W. H. Linda; Caulfield, Mark; Toniolo, Daniela; Voelzke, Henry; Gieger, Christian; Koettgen, Anna; Vitart, Veronique

    2015-01-01

    We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-s

  20. Genetic and Environmental Risk Factors for Childhood Eczema Development and Allergic Sensitization in the CCAAPS Cohort

    OpenAIRE

    Myers, Jocelyn M. Biagini; Wang, Ning; LeMasters, Grace; Bernstein, David I; Epstein, Tolly; Lindsey, Mark; Ericksen, Mark; Chakraborty, Ranajit; Ryan, Patrick; Villareal, Manuel; Burkle, Jeff; Lockey, James; Reponen, Tiina; Hershey, Gurjit K Khurana

    2009-01-01

    Eczema is very common and increasing in prevalence. Prospective studies investigating environmental and genetic risk factors for eczema in a birth cohort are lacking. We evaluated risk factors that may promote development of childhood eczema in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort (n = 762) of infants with at least one atopic parent. Objective environmental exposure data were available for each participant. At annual physical examinations, children un...

  1. Genetic factors in human reproduction : a trade off between procreation and longevity

    NARCIS (Netherlands)

    Dunné, Frédérique Margo van

    2006-01-01

    Genetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human reproduction. It is argued that an innate cytokine profile supportive of Th1-type T cells favors survival of infec

  2. Breed effect and non-genetic factors affecting growth performance of ...

    African Journals Online (AJOL)

    SARAH

    2013-07-30

    Jul 30, 2013 ... Breed effect and non-genetic factors of growth performance of sheep. 5302. Breed effect and .... consisting of 25% cottonseed cake and 75% maize. The General Liner Model ..... and environmental changes have effect on the quality and quantity of pasture forages, which also affect the provision of food and ...

  3. Spina bifida and genetic factors related to myo-inositol, glucose, and zinc.

    NARCIS (Netherlands)

    Groenen, P.; Klootwijk, E.D.; Schijvenaars, M.M.V.A.P.; Straatman, H.M.P.M.; Mariman, E.C.M.; Franke, B.; Steegers-Theunissen, R.P.M.

    2004-01-01

    BACKGROUND: Myo-inositol, glucose and zinc and related genetic factors are suggested to be implicated in the etiology of spina bifida. We investigated the biochemical concentrations of these nutrients and polymorphisms in the myo-inositol transporter SLC5A11, myo-inositol synthase ISYNA1, and zinc

  4. Parenting Moderates a Genetic Vulnerability Factor in Longitudinal Increases in Youths' Substance Use

    Science.gov (United States)

    Brody, Gene H.; Beach, Steven R. H.; Philibert, Robert A.; Chen, Yi-fu; Lei, Man-Kit; Murry, Velma McBride; Brown, Anita C.

    2009-01-01

    The authors used a longitudinal, prospective design to investigate a moderation effect in the association between a genetic vulnerability factor, a variable nucleotide repeat polymorphism in the promoter region of "5HTT" (5-HTTLPR), and increases in youths' substance use. The primary study hypothesis predicted that involved-supportive parenting…

  5. Genetic and environmental influences on cardiovascular risk factors and cognitive function

    DEFF Research Database (Denmark)

    Xu, Chunsheng; Tian, Xiaocao; Sun, Jianping

    2017-01-01

    AIM: To explore the genetic and environmental influences on cardiovascular risk factors (CVRF) and cognitive function in the world's largest and rapidly aging Chinese population. METHODS: Cognitive function and CVRF, including body mass index, systolic blood pressure, diastolic blood pressure, pu...

  6. The bipolar puzzle, adding new pieces. Factors associated with bipolar disorder, Genetic and environmental influences

    NARCIS (Netherlands)

    van der Schot, A.C.

    2009-01-01

    The focus of this thesis is twofold. The first part will discuss the structural brain abnormalities and schoolperformance associated with bipolar disorder and the influence of genetic and/or environmental factors to this association. It is part of a large twin study investigating several potential b

  7. Novel genetic risk factors for venous thrombosis; a haplotype-based candidate gene approach

    NARCIS (Netherlands)

    Uitte de Willige, Shirley

    2007-01-01

    Venous thrombosis (VT) is a common disease, which occurs mostly in the deep veins of the leg. VT clusters within families and is a multicausal disease, in which both genetic and environmental factors interact in the onset of the disease. The aim of the study described in this thesis was to find new

  8. Genetic factors influence the clustering of depression among individuals with lower socioeconomic status

    NARCIS (Netherlands)

    S. López León (Sandra); W.C. Choy (Wing Chi); Y.S. Aulchenko (Yurii); S. Claes (Stephan); B.A. Oostra (Ben); J.P. Mackenbach (Johan); C.M. van Duijn (Cock); A.C.J.W. Janssens (Cécile)

    2009-01-01

    textabstractObjective: To investigate the extent to which shared genetic factors can explain the clustering of depression among individuals with lower socioeconomic status, and to examine if neuroticism or intelligence are involved in these pathways. Methods: In total 2,383 participants (1,028 men a

  9. Genetic, behavioral, and sociodemographic risk factors for second eye progression in age-related macular degeneration

    NARCIS (Netherlands)

    Lechanteur, Y.T.; Ven, J.P. van de; Smailhodzic, D.; Boon, C.J.F.; Klevering, B.J.; Fauser, S.; Groenewoud, J.M.; Wilt, G.J. van der; Hollander, A.I. den; Hoyng, C.B.

    2012-01-01

    PURPOSE: This study was conducted to investigate the correlation of genetic, sociodemographic, and behavioral risk factors with second eye progression to end-stage AMD. METHODS: One hundred and eight patients with end-stage AMD in one or both eyes were included in a retrospective time-to-event analy

  10. Estimating interaction between genetic and environmental risk factors efficiency of sampling designs within a cohort

    Science.gov (United States)

    Large prospective cohorts originally assembled to study environmental risk factors are increasingly exploited to study gene-environment interactions. Given the cost of genetic studies in large numbers of subjects, being able to select a sub-sample for genotyping that contains most of the information...

  11. Non-genetic factors influencing early growth traits in the Elsenburg ...

    African Journals Online (AJOL)

    investigate non-genetic factors contributing to early growth traits. The fixed effects ... as age, sex, birth status (type of birth) and age of dam have been well ..... Mutton Sheep Performance and Progeny Testing Scheme for kind permission to use ...

  12. Homocysteine related Nutritional and Genetic Risk Factors for Human Congenital Heart Defects

    NARCIS (Netherlands)

    A.C. Verkleij-Hagoort (Anna)

    2007-01-01

    textabstractCongenital heart defects (CHDs) belong to the most common group of major congenital malformations in newborns. Most CHDs are considered complex diseases with a multifactorial aetiology, which are thought to result from interactions between genetic and environmental factors. This thesis p

  13. Genetic, environmental and cultural factors influencing the resistance to septoria tritici blotch (Mycosphaerella graminicola) in wheat

    NARCIS (Netherlands)

    Simón, M.R.

    2003-01-01

    KeyWord:Genetic, environmental and cultural factors influencing the resistance to septoria tritici blotch (Mycosphaerella

  14. Importance of genetic factors in the etiology of atopic dermatitis: a twin study

    DEFF Research Database (Denmark)

    Thomsen, Simon F; Ulrik, Charlotte S; Kyvik, Kirsten O;

    2007-01-01

    ?" Latent factor models of genetic and environmental influences were fitted to the observed data using maximum likelihood methods. The overall lifetime prevalence of atopic dermatitis was 7.3%. A cotwin of an affected identical twin had a sevenfold increased risk of atopic dermatitis compared...

  15. Genetic and Environmental Factors That Impact Gestation Length in Dairy Cattle

    Science.gov (United States)

    Genetic and environmental factors that might affect gestation length (GL) were investigated. Data from over 9 million parturitions from 1999 through 2006 for 7 dairy breeds were assembled from lactation, reproduction, and dystocia records from across the United States. Effects examined were year of ...

  16. Genetic risk factors for venous thrombosis : key players or minor risk modifiers?

    NARCIS (Netherlands)

    Vossen, Carolina Yvonne

    2005-01-01

    Venous thrombosis is a common disease, which manifests itself mostly in the deep veins of the leg, with a reported incidence of 1-2 per 1000 individuals per year. Several genetic risk factors have been identified for venous thrombosis. It is, however, difficult to predict the risk of venous

  17. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci

    NARCIS (Netherlands)

    S. Reppe (Sjur); Y. Wang (Yunpeng); W.K. Thompson (Wesley K.); L.K. McEvoy (Linda K.); N.J. Schork (Nicholas); V. Zuber (Verena); M. Leblanc (Marissa); F. Bettella (Francesco); I.G. Mills (Ian G.); R.S. Desikan (Rahul S.); S. Djurovic (Srdjan); K.M. Gautvik (Kaare); A.M. Dale (Anders); O.A. Andreassen (Ole A.); K. Estrada Gil (Karol); U. Styrkarsdottir (Unnur); E. Evangelou (Evangelos); Y.-H. Hsu (Yi-Hsiang); E.L. Duncan (Emma); E.E. Ntzani (Evangelia); L. Oei (Ling); O.M.E. Albagha (Omar M.); N. Amin (Najaf); J.P. Kemp (John); D.L. Koller (Daniel); G. Li (Guo); C.-T. Liu (Ching-Ti); R.L. Minster (Ryan); A. Moayyeri (Alireza); L. Vandenput (Liesbeth); D. Willner (Dana); S.-M. Xiao (Su-Mei); L.M. Yerges-Armstrong (Laura); H.-F. Zheng (Hou-Feng); N. Alonso (Nerea); J. Eriksson (Joel); C.M. Kammerer (Candace); S. Kaptoge (Stephen); P.J. Leo (Paul); G. Thorleifsson (Gudmar); S.G. Wilson (Scott); J.F. Wilson (James F); V. Aalto (Ville); M. Alen (Markku); A.K. Aragaki (Aaron); T. Aspelund (Thor); J.R. Center (Jacqueline); Z. Dailiana (Zoe); C. Duggan; M. Garcia (Melissa); N. Garcia-Giralt (Natàlia); S. Giroux (Sylvie); G. Hallmans (Göran); L.J. Hocking (Lynne); L.B. Husted (Lise Bjerre); K. Jameson (Karen); R. Khusainova (Rita); G.S. Kim (Ghi Su); C. Kooperberg (Charles); T. Koromila (Theodora); M. Kruk (Marcin); M. Laaksonen (Marika); A.Z. Lacroix (Andrea Z.); S.H. Lee (Seung Hun); P.C. Leung (Ping C.); J.R. Lewis (Joshua); L. Masi (Laura); S. Mencej-Bedrac (Simona); T.V. Nguyen (Tuan); X. Nogues (Xavier); M.S. Patel (Millan); J. Prezelj (Janez); L.M. Rose (Lynda); S. Scollen (Serena); K. Siggeirsdottir (Kristin); G.D. Smith; O. Svensson (Olle); S. Trompet (Stella); O. Trummer (Olivia); N.M. van Schoor (Natasja); J. Woo (Jean); K. Zhu (Kun); S. Balcells (Susana); M.L. Brandi; B.M. Buckley (Brendan M.); S. Cheng (Sulin); C. Christiansen; C. Cooper (Charles); G.V. Dedoussis (George); I. Ford (Ian); M. Frost (Morten); D. Goltzman (David); J. González-Macías (Jesús); M. Kähönen (Mika); M. Karlsson (Magnus); E.K. Khusnutdinova (Elza); J.-M. Koh (Jung-Min); P. Kollia (Panagoula); B.L. Langdahl (Bente); W.D. Leslie (William D.); P. Lips (Paul); O. Ljunggren (Östen); R. Lorenc (Roman); J. Marc (Janja); D. Mellström (Dan); B. Obermayer-Pietsch (Barbara); D. Olmos (David); U. Pettersson-Kymmer (Ulrika); D.M. Reid (David); J.A. Riancho (José); P.M. Ridker (Paul); M.F. Rousseau (Francois); P.E. Slagboom (Eline); N.L.S. Tang (Nelson L.S.); R. Urreizti (Roser); W. Van Hul (Wim); J. Viikari (Jorma); M.T. Zarrabeitia (María); Y.S. Aulchenko (Yurii); M.C. Castaño Betancourt (Martha); E. Grundberg (Elin); L. Herrera (Lizbeth); T. Ingvarsson (Torvaldur); H. Johannsdottir (Hrefna); T. Kwan (Tony); R. Li (Rui); R.N. Luben (Robert); M.C. Medina-Gomez (Carolina); S.T. Palsson (Stefan Th); J.I. Rotter (Jerome I.); G. Sigurdsson (Gunnar); J.B.J. van Meurs (Joyce); D.J. Verlaan (Dominique); F.M. Williams (Frances); A.R. Wood (Andrew); Y. Zhou (Yanhua); T. Pastinen (Tomi); S. Raychaudhuri (Soumya); J.A. Cauley (Jane); D.I. Chasman (Daniel); G.R. Clark (Graeme); S.R. Cummings (Steven R.); P. Danoy (Patrick); E.M. Dennison (Elaine); R. Eastell (Richard); J.A. Eisman (John); V. Gudnason (Vilmundur); A. Hofman (Albert); R.D. Jackson (Rebecca); G. Jones (Graeme); J.W. Jukema (Jan Wouter); K.T. Khaw; T. Lehtimäki (Terho); Y. Liu (Yongmei); M. Lorentzon (Mattias); E. McCloskey (Eugene); B.D. Mitchell (Braxton); K. Nandakumar (Kannabiran); G.C. Nicholson (Geoffrey); B.A. Oostra (Ben); M. Peacock (Munro); H.A.P. Pols (Huibert A. P.); R.L. Prince (Richard); O. Raitakari (Olli); I.R. Reid (Ian); J. Robbins (John); P.N. Sambrook (Philip); P.C. Sham (Pak Chung); A.R. Shuldiner (Alan); F.A. Tylavsky (Frances); C.M. van Duijn (Cock); N.J. Wareham (Nicholas J.); L.A. Cupples (Adrienne); M.J. Econs (Michael); D.M. Evans (David); T.B. Harris (Tamara B.); A.W.C. Kung (Annie Wai Chee); B.M. Psaty (Bruce); J. Reeve (Jonathan); T.D. Spector (Timothy); E.A. Streeten (Elizabeth); M.C. Zillikens (Carola); U. Thorsteinsdottir (Unnur); C. Ohlsson (Claes); D. Karasik (David); J.B. Richards (J. Brent); M.A. Brown (Matthew); J-A. Zwart (John-Anker); A.G. Uitterlinden (André); S.H. Ralston (Stuart); J.P.A. Ioannidis (John P.A.); D.P. Kiel (Douglas P.); F. Rivadeneira Ramirez (Fernando)

    2015-01-01

    textabstractBone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. W

  18. Genetic, environmental and cultural factors influencing the resistance to septoria tritici blotch (Mycosphaerella graminicola) in wheat

    NARCIS (Netherlands)

    Simón, M.R.

    2003-01-01

    KeyWord:Genetic, environmental and cultural factors influencing the resistance to septoria tritici blotch (Mycosphaerella

  19. Parenting Moderates a Genetic Vulnerability Factor in Longitudinal Increases in Youths' Substance Use

    Science.gov (United States)

    Brody, Gene H.; Beach, Steven R. H.; Philibert, Robert A.; Chen, Yi-fu; Lei, Man-Kit; Murry, Velma McBride; Brown, Anita C.

    2009-01-01

    The authors used a longitudinal, prospective design to investigate a moderation effect in the association between a genetic vulnerability factor, a variable nucleotide repeat polymorphism in the promoter region of "5HTT" (5-HTTLPR), and increases in youths' substance use. The primary study hypothesis predicted that involved-supportive…

  20. Genetics University of Toronto Thrombophilia Study in Women (GUTTSI: genetic and other risk factors for venous thromboembolism in women

    Directory of Open Access Journals (Sweden)

    Evrovski Jovan

    2001-05-01

    Full Text Available Abstract Background Women may be at increased risk for venous thromboembolism (VTE as compared with men. We studied the effects of genetic and biochemical markers of thrombophilia in women, in conjunction with other established risk factors for VTE. Method The present retrospective case-control study was conducted in a thrombosis treatment programme at a large Toronto hospital. The cases were 129 women aged 16-79 years with objectively confirmed VTE. Age-matched control individuals were women who were free of venous thrombosis. Neither cases nor control individuals had known cardiovascular disease. Participants were interviewed regarding personal risk factors for VTE, including smoking, history of malignancy, pregnancy, and oestrogen or oral contraceptive use. Blood specimens were analyzed for common single nucleotide polymorphisms of prothrombin, factor V and methylenetetrahydrofolate reductase (MTHFR; C677T, A1298C and T1317C, and the A66G polymorphism for methionine synthase reductase (MTRR.Fasting plasma homocysteine was also analyzed. Results Women with VTE were significantly more likely than female control individuals to carry the prothrombin polymorphism and the factor V polymorphism, or to have fasting hyperhomocysteinaemia. Homozygosity for the C677T MTHFR gene was not a significant risk factor for VTE, or were the A1298C or T1317C MTHFR homozygous variants. Also, the A66G MTRR homozygous state did not confer an increased risk for VTE. Conclusion Prothrombin and factor V polymorphisms increased the risk for VTE in women, independent from other established risk factors. Although hyperhomocysteinaemia also heightens this risk, common polymorphisms in two genes that are responsible for homocysteine remethylation do not. These findings are consistent with previous studies that included both men and women.

  1. Factors influencing and modifying the decision to pursue genetic testing for skin cancer risk.

    Science.gov (United States)

    Fogel, Alexander L; Jaju, Prajakta D; Li, Shufeng; Halpern-Felsher, Bonnie; Tang, Jean Y; Sarin, Kavita Y

    2017-05-01

    Across cancers, the decision to pursue genetic testing is influenced more by subjective than objective factors. However, skin cancer, which is more prevalent, visual, and multifactorial than many other malignancies, may offer different motivations for pursuing such testing. The primary objective was to determine factors influencing the decision to receive genetic testing for skin cancer risk. A secondary objective was to assess the impact of priming with health questions on the decision to receive testing. We distributed anonymous online surveys through ResearchMatch.org to assess participant health, demographics, motivations, and interest in pursuing genetic testing for skin cancer risk. Two surveys with identical questions but different question ordering were used to assess the secondary objective. We received 3783 responses (64% response rate), and 85.8% desired testing. Subjective factors, including curiosity, perceptions of skin cancer, and anxiety, were the most statistically significant determinants of the decision to pursue testing (P skin cancer (odds ratio 0.5, P = .01). Age and family history of skin cancer did not influence this decision. Participants increasingly chose testing if first queried about health behaviors (P skin cancer is primarily determined by subjective factors, such as anxiety and curiosity. Health factors, including skin cancer history, also influenced decision-making. Priming with consideration of objective health factors can increase the desire to pursue testing. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  2. Environmental Factors Shape the Community of Symbionts in the Hoopoe Uropygial Gland More than Genetic Factors

    OpenAIRE

    Ruiz-Rodríguez, Magdalena; Soler, Juan J.; Martín-Vivaldi, Manuel; Martín-Platero, Antonio M.; Méndez, María; Peralta-Sánchez, Juan M.; Ananou, Samir; Valdivia, Eva; Martínez-Bueno, Manuel

    2014-01-01

    Exploring processes of coevolution of microorganisms and their hosts is a new imperative for life sciences. If bacteria protect hosts against pathogens, mechanisms facilitating the intergenerational transmission of such bacteria will be strongly selected by evolution. By disentangling the diversity of bacterial strains from the uropygium of hoopoes (Upupa epops) due to genetic relatedness or to a common environment, we explored the importance of horizontal (from the environment) and vertical ...

  3. The five-factor model of personality and borderline personality disorder: a genetic analysis of comorbidity.

    Science.gov (United States)

    Distel, Marijn A; Trull, Timothy J; Willemsen, Gonneke; Vink, Jacqueline M; Derom, Catherine A; Lynskey, Michael; Martin, Nicholas G; Boomsma, Dorret I

    2009-12-15

    Recently, the nature of personality disorders and their relationship with normal personality traits has received extensive attention. The five-factor model (FFM) of personality, consisting of the personality traits neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness, is one of the proposed models to conceptualize personality disorders as maladaptive variants of continuously distributed personality traits. The present study examined the phenotypic and genetic association between borderline personality and FFM personality traits. Data were available for 4403 monozygotic twins, 4425 dizygotic twins, and 1661 siblings from 6140 Dutch, Belgian, and Australian families. Broad-sense heritability estimates for neuroticism, agreeableness, conscientiousness, extraversion, openness to experience, and borderline personality were 43%, 36%, 43%, 47%, 54%, and 45%, respectively. Phenotypic correlations between borderline personality and the FFM personality traits ranged from .06 for openness to experience to .68 for neuroticism. Multiple regression analyses showed that a combination of high neuroticism and low agreeableness best predicted borderline personality. Multivariate genetic analyses showed the genetic factors that influence individual differences in neuroticism, agreeableness, conscientiousness, and extraversion account for all genetic liability to borderline personality. Unique environmental effects on borderline personality, however, were not completely shared with those for the FFM traits (33% is unique to borderline personality). Borderline personality shares all genetic variation with neuroticism, agreeableness, conscientiousness, and extraversion. The unique environmental influences specific to borderline personality may cause individuals with a specific pattern of personality traits to cross a threshold and develop borderline personality.

  4. Hepatocyte growth factor/scatter factor modulates cell motility, proliferation, and proteoglycan synthesis of chondrocytes.

    Science.gov (United States)

    Takebayashi, T; Iwamoto, M; Jikko, A; Matsumura, T; Enomoto-Iwamoto, M; Myoukai, F; Koyama, E; Yamaai, T; Matsumoto, K; Nakamura, T

    1995-06-01

    Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that promotes proliferation, motility, and morphogenesis in epithelial cells. Recently the HGF receptor, c-met protooncogene product, has been shown to be expressed in developing limb buds (Sonnenberg, E., D. Meyer, M. Weidner, and C. Birchmeiyer, 1993. J. Cell Biol. 123: 223-235), suggesting that some populations of mesenchymal cells in limb buds respond to HGF/SF. To test the possibility that HGF/SF is involved in regulation of cartilage development, we isolated chondrocytes from knee joints and costal cartilages of 23-d embryonic and 4-wk-old rabbits, and analyzed the effects of HGF/SF on migration and proliferation of these cells. We found that HGF/SF stimulated migration of cultured articular chondrocytes but did not scatter limb mesenchymal fibroblasts or synovial fibroblasts in culture. HGF/SF also stimulated proliferation of chondrocytes; a maximum three-fold stimulation in DNA synthesis was observed at the concentration of 3 ng/ml of HGF/SF. Moreover, HGF/SF had the ability to enhance proteoglycan synthesis in chondrocytes. The responsiveness of chondrocytes to HGF/SF was also supported by the observation that they expressed the HGF/SF receptor. Addition of the neutralizing antibody to rat HGF/SF affected neither DNA synthesis nor proteoglycan synthesis in rat chondrocytes, suggesting a paracine mechanism of action of HGF/SF on these cells. In situ hybridization analysis showed that HGF/SF mRNA was restrictively expressed in the areas of future joint regions in developing limb buds and in the intercostal spaces of developing costal cartilages. These findings suggest that HGF/SF plays important roles in cartilage development through its multiple activities.

  5. Hepatocyte growth factor/scatter factor modulates cell motility, proliferation, and proteoglycan synthesis of chondrocytes

    Science.gov (United States)

    1995-01-01

    Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that promotes proliferation, motility, and morphogenesis in epithelial cells. Recently the HGF receptor, c-met protooncogene product, has been shown to be expressed in developing limb buds (Sonnenberg, E., D. Meyer, M. Weidner, and C. Birchmeiyer, 1993. J. Cell Biol. 123: 223-235), suggesting that some populations of mesenchymal cells in limb buds respond to HGF/SF. To test the possibility that HGF/SF is involved in regulation of cartilage development, we isolated chondrocytes from knee joints and costal cartilages of 23-d embryonic and 4-wk-old rabbits, and analyzed the effects of HGF/SF on migration and proliferation of these cells. We found that HGF/SF stimulated migration of cultured articular chondrocytes but did not scatter limb mesenchymal fibroblasts or synovial fibroblasts in culture. HGF/SF also stimulated proliferation of chondrocytes; a maximum three-fold stimulation in DNA synthesis was observed at the concentration of 3 ng/ml of HGF/SF. Moreover, HGF/SF had the ability to enhance proteoglycan synthesis in chondrocytes. The responsiveness of chondrocytes to HGF/SF was also supported by the observation that they expressed the HGF/SF receptor. Addition of the neutralizing antibody to rat HGF/SF affected neither DNA synthesis nor proteoglycan synthesis in rat chondrocytes, suggesting a paracine mechanism of action of HGF/SF on these cells. In situ hybridization analysis showed that HGF/SF mRNA was restrictively expressed in the areas of future joint regions in developing limb buds and in the intercostal spaces of developing costal cartilages. These findings suggest that HGF/SF plays important roles in cartilage development through its multiple activities. PMID:7775584

  6. ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition

    Science.gov (United States)

    Wang, Belinda; Krall, Elsa Beyer; Aguirre, Andrew James; Kim, Miju; Widlund, Hans Ragnar; Doshi, Mihir Bhavik; Sicinska, Ewa; Sulahian, Rita; Goodale, Amy; Cowley, Glenn Spencer; Piccioni, Federica; Doench, John Gerard; Root, David Edward; Hahn, William Chun

    2017-01-01

    SUMMARY Intrinsic resistance and RTK-RAS-MAPK pathway reactivation has limited the effectiveness of MEK and RAF inhibitors (MAPKi) in RAS- and RAF-mutant cancers. To identify genes that modulate sensitivity to MAPKi, we performed genome scale CRISPR-Cas9 loss-of-function screens in two KRAS-mutant pancreatic cancer cell lines treated with the MEK1/2 inhibitor trametinib. Loss of CIC, a transcriptional repressor of ETV1, 4, and 5, promoted survival in the setting of MAPKi in cancer cells derived from several lineages. ATXN1L deletion, which reduces CIC protein, or ectopic expression of ETV1, 4, or 5 also modulated sensitivity to trametinib. ATXN1L expression inversely correlates with response to MAPKi inhibition in clinical studies. These observations identify the ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPKi. PMID:28178529

  7. Genetic networks controlled by the bacterial replication initiator and transcription factor DnaA in Bacillus subtilis.

    Science.gov (United States)

    Washington, Tracy A; Smith, Janet L; Grossman, Alan D

    2017-10-01

    DnaA is the widely conserved bacterial AAA+ ATPase that functions as both the replication initiator and a transcription factor. In many organisms, DnaA controls expression of its own gene and likely several others during growth and in response to replication stress. To evaluate the effects of DnaA on gene expression, separate from its role in replication initiation, we analyzed changes in mRNA levels in Bacillus subtilis cells with and without dnaA, using engineered strains in which dnaA is not essential. We found that dnaA was required for many of the changes in gene expression in response to replication stress. We also found that dnaA indirectly affected expression of several regulons during growth, including those controlled by the transcription factors Spo0A, AbrB, PhoP, SinR, RemA, Rok and YvrH. These effects were largely mediated by the effects of DnaA on expression of sda. DnaA activates transcription of sda, and Sda inhibits histidine protein kinases required for activation of the transcription factor Spo0A. We also found that loss of dnaA caused a decrease in the development of genetic competence. Together, our results indicate that DnaA plays an important role in modulating cell physiology, separate from its role in replication initiation. © 2017 John Wiley & Sons Ltd.

  8. Environmental factors as modulators of neurodegeneration: insights from gene-environment interactions in Huntington's disease.

    Science.gov (United States)

    Mo, Christina; Hannan, Anthony J; Renoir, Thibault

    2015-05-01

    Unlike many other neurodegenerative diseases with established gene-environment interactions, Huntington's disease (HD) is viewed as a disorder governed by genetics. The cause of the disease is a highly penetrant tandem repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. In the year 2000, a pioneering study showed that the disease could be delayed in transgenic mice by enriched housing conditions. This review describes subsequent human and preclinical studies identifying environmental modulation of motor, cognitive, affective and other symptoms found in HD. Alongside the behavioral observations we also discuss potential mechanisms and the relevance to other neurodegenerative disorders, including Alzheimer's and Parkinson's disease. In mouse models of HD, increased sensorimotor and cognitive stimulation can delay or ameliorate various endophenotypes. Potential mechanisms include increased trophic support, synaptic plasticity, adult neurogenesis, and other forms of experience-dependent cellular plasticity. Subsequent clinical investigations support a role for lifetime activity levels in modulating the onset and progression of HD. Stress can accelerate memory and olfactory deficits and exacerbate cellular dysfunctions in HD mice. In the absence of effective treatments to slow the course of HD, environmental interventions offer feasible approaches to delay the disease, however further preclinical and human studies are needed in order to generate clinical recommendations. Environmental interventions could be combined with future pharmacological therapies and stimulate the identification of enviromimetics, drugs which mimic or enhance the beneficial effects of cognitive stimulation and physical activity.

  9. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians

    Directory of Open Access Journals (Sweden)

    Utama Andi

    2011-06-01

    Full Text Available Abstract Background CYP2C9 and VKORC1 are two major genetic factors associated with inter-individual variability in warfarin dose. Additionally, genes in the warfarin metabolism pathway have also been associated with dose variance. We analyzed Single Nucleotide Polymorphisms (SNPs in these genes to identify genetic factors that might confer warfarin sensitivity in Indonesian patients. Methods Direct sequencing method was used to identify SNPs in CYP2C9, VKORC1, CYP4F2, EPHX1, PROC and GGCX genes in warfarin-treated patients. Multiple linear regressions were performed to model the relationship warfarin daily dose requirement with genetic and non-genetic variables measured and used to develop a novel algorithm for warfarin dosing. Results From the 40 SNPs analyzed, CYP2C9 rs17847036 and VKORC1 rs9923231 showed significant association with warfarin sensitivity. In our study population, no significant correlation could be detected between CYP2C9*3, CYP2C9C-65 (rs9332127, CYP4F2 rs2108622, GGCX rs12714145, EPHX1 rs4653436 and PROC rs1799809 with warfarin sensitivity. Conclusions VKORC1 rs9923231 AA and CYP2C9 rs17847036 GG genotypes were associated with low dosage requirements of most patients (2.05 ± 0.77 mg/day and 2.09 ± 0.70 mg/day, respectively. CYP2C9 and VKORC1 genetic variants as well as non-genetic factors such as age, body weight and body height account for 15.4% of variance in warfarin dose among our study population. Additional analysis of this combination could allow for personalized warfarin treatment in ethnic Indonesians.

  10. Demographic Histories, Isolation and Social Factors as Determinants of the Genetic Structure of Alpine Linguistic Groups

    Science.gov (United States)

    Coia, Valentina; Capocasa, Marco; Anagnostou, Paolo; Pascali, Vincenzo; Scarnicci, Francesca; Boschi, Ilaria; Battaggia, Cinzia; Crivellaro, Federica; Ferri, Gianmarco; Alù, Milena; Brisighelli, Francesca; Busby, George B. J.; Capelli, Cristian; Maixner, Frank; Cipollini, Giovanna; Viazzo, Pier Paolo; Zink, Albert; Destro Bisol, Giovanni

    2013-01-01

    Great European mountain ranges have acted as barriers to gene flow for resident populations since prehistory and have offered a place for the settlement of small, and sometimes culturally diverse, communities. Therefore, the human groups that have settled in these areas are worth exploring as an important potential source of diversity in the genetic structure of European populations. In this study, we present new high resolution data concerning Y chromosomal variation in three distinct Alpine ethno-linguistic groups, Italian, Ladin and German. Combining unpublished and literature data on Y chromosome and mitochondrial variation, we were able to detect different genetic patterns. In fact, within and among population diversity values observed vary across linguistic groups, with German and Italian speakers at the two extremes, and seem to reflect their different demographic histories. Using simulations we inferred that the joint effect of continued genetic isolation and reduced founding group size may explain the apportionment of genetic diversity observed in all groups. Extending the analysis to other continental populations, we observed that the genetic differentiation of Ladins and German speakers from Europeans is comparable or even greater to that observed for well known outliers like Sardinian and Basques. Finally, we found that in south Tyroleans, the social practice of Geschlossener Hof, a hereditary norm which might have favored male dispersal, coincides with a significant intra-group diversity for mtDNA but not for Y chromosome, a genetic pattern which is opposite to those expected among patrilocal populations. Together with previous evidence regarding the possible effects of “local ethnicity” on the genetic structure of German speakers that have settled in the eastern Italian Alps, this finding suggests that taking socio-cultural factors into account together with geographical variables and linguistic diversity may help unveil some yet to be understood

  11. Demographic histories, isolation and social factors as determinants of the genetic structure of Alpine linguistic groups.

    Science.gov (United States)

    Coia, Valentina; Capocasa, Marco; Anagnostou, Paolo; Pascali, Vincenzo; Scarnicci, Francesca; Boschi, Ilaria; Battaggia, Cinzia; Crivellaro, Federica; Ferri, Gianmarco; Alù, Milena; Brisighelli, Francesca; Busby, George B J; Capelli, Cristian; Maixner, Frank; Cipollini, Giovanna; Viazzo, Pier Paolo; Zink, Albert; Destro Bisol, Giovanni

    2013-01-01

    Great European mountain ranges have acted as barriers to gene flow for resident populations since prehistory and have offered a place for the settlement of small, and sometimes culturally diverse, communities. Therefore, the human groups that have settled in these areas are worth exploring as an important potential source of diversity in the genetic structure of European populations. In this study, we present new high resolution data concerning Y chromosomal variation in three distinct Alpine ethno-linguistic groups, Italian, Ladin and German. Combining unpublished and literature data on Y chromosome and mitochondrial variation, we were able to detect different genetic patterns. In fact, within and among population diversity values observed vary across linguistic groups, with German and Italian speakers at the two extremes, and seem to reflect their different demographic histories. Using simulations we inferred that the joint effect of continued genetic isolation and reduced founding group size may explain the apportionment of genetic diversity observed in all groups. Extending the analysis to other continental populations, we observed that the genetic differentiation of Ladins and German speakers from Europeans is comparable or even greater to that observed for well known outliers like Sardinian and Basques. Finally, we found that in south Tyroleans, the social practice of Geschlossener Hof, a hereditary norm which might have favored male dispersal, coincides with a significant intra-group diversity for mtDNA but not for Y chromosome, a genetic pattern which is opposite to those expected among patrilocal populations. Together with previous evidence regarding the possible effects of "local ethnicity" on the genetic structure of German speakers that have settled in the eastern Italian Alps, this finding suggests that taking socio-cultural factors into account together with geographical variables and linguistic diversity may help unveil some yet to be understood

  12. Demographic histories, isolation and social factors as determinants of the genetic structure of Alpine linguistic groups.

    Directory of Open Access Journals (Sweden)

    Valentina Coia

    Full Text Available Great European mountain ranges have acted as barriers to gene flow for resident populations since prehistory and have offered a place for the settlement of small, and sometimes culturally diverse, communities. Therefore, the human groups that have settled in these areas are worth exploring as an important potential source of diversity in the genetic structure of European populations. In this study, we present new high resolution data concerning Y chromosomal variation in three distinct Alpine ethno-linguistic groups, Italian, Ladin and German. Combining unpublished and literature data on Y chromosome and mitochondrial variation, we were able to detect different genetic patterns. In fact, within and among population diversity values observed vary across linguistic groups, with German and Italian speakers at the two extremes, and seem to reflect their different demographic histories. Using simulations we inferred that the joint effect of continued genetic isolation and reduced founding group size may explain the apportionment of genetic diversity observed in all groups. Extending the analysis to other continental populations, we observed that the genetic differentiation of Ladins and German speakers from Europeans is comparable or even greater to that observed for well known outliers like Sardinian and Basques. Finally, we found that in south Tyroleans, the social practice of Geschlossener Hof, a hereditary norm which might have favored male dispersal, coincides with a significant intra-group diversity for mtDNA but not for Y chromosome, a genetic pattern which is opposite to those expected among patrilocal populations. Together with previous evidence regarding the possible effects of "local ethnicity" on the genetic structure of German speakers that have settled in the eastern Italian Alps, this finding suggests that taking socio-cultural factors into account together with geographical variables and linguistic diversity may help unveil some yet

  13. Sex-specific genetic diversity is shaped by cultural factors in Inner Asian human populations.

    Science.gov (United States)

    Marchi, Nina; Hegay, Tatyana; Mennecier, Philippe; Georges, Myriam; Laurent, Romain; Whitten, Mark; Endicott, Philipp; Aldashev, Almaz; Dorzhu, Choduraa; Nasyrova, Firuza; Chichlo, Boris; Ségurel, Laure; Heyer, Evelyne

    2017-04-01

    Sex-specific genetic structures have been previously documented worldwide in humans, even though causal factors have not always clearly been identified. In this study, we investigated the impact of ethnicity, geography and social organization on the sex-specific genetic structure in Inner Asia. Furthermore, we explored the process of ethnogenesis in multiple ethnic groups. We sampled DNA in Central and Northern Asia from 39 populations of Indo-Iranian and Turkic-Mongolic native speakers. We focused on genetic data of the Y chromosome and mitochondrial DNA. First, we compared the frequencies of haplogroups to South European and East Asian populations. Then, we investigated the genetic differentiation for eight Y-STRs and the HVS1 region, and tested for the effect of geography and ethnicity on such patterns. Finally, we reconstructed the male demographic history, inferred split times and effective population sizes of different ethnic groups. Based on the haplogroup data, we observed that the Indo-Iranian- and Turkic-Mongolic-speaking populations have distinct genetic backgrounds. However, each population showed consistent mtDNA and Y chromosome haplogroups patterns. As expected in patrilocal populations, we found that the Y-STRs were more structured than the HVS1. While ethnicity strongly influenced the genetic diversity on the Y chromosome, geography better explained that of the mtDNA. Furthermore, when looking at various ethnic groups, we systematically found a genetic split time older than historical records, suggesting a cultural rather than biological process of ethnogenesis. This study highlights that, in Inner Asia, specific cultural behaviors, especially patrilineality and patrilocality, leave a detectable signature on the sex-specific genetic structure. © 2017 Wiley Periodicals, Inc.

  14. Genetic control of ATGL-mediated lipolysis modulates adipose triglyceride stores in leptin-deficient mice.

    Science.gov (United States)

    Marcelin, Genevieve; Liu, Shun-Mei; Li, Xiaosong; Schwartz, Gary J; Chua, Streamson

    2012-05-01

    Dissecting the genetics of complex traits such as obesity allows the identification of causal genes for disease. Here, we show that the BALB/c mouse strain carries genetic variants that confer resistance to obesity induced by leptin-deficiency or a high-fat diet (HFD). We set out to identify the physiological and genetic bases underlying this phenotype. When compared with C57BL6/J ob/ob mice (B6), BALB/c ob/ob mice exhibited decreased food intake, increased thermogenic capacity, and improved fat catabolism, each of which can potentially modify obesity. Interestingly, analysis of F1 ob/ob (progeny of B6 ob/+ × BALB/c ob+) mice revealed that obesity resistance in BALB/c ob/ob mice principally relied upon improved fat mobilization. This was mechanistically explained by increased adipose triglyceride lipase (ATGL) content in adipocytes, along with increased lipolysis and fatty acid oxidation. We conducted a genome-wide scan and defined a quantitative trait locus (QTL) on chromosome 2. BALB/c alleles on chromosome 2 not only associated with the obesity resistance phenotype but also supported increased ATGL content in adipose tissue. In summary, our study provides evidence that leptin-independent control of adipocyte lipolysis rates directly modifies the balance of macronutrient handling and is sufficient to regulate fat mass in the absence of alterations in food intake and energy expenditure.-Marcelin, G., S-M. Liu, X. Li, G. J. Schwartz, and S. Chua.

  15. Genetic and epigenetic factors affecting meiosis induction in eukaryotes revealed in paramecium research.

    Science.gov (United States)

    Prajer, Małgorzata

    2008-01-01

    This review presents studies of the induction of meiosis undertaken on the ciliate Paramecium, a unicellular model eukaryotic organism. Meiosis in Paramecium, preceding the process of fertilization, appears in starved cells after passing a defined number of divisions (cell generations), starting from the last fertilization. Investigations were performed on clones of cells entering autogamy, a self-fertilization process. Genetic as well as epigenetic factors, i.e. endo- and exogenous factors, affecting the induction ofmeiosis and changing the duration of the interautogamous interval (IAI), were analyzed. The results show that: (1) Meiosis induction is controlled genetically by the somatic macronucleus. However, besides the nuclear factors, the cytoplasmic protein immaturin also affects this process (Haga & Hiwatashi 1981); (2) Epigenetic factors, such as non-genetically disturbed cytoskeleton structures and changes in the cell architecture observed in doublet Paramecium cells, exert internal mechanical stress (Ingber 2003), which constitutes the endogenous impulse accelerating meiosis; (3) Mild osmotic stress, acting as an exogenous factor, can initiate the specific MAP kinases signaling pathway resulting in earlier meiosis induction, as in other unicellular eukaryotes (Seet & Pawson 2004).

  16. Genetic parameters and factors influencing survival to 24 hrs after birth in Danish meat sheep breeds

    DEFF Research Database (Denmark)

    Maxa, J; Sharifi, A R; Pedersen, J;

    2009-01-01

    negative, which will make breeding for this trait more difficult. However, on the basis of estimated genetic parameters, it can be concluded that it is possible to improve survival to 24 h after birth in meat sheep breeds by accounting for both direct and maternal genetic effects in breeding programs......In this study, influential factors and (co)variance components for survival to 24 h after birth were determined and estimated for Texel, Shropshire, and Oxford Down, the most common sheep breeds in Denmark. Data from 1992 to 2006 containing 138,813 survival records were extracted from the sheep...

  17. Genetic and non-iodine-related factors in the aetiology of nodular goitre

    DEFF Research Database (Denmark)

    Knudsen, Nils; Brix, Thomas Heiberg

    2014-01-01

    Genetic and a large number of environmental non-iodine-related factors play a role in the cause of nodular goitre. Most evidence for the influence of genetic and environmental factors in the cause of goitre is from cross-sectional, population-based studies. Only a few studies have included...... prospective data on risk factors for nodular goitre, although few prospective data are available on the effect of iodine and tobacco smoking on goitre development. Goitre is not one single phenotype. Many epidemiological studies do not distinguish diffuse from nodular goitre, as the investigated parameter...... is often thyroid volume or frequency with increased thyroid volume. Moreover, information on the presence and effect of gene-environment, gene-gene, and environment-environment effect modifications is limited. Thus, firm conclusions about the relative contributions and causality of the investigated risk...

  18. Evaluation of Animal Genetic and Physiological Factors That Affect the Prevalence of Escherichia coli O157 in Cattle

    Science.gov (United States)

    Jeon, Soo Jin; Elzo, Mauricio; DiLorenzo, Nicolas; Lamb, G. Cliff; Jeong, Kwang Cheol

    2013-01-01

    Controlling the prevalence of Escherichia coli O157 in cattle at the pre-harvest level is critical to reduce outbreaks of this pathogen in humans. Multilayers of factors including the environmental and bacterial factors modulate the colonization and persistence of E. coli O157 in cattle that serve as a reservoir of this pathogen. Here, we report animal factors contributing to the prevalence of E. coli O157 in cattle. We observe the lowest number of E. coli O157 in Brahman breed when compared with other crosses in an Angus-Brahman multibreed herd, and bulls excrete more E. coli O157 than steers in the pens where cattle were housed together. The presence of super-shedders, cattle excreting >105 CFU/rectal anal swab, increases the concentration of E. coli O157 in the pens; thereby super-shedders enhance transmission of this pathogen among cattle. Molecular subtyping analysis reveal only one subtype of E. coli O157 in the multibreed herd, indicating the variance in the levels of E. coli O157 in cattle is influenced by animal factors. Furthermore, strain tracking after relocation of the cattle to a commercial feedlot reveals farm-to-farm transmission of E. coli O157, likely via super-shedders. Our results reveal high risk factors in the prevalence of E. coli O157 in cattle whereby animal genetic and physiological factors influence whether this pathogen can persist in cattle at high concentration, providing insights to intervene this pathogen at the pre-harvest level. PMID:23405204

  19. Genetic and non-iodine-related factors in the aetiology of nodular goitre.

    Science.gov (United States)

    Knudsen, Nils; Brix, Thomas Heiberg

    2014-08-01

    Genetic and a large number of environmental non-iodine-related factors play a role in the cause of nodular goitre. Most evidence for the influence of genetic and environmental factors in the cause of goitre is from cross-sectional, population-based studies. Only a few studies have included prospective data on risk factors for nodular goitre, although few prospective data are available on the effect of iodine and tobacco smoking on goitre development. Goitre is not one single phenotype. Many epidemiological studies do not distinguish diffuse from nodular goitre, as the investigated parameter is often thyroid volume or frequency with increased thyroid volume. Moreover, information on the presence and effect of gene-environment, gene-gene, and environment-environment effect modifications is limited. Thus, firm conclusions about the relative contributions and causality of the investigated risk factors should be made with caution. Smoking seems to be an established risk factor for nodular goitre, possibly with effect modification from iodine intake, as the risk associated with smoking is smaller or absent in areas with sufficient iodine intake. The use of oral contraceptives might have protective effects against goitre, and childbirth is an increased risk factor for goitre in areas with non-optimal iodine intake. Insulin resistance is a recently investigated risk factor, and the risk of goitre may be reversible with metformin treatment. Iodine remains the major environmental risk factor for nodular goitre.

  20. Association of genetic and psychological factors with persistent pain after cosmetic thoracic surgery

    Directory of Open Access Journals (Sweden)

    Dimova V

    2015-11-01

    no significant additional explanation could be gained by the genetic predictors. In contrast, the preoperative PVAQ score was also, in the present enlarged sample, a meaningful predictor for lasting pain disability after surgery. Effect size measures suggested some genetic variables, for example, the polymorphism rs1800587G>A in the interleukin 1 alpha gene (IL1A and the COMT haplotype rs4646312T>C/rs165722T>C/rs6269A>G/rs4633T>C/rs4818C>G/rs4680A>G, as possible relevant modulators of long-term postsurgical pain outcome. A comparison between pathophysiologically different predictor groups appears to be helpful in identifying clinically relevant predictors of chronic pain. Keywords: genetics, COMT, OPRM1, postoperative pain, PVAQ

  1. Effects of genetic and non-genetic factors on growth traits of high yielding dairy seed calves and genetic parameter estimates

    Directory of Open Access Journals (Sweden)

    Syed Mohammad Ashiqur Rahman

    2015-12-01

    Full Text Available The study was conducted to know the effects of several genetic and non-genetic factors like season, sex, year of birth, genotype of calves and milk yield of dam associated with growth performance of crossbred calves. Data were collected from registered farmers during the period of May, 2011 to April, 2013. Birth weight, three-month weight, six-month weight, weaning weight and heritability estimates of those growth performances were performed using a total of 82 registered calves which had pedigree information having the genotypes of 25% Local - 75% Friesian and 37.5% Local - 62.5% Friesian. The average birth, three-month, six-month and weaning weight of calves were 29.33, 64.32, 99.06 and 151.77 kg, respectively. The effects of non-genetic factors like sex, season of birth and genotype were non-significant (P>0.05 for the traits birth weight, three-month, six-month, weaning weight and average daily gain of calves. However, year of birth was found significant on birth (P0.05 on weaning weight and average daily gain of calves. The heritability estimates were 0.40±0.09, 0.46±0.08, 0.39±0.12 and 0.50±0.12 for the traits birth weight, three-month weight, six-month weight and weaning weight, respectively. Estimated heritabilities of live weights suggest that individual own performance basis selection would be more effective for increasing growth and therefore, should be paid more emphasis in cattle improvement program.

  2. Age and lactation specific disposal pattern in Sahiwal cattle and influence of various genetic and non-genetic factors

    Directory of Open Access Journals (Sweden)

    A. Upadhyay

    2014-10-01

    Full Text Available Premature disposal of female calves before reaching milch herd and undesirable disposal of lactating cows are the major constraints in achieving larger herd size. During the early lactations, younger cows are supposed to give higher milk yield and undesirable disposal of early calvers, thereby, greatly hampers profitability of a dairy farm. Knowledge of the incidence of disposal along with reasons in various age groups and at various parities is essential to identify which age group or parity is more vulnerable for disposal. Moreover, knowledge of various genetic and non-genetic factors associated with disposal of animals may also be helpful in developing breeding and management strategies to reduce the incidence of disposal. In most of the studies, it was found that major reasons of disposal of dairy cattle were mortality among female calves and involuntary culling among adult lactating cows. Maximum mortality in female calves was observed during earlier ages and pneumonia, gastro-enteritis and debility were major reasons of female calf mortality. Whereas, most of the adult cows left the herd, due to teat and udder and reproductive problems. Moreover, indigenous breeds were found to be more adapted to Indian tropical climatic conditions in comparison to crossbred and exotic cattle breeds.

  3. Genetic, psychosocial and clinical factors associated with hippocampal volume in the general population.

    Science.gov (United States)

    Janowitz, D; Schwahn, C; Borchardt, U; Wittfeld, K; Schulz, A; Barnow, S; Biffar, R; Hoffmann, W; Habes, M; Homuth, G; Nauck, M; Hegenscheid, K; Lotze, M; Völzke, H; Freyberger, H J; Debette, S; Grabe, H J

    2014-10-14

    The hippocampus--crucial for memory formation, recall and mood regulation--is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (Psmoking (P=0.0058), diastolic blood pressure (P=0.0211), rs7294919 (P=0.0065), rs17178006 (P=0.0002), rs6581612 (P=0.0036), rs6741949 (P=0.0112) and rs7852872 (P=0.0451). In addition, we found three significant interactions: between rs7294919 and smoking (P=0.0473), rs7294919 and diastolic blood pressure (P=0.0447) and between rs7852872 and rs6581612 (P=0.0114). We suggest that these factors might have a role in the individual susceptibility to hippocampus-associated disorders.

  4. Genetic susceptibility and environmental factors of esophageal cancer in Xi'an

    Institute of Scientific and Technical Information of China (English)

    An-Hui Wang; Chang-Sheng Sun; Liang-Shou Li; Jiu-Yi Huang; Qing-Shu Chen; De-Zhong Xu

    2004-01-01

    AIM: To analyse the role of genetic susceptibility and environmental factors in the process of esophageal cancer (EC) formation in Xi'an, China.METHODS: A hospital based case-control study, combined with molecular epidemiological method, was carried out. A total of 127 EC cases and 101 controls were interviewed with questionnaires containing demographic items, habit of tobacco smoking, alcohol drinking, and family history of EC.Polymorphism of CYP1A1 and GSTM1 of 127 EC cases and 101 controls were detected by PCR method. The interactions between genetic susceptibility and environmental factors were also discussed.RESULTS: Tobacco smoking, alcohol drinking and a family history of EC were risk factors for EC with an OR of 2.04(95% CI 1.15-3.60), 3.45(95% CI 1.74-6.91), 3.14 (95%CI 1.28-7.94), respectively. Individuals carrying CYP1A1 Val/Valgenotype compared to those with CYP1A1 Ile/Ile genotype had an increased risk for EC (OR 3.35, 95% CI 1.49-7.61). GSTM1 deletion genotype was a risk factor for EC (OR1.81, 95% CI 1.03-3.18). Gene-environment interaction analysis showed that CYP1A1 Val/Valgenotype, GSTM1 deletion genotype had synergetic interactions with tobacco smoking, alcohol drinking and family history of EC.CONCLUSION: Tobacco smoking, alcohol drinking and a family history of EC are risk factors for EC. CYP1A1 Val/'Va/and GSTM1 deletion genotypes are genetic susceptibility biomarkers for EC. There are synergic interactions between genetic susceptibility and environmental factors.

  5. Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

    DEFF Research Database (Denmark)

    Heintz, Caroline; Doktor, Thomas K; Lanjuin, Anne;

    2017-01-01

    via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also...... homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction...

  6. Behavioral phenotypes in schizophrenic animal models with multiple combinations of genetic and environmental factors.

    Science.gov (United States)

    Hida, Hirotake; Mouri, Akihiro; Noda, Yukihiro

    2013-01-01

    Schizophrenia is a multifactorial psychiatric disorder in which both genetic and environmental factors play a role. Genetic [e.g., Disrupted-in-schizophrenia 1 (DISC1), Neuregulin-1 (NRG1)] and environmental factors (e.g., maternal viral infection, obstetric complications, social stress) may act during the developmental period to increase the incidence of schizophrenia. In animal models, interactions between susceptibility genes and the environment can be controlled in ways not possible in humans; therefore, such models are useful for investigating interactions between or within factors in the pathogenesis and pathophysiology of schizophrenia. We provide an overview of schizophrenic animal models investigating interactions between or within factors. First, we reviewed gene-environment interaction animal models, in which schizophrenic candidate gene mutant mice were subjected to perinatal immune activation or adolescent stress. Next, environment-environment interaction animal models, in which mice were subjected to a combination of perinatal immune activation and adolescent administration of drugs, were described. These animal models showed interaction between or within factors; behavioral changes, which were obscured by each factor, were marked by interaction of factors and vice versa. Appropriate behavioral approaches with such models will be invaluable for translational research on novel compounds, and also for providing insight into the pathogenesis and pathophysiology of schizophrenia.

  7. Identification of small molecule and genetic modulators of AON-induced dystrophin exon skipping by high-throughput screening.

    Directory of Open Access Journals (Sweden)

    Debra A O'Leary

    Full Text Available One therapeutic approach to Duchenne Muscular Dystrophy (DMD recently entering clinical trials aims to convert DMD phenotypes to that of a milder disease variant, Becker Muscular Dystrophy (BMD, by employing antisense oligonucleotides (AONs targeting splice sites, to induce exon skipping and restore partial dystrophin function. In order to search for small molecule and genetic modulators of AON-dependent and independent exon skipping, we screened approximately 10,000 known small molecule drugs, >17,000 cDNA clones, and >2,000 kinase- targeted siRNAs against a 5.6 kb luciferase minigene construct, encompassing exon 71 to exon 73 of human dystrophin. As a result, we identified several enhancers of exon skipping, acting on both the reporter construct as well as endogenous dystrophin in mdx cells. Multiple mechanisms of action were identified, including histone deacetylase inhibition, tubulin modulation and pre-mRNA processing. Among others, the nucleolar protein NOL8 and staufen RNA binding protein homolog 2 (Stau2 were found to induce endogenous exon skipping in mdx cells in an AON-dependent fashion. An unexpected but recurrent theme observed in our screening efforts was the apparent link between the inhibition of cell cycle progression and the induction of exon skipping.

  8. The Factor Decomposition Theorem of Bounded Generalized Inverse Modules and Their Topological Continuity

    Institute of Scientific and Technical Information of China (English)

    Lun Chuan ZHANG

    2007-01-01

    In this paper we obtain a Douglas type factor decomposition theorem about certain important bounded module maps. Thus, we come to the discussion of the topological continuity of bounded generalized inverse module maps .Let be a topological space, x →T x : X→L (E)be a continuous map, and each R (x) be a closed submodule in E , for every fixed x ∈X . Then the map x →T+x : X→L (E) is continuous if and only if ||T+x||is locally bounded, where T+x is the bounded generalized inverse module map of T x. Furthermore, this is equivalent to the following statement:For each x 0 in X , there exists a neighborhood U 0 at x 0 and a positive number λ such that (0λ2)(C)∩x ∈U 0 C \\σ (T*x T x), where σ (T) denotes the spectrum of operator T .

  9. Factors associated with the modulation of pain by visual distortion of body size.

    Directory of Open Access Journals (Sweden)

    Michihiro eOsumi

    2014-03-01

    Full Text Available Modulation of pain using visual distortion of body size (VDBS has been the subject of various reports. However, the mechanism underlying the effect of VDBS on pain has been less often studied. In the present study, factors associated with modulation of pain threshold by VDBS were investigated. Visual feedback in the form of a magnified image of the hand was provided to 44 healthy adults to examine changes in pain. In participants with a higher pain threshold when visual feedback of a magnified image of the hand was provided, the two-point discrimination threshold decreased. In contrast, participants with a lower pain threshold with visual feedback of a magnified image of the hand experienced unpleasant emotions toward the magnified image of the hand. Interestingly, this emotional reaction was strongly associated with negative body consciousness in several subjects. These data suggested an analgesic effect of visual feedback in the form of a magnified image of the hand is only when tactile perception is vivid and the emotional reaction toward the magnified image is moderate. The results also suggested that negative body consciousness is important for the modulation of pain using VDBS.

  10. The functional tumor necrosis factor-α (308A/G) polymorphism modulates attentional selection in elderly individuals.

    Science.gov (United States)

    Gajewski, Patrick D; Hengstler, Jan G; Golka, Klaus; Falkenstein, Michael; Beste, Christian

    2013-11-01

    There has been increasing interest in understanding the role of inflammatory processes for cognitive functions in aging using molecular genetic approaches. Though this has mostly been evaluated in pathological aging, little is known about the relevance for cognitive functions in healthy aging in humans. On the basis of behavioral data and neurophysiological data (event-related potentials and time-frequency decomposition) we show that the A-allele of the functional tumor necrosis factor (TNF)-α -308 A/G polymorphism confers dysfunction in a number of cognitive processes: prolonged attentional selection indexed by a delayed P1/N1 complex, an increased P3a, which is interpreted as an enhanced distractibility by nonrelevant stimuli and compromised response selection mechanisms, as indexed by a reduced frontocentral N2. Time-frequency analyses show that allelic variations further exert their effects by modulating alpha and beta frequency oscillations. On a neurobiological level, these effects might be because of the interaction of TNF-α with glutamatergic neural transmission by which TNF-α is known to boost apoptotic mechanisms in elderly individuals.

  11. A pair of light signaling factors FHY3 and FAR1 regulates plant immunity by modulating chlorophyll biosynthesis.

    Science.gov (United States)

    Wang, Wanqing; Tang, Weijiang; Ma, Tingting; Niu, De; Jin, Jing Bo; Wang, Haiyang; Lin, Rongcheng

    2016-01-01

    Light and chloroplast function is known to affect the plant immune response; however, the underlying mechanism remains elusive. We previously demonstrated that two light signaling factors, FAR-RED ELONGATED HYPOCOTYL 3 (FHY3) and FAR-RED IMPAIRED RESPONSE 1 (FAR1), regulate chlorophyll biosynthesis and seedling growth via controlling HEMB1 expression in Arabidopsis thaliana. In this study, we reveal that FHY3 and FAR1 are involved in modulating plant immunity. We showed that the fhy3 far1 double null mutant displayed high levels of reactive oxygen species and salicylic acid (SA) and increased resistance to Pseudomonas syringae pathogen infection. Microarray analysis revealed that a large proportion of pathogen-related genes, particularly genes encoding nucleotide-binding and leucine-rich repeat domain resistant proteins, are highly induced in fhy3 far1. Genetic studies indicated that the defects of fhy3 far1 can be largely rescued by reducing SA signaling or blocking SA accumulation, and by overexpression of HEMB1, which encodes a 5-aminolevulinic acid dehydratase in the chlorophyll biosynthetic pathway. Furthermore, we found that transgenic plants with reduced expression of HEMB1 exhibit a phenotype similar to fhy3 far1. Taken together, this study demonstrates an important role of FHY3 and FAR1 in regulating plant immunity, through integrating chlorophyll biosynthesis and the SA signaling pathway.

  12. Does positive selection drive transcription factor binding site turnover? A test with Drosophila cis-regulatory modules.

    Directory of Open Access Journals (Sweden)

    Bin Z He

    2011-04-01

    Full Text Available Transcription factor binding site(s (TFBS gain and loss (i.e., turnover is a well-documented feature of cis-regulatory module (CRM evolution, yet little attention has been paid to the evolutionary force(s driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time.

  13. Aortic root dimensions are predominantly determined by genetic factors: a classical twin study

    Energy Technology Data Exchange (ETDEWEB)

    Celeng, Csilla; Kolossvary, Marton; Kovacs, Attila; Molnar, Andrea Agnes; Szilveszter, Balint; Karolyi, Mihaly; Jermendy, Adam L.; Karady, Julia; Merkely, Bela; Maurovich-Horvat, Pal [Semmelweis University, MTA-SE Cardiovascular Imaging Research Group, Heart and Vascular Center, Budapest (Hungary); Horvath, Tamas [Budapest University of Technology and Economics, Department of Hydrodynamic Systems, Budapest (Hungary); Tarnoki, Adam D.; Tarnoki, David L. [Semmelweis University, Department of Radiology and Oncotherapy, Budapest (Hungary); Voros, Szilard [Global Genomics Group, Atlanta, GA (United States); Jermendy, Gyoergy [Bajcsy-Zsilinszky Hospital, Medical Department, Budapest (Hungary)

    2017-06-15

    Previous studies using transthoracic echocardiography (TTE) observed moderate heritability of aortic root dimensions. Computed tomography angiography (CTA) might provide more accurate heritability estimates. Our primary aim was to assess the heritability of the aortic root with CTA. Our secondary aim was to derive TTE-based heritability and compare this with the CTA-based results. In the BUDAPEST-GLOBAL study 198 twin subjects (118 monozygotic, 80 dizygotic; age 56.1 ± 9.4 years; 126 female) underwent CTA and TTE. We assessed the diameter of the left ventricular outflow tract (LVOT), annulus, sinus of Valsalva, sinotubular junction and ascending aorta. Heritability was assessed using ACDE model (A additive genetic, C common environmental, D dominant genetic, E unique environmental factors). Based on CTA, additive genetic effects were dominant (LVOT: A = 0.67, E = 0.33; annulus: A = 0.76, E = 0.24; sinus of Valsalva: A = 0.83, E = 0.17; sinotubular junction: A = 0.82, E = 0.18; ascending aorta: A = 0.75, E = 0.25). TTE-derived measurements showed moderate to no genetic influence (LVOT: A = 0.38, E = 0.62; annulus: C = 0.47, E = 0.53; sinus of Valsalva: C = 0.63, E = 0.37; sinotubular junction: C = 0.45, E = 0.55; ascending aorta: A = 0.67, E = 0.33). CTA-based assessment suggests that aortic root dimensions are predominantly determined by genetic factors. TTE-based measurements showed moderate to no genetic influence. The choice of measurement method has substantial impact on heritability estimates. (orig.)

  14. Culturally relevant inquiry-based laboratory module implementations in upper-division genetics and cell biology teaching laboratories.

    Science.gov (United States)

    Siritunga, Dimuth; Montero-Rojas, María; Carrero, Katherine; Toro, Gladys; Vélez, Ana; Carrero-Martínez, Franklin A

    2011-01-01

    Today, more minority students are entering undergraduate programs than ever before, but they earn only 6% of all science or engineering PhDs awarded in the United States. Many studies suggest that hands-on research activities enhance students' interest in pursuing a research career. In this paper, we present a model for the implementation of laboratory research in the undergraduate teaching laboratory using a culturally relevant approach to engage students. Laboratory modules were implemented in upper-division genetics and cell biology courses using cassava as the central theme. Students were asked to bring cassava samples from their respective towns, which allowed them to compare their field-collected samples against known lineages from agricultural stations at the end of the implementation. Assessment of content and learning perceptions revealed that our novel approach allowed students to learn while engaged in characterizing Puerto Rican cassava. In two semesters, based on the percentage of students who answered correctly in the premodule assessment for content knowledge, there was an overall improvement of 66% and 55% at the end in the genetics course and 24% and 15% in the cell biology course. Our proposed pedagogical model enhances students' professional competitiveness by providing students with valuable research skills as they work on a problem to which they can relate.

  15. AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.

    Science.gov (United States)

    Wang, Xiaowen; Li, Kai; Liu, Ling; Shi, Qiong; Song, Pu; Jian, Zhe; Guo, Sen; Wang, Gang; Li, Chunying; Gao, Tianwen

    2015-09-15

    Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process, and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR -129C > T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that -129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with -129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than -129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo.

  16. Demographic factors and genetic variation influence population persistence under environmental change.

    Science.gov (United States)

    Willi, Yvonne; Hoffmann, Ary A

    2009-01-01

    Population persistence has been studied in a conservation context to predict the fate of small or declining populations. Persistence models have explored effects on extinction of random demographic and environmental fluctuations, but in the face of directional environmental change they should also integrate factors affecting whether a population can adapt. Here, we examine the population-size dependence of demographic and genetic factors and their likely contributions to extinction time under scenarios of environmental change. Parameter estimates were derived from experimental populations of the rainforest species, Drosophila birchii, held in the lab for 10 generations at census sizes of 20, 100 and 1000, and later exposed to five generations of heat-knockdown selection. Under a model of directional change in the thermal environment, rapid extinction of populations of size 20 was caused by a combination of low growth rate (r) and high stochasticity in r. Populations of 100 had significantly higher reproductive output, lower stochasticity in r and more additive genetic variance (V(A)) than populations of 20, but they were predicted to persist less well than the largest size class. Even populations of 1000 persisted only a few hundred generations under realistic estimates of environmental change because of low V(A) for heat-knockdown resistance. The experimental results document population-size dependence of demographic and adaptability factors. The simulations illustrate a threshold influence of demographic factors on population persistence, while genetic variance has a more elastic impact on persistence under environmental change.

  17. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming;

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than...... the triple Ig-module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR-ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1-Ig2 interaction....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...

  18. Asian flushing: genetic and sociocultural factors of alcoholism among East asians.

    Science.gov (United States)

    Lee, Haeok; Kim, Sun S; You, Kwang Soo; Park, Wanju; Yang, Jin Hyang; Kim, Minjin; Hayman, Laura L

    2014-01-01

    Alcohol use can lead to a cascade of problems such as increased chances of risky behavior and negative health consequences, including alcoholic liver disease and upper gastric and liver cancer. Ethanol is metabolized mainly by 2 major enzymes: alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Genetic variations of genes encoding the 2 enzymes are very common among East Asians but relatively rare for most other populations. Facial flushing and other physical discomforts after alcohol drinking triggered by accumulation of acetaldehyde through defective genes for ADH and ALDH have been reported. Approximately 40% of East Asians (Chinese, Japanese, and Korean) show facial flushing after drinking alcohol, known as "Asian flush," which is characterized by adverse reactions on alcohol drinking in individuals possessing the fasting metabolizing alleles for ADH, ADH1B*2, and ADH1C*1, and the null allele for ALDH and ALDH2*2. Alcoholism is determined not only by the genetic deficiency but also by behaviors that involve complex interactions between genetic and sociocultural factors. The purpose of this article was to provide nurses with the most current information about genetic and sociocultural influences on alcoholism and alcohol-related health problems specifically for East Asians and implications of this knowledge to nursing practice. The physiological phenomenon of genes and genetics in relation to alcohol metabolism in this special population is emphasized.

  19. The nature of creativity: The roles of genetic factors, personality traits, cognitive abilities, and environmental sources.

    Science.gov (United States)

    Kandler, Christian; Riemann, Rainer; Angleitner, Alois; Spinath, Frank M; Borkenau, Peter; Penke, Lars

    2016-08-01

    This multitrait multimethod twin study examined the structure and sources of individual differences in creativity. According to different theoretical and metrological perspectives, as well as suggestions based on previous research, we expected 2 aspects of individual differences, which can be described as perceived creativity and creative test performance. We hypothesized that perceived creativity, reflecting typical creative thinking and behavior, should be linked to specific personality traits, whereas test creativity, reflecting maximum task-related creative performance, should show specific associations with cognitive abilities. Moreover, we tested whether genetic variance in intelligence and personality traits account for the genetic component of creativity. Multiple-rater and multimethod data (self- and peer reports, observer ratings, and test scores) from 2 German twin studies-the Bielefeld Longitudinal Study of Adult Twins and the German Observational Study of Adult Twins-were analyzed. Confirmatory factor analyses yielded the expected 2 correlated aspects of creativity. Perceived creativity showed links to openness to experience and extraversion, whereas tested figural creativity was associated with intelligence and also with openness. Multivariate behavioral genetic analyses indicated that the heritability of tested figural creativity could be accounted for by the genetic component of intelligence and openness, whereas a substantial genetic component in perceived creativity could not be explained. A primary source of individual differences in creativity was due to environmental influences, even after controlling for random error and method variance. The findings are discussed in terms of the multifaceted nature and construct validity of creativity as an individual characteristic. (PsycINFO Database Record

  20. Saturated fat intake modulates the association between an obesity genetic risk score and body mass index in two US populations.

    Science.gov (United States)

    Casas-Agustench, Patricia; Arnett, Donna K; Smith, Caren E; Lai, Chao-Qiang; Parnell, Laurence D; Borecki, Ingrid B; Frazier-Wood, Alexis C; Allison, Matthew; Chen, Yii-Der Ida; Taylor, Kent D; Rich, Stephen S; Rotter, Jerome I; Lee, Yu-Chi; Ordovás, José M

    2014-12-01

    Combining multiple genetic variants related to obesity into a genetic risk score (GRS) might improve identification of individuals at risk of developing obesity. Moreover, characterizing gene-diet interactions is a research challenge to establish dietary recommendations to individuals with higher predisposition to obesity. Our objective was to analyze the association between an obesity GRS and body mass index (BMI) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) population, focusing on gene-diet interactions with total fat and saturated fatty acid (SFA) intake, and to replicate findings in the Multi-Ethnic Study of Atherosclerosis (MESA) population. Cross-sectional analyses included 783 white US participants from GOLDN and 2,035 from MESA. Dietary intakes were estimated with validated food frequency questionnaires. Height and weight were measured. A weighted GRS was calculated on the basis of 63 obesity-associated variants. Multiple linear regression models adjusted by potential confounders were used to examine gene-diet interactions between dietary intake (total fat and SFA) and the obesity GRS in determining BMI. Significant interactions were found between total fat intake and the obesity GRS using these variables as continuous for BMI (P for interaction=0.010, 0.046, and 0.002 in GOLDN, MESA, and meta-analysis, respectively). These association terms were stronger when assessing interactions between SFA intake and GRS for BMI (P for interaction=0.005, 0.018, and intake interacts with an obesity GRS in modulating BMI in two US populations. Although determining the causal direction requires further investigation, these findings suggest that potential dietary recommendations to reduce BMI effectively in populations with high obesity GRS would be to reduce total fat intake mainly by limiting SFAs. Copyright © 2014 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

  1. Saturated fat intake modulates the association between a genetic risk score of obesity and BMI in two US populations

    Science.gov (United States)

    Casas-Agustench, Patricia; Arnett, Donna K.; Smith, Caren E.; Lai, Chao-Qiang; Parnell, Laurence D.; Borecki, Ingrid B.; Frazier-Wood, Alexis C.; Allison, Matthew; Chen, Yii-Der Ida; Taylor, Kent D.; Rich, Stephen S.; Rotter, Jerome I.; Lee, Yu-Chi; Ordovás, José M.

    2014-01-01

    Combining multiple genetic variants related to obesity into a genetic risk score (GRS) might improve identification of individuals at risk of developing obesity. Moreover, characterizing gene-diet interactions is a research challenge to establish dietary recommendations to individuals with higher predisposition to obesity. Our objective was to analyze the association between an obesity GRS and BMI in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) population, focusing on gene-diet interactions with total fat and saturated fatty acid (SFA) intake and to replicate findings in Multi-Ethnic Study of Atherosclerosis (MESA) population. Cross-sectional analyses included 783 US Caucasian participants from GOLDN and 2035 from MESA. Dietary intakes were estimated with validated food frequency questionnaires. Height and weight were measured. A weighted GRS was calculated on the basis of 63 obesity-associated variants. Multiple linear regression models adjusted by potential confounders were used to examine gene-diet interactions between dietary intake (total fat and SFA) and the obesity GRS in determining BMI. Significant interactions were found between total fat intake and the obesity GRS using these variables as continuous for BMI (P for interaction=0.010, 0.046, and 0.002 in GOLDN, MESA and meta-analysis, respectively). These association terms were stronger when assessing interactions between SFA intake and GRS for BMI (P for interaction=0.005, 0.018, and intake interacts with an obesity GRS in modulating BMI in two US populations. Although to determine the causal direction requires further investigation, these findings suggest that potential dietary recommendations to reduce BMI effectively in populations with high obesity GRS would be to reduce total fat intake mainly by limiting SFAs. PMID:24794412

  2. Factors Affecting the Incidence of Angel Wing in White Roman Geese: Stocking Density and Genetic Selection.

    Science.gov (United States)

    Lin, M J; Chang, S C; Lin, T Y; Cheng, Y S; Lee, Y P; Fan, Y K

    2016-06-01

    The present study investigated stocking density and genetic lines, factors that may alter the severity and incidence of angel wing (AW), in White Roman geese. Geese (n = 384) from two genetically selected lines (normal- winged line, NL, and angel-winged line, AL, respectively) and one commercial line (CL) were raised in four pens. Following common commercial practice, low-stocking-density (LD), medium-stocking-density, and high-stocking-density treatments were respectively administered to 24, 32, and 40 geese per pen at 0 to 3 weeks (1.92 m(2)/pen) and 4 to 6 weeks (13.2 m(2)/pen) of age and to 24, 30, and 36 geese at 7 to 14 weeks (20.0 m(2)/pen) of age. The results revealed that stocking density mainly affected body weight gain in geese younger than 4 weeks, and that geese subjected to LD had a high body weight at 2 weeks of age. However, the effect of stocking density on the severity score of AW (SSAW) and incidence of AW (IAW) did not differ significantly among the treatments. Differences were observed among the genetic stocks; that is, SSAW and IAW were significantly higher in AL than in NL and CL. Genetic selection generally aggravates AW, complicating its elimination. To effectively reduce IAW, stocking density, a suspected causal factor, should be lower than that presently applied commercially.

  3. Genetic and environmental factors in associations between infant growth and adult cardiometabolic risk profile in twins.

    Science.gov (United States)

    Touwslager, Robbert N H; Gielen, Marij; Mulder, Antonius L M; Gerver, Willem J M; Zimmermann, Luc J; Dagnelie, Pieter C; Houben, Alfons J H M; Stehouwer, Coen D A; Derom, Catherine; Vlietinck, Robert; Loos, Ruth J F; Zeegers, Maurice P

    2013-10-01

    Accelerated infant growth is associated with an altered, mostly adverse adult cardiometabolic risk profile. The importance of genetic and environmental factors to these associations is unclear. The objective was to examine the importance of genetic and environmental factors in the associations between infant growth and adult cardiometabolic risk factors (anthropometric characteristics, lipids, insulin sensitivity, leptin, blood pressure, and fibrinogen) in twins. Cardiometabolic risk factors were assessed in 240 twin pairs (aged 18-34 y) from the East Flanders Prospective Twin Survey. Infant growth was defined as change in weight z score. We regressed intrapair differences in growth during 4 growth windows (0-1, 1-6, 6-12, and 12-24 mo) against intrapair differences in the risk factors in monozygotic and dizygotic twins separately. Within monozygotic twin pairs only, associations between infant growth and most adult lipids, glucose, leptin, and blood pressure (eg, systolic blood pressure: b = 5.95 mm Hg per change in z score, P = 0.01 in monozygotic twins; b = -1.64, P = 0.82 in dizygotic twins from 12 to 24 mo) were found. Within dizygotic twin pairs only, associations between growth and triglycerides and fibrinogen (eg, fibrinogen: b = 0.07 ln mg/dL per change in z score, P = 0.31 in monozygotic twins; b = 0.79, P = 0.01 in dizygotic twins from 0 to 1 mo) were identified. Most associations showed a detrimental effect of accelerated growth, but beneficial associations were also identified (eg, total-to-high-density-lipoprotein cholesterol ratio: b = -0.22 per change in z score from 1 to 6 mo, P = 0.008 in monozygotic twins). Our data showed that environmental factors play a role in the associations between infant growth and most adult lipids, glucose, leptin, and blood pressure, whereas genetic factors are involved regarding triglycerides and fibrinogen.

  4. Environmental factors shape the community of symbionts in the hoopoe uropygial gland more than genetic factors.

    Science.gov (United States)

    Ruiz-Rodríguez, Magdalena; Soler, Juan J; Martín-Vivaldi, Manuel; Martín-Platero, Antonio M; Méndez, María; Peralta-Sánchez, Juan M; Ananou, Samir; Valdivia, Eva; Martínez-Bueno, Manuel

    2014-11-01

    Exploring processes of coevolution of microorganisms and their hosts is a new imperative for life sciences. If bacteria protect hosts against pathogens, mechanisms facilitating the intergenerational transmission of such bacteria will be strongly selected by evolution. By disentangling the diversity of bacterial strains from the uropygium of hoopoes (Upupa epops) due to genetic relatedness or to a common environment, we explored the importance of horizontal (from the environment) and vertical (from parents) acquisition of antimicrobial-producing symbionts in this species. For this purpose, we compared bacterial communities among individuals in nonmanipulated nests; we also performed a cross-fostering experiment using recently hatched nestlings before uropygial gland development and some nestlings that were reared outside hoopoe nests. The capacity of individuals to acquire microbial symbionts horizontally during their development was supported by our results, since cross-fostered nestlings share bacterial strains with foster siblings and nestlings that were not in contact with hoopoe adults or nests also developed the symbiosis. Moreover, nestlings could change some bacterial strains over the course of their stay in the nest, and adult females changed their bacterial community in different years. However, a low rate of vertical transmission was inferred, since genetic siblings reared in different nests shared more bacterial strains than they shared with unrelated nestlings raised in different nests. In conclusion, hoopoes are able to incorporate new symbionts from the environment during the development of the uropygium, which could be a selective advantage if strains with higher antimicrobial capacity are incorporated into the gland and could aid hosts in fighting against pathogenic and disease-causing microbes.

  5. Environmental Factors Shape the Community of Symbionts in the Hoopoe Uropygial Gland More than Genetic Factors

    Science.gov (United States)

    Soler, Juan J.; Martín-Vivaldi, Manuel; Martín-Platero, Antonio M.; Méndez, María; Peralta-Sánchez, Juan M.; Ananou, Samir; Valdivia, Eva; Martínez-Bueno, Manuel

    2014-01-01

    Exploring processes of coevolution of microorganisms and their hosts is a new imperative for life sciences. If bacteria protect hosts against pathogens, mechanisms facilitating the intergenerational transmission of such bacteria will be strongly selected by evolution. By disentangling the diversity of bacterial strains from the uropygium of hoopoes (Upupa epops) due to genetic relatedness or to a common environment, we explored the importance of horizontal (from the environment) and vertical (from parents) acquisition of antimicrobial-producing symbionts in this species. For this purpose, we compared bacterial communities among individuals in nonmanipulated nests; we also performed a cross-fostering experiment using recently hatched nestlings before uropygial gland development and some nestlings that were reared outside hoopoe nests. The capacity of individuals to acquire microbial symbionts horizontally during their development was supported by our results, since cross-fostered nestlings share bacterial strains with foster siblings and nestlings that were not in contact with hoopoe adults or nests also developed the symbiosis. Moreover, nestlings could change some bacterial strains over the course of their stay in the nest, and adult females changed their bacterial community in different years. However, a low rate of vertical transmission was inferred, since genetic siblings reared in different nests shared more bacterial strains than they shared with unrelated nestlings raised in different nests. In conclusion, hoopoes are able to incorporate new symbionts from the environment during the development of the uropygium, which could be a selective advantage if strains with higher antimicrobial capacity are incorporated into the gland and could aid hosts in fighting against pathogenic and disease-causing microbes. PMID:25172851

  6. Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota.

    Science.gov (United States)

    Devlin, A Sloan; Marcobal, Angela; Dodd, Dylan; Nayfach, Stephen; Plummer, Natalie; Meyer, Tim; Pollard, Katherine S; Sonnenburg, Justin L; Fischbach, Michael A

    2016-12-14

    Renal disease is growing in prevalence and has striking co-morbidities with metabolic and cardiovascular disease. Indoxyl sulfate (IS) is a toxin that accumulates in plasma when kidney function declines and contributes to the progression of chronic kidney disease. IS derives exclusively from the gut microbiota. Bacterial tryptophanases convert tryptophan to indole, which is absorbed and modified by the host to produce IS. Here, we identify a widely distributed family of tryptophanases in the gut commensal Bacteroides and find that deleting this gene eliminates the production of indole in vitro. By altering the status or abundance of the Bacteroides tryptophanase, we can modulate IS levels in gnotobiotic mice and in the background of a conventional murine gut community. Our results demonstrate that it is possible to control host IS levels by targeting the microbiota and suggest a possible strategy for treating renal disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Genetic interplay between the transcription factors Sp8 and Emx2 in the patterning of the forebrain

    Directory of Open Access Journals (Sweden)

    Stoykova Anastasia

    2007-04-01

    Full Text Available Abstract Background The forebrain consists of multiple structures necessary to achieve elaborate functions. Proper patterning is, therefore, a prerequisite for the generation of optimal functional areas. Only a few factors have been shown to control the genetic networks that establish early forebrain patterning. Results and conclusion Using conditional inactivation, we show that the transcription factor Sp8 has an essential role in the molecular and functional patterning of the developing telencephalon along the anteroposterior axis by modulating the expression gradients of Emx2 and Pax6. Moreover, Sp8 is essential for the maintenance of ventral cell identity in the septum and medial ganglionic eminence (MGE. This is probably mediated through a positive regulatory interaction with Fgf8 in the medial wall, and Nkx2.1 in the rostral MGE anlage, and independent of SHH and WNT signaling. Furthermore, Sp8 is required during corticogenesis to sustain a normal progenitor pool, and to control preplate splitting, as well as the specification of cellular diversity within distinct cortical layers.

  8. Ancient mtDNA genetic variants modulate mtDNA transcription and replication.

    Directory of Open Access Journals (Sweden)

    Sarit Suissa

    2009-05-01

    Full Text Available Although the functional consequences of mitochondrial DNA (mtDNA genetic backgrounds (haplotypes, haplogroups have been demonstrated by both disease association studies and cell culture experiments, it is not clear which of the mutations within the haplogroup carry functional implications and which are "evolutionary silent hitchhikers". We set forth to study the functionality of haplogroup-defining mutations within the mtDNA transcription/replication regulatory region by in vitro transcription, hypothesizing that haplogroup-defining mutations occurring within regulatory motifs of mtDNA could affect these processes. We thus screened >2500 complete human mtDNAs representing all major populations worldwide for natural variation in experimentally established protein binding sites and regulatory regions comprising a total of 241 bp in each mtDNA. Our screen revealed 77/241 sites showing point mutations that could be divided into non-fixed (57/77, 74% and haplogroup/sub-haplogroup-defining changes (i.e., population fixed changes, 20/77, 26%. The variant defining Caucasian haplogroup J (C295T increased the binding of TFAM (Electro Mobility Shift Assay and the capacity of in vitro L-strand transcription, especially of a shorter transcript that maps immediately upstream of conserved sequence block 1 (CSB1, a region associated with RNA priming of mtDNA replication. Consistent with this finding, cybrids (i.e., cells sharing the same nuclear genetic background but differing in their mtDNA backgrounds harboring haplogroup J mtDNA had a >2 fold increase in mtDNA copy number, as compared to cybrids containing haplogroup H, with no apparent differences in steady state levels of mtDNA-encoded transcripts. Hence, a haplogroup J regulatory region mutation affects mtDNA replication or stability, which may partially account for the phenotypic impact of this haplogroup. Our analysis thus demonstrates, for the first time, the functional impact of particular mt

  9. Dimerization of complement factor H-related proteins modulates complement activation in vivo.

    Science.gov (United States)

    Goicoechea de Jorge, Elena; Caesar, Joseph J E; Malik, Talat H; Patel, Mitali; Colledge, Matthew; Johnson, Steven; Hakobyan, Svetlana; Morgan, B Paul; Harris, Claire L; Pickering, Matthew C; Lea, Susan M

    2013-03-19

    The complement system is a key component regulation influences susceptibility to age-related macular degeneration, meningitis, and kidney disease. Variation includes genomic rearrangements within the complement factor H-related (CFHR) locus. Elucidating the mechanism underlying these associations has been hindered by the lack of understanding of the biological role of CFHR proteins. Here we present unique structural data demonstrating that three of the CFHR proteins contain a shared dimerization motif and that this hitherto unrecognized structural property enables formation of both homodimers and heterodimers. Dimerization confers avidity for tissue-bound complement fragments and enables these proteins to efficiently compete with the physiological complement inhibitor, complement factor H (CFH), for ligand binding. Our data demonstrate that these CFHR proteins function as competitive antagonists of CFH to modulate complement activation in vivo and explain why variation in the CFHRs predisposes to disease.

  10. Sudden infant death syndrome, childhood thrombosis, and presence of genetic risk factors for thrombosis

    DEFF Research Database (Denmark)

    Larsen, T B; Nørgaard-Pedersen, B; Banner, Jytte

    2000-01-01

    in the child. This prompted us to investigate these genetic markers of thromboembolic disease in 121 cases of sudden infant death syndrome and in relevant controls, in the expectation of a more frequent occurrence of these markers if thrombosis is an etiological factor in sudden infant death syndrome......Sudden infant death syndrome or "cot death" has until the late eighties been a significant cause of death in children between the ages of 1 month and 1 year. Approximately two per 1000 children born alive dies of sudden infant death syndrome each year in Western Europe, North America, and Australia....... The vulnerability of the infant brain stem to ischemia has been suggested to be a conceivable cause of sudden infant death syndrome. This is compatible with a hypothesis that genetic risk factors for cerebral thrombosis could cause microinfarction in the brain stem during the first month of life, affecting vital...

  11. Genetic and modifying factors that determine the risk of brain tumors

    DEFF Research Database (Denmark)

    Montelli, Terezinha de Cresci Braga; Peraçoli, Maria Terezinha Serrão; Rogatto, Silvia Regina

    2011-01-01

    of tumor escape, CNS tumor immunology, immune defects that impair anti-tumor systemic immunity in brain tumor patients and local immuno-suppressive factors within CNS are also reviewed. New hope to treatment perspectives, as dendritic-cell-based vaccines is summarized too. Concluding, it seems well...... of these treatments, the prognosis for patients is poor. In this review, we highlight general aspects concerning genetic alterations in brain tumors, namely astrocytomas, glioblastomas, oligodendrogliomas, medulloblastomas and ependymomas. The influence of these genetic alterations in patients' prognosis is discussed....... Mutagen sensitivity is associated with cancer risk. The convincing studies that linked DNA damages and DNA repair alterations with brain tumors are also described. Another important modifying factor is immunity. General immune response against cancer, tumor microenvironment and immune response, mechanisms...

  12. Influence Factors on Consumers’ Cognition Level to Genetically Modified Food-taking Huangshi as an Example

    Directory of Open Access Journals (Sweden)

    Ruishan Chen

    2015-07-01

    Full Text Available This study aims to analyze the influence factors on consumers’ cognition level to genetically modified food and improve the consumers’ cognition level. In recent years, genetically modified foods in people’s daily life are becoming more and more common, but there is a lot of controversy about them. Based on the analysis of influence factors on consumers’ cognition level to GMF, a comprehensive system is established from four aspects, including the consumers’ personal characteristics, social-economic characteristics, household characteristics and awareness of risk. And Analytic Hierarchy Process (AHP method is used to make the quantitative research via investigation data of Huangshi, analyze the major influence on consumers’ cognition level to GMF. Finally some suggestions are proposed to promote the consumers’ cognition level to GMF.

  13. Importance of genetic factors in the occurrence of epilepsy syndrome type: a twin study

    DEFF Research Database (Denmark)

    Corey, Linda A; Pellock, John M; Kjeldsen, Marianne J

    2011-01-01

    Although there is strong evidence that genetic factors contribute to risk for epilepsy, their role in the determination of syndrome type is less clear. This study was undertaken to address this question. Information related to epilepsy was obtained from twins included in 455 monozygotic and 868...... dizygotic pairs ascertained from population-based twin registries in Denmark, Norway and the United States. Syndrome type was determined based on medical record information and detailed clinical interviews and classified using the International Classification Systems for the Epilepsies and Epileptic...... Syndromes. Concordance rates were significantly increased in monozygotic versus dizygotic pairs for all major syndrome groups except localization-related cryptogenic epilepsy. Among generalized epilepsies, genetic factors were found to play an important role in the determination of childhood absence...

  14. Sudden infant death syndrome, childhood thrombosis, and presence of genetic risk factors for thrombosis

    DEFF Research Database (Denmark)

    Larsen, TB; Nørgaard-Pedersen, B; Lundemose, JB

    2000-01-01

    . The vulnerability of the infant brain stem to ischemia has been suggested to be a conceivable cause of sudden infant death syndrome. This is compatible with a hypothesis that genetic risk factors for cerebral thrombosis could cause microinfarction in the brain stem during the first month of life, affecting vital......Sudden infant death syndrome or "cot death" has until the late eighties been a significant cause of death in children between the ages of 1 month and 1 year. Approximately two per 1000 children born alive dies of sudden infant death syndrome each year in Western Europe, North America, and Australia...... in the child. This prompted us to investigate these genetic markers of thromboembolic disease in 121 cases of sudden infant death syndrome and in relevant controls, in the expectation of a more frequent occurrence of these markers if thrombosis is an etiological factor in sudden infant death syndrome...

  15. Summer eczema in exported Icelandic horses: influence of environmental and genetic factors

    Directory of Open Access Journals (Sweden)

    Broström Hans

    2006-05-01

    Full Text Available Abstract A cross sectional study was designed to estimate the prevalence of summer eczema (a chronic, recurrent seasonal dermatitis in exported Icelandic horses and the influence of environmental and genetic factors on the development of the disease. Among 330 horses, which had been exported to Germany, Denmark and Sweden, 114 (34.5% were found to have clinical signs of summer eczema. The prevalence was highest 2 years after export and the exposure to the biting midges Culicoides spp., was found to be the main risk factor for developing the disease. Genetic influence on the sensitivity for the disease was not established. It was concluded that exported Icelandic horses are predisposed for summer dermatitis and the fact that they are not introduced to the antigens of the biting midges early in live, due to it's absence in Iceland, is likely to explain the high prevalence of the disease after export.

  16. Glycosaminoglycan remodeling during diabetes and the role of dietary factors in their modulation

    Institute of Scientific and Technical Information of China (English)

    Vemana; Gowd; Abhignan; Gurukar; Nandini; D; Chilkunda

    2016-01-01

    Glycosaminoglycans(GAGs) play a significant role in various aspects of cell physiology.These are complex polymeric molecules characterized by disaccharides comprising of uronic acid and amino sugar.Compounded to the heterogeneity,these are variously sulfated and epimerized depending on the class of GAG.Among the various classes of GAG,namely,chondroitin/dermatan sulfate,heparin/heparan sulfate,keratan sulfate and hyaluronic acid(HA),only HA is non-sulfated.GAGs are known to undergo remodeling in various tissues during various pathophysiological conditions,diabetes mellitus being one among them.These changes will likely affect their structure thereby impinging on their functionality.Till date,diabetes has been shown to affect GAGs in organs such as kidney,liver,aorta,skin,erythrocytes,etc.to name a few,with deleterious consequences.One of the mainstays in the treatment of diabetes is though dietary means.Various dietary factors are known to play a significant role in regulating glucose homeostasis.Furthermore,in recent years,there has been a keen interest to decipher the role of dietary factors on GAG metabolism.This review focuses on the remodeling of GAGs in various organs during diabetes and their modulation by dietary factors.While effect of diabetes on GAG metabolism has been worked out quite a bit,studies on the role of dietary factors in their modulation has been few and far between.We have tried our best to give the latest reports available on this subject.

  17. A twin and molecular genetics study of sleep paralysis and associated factors.

    OpenAIRE

    Denis, Dan; French, Christopher C.; Rowe, Richard; Zavos, Helena M S; Nolan, Patrick M.; Parsons, Michael J.; Gregory, Alice M

    2015-01-01

    Sleep paralysis is a relatively common but under-researched phenomenon. In this paper we examine prevalence in a UK sample and associations with candidate risk factors. This is the first study to investigate the heritability of sleep paralysis in a twin sample and to explore genetic associations between sleep paralysis and a number of circadian expressed single nucleotide polymorphisms. Analyses are based on data from the Genesis1219 twin/sibling study, a community sample of twins/siblings fr...

  18. A twin and molecular genetics study of sleep paralysis and associated factors.

    OpenAIRE

    Denis, Dan; French, Christopher C.; Rowe, Richard; Zavos, Helena M. S.; Nolan, Patrick M.; Parsons, Michael J.; Gregory, Alice M.

    2015-01-01

    Sleep paralysis is a relatively common but under-researched phenomenon. In this paper we examine prevalence in a UK sample and associations with candidate risk factors. This is the first study to investigate the heritability of sleep paralysis in a twin sample and to explore genetic associations between sleep paralysis and a number of circadian expressed single nucleotide polymorphisms. Analyses are based on data from the Genesis1219 twin/sibling study, a community sample of twins/siblings fr...

  19. Confounding factors and genetic polymorphism in the evaluation of individual steroid profiling.

    Science.gov (United States)

    Kuuranne, Tiia; Saugy, Martial; Baume, Norbert

    2014-05-01

    In the fight against doping, steroid profiling is a powerful tool to detect drug misuse with endogenous anabolic androgenic steroids. To establish sensitive and reliable models, the factors influencing profiling should be recognised. We performed an extensive literature review of the multiple factors that could influence the quantitative levels and ratios of endogenous steroids in urine matrix. For a comprehensive and scientific evaluation of the urinary steroid profile, it is necessary to define the target analytes as well as testosterone metabolism. The two main confounding factors, that is, endogenous and exogenous factors, are detailed to show the complex process of quantifying the steroid profile within WADA-accredited laboratories. Technical aspects are also discussed as they could have a significant impact on the steroid profile, and thus the steroid module of the athlete biological passport (ABP). The different factors impacting the major components of the steroid profile must be understood to ensure scientifically sound interpretation through the Bayesian model of the ABP. Not only should the statistical data be considered but also the experts in the field must be consulted for successful implementation of the steroidal module.

  20. Interaction of genetic predisposition and environmental factors in the pathogenesis of idiopathic orthostatic intolerance

    Science.gov (United States)

    Jordan, J.; Shannon, J. R.; Jacob, G.; Pohar, B.; Robertson, D.

    1999-01-01

    BACKGROUND: The hemodynamic and autonomic abnormalities in idiopathic orthostatic intolerance (IOI) have been studied extensively. However, the mechanisms underlying these abnormalities are not understood. If genetic predisposition were important in the pathogenesis of IOI, monozygotic twins of patients with IOI should have similar hemodynamic and autonomic abnormalities. METHODS: We studied two patients with IOI and their identical twins. Both siblings in the first twin pair had orthostatic symptoms, significant orthostatic tachycardia, increased plasma norepinephrine levels with standing, and a greater than normal decrease in systolic blood pressure with trimethaphan infusion. RESULTS: Both siblings had a normal response of plasma renin activity to upright posture. In the second twin pair, only one sibling had symptoms of orthostatic intolerance, an orthostatic tachycardia, and raised plasma catecholamines with standing. The affected sibling had inappropriately low plasma renin activity with standing and was 8-fold more sensitive to the pressor effect of phenylephrine than the unaffected sibling. CONCLUSIONS: We conclude that in some patients, IOI seems to be strongly influenced by genetic factors. In others, however, IOI may be mainly caused by nongenetic factors. These findings suggest that IOI is heterogenous, and that both genetic and environmental factors contribute individually or collectively to create the IOI phenotype.

  1. Use of a twin dataset to identify AMD-related visual patterns controlled by genetic factors

    Science.gov (United States)

    Quellec, Gwénolé; Abràmoff, Michael D.; Russell, Stephen R.

    2010-03-01

    The mapping of genotype to the phenotype of age-related macular degeneration (AMD) is expected to improve the diagnosis and treatment of the disease in a near future. In this study, we focused on the first step to discover this mapping: we identified visual patterns related to AMD which seem to be controlled by genetic factors, without explicitly relating them to the genes. For this purpose, we used a dataset of eye fundus photographs from 74 twin pairs, either monozygotic twins, who have the same genotype, or dizygotic twins, whose genes responsible for AMD are less likely to be identical. If we are able to differentiate monozygotic twins from dizygotic twins, based on a given visual pattern, then this pattern is likely to be controlled by genetic factors. The main visible consequence of AMD is the apparition of drusen between the retinal pigment epithelium and Bruch's membrane. We developed two automated drusen detectors based on the wavelet transform: a shape-based detector for hard drusen, and a texture- and color- based detector for soft drusen. Forty visual features were evaluated at the location of the automatically detected drusen. These features characterize the texture, the shape, the color, the spatial distribution, or the amount of drusen. A distance measure between twin pairs was defined for each visual feature; a smaller distance should be measured between monozygotic twins for visual features controlled by genetic factors. The predictions of several visual features (75.7% accuracy) are comparable or better than the predictions of human experts.

  2. Genetic and non-genetic factors affecting rabbit doe sexual receptivity as estimated from one generation of divergent selection

    Directory of Open Access Journals (Sweden)

    M. Theau.Clément

    2015-09-01

    Full Text Available Sexual receptivity of rabbit does at insemination greatly influences fertility and is generally induced by hormones or techniques known as “biostimulation”. Searching for more sustainable farming systems, an original alternative would be to utilise the genetic pathway to increase the does’receptivity. The purpose of the present study was to identify genetic and non-genetic factors that influence rabbit doe sexual receptivity, in the context of a divergent selection experiment over 1 generation. The experiment spanned 2 generations: the founder generation (G0 consisting of 140 rabbit does, and the G1 generation comprising 2 divergently selected lines (L and H lines with 70 does each and 2 successive batches from each generation. The selection rate of the G0 females to form the G1 lines was 24/140. The selection tests consisted of 16 to 18 successive receptivity tests at the rate of 3 tests per week. On the basis of 4716 tests from 275 females, the average receptivity was 56.6±48.2%. A batch effect and a test operator effect were revealed. The contribution of females to the total variance was 20.0%, whereas that of bucks was only 1.1%. Throughout the experiment, 18.2% of does expressed a low receptivity (< 34%, 50.7% a medium one and 33.1% a high one (>66%. Some does were frequently receptive, whereas others were rarely receptive. The repeatability of sexual receptivity was approximately 20%. The results confirmed the high variability of sexual receptivity of non-lactating rabbit does maintained without any biostimulation or hormonal treatment. A lack of selection response on receptivity was observed. Accordingly, the heritability of receptivity was estimated at 0.01±0.02 from an animal model and at 0.02±0.03 from a  sire and dam model. The heritability of the average receptivity of a doe was calculated as 0.04. In agreement with the low estimated heritability, the heritability determined was no different from zero

  3. Cavity Preparation/assembly Techniques and Impact on Q, Realistic Q - Factors in a Module, Review of Modules

    Energy Technology Data Exchange (ETDEWEB)

    Peter Kneisel

    2005-03-19

    This contribution summarizes the surface preparation procedures for niobium cavities presently used both in laboratory experiments and for modules, such as buffered chemical polishing (BCP), electropolishing (EP), high pressure ultrapure water rinsing (HPR), CO{sub 2} snow cleaning and high temperature heat treatments for hydrogen degassing or postpurification. The impact of surface treatments and the degree of cleanliness during assembly procedures on cavity performance (Q - value and accelerating gradient E{sub acc}) will be discussed. In addition, an attempt will be made to summarize the experiences made in module assemblies in different labs/projects such as DESY(TTF), Jlab (Upgrade) and SNS.

  4. Cavity preparation/assembly techniques and impact on Q, realistic Q-factors in a module, review of modules

    Science.gov (United States)

    Kneisel, Peter

    2006-02-01

    This contribution summarizes the surface preparation procedures for niobium cavities presently used both in laboratory experiments and for modules, such as buffered chemical polishing (BCP), electropolishing (EP), high pressure ultrapure water rinsing (HPR), CO 2 snow cleaning and high temperature heat treatments for hydrogen degassing or post-purification. The impact of surface treatments and the degree of cleanliness during assembly procedures on cavity performance ( Q-value and accelerating gradient Eacc) will be discussed. In addition, an attempt will be made to summarize the experiences made in module assemblies in different labs/projects such as DESY (TTF), Jlab (Upgrade) and SNS.

  5. Cavity preparation/assembly techniques and impact on Q, realistic Q-factors in a module, review of modules

    Energy Technology Data Exchange (ETDEWEB)

    Kneisel, Peter [Jefferson Laboratory, 12000 Jefferson Avenue, Newport News, VA 23606 (United States)]. E-mail: kneisel@jlab.org

    2006-02-01

    This contribution summarizes the surface preparation procedures for niobium cavities presently used both in laboratory experiments and for modules, such as buffered chemical polishing (BCP), electropolishing (EP), high pressure ultrapure water rinsing (HPR), CO{sub 2} snow cleaning and high temperature heat treatments for hydrogen degassing or post-purification. The impact of surface treatments and the degree of cleanliness during assembly procedures on cavity performance (Q-value and accelerating gradient E {sub acc}) will be discussed. In addition, an attempt will be made to summarize the experiences made in module assemblies in different labs/projects such as DESY (TTF), Jlab (Upgrade) and SNS.

  6. Bilirubin modulated cytokines, growth factors and angiogenesis to improve cutaneous wound healing process in diabetic rats.

    Science.gov (United States)

    Ram, Mahendra; Singh, Vishakha; Kumawat, Sanjay; Kant, Vinay; Tandan, Surendra Kumar; Kumar, Dinesh

    2016-01-01

    Bilirubin has shown cutaneous wound healing potential in some preliminary studies. Here we hypothesize that bilirubin facilitates wound healing in diabetic rats by modulating important healing factors/candidates and antioxidant parameters in a time-dependent manner. Diabetes was induced in male Wistar rats by streptozotocin. In all diabetic rats wounds were created under pentobarbitone anesthesia. All the rats were divided into two groups, of which one (control) was treated with ointment base and other with bilirubin ointment (0.3%). Wound closer measurement and tissue collection were done on days 3, 7, 14 and 19 post-wounding. The relative expressions of hypoxia inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 alpha (SDF-1α), transforming growth factor- beta1 (TGF-β1()), tumor necrosis factor-α (TNF-α) and interlukin-10 (IL-10) mRNA and proteins and the mRNA of interlukin-1 beta (IL-1β) and matrix metalloprteinase-9 (MMP-9) were determined in the wound tissues. CD-31 staining and collagen content were evaluated by immunohistochemistry and picrosirius red staining, respectively. Histopathological changes were assessed by H&E staining. The per cent wound closer was significantly higher from day 7 onwards in bilirubin-treated rats. HIF-1α, VEGF, SDF-1α, TGF-β1, IL-10 mRNA and protein levels were significantly higher on days 3, 7 and 14 in bilirubin-treated rats. The mRNA expression and protein level of TNF-α and the mRNA of IL-1β and MMP-9 were progressively and markedly reduced in bilirubin-treated rats. The collagen deposition and formation of blood vessels were greater in bilirubin-treated rats. Bilirubin markedly facilitated cutaneous wound healing in diabetic rats by modulating growth factors, cytokines, neovasculogenesis and collagen contents to the wound site. Topical application of bilirubin ointment might be of great use in cutaneous wound healing in diabetic patients.

  7. Host genetic factors in susceptibility to HIV-1 infection and progression to AIDS

    Indian Academy of Sciences (India)

    Koushik Chatterjee

    2010-04-01

    HIV-1 infection has rapidly spread worldwide and has become the leading cause of mortality in infectious diseases. The duration for development of AIDS (AIDS progression) is highly variable among HIV–1 infected individuals, ranging from 2–3 years to no signs of AIDS development in the entire lifetime. Several factors regulate the rate at which HIV-1 infection progresses to AIDS. Host genetic factors play an important role in the outcome of such complex or multifactor diseases as AIDS and are also known to regulate the rate of disease progression. This review focuses on the major host genes reported to affect the progression to AIDS in HIV-1 infected individuals.

  8. Advances in behavioral genetics modeling using Mplus: applications of factor mixture modeling to twin data.

    Science.gov (United States)

    Muthén, Bengt; Asparouhov, Tihomir; Rebollo, Irene

    2006-06-01

    This article discusses new latent variable techniques developed by the authors. As an illustration, a new factor mixture model is applied to the monozygotic-dizygotic twin analysis of binary items measuring alcohol-use disorder. In this model, heritability is simultaneously studied with respect to latent class membership and within-class severity dimensions. Different latent classes of individuals are allowed to have different heritability for the severity dimensions. The factor mixture approach appears to have great potential for the genetic analyses of heterogeneous populations. Generalizations for longitudinal data are also outlined.

  9. Modulation of endotoxicity of Shigella generalized modules for membrane antigens (GMMA) by genetic lipid A modifications: relative activation of TLR4 and TLR2 pathways in different mutants.

    Science.gov (United States)

    Rossi, Omar; Pesce, Isabella; Giannelli, Carlo; Aprea, Susanna; Caboni, Mariaelena; Citiulo, Francesco; Valentini, Sara; Ferlenghi, Ilaria; MacLennan, Calman Alexander; D'Oro, Ugo; Saul, Allan; Gerke, Christiane

    2014-09-05

    Outer membrane particles from Gram-negative bacteria are attractive vaccine candidates as they present surface antigens in their natural context. We previously developed a high yield production process for genetically derived particles, called generalized modules for membrane antigens (GMMA), from Shigella. As GMMA are derived from the outer membrane, they contain immunostimulatory components, especially lipopolysaccharide (LPS). We examined ways of reducing their reactogenicity by modifying lipid A, the endotoxic part of LPS, through deletion of late acyltransferase genes, msbB or htrB, in GMMA-producing Shigella sonnei and Shigella flexneri strains. GMMA with resulting penta-acylated lipid A from the msbB mutants showed a 600-fold reduced ability, and GMMA from the S. sonnei ΔhtrB mutant showed a 60,000-fold reduced ability compared with GMMA with wild-type lipid A to stimulate human Toll-like receptor 4 (TLR4) in a reporter cell line. In human peripheral blood mononuclear cells, GMMA with penta-acylated lipid A showed a marked reduction in induction of inflammatory cytokines (S. sonnei ΔhtrB, 800-fold; ΔmsbB mutants, 300-fold). We found that the residual activity of these GMMA is largely due to non-lipid A-related TLR2 activation. In contrast, in the S. flexneri ΔhtrB mutant, a compensatory lipid A palmitoleoylation resulted in GMMA with hexa-acylated lipid A with ∼10-fold higher activity to stimulate peripheral blood mononuclear cells than GMMA with penta-acylated lipid A, mostly due to retained TLR4 activity. Thus, for use as vaccines, GMMA will likely require lipid A penta-acylation. The results identify the relative contributions of TLR4 and TLR2 activation by GMMA, which need to be taken into consideration for GMMA vaccine development.

  10. THE EFFECT OF GENETIC AND ENVIRONMENTAL FACTORS TO FACIAL SHAPE IN DOWN’S SYNDROME PATIENTS

    Directory of Open Access Journals (Sweden)

    Margaretha Suharsini

    2006-04-01

    Full Text Available Down’s syndrome is caused by chromosomal aberration, namely 21 trisomy. Skeletal and neurological disorders are found in Down’s syndrome patients. Skeletal disorder may cause craniofacial growth abnormalities whereas neurological disorder may cause brain growth defects, which result in mental retardation, as well as neuromuscular disorder, which results in muscular hypotonia. The aim of this study was to prove that facial shape in Down’s syndrome patient was not only influenced by genetic factors, but also by environmental factors such as cognitive capability, oral muscular exercises and oral muscular tone. The population consisted of Down’s syndrome children aged 14 to 18 years from Sekolah Luar Biasa (Special School in Jakarta. Samples used in the study consisted of 25 Down’s syndrome patients. Clinical and cytogenic test were conducted to ensure a diagnosis. Lateral cephalograms were made to analyze facial shape by Fourier analysis on gonion angle. Intelligence Quotient (IQ and Social Quotient (SQ tests, electromyography examination of the masseter and temporal muscles, oral function examination and speech therapy questionnaires to the respondents were performed. The data were analyzed using path analysis. Based on the results of the study, it could be concluded that the genetic factor is the main factor causing Down’s syndrome facial shape abnormalities. The environmental factors such as oral muscular tone, cognitive capability, and oral muscular exercises may also play a role in Down’s syndrome facial shape.

  11. [Influences of genetic and environmental factors on smoking related behaviors among male twin adults in China].

    Science.gov (United States)

    Bao, Z Q; Yu, C Q; Wang, B Q; Cao, W H; Gao, W J; Lyu, J; Wang, S F; Pang, Z C; Cong, L M; Dong, Z; Wu, F; Wang, H; Wu, X P; Wang, D Z; Wang, X J; Wang, B Y; Li, L M

    2016-05-01

    To analyze the influences of genetic and environmental factors on smoking behavior, smoking cessation and onset age of smoking less than 20 years in male twin adults. A face-to-face questionnaire was conducted to collect data from 6 458 pair male twins aged ≥25 years registered in 9 provinces(municipality)in China. The heritability of three smoking related behaviors were calculated by using structural equation models. The ACE models were the best models of the three dimensions of smoking, i.e. smoking behavior, smoking cessation and onset age of smoking less than 20 years for male twins, and the corresponding heritability of these behaviors were 0.26(0.19-0.34), 0.27(0.19-0.37)and 0.05(0.00-0.14), respectively. When adjusted for area and age, the heritability of these three behaviors were 0.26(0.19-0.34), 0.31(0.00-0.74)and 0.05(0.00-0.14), respectively. All the three smoking related behaviors were affected by genetic factors, but environment factors had more effect on them. For smoking cessation, the heritability was highest, but the influence of environmental factors was lowest. Meanwhile, for onset age of smoking, the influence of environmental factors was highest.

  12. Evidence for an intrinsic factor promoting landscape genetic divergence in Madagascan leaf-litter frogs.

    Science.gov (United States)

    Wollenberg Valero, Katharina C

    2015-01-01

    The endemic Malagasy frog radiations are an ideal model system to study patterns and processes of speciation in amphibians. Large-scale diversity patterns of these frogs, together with other endemic animal radiations, led to the postulation of new and the application of known hypotheses of species diversification causing diversity patterns in this biodiversity hotspot. Both extrinsic and intrinsic factors have been studied in a comparative framework, with extrinsic factors usually being related to the physical environment (landscape, climate, river catchments, mountain chains), and intrinsic factors being clade-specific traits or constraints (reproduction, ecology, morphology, physiology). Despite some general patterns emerging from such large-scale comparative analyses, it became clear that the mechanism of diversification in Madagascar may vary among clades, and may be a multifactorial process. In this contribution, I test for intrinsic factors promoting population-level divergence within a clade of terrestrial, diurnal leaf-litter frogs (genus Gephyromantis) that has previously been shown to diversify according to extrinsic factors. Landscape genetic analyses of the microendemic species Gephyromantis enki and its widely distributed, larger sister species Gephyromantis boulengeri over a rugged landscape in the Ranomafana area shows that genetic variance of the smaller species cannot be explained by landscape resistance alone. Both topographic and riverine barriers are found to be important in generating this divergence. This case study yields additional evidence for the probable importance of body size in lineage diversification.

  13. A genetic polymorphism of the endogenous opioid dynorphin modulates monetary reward anticipation in the corticostriatal loop.

    Directory of Open Access Journals (Sweden)

    Mikhail Votinov

    Full Text Available The dynorphin/κ-opioid receptor (KOP-R system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype of the variable nucleotide tandem repeat (68-bp VNTR functional polymorphism of the prodynorphin (PDYN gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype. We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.

  14. Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions.

    Science.gov (United States)

    Silberman, Yuval; Winder, Danny G

    2015-05-01

    The central amygdala is a critical brain region for many aspects of alcohol dependence. Much of the work examining the mechanisms by which the central amygdala mediates the development of alcohol dependence has focused on the interaction of acute and chronic ethanol with central amygdala corticotropin releasing factor signaling. This work has led to a great deal of success in furthering the general understanding of central amygdala neurocircuitry and its role in alcohol dependence. Much of this work has primarily focused on the hypothesis that ethanol utilizes endogenous corticotropin releasing factor signaling to upregulate inhibitory GABAergic transmission in the central amygdala. Work that is more recent suggests that corticotropin releasing factor also plays an important role in mediating anxiety-like behaviors via the enhancement of central amygdala glutamatergic transmission, implying that ethanol/corticotropin releasing factor interactions may modulate excitatory neurotransmission in this brain region. In addition, a number of studies utilizing optogenetic strategies or transgenic mouse lines have begun to examine specific central amygdala neurocircuit dynamics and neuronal subpopulations to better understand overall central amygdala neurocircuitry and the role of neuronal subtypes in mediating anxiety-like behaviors. This review will provide a brief update on this literature and describe some potential future directions that may be important for the development of better treatments for alcohol addiction.

  15. Trophic factor-induced excitatory synaptogenesis involves postsynaptic modulation of nicotinic acetylcholine receptors.

    Science.gov (United States)

    Woodin, Melanie A; Munno, David W; Syed, Naweed I

    2002-01-15

    Neurotrophic factors have well established roles in neuronal development, although their precise involvement in synapse formation and plasticity is yet to be fully determined. Using soma-soma synapses between identified Lymnaea neurons, we have shown recently that trophic factors are required for excitatory but not inhibitory synapse formation. However, neither the precise site (presynaptic versus postsynaptic cell) nor the underlying mechanisms have yet been defined. In the present study, synapse formation between the presynaptic cell visceral dorsal 4 (VD4) and its postsynaptic partner right pedal dorsal 1 (RPeD1) was examined to define the cellular mechanisms mediating trophic factor-induced excitatory synaptogenesis in cell culture. When paired in a soma-soma configuration in the presence of defined media (DM, nonproteinacious), mutually inhibitory synapses were appropriately reconstructed between VD4 and RPeD1. However, when cells were paired in the presence of increasing concentrations of Lymnaea brain-conditioned medium (CM), a biphasic synapse (initial excitatory synaptic component followed by inhibition) developed. The CM-induced excitatory synapse formation required trophic factor-mediated activation of receptor tyrosine kinases in the postsynaptic cell, RPeD1, and a concomitant modulation of existing postsynaptic nicotinic acetylcholine receptors (nAChRs). Specifically, when RPeD1 was isolated in DM, exogenously applied ACh induced a hyperpolarizing response that was sensitive to the AChR antagonist methyllycaconitine (MLA). In contrast, a single RPeD1 isolated in CM exhibited a biphasic response to exogenously applied ACh. The initial depolarizing phase of the biphasic response was sensitive to both mecamylamine and hexamethonium chloride, whereas the hyperpolarizing phase was blocked by MLA. In soma-soma-paired neurons, the VD4-induced synaptic responses in RPeD1 were sensitive to the cholinergic antagonists in a concentration range similar to that

  16. Common genetic risk factors for venous thrombosis in the Chinese population.

    Science.gov (United States)

    Tang, Liang; Wang, Hua-Fang; Lu, Xuan; Jian, Xiao-Rong; Jin, Bi; Zheng, Hong; Li, Yi-Qing; Wang, Qing-Yun; Wu, Tang-Chun; Guo, Huan; Liu, Hui; Guo, Tao; Yu, Jian-Ming; Yang, Rui; Yang, Yan; Hu, Yu

    2013-02-07

    Venous thrombosis is a major medical disorder caused by both genetic and environmental factors. Little is known about the genetic background of venous thrombosis in the Chinese population. A total of 1,304 individuals diagnosed with a first venous thrombosis and 1,334 age- and sex-matched healthy participants were enrolled in this study. Resequencing of THBD (encoding thrombomodulin) in 60 individuals with venous thrombosis and 60 controls and a functional assay showed that a common variant, c.-151G>T (rs16984852), in the 5' UTR significantly reduced the gene expression and could cause a predisposition to venous thrombosis. Therefore, this variant was genotyped in a case-control study, and results indicated that heterozygotes had a 2.80-fold (95% confidence interval = 1.88-4.29) increased risk of venous thrombosis. The THBD c.-151G>T variant was further investigated in a family analysis involving 176 first-degree relatives from 38 index families. First-degree relatives with this variant had a 3.42-fold increased risk of venous thrombosis, and their probability of remaining thrombosis-free was significantly lower than that of relatives without the variant. In addition, five rare mutations that might be deleterious were also identified in thrombophilic individuals by sequencing. This study is the largest genetic investigation of venous thrombosis in the Chinese population. Further study on genetics of thrombosis should focus on resequencing of THBD and other hemostasis genes in different populations.

  17. Mouse models for studying genetic influences on factors determining smoking cessation success in humans

    Science.gov (United States)

    Hall, F. Scott; Markou, Athina; Levin, Edward D.; Uhl, George R.

    2014-01-01

    Humans differ in their ability to quit using addictive substances, including nicotine, the major psychoactive ingredient in tobacco. For tobacco smoking, a substantial body of evidence, largely derived from twin studies, indicates that approximately half of these individual differences in ability to quit are heritable [1, 2], genetic influences that likely overlap with those for other addictive substances [3]. Both twin and molecular genetic studies support overlapping influences on nicotine addiction vulnerability and smoking cessation success, although there is little formal analysis of the twin data that supports this important point [2, 3]. None of the current datasets provides clear data concerning which heritable factors might provide robust dimensions around which individuals differ in ability to quit smoking. One approach to this problem is to test mice with genetic variations in genes that contain human variants that alter quit-success. This review considers which features of quit success should be included in a comprehensive approach to elucidating the genetics of quit success, and how those features may be modeled in mice. PMID:22304675

  18. [Progress in studies on the genetic risk factors for nonsyndromic cleft lip or palate in China].

    Science.gov (United States)

    Huang, Y Q

    2017-04-09

    Cleft lip and palate is the most common congenital defects of oral and maxillofacial region in human beings. The etiology of this malformation is complex, with both genetic and environmental causal factors are involved. To provide a better understanding in the genetic etiology of cleft lip or palate, the author summarized recent years studies based on Chinese population. Those researches included validation of some candidate genes for cleft lip or palate, using genome wide association analysis which included six independent cohorts from China to elucidate the genetic architecture of non-syndromic cleft lip with or without cleft palate in Chinese population and finally found a new susceptibility locus. This locus was on the 16p13.3 (rs8049367) between CREBBP and ADCY9. It has been mentioned common methods of genetic analysis involved in the researches on cleft lip or palate in this paper. Furthermore, we try to discuss new methods to illustrate the etiology of cleft lip and palate that could provide more inspiration on future researches.

  19. Differential expression of migration inhibitory and migration stimulatory factors in two lines of mice genetically selected for high or low responsiveness to phytohemagglutinin. 1. Migration stimulatory factor(s) from T and B cells of immune spleen.

    Science.gov (United States)

    Gauthier-Rahman, S; el-Gharbi, N; Siddiqui, M U; Couderc, J; Decreusefond, C; Stiffel, C

    1991-01-01

    Expression of the lymphokine migration inhibition factor in two lines of mice genetically selected for the high (Hi/PHA) or low (Lo/PHA) response of their lymph node cells to phytohemagglutinin was found to be modulated by concomitant expression of migration stimulation factor(s) [MStF(s)]. The expression of both lymphokines was dependent on genetic character and the immunizing dose of antigen. In mice immunized 5 days earlier with 50 micrograms ovalbumin in Freund's complete adjuvant (Ova in FCA immune), migration inhibition factor, assessed with a sensitive photoelectric method, was well expressed by male spleen or lymph node 24-hour culture supernatants of Lo/PHA but Hi/PHA, especially female, expressed marked MStF(s) instead. Immunization with 500 micrograms Ova in FCA markedly enhanced expression of MStF(s) in Lo/PHA but inhibited it in Hi/PHA. MStF(s) of Ova in FCA immune spleens of the two lines were found to derive from both T and B cells, B cell activity being greater. Lo/PHA were by far better expressors of both T- and B-cell-derived MStF(s) as compared to Hi/PHA (p less than 0.01). Spleen cells of mice immunized with FCA alone also expressed MStF(s) but to lesser extent than Ova in FCA immune spleens, expression by Lo/PHA B cells being significantly higher than in Hi/PHA (p less than 0.05). The MStF(s) of Ova in FCA immune spleens was found to be non-immunoglobulin in nature.

  20. A Novel Technique of Measuring SOA Differential Carrier Lifetime and a -Factor Using SOA Optical Modulation Response

    Institute of Scientific and Technical Information of China (English)

    Ki-Hyuk Lee; Woo-Young Choi

    2003-01-01

    We demonstrate a new technique of measuring differential carrier lifetime and linewidth enhancement factor in a semiconductor optical amplifier. In our method, the optical responses and fiber transfer functions of a self-gain modulated SOA are measured and, from these, values of carrier lifetimes and linewidth enhancement factors are determined for various SOA input optical powers.

  1. Estrogens and Insulin-Like Growth Factor 1 Modulate Neoplastic Cell Growth in Human Cholangiocarcinoma

    Science.gov (United States)

    Alvaro, Domenico; Barbaro, Barbara; Franchitto, Antonio; Onori, Paolo; Glaser, Shannon S.; Alpini, Gianfranco; Francis, Heather; Marucci, Luca; Sterpetti, Paola; Ginanni-Corradini, Stefano; Onetti Muda, Andrea; Dostal, David E.; De Santis, Adriano; Attili, Adolfo F.; Benedetti, Antonio; Gaudio, Eugenio

    2006-01-01

    We investigated the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF-1), and IGF-1R (receptor) in human cholangiocarcinoma and cholangiocarcinoma cell lines (HuH-28, TFK-1, Mz-ChA-1), evaluating the role of estrogens and IGF-1 in the modulation of neoplastic cell growth. ER-α, ER-β, IGF-1, and IGF-1R were expressed (immunohistochemistry) in all biopsies (18 of 18) of intrahepatic cholangiocarcinoma. ER-α was expressed (Western blot) only by the HuH-28 cell line (intrahepatic cholangiocarcinoma), whereas ER-β, IGF-1, and IGF-1R were expressed in the three cell lines examined. In serum-deprived HuH-28 cells, serum readmission induced stimulation of cell proliferation that was inhibited by ER and IGF-1R antagonists. 17β-Estradiol and IGF-1 stimulated proliferation of HuH-28 cells to a similar extent to that of MCF7 (breast cancer) but greater than that of TFK-1 and Mz-ChA-1, inhibiting apoptosis and exerting additive effects. These effects of 17β-estradiol and IGF-1 were associated with enhanced protein expression of ER-α, phosphorylated (p)-ERK1/2 and pAKT but with decreased expression of ER-β. Finally, transfection of IGF-1R anti-sense oligonucleotides in HuH-28 cells markedly decreased cell proliferation. In conclusion, human intrahepatic cholangiocarcinomas express receptors for estrogens and IGF-1, which cooperate in the modulation of cell growth and apoptosis. Modulation of ER and IGF-1R could represent a strategy for the management of cholangiocarcinoma. PMID:16936263

  2. Motivational salience and genetic variability of dopamine D2 receptor expression interact in the modulation of interference processing

    Directory of Open Access Journals (Sweden)

    Anni eRichter

    2013-06-01

    Full Text Available Dopamine has been implicated in the fine-tuning of complex cognitive and motor function and also in the anticipation of future rewards. This dual function of dopamine suggests that dopamine might be involved in the generation of active motivated behavior. The DRD2 TaqIA polymorphism of the dopamine D2 receptor gene (rs1800497 has previously been suggested to affect striatal function with carriers of the less common A1 allele exhibiting reduced striatal D2 receptor density and increased risk for addiction. Here we aimed to investigate the influences of DRD2 TaqIA genotype on the modulation of interference processing by reward and punishment. 46 young, healthy volunteers participated in a behavioral experiment, and 32 underwent functional magnetic resonance imaging (fMRI. Participants performed a flanker task with a motivation manipulation (monetary reward, monetary loss, neither, or both. Reaction times (RTs were shorter in motivated flanker trials, irrespective of congruency. In the fMRI experiment motivation was associated with reduced prefrontal activation during incongruent versus congruent flanker trials, possibly reflecting increased processing efficiency. DRD2 TaqIA genotype did not affect overall RTs, but interacted with motivation on the congruency-related RT differences, with A1 carriers showing smaller interference effects to reward alone and A2 homozygotes exhibiting a specific interference reduction during combined reward and punishment trials. In fMRI, anterior cingulate activity showed a similar pattern of genotype-related modulation. Additionally, A1 carriers showed increased anterior insula activation relative to A2 homozygotes. Our results point to a role for genetic variations of the dopaminergic system in individual differences of cognition-motivation interaction.

  3. Electrical stimulation of cardiac adipose tissue-derived progenitor cells modulates cell phenotype and genetic machinery.

    Science.gov (United States)

    Llucià-Valldeperas, A; Sanchez, B; Soler-Botija, C; Gálvez-Montón, C; Prat-Vidal, C; Roura, S; Rosell-Ferrer, J; Bragos, R; Bayes-Genis, A

    2015-11-01

    A major challenge of cardiac tissue engineering is directing cells to establish the physiological structure and function of the myocardium being replaced. Our aim was to examine the effect of electrical stimulation on the cardiodifferentiation potential of cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs). Three different electrical stimulation protocols were tested; the selected protocol consisted of 2 ms monophasic square-wave pulses of 50 mV/cm at 1 Hz over 14 days. Cardiac and subcutaneous ATDPCs were grown on biocompatible patterned surfaces. Cardiomyogenic differentiation was examined by real-time PCR and immunocytofluorescence. In cardiac ATDPCs, MEF2A and GATA-4 were significantly upregulated at day 14 after stimulation, while subcutaneous ATDPCs only exhibited increased Cx43 expression. In response to electrical stimulation, cardiac ATDPCs elongated, and both cardiac and subcutaneous ATDPCs became aligned following the linear surface pattern of the construct. Cardiac ATDPC length increased by 11.3%, while subcutaneous ATDPC length diminished by 11.2% (p = 0.013 and p = 0.030 vs unstimulated controls, respectively). Compared to controls, electrostimulated cells became aligned better to the patterned surfaces when the pattern was perpendicular to the electric field (89.71 ± 28.47º for cardiac ATDPCs and 92.15 ± 15.21º for subcutaneous ATDPCs). Electrical stimulation of cardiac ATDPCs caused changes in cell phenotype and genetic machinery, making them more suitable for cardiac regeneration approaches. Thus, it seems advisable to use electrical cell training before delivery as a cell suspension or within engineered tissue.

  4. Genetic Variations at ABCG5/G8 Genes Modulate Plasma Lipids Concentrations in Patients with Familial Hypercholesterolemia

    Science.gov (United States)

    Garcia-Rios, A; Perez-Martinez, P; Fuentes, F; Mata, P; Lopez-Miranda, J; Alonso, R; Rodriguez, F; Garcia-Olid, A; Ruano, J; Ordovas, JM; Perez-Jimenez, F

    2010-01-01

    Objective To investigate the association of four common single nucleotide polymorphisms (SNPs) at ABCG5 (i7892A>G, i18429C>T, Gln604GluC>G, i11836G>A) and five at ABCG8 (5U145T>G, Tyr54CysA>G, Asp19HisG>C, i14222T>C, and Thr400LysG>T) with plasma lipids concentrations and to explore the interaction between those SNPs and smoking in patients with FH. Methods and Results ABCG5/G8 SNPs were genotyped in 500 subjects with genetic diagnosis of FH. Carriers of the minor A allele at the ABCG5_i11836G>A SNP displayed significantly higher HDL-C concentrations (P=0.023) than G/G subjects. In addition, carriers of the minor G allele at the ABCG5_Gln604GluC>G SNP had significantly lower VLDL-C (P=0.011) and lower TG (P=0.017) concentrations than homozygous C/C. Interestingly, a significant gene-smoking interaction was found, in which carriers of the minor alleles at ABCG5 (i7892A>G, i18429C>T, i11836G>A) SNPs displayed significantly lower HDL-C, higher TC and higher TG respectively, only in smokers. On the other hand, non-smokers carriers of the minor alleles at ABCG5 (i18429C>T and Gln604GluC>G) SNPs had significantly lower TG concentrations (P=0.012 and P=0.035) compared with homozygous for the major allele. Conclusions Our data support the notion that ABCG5/G8 genetic variants modulate plasma lipids concentrations in patients with FH and confirm that this effect could be influenced by smoking. Therefore, these results suggest that gene-environmental interactions can affect the clinical phenotype of FH. PMID:20172523

  5. Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia.

    Science.gov (United States)

    Wakita, S; Yamaguchi, H; Ueki, T; Usuki, K; Kurosawa, S; Kobayashi, Y; Kawata, E; Tajika, K; Gomi, S; Koizumi, M; Fujiwara, Y; Yui, S; Fukunaga, K; Ryotokuji, T; Hirakawa, T; Arai, K; Kitano, T; Kosaka, F; Tamai, H; Nakayama, K; Fukuda, T; Inokuchi, K

    2016-03-01

    We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P=0.0006) and cumulative incidence of relapse (CIR) significantly higher (P=0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P=0.0010; CIR: P=0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P=0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P=0.0002. CIR: Pmutation analysis to have clinical usefulness and applicability.

  6. Twins and virtual twins: Do genetic (as well as experiential) factors affect developmental risks?

    Science.gov (United States)

    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.

  7. Characterization of Clinical and Genetic Risk Factors Associated with Dyslipidemia after Kidney Transplantation

    Directory of Open Access Journals (Sweden)

    Kazuyuki Numakura

    2015-01-01

    Full Text Available We determined the prevalence of dyslipidemia in a Japanese cohort of renal allograft recipients and investigated clinical and genetic characteristics associated with having the disease. In total, 126 patients that received renal allograft transplants between February 2002 and August 2011 were studied, of which 44 recipients (34.9% were diagnosed with dyslipidemia at 1 year after transplantation. Three clinical factors were associated with a risk of having dyslipidemia: a higher prevalence of disease observed among female than male patients P=0.021 and treatment with high mycophenolate mofetil P=0.012 and prednisolone P=0.023 doses per body weight at 28 days after transplantation. The genetic association between dyslipidemia and 60 previously described genetic polymorphisms in 38 putative disease-associated genes was analyzed. The frequency of dyslipidemia was significantly higher in patients with the glucocorticoid receptor (NR3C1 Bcl1 G allele than in those with the CC genotype P=0.001. A multivariate analysis revealed that the NR3C1 Bcl1 G allele was a significant risk factor for the prevalence of dyslipidemia (odds ratio = 4.6; 95% confidence interval = 1.8–12.2. These findings may aid in predicting a patient’s risk of developing dyslipidemia.

  8. [Role of genetic and environmental factors in the development of polycystic ovary syndrome].

    Science.gov (United States)

    Ságodi, László; Kiss-Tóth, Emőke; Barkai, László

    2013-04-28

    Polycystic ovary syndrome is the most common heterogeneous endocrine abnormality in women in the reproductive age. The syndrome remains an enigmatic disorder because the aetiology is still unclear. Familial aggreagation is relatively common among patients with polycystic ovary syndrome suggesting a significant genetic component, although the way of inheritance has not been established firmly. The authors review the relevant medical literature and suggest that genetic and environmental factors play a role in the development of polycystic ovary syndrome. To date, no gene has been identified that causes or contributes substantially to the development of a polycystic ovary syndrome phenotype. Polycystic ovarian syndrome is considered to be an oligogenic disorder in which the interaction of a number of genetic and environmental factors determines the heterogeneous clinical and biochemical phenotype. To summarize current evidence the authors conclude, that when we are able to identify and then modify environmental determinants, then we will be able to safeguard better the health of those patients who are predisposed to disease development due to genotype or previous environmental effects.

  9. Adrenomedullin A Novel Peptide Requires Coordination Of Genetic Physiologic And Environmental Factors

    Directory of Open Access Journals (Sweden)

    K. R. Padma

    2015-08-01

    Full Text Available A healthy pregnancy requires strict coordination of genetic physiologic and environmental factors. The relatively common incidence of infertility and pregnancy complications has resulted in increased interest in understanding the mechanisms that underlie normal versus abnormal pregnancy. The peptide hormone adrenomedullin has recently been the focus of some exciting breakthroughs in the pregnancy field. Adrenomedullin ADM is a 52-amino acid peptide with structural homology to calcitonin gene-related peptide CGRP initially isolated from human pheochromocytoma. ADM is synthesized by many mammalian tissues including the adrenal medulla endothelial and vascular smooth muscle cells myocardium and central nervous system. ADM binds to plasma membrane receptors composed of calcitonin receptor-like receptor CRLR a member of serpentine receptor superfamily and receptor activity modifying protein RAMP type 2 or 3. ADM has also some affinity for CGRP receptor composed of CRLR and RAMP1. Supported by mechanistic studies in genetic animal models there continues to be a growing body of evidence demonstrating the importance of adrenomedullin protein levels in a variety of human pregnancy complications. With measurement of foetal resorption sites we can examine the importance of adrenomedullin a peptide hormone in pregnancy which alters due to genetic physiologic and environmental factors. A growing body of evidence illustrates AM as a pivotal component in normal physiology and disease with marked beneficial effects in the host defense mechanism.

  10. Spermatogenesis associated 4 promotes Sertoli cell proliferation modulated negatively by regulatory factor X1.

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    Junjun Jiang

    Full Text Available Spermatogenesis associated 4 (Spata4, a testis-specific and CpG island associated gene, is involved in regulating cell proliferation, differentiation and apoptosis. To obtain insight into the role of Spata4 in cell cycling control, we characterized the promoter region of Spata4 and investigated its transcriptional regulation mechanism. The Spata4 promoter is unidirectional transcribed and possesses multiple transcription start sites. Moreover, we present evidence that regulatory factor X1 (RFX1 could bind the typical 14-bp cis-elements of Spata4 promoter, modulate transcriptional activity and endogenous expression of Spata4, and further regulate the proliferation of Sertoli cells. Overexpression of RFX1 was shown to down-regulate both the promoter activity and mRNA expression of Spata4, whereas knockdown of RFX1 demonstrated the opposite effects. Our studies provide insight into Spata4 gene regulation and imply the potential role of RFX1 in growth of Sertoli cells. RFX1 may have negative effect on cell proliferation of Sertoli cells via modulating Spata4 expression levels by binding the conserved 14-bp cis-elements of Spata4 promoter.

  11. Material-mediated proangiogenic factor release pattern modulates quality of regenerated blood vessels.

    Science.gov (United States)

    Rich, Max H; Lee, Min Kyung; Baek, Kwanghyun; Jeong, Jae Hyun; Kim, Dong Hyun; Millet, Larry J; Bashir, Rashid; Kong, Hyunjoon

    2014-12-28

    Hydrogels designed to sustainably release bioactive molecules are extensively used to enhance tissue repair and regenerative therapies. Along this line, numerous efforts are made to control the molecular release rate and amount. In contrast, few efforts are made to control the molecular release pattern, and, subsequently, modulate the spatial organization of newly forming tissues, including blood vessels. Therefore, using a hydrogel printed to release vascular endothelial growth factor (VEGF) into a pre-defined pattern, this study demonstrates that spatial distribution of VEGF is important in guiding growth direction of new blood vessels, and also in retaining the structural integrity of pre-existing vasculature. Guided by a computational model, we fabricated a patch composed of micro-sized VEGF-releasing poly(ethylene glycol) diacrylate (PEGDA) hydrogel cylinders using an ink-jet printer. Interestingly, hydrogel printed with computationally optimized spacing created anisotropically aligned vasculature exclusively when the printed gel pattern was placed parallel to pre-existing blood vessels. In contrast, vascular sprouting from placing the printed gel pattern perpendicular to pre-existing vessels resulted in deformation and structural disintegration of the original vasculature. We envision that this study will be useful to better understand angiogenesis-modulated neovascularization and further improve the treatment quality for various wounds and tissue defects.

  12. [Methylmercury exposure in the general population; toxicokinetics; differences by gender, nutritional and genetic factors].

    Science.gov (United States)

    González-Estecha, Montserrat; Bodas-Pinedo, Andrés; Guillén-Pérez, José Jesús; Rubio-Herrera, Miguel Ángel; Ordóñez-Iriarte, José M; Trasobares-Iglesias, Elena M; Martell-Claros, Nieves; Martínez-Álvarez, Jesús Román; Farré-Rovira, Rosaura; Herráiz-Martínez, Miguel Ángel; Martínez-Astorquiza, Txantón; Calvo-Manuel, Elpidio; Sáinz-Martín, María; Bretón-Lesmes, Irene; Prieto-Menchero, Santiago; Llorente-Ballesteros, M Teresa; Martínez-García, M José; Salas-Salvadó, Jordi; Bermejo-Barrera, Pilar; García-Donaire, José Antonio; Cuadrado-Cenzual, M Ángeles; Gallardo-Pino, Carmen; Moreno-Rojas, Rafael; Arroyo-Fernández, Manuel; Calle-Pascual, Alfonso

    2014-11-01

    Mercury is an environmental toxicant that causes numerous adverse effects on human health and natural ecosystems. The factors that determine the existance of adverse effects, as well as their severity are, among others: the chemical form of mercury (elemental, inorganic, organic), dosis, age, period of exposure, pathways of exposure and environmental, nutritional and genetic factors. In the aquatic cycle of mercury, once it has been deposited, it is transformed into methylmercury due to the action of certain sulphate-reducing bacteria, which bioaccumulates in the aquatic organisms and moves into the food chain. The methylmercury content of large, long-lived fish such as swordfish, shark, tuna or marlin, is higher. Methylmercury binds to protein in fish and is therefore not eliminated by cleaning or cooking the fish. Fetuses and small children are more vulnerable to the neurotoxic effects of methylmercury from the consumption of contaminated fish. Methylmercury is absorbed in the gastrointestinal tract and crosses the blood-brain barrier and the placenta. The intake of certain dietary components such as polyunsaturated fatty acids, selenium, fiber, thiol compounds, certain phytochemicals and other nutrients can modify methylmercury bioaccesibility and its toxicity. Apart from environmental factors, genetic factors can influence mercury toxicity and explain part of the individual vulnerability.

  13. Genetically Determined Chronic Pancreatitis but not Alcoholic Pancreatitis Is a Strong Risk Factor for Pancreatic Cancer.

    Science.gov (United States)

    Midha, Shallu; Sreenivas, Vishnubhatla; Kabra, Madhulika; Chattopadhyay, Tushar Kanti; Joshi, Yogendra Kumar; Garg, Pramod Kumar

    2016-11-01

    To study if chronic pancreatitis (CP) is a risk factor for pancreatic cancer. Through a cohort and a case-control study design, CP and other important risk factors including smoking, diabetes, alcohol, obesity, and genetic mutations were studied for their association with pancreatic cancer. In the cohort study, 402 patients with CP were included. During 3967.74 person-years of exposure, 5 of the 402 patients (4 idiopathic CP, 1 hereditary CP) developed pancreatic cancer after 16.60 ± 3.51 years of CP. The standardized incidence ratio was 121. In the case-control study, 249 pancreatic cancer patients and 1000 healthy controls were included. Of the 249 patients with pancreatic cancer, 24 had underlying idiopathic CP, and none had alcoholic pancreatitis. SPINK1 gene mutation was present in 16 of 26 patients with idiopathic CP who had pancreatic cancer. Multivariable analysis showed CP (odds ratio [OR], 97.67; 95% confidence interval [CI], 12.69-751.36), diabetes (>4 years duration) (OR, 3.05; 95% CI, 1.79-5.18), smoking (OR, 1.93; 95% CI, 1.38-2.69) as significant risk factors for pancreatic cancer. The population attributable risk was 9.41, 9.06, and 9.50 for diabetes, CP, and smoking, respectively. Genetically determined CP but not alcoholic CP is a strong risk factor for pancreatic cancer.

  14. Genetics and Molecular Biology of Epstein-Barr Virus-Encoded BART MicroRNA: A Paradigm for Viral Modulation of Host Immune Response Genes and Genome Stability

    Directory of Open Access Journals (Sweden)

    David H. Dreyfus

    2017-01-01

    Full Text Available Epstein-Barr virus, a ubiquitous human herpesvirus, is associated through epidemiologic evidence with common autoimmune syndromes and cancers. However, specific genetic mechanisms of pathogenesis have been difficult to identify. In this review, the author summarizes evidence that recently discovered noncoding RNAs termed microRNA encoded by Epstein-Barr virus BARF (BamHI A right frame termed BART (BamHI A right transcripts are modulators of human immune response genes and genome stability in infected and bystander cells. BART expression is apparently regulated by complex feedback loops with the host immune response regulatory NF-κB transcription factors. EBV-encoded BZLF-1 (ZEBRA protein could also regulate BART since ZEBRA contains a terminal region similar to ankyrin proteins such as IκBα that regulate host NF-κB. BALF-2 (BamHI A left frame transcript, a viral homologue of the immunoglobulin and T cell receptor gene recombinase RAG-1 (recombination-activating gene-1, may also be coregulated with BART since BALF-2 regulatory sequences are located near the BART locus. Viral-encoded microRNA and viral mRNA transferred to bystander cells through vesicles, defective viral particles, or other mechanisms suggest a new paradigm in which bystander or hit-and-run mechanisms enable the virus to transiently or chronically alter human immune response genes as well as the stability of the human genome.

  15. Metabolic factors and genetic risk mediate familial type 2 diabetes risk in the Framingham Heart Study

    Science.gov (United States)

    Raghavan, Sridharan; Porneala, Bianca; McKeown, Nicola; Fox, Caroline S.; Dupuis, Josée; Meigs, James B.

    2015-01-01

    Aims/hypothesis Type 2 diabetes mellitus in parents is a strong determinant of diabetes risk in their offspring. We hypothesise that offspring diabetes risk associated with parental diabetes is mediated by metabolic risk factors. Methods We studied initially non-diabetic participants of the Framingham Offspring Study. Metabolic risk was estimated using beta cell corrected insulin response (CIR), HOMA-IR or a count of metabolic syndrome components (metabolic syndrome score [MSS]). Dietary risk and physical activity were estimated using questionnaire responses. Genetic risk score (GRS) was estimated as the count of 62 type 2 diabetes risk alleles. The outcome of incident diabetes in offspring was examined across levels of parental diabetes exposure, accounting for sibling correlation and adjusting for age, sex and putative mediators. The proportion mediated was estimated by comparing regression coefficients for parental diabetes with (βadj) and without (βunadj) adjustments for CIR, HOMA-IR, MSS and GRS (percentage mediated = 1 – βadj / βunadj). Results Metabolic factors mediated 11% of offspring diabetes risk associated with parental diabetes, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.96. GRS mediated 9% of risk, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.99. Conclusions/interpretation Metabolic risk factors partially mediated offspring type 2 diabetes risk conferred by parental diabetes to a similar magnitude as genetic risk. However, a substantial proportion of offspring diabetes risk associated with parental diabetes remains unexplained by metabolic factors, genetic risk, diet and physical activity, suggesting that important familial influences on diabetes risk remain undiscovered. PMID:25619168

  16. STAT3-Interacting Proteins as Modulators of Transcription Factor Function: Implications to Targeted Cancer Therapy.

    Science.gov (United States)

    Yeh, Jennifer E; Frank, David A

    2016-04-19

    The oncogenic transcription factor STAT3 is inappropriately activated in multiple hematopoietic and solid malignancies, in which it drives the expression of genes involved in cell proliferation, differentiation, survival, and angiogenesis. Thus far, strategies to inhibit the function of STAT3 have focused on blocking the function of its activating kinases or sequestering its DNA binding ability. A less well-explored aspect of STAT3 function is its interaction with other proteins, which can modulate the oncogenic activity of STAT3 via its subcellular localization, DNA binding ability, and recruitment of transcriptional machinery. Herein we summarize what is currently known about STAT3-interacting proteins and describe the utility of a proteomics-based approach for successfully identifying and characterizing novel STAT3-interacting proteins that affect STAT3 transcriptional activity and oncogenic function.

  17. Modulation of Food Reward by Endocrine and Environmental Factors: Update and Perspective.

    Science.gov (United States)

    Figlewicz, Dianne P

    2015-01-01

    Palatable foods are frequently high in energy density. Chronic consumption of high-energy density foods can contribute to the development of cardiometabolic pathology including obesity, diabetes, and cardiovascular disease. This article reviews the contributions of extrinsic and intrinsic factors that influence the reward components of food intake. A narrative review was conducted to determine the behavioral and central nervous system (CNS) related processes involved in the reward components of high-energy density food intake. The rewarding aspects of food, particularly palatable and preferred foods, are regulated by CNS circuitry. Overlaying this regulation is modulation by intrinsic endocrine systems and metabolic hormones relating to energy homeostasis, developmental stage, or gender. It is now recognized that extrinsic or environmental factors, including ambient diet composition and the provocation of stress or anxiety, also contribute substantially to the expression of food reward behaviors such as motivation for, and seeking of, preferred foods. High-energy density food intake is influenced by both physiological and pathophysiological processes. Contextual, behavioral, and psychological factors and CNS-related processes represent potential targets for multiple types of therapeutic intervention.

  18. Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.

    Science.gov (United States)

    Corominas, Roser; Yang, Xinping; Lin, Guan Ning; Kang, Shuli; Shen, Yun; Ghamsari, Lila; Broly, Martin; Rodriguez, Maria; Tam, Stanley; Trigg, Shelly A; Fan, Changyu; Yi, Song; Tasan, Murat; Lemmens, Irma; Kuang, Xingyan; Zhao, Nan; Malhotra, Dheeraj; Michaelson, Jacob J; Vacic, Vladimir; Calderwood, Michael A; Roth, Frederick P; Tavernier, Jan; Horvath, Steve; Salehi-Ashtiani, Kourosh; Korkin, Dmitry; Sebat, Jonathan; Hill, David E; Hao, Tong; Vidal, Marc; Iakoucheva, Lilia M

    2014-04-11

    Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of genetic loci. The convergence of ASD variants have been investigated using various approaches, including protein interactions extracted from the published literature. However, these datasets are frequently incomplete, carry biases and are limited to interactions of a single splicing isoform, which may not be expressed in the disease-relevant tissue. Here we introduce a new interactome mapping approach by experimentally identifying interactions between brain-expressed alternatively spliced variants of ASD risk factors. The Autism Spliceform Interaction Network reveals that almost half of the detected interactions and about 30% of the newly identified interacting partners represent contribution from splicing variants, emphasizing the importance of isoform networks. Isoform interactions greatly contribute to establishing direct physical connections between proteins from the de novo autism CNVs. Our findings demonstrate the critical role of spliceform networks for translating genetic knowledge into a better understanding of human diseases.

  19. Role of Host Genetic Factors in the Outcome of Hepatitis C Virus Infection

    Directory of Open Access Journals (Sweden)

    Hubert E. Blum

    2009-08-01

    Full Text Available The natural history of hepatitis C virus (HCV infection is determined by a complex interplay between host genetic, immunological and viral factors. This review highlights genes involved in innate and adaptive immune responses associated with different outcomes of HCV infection. For example, an association of HCV clearance with certain HLA alleles has been demonstrated. The mechanisms responsible for these associations have been linked to specific T cell responses for some particular alleles (e.g., HLA-B27. Genetic associations involved in T cell regulation and function further underline the role of the adaptive immune response in the natural history of HCV infection. In addition, some genes involved in innate NK cell responses demonstrate the complex interplay between components of the immune system necessary for a successful host response to HCV infection.

  20. Zinc Finger Transcription Factors as Novel Genetic Switches to Modulate Metastatic Progression of Breast Tumors

    Science.gov (United States)

    2008-05-01

    Program, Biochemistry, Université de Montréal with Robert Cedergren 1999-2003 - Research Associate in Dr. Carlos Barbas, III laboratory...PCT/US03/03705 (2001). B. Peer Reviewed Publications (* most significant to proposed work) Blancafort, P., Ferbeyre, G., Sariol, C., and Cedergren , R...and Cedergren , R. The recognition of a non-canonical base pair by a zinc finger protein. Chem Biol. 1999; 6:585-97. Segal, D.J., Beerli R.R, Blancafort

  1. Genetic factors control nicotine self-administration in isogenic adolescent rat strains.

    Directory of Open Access Journals (Sweden)

    Hao Chen

    Full Text Available Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis and six selected F1 hybrids. All rats were trained to press a lever to obtain food starting on postnatal day (PN 32, and then nicotine (0.03 mg/kg/infusion, i.v. reinforcement was made available on PN41-42 (10 consecutive daily 2 h sessions. Of the 12 isogenic strains, Fisher rats self-administered the fewest nicotine infusions (1.45 ± 0.36/d during the last 3 d, while Lewis rats took the most nicotine (13.0 ± 1.4/d. These strains sorted into high, intermediate and low self-administration groups in 2, 2, and 8 strains, respectively. The influence of heredity on nicotine SA (0.64 is similar to that reported for humans. Therefore, this panel of isogenic rat strains effectively models the overall impact of genetics on the vulnerability to acquire nicotine-reinforced behavior during adolescence. Separate groups of rats responded for food starting on PN41. The correlation between nicotine and food reward was not significant. Hence, the genetic control of the motivation to obtain nicotine is distinctly different from food reward, indicating the specificity of the underlying genetic mechanisms. Lastly, the behavior of F1 hybrids was not predicted from the additive behavior of the parental strains, indicating the impact of significant gene-gene interactions on the susceptibility to nicotine reward. Taken together, the behavioral characteristics of this model indicate its strong potential to identify specific genes mediating the human vulnerability to smoke cigarettes.

  2. Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.

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    Robyn A Honea

    Full Text Available There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF, may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs impact Alzheimer's Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer's Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154 who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met, rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459. We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108. No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850. We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD

  3. Cycle modulation of insulin-like growth factor-binding protein 1 in human endometrium

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    Corleta H.

    2000-01-01

    Full Text Available Endometrium is one of the fastest growing human tissues. Sex hormones, estrogen and progesterone, in interaction with several growth factors, control its growth and differentiation. Insulin-like growth factor 1 (IGF-1 interacts with cell surface receptors and also with specific soluble binding proteins. IGF-binding proteins (IGF-BP have been shown to modulate IGF-1 action. Of six known isoforms, IGF-BP-1 has been characterized as a marker produced by endometrial stromal cells in the late secretory phase and in the decidua. In the current study, IGF-1-BP concentration and affinity in the proliferative and secretory phase of the menstrual cycle were measured. Endometrial samples were from patients of reproductive age with regular menstrual cycles and taking no steroid hormones. Cytosolic fractions were prepared and binding of 125I-labeled IGF-1 performed. Cross-linking reaction products were analyzed by SDS-polyacrylamide gel electrophoresis (7.5% followed by autoradiography. 125I-IGF-1 affinity to cytosolic proteins was not statistically different between the proliferative and secretory endometrium. An approximately 35-kDa binding protein was identified when 125I-IGF-1 was cross-linked to cytosol proteins. Secretory endometrium had significantly more IGF-1-BP when compared to proliferative endometrium. The specificity of the cross-linking process was evaluated by the addition of 100 nM unlabeled IGF-1 or insulin. Unlabeled IGF-1 totally abolished the radioactivity from the band, indicating specific binding. Insulin had no apparent effect on the intensity of the labeled band. These results suggest that IGF-BP could modulate the action of IGF-1 throughout the menstrual cycle. It would be interesting to study this binding protein in other pathologic conditions of the endometrium such as adenocarcinomas and hyperplasia.

  4. At risk, or not at risk: Epidemiological approaches for assessing psychiatric (genetic) risk factors in the general population

    NARCIS (Netherlands)

    Breetvelt, E.J.

    2013-01-01

    This thesis “At risk, or not at risk” describes several approaches - cross-sectional, prospective, phenotype mining and forward genetics - for assessing psychiatric (genetic) risk factors in a general population study. The aims were 1) to investigate how routine and follow-up data from populationbas

  5. Cannabis Beyond Good and Evil. How genetic and epidemiological factors shape the relationship between cannabis and psychosis

    NARCIS (Netherlands)

    Schubart, C.D.

    2013-01-01

    The studies presented in this thesis aimed to identify genetic and non-genetic (epidemiological) factors that shape the association between cannabis use and psychosis. We showed that the age of first use of cannabis is a determinant for the strength of the association between cannabis use and psycho

  6. Cell state switching factors and dynamical patterning modules: complementary mediators of plasticity in development and evolution

    Indian Academy of Sciences (India)

    Stuart A Newman; Ramray Bhat; Nadejda V Mezentseva

    2009-10-01

    Ancient metazoan organisms arose from unicellular eukaryotes that had billions of years of genetic evolution behind them. The transcription factor networks present in single-celled ancestors at the origin of the Metazoa (multicellular animals) were already capable of mediating the switching of the unicellular phenotype among alternative states of gene activity in response to environmental conditions. Cell differentiation, therefore, had its roots in phenotypic plasticity, with the ancient regulatory proteins acquiring new targets over time and evolving into the ``developmental transcription factors” (DTFs) of the ``developmental-genetic toolkit.” In contrast, the emergence of pattern formation and morphogenesis in the Metazoa had a different trajectory. Aggregation of unicellular metazoan ancestors changed the organisms’ spatial scale, leading to the first ``dynamical patterning module” (DPM): cell-cell adhesion. Following this, other DPMs (defined as physical forces and processes pertinent to the scale of the aggregates mobilized by a set of toolkit gene products distinct from the DTFs), transformed simple cell aggregates into hollow, multilayered, segmented, differentiated and additional complex structures, with minimal evolution of constituent genes. Like cell differentiation, therefore, metazoan morphologies also originated from plastic responses of cells and tissues. Here we describe examples of DTFs and most of the important DPMs, discussing their complementary roles in the evolution of developmental mechanisms. We also provide recently characterized examples of DTFs in cell type switching and DPMs in morphogenesis of avian limb bud mesenchyme, an embryo-derived tissue that retains a high degree of developmental plasticity.

  7. Common genetic influences on negative emotionality and a general psychopathology factor in childhood and adolescence.

    Science.gov (United States)

    Tackett, Jennifer L; Lahey, Benjamin B; van Hulle, Carol; Waldman, Irwin; Krueger, Robert F; Rathouz, Paul J

    2013-11-01

    Previous research using confirmatory factor analysis to model psychopathology comorbidity has supported the hypothesis of a broad general factor (i.e., a "bifactor"; Holzinger & Swineford, 1937) of psychopathology in children, adolescents, and adults, with more specific higher order internalizing and externalizing factors reflecting additional shared variance in symptoms (Lahey et al., 2012; Lahey, van Hulle, Singh, Waldman, & Rathouz, 2011). The psychological nature of this general factor has not been explored, however. The current study tested a prediction, derived from the spectrum hypothesis of personality and psychopathology, that variance in a general psychopathology bifactor overlaps substantially-at both phenotypic and genetic levels-with the dispositional trait of negative emotionality. Data on psychopathology symptoms and dispositional traits were collected from both parents and youth in a representative sample of 1,569 twin pairs (ages 9-17 years) from Tennessee. Predictions based on the spectrum hypothesis were supported, with variance in negative emotionality and the general factor overlapping substantially at both phenotypic and etiologic levels. Furthermore, stronger correlations were found between negative emotionality and the general psychopathology factor than among other dispositions and other psychopathology factors.

  8. Common Genetic Influences on Negative Emotionality and a General Psychopathology Factor in Childhood and Adolescence

    Science.gov (United States)

    Tackett, Jennifer L.; Lahey, Benjamin B.; Hulle, Carol Van; Waldman, Irwin; Krueger, Robert F.; Rathouz, Paul J.

    2014-01-01

    Previous research using confirmatory factor analysis to model psychopathology comorbidity supported the hypothesis of a broad general factor (i.e., a “bifactor”; Holzinger & Swineford, 1937) of psychopathology in children, adolescents, and adults, with more specific higher-order internalizing and externalizing factors reflecting additional shared variance in symptoms (Lahey et al., 2012; Lahey, Van Hulle, Singh, Waldman, & Rathouz, 2011). The psychological nature of this general factor has not been explored, however. The current study tests a prediction derived from the spectrum hypothesis of personality and psychopathology, that variance in a general psychopathology bifactor overlaps substantially—at both phenotypic and genetic levels—with the dispositional trait of negative emotionality. Data on psychopathology symptoms and dispositional traits were collected from both parents and youth in a representative sample of 1,569 twin pairs (ages 9–17) from Tennessee. Predictions based on the spectrum hypothesis were supported, with variance in negative emotionality and the general factor overlapping substantially at both phenotypic and etiologic levels. Furthermore, stronger correlations were found between negative emotionality and the general psychopathology factor than among other dispositions and other psychopathology factors. PMID:24364617

  9. Role of Genetic and Environmental Factors in the Development of Empathy

    Directory of Open Access Journals (Sweden)

    Yudina T.O.,

    2017-08-01

    Full Text Available The paper provides a review of studies on factors influencing empathy development in early childhood and on conditions promoting manifestation of empathy in children later in life. The outcomes of several studies shed light on the character of empathic response at early stages of child development, particularly in infancy and toddlerhood. This review covers research on the role of biological factors and mechanisms in empathy development (for instance, features of temperament and neuronal bases, as well as research on the relationship between genetic and environmental factors in the development of empathy in ontogenesis. Another part of the paper describes studies on the role of social conditions in the development of empathy in childhood: it focuses primarily on family relations and, in particular, on the mother/child relationship. The paper concludes with several suggestions concerning further research of the specified problem.

  10. Identification of genetic loci in Lactobacillus plantarum that modulate the immune response of dendritic cells using comparative genome hybridization.

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    Marjolein Meijerink

    Full Text Available BACKGROUND: Probiotics can be used to stimulate or regulate epithelial and immune cells of the intestinal mucosa and generate beneficial mucosal immunomodulatory effects. Beneficial effects of specific strains of probiotics have been established in the treatment and prevention of various intestinal disorders, including allergic diseases and diarrhea. However, the precise molecular mechanisms and the strain-dependent factors involved are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we aimed to identify gene loci in the model probiotic organism Lactobacillus plantarum WCFS1 that modulate the immune response of host dendritic cells. The amounts of IL-10 and IL-12 secreted by dendritic cells (DCs after stimulation with 42 individual L. plantarum strains were measured and correlated with the strain-specific genomic composition using comparative genome hybridisation and the Random Forest algorithm. This in silico "gene-trait matching" approach led to the identification of eight candidate genes in the L. plantarum genome that might modulate the DC cytokine response to L. plantarum. Six of these genes were involved in bacteriocin production or secretion, one encoded a bile salt hydrolase and one encoded a transcription regulator of which the exact function is unknown. Subsequently, gene deletions mutants were constructed in L. plantarum WCFS1 and compared to the wild-type strain in DC stimulation assays. All three bacteriocin mutants as well as the transcription regulator (lp_2991 had the predicted effect on cytokine production confirming their immunomodulatory effect on the DC response to L. plantarum. Transcriptome analysis and qPCR data showed that transcript level of gtcA3, which is predicted to be involved in glycosylation of cell wall teichoic acids, was substantially increased in the lp_2991 deletion mutant (44 and 29 fold respectively. CONCLUSION: Comparative genome hybridization led to the identification of gene loci in L

  11. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria.

    Science.gov (United States)

    Sutton, Angela; Khoury, Hania; Prip-Buus, Carina; Cepanec, Claude; Pessayre, Dominique; Degoul, Françoise

    2003-03-01

    A genetic dimorphism encodes for either alanine (Ala) or valine (Val) in the mitochondrial targeting sequence (MTS) of human manganese superoxide dismutase (MnSOD) and has been reported to modulate the risk of some cancers, neurodegenerative diseases and severe alcoholic liver disease. Although functional consequences of this dimorphism on MnSOD activity have not been assessed, computer models predict a partial alpha-helix structure for the Ala-MnSOD/MTS, but a beta-sheet structure for the Val-variant, which could hamper mitochondrial import. To investigate this hypothesis, we studied the in-vitro import of chimaeric proteins composed of either one of the MnSOD/MTS fused to the mouse dihydrofolate reductase (DHFR) protein, and the import of the two human MnSOD precursor variants into rat liver mitochondria. Compared to Ala-proteins, the Val-MnSOD/MTS-DHFR precursor and Val-MnSOD precursor were both partly arrested within the inner mitochondrial membrane. The Ala-MnSOD precursor generated 30-40% more of the active, matricial, processed MnSOD homotetramer than the Val-MnSOD precursor. These results show that the Ala-MnSOD/MTS allows efficient MnSOD import into the mitochondrial matrix, while the Val-variant causes partial arrest of the precursor within the inner membrane and decreased formation of the active MnSOD tetramer in the mitochondrial matrix.

  12. Modulating electronic transport properties of carbon nanotubes to improve the thermoelectric power factor via nanoparticle decoration.

    Science.gov (United States)

    Yu, Choongho; Ryu, Yeontack; Yin, Liang; Yang, Hongjoo

    2011-02-22

    Nanoparticle decoration on carbon nanotubes was employed to modulate their electrical conductance and thermopower and thereby improved the thermoelectric power factor. Nanotubes were made into films by spraying nanotube solutions on glass substrates, and then the films were immersed in different concentrations of CuSO(4) or HAuCl(4) solutions for various time periods. Copper ions in the solutions were reduced on nanotubes by obtaining electrons from zinc electrodes, whose reduction potential is lower than that of copper (galvanic displacement). Gold ions were reduced on nanotubes by both silver counter electrodes and spontaneous reaction due to larger reduction potentials than those of nanotubes. These reactions made electrons donated to (copper incorporation) or withdrawn from (gold incorporation) nanotubes depending on the difference in their work functions and reduction potentials, resulting in considerable changes in electron transport. In this paper, a series of experiments at different ion concentrations and reaction time periods were systematically performed in order to find optimum nanoparticle formation conditions and corresponding electronic transport changes for better thermoelectric power factor. Transport measurement results show that electronic properties can be considerably altered and modulated, resulting in 2-fold improvement in the thermoelectric power factor with 1 mM/30 min reaction. Reactions with solutions of a low metal ion concentration, such as 1 mM, yielded well-distributed small particles over large surface areas, which strongly affected electron transfer between nanoparticles and nanotubes. Successive copper and gold decorations on nanotubes made electrical conductance (or thermopower) serially decreased and increased (or increased and decreased) upon precipitating different metal particles. This transport behavior is believed to be from the changes in the Fermi level as a result of electron exchanges between reduced metals and nanotubes

  13. Genetic and environmental risk factors for primary open-angle glaucoma

    Institute of Scientific and Technical Information of China (English)

    范宝剑; 梁旭辉; 汪宁; 林顺潮; 刘瑶; 谭霭仙; 彭智培

    2004-01-01

    Background Primary open-angle glaucoma (POAG) is characterized by optic nerve damage and consists of a group of genetically heterogeneous disorders. This study was to investigate the associations of genetic and environmental factors with POAG in a hospital-based Chinese population.Methods Thirty-two adult onset POAG patients and 96 age-sex matched control subjects were studied by multivariable logistic regression analysis for the relationships between POAG and its risk factors including family history, diabetes, hypertension, cardiovascular diseases, cigarette smoking, alcohol consumption and polymorphisms of the myocilin and the optineurin genes.Results Univariate analysis showed that POAG was related to family history, cardiovascular disease, alcohol consumption and a myocilin sequence alteration (T353I) (P<0.04). Multivariable logistic regression analysis confirmed that POAG was significantly associated with family history (OR=20.2), hypertension (OR=3.58), cigarette smoking (OR=10.8), alcohol consumption (OR=0.028) and T353I (OR=6.03, all P<0.05).Conclusions Family history, hypertension, cigarette smoking and T353I in the myocilin gene are risk factors for POAG. Alcohol consumption, however, has a protective effect.

  14. Genetic factors influencing inhibitor development in a cohort of South African haemophilia A patients.

    Science.gov (United States)

    Lochan, A; Macaulay, S; Chen, W C; Mahlangu, J N; Krause, A

    2014-09-01

    A critical complication of factor VIII (FVIII) replacement therapy in Haemophilia A (HA) treatment is inhibitor development. Known genetic factors predisposing to inhibitor development include FVIII (F8) gene mutations, ethnicity, a family history of inhibitors and FVIII haplotype mismatch. The aim of this study was to characterize and correlate these genetic factors in a cohort of South African HA patients. This was a retrospective study that included 229 patients and involved the analysis of patient files, HA molecular and clinical databases and molecular analysis of the F8 gene haplotype. Of the 229 patients, 51% were of black ethnicity, 49% were white, 5% had mild HA, 4% were moderate and 91% were severe, 36% were int22 positive and 13% were inhibitor positive. Of the inhibitor positive patients, 72% were black patients. Inhibitors were reported in 27% of black int22 positive patients, 13% of black int22 negative patients, 9% of white int22 positive patients and 7% of white int22 negative. The H1 haplotype was more common in whites (75%) and H2 was more common in blacks (74%). H3 and H5 were only found in black patients and had a higher frequency of inhibitor development than H1 and H2. In this small HA cohort, black patients had a significantly higher frequency of inhibitor development and the results were indicative of an association between inhibitor development, ethnicity and haplotype. © 2014 John Wiley & Sons Ltd.

  15. CD24: from a Hematopoietic Differentiation Antigen to a Genetic Risk Factor for Multiple Autoimmune Diseases.

    Science.gov (United States)

    Tan, Yixin; Zhao, Ming; Xiang, Bo; Chang, Christopher; Lu, Qianjin

    2016-02-01

    The autoantibody is an essential characteristic of inflammatory disorders, including autoimmune diseases. Although the exact pathogenic mechanisms of these diseases remain elusive, accumulated evidence has implicated that genetic factors play important roles in autoimmune inflammation. Among these factors, CD24 was first identified as a heat-stable antigen in 1978 and first successfully cloned in 1990. Thereafter, its functional roles have been intensively investigated in various human diseases, especially autoimmune diseases and cancers. It is currently known that CD24 serves as a costimulatory factor of T cells that regulate their homeostasis and proliferation, while in B cells, CD24 is functionally involved in cell activation and differentiation. CD24 can enhance autoimmune diseases in terms of its protective role in the clonal deletion of autoreactive thymocytes. Furthermore, CD24 deficiency has been linked to mouse experimental autoimmune encephalomyelitis. Finally, CD24 genetic variants, including single-nucleotide polymorphisms and deletions, are etiologically relevant to autoimmune diseases, such as multiple sclerosis and systemic lupus erythematosus. Therefore, CD24 is a promising biomarker and novel therapeutic target for autoimmune diseases.

  16. The relative contribution of environmental and genetic factors to phenotypic variation in familial Mediterranean fever (FMF).

    Science.gov (United States)

    Ben-Zvi, Ilan; Brandt, Benny; Berkun, Yackov; Lidar, Merav; Livneh, Avi

    2012-01-10

    Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown. To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins. The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P valueFMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average. In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Congenic mice provide evidence for a genetic locus that modulates spontaneous arthritis caused by deficiency of IL-1RA.

    Directory of Open Access Journals (Sweden)

    Yanhong Cao

    Full Text Available To understand the role of genetic factors involved in the development of spontaneous arthritis in mice deficient in IL-1 receptor antagonist protein (IL_1RA, we have identified a genomic region containing a major quantitative trait locus (QTL for this disease. The QTL is on chromosome 1 and appears to be the strongest genetic region regulating arthritis. To confirm the importance of the QTL and to identify potential candidate genes within it, we conducted speed congenic breeding to transfer the QTL region from DBA/1 mice that are resistant to spontaneous arthritis into BALB/c(-/- which are susceptible. Genetic markers along every chromosome were used to assist in the selection of progeny in each generation to backcross to BALB/c(-/-. By the 6th generation we determined that all of the chromosomes in the progeny were of BALB/c origin with the exception of portions of chromosome 1. At this stage we intercrossed selected mice to produce homozygous strains containing the genomic background of BALB/c(-/- except for the QTL region on chromosome 1, which was from DBA/1. We were able to establish two congenic strains with overlapping DBA/1 DNA segments. These strains were observed for the development of spontaneous arthritis. Both congenic strains were relatively resistant to spontaneous arthritis and had delayed onset and reduced severity of disease. The gene/s that regulates this major QTL would appear to be located in the region of the QTL that is shared by both strains. The common transferred region is between D1Mit110 and D1Mit209 on chromosome 1. We evaluated this region for candidate genes and have identified a limited number of candidates. Confirmation of the identity and precise role of the candidates will require additional study.

  18. Efficacy and prognostic factors of intensity-modulated radiotherapy for large primary hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    FANG Ziyan

    2015-06-01

    Full Text Available ObjectiveTo investigate the efficacy of intensity-modulated radiotherapy (IMRT in treating large primary hepatocellular carcinoma (LHCC which is unsuitable for surgery or has poor response to radiofrequency ablation, interventional therapy, and other local treatments, and to identify the prognostic factors for survival. MethodsWe retrospectively analyzed the clinical data of 29 LHCC patients who received IMRT from April 2008 to August 2011. There were five fractions per week and the dose for each fraction was 2 to 6 Gy; the total dose was 50 to 70 Gy. The short-term efficacy and prognosis were observed and analyzed. The Kaplan-Meier method was used to calculate survival rates and the log-rank test was used for survival difference analysis. Multivariate analysis was performed using the Cox regression model. ResultsThe complete remission, partial remission, stable disease, and disease progression rates were 3.57%, 32.14%, 53.57%, and 10.72%, respectively. The overall median progression-free survival (PFS time was 6.43 months, and the median overall survival (OS time was 11.43 months. The 1- and 2-year survival rates were 46.79% and 25.23%, respectively. Univariate analysis showed tumor response rate was an independent prognostic factor for PFS. The Cox proportional hazard model suggested the tumor response rate and prescribed dose were the independent prognostic factors for PFS. In addition, the independent prognostic factors for OS included tumor response rate, tumor diameter, and tumor volume. The common acute radiotherapy toxicities included gastrointestinal discomfort, radiation-induced liver damage, and myelosuppression. ConclusionIMRT is a safe and effective option for the LHCC patients who are unsuitable for surgery or in the cases that other local therapies fail.

  19. Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma.

    Science.gov (United States)

    Thomas, Alissa A; Fisher, Jan L; Hampton, Thomas H; Christensen, Brock C; Tsongalis, Gregory J; Rahme, Gilbert J; Whipple, Chery A; Steel, Sandra E; Davis, Melissa C; Gaur, Arti B; Lewis, Lionel D; Ernstoff, Marc S; Fadul, Camilo E

    2017-03-01

    Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV). Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment. The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed. Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

  20. Etiology of Waldenström macroglobulinemia: genetic factors and immune-related conditions.

    Science.gov (United States)

    Manasanch, Elisabet E; Kristinsson, Sigurdur Y; Landgren, Ola

    2013-04-01

    Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, which indicates that repetitive immune stimulation and genetic factors play an important role. Here, the current understanding on the causes of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia are reviewed. Recent studies of the literature are discussed, and future population-based studies are proposed to further elucidate the molecular mechanisms that underlie these associations. Finally, the clinical implications of these data are outlined, and perspectives on clinical follow-up and counseling are provided.

  1. Genetic structure in the seabuckthorn carpenter moth (Holcocerus hippophaecolus in China: the role of outbreak events, geographical and host factors.

    Directory of Open Access Journals (Sweden)

    Jing Tao

    Full Text Available Understanding factors responsible for structuring genetic diversity is of fundamental importance in evolutionary biology. The seabuckthorn carpenter moth (Holcocerus hippophaecolus Hua is a native species throughout the north of China and is considered the main threat to seabuckthorn, Hippophae rhamnoides L. We assessed the influence of outbreaks, environmental factors and host species in shaping the genetic variation and structure of H. hippophaecolus by using Amplified Fragment Length Polymorphism (AFLP markers. We rejected the hypothesis that outbreak-associated genetic divergence exist, as evidenced by genetic clusters containing a combination of populations from historical outbreak areas, as well as non-outbreak areas. Although a small number of markers (4 of 933 loci were identified as candidates under selection in response to population densities. H. hippophaecolus also did not follow an isolation-by-distance pattern. We rejected the hypothesis that outbreak and drought events were driving the genetic structure of H. hippophaecolus. Rather, the genetic structure appears to be influenced by various confounding bio-geographical factors. There were detectable genetic differences between H. hippophaecolus occupying different host trees from within the same geographic location. Host-associated genetic divergence should be confirmed by further investigation.

  2. Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Marta Pajares

    2017-04-01

    Full Text Available Neurodegenerative diseases are linked to the accumulation of specific protein aggregates, suggesting an intimate connection between injured brain and loss of proteostasis. Proteostasis refers to all the processes by which cells control the abundance and folding of the proteome thanks to a wide network that integrates the regulation of signaling pathways, gene expression and protein degradation systems. This review attempts to summarize the most relevant findings about the transcriptional modulation of proteostasis exerted by the transcription factor NRF2 (nuclear factor (erythroid-derived 2-like 2. NRF2 has been classically considered as the master regulator of the antioxidant cell response, although it is currently emerging as a key component of the transduction machinery to maintain proteostasis. As we will discuss, NRF2 could be envisioned as a hub that compiles emergency signals derived from misfolded protein accumulation in order to build a coordinated and perdurable transcriptional response. This is achieved by functions of NRF2 related to the control of genes involved in the maintenance of the endoplasmic reticulum physiology, the proteasome and autophagy.

  3. Modulation of the response to stress factors of Xerolycosa nemoralis (Lycosidae) spiders living in contaminated environments.

    Science.gov (United States)

    Bednarek, Agata; Sawadro, Marta; Babczyńska, Agnieszka

    2016-09-01

    The rapid development of industry has caused widespread pollution in the environment, which has a negative impact on living organisms. Spiders belong to the group of animals that can exist in these anthropogenically changed areas. This is probably due to the development of tolerance mechanisms in these organisms. The impact of long-term pollution on the development of the pre-adaptation to various stress factors in spiders is unknown. In this paper, we show that living in polluted areas affects the modulation of the response to other stress factors through changes in the Hsp70 level. We observed a positive reaction to heat shock in all of the experimental groups, which was expressed by an increase in Hsp70 synthesis compared to the control. The analysis of the protein level, which was a manifestation of the pre-adaptation, was dependent on the degree of pollution on the study sites, the sexes and the type of bioassay that was performed. Our results demonstrate the reaction of spiders living in contaminated areas to the presence of additional stressors. We anticipate our results will be another voice in the discussion on the use of Hsp70 as a stress biomarker in environmental biomonitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Genetic determinants of risk factors for cardiovascular disease in a population from rural Brazil.

    Science.gov (United States)

    Velásquez-Meléndez, Gustavo; Parra, Flavia C; Gazzinelli, Andrea; Williams-Blangero, Sarah; Correa-Oliveira, Rodrigo

    2007-04-01

    We investigate the heritability of and pleiotropic relationships among triglycerides and cholesterol lipoproteins that have long been considered traditional risk factors for cardiovascular disease. Quantitative lipid and lipoprotein phenotypes were determined for a cross-sectional sample of a community in Jequitinhonha valley in northern Minas Gerais state, Brazil. The sample consisted primarily of subsistence farmers. Two hundred sixty-nine individuals (128 males and 141 females), ages 18-88 years, were sampled. Eighty-eight percent (n = 252) of the individuals belonged to a single pedigree, which was highly informative for genetic analysis. Data on anthropometrics, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglycerides were available for each study participant. Extended pedigrees were constructed using the pedigree-based data management software PedSys. Univariate and bivariate variance-components analyses, adjusted by sex and age, were performed using the SOLAR software package. Heritability estimates of lipids and lipoproteins ranged from 29% to 45% (p genetic correlations were found between triglycerides and very low density lipoprotein (VLDL) (rhog = 0.998) and between total cholesterol and LDL-C (rhog = 0.948). Significant genetic correlations were also found between triglycerides and LDL-C, between total cholesterol and VLDL, and between total cholesterol and LDL-C and VLDL, and finally between LDL and VLDL. There was a significant negative environmental correlation between triglycerides and HDL-C (rhoe = -0.406).

  5. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...... overlaps the Ig2-Ig2 contact site. This suggests that the function of the Ig1 module is not only regulation of the FGFR-ligand binding affinity but also prevention of spontaneous FGFR dimerization (through a direct Ig2-Ig2 interaction) in the absence of FGF....

  6. Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.

    Science.gov (United States)

    Dulak, Jozef; Józkowicz, Alicja; Foresti, Roberta; Kasza, Aneta; Frick, Matthias; Huk, Ihor; Green, Colin J; Pachinger, Otmar; Weidinger, Franz; Motterlini, Roberto

    2002-04-01

    Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-1 activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-1 gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.

  7. Transcription factors, transcriptional coregulators, and epigenetic modulation in the control of pulmonary vascular cell phenotype: therapeutic implications for pulmonary hypertension (2015 Grover Conference series).

    Science.gov (United States)

    Pullamsetti, Soni S; Perros, Frédéric; Chelladurai, Prakash; Yuan, Jason; Stenmark, Kurt

    2016-12-01

    Pulmonary hypertension (PH) is a complex and multifactorial disease involving genetic, epigenetic, and environmental factors. Numerous stimuli and pathological conditions facilitate severe vascular remodeling in PH by activation of a complex cascade of signaling pathways involving vascular cell proliferation, differentiation, and inflammation. Multiple signaling cascades modulate the activity of certain sequence-specific DNA-binding transcription factors (TFs) and coregulators that are critical for the transcriptional regulation of gene expression that facilitates PH-associated vascular cell phenotypes, as demonstrated by several studies summarized in this review. Past studies have largely focused on the role of the genetic component in the development of PH, while the presence of epigenetic alterations such as microRNAs, DNA methylation, histone levels, and histone deacetylases in PH is now also receiving increasing attention. Epigenetic regulation of chromatin structure is also recognized to influence gene expression in development or disease states. Therefore, a complete understanding of the mechanisms involved in altered gene expression in diseased cells is vital for the design of novel therapeutic strategies. Recent technological advances in DNA sequencing will provide a comprehensive improvement in our understanding of mechanisms involved in the development of PH. This review summarizes current concepts in TF and epigenetic control of cell phenotype in pulmonary vascular disease and discusses the current issues and possibilities in employing potential epigenetic or TF-based therapies for achieving complete reversal of PH.

  8. [Combined Effect of Genetic Factors, Age, and Smoking on the Risk of Developing Myocardial Infarction].

    Science.gov (United States)

    Osmak G, J; Matveeva, N A; Titov, B V; Nasibullin, T R; Mustafina, O E; Shakhnovich, R M; Kukava, N G; Ruda, M Ya; Favorova, O O

    2016-12-01

    to elaborate a complex model for myocardial infarction (MI) risk assessment considering the combined effect of genetic predisposition, age and smoking. The study included two independent samples of ethnic Russians: 325 patients with MI and 185 individuals without history of cardiovascular diseases (controls) from the Moscow region, and 220 patients and 197 controls from the Republic of Bashkortostan. Genotyping of polymorphic loci of genes CRP (rs1130864), IFNG (rs2430561), TGFB1 (rs1982073), FGB (rs1800788) and PTGS1 (rs3842787) was performed. To construct the predictive models, we used logistic regression with stepwise inclusion of variables. The predictive value was evaluated by the area under the curve (AUC) in a ROC-analysis. The factor was considered as a marker at pAUC 0.60. Three separate genetic variants FGB rs1800788*T, TGFB1 rs1982073*TT, CRP rs1130864*TT, and biallelic combination IFNG rs2430561*A + PTGS1 rs3842787*T whose association with MI we described earlier, were used to construct the composite genetic marker (AUC=0.66 in the training and test samples) by the logistic regression method. Adding to the obtained composite genetic marker such parameters as age and smoking allowed to create a complex MI risk marker, which was characterized by the predictive value stability (AUC=0.77 in the training sample and 0.82 in the test sample). The obtained complex model for MI risk assessment was reproduced in two independent samples of Russian ethnicity individuals from different regions of Russia with different gender identities, and allowed to have a reasonable chance (about 80%) of distinguishing patients and healthy individuals.

  9. Genetic and clinical risk factors for fluid overload following open-heart surgery.

    Science.gov (United States)

    Enger, T B; Pleym, H; Stenseth, R; Wahba, A; Videm, V

    2014-05-01

    Post-operative fluid overload following cardiac surgery is associated with increased morbidity and mortality. We hypothesised that genetic variations and pre-operative clinical factors predispose some patients to post-operative fluid overload. Perioperative variables were collected prospectively for 1026 consecutive adults undergoing open-heart surgery at St. Olavs University Hospital, Norway from 2008-2010. Post-operative fluid overload was defined as a post-operative fluid balance/kg ≥ the 90th percentile of the study population. Genotyping was performed for 31 single-nucleotide polymorphisms related to inflammatory/vascular responses or previously associated with complications following open-heart surgery. Data were analysed using logistic regression modelling, and the findings were internally validated by bootstrapping (n = 100). Homozygous carriers of the common G allele of rs12917707 in the UMOD gene had a 2.2 times greater risk of post-operative fluid overload (P = 0.005) after adjustment for significant clinical variables (age, duration of cardiopulmonary bypass, and intraoperative red cell transfusion). A genetic risk score including 14 single-nucleotide polymorphisms was independently associated with post-operative fluid overload (P = 0.001). The number of risk alleles was linearly associated with the frequency of fluid overload (odds ratio per risk allele 1.153, 95 % confidence interval 1.056-1.258). Nagelkerke's R(2) increased with 7.5% to a total of 25% for the combined clinical and genetic model. Hemofiltration did not reduce the risk. A common variation in the UMOD gene previously shown to be related to renal function was associated with increased risk of post-operative fluid overload following cardiac surgery. Our findings support a genetic susceptibility to disturbed fluid handling following cardiac surgery. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  10. Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study.

    Science.gov (United States)

    Hasler, Gregor; Pinto, Anthony; Greenberg, Benjamin D; Samuels, Jack; Fyer, Abby J; Pauls, David; Knowles, James A; McCracken, James T; Piacentini, John; Riddle, Mark A; Rauch, Scott L; Rasmussen, Steven A; Willour, Virginia L; Grados, Marco A; Cullen, Bernadette; Bienvenu, O Joseph; Shugart, Yin-Yao; Liang, Kung-Yee; Hoehn-Saric, Rudolf; Wang, Ying; Ronquillo, Jonne; Nestadt, Gerald; Murphy, Dennis L

    2007-03-01

    Identification of familial, more homogenous characteristics of obsessive-compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions. Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale-Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales. After controlling for sex, age, and age of onset, robust sib-sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor II (symmetry/ordering/arranging; p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor II (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor II (p < .01). Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD.

  11. Assessing educational priorities in genetics for general practitioners and specialists in five countries: factor structure of the Genetic-Educational Priorities (Gen-EP) scale.

    NARCIS (Netherlands)

    Calefato, J.M.; Nippert, I.; Harris, H.J.; Kristoffersson, U.; Schmidtke, J.; Kate, L.P. ten; Anionwu, E.; Benjamin, C.; Challen, K.; Plass, A.M.; Harris, R.; Julian-Reynier, C.

    2008-01-01

    Purpose: A scale assessing primary care physicians' priorities for genetic education (The Gen-EP scale) was developed and tested in five European countries. The objective of this study was to determine its factor structure, to test scaling assumptions and to determine internal consistency. Methods:

  12. The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids

    Science.gov (United States)

    Gutierrez-Aguilar, Ruth; Thompson, Abigail; Marchand, Nathalie; Dumont, Patrick; Woods, Stephen C.; de Launoit, Yvan; Seeley, Randy J.; Ulrich-Lai, Yvonne M.

    2015-01-01

    The transcription factor E-twenty-six version 5 (ETV5) has been linked with obesity in genome-wide association studies. Moreover, ETV5-deficient mice (knockout; KO) have reduced body weight, lower fat mass, and are resistant to diet-induced obesity, directly linking ETV5 to the regulation of energy balance and metabolism. ETV5 is expressed in hypothalamic brain regions that regulate both metabolism and HPA axis activity, suggesting that ETV5 may also modulate HPA axis function. In order to test this possibility, plasma corticosterone levels were measured in ETV5 KO and wildtype (WT) mice before (pre-stress) and after (post-stress) a mild stressor (intraperitoneal injection). ETV5 deficiency increased both pre- and post-stress plasma corticosterone, suggesting that loss of ETV5 elevated glucocorticoid tone. Consistent with this idea, ETV5 KO mice have reduced thymus weight, suggestive of increased glucocorticoid-induced thymic involution. ETV5 deficiency also decreased the mRNA expression of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and vasopressin receptor 1A in the hypothalamus, without altering vasopressin, corticotropin-releasing hormone, or oxytocin mRNA expression. In order to test whether reduced MR and GR expression affected glucocorticoid negative feedback, a dexamethasone suppression test was performed. Dexamethasone reduced plasma corticosterone in both ETV5 KO and WT mice, suggesting that glucocorticoid negative feedback was unaltered by ETV5 deficiency. In summary, these data suggest that the obesity-associated transcription factor ETV5 normally acts to diminish circulating glucocorticoids. This might occur directly via ETV5 actions on HPA-regulatory brain circuitry, and/or indirectly via ETV5-induced alterations in metabolic factors that then influence the HPA axis. PMID:25813907

  13. The role of molecular genetic factors in age-related macular degeneration.

    Science.gov (United States)

    Almeida, Luciana Negrão Frota de; Carolino, Rachel Melilo; Sperandio, Diogo Cazelli; Nehemy, Márcio Bittar; De Marco, L A

    2009-01-01

    Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Although the etiology of AMD remains largely unknown, numerous studies have suggested that both genes and environmental risk factors significantly influence the risk of developing AMD. Recently, single nucleotide polymorphisms, DNA sequence variations found within the complement factor H (CFH) gene, have been found to be strongly associated with the development of AMD. Several other genes have had at least one positive association finding and deserve further exploration. The purpose of this review is to provide an extensive report of the current data of AMD genetics and the contribution of this knowledge helps to the better understanding of its pathophysiology.

  14. Influence of Space Flight Factors on the Genetic Properties of Streptomyces Lividans 66 (PIJ702)

    Science.gov (United States)

    Tabakov, V. Yu.; Voeikova, T. A.; Tairbekov, M. G.; Goins, T. L.; Martinson, V. G.; Pyle, B. H.

    2006-01-01

    Gram-positive Streptomyces bacteria display genetic instability in response to external factors. Strain S. lividans 66 harbors the multicopy plasmid pIJ702 with selective and differential marker genes for antibiotic thiostrepton resistance and melanin production. Culture plates of modified ISP agar medium with and without thiostrepton were flown on Foton-M2. Suboptimal flight temperatures, which were simulated for asynchronous ground controls, resulted in slow growth and failure to differentiate and sporulate. Flight samples and asynchronous controls showed a high frequency of failing to express plasmid markers compared to laboratory controls. This was associated with loss of plasmid DNA and likely resulted from suboptimal temperatures for flight cultures and controls. Neither restriction fragment length polymorphism, nor polymerase chain reaction amplification coupled with denaturing gradient gel electrophoresis, revealed differences between pIJ702 DNA from flight vs. control clones. Mutations of the plasmid marker genes resulting from specific spaceflight factors, e.g., microgravity and radiation, were not detected.

  15. Interaction of genetic and exposure factors in the prevalence of berylliosis.

    Science.gov (United States)

    Richeldi, L; Kreiss, K; Mroz, M M; Zhen, B; Tartoni, P; Saltini, C

    1997-10-01

    Prevalence of berylliosis, a lung disorder driven by the activation of beryllium-specific T cells, is associated with a major histocompatibility complex (MHC) class II marker (HLA-DPB1Glu69) and with the type of industrial exposure. We evaluated the interaction between marker and exposure in a beryllium-exposed population in which the prevalence of berylliosis was associated with machining beryllium. The presence of the marker was associated with higher prevalence (HLA-DPB1Glu69-positive machinists 25%; HLA-DPB1Glu69-negative machinists 3.2%, P = 0.05) and predicted berylliosis independent of machining history (odds ratios 11.8 and 10.1). The study shows that in berylliosis the carrier status of a genetic susceptibility factor adds to the effect of process-related risk factors.

  16. Optimization of Q-factor of AFM cantilevers using genetic algorithms.

    Science.gov (United States)

    Perez-Cruz, Angel; Dominguez-Gonzalez, Aurelio; Stiharu, Ion; Osornio-Rios, Roque A

    2012-04-01

    Micro cantilever beams have been intensively used in sensing applications including to scanning profiles and surfaces where there resolution and imaging speed are critical. Force resolution is related to the Q-factor. When the micro-cantilever operates in air with small separation gaps, the Q-factor is even more reduced due to the squeeze-film damping effect. Thus, the optimization of the configuration of an AFM micro-cantilever is presented in this work with the objective of improving its Q-factor. To accomplish this task, we propose the inclusion of holes as breathing chimneys in the initial design to reduce the squeeze-film damping effect. The evaluation of the Q-factor was carried out using finite element model, which is implemented to work together with the squeeze-film damping model. The methodology applied in the optimization process was genetic algorithms, which considers as constraints the maximum allowable stress, fundamental frequency and spring constant with respect to the initial design. The results show that the optimum design, which includes holes with an optimal location, increases the Q-factor almost five times compared to the initial design.

  17. Some Non Genetic Factors Effects on Morphostructural Growth of Local Kids in Tunisian Arid Area

    Directory of Open Access Journals (Sweden)

    Ben Ammar Elgaaied Amel

    2008-01-01

    Full Text Available Data corresponding of 276 local kids` periodic control, harvested during 4 years (2001-2005 under pastoral mode in Tunisian arid region, was used to study some factors effects upon body parts evolution after birth. Morphostructural variables were; body length, height-at-withers and heart girth. The linear measurement periodically registered at every control day from birth and till 5 months age. For each kid, performances were standardized at typical ages; birth, 30, 60, 90, 120 and 150 days. Statistical analysis were achieved by GLM procedure and SNK (a = 5% means comparison test to identify factors effects upon studied variables and the homogeneous classes. The kid`s body parts seem affected (p<0.05 by several environmental factors, sex, type of birth and age of dam. The type of birth and the age of dam exerts a high effect (p<0.01 on all characters after the birth. However, the factors statistical effects depend to the kid`s age. The sex acts differently on the morphometric characters before and afterwards of two month age. Thus, phenotypic individual differences can be elapsed by environmental factors of arid harsh conditions. Such conclusion underlines the necessity to study the particularities of the genetic expression of adapted populations towards restrictive resources.

  18. Clinical and genetic factors associated with suicide in mood disorder patients.

    Science.gov (United States)

    Antypa, Niki; Souery, Daniel; Tomasini, Mario; Albani, Diego; Fusco, Federica; Mendlewicz, Julien; Serretti, Alessandro

    2016-03-01

    Suicidality is a continuum ranging from ideation to attempted and completed suicide, with a complex etiology involving both genetic heritability and environmental factors. The majority of suicide events occur in the context of psychiatric conditions, preeminently major depression and bipolar disorder. The present study investigates clinical factors associated with suicide in a sample of 553 mood disorder patients, recruited within the 'Psy Pluriel' center, Centre Européen de Psychologie Médicale, and the Department of Psychiatry of Erasme Hospital (Brussels). Furthermore, genetic association analyses examining polymorphisms within COMT, BDNF, MAPK1 and CREB1 genes were performed in a subsample of 259 bipolar patients. The presence or absence of a previous suicide attempt and of current suicide risk were assessed. A positive association with suicide attempt was reported for younger patients, females, lower educated, smokers, those with higher scores on depressive symptoms and higher functional disability and those with anxiety comorbidity and familial history of suicidality in first- and second-degree relatives. Anxiety disorder comorbidity was the stronger predictor of current suicide risk. No associations were found with polymorphisms within COMT and BDNF genes, whereas significant associations were found with variations in rs13515 (MAPK1) and rs6740584 (CREB1) polymorphisms. From a clinical perspective, our study proposes several clinical characteristics, such as increased depressive symptomatology, anxiety comorbidity, functional disability and family history of suicidality, as correlates associated with suicide. Genetic risk variants in MAPK1 and CREB1 genes might be involved in a dysregulation of inflammatory and neuroplasticity pathways and are worthy of future investigation.

  19. Variation in salamander tail regeneration is associated with genetic factors that determine tail morphology.

    Directory of Open Access Journals (Sweden)

    Gareth J Voss

    Full Text Available Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander's tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66-68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (<4% and correlated with tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site.

  20. Variation in salamander tail regeneration is associated with genetic factors that determine tail morphology.

    Science.gov (United States)

    Voss, Gareth J; Kump, D Kevin; Walker, John A; Voss, S Randal

    2013-01-01

    Very little is known about the factors that cause variation in regenerative potential within and between species. Here, we used a genetic approach to identify heritable genetic factors that explain variation in tail regenerative outgrowth. A hybrid ambystomatid salamander (Ambystoma mexicanum x A. andersoni) was crossed to an A. mexicanum and 217 offspring were induced to undergo metamorphosis and attain terrestrial adult morphology using thyroid hormone. Following metamorphosis, each salamander's tail tip was amputated and allowed to regenerate, and then amputated a second time and allowed to regenerate. Also, DNA was isolated from all individuals and genotypes were determined for 187 molecular markers distributed throughout the genome. The area of tissue that regenerated after the first and second amputations was highly positively correlated across males and females. Males presented wider tails and regenerated more tail tissue during both episodes of regeneration. Approximately 66-68% of the variation in regenerative outgrowth was explained by tail width, while tail length and genetic sex did not explain a significant amount of variation. A small effect QTL was identified as having a sex-independent effect on tail regeneration, but this QTL was only identified for the first episode of regeneration. Several molecular markers significantly affected regenerative outgrowth during both episodes of regeneration, but the effect sizes were small (<4%) and correlated with tail width. The results show that ambysex and minor effect QTL explain variation in adult tail morphology and importantly, tail width. In turn, tail width at the amputation plane largely determines the rate of regenerative outgrowth. Because amputations in this study were made at approximately the same position of the tail, our results resolve an outstanding question in regenerative biology: regenerative outgrowth positively co-varies as a function of tail width at the amputation site.

  1. Genetic mapping and comparative expression analysis of transcription factors in cotton.

    Science.gov (United States)

    Chen, Xuemei; Jin, Xin; Li, Ximei; Lin, Zhongxu

    2015-01-01

    Transcription factors (TFs) play an important role in the regulation of plant growth and development. The study of the structure and function of TFs represents a research frontier in plant molecular biology. The findings of these studies will provide significant information regarding genetic improvement traits in crops. Currently, a large number of TFs have been cloned, and their function has been verified. However, relatively few studies that genetically map TFs in cotton are available. To genetically map TFs in cotton in this study, specific primers were designed for TF genes that were published in the Plant Transcription Factor Database. A total of 977 TF primers were obtained, and 31 TF polymorphic loci were mapped on 15 cotton chromosomes. These polymorphic loci were clearly preferentially distributed on chromosomes 5, 11, 19 and 20; and TFs from the same family mapped to homologous cotton chromosomes. In-silico mapping verified that many mapped TFs were mapped on their corresponding chromosomes or their homologous chromosomes' corresponding chromosomes in the diploid genomes. QTL mapping for fiber quality revealed that TF-Ghi005602-2 mapped on Chr19 was associated with fiber length. Eighty-five TF genes were selected for RT-PCR analysis, and 4 TFs were selected for qRT-PCR analysis, revealing unique expression patterns across different stages of fiber development between the mapping parents. Our data offer an overview of the chromosomal distribution of TFs in cotton, and the comparative expression analysis between Gossypium hirsutum and G. barbadense provides a rough understanding of the regulation of TFs during cotton fiber development.

  2. Host genetics and environmental factors regulate ecological succession of the mouse colon tissue-associated microbiota.

    Directory of Open Access Journals (Sweden)

    Philip Smith

    Full Text Available BACKGROUND: The integration of host genetics, environmental triggers and the microbiota is a recognised factor in the pathogenesis of barrier function diseases such as IBD. In order to determine how these factors interact to regulate the host immune response and ecological succession of the colon tissue-associated microbiota, we investigated the temporal interaction between the microbiota and the host following disruption of the colonic epithelial barrier. METHODOLOGY/PRINCIPAL FINDINGS: Oral administration of DSS was applied as a mechanistic model of environmental damage of the colon and the resulting inflammation characterized for various parameters over time in WT and Nod2 KO mice. RESULTS: In WT mice, DSS damage exposed the host to the commensal flora and led to a migration of the tissue-associated bacteria from the epithelium to mucosal and submucosal layers correlating with changes in proinflammatory cytokine profiles and a progressive transition from acute to chronic inflammation of the colon. Tissue-associated bacteria levels peaked at day 21 post-DSS and declined thereafter, correlating with recruitment of innate immune cells and development of the adaptive immune response. Histological parameters, immune cell infiltration and cytokine biomarkers of inflammation were indistinguishable between Nod2 and WT littermates following DSS, however, Nod2 KO mice demonstrated significantly higher tissue-associated bacterial levels in the colon. DSS damage and Nod2 genotype independently regulated the community structure of the colon microbiota. CONCLUSIONS/SIGNIFICANCE: The results of these experiments demonstrate the integration of environmental and genetic factors in the ecological succession of the commensal flora in mammalian tissue. The association of Nod2 genotype (and other host polymorphisms and environmental factors likely combine to influence the ecological succession of the tissue-associated microflora accounting in part for their

  3. Role of genetic and environmental factors in British twins with inflammatory bowel disease.

    Science.gov (United States)

    Ng, Siew C; Woodrow, Susannah; Patel, Nisha; Subhani, Javaid; Harbord, Marcus

    2012-04-01

    Twin studies provide insight into the complex interaction between genetic and environmental factors in the development of inflammatory bowel disease (IBD). We assessed associations between childhood environmental factors and development of Crohn's disease (CD) and ulcerative colitis (UC) in twins. Questionnaires on clinical demographics and exposure to environmental factors were sent to twins with IBD, their healthy co-twins, and their doctors. Kappa statistics were used to examine agreement between twin pairs and odds ratios were calculated by conditional logistic regression. In all, 250 IBD twin pairs (122 CD; 125 UC; 3 CD/UC; 28 concordant pairs) were analyzed. Concordant monozygotic twins with CD showed good agreement for disease location (κ 0.88; 95% confidence interval [CI]: 0.45-1.00), disease behavior (κ 1.00; 95% CI: 0.43-1.00), and moderate agreement for age at diagnosis and need for medical and surgical therapy. Concordant monozygotic twins with UC showed good agreement for disease extent (κ 0.60; CI 0.13-1.00) and use of thiopurines (κ 0.73; CI 0.10-1.00). In discordant twins, symptomatic childhood mumps infection (odds ratio [OR], 3.8; 95% CI, 1.2-11.3) and oral contraceptives (OR, 4.0; 1.1-14.2) were associated with CD. Smoking was associated with CD (OR, 4.3; 95% CI, 1.9-9.8) but inversely associated with UC (OR, 0.3; 95% CI, 0.1-0.9). Both CD and UC twins had suffered more "gastroenteritis" and spent more time with animals than their co-twins. Disease phenotype in CD and disease extent in UC appeared to be genetically influenced. Smoking is a risk factor for CD but is protective for UC. Early exposure to "infections" during childhood may be associated with the development of IBD. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  4. Genetics and Other Risk Factors for Past Concussions in Active-Duty Soldiers.

    Science.gov (United States)

    Dretsch, Michael N; Silverberg, Noah; Gardner, Andrew J; Panenka, William J; Emmerich, Tanja; Crynen, Gogce; Ait-Ghezala, Ghania; Chaytow, Helena; Mathura, Venkat; Crawford, Fiona C; Iverson, Grant L

    2017-02-15

    Risk factors for concussion in active-duty military service members are poorly understood. The present study examined the association between self-reported concussion history and genetics (apolipoprotein E [APOE], brain-derived neurotrophic factor [BDNF], and D2 dopamine receptor genes [DRD2]), trait personality measures (impulsive-sensation seeking and trait aggression-hostility), and current alcohol use. The sample included 458 soldiers who were preparing to deploy for Operation Iraqi Freedom/Operation Enduring Freedom. For those with the BDNF Met/Met genotype, 57.9% (11/19) had a history of one or more prior concussions, compared with 35.6% (154/432) of those with other BDNF genotypes (p = 0.049, odds ratio [OR] = 2.48). APOE and DRD2 genotypes were not associated with risk for past concussions. Those with the BDNF Met/Met genotype also reported greater aggression and hostility personality characteristics. When combined in a predictive model, prior military deployments, being male, and having the BDNF Met/Met genotype were independently associated with increased lifetime history of concussions in active-duty soldiers. Replication in larger independent samples is necessary to have more confidence in both the positive and negative genetic associations reported in this study.

  5. A twin and molecular genetics study of sleep paralysis and associated factors.

    Science.gov (United States)

    Denis, Dan; French, Christopher C; Rowe, Richard; Zavos, Helena M S; Nolan, Patrick M; Parsons, Michael J; Gregory, Alice M

    2015-08-01

    Sleep paralysis is a relatively common but under-researched phenomenon. In this paper we examine prevalence in a UK sample and associations with candidate risk factors. This is the first study to investigate the heritability of sleep paralysis in a twin sample and to explore genetic associations between sleep paralysis and a number of circadian expressed single nucleotide polymorphisms. Analyses are based on data from the Genesis1219 twin/sibling study, a community sample of twins/siblings from England and Wales. In total, data from 862 participants aged 22-32 years (34% male) were used in the study. This sample consisted of monozygotic and dizygotic twins and siblings. It was found that self-reports of general sleep quality, anxiety symptoms and exposure to threatening events were all associated independently with sleep paralysis. There was moderate genetic influence on sleep paralysis (53%). Polymorphisms in the PER2 gene were associated with sleep paralysis in additive and dominant models of inheritance-although significance was not reached once a Bonferroni correction was applied. It is concluded that factors associated with disrupted sleep cycles appear to be associated with sleep paralysis. In this sample of young adults, sleep paralysis was moderately heritable. Future work should examine specific polymorphisms associated with differences in circadian rhythms and sleep homeostasis further in association with sleep paralysis.

  6. Host genetic risk factors for West Nile virus infection and disease progression.

    Directory of Open Access Journals (Sweden)

    Abigail W Bigham

    Full Text Available West Nile virus (WNV, a category B pathogen endemic in parts of Africa, Asia and Europe, emerged in North America in 1999, and spread rapidly across the continental U.S. Outcomes of infection with WNV range from asymptomatic to severe neuroinvasive disease manifested as encephalitis, paralysis, and/or death. Neuroinvasive WNV disease occurs in less than one percent of cases, and although host genetic factors are thought to influence risk for symptomatic disease, the identity of these factors remains largely unknown. We tested 360 common haplotype tagging and/or functional SNPs in 86 genes that encode key regulators of immune function in 753 individuals infected with WNV including: 422 symptomatic WNV cases and 331 cases with asymptomatic infections. After applying a Bonferroni correction for multiple tests and controlling for population stratification, SNPs in IRF3 (OR 0.54, p = 0.035 and MX1, (OR 0.19, p = 0.014 were associated with symptomatic WNV infection and a single SNP in OAS1 (OR 9.79, p = 0.003 was associated with increased risk for West Nile encephalitis and paralysis (WNE/P. Together, these results suggest that genetic variation in the interferon response pathway is associated with both risk for symptomatic WNV infection and WNV disease progression.

  7. Genetic risk factors for longitudinal changes in structural MRI in former organolead workers.

    Science.gov (United States)

    James, Bryan D; Caffo, Brian; Stewart, Walter F; Yousem, David; Davatzikos, Christos; Schwartz, Brian S

    2011-01-01

    This study examined associations between polymorphisms in three genes, apolipoprotein E (APOE), angiotensin converting enzyme (ACE), and vitamin D receptor (VDR), and longitudinal change in brain volumes and white matter lesions (WML) as well as effect modification by cardiovascular factors and tibia lead concentrations. Two MRIs, an average of 5 years apart, were obtained for 317 former organolead workers and 45 population-based controls. Both regions-of-interest and voxel-wise analyses were conducted. APOE ε3/ε4 and ε4/ε4 genotypes were associated with less decline in white matter volumes. There was some evidence of interaction between genetic polymorphisms and cardiovascular risk factors (ACE and high-density lipoprotein; VDR and diabetes) on brain volume decline. The VDR FokI ff genotype was associated with an increase in WML (no association for APOE or ACE). This study expands our understanding of how genetic precursors of dementia and cardiovascular diseases are related to changes in brain structure.

  8. Ecological and genetic factors linked to contrasting genome dynamics in seed plants.

    Science.gov (United States)

    Leitch, A R; Leitch, I J

    2012-05-01

    The large-scale replacement of gymnosperms by angiosperms in many ecological niches over time and the huge disparity in species numbers have led scientists to explore factors (e.g. polyploidy, developmental systems, floral evolution) that may have contributed to the astonishing rise of angiosperm diversity. Here, we explore genomic and ecological factors influencing seed plant genomes. This is timely given the recent surge in genomic data. We compare and contrast the genomic structure and evolution of angiosperms and gymnosperms and find that angiosperm genomes are more dynamic and diverse, particularly amongst the herbaceous species. Gymnosperms typically have reduced frequencies of a number of processes (e.g. polyploidy) that have shaped the genomes of other vascular plants and have alternative mechanisms to suppress genome dynamism (e.g. epigenetics and activity of transposable elements). Furthermore, the presence of several characters in angiosperms (e.g. herbaceous habit, short minimum generation time) has enabled them to exploit new niches and to be viable with small population sizes, where the power of genetic drift can outweigh that of selection. Together these processes have led to increased rates of genetic divergence and faster fixation times of variation in many angiosperms compared with gymnosperms.

  9. Fluorescent nanodiamond tracking reveals intraneuronal transport abnormalities induced by brain-disease-related genetic risk factors

    Science.gov (United States)

    Haziza, Simon; Mohan, Nitin; Loe-Mie, Yann; Lepagnol-Bestel, Aude-Marie; Massou, Sophie; Adam, Marie-Pierre; Le, Xuan Loc; Viard, Julia; Plancon, Christine; Daudin, Rachel; Koebel, Pascale; Dorard, Emilie; Rose, Christiane; Hsieh, Feng-Jen; Wu, Chih-Che; Potier, Brigitte; Herault, Yann; Sala, Carlo; Corvin, Aiden; Allinquant, Bernadette; Chang, Huan-Cheng; Treussart, François; Simonneau, Michel

    2017-05-01

    Brain diseases such as autism and Alzheimer's disease (each inflicting >1% of the world population) involve a large network of genes displaying subtle changes in their expression. Abnormalities in intraneuronal transport have been linked to genetic risk factors found in patients, suggesting the relevance of measuring this key biological process. However, current techniques are not sensitive enough to detect minor abnormalities. Here we report a sensitive method to measure the changes in intraneuronal transport induced by brain-disease-related genetic risk factors using fluorescent nanodiamonds (FNDs). We show that the high brightness, photostability and absence of cytotoxicity allow FNDs to be tracked inside the branches of dissociated neurons with a spatial resolution of 12 nm and a temporal resolution of 50 ms. As proof of principle, we applied the FND tracking assay on two transgenic mouse lines that mimic the slight changes in protein concentration (∼30%) found in the brains of patients. In both cases, we show that the FND assay is sufficiently sensitive to detect these changes.

  10. Total and regional fat distribution is strongly influenced by genetic factors in young and elderly twins

    DEFF Research Database (Denmark)

    Malis, Charlotte; Rasmussen, Eva L; Poulsen, Pernille

    2005-01-01

    OBJECTIVE: Indirect estimates of obesity such as BMI seem to be strongly influenced by genetic factors in twins. Precise measurements of total and regional fat as determined by direct techniques such as DXA scan have only been applied in a few twin studies. The aim of the present study was to est......OBJECTIVE: Indirect estimates of obesity such as BMI seem to be strongly influenced by genetic factors in twins. Precise measurements of total and regional fat as determined by direct techniques such as DXA scan have only been applied in a few twin studies. The aim of the present study...... was to estimate the heritability (h(2)) of total and regional fat distribution in young and elderly Danish twins. RESEARCH METHODS AND PROCEDURES: Monozygotic (108) and dizygotic (88) twins in two age groups (25 to 32 and 58 to 66 years) underwent anthropometric measurements and DXA scans. Intraclass correlations...... and etiologic components of variance were estimated for total and regional fat percentages using biometric modeling. RESULTS: The intraclass correlations demonstrated higher correlations for all fat percentages among monozygotic twins as compared with dizygotic twins. The biometric modeling revealed a major...

  11. A forward genetic screen reveals essential and non-essential RNAi factors in Paramecium tetraurelia.

    Science.gov (United States)

    Marker, Simone; Carradec, Quentin; Tanty, Véronique; Arnaiz, Olivier; Meyer, Eric

    2014-06-01

    In most eukaryotes, small RNA-mediated gene silencing pathways form complex interacting networks. In the ciliate Paramecium tetraurelia, at least two RNA interference (RNAi) mechanisms coexist, involving distinct but overlapping sets of protein factors and producing different types of short interfering RNAs (siRNAs). One is specifically triggered by high-copy transgenes, and the other by feeding cells with double-stranded RNA (dsRNA)-producing bacteria. In this study, we designed a forward genetic screen for mutants deficient in dsRNA-induced silencing, and a powerful method to identify the relevant mutations by whole-genome sequencing. We present a set of 47 mutant alleles for five genes, revealing two previously unknown RNAi factors: a novel Paramecium-specific protein (Pds1) and a Cid1-like nucleotidyl transferase. Analyses of allelic diversity distinguish non-essential and essential genes and suggest that the screen is saturated for non-essential, single-copy genes. We show that non-essential genes are specifically involved in dsRNA-induced RNAi while essential ones are also involved in transgene-induced RNAi. One of the latter, the RNA-dependent RNA polymerase RDR2, is further shown to be required for all known types of siRNAs, as well as for sexual reproduction. These results open the way for the dissection of the genetic complexity, interconnection, mechanisms and natural functions of RNAi pathways in P. tetraurelia.

  12. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

    DEFF Research Database (Denmark)

    Rotger, Margalida; Glass, Tracy R; Junier, Thomas

    2013-01-01

    BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the set...

  13. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons

    NARCIS (Netherlands)

    Rotger, Margalida; Glass, Tracy R; Junier, Thomas; Lundgren, Jens; Neaton, James D; Poloni, Estella S; van 't Wout, Angélique B; Lubomirov, Rubin; Colombo, Sara; Martinez, Raquel; Rauch, Andri; Günthard, Huldrych F; Neuhaus, Jacqueline; Wentworth, Deborah; van Manen, Danielle; Gras, Luuk A; Schuitemaker, Hanneke; Albini, Laura; Torti, Carlo; Jacobson, Lisa P; Li, Xiuhong; Kingsley, Lawrence A; Carli, Federica; Guaraldi, Giovanni; Ford, Emily S; Sereti, Irini; Hadigan, Colleen; Martinez, Esteban; Arnedo, Mireia; Egaña-Gorroño, Lander; Gatell, Jose M; Law, Matthew; Bendall, Courtney; Petoumenos, Kathy; Rockstroh, Jürgen; Wasmuth, Jan-Christian; Kabamba, Kabeya; Delforge, Marc; De Wit, Stephane; Berger, Florian; Mauss, Stefan; de Paz Sierra, Mariana; Losso, Marcelo; Belloso, Waldo H; Leyes, Maria; Campins, Antoni; Mondi, Annalisa; De Luca, Andrea; Bernardino, Ignacio; Barriuso-Iglesias, Mónica; Torrecilla-Rodriguez, Ana; Gonzalez-Garcia, Juan; Arribas, José R; Fanti, Iuri; Gel, Silvia; Puig, Jordi; Negredo, Eugenia; Gutierrez, Mar; Domingo, Pere; Fischer, Julia; Fätkenheuer, Gerd; Alonso-Villaverde, Carlos; Macken, Alan; Woo, James; McGinty, Tara; Mallon, Patrick; Mangili, Alexandra; Skinner, Sally; Wanke, Christine A; Reiss, Peter; Weber, Rainer; Bucher, Heiner C; Fellay, Jacques; Telenti, Amalio; Tarr, Philip E; Schölvinck, Elisabeth H.

    2013-01-01

    BACKGROUND: Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the settin

  14. Optimization of beam angles for intensity modulated radiation therapy treatment planning using genetic algorithm on a distributed computing platform.

    Science.gov (United States)

    Nazareth, Daryl P; Brunner, Stephen; Jones, Matthew D; Malhotra, Harish K; Bakhtiari, Mohammad

    2009-07-01

    Planning intensity modulated radiation therapy (IMRT) treatment involves selection of several angle parameters as well as specification of structures and constraints employed in the optimization process. Including these parameters in the combinatorial search space vastly increases the computational burden, and therefore the parameter selection is normally performed manually by a clinician, based on clinical experience. We have investigated the use of a genetic algorithm (GA) and distributed-computing platform to optimize the gantry angle parameters and provide insight into additional structures, which may be necessary, in the dose optimization process to produce optimal IMRT treatment plans. For an IMRT prostate patient, we produced the first generation of 40 samples, each of five gantry angles, by selecting from a uniform random distribution, subject to certain adjacency and opposition constraints. Dose optimization was performed by distributing the 40-plan workload over several machines running a commercial treatment planning system. A score was assigned to each resulting plan, based on how well it satisfied clinically-relevant constraints. The second generation of 40 samples was produced by combining the highest-scoring samples using techniques of crossover and mutation. The process was repeated until the sixth generation, and the results compared with a clinical (equally-spaced) gantry angle configuration. In the sixth generation, 34 of the 40 GA samples achieved better scores than the clinical plan, with the best plan showing an improvement of 84%. Moreover, the resulting configuration of beam angles tended to cluster toward the patient's sides, indicating where the inclusion of additional structures in the dose optimization process may avoid dose hot spots. Additional parameter selection in IMRT leads to a large-scale computational problem. We have demonstrated that the GA combined with a distributed-computing platform can be applied to optimize gantry angle

  15. Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD).

    Science.gov (United States)

    Ornoy, Asher; Weinstein-Fudim, Liza; Ergaz, Zivanit

    2016-01-01

    Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan-McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are only partially proven, and not

  16. Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD)

    Science.gov (United States)

    Ornoy, Asher; Weinstein- Fudim, Liza; Ergaz, Zivanit

    2016-01-01

    Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan–McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are

  17. Kinetic Model Facilitates Analysis of Fibrin Generation and Its Modulation by Clotting Factors: Implications for Hemostasis-Enhancing Therapies

    Science.gov (United States)

    2014-01-01

    facilitates analysis of fibrin generation and its modulation by clotting factors: implications for hemostasis-enhancing therapies† Alexander Y...Syst. Biol.Med., 2011, 3, 136–146. 62 M. Schneider, N. Brufatto, E. Neill and M. Nesheim, J. Biol. Chem., 2004, 279, 13340–13345. 63 J. H. Foley, P. F

  18. TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle

    NARCIS (Netherlands)

    Pera, Tonio; Sami, Riham; Zaagsma, Johan; Meurs, Herman

    2011-01-01

    Pera T, Sami R, Zaagsma J, Meurs H. TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 301: L822-L828, 2011. First published August 26, 2011; doi:10.1152/ajplung.00017.2011.-Increased airway smooth muscle (ASM) mass is a

  19. The genetic susceptibility to type 2 diabetes may be modulated by obesity status: implications for association studies

    Directory of Open Access Journals (Sweden)

    Charpentier Guillaume

    2008-05-01

    Full Text Available Abstract Background Considering that a portion of the heterogeneity amongst previous replication studies may be due to a variable proportion of obese subjects in case-control designs, we assessed the association of genetic variants with type 2 diabetes (T2D in large groups of obese and non-obese subjects. Methods We genotyped RETN, KCNJ11, HNF4A, HNF1A, GCK, SLC30A8, ENPP1, ADIPOQ, PPARG, and TCF7L2 polymorphisms in 1,283 normoglycemic (NG and 1,581 T2D obese individuals as well as in 3,189 NG and 1,244 T2D non-obese subjects of European descent, allowing us to examine T2D risk over a wide range of BMI. Results Amongst non-obese individuals, we observed significant T2D associations with HNF1A I27L [odds ratio (OR = 1.14, P = 0.04], GCK -30G>A (OR = 1.23, P = 0.01, SLC30A8 R325W (OR = 0.87, P = 0.04, and TCF7L2 rs7903146 (OR = 1.89, P = 4.5 × 10-23, and non-significant associations with PPARG Pro12Ala (OR = 0.85, P = 0.14, ADIPOQ -11,377C>G (OR = 1.00, P = 0.97 and ENPP1 K121Q (OR = 0.99, P = 0.94. In obese subjects, associations with T2D were detected with PPARG Pro12Ala (OR = 0.73, P = 0.004, ADIPOQ -11,377C>G (OR = 1.26, P = 0.02, ENPP1 K121Q (OR = 1.30, P = 0.003 and TCF7L2 rs7903146 (OR = 1.30, P = 1.1 × 10-4, and non-significant associations with HNF1A I27L (OR = 0.96, P = 0.53, GCK -30G>A (OR = 1.15, P = 0.12 and SLC30A8 R325W (OR = 0.95, P = 0.44. However, a genotypic heterogeneity was only found for TCF7L2 rs7903146 (P = 3.2 × 10-5 and ENPP1 K121Q (P = 0.02. No association with T2D was found for KCNJ11, RETN, and HNF4A polymorphisms in non-obese or in obese individuals. Conclusion Genetic variants modulating insulin action may have an increased effect on T2D susceptibility in the presence of obesity, whereas genetic variants acting on insulin secretion may have a greater impact on T2D susceptibility in non-obese individuals.

  20. The allergy adjuvant effect of particles – genetic factors influence antibody and cytokine responses

    Directory of Open Access Journals (Sweden)

    Løvik Martinus

    2005-06-01

    Full Text Available Abstract Background There is increasing epidemiological and experimental evidence for an aggravating effect of particulate air pollution on asthma and allergic symptoms and, to a lesser extent, on allergic sensitization. Genetic factors appear to influence not only the magnitude, but also the quality of the adjuvant effect of particles with respect to allergen-specific IgE (Th2-associated and IgG2a (Th1-associated responses. In the present study, we aimed to investigate how the genetic background influences the responses to the allergen and particles alone and in combination. We examined how polystyrene particles (PSP affected the IgE and IgG2a responses against the model allergen ovalbumin (OVA, after subcutaneous injection into the footpad of BALB/cA, BALB/cJ, NIH and C3H/HeN mice, Further, ex vivo IL-4, IFN-γ and IL-10 cytokine secretion by Con A-stimulated cells from the draining popliteal lymph node (PLN five days after injection of OVA and PSP separately or in combination was determined. Results PSP injected with OVA increased the levels of OVA-specific IgE antibodies in all strains examined. In contrast, the IgG2a levels were significantly increased only in NIH and C3H/HeN mice. PSP in the presence of OVA increased cell numbers and IL-4, IL-10 and IFN-γ levels in BALB/cA, NIH and C3H/HeN mice, with the exception of IFN-γ in NIH mice. However, each mouse strain had their unique pattern of response to OVA+PSP, OVA and PSP, and also their unique background cytokine response (i.e. the cytokine response in cells from mice injected with buffer only. Conclusion Genetic factors (i.e. the strain of mice influenced the susceptibility to the adjuvant effect of PSP on both secondary antibody responses and primary cellular responses in the lymph node, as well as the cellular responses to both OVA and PSP given separately. Interestingly, PSP alone induced cytokine responses in the lymph node in some of the mouse strains. Furthermore, we found that

  1. Transcription closed and open complex dynamics studies reveal balance between genetic determinants and co-factors.

    Science.gov (United States)

    Sala, Adrien; Shoaib, Muhammad; Anufrieva, Olga; Mutharasu, Gnanavel; Jahan Hoque, Rawnak; Yli-Harja, Olli; Kandhavelu, Meenakshisundaram

    2015-05-19

    In E. coli, promoter closed and open complexes are key steps in transcription initiation, where magnesium-dependent RNA polymerase catalyzes RNA synthesis. However, the exact mechanism of initiation remains to be fully elucidated. Here, using single mRNA detection and dual reporter studies, we show that increased intracellular magnesium concentration affects Plac initiation complex formation resulting in a highly dynamic process over the cell growth phases. Mg2+ regulates transcription transition, which modulates bimodality of mRNA distribution in the exponential phase. We reveal that Mg2+ regulates the size and frequency of the mRNA burst by changing the open complex duration. Moreover, increasing magnesium concentration leads to higher intrinsic and extrinsic noise in the exponential phase. RNAP-Mg2+ interaction simulation reveals critical movements creating a shorter contact distance between aspartic acid residues and Nucleotide Triphosphate residues and increasing electrostatic charges in the active site. Our findings provide unique biophysical insights into the balanced mechanism of genetic determinants and magnesium ion in transcription initiation regulation during cell growth.

  2. Cobalt and nickel stabilize stem cell transcription factor OCT4 through modulating its sumoylation and ubiquitination.

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    Yixin Yao

    Full Text Available Stem cell research can lead to the development of treatments for a wide range of ailments including diabetes, heart disease, aging, neurodegenerative diseases, spinal cord injury, and cancer. OCT4 is a master regulator of self-renewal of undifferentiated embryonic stem cells. OCT4 also plays a crucial role in reprogramming of somatic cells into induced pluripotent stem (iPS cells. Given known vivo reproductive toxicity of cobalt and nickel metals, we examined the effect of these metals on expression of several stem cell factors in embryonic Tera-1 cells, as well as stem cells. Cobalt and nickel induced a concentration-dependent increase of OCT4 and HIF-1α, but not NANOG or KLF4. OCT4 induced by cobalt and nickel was due primarily to protein stabilization because MG132 stabilized OCT4 in cells treated with either metals and because neither nickel nor cobalt significantly modulated its steady-state mRNA level. OCT4 stabilization by cobalt and nickel was mediated largely through reactive oxygen species (ROS as co-treatment with ascorbic acid abolished OCT4 increase. Moreover, nickel and cobalt treatment increased sumoylation and mono-ubiquitination of OCT4 and K123 was crucial for mediating these modifications. Combined, our observations suggest that nickel and cobalt may exert their reproductive toxicity through perturbing OCT4 activity in the stem cell compartment.

  3. Vascular endothelial growth factor A (VEGFA) modulates bovine placenta steroidogenesis in vitro.

    Science.gov (United States)

    Sousa, L M M C; Campos, D B; Fonseca, V U; Viau, P; Kfoury, J R; Oliveira, C A; Binelli, M; Buratini, J; Papa, P C

    2012-10-01

    Our objectives were to investigate the possible role of VEGFA in bovine placenta steroid synthesis and to determine whether cloned derived placental cells present similar responses as non-cloned ones. Placental cells from cloned (term) and non-cloned (days 90, 150, 210 and term) pregnancies were isolated and treated with VEGFA (50 ng/ml) for 24, 48 or 96 h. Progesterone (P(4)) and estrone sulfate (E(1)S) were assessed by RIA, while aromatase P450-positive cells were quantified using the point counting test. The percentages of steroidogenic and non-steroidogenic populations were determined by flow cytometry. VEGFA augmented or decreased P(4) and E(1)S concentrations as well as aromatase P450-positive cell density, depending on gestational age and time in culture. The percentage of steroidogenic cells was lower than that of non-steroidogenic ones for each culture time (P 0.05). VEGFA treatment altered P(4) and E(1)S levels in placental cells depending on type of gestation. These results suggest that VEGFA acts locally in the bovine placenta to modulate steroidogenesis during gestation, but in a different pattern between cloned and non-cloned derived placental cells at term. Therefore, this factor can be considered an important regulator of placental development and function.

  4. Analysis of modulation factor to shorten the delivery time in helical tomotherapy.

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    Shimizu, Hidetoshi; Sasaki, Koji; Tachibana, Hiroyuki; Tomita, Natsuo; Makita, Chiyoko; Nakashima, Kuniyasu; Yokoi, Kazushi; Kubota, Takashi; Yoshimoto, Manabu; Iwata, Tohru; Kodaira, Takeshi

    2017-05-01

    A low modulation factor (MF) maintaining a good dose distribution contributes to the shortening of the delivery time and efficiency of the treatment plan in helical tomotherapy. The purpose of this study was to reduce the delivery time using initial values and the upper limit values of MF. First, patients with head and neck cancer (293 cases) or prostate cancer (181 cases) treated between June 2011 and July 2015 were included in the analysis of MF values. The initial MF value (MFinitial ) was defined as the average MFactual value, and the upper limit of the MF value (MFUL ) was defined according the following equation: MFUL = 2 × standard deviation of MFactual value + the average MFactual Next, a treatment plan was designed for patients with head and neck cancer (62 cases) and prostate cancer (13 cases) treated between December 2015 and June 2016. The average MFactual value for the nasopharynx, oropharynx, hypopharynx, and prostate cases decreased from 2.1 to 1.9 (p = 0.0006), 1.9 to 1.6 (p delivery time for the nasopharynx, oropharynx, hypopharynx, and prostate cases also decreased from 19.9 s cm(-1) to 16.7 s cm(-1) (p delivery time was shortened by the adaptation of MFinitial and MFUL values with a reduction in the average MFactual for head and neck cancer and prostate cancer cases. © 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

  5. Nerve growth factor modulate proliferation of cultured rabbit corneal endothelial cells and epithelial cells.

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    Li, Xinyu; Li, Zhongguo; Qiu, Liangxiu; Zhao, Changsong; Hu, Zhulin

    2005-01-01

    In order to investigate the effect of nerve growth factor (NGF) on the proliferation of rabbit corneal endothelial cells and epithelial cells, the in vitro cultured rabbit corneal endothelial cells and epithelial cells were treated with different concentrations of NGF. MTT assay was used to examine the clonal growth and proliferation of the cells by determining the absorbency values at 570 nm. The results showed that NGF with three concentrations ranging from 5 U/mL to 500 U/mL enhanced the proliferation of rabbit corneal endothelial cells in a concentration-dependent manner. 50 U/mL and 500 U/mL NGF got more increase of proliferation than that of 5 U/mL NGF did. Meanwhile, 50 U/mL and 500 U/mL NGF could promote the proliferation of the rabbit corneal epithelial cells significantly in a concentration-dependent manner. However, 5 U/mL NGF did not enhance the proliferation of epithelial cells. It was suggested that exogenous NGF can stimulate the proliferation of both rabbit corneal endothelial and epithelial cells, but the extent of modulation is different.

  6. The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation.

    Science.gov (United States)

    Moskot, Marta; Montefusco, Sandro; Jakóbkiewicz-Banecka, Joanna; Mozolewski, Paweł; Węgrzyn, Alicja; Di Bernardo, Diego; Węgrzyn, Grzegorz; Medina, Diego L; Ballabio, Andrea; Gabig-Cimińska, Magdalena

    2014-06-13

    Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) has been previously proposed as a potential drug for use in substrate reduction therapy for mucopolysaccharidoses, a group of inherited metabolic diseases caused by mutations leading to inefficient degradation of glycosaminoglycans (GAGs) in lysosomes. It was demonstrated that this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases. So far, no comprehensive genomic analyses have been performed to elucidate the molecular mechanisms underlying the effect elicited by genistein. Therefore, the aim of this work was to identify the genistein-modulated gene network regulating GAG biosynthesis and degradation, taking into consideration the entire lysosomal metabolism. Our analyses identified over 60 genes with known roles in lysosomal biogenesis and/or function whose expression was enhanced by genistein. Moreover, 19 genes whose products are involved in both GAG synthesis and degradation pathways were found to be remarkably differentially regulated by genistein treatment. We found a regulatory network linking genistein-mediated control of transcription factor EB (TFEB) gene expression, TFEB nuclear translocation, and activation of TFEB-dependent lysosome biogenesis to lysosomal metabolism. Our data indicate that the molecular mechanism of genistein action involves not only impairment of GAG synthesis but more importantly lysosomal enhancement via TFEB. These findings contribute to explaining the beneficial effects of genistein in lysosomal storage diseases as well as envisage new therapeutic approaches to treat these devastating diseases.

  7. Expression of Aedes trypsin-modulating oostatic factor on the virion of TMV: A potential larvicide.

    Science.gov (United States)

    Borovsky, Dov; Rabindran, Shailaja; Dawson, William O; Powell, Charles A; Iannotti, Donna A; Morris, Timothy J; Shabanowitz, Jeffry; Hunt, Donald F; DeBondt, Hendrik L; DeLoof, Arnold

    2006-12-12

    We report the engineering of the surface of the tobacco mosaic virus (TMV) virion with a mosquito decapeptide hormone, trypsin-modulating oostatic factor (TMOF). The TMV coat protein (CP) was fused to TMOF at the C terminus by using a read-through, leaky stop codon that facilitated expression of CP and chimeric CP-TMOF (20:1 ratio) that were coassembled into virus particles in infected Nicotiana tabacum. Plants that were infected with the hybrid TMV RNA accumulated TMOF to levels of 1.3% of total soluble protein. Infected tobacco leaf discs that were fed to Heliothis virescens fourth-instar larvae stunted their growth and inhibited trypsin and chymotrypsin activity in their midgut. Purified CP-TMOF virions fed to mosquito larvae stopped larval growth and caused death. Because TMV has a wide host range, expressing TMV-TMOF in plants can be used as a general method to protect them against agricultural insect pests and to control vector mosquitoes.

  8. CLONING AND EXPRESSING TRYPSIN MODULATING OOSTATIC FACTOR IN Chlorella desiccata TO CONTROL MOSQUITO LARVAE.

    Science.gov (United States)

    Borovsky, Dov; Sterner, Andeas; Powell, Charles A

    2016-01-01

    The insect peptide hormone trypsin modulating oostatic factor (TMOF), a decapeptide that is synthesized by the mosquito ovary and controls the translation of the gut's trypsin mRNA was cloned and expressed in the marine alga Chlorella desiccata. To express Aedes aegypti TMOF gene (tmfA) in C. desiccata cells, two plasmids (pYES2/TMOF and pYDB4-tmfA) were engineered with pKYLX71 DNA (5 Kb) carrying the cauliflower mosaic virus (CaMV) promoter 35S(2) and the kanamycin resistant gene (neo), as well as, a 8 Kb nitrate reductase gene (nit) from Chlorella vulgaris. Transforming C. desiccata with pYES2/TMOF and pYDB4-tmfA show that the engineered algal cells express TMOF (20 ± 4 μg ± SEM and 17 ± 3 μg ± SEM, respectively in 3 × 10(8) cells) and feeding the cells to mosquito larvae kill 75 and 60% of Ae. aegypti larvae in 4 days, respectively. Southern and Northern blots analyses show that tmfA integrated into the genome of C. desiccata by homologous recombination using the yeast 2 μ circle of replication and the nit in pYES2/TMOF and pYDB4-tmfA, respectively, and the transformed algal cells express tmfA transcript. Using these algal cells it will be possible in the future to control mosquito larvae in the marsh.

  9. Analysis of Factors Influencing the Development of Xerostomia during Intensity-Modulated Radiotherapy

    Science.gov (United States)

    Randall, Ken; Stevens, Jason; Yepes, Juan Fernando; Randall, Marcus E.; Kudrimoti, Mahesh; Feddock, Jonathan; Xi, Jing; Kryscio, Richard J.; Miller, Craig S.

    2013-01-01

    OBJECTIVES Factors influencing xerostomia during intensity-modulated radiation therapy (IMRT) were assessed. METHODS A 6-week study of 32 head and neck cancer (HNC) patients was performed. Subjects completed the Xerostomia Inventory (XI) and provided stimulated saliva (SS) at baseline, week two and at end of IMRT. Influence of SS flow rate (SSFR), calcium and mucin 5b (MUC5b) concentrations and radiation dose on xerostomia was determined. RESULTS HNC subjects experienced mean SSFR decline of 36% by visit two (N=27; p=0.012) and 57% by visit three (N=20; p=0.0004), Concentrations of calcium and MUC5b increased, but not significantly during IMRT (p>0.05). Xerostomia correlated most with decreasing salivary flow rate as determined by Spearman correlations (p<0.04) and linear mixed models (p<0.0001). CONCLUSIONS Although IMRT is sparing to the parotid glands, it has an early effect on SSFR and the constituents in saliva in a manner that is associated with the perception of xerostomia. PMID:23523462

  10. Cobalt and Nickel Stabilize Stem Cell Transcription Factor OCT4 through Modulating Its Sumoylation and Ubiquitination

    Science.gov (United States)

    Yao, Yixin; Lu, Yinghua; Chen, Wen-chi; Jiang, Yongping; Cheng, Tao; Ma, Yupo; Lu, Lou; Dai, Wei

    2014-01-01

    Stem cell research can lead to the development of treatments for a wide range of ailments including diabetes, heart disease, aging, neurodegenerative diseases, spinal cord injury, and cancer. OCT4 is a master regulator of self-renewal of undifferentiated embryonic stem cells. OCT4 also plays a crucial role in reprogramming of somatic cells into induced pluripotent stem (iPS) cells. Given known vivo reproductive toxicity of cobalt and nickel metals, we examined the effect of these metals on expression of several stem cell factors in embryonic Tera-1 cells, as well as stem cells. Cobalt and nickel induced a concentration-dependent increase of OCT4 and HIF-1α, but not NANOG or KLF4. OCT4 induced by cobalt and nickel was due primarily to prot