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Sample records for genetic pathways leading

  1. The Socioeconomic Pathways Leading to Romantic Relationship Outcomes: A Genetically Informed Early Life Course Investigation.

    PubMed

    Wickrama, Kandauda K A S; O'Neal, Catherine W

    2016-09-01

    The present study tests a multilevel comprehensive model incorporating both life course processes and genetic influences leading to young adults' romantic relationship quality using data from 1,560 adolescents over 13 years in the nationally representative Add Health sample. Results provided evidence of a socioeconomic mediating pathway linking early family and community contexts to young adults' romantic relationship quality, and novel evidence for both direct and interactive genetic associations that relate to these mediating pathways. A cumulative genetic index showed (a) direct associations with young adults' socioeconomic attainment and (b) interactions with community adversity and mothers' marital stability on young adults' achieved socioeconomic context and relationship quality. © 2015 The Authors. Journal of Research on Adolescence © 2015 Society for Research on Adolescence.

  2. Under the Influence of Genetics: How Transdisciplinarity Leads Us to Rethink Social Pathways to Illness

    PubMed Central

    Pescosolido, Bernice A.; Perry, Brea L.; Long, J. Scott; Martin, Jack K.; Nurnberger, John I.; Hesselbrock, Victor

    2015-01-01

    To extend our understanding of how social structures and social processes impact behavior, sociologists have been challenged to incorporate the potential explanatory role of genetics in their models. Here, we draw propositions from three major understandings of illness causation offered by social theory – fundamental causes, social stress processes, and social safety net theories. We tailor hypotheses to the case of alcohol dependence, long considered a multifaceted problem, defying simple explanation and having both biological and social roots. After briefly reviewing current appeals for transdisciplinary research, we describe both sociological and genetic theories, and derive propositions expected under each and under a transdisciplinary theoretical frame. Analyses of a later wave of the preeminent medical science study, the Collaborative Study on the Genetics of Alcoholism (COGA), reveals a complex interplay of how the GABRA2 gene works with and against social structural factors to produce cases meeting DSM/ICD diagnoses. When both genetic and social factors are controlled, virtually equivalent effects of each remain; and, only modest evidence suggests that genetic influence works through social structural conditions and experiences. Further exploratory analyses using multiplicative terms reveal enhanced gene-environment interactions: 1) women are largely unaffected in their risk for alcohol dependence by allele status at this candidate gene; 2) family support attenuates genetic influence; 3) childhood deprivation exacerbates genetic predispositions. We discuss how these findings lead us to consider the essential intradisciplinary tension in sociological theories (i.e., the role of proximal and distal influences in social processes). Overall, our findings point to the promise of theories blending social and genetic influences by focusing directly on dynamic, networked sequences that produce different pathways to health and illness. PMID:19569404

  3. Under the influence of genetics: how transdisciplinarity leads us to rethink social pathways to illness.

    PubMed

    Pescosolido, Bernice A; Perry, Brea L; Long, J Scott; Martin, Jack K; Nurnberger, John I; Hesselbrock, Victor

    2008-01-01

    This article describes both sociological and genetic theories of illness causation and derives propositions expected under each and under a transdisciplinary theoretical frame. The authors draw propositions from three theories -- fundamental causes, social stress processes, and social safety net theories -- and tailor hypotheses to the case of alcohol dependence. Analyses of a later wave of the Collaborative Study on the Genetics of Alcoholism reveal a complex interplay of the GABRA2 gene with social structural factors to produce cases meeting DSM/ICD diagnoses. Only modest evidence suggests that genetic influence works through social conditions and experiences. Further, women are largely unaffected in their risk for alcohol dependence by allele status at this candidate gene; family support attenuates genetic influence; and childhood deprivation exacerbates genetic predispositions. These findings highlight the essential intradisciplinary tension in the role of proximal and distal influences in social processes and point to the promise of focusing directly on dynamic, networked sequences that produce different pathways to health and illness.

  4. Shared Selective Pressures on Fungal and Human Metabolic Pathways Lead to Divergent yet Analogous Genetic Responses.

    PubMed

    Eidem, Haley R; McGary, Kriston L; Rokas, Antonis

    2015-06-01

    Reduced metabolic efficiency, toxic intermediate accumulation, and deficits of molecular building blocks, which all stem from disruptions of flux through metabolic pathways, reduce organismal fitness. Although these represent shared selection pressures across organisms, the genetic signatures of the responses to them may differ. In fungi, a frequently observed signature is the physical linkage of genes from the same metabolic pathway. In contrast, human metabolic genes are rarely tightly linked; rather, they tend to show tissue-specific coexpression. We hypothesized that the physical linkage of fungal metabolic genes and the tissue-specific coexpression of human metabolic genes are divergent yet analogous responses to the range of selective pressures imposed by disruptions of flux. To test this, we examined the degree to which the human homologs of physically linked metabolic genes in fungi (fungal linked homologs or FLOs) are coexpressed across six human tissues. We found that FLOs are significantly more correlated in their expression profiles across human tissues than other metabolic genes. We obtained similar results in analyses of the same six tissues from chimps, gorillas, orangutans, and macaques. We suggest that when selective pressures remain stable across large evolutionary distances, evidence of selection in a given evolutionary lineage can become a highly reliable predictor of the signature of selection in another, even though the specific adaptive response in each lineage is markedly different.

  5. Genetic and Biochemical Characterization of the Pathway in Pantoea citrea Leading to Pink Disease of Pineapple

    PubMed Central

    Pujol, Catherine J.; Kado, Clarence I.

    2000-01-01

    Pink disease of pineapple, caused by Pantoea citrea, is characterized by a dark coloration on fruit slices after autoclaving. This coloration is initiated by the oxidation of glucose to gluconate, which is followed by further oxidation of gluconate to as yet unknown chromogenic compounds. To elucidate the biochemical pathway leading to pink disease, we generated six coloration-defective mutants of P. citrea that were still able to oxidize glucose into gluconate. Three mutants were found to be affected in genes involved in the biogenesis of c-type cytochromes, which are known for their role as specific electron acceptors linked to dehydrogenase activities. Three additional mutants were affected in different genes within an operon that probably encodes a 2-ketogluconate dehydrogenase protein. These six mutants were found to be unable to oxidize gluconate or 2-ketogluconate, resulting in an inability to produce the compound 2,5-diketogluconate (2,5-DKG). Thus, the production of 2,5-DKG by P. citrea appears to be responsible for the dark color characteristic of the pink disease of pineapple. PMID:10735866

  6. CD38/CD31 interactions activate genetic pathways leading to proliferation and migration in chronic lymphocytic leukemia cells

    PubMed Central

    Deaglio, Silvia; Aydin, Semra; Grand, Maurizia Mello; Vaisitti, Tiziana; Bergui, Luciana; D’Arena, Giovanni; Chiorino, Giovanna; Malavasi, Fabio

    2010-01-01

    Human CD38 is a pleiotropic glycoprotein belonging to a family of genes coding for enzymes/receptors involved in the catabolism of extracellular nucleotides. CD38 receptor activities are regulated through binding to the non-substrate ligand CD31. CD38 expression above a critical threshold represents a negative prognostic marker for CLL patients. Activation of CD38 by means of agonistic monoclonal antibodies or the CD31 ligand induces proliferation and immunoblast differentiation of CLL cells. Here we define the genetic signature that follows long-term in vitro interactions between CD38+ CLL lymphocytes and CD31+ cells. The emerging profile confirms that the CD31/CD38 axis activates genetic programs relevant for proliferative responses. It also indicates a contribution of this pathway to the processes mediating migration and homing. These results further support the notion that the CD31/CD38 axis is part of a network of accessory signals that modify the microenvironment, favoring localization of leukemic cells to growth-permissive sites. PMID:19956559

  7. The Root Hair Assay Facilitates the Use of Genetic and Pharmacological Tools in Order to Dissect Multiple Signalling Pathways That Lead to Programmed Cell Death

    PubMed Central

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F.

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  8. Genetic Pathways to Insomnia

    PubMed Central

    Lind, Mackenzie J.; Gehrman, Philip R.

    2016-01-01

    This review summarizes current research on the genetics of insomnia, as genetic contributions are thought to be important for insomnia etiology. We begin by providing an overview of genetic methods (both quantitative and measured gene), followed by a discussion of the insomnia genetics literature with regard to each of the following common methodologies: twin and family studies, candidate gene studies, and genome-wide association studies (GWAS). Next, we summarize the most recent gene identification efforts (primarily GWAS results) and propose several potential mechanisms through which identified genes may contribute to the disorder. Finally, we discuss new genetic approaches and how these may prove useful for insomnia, proposing an agenda for future insomnia genetics research. PMID:27999387

  9. An analysis using the hobo genetic system reveals that combinatorial signaling by the Dpp and Wg pathways regulates dpp expression in leading edge cells of the dorsal ectoderm in Drosophila melanogaster.

    PubMed Central

    Newfeld, S J; Takaesu, N T

    2002-01-01

    Our laboratory has contributed to the development of a genetic system based upon the hobo transposable element in Drosophila melanogaster. We recently reported that hobo, like the better-known P element, is capable of local transposition. In that study, we mobilized a hobo enhancer trap vector and generated two unique alleles of decapentaplegic (dpp), a transforming growth factor-beta family member with numerous roles during development. Here we report a detailed study of one of those alleles (dpp(F11)). To our knowledge, this is the first application of the hobo genetic system to understanding developmental processes. First, we demonstrate that lacZ expression from the dpp(F11) enhancer trap accurately reflects dpp mRNA accumulation in leading edge cells of the dorsal ectoderm. Then we show that combinatorial signaling by the Wingless (Wg) pathway, the Dpp pathway, and the transcriptional coactivator Nejire (CBP/p300) regulates dpp(F11) expression in these cells. Our analysis of dpp(F11) suggests a model for the integration of Wg and Dpp signals that may be applicable to other developmental systems. Our analysis also illustrates several new features of the hobo genetic system and highlights the value of hobo, as an alternative to P, in addressing developmental questions. PMID:12072465

  10. Different Pathways Leading to Integrase Inhibitors Resistance

    PubMed Central

    Thierry, Eloïse; Deprez, Eric; Delelis, Olivier

    2017-01-01

    Integrase strand-transfer inhibitors (INSTIs), such as raltegravir (RAL), elvitegravir, or dolutegravir (DTG), are efficient antiretroviral agents used in HIV treatment in order to inhibit retroviral integration. By contrast to RAL treatments leading to well-identified mutation resistance pathways at the integrase level, recent clinical studies report several cases of patients failing DTG treatment without clearly identified resistance mutation in the integrase gene raising questions for the mechanism behind the resistance. These compounds, by impairing the integration of HIV-1 viral DNA into the host DNA, lead to an accumulation of unintegrated circular viral DNA forms. This viral DNA could be at the origin of the INSTI resistance by two different ways. The first one, sustained by a recent report, involves 2-long terminal repeat circles integration and the second one involves expression of accumulated unintegrated viral DNA leading to a basal production of viral particles maintaining the viral information. PMID:28123383

  11. Pathway-based discovery of genetic interactions in breast cancer.

    PubMed

    Wang, Wen; Xu, Zack Z; Costanzo, Michael; Boone, Charles; Lange, Carol A; Myers, Chad L

    2017-09-01

    Breast cancer is the second largest cause of cancer death among U.S. women and the leading cause of cancer death among women worldwide. Genome-wide association studies (GWAS) have identified several genetic variants associated with susceptibility to breast cancer, but these still explain less than half of the estimated genetic contribution to the disease. Combinations of variants (i.e. genetic interactions) may play an important role in breast cancer susceptibility. However, due to a lack of statistical power, the current tests for genetic interactions from GWAS data mainly leverage prior knowledge to focus on small sets of genes or SNPs that are known to have an association with breast cancer. Thus, many genetic interactions, particularly among novel variants, remain understudied. Reverse-genetic interaction screens in model organisms have shown that genetic interactions frequently cluster into highly structured motifs, where members of the same pathway share similar patterns of genetic interactions. Based on this key observation, we recently developed a method called BridGE to search for such structured motifs in genetic networks derived from GWAS studies and identify pathway-level genetic interactions in human populations. We applied BridGE to six independent breast cancer cohorts and identified significant pathway-level interactions in five cohorts. Joint analysis across all five cohorts revealed a high confidence consensus set of genetic interactions with support in multiple cohorts. The discovered interactions implicated the glutathione conjugation, vitamin D receptor, purine metabolism, mitotic prometaphase, and steroid hormone biosynthesis pathways as major modifiers of breast cancer risk. Notably, while many of the pathways identified by BridGE show clear relevance to breast cancer, variants in these pathways had not been previously discovered by traditional single variant association tests, or single pathway enrichment analysis that does not consider SNP

  12. Genetic Pathways of Vascular Calcification

    PubMed Central

    Bowman, Marion A. Hofmann; McNally, Elizabeth M.

    2012-01-01

    Vascular calcification is an independent risk factor for cardiovascular disease. Arterial calcification of the aorta, coronary, carotid and peripheral arteries becomes more prevalent with age. Genomewide association studies have identified regions of the genome linked to vascular calcification, and these same regions are linked to myocardial infarction risk. The 9p21 region linked to vascular disease and inflammation also associates with vascular calcification. In addition to these common variants, rare genetic defects can serve as primary triggers of accelerated and premature calcification. Infancy-associated calcific disorders are caused by loss of function mutations in ENPP1 an enzyme that produces extracellular pyrophosphate. Adult onset vascular calcification is linked to mutations NTE5, another enzyme that regulates extracellular phosphate metabolism. Common conditions that secondarily enhance vascular calcification include atherosclerosis, metabolic dysfunction, diabetes, and impaired renal clearance. Oxidative stress and vascular inflammation, along with biophysical properties, converge with these predisposing factors to promote soft tissue mineralization. Vascular calcification is accompanied by an osteogenic profile, and this osteogenic conversion is seen within the vascular smooth muscle itself as well as the matrix. Herein we will review the genetic causes of medial calcification in the smooth muscle layer, focusing on recent discoveries of gene mutations that regulate extracellular matrix phosphate production and the role of S100 proteins as promoters of vascular calcification. PMID:23040839

  13. Genetic Variations Leading to Familial Dilated Cardiomyopathy

    PubMed Central

    Cho, Kae Won; Lee, Jongsung; Kim, Youngjo

    2016-01-01

    Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions. PMID:27802374

  14. Genetic Variations Leading to Familial Dilated Cardiomyopathy.

    PubMed

    Cho, Kae Won; Lee, Jongsung; Kim, Youngjo

    2016-10-01

    Cardiomyopathy is a major cause of death worldwide. Based on pathohistological abnormalities and clinical manifestation, cardiomyopathies are categorized into several groups: hypertrophic, dilated, restricted, arrhythmogenic right ventricular, and unclassified. Dilated cardiomyopathy, which is characterized by dilation of the left ventricle and systolic dysfunction, is the most severe and prevalent form of cardiomyopathy and usually requires heart transplantation. Its etiology remains unclear. Recent genetic studies of single gene mutations have provided significant insights into the complex processes of cardiac dysfunction. To date, over 40 genes have been demonstrated to contribute to dilated cardiomyopathy. With advances in genetic screening techniques, novel genes associated with this disease are continuously being identified. The respective gene products can be classified into several functional groups such as sarcomere proteins, structural proteins, ion channels, and nuclear envelope proteins. Nuclear envelope proteins are emerging as potential molecular targets in dilated cardiomyopathy. Because they are not directly associated with contractile force generation and transmission, the molecular pathways through which these proteins cause cardiac muscle disorder remain unclear. However, nuclear envelope proteins are involved in many essential cellular processes. Therefore, integrating apparently distinct cellular processes is of great interest in elucidating the etiology of dilated cardiomyopathy. In this mini review, we summarize the genetic factors associated with dilated cardiomyopathy and discuss their cellular functions.

  15. Soil is an important pathway of human lead exposure.

    PubMed Central

    Mielke, H W; Reagan, P L

    1998-01-01

    This review shows the equal or greater importance of leaded gasoline-contaminated dust compared to lead-based paint to the child lead problem, and that soil lead, resulting from leaded gasoline and pulverized lead-based paint, is at least or more important than lead-based paint (intact and not pulverized) as a pathway of human lead exposure. Because lead-based paint is a high-dose source, the biologically relevant dosage is similar to lead in soil. Both lead-based paint and soil lead are associated with severe lead poisoning. Leaded gasoline and lead in food, but not lead-based paint, are strongly associated with population blood lead levels in both young children and adults. Soil lead and house dust, but not lead-based paint, are associated with population blood lead levels in children. Most soil lead and house dust are associated with leaded gasoline. Lead-based paint dust is associated with cases of renovation of either exterior or interior environments in which the paint was pulverized. Based upon the limited data to date, abatement of soil lead is more effective than abatement of lead-based paint in reducing blood lead levels of young children. About equal numbers of children under 7 years of age are exposed to soil lead and lead-based paint. Seasonality studies point to soil lead as the main source of population blood lead levels. Soil lead is a greater risk factor than lead-based paint to children engaged in hand-to-mouth and pica behavior. In summary, soil lead is important for addressing the population of children at risk of lead poisoning. When soil lead is acknowledged by regulators and the public health community as an important pathway of human lead exposure, then more effective opportunities for improving primary lead prevention can become a reality. Images Figure 1 PMID:9539015

  16. AMD and the alternative complement pathway: genetics and functional implications.

    PubMed

    Tan, Perciliz L; Bowes Rickman, Catherine; Katsanis, Nicholas

    2016-06-21

    Age-related macular degeneration (AMD) is an ocular neurodegenerative disorder and is the leading cause of legal blindness in Western societies, with a prevalence of up to 8 % over the age of 60, which continues to increase with age. AMD is characterized by the progressive breakdown of the macula (the central region of the retina), resulting in the loss of central vision including visual acuity. While its molecular etiology remains unclear, advances in genetics and genomics have illuminated the genetic architecture of the disease and have generated attractive pathomechanistic hypotheses. Here, we review the genetic architecture of AMD, considering the contribution of both common and rare alleles to susceptibility, and we explore the possible mechanistic links between photoreceptor degeneration and the alternative complement pathway, a cascade that has emerged as the most potent genetic driver of this disorder.

  17. Genetic and environmental pathways to complex diseases

    PubMed Central

    Gohlke, Julia M; Thomas, Reuben; Zhang, Yonqing; Rosenstein, Michael C; Davis, Allan P; Murphy, Cynthia; Becker, Kevin G; Mattingly, Carolyn J; Portier, Christopher J

    2009-01-01

    Background Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches. Results Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes. Conclusion Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions. PMID:19416532

  18. Adoption study demonstrating two genetic pathways to drug abuse.

    PubMed

    Cadoret, R J; Yates, W R; Troughton, E; Woodworth, G; Stewart, M A

    1995-01-01

    Studies of adoptees have demonstrated that there are two genetic factors leading to alcohol abuse and/or dependence (abuse/dependence). In addition, environmental factors found in the adoptive family also predict alcohol abuse/dependency independently. One study has found evidence that a similar model of two genetic factors and independent adoptive family factors were involved in drug abuse. Our study was designed to test the hypothesis that genetic factors defined by alcohol abuse/dependency and anti-social personality disorder in biologic parents were etiologic in drug abuse/dependency and that psychiatric problems in adoptive parents were an additional factor associated with drug abuse/dependence. A sample of 95 male adoptees, separated at birth from their biologic parents, were followed up as adults to determine their psychiatric diagnosis and their substance use/abuse in a structured interview administered blind to biologic parent diagnoses. A high-risk, case-control design was used wherein half of the adoptees came from biologic parents known to be alcohol abuser/dependent and/or have antisocial personalities (diagnoses from hospital or prison records). These adoptees were matched for age, sex, and adoption agency to a control group of adoptees whose biologic parents were not found in the hospital and prison record search. Adoptive home environment was assessed by structured interviews, including psychiatric assessment of both adoptive parents. Data were analyzed by log-linear modeling, which showed evidence of two genetic pathways to drug abuse/dependency. One pathway went directly from a biologic parent's alcoholism to drug abuse/dependency. The second pathway was more circuitous, and started with anti-social personality disorder in the biologic parent and proceeded through intervening variables of adoptee aggressivity, conduct disorder, antisocial personality disorder, and, eventually, ended in drug abuse/dependency. Environmental factors defined by

  19. An empirical comparison of lead exposure pathway models.

    PubMed Central

    Succop, P; Bornschein, R; Brown, K; Tseng, C Y

    1998-01-01

    Structural equation modeling is a statistical method for partitioning the variance in a set of interrelated multivariate outcomes into that which is due to direct, indirect, and covariate (exogenous) effects. Despite this model's flexibility to handle different experimental designs, postulation of a causal chain among the endogenous variables and the points of influence of the covariates is required. This has motivated the researchers at the University of Cincinnati Department of Environmental Health to be guided by a theoretical model for movement of lead from distal sources (exterior soil or dust and paint lead) to proximal sources (interior dust lead) and then finally to biologic outcomes (handwipe and blood lead). The question of whether a single structural equation model built from proximity arguments can be applied to diverse populations observed in different communities with varying lead amounts, sources, and bioavailabilities is addressed in this article. This reanalysis involved data from 1855 children less than 72 months of age enrolled in 11 studies performed over approximately 15 years. Data from children residing near former ore-processing sites were included in this reanalysis. A single model adequately fit the data from these 11 studies; however, the model needs to be flexible to include pathways that are not frequently observed. As expected, the more proximal sources of interior dust lead and handwipe lead were the most important predictors of blood lead; soil lead often had a number of indirect influences. A limited number of covariates were also isolated as usually affecting the endogenous lead variables. The blood lead levels surveyed at the ore-processing sites were comparable to and actually somewhat lower than those reported in the the Third National Health and Nutrition Examination Survey. Lessened bioavailability of the lead at certain of these sites is a probable reason for this finding. PMID:9860917

  20. Genetic strategies to understand physiological pathways regulating body weight.

    PubMed

    Farooqi, Sadaf

    2014-10-01

    Body weight is a highly heritable trait across species. In humans, genetic variation plays a major role in determining the inter-individual differences in susceptibility or resistance to environmental factors which influence energy intake and expenditure. In this review, I discuss how genetic studies have contributed to our understanding of the central pathways that govern energy homeostasis. The study of individuals harboring highly penetrant genetic variants that disrupt the leptin-melanocortin pathway has informed our understanding of the physiological pathways involved in mammalian energy homeostasis.

  1. Valproic acid, a molecular lead to multiple regulatory pathways.

    PubMed

    Kostrouchová, M; Kostrouch, Z; Kostrouchová, M

    2007-01-01

    Valproic acid (2-propyl pentanoic acid) is a drug used for the treatment of epilepsy and bipolar disorder. Although very rare, side effects such as spina bifida and other defects of neural tube closure indicate that valproic acid interferes with developmental regulatory pathways. Recently obtained data show that valproic acid affects cell growth, differentiation, apoptosis and immunogenicity of cultured cancer cells and tumours. Focused studies uncovered the potential of valproic acid to interfere with multiple regulatory mechanisms including histone deacetylases, GSK3 alpha and beta, Akt, the ERK pathway, the phosphoinositol pathway, the tricarboxylic acid cycle, GABA, and the OXPHOS system. Valproic acid is emerging as a potential anticancer drug and may also serve as a molecular lead that can help design drugs with more specific and more potent effects on the one side and drugs with wide additive but weaker effects on the other. Valproic acid is thus a powerful molecular tool for better understanding and therapeutic targeting of pathways that regulate the behaviour of cancer cells.

  2. Divergent pathways lead to ESCRT-III-catalyzed membrane fission.

    PubMed

    Peel, Suman; Macheboeuf, Pauline; Martinelli, Nicolas; Weissenhorn, Winfried

    2011-04-01

    Endosomal sorting complexes required for transport (ESCRT) have been implicated in topologically similar but diverse cellular and pathological processes including multivesicular body (MVB) biogenesis, cytokinesis and enveloped virus budding. Although receptor sorting at the endosomal membrane producing MVBs employs the regulated assembly of ESCRT-0 followed by ESCRT-I, -II, -III and the vacuolar protein sorting (VPS)4 complex, other ESCRT-catalyzed processes require only a subset of complexes which commonly includes ESCRT-III and VPS4. Recent progress has shed light on the pathway of ESCRT assembly and highlights the separation of tasks of different ESCRT complexes and associated partners. The emerging picture suggests that among all ESCRT-catalyzed processes, divergent pathways lead to ESCRT-III assembly within the neck of a budding structure catalyzing membrane fission.

  3. The Genetic Basis for Variation in Sensitivity to Lead Toxicity in Drosophila melanogaster

    PubMed Central

    Zhou, Shanshan; Morozova, Tatiana V.; Hussain, Yasmeen N.; Luoma, Sarah E.; McCoy, Lenovia; Yamamoto, Akihiko; Mackay, Trudy F.C.; Anholt, Robert R.H.

    2016-01-01

    Background: Lead toxicity presents a worldwide health problem, especially due to its adverse effects on cognitive development in children. However, identifying genes that give rise to individual variation in susceptibility to lead toxicity is challenging in human populations. Objectives: Our goal was to use Drosophila melanogaster to identify evolutionarily conserved candidate genes associated with individual variation in susceptibility to lead exposure. Methods: To identify candidate genes associated with variation in susceptibility to lead toxicity, we measured effects of lead exposure on development time, viability and adult activity in the Drosophila melanogaster Genetic Reference Panel (DGRP) and performed genome-wide association analyses to identify candidate genes. We used mutants to assess functional causality of candidate genes and constructed a genetic network associated with variation in sensitivity to lead exposure, on which we could superimpose human orthologs. Results: We found substantial heritabilities for all three traits and identified candidate genes associated with variation in susceptibility to lead exposure for each phenotype. The genetic architectures that determine variation in sensitivity to lead exposure are highly polygenic. Gene ontology and network analyses showed enrichment of genes associated with early development and function of the nervous system. Conclusions: Drosophila melanogaster presents an advantageous model to study the genetic underpinnings of variation in susceptibility to lead toxicity. Evolutionary conservation of cellular pathways that respond to toxic exposure allows predictions regarding orthologous genes and pathways across phyla. Thus, studies in the D. melanogaster model system can identify candidate susceptibility genes to guide subsequent studies in human populations. Citation: Zhou S, Morozova TV, Hussain YN, Luoma SE, McCoy L, Yamamoto A, Mackay TF, Anholt RR. 2016. The genetic basis for variation in

  4. Analysis of membrane lipid biogenesis pathways using yeast genetics.

    PubMed

    Gsell, Martina; Daum, Günther

    2013-01-01

    The yeast Saccharomyces cerevisiae has become a valuable eukaryotic model organism to study biochemical and cellular processes at a molecular basis. A common strategy for such studies is the use of single and multiple mutants constructed by genetic manipulation which are compromised in individual enzymatic steps or certain metabolic pathways. Here, we describe selected examples of yeast research on phospholipid metabolism with emphasis on our own work dealing with investigations of phosphatidylethanolamine synthesis. Such studies start with the selection and construction of appropriate mutants and lead to phenotype analysis, lipid profiling, enzymatic analysis, and in vivo experiments. Comparing results obtained with wild-type and mutant strains allows us to understand the role of gene products and metabolic processes in more detail. Such studies are valuable not only for contributing to our knowledge of the complex network of lipid metabolism, but also of effects of lipids on structure and function of cellular membranes.

  5. An Interactive, Integrated, Instructional Pathway to the LEAD Science Gateway

    NASA Astrophysics Data System (ADS)

    Yalda, S.; Clark, R.; Davis, L.; Wiziecki, E. N.

    2008-12-01

    Linked Environments for Atmospheric Discovery (LEAD) is a bold and revolutionary paradigm that through a Web-based Service Oriented Architecture (SOA) exposes the user to a rich environment of data, models, data mining and visualization and analysis tools, enabling the user to ask science questions of applications while the complexity of the software and middleware managing these applications is hidden from the user. From its inception in 2003, LEAD has championed goals that have context for the future of weather and related research and education. LEAD espouses to lowering the barrier for using complex end-to-end weather technologies by a) democratizing the availability of advanced weather technologies, b) empowering the user of these technologies to tackle a variety of problems, and c) facilitating learning and understanding. LEAD, as it exists today, is poised to enable a diverse community of scientists, educators, students, and operational practitioners. The project has been informed by atmospheric and computer scientists, educators, and educational consultants who, in search of new knowledge, understanding, ideas, and learning methodologies, seek easy access to new capabilities that allow for user-directed and interactive query and acquisition, simulation, assimilation, data mining, computational modeling, and visualization. As one component of the total LEAD effort, the LEAD education team has designed interactive, integrated, instructional pathways within a set of learning modules (LEAD-to-Learn) to facilitate, enhance, and enable the use of the LEAD gateway in the classroom. The LEAD education initiative focuses on the means to integrate data, tools, and services used by researchers into undergraduate meteorology education in order to provide an authentic and contextualized environment for teaching and learning. Educators, educational specialists, and students from meteorology and computer science backgrounds have collaborated on the design and development

  6. Genetic dissection of cardiac growth control pathways

    NASA Technical Reports Server (NTRS)

    MacLellan, W. R.; Schneider, M. D.

    2000-01-01

    Cardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.

  7. Genetic dissection of cardiac growth control pathways

    NASA Technical Reports Server (NTRS)

    MacLellan, W. R.; Schneider, M. D.

    2000-01-01

    Cardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.

  8. A Newton Cooperative Genetic Algorithm Method for In Silico Optimization of Metabolic Pathway Production

    PubMed Central

    Mohamad, Mohd Saberi; Abdullah, Afnizanfaizal

    2015-01-01

    This paper presents an in silico optimization method of metabolic pathway production. The metabolic pathway can be represented by a mathematical model known as the generalized mass action model, which leads to a complex nonlinear equations system. The optimization process becomes difficult when steady state and the constraints of the components in the metabolic pathway are involved. To deal with this situation, this paper presents an in silico optimization method, namely the Newton Cooperative Genetic Algorithm (NCGA). The NCGA used Newton method in dealing with the metabolic pathway, and then integrated genetic algorithm and cooperative co-evolutionary algorithm. The proposed method was experimentally applied on the benchmark metabolic pathways, and the results showed that the NCGA achieved better results compared to the existing methods. PMID:25961295

  9. Multiple Sensory-Motor Pathways Lead to Coordinated Visual Attention.

    PubMed

    Yu, Chen; Smith, Linda B

    2017-02-01

    Joint attention has been extensively studied in the developmental literature because of overwhelming evidence that the ability to socially coordinate visual attention to an object is essential to healthy developmental outcomes, including language learning. The goal of this study was to understand the complex system of sensory-motor behaviors that may underlie the establishment of joint attention between parents and toddlers. In an experimental task, parents and toddlers played together with multiple toys. We objectively measured joint attention-and the sensory-motor behaviors that underlie it-using a dual head-mounted eye-tracking system and frame-by-frame coding of manual actions. By tracking the momentary visual fixations and hand actions of each participant, we precisely determined just how often they fixated on the same object at the same time, the visual behaviors that preceded joint attention and manual behaviors that preceded and co-occurred with joint attention. We found that multiple sequential sensory-motor patterns lead to joint attention. In addition, there are developmental changes in this multi-pathway system evidenced as variations in strength among multiple routes. We propose that coordinated visual attention between parents and toddlers is primarily a sensory-motor behavior. Skill in achieving coordinated visual attention in social settings-like skills in other sensory-motor domains-emerges from multiple pathways to the same functional end.

  10. Genetic relations of oceanic basalts as indicated by lead isotopes

    USGS Publications Warehouse

    Tatsumoto, M.

    1966-01-01

    The isotopic compositions of lead and the concentrations of lead, uranium, and thorium in samples of oceanic tholeiite and alkali suites are determined, and the genetic relations of the oceanic basalts are discussed. Lead of the oceanic tholeiites has a varying lead-206 : lead-204 ratio between 17.8 and 18.8, while leads of the alkali basalt suites from Easter Island and Guadalupe Island are very radiogenic with lead-206 : lead-204 ratios between 19.3 and 20.4. It is concluded that (i) the isotopic composition of lead in oceanic tholeiite suggests that the upper mantle source region of the tholeiite was differentiated from an original mantle material more than 1 billion years ago and that the upper mantle is not homogeneous at the present time, (ii) less than 20 million years was required for the crystal differentiation within the alkali suite from Easter Island, (iii) no crustal contamination was involved in the course of differentiation of rocks from Easter Island; however, some crustal contamination may have affected Guadalupe Island rocks, and (iv) alkali basalt may be produced from the tholeiite in the oceanic region by crystal differentiation. Alternatively the difference in the isotopic composition of lead in oceanic basalts may be produced by partial melting at different depths of a differentiated upper mantle.

  11. A molecular pathway analysis informs the genetic background at risk for schizophrenia.

    PubMed

    Crisafulli, Concetta; Drago, Antonio; Calabrò, Marco; Spina, Edoardo; Serretti, Alessandro

    2015-06-03

    Schizophrenia is a complex mental disorder marked by severely impaired thinking, delusional thoughts, hallucinations and poor emotional responsiveness. The biological mechanisms that lead to schizophrenia may be related to the genetic background of patients. Thus, a genetic perspective may help to unravel the molecular pathways disrupted in schizophrenia. In the present work, we used a molecular pathway analysis to identify the molecular pathways associated with schizophrenia. We collected data of genetic loci previously associated with schizophrenia, identified the genes located in those positions and created the metabolic pathways that are related to those genes' products. These pathways were tested for enrichment (a number of SNPs associated with the phenotype significantly higher than expected by chance) in a sample of schizophrenic patients and controls (4486 and 4477, respectively). The molecular pathway that resulted from the identification of all the genes located in the loci previously found to be associated with schizophrenia was found to be enriched, as expected (permutated p(10(6))=9.9999e-06).We found 60 SNPs amongst 30 different genes with a strong association with schizophrenia. The genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPK cascade. The pathway related to the toll-like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia. This pathway is related to the innate immune system, further stressing the role of immunological-related events in increasing the risk to schizophrenia. Copyright © 2014. Published by Elsevier Inc.

  12. Genetic diversity and selection in the maize starch pathway

    PubMed Central

    Whitt, Sherry R.; Wilson, Larissa M.; Tenaillon, Maud I.; Gaut, Brandon S.; Buckler, Edward S.

    2002-01-01

    Maize is both phenotypically and genetically diverse. Sequence studies generally confirm the extensive genetic variability in modern maize is consistent with a lack of selection. For more than 6,000 years, Native Americans and modern breeders have exploited the tremendous genetic diversity of maize (Zea mays ssp. mays) to create the highest yielding grain crop in the world. Nonetheless, some loci have relatively low levels of genetic variation, particularly loci that have been the target of artificial selection, like c1 and tb1. However, there is limited information on how selection may affect an agronomically important pathway for any crop. These pathways may retain the signature of artificial selection and may lack genetic variation in contrast to the rest of the genome. To evaluate the impact of selection across an agronomically important pathway, we surveyed nucleotide diversity at six major genes involved in starch metabolism and found unusually low genetic diversity and strong evidence of selection. Low diversity in these critical genes suggests that a paradigm shift may be required for future maize breeding. Rather than relying solely on the diversity within maize or on transgenics, future maize breeding would perhaps benefit from the incorporation of alleles from maize's wild relatives. PMID:12244216

  13. Genetic contribution of the leukotriene pathway to coronary artery disease

    USDA-ARS?s Scientific Manuscript database

    We evaluated the genetic contribution of the leukotriene (LT) pathway to risk of coronary artery disease (CAD) in 4,512 Caucasian and African American subjects ascertained through elective cardiac evaluation. Of the three previously associated variants, the shorter "3" and "4" alleles of a promoter ...

  14. Network-Based Study Reveals Potential Infection Pathways of Hepatitis-C Leading to Various Diseases

    PubMed Central

    Mukhopadhyay, Anirban; Maulik, Ujjwal

    2014-01-01

    Protein-protein interaction network-based study of viral pathogenesis has been gaining popularity among computational biologists in recent days. In the present study we attempt to investigate the possible pathways of hepatitis-C virus (HCV) infection by integrating the HCV-human interaction network, human protein interactome and human genetic disease association network. We have proposed quasi-biclique and quasi-clique mining algorithms to integrate these three networks to identify infection gateway host proteins and possible pathways of HCV pathogenesis leading to various diseases. Integrated study of three networks, namely HCV-human interaction network, human protein interaction network, and human proteins-disease association network reveals potential pathways of infection by the HCV that lead to various diseases including cancers. The gateway proteins have been found to be biologically coherent and have high degrees in human interactome compared to the other virus-targeted proteins. The analyses done in this study provide possible targets for more effective anti-hepatitis-C therapeutic involvement. PMID:24743187

  15. Integration of biological networks and pathways with genetic association studies.

    PubMed

    Sun, Yan V

    2012-10-01

    Millions of genetic variants have been assessed for their effects on the trait of interest in genome-wide association studies (GWAS). The complex traits are affected by a set of inter-related genes. However, the typical GWAS only examine the association of a single genetic variant at a time. The individual effects of a complex trait are usually small, and the simple sum of these individual effects may not reflect the holistic effect of the genetic system. High-throughput methods enable genomic studies to produce a large amount of data to expand the knowledge base of the biological systems. Biological networks and pathways are built to represent the functional or physical connectivity among genes. Integrated with GWAS data, the network- and pathway-based methods complement the approach of single genetic variant analysis, and may improve the power to identify trait-associated genes. Taking advantage of the biological knowledge, these approaches are valuable to interpret the functional role of the genetic variants, and to further understand the molecular mechanism influencing the traits. The network- and pathway-based methods have demonstrated their utilities, and will be increasingly important to address a number of challenges facing the mainstream GWAS.

  16. Distinct pathways leading to TDP-43-induced cellular dysfunctions.

    PubMed

    Yamashita, Makiko; Nonaka, Takashi; Hirai, Shinobu; Miwa, Akiko; Okado, Haruo; Arai, Tetsuaki; Hosokawa, Masato; Akiyama, Haruhiko; Hasegawa, Masato

    2014-08-15

    TAR DNA-binding protein of 43 kDa (TDP-43) is the major component protein of inclusions found in brains of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the molecular mechanisms by which TDP-43 causes neuronal dysfunction and death remain unknown. Here, we report distinct cytotoxic effects of full-length TDP-43 (FL-TDP) and its C-terminal fragment (CTF) in SH-SY5Y cells. When FL-TDP was overexpressed in the cells using a lentiviral system, exogenous TDP-43, like endogenous TDP-43, was expressed mainly in nuclei of cells without any intracellular inclusions. However, these cells showed striking cell death, caspase activation and growth arrest at G2/M phase, indicating that even simple overexpression of TDP-43 induces cellular dysfunctions leading to apoptosis. On the other hand, cells expressing TDP-43 CTF showed cytoplasmic aggregates but without significant cell death, compared with cells expressing FL-TDP. Confocal microscopic analyses revealed that RNA polymerase II (RNA pol II) and several transcription factors, such as specificity protein 1 and cAMP-response-element-binding protein, were co-localized with the aggregates of TDP-43 CTF, suggesting that sequestration of these factors into TDP-43 aggregates caused transcriptional dysregulation. Indeed, accumulation of RNA pol II at TDP-43 inclusions was detected in brains of patients with FTLD-TDP. Furthermore, apoptosis was not observed in affected neurons of FTLD-TDP brains containing phosphorylated and aggregated TDP-43 pathology. Our results suggest that different pathways of TDP-43-induced cellular dysfunction may contribute to the degeneration cascades involved in the onset of ALS and FTLD-TDP. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Molecular population genetics and selection in the glycolytic pathway.

    PubMed

    Eanes, Walter F

    2011-01-15

    In this review, I discuss the evidence for differential natural selection acting across enzymes in the glycolytic pathway in Drosophila. Across the genome, genes evolve at very different rates and possess markedly varying levels of molecular polymorphism, codon bias and expression variation. Discovering the underlying causes of this variation has been a challenge in evolutionary biology. It has been proposed that both the intrinsic properties of enzymes and their pathway position have direct effects on their molecular evolution, and with the genomic era the study of adaptation has been taken to the level of pathways and networks of genes and their products. Of special interest have been the energy-producing pathways. Using both population genetic and experimental approaches, our laboratory has been engaged in a study of molecular variation across the glycolytic pathway in Drosophila melanogaster and its close relatives. We have observed a pervasive pattern in which genes at the top of the pathway, especially around the intersection at glucose 6-phosphate, show evidence for both contemporary selection, in the form of latitudinal allele clines, and inter-specific selection, in the form of elevated levels of amino acid substitutions between species. To further explore this question, future work will require corroboration in other species, expansion into tangential pathways, and experimental work to better characterize metabolic control through the pathway and to examine the pleiotropic effects of these genes on other traits and fitness components.

  18. Investigating the phytohormone ethylene response pathway by chemical genetics.

    PubMed

    Lin, Lee-Chung; Chueh, Chiao-Mei; Wang, Long-Chi

    2014-01-01

    Conventional mutant screening in forward genetics research is indispensible to understand the biological operation behind any given phenotype. However, several issues, such as functional redundancy and lethality or sterility resulting from null mutations, frequently impede the functional characterization of genetic mutants. As an alternative approach, chemical screening with natural products or synthetic small molecules that act as conditional mutagens allows for identifying bioactive compounds as bioprobes to overcome the above-mentioned issues. Ethylene is the simplest olefin and is one of the major phytohormones playing crucial roles in plant physiology. Most of the current information on how ethylene works in plants came primarily from genetic studies of ethylene mutants identified by conventional genetic screening two decades ago. However, we lack a complete picture of functional interaction among components in the ethylene pathway and cross talk of ethylene with other phytohormones. Here, we describe our methodology for using chemical genetics to identify small molecules that interfere with the ethylene response. We set up a phenotype-based screening platform and a reporter gene-based system for verification of the hit compounds identified by chemical screening. We have successfully identified small molecules affecting the ethylene phenotype in etiolated seedlings and showed that a group of structurally similar compounds are novel inhibitors of ACC synthase, a rate-limiting enzyme in the ethylene biosynthesis pathway.

  19. Differential genetic interactions of yeast stress response MAPK pathways

    PubMed Central

    Martin, Humberto; Shales, Michael; Fernandez-Piñar, Pablo; Wei, Ping; Molina, Maria; Fiedler, Dorothea; Shokat, Kevan M; Beltrao, Pedro; Lim, Wendell; Krogan, Nevan J

    2015-01-01

    Genetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large-scale genetic interaction analysis in Saccharomyces cerevisiae involving approximately 49 × 1,200 double mutants in the presence of five different stress conditions, including osmotic, oxidative and cell wall-altering stresses. This resulted in the generation of a differential E-MAP (or dE-MAP) comprising over 250,000 measurements of conditional interactions. We found an extensive number of conditional genetic interactions that recapitulate known stress-specific functional associations. Furthermore, we have also uncovered previously unrecognized roles involving the phosphatase regulator Bud14, the histone methylation complex COMPASS and membrane trafficking complexes in modulating the cell wall integrity pathway. Finally, the osmotic stress differential genetic interactions showed enrichment for genes coding for proteins with conditional changes in phosphorylation but not for genes with conditional changes in gene expression. This suggests that conditional genetic interactions are a powerful tool to dissect the functional importance of the different response mechanisms of the cell. PMID:25888283

  20. Differential genetic interactions of yeast stress response MAPK pathways.

    PubMed

    Martin, Humberto; Shales, Michael; Fernandez-Piñar, Pablo; Wei, Ping; Molina, Maria; Fiedler, Dorothea; Shokat, Kevan M; Beltrao, Pedro; Lim, Wendell; Krogan, Nevan J

    2015-04-17

    Genetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large-scale genetic interaction analysis in Saccharomyces cerevisiae involving approximately 49 × 1,200 double mutants in the presence of five different stress conditions, including osmotic, oxidative and cell wall-altering stresses. This resulted in the generation of a differential E-MAP (or dE-MAP) comprising over 250,000 measurements of conditional interactions. We found an extensive number of conditional genetic interactions that recapitulate known stress-specific functional associations. Furthermore, we have also uncovered previously unrecognized roles involving the phosphatase regulator Bud14, the histone methylation complex COMPASS and membrane trafficking complexes in modulating the cell wall integrity pathway. Finally, the osmotic stress differential genetic interactions showed enrichment for genes coding for proteins with conditional changes in phosphorylation but not for genes with conditional changes in gene expression. This suggests that conditional genetic interactions are a powerful tool to dissect the functional importance of the different response mechanisms of the cell.

  1. Biochemical Genetic Pathways that Modulate Aging in Multiple Species

    PubMed Central

    Bitto, Alessandro; Wang, Adrienne M.; Bennett, Christopher F.; Kaeberlein, Matt

    2016-01-01

    The mechanisms underlying biological aging have been extensively studied in the past 20 years with the avail of mainly four model organisms: the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, the fruitfly Drosophila melanogaster, and the domestic mouse Mus musculus. Extensive research in these four model organisms has identified a few conserved genetic pathways that affect longevity as well as metabolism and development. Here, we review how the mechanistic target of rapamycin (mTOR), sirtuins, adenosine monophosphate-activated protein kinase (AMPK), growth hormone/insulin-like growth factor 1 (IGF-1), and mitochondrial stress-signaling pathways influence aging and life span in the aforementioned models and their possible implications for delaying aging in humans. We also draw some connections between these biochemical pathways and comment on what new developments aging research will likely bring in the near future. PMID:26525455

  2. Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

    PubMed Central

    Traglia, Michela; Tsang, Kathryn; Bearden, Carrie E.; Rauen, Katherine A.

    2017-01-01

    Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway. PMID:28076348

  3. [Lead compound optimization strategy (1)--changing metabolic pathways and optimizing metabolism stability].

    PubMed

    Wang, Jiang; Liu, Hong

    2013-10-01

    Lead compound optimization plays an important role in new drug discovery and development. The strategies for changing metabolic pathways can modulate pharmacokinetic properties, prolong the half life, improve metabolism stability and bioavailability of lead compounds. The strategies for changing metabolic pathways and improving metabolism stability are reviewed. These methods include blocking metabolic site, reduing lipophilicity, changing ring size, bioisosterism, and prodrug.

  4. Race does not explain genetic heterogeneity in pharmacogenomic pathways

    PubMed Central

    Yen-Revollo, Jane L; Auman, J Todd; McLeod, Howard L

    2009-01-01

    Introduction Polymorphic alleles in the human genome have been identified as affecting numerous drug responses. Currently, genotyping of all patients before starting a drug regimen is impractical. Since many polymorphisms occur at varying rates in different racial groups, we investigated whether a patient's race could predict presence of drug-relevant genetic variants well enough to be used as a substitute for individual genotyping. Methods We performed hierarchical clustering and principal components analysis on tagSNPs from three pathways (irinotecan, 5-fluorouracil and insulin) across 270 individuals from four racial groups available from the International HapMap Project. Results For the drug pathways, irinotecan and 5-fluorouracil, individuals from each race were widely dispersed, although several subclusters consisted entirely of individuals from a single racial group. Principal components analysis confirmed race was not a major contributor to the SNP data variance. Interestingly, individuals tended to cluster more by race across the endogenous insulin signaling pathway SNPs. Conclusions Most genetic variation was determined by individual variation, not racial grouping, indicating race is not adequate as a surrogate to individualized therapy. PMID:19018720

  5. Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

    PubMed Central

    Gan-Or, Ziv; Dion, Patrick A; Rouleau, Guy A

    2015-01-01

    Parkinson disease (PD), once considered as a prototype of a sporadic disease, is now known to be considerably affected by various genetic factors, which interact with environmental factors and the normal process of aging, leading to PD. Large studies determined that the hereditary component of PD is at least 27%, and in some populations, single genetic factors are responsible for more than 33% of PD patients. Interestingly, many of these genetic factors, such as LRRK2, GBA, SMPD1, SNCA, PARK2, PINK1, PARK7, SCARB2, and others, are involved in the autophagy-lysosome pathway (ALP). Some of these genes encode lysosomal enzymes, whereas others correspond to proteins that are involved in transport to the lysosome, mitophagy, or other autophagic-related functions. Is it possible that all these factors converge into a single pathway that causes PD? In this review, we will discuss these genetic findings and the role of the ALP in the pathogenesis of PD and will try to answer this question. We will suggest a novel hypothesis for the pathogenic mechanism of PD that involves the lysosome and the different autophagy pathways. PMID:26207393

  6. Excited State Pathways Leading to Formation of Adenine Dimers.

    PubMed

    Banyasz, Akos; Martinez-Fernandez, Lara; Ketola, Tiia-Maaria; Muñoz-Losa, Aurora; Esposito, Luciana; Markovitsi, Dimitra; Improta, Roberto

    2016-06-02

    The reaction intermediate in the path leading to UV-induced formation of adenine dimers A═A and AA* is identified for the first time quantum mechanically, using PCM/TD-DFT calculations on (dA)2 (dA: 2'deoxyadenosine). In parallel, its fingerprint is detected in the absorption spectra recorded on the millisecond time-scale for the single strand (dA)20 (dA: 2'deoxyadenosine).

  7. Population Genetics of Anopheles coluzzii Immune Pathways and Genes

    PubMed Central

    Rottschaefer, Susan M.; Crawford, Jacob E.; Riehle, Michelle M.; Guelbeogo, Wamdaogo M.; Gneme, Awa; Sagnon, N’Fale; Vernick, Kenneth D.; Lazzaro, Brian P.

    2014-01-01

    Natural selection is expected to drive adaptive evolution in genes involved in host–pathogen interactions. In this study, we use molecular population genetic analyses to understand how natural selection operates on the immune system of Anopheles coluzzii (formerly A. gambiae “M form”). We analyzed patterns of intraspecific and interspecific genetic variation in 20 immune-related genes and 17 nonimmune genes from a wild population of A. coluzzii and asked if patterns of genetic variation in the immune genes are consistent with pathogen-driven selection shaping the evolution of defense. We found evidence of a balanced polymorphism in CTLMA2, which encodes a C-type lectin involved in regulation of the melanization response. The two CTLMA2 haplotypes, which are distinguished by fixed amino acid differences near the predicted peptide cleavage site, are also segregating in the sister species A. gambiae (“S form”) and A. arabiensis. Comparison of the two haplotypes between species indicates that they were not shared among the species through introgression, but rather that they arose before the species divergence and have been adaptively maintained as a balanced polymorphism in all three species. We additionally found that STAT-B, a retroduplicate of STAT-A, shows strong evidence of adaptive evolution that is consistent with neofunctionalization after duplication. In contrast to the striking patterns of adaptive evolution observed in these Anopheles-specific immune genes, we found no evidence of adaptive evolution in the Toll and Imd innate immune pathways that are orthologously conserved throughout insects. Genes encoding the Imd pathway exhibit high rates of amino acid divergence between Anopheles species but also display elevated amino acid diversity that is consistent with relaxed purifying selection. These results indicate that adaptive coevolution between A. coluzzii and its pathogens is more likely to involve novel or lineage-specific molecular mechanisms

  8. Pathways of genetic transfer from Tripsacum to Zea mays

    PubMed Central

    Harlan, Jack R.; Wet, J. M. J. De

    1977-01-01

    The cytogenetic interactions in maize × Tripsacum hybrid derivatives can be remarkably complex. The number of viable, somewhat female fertile chromosome combinations is astonishing. Fifty-four different combinations are listed in this paper, and others are certainly possible. In successive backcrosses to maize, chromosome numbers scale both up and down with ease, sometimes stabilizing for a few generations via apomixis, but in most cases finally generate balanced maize genomes and emerge as recovered maize. The maize, however, can produce strange and unusual phenotypes as a result of genetic transfers from Tripsacum. Highly tripsacoid maize lines with 2n = 20 chromosomes were recovered in pathways where the maize genome had first contaminated the Tripsacum genome in early backcross generations. In other pathways interaction of the two genomes is rare. Dominant resistances to six maize diseases were found in BC8 populations. PMID:16592431

  9. Automated identification of pathways from quantitative genetic interaction data

    PubMed Central

    Battle, Alexis; Jonikas, Martin C; Walter, Peter; Weissman, Jonathan S; Koller, Daphne

    2010-01-01

    High-throughput quantitative genetic interaction (GI) measurements provide detailed information regarding the structure of the underlying biological pathways by reporting on functional dependencies between genes. However, the analytical tools for fully exploiting such information lag behind the ability to collect these data. We present a novel Bayesian learning method that uses quantitative phenotypes of double knockout organisms to automatically reconstruct detailed pathway structures. We applied our method to a recent data set that measures GIs for endoplasmic reticulum (ER) genes, using the unfolded protein response as a quantitative phenotype. The results provided reconstructions of known functional pathways including N-linked glycosylation and ER-associated protein degradation. It also contained novel relationships, such as the placement of SGT2 in the tail-anchored biogenesis pathway, a finding that we experimentally validated. Our approach should be readily applicable to the next generation of quantitative GI data sets, as assays become available for additional phenotypes and eventually higher-level organisms. PMID:20531408

  10. Serrated pathway colorectal cancer in the population: genetic consideration

    PubMed Central

    Young, Joanne; Jenkins, Mark; Parry, Susan; Young, Bruce; Nancarrow, Derek; English, Dallas; Giles, Graham; Jass, Jeremy

    2007-01-01

    A significant proportion of colorectal cancer (CRC) develops through the serrated neoplasia pathway. Such tumours show a distinctive molecular phenotype of somatic BRAF mutations and widespread concordant methylation events in CpG islands (CIMP). These features are also observed in the polyps developing in individuals with hyperplastic polyposis syndrome (HPS). In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC. Observations of rare affected sibships including identical twins, suggest a recessive or co‐dominant mode of inheritance. In addition, up to 50% of individuals with HPS report a family history of CRC. At a population level, recent work has demonstrated that patients with serrated pathway cancers characterised by BRAF mutation are four times more likely to have a family history of CRC than patients with common CRC. These findings suggest an increased genetic predisposition for serrated pathway CRC in the wider population. We propose that HPS results from the inheritance of two putative co‐dominant alleles in approximately 1 in 2000 individuals. Therefore carriers of one co‐dominant allele may number up to 1 in 25, and it is likely that these carriers are at increased risk of CRC, accounting for, at least in part, the burden of serrated pathway CRC in the population. This proposition may have important implications for screening and prevention of CRC in individuals who have an increased risk for development of serrated pathway cancers, namely those with multiple, proximal, large or advanced serrated polyps, and their relatives. PMID:17566021

  11. Genetic variation in the dopamine pathway and smoking cessation.

    PubMed

    David, Sean P; Munafò, Marcus R

    2008-09-01

    Twin and family studies have established that genetic factors account for much of the variation in tobacco dependence. Therefore, identification of genetic variants predictive of successful smoking cessation has implications for the future prospect of personalized smoking cessation therapies. Converging data implicate the dopamine pathway as an important neural substrate for tobacco dependence. Several candidate genes within the dopamine pathway (e.g., DRD2 and COMT) have been reported to be associated with the efficacy of bupropion and nicotine replacement therapy, and others (e.g., SLC6A3 and DRD4) have been reported to be associated with smoking cessation independent of pharmacotherapy. However, few of these candidate genes are present within regions of suggestive or significant linkage or overlap with genome-wide linkage or association studies of tobacco dependence or smoking cessation. Future studies should seek to replicate genome-wide association analyses with individual-level genotyping, and use better-defined smoking cessation phenotypes. Once robust evidence for association is established, which may take several more years, further research into the likely cost-effectiveness, feasibility and acceptability of personalized medicine for smoking cessation will be necessary before it can be translated into practice.

  12. Quantum control via a genetic algorithm of the field ionization pathway of a Rydberg electron

    NASA Astrophysics Data System (ADS)

    Gregoric, Vincent C.; Kang, Xinyue; Liu, Zhimin Cheryl; Rowley, Zoe A.; Carroll, Thomas J.; Noel, Michael W.

    2017-08-01

    Quantum control of the pathway along which a Rydberg electron field ionizes is experimentally and computationally demonstrated. Selective field ionization is typically done with a slowly rising electric field pulse. The (1/n*)4 scaling of the classical ionization threshold leads to a rough mapping between arrival time of the electron signal and principal quantum number of the Rydberg electron. This is complicated by the many avoided level crossings that the electron must traverse on the way to ionization, which in general leads to broadening of the time-resolved field ionization signal. In order to control the ionization pathway, thus directing the signal to the desired arrival time, a perturbing electric field produced by an arbitrary wave-form generator is added to a slowly rising electric field. A genetic algorithm evolves the perturbing field in an effort to achieve the target time-resolved field ionization signal.

  13. MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

    SciTech Connect

    Simões, Maylla Ronacher; Aguado, Andrea; Fiorim, Jonaína; Silveira, Edna Aparecida; Azevedo, Bruna Fernandes; Toscano, Cindy Medice; Zhenyukh, Olha; Briones, Ana María; Alonso, María Jesús; Vassallo, Dalton Valentim; Salaices, Mercedes

    2015-03-01

    Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension. - Highlights: • Lead-exposure increases oxidative stress, COX-2 expression and vascular reactivity. • Lead exposure activates MAPK signaling pathway. • ROS and COX-2 activation by

  14. Innate and adaptive genetic pathways in HCV infection.

    PubMed

    Buchanan, R; Hydes, T; Khakoo, S I

    2015-04-01

    Infection with hepatitis C virus (HCV) leads to a wide spectrum of clinical manifestations. This heterogeneity is underpinned by the host immune response and the genetic factors that govern it. Polymorphisms affecting both the innate and adaptive immunity determine the outcome of exposure. However the innate immune system appears to play a greater role in determining treatment-associated responses. Overall the effects of IFNL3/4 appear dominant over other polymorphic genes. Understanding how host genetics determines the disease phenotype has not been as intensively studied. This review summarizes our current understanding of innate and adaptive immunogenetic factors in the outcome of HCV infection. It focuses on how they relate to resolution and the progression of HCV-related liver disease, in the context of current and future treatment regimes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway.

    PubMed

    Svärd, Jessica; Heby-Henricson, Karin; Henricson, Karin Heby; Persson-Lek, Madelen; Rozell, Björn; Lauth, Matthias; Bergström, Asa; Ericson, Johan; Toftgård, Rune; Teglund, Stephan

    2006-02-01

    The Hedgehog (Hh) pathway plays important roles during embryogenesis and carcinogenesis. Here, we show that ablation of the mouse Suppressor of fused (Sufu), an intracellular pathway component, leads to embryonic lethality at approximately E9.5 with cephalic and neural tube defects. Fibroblasts derived from Sufu(-/-) embryos showed high Gli-mediated Hh pathway activity that could not be modulated at the level of Smoothened and could only partially be blocked by PKA activation. Despite the robust constitutive pathway activation in the Sufu(-/-) fibroblasts, the GLI1 steady-state localization remained largely cytoplasmic, implying the presence of an effective nuclear export mechanism. Sufu(+/-) mice develop a skin phenotype with basaloid changes and jaw keratocysts, characteristic features of Gorlin syndrome, a human genetic disease linked to enhanced Hh signaling. Our data demonstrate that, in striking contrast to Drosophila, in mammals, Sufu has a central role, and its loss of function leads to potent ligand-independent activation of the Hh pathway.

  16. Genetic analysis of photoreceptor action pathways in Arabidopsis thaliana

    SciTech Connect

    Not Available

    1991-01-01

    The specific strategies and long-term goals of this proposal remain intact relative to the original proposal. We continue to isolate and characterize photomorphogenic mutants of Arabidopsis thaliana. The molecular and biochemical characterization of one of these mutants, det1, has led to one publication of original data and to one Society for Experimental Biology Symposium paper (see below). The phenotype of a second mutant, det2, has also been studied during this funding period. In addition, we have continued work on a general strategy to isolate mutations in trans-acting regulatory factors that mediate light-regulated gene expression, and have identified several potentially interesting regulatory mutants. In the third funding period, we will concentrate on the genetical, biochemical, and molecular characterization of these new mutants. Construction of double mutants between the new mutants and the previously characterized morphological mutants should allow us to construct a pathway for light-regulated seedling development in Arabidopsis.

  17. The adverse outcome pathway (AOP) for chemical binding to tubulin in oocytes leading to aneuploid offspring.

    PubMed

    Marchetti, Francesco; Massarotti, Alberto; Yauk, Carole L; Pacchierotti, Francesca; Russo, Antonella

    2016-03-01

    The Organisation for Economic Co-operation and Development (OECD) has launched the Adverse Outcome Pathway (AOP) Programme to advance knowledge of pathways of toxicity and improve the use of mechanistic information in risk assessment. An AOP links a molecular initiating event (MIE) to an adverse outcome (AO) through intermediate key events (KE). Here, we present the scientific evidence in support of an AOP whereby chemicals that bind to tubulin cause microtubule depolymerization resulting in spindle disorganization followed by altered chromosome alignment and segregation and the generation of aneuploidy in female germ cells, ultimately leading to aneuploidy in the offspring. Aneuploidy, an abnormal number of chromosomes that is not an exact multiple of the haploid number, is a well-known cause of human disease and represents a major cause of infertility, pregnancy failure, and serious genetic disorders in the offspring. Among chemicals that induce aneuploidy in female germ cells, a large majority impairs microtubule dynamics and spindle function. Colchicine, a prototypical chemical that binds to tubulin and causes microtubule depolymerization, is used here to illustrate the AOP. This AOP is specific to female germ cells exposed during the periovulation period. Although the majority of the data come from rodent studies, the available evidence suggests that the MIE and KEs are conserved across species and would occur in human oocytes. The development of AOPs related to mutagenicity in germ cells is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health. © 2015 Her Majesty the Queen in Right of Canada.

  18. Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study

    PubMed Central

    Weisskopf, Marc G.; Sparrow, David; Schwartz, Joel; Hu, Howard; Park, Sung Kyun

    2016-01-01

    Background Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. Objectives We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. Methods We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Results Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50–3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Conclusions Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data. PMID:27584680

  19. Pathways of Genetic Code Evolution in Ancient and Modern Organisms.

    PubMed

    Sengupta, Supratim; Higgs, Paul G

    2015-06-01

    There have been two distinct phases of evolution of the genetic code: an ancient phase--prior to the divergence of the three domains of life, during which the standard genetic code was established--and a modern phase, in which many alternative codes have arisen in specific groups of genomes that differ only slightly from the standard code. Here we discuss the factors that are most important in these two phases, and we argue that these are substantially different. In the modern phase, changes are driven by chance events such as tRNA gene deletions and codon disappearance events. Selection acts as a barrier to prevent changes in the code. In contrast, in the ancient phase, selection for increased diversity of amino acids in the code can be a driving force for addition of new amino acids. The pathway of code evolution is constrained by avoiding disruption of genes that are already encoded by earlier versions of the code. The current arrangement of the standard code suggests that it evolved from a four-column code in which Gly, Ala, Asp, and Val were the earliest encoded amino acids.

  20. Presenilin-Based Genetic Screens in Drosophila melanogaster Identify Novel Notch Pathway Modifiers

    PubMed Central

    Mahoney, Matt B.; Parks, Annette L.; Ruddy, David A.; Tiong, Stanley Y. K.; Esengil, Hanife; Phan, Alexander C.; Philandrinos, Panos; Winter, Christopher G.; Chatterjee, Runa; Huppert, Kari; Fisher, William W.; L'Archeveque, Lynn; Mapa, Felipa A.; Woo, Wendy; Ellis, Michael C.; Curtis, Daniel

    2006-01-01

    Presenilin is the enzymatic component of γ-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for γ-tubulin in the pathway. PMID:16415372

  1. Presenilin-based genetic screens in Drosophila melanogaster identify novel notch pathway modifiers.

    PubMed

    Mahoney, Matt B; Parks, Annette L; Ruddy, David A; Tiong, Stanley Y K; Esengil, Hanife; Phan, Alexander C; Philandrinos, Panos; Winter, Christopher G; Chatterjee, Runa; Huppert, Kari; Fisher, William W; L'Archeveque, Lynn; Mapa, Felipa A; Woo, Wendy; Ellis, Michael C; Curtis, Daniel

    2006-04-01

    Presenilin is the enzymatic component of gamma-secretase, a multisubunit intramembrane protease that processes several transmembrane receptors, such as the amyloid precursor protein (APP). Mutations in human Presenilins lead to altered APP cleavage and early-onset Alzheimer's disease. Presenilins also play an essential role in Notch receptor cleavage and signaling. The Notch pathway is a highly conserved signaling pathway that functions during the development of multicellular organisms, including vertebrates, Drosophila, and C. elegans. Recent studies have shown that Notch signaling is sensitive to perturbations in subcellular trafficking, although the specific mechanisms are largely unknown. To identify genes that regulate Notch pathway function, we have performed two genetic screens in Drosophila for modifiers of Presenilin-dependent Notch phenotypes. We describe here the cloning and identification of 19 modifiers, including nicastrin and several genes with previously undescribed involvement in Notch biology. The predicted functions of these newly identified genes are consistent with extracellular matrix and vesicular trafficking mechanisms in Presenilin and Notch pathway regulation and suggest a novel role for gamma-tubulin in the pathway.

  2. Sources and pathways of environmental lead to children in a Derbyshire mining village.

    PubMed

    Cotter-Howells, J; Thornton, I

    1991-06-01

    Garden soil and housedust samples, from households in a Derbyshire village closely associated with historic lead mining, have highly elevated lead levels. Handwipe samples from children also have relatively high lead concentrations suggesting that elevated levels of lead are transferred to the child by the soil-dust-hand-mouth pathway. However, this is not reflected in their blood lead concentrations which are within normal UK ranges and less than predicted by some lead exposure models. SEM analysis of soil grains has revealed that many are composed of pyromorphite [Pb5(PO4)3Cl], a stable soil-lead mineral. This mineral is formed from the weathering of galena [PbS] but it is not clear to what extent weathering has occurred in the soil. Pyromorphite has an extremely low solubility which may contribute to a low human bioavailability of lead in these soils, resulting in the lower than expected blood lead concentrations.

  3. Genetic variation within the histamine pathway among patients with asthma

    PubMed Central

    Raje, Nikita; Vyhlidal, Carrie A.; Dai, Hongying; Jones, Bridgette L.

    2015-01-01

    Objective Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway and determine their association with asthma and HRH1 mRNA expression. Methods We enrolled children and adults (n=93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for 9 known SNPs in the HDC, HRH1, HRH4, HNMT, and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher's exact test, and Chi-square test were used to determine differences in allele, genotype, and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p<0.05. Results No difference was observed in genotype/allele frequency for the 9 SNPs between subjects with and without asthma. The HNMT-1639C/ −464C/ 314C/ 3’UTRA haplotype was more frequently observed in those without asthma than those with asthma (p=0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p=0.04). Conclusions Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings. PMID:25295384

  4. Modeling signaling pathways leading to wrinkle formation: identification of the skin aging target.

    PubMed

    Chauhan, Pallavi; Shakya, Madhvi

    2009-01-01

    In the present scenario, wrinkle formation, prominent sign of skin ageing, is one of the most demanding areas of research. This burgeoning research demand to reduce, delay and restore the effects of skin ageing has led to the study of various signaling pathways leading to wrinkle formation. Wrinkles appear on skin due to influence of intrinsic and extrinsic factors on mitogenic reactions and signal transduction pathways. The aim of the present study is to analyze each protein involved in the signaling pathway leading to dilapidation of collagen and an attempt has been made to compare different signal transduction pathways to identify a common target for skin ageing. In the present work, bioinformatics tools have been used to extract information from already existing experimental data. The statistical techniques are used for further analysis and make useful predictions for skin ageing. Stressors like UV irradiation, osmotic stress and heat shock have been reported to activate epidermal growth factor receptor, interleukin 1 receptor, tumor necrosis factor receptor, platelet-derived growth factor receptor and platelet activation factor receptor signaling pathways, which lead to the production of matrix metalloproteinases, collagen degradation and, consequently, wrinkle formation. When all the five signaling pathways were modeled, the c-jun part of the AP-1 transcription factor was found to be a common intermediate protein involved in all the signaling cascades. Moreover, it shows differential expression in the skin on response to stressors. We proposed c-jun to be the most potent target for drug designing against wrinkle formation.

  5. Dynamic regulation of genetic pathways and targets during aging in Caenorhabditis elegans.

    PubMed

    He, Kan; Zhou, Tao; Shao, Jiaofang; Ren, Xiaoliang; Zhao, Zhongying; Liu, Dahai

    2014-03-01

    Numerous genetic targets and some individual pathways associated with aging have been identified using the worm model. However, less is known about the genetic mechanisms of aging in genome wide, particularly at the level of multiple pathways as well as the regulatory networks during aging. Here, we employed the gene expression datasets of three time points during aging in Caenorhabditis elegans (C. elegans) and performed the approach of gene set enrichment analysis (GSEA) on each dataset between adjacent stages. As a result, multiple genetic pathways and targets were identified as significantly down- or up-regulated. Among them, 5 truly aging-dependent signaling pathways including MAPK signaling pathway, mTOR signaling pathway, Wnt signaling pathway, TGF-beta signaling pathway and ErbB signaling pathway as well as 12 significantly associated genes were identified with dynamic expression pattern during aging. On the other hand, the continued declines in the regulation of several metabolic pathways have been demonstrated to display age-related changes. Furthermore, the reconstructed regulatory networks based on three of aging related Chromatin immunoprecipitation experiments followed by sequencing (ChIP-seq) datasets and the expression matrices of 154 involved genes in above signaling pathways provide new insights into aging at the multiple pathways level. The combination of multiple genetic pathways and targets needs to be taken into consideration in future studies of aging, in which the dynamic regulation would be uncovered.

  6. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites, and Metabolic Pathways.

    PubMed

    Gao, Bei; Chi, Liang; Mahbub, Ridwan; Bian, Xiaoming; Tu, Pengcheng; Ru, Hongyu; Lu, Kun

    2017-03-16

    Lead exposure remains a global public health issue, and the recent Flint water crisis has renewed public concern about lead toxicity. The toxicity of lead has been well established in a variety of systems and organs. The gut microbiome has been shown to be highly involved in many critical physiological processes, including food digestion, immune system development, and metabolic homeostasis. However, despite the key role of the gut microbiome in human health, the functional impact of lead exposure on the gut microbiome has not been studied. The aim of this study is to define gut microbiome toxicity induced by lead exposure in C57BL/6 mice using multiomics approaches, including 16S rRNA sequencing, whole genome metagenomics sequencing, and gas chromatography-mass spectrometry (GC-MS) metabolomics. 16S rRNA sequencing revealed that lead exposure altered the gut microbiome trajectory and phylogenetic diversity. Metagenomics sequencing and metabolomics profiling showed that numerous metabolic pathways, including vitamin E, bile acids, nitrogen metabolism, energy metabolism, oxidative stress, and the defense/detoxification mechanism, were significantly disturbed by lead exposure. These perturbed molecules and pathways may have important implications for lead toxicity in the host. Taken together, these results demonstrated that lead exposure not only altered the gut microbiome community structures/diversity but also greatly affected metabolic functions, leading to gut microbiome toxicity.

  7. Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro

    PubMed Central

    Hu, Fan; Xu, Li; Liu, Zhi-Hua; Ge, Meng-Meng; Ruan, Di-Yun; Wang, Hui-Li

    2014-01-01

    Lead (Pb) exposure has been implicated in the impairment of synaptic plasticity in the developing hippocampus, but the mechanism remains unclear. Here, we investigated whether developmental lead exposure affects the dendritic spine formation through Wnt signaling pathway in vivo and in vitro. Sprague–Dawley rats were exposed to lead throughout the lactation period and Golgi-Cox staining method was used to examine the spine density of pyramidal neurons in the hippocampal CA1 area of rats. We found that lead exposure significantly decreased the spine density in both 14 and 21 days-old pups, accompanied by a significant age-dependent decline of the Wnt7a expression and stability of its downstream protein (β-catenin). Furthermore, in cultured hippocampal neurons, lead (0.1 and 1 µM lead acetate) significantly decreased the spine density in a dose-dependent manner. Exogenous Wnt7a application attenuated the decrease of spine density and increased the stability of the downstream molecules in Wnt signaling pathway. Together, our results suggest that lead has a negative impact on spine outgrowth in the developing hippocampus through altering the canonical Wnt pathway. PMID:24999626

  8. OptForce: An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions

    PubMed Central

    Ranganathan, Sridhar; Suthers, Patrick F.; Maranas, Costas D.

    2010-01-01

    Computational procedures for predicting metabolic interventions leading to the overproduction of biochemicals in microbial strains are widely in use. However, these methods rely on surrogate biological objectives (e.g., maximize growth rate or minimize metabolic adjustments) and do not make use of flux measurements often available for the wild-type strain. In this work, we introduce the OptForce procedure that identifies all possible engineering interventions by classifying reactions in the metabolic model depending upon whether their flux values must increase, decrease or become equal to zero to meet a pre-specified overproduction target. We hierarchically apply this classification rule for pairs, triples, quadruples, etc. of reactions. This leads to the identification of a sufficient and non-redundant set of fluxes that must change (i.e., MUST set) to meet a pre-specified overproduction target. Starting with this set we subsequently extract a minimal set of fluxes that must actively be forced through genetic manipulations (i.e., FORCE set) to ensure that all fluxes in the network are consistent with the overproduction objective. We demonstrate our OptForce framework for succinate production in Escherichia coli using the most recent in silico E. coli model, iAF1260. The method not only recapitulates existing engineering strategies but also reveals non-intuitive ones that boost succinate production by performing coordinated changes on pathways distant from the last steps of succinate synthesis. PMID:20419153

  9. Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma.

    PubMed

    Hyland, Paula L; Freedman, Neal D; Hu, Nan; Tang, Ze-Zhong; Wang, Lemin; Wang, Chaoyu; Ding, Ti; Fan, Jin-Hu; Qiao, You-Lin; Golozar, Asieh; Wheeler, William; Yu, Kai; Yuenger, Jeff; Burdett, Laurie; Chanock, Stephen J; Dawsey, Sanford M; Tucker, Margaret A; Goldstein, Alisa M; Abnet, Christian C; Taylor, Philip R

    2013-05-01

    In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.

  10. Multiple genetic pathways regulate replicative senescence in telomerase-deficient yeast

    PubMed Central

    Ballew, Bari J.; Lundblad, Victoria

    2013-01-01

    Summary Most human tissues express low levels of telomerase and undergo telomere shortening and eventual senescence; the resulting limitation on tissue renewal can lead to a wide range of age-dependent pathophysiologies. Increasing evidence indicates that the decline in cell division capacity in cells that lack telomerase can be influenced by numerous genetic factors. Here, we use telomerase-defective strains of budding yeast to probe whether replicative senescence can be attenuated or accelerated by defects in factors previously implicated in handling of DNA termini. We show that the MRX (Mre11-Rad50-Xrs2) complex, as well as negative (Rif2) and positive (Tel1) regulators of this complex, comprise a single pathway that promotes replicative senescence, in a manner that recapitulates how these proteins modulate resection of DNA ends. In contrast, the Rad51 recombinase, which acts downstream of the MRX complex in double-strand break (DSB) repair, regulates replicative senescence through a separate pathway operating in opposition to the MRX-Tel1-Rif2 pathway. Moreover, defects in several additional proteins implicated in DSB repair (Rif1 and Sae2) confer only transient effects during early or late stages of replicative senescence, respectively, further suggesting that a simple analogy between DSBs and eroding telomeres is incomplete. These results indicate that the replicative capacity of telomerase-defective yeast is controlled by a network comprised of multiple pathways. It is likely that telomere shortening in telomerase-depleted human cells is similarly under a complex pattern of genetic control; mechanistic understanding of this process should provide crucial information regarding how human tissues age in response to telomere erosion. PMID:23672410

  11. Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma

    PubMed Central

    Hyland, Paula L.

    2013-01-01

    In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations. PMID:23358850

  12. Genetic alterations in the phosphatidylinositol-3 kinase/Akt pathway in thyroid cancer.

    PubMed

    Xing, Mingzhao

    2010-07-01

    Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a fundamental role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and aggressive thyroid cancer, such as anaplastic thyroid cancer (ATC). As the drivers of this process, many genetic alterations activating the PI3K/Akt pathway have been identified in thyroid cancer in recent years. This review summarizes the current knowledge on major genetic alterations in the PI3K/Akt pathway. These include PIK3CA mutations and genomic amplification/copy gain, Ras mutations, PTEN mutations, RET/PTC and PPARgamma/Pax8 rearrangements, as well as amplification/copy gain of PIK3CB, PDK1, Akt, and various receptor tyrosine kinase genes. Most of these genetic alterations are particularly common in FTC and many of them are even more common in ATC; they are generally less common in papillary thyroid cancer (PTC), in which the MAP kinase (MAPK) pathway activated by the BRAF mutation instead plays a major role. Methylation and, thus, epigenetic silencing of PTEN, a major negative regulator of the PI3K/Akt pathway, occurs in close association with activating genetic alterations of the PI3K/Akt pathway, constituting a unique self-enhancement mechanism for this pathway. Many of these genetic alterations are mutually exclusive in differentiated thyroid tumors, but with increasing concurrence from benign tumors to FTC to ATC. RET/PTC, Ras, and receptor tyrosine kinase could dually activate the PI3K/Akt and MAPK pathways. Most cases of ATC harbor genetic alterations in these genes or other genetic combinations that can activate both pathways. It is proposed that genetic alterations in the PI3K/Akt pathway promote thyroid cell transformation to FTC and that genetic alterations in the MAPK pathway promote cell transformation to PTC; accumulation of multiple genetic alterations that can activate both pathways promotes thyroid cancer aggressiveness and progression to ATC. Genetic alterations

  13. Genetic Alterations in the Phosphatidylinositol-3 Kinase/Akt Pathway in Thyroid Cancer

    PubMed Central

    2010-01-01

    Background Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a fundamental role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and aggressive thyroid cancer, such as anaplastic thyroid cancer (ATC). As the drivers of this process, many genetic alterations activating the PI3K/Akt pathway have been identified in thyroid cancer in recent years. Summary This review summarizes the current knowledge on major genetic alterations in the PI3K/Akt pathway. These include PIK3CA mutations and genomic amplification/copy gain, Ras mutations, PTEN mutations, RET/PTC and PPARγ/Pax8 rearrangements, as well as amplification/copy gain of PIK3CB, PDK1, Akt, and various receptor tyrosine kinase genes. Most of these genetic alterations are particularly common in FTC and many of them are even more common in ATC; they are generally less common in papillary thyroid cancer (PTC), in which the MAP kinase (MAPK) pathway activated by the BRAF mutation instead plays a major role. Methylation and, thus, epigenetic silencing of PTEN, a major negative regulator of the PI3K/Akt pathway, occurs in close association with activating genetic alterations of the PI3K/Akt pathway, constituting a unique self-enhancement mechanism for this pathway. Many of these genetic alterations are mutually exclusive in differentiated thyroid tumors, but with increasing concurrence from benign tumors to FTC to ATC. RET/PTC, Ras, and receptor tyrosine kinase could dually activate the PI3K/Akt and MAPK pathways. Most cases of ATC harbor genetic alterations in these genes or other genetic combinations that can activate both pathways. It is proposed that genetic alterations in the PI3K/Akt pathway promote thyroid cell transformation to FTC and that genetic alterations in the MAPK pathway promote cell transformation to PTC; accumulation of multiple genetic alterations that can activate both pathways promotes thyroid cancer aggressiveness and progression to ATC

  14. Genetics of the type I interferon pathway in systemic lupus erythematosus

    PubMed Central

    Ghodke-Puranik, Yogita; Niewold, Timothy B

    2013-01-01

    Genetic studies of systemic lupus erythematosus (SLE) have been successful, identifying numerous risk factors for human disease. While the list is not yet complete, it is clear that important immune system pathways are represented, one of which being type I interferon (IFN). Circulating type I IFN levels are high in SLE patients and this IFN pathway activation is heritable in families with SLE. We summarize our current understanding of the genetics of the type I IFN pathway in SLE, with an emphasis on studies that demonstrate an impact of the SLE-risk alleles upon type I IFN pathway activation in SLE patients. These studies illustrate that variations in type I IFN pathway genes represent a common genetic feature of SLE. By understanding the genetic regulation of type I IFN, we may be able to intervene in a more personalized fashion, based upon the molecular dysregulation present in a given individual. PMID:24416080

  15. A novel genetic score approach using instruments to investigate interactions between pathways and environment: application to air pollution.

    PubMed

    Bind, Marie-Abele; Coull, Brent; Suh, Helen; Wright, Robert; Baccarelli, Andrea; Vokonas, Pantel; Schwartz, Joel

    2014-01-01

    Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (p(interaction) = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (p(interaction) = 0.12), CRP (p(interaction) = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications.

  16. Lead concentration in the blood of the general population living near a lead-zinc mine site, Nigeria: Exposure pathways.

    PubMed

    Bello, Olanrewaju; Naidu, Ravi; Rahman, Mohammad Mahmudur; Liu, Yanju; Dong, Zhaomin

    2016-01-15

    Lead (Pb) poisoning in children is a major public health catastrophe worldwide. This report summarises both exposure pathways and blood Pb levels in children below 7 years of age and adults (above 18 years) from the Adudu community living near a lead-zinc mine in Nasawara, Nigeria. The average and median blood Pb levels in children and adults were 2.1 and 1.3 μg/dL, 3.1 and 1.8 μg/dL, respectively. However, Pb in 14% of adults' blood exceeded 5 μg/dL, which is the recommended threshold blood Pb concentration in adults as established by the Centers for Disease Control and Prevention (CDC). Furthermore 68% of adults' blood exceeded blood Pb action level of 2 μg/dL. For children, 11.4% and 31% of the blood samples exceeded 5 μg/dL and 2 μg/dL, respectively, while no safe blood Pb level in children has been recommended. In Nasawara, a significant difference (p<0.05) was observed between the various age groups in children with 2-4 years old having the highest levels and 6 year old children having the lowest Pb levels. Although this study did not detect elevated levels of Pb in children's blood in regions such as Zamfara, Nigeria and Kabwe, Zambia, a high percentage of samples exceeded 2 μg/dL. Soils, floor dusts, water and crops also reveal that Pb contamination in the study area could potentially be the major cause of blood Pb in the community exposed to mining. This study also observed a significant correlation between water Pb levels of adults and blood Pb levels, suggesting that water is the major exposure pathway. This analysis highlights the need to properly manage mining activities so that the health of communities living in the vicinity of a Pb-Zn mine is not compromised.

  17. Pathways of behavior problems from childhood to late adolescence leading to delinquency and academic underachievement.

    PubMed

    Timmermans, Maartje; van Lier, Pol A C; Koot, Hans M

    2009-09-01

    Adolescent delinquency and academic underachievement are both linked with child and adolescent behavior problems. However, little is known about behavioral pathways leading to these adverse outcomes. Children's aggression, opposition, status violations, and property violations scores were collected at ages 5, 10, and 18. Delinquency and academic functioning was rated at age 18. Age 18 status violations were linked to delinquency, and property violations to academic underachievement. Engagement in status and property violations was predicted by childhood opposition. Findings suggest that (a) disaggregated forms of externalizing behavior are needed to understand behavioral pathways to adverse outcomes and (b) prevention of adolescent delinquency and academic underachievement should target childhood opposition.

  18. The importance of p53 pathway genetics in inherited and somatic cancer genomes.

    PubMed

    Stracquadanio, Giovanni; Wang, Xuting; Wallace, Marsha D; Grawenda, Anna M; Zhang, Ping; Hewitt, Juliet; Zeron-Medina, Jorge; Castro-Giner, Francesc; Tomlinson, Ian P; Goding, Colin R; Cygan, Kamil J; Fairbrother, William G; Thomas, Laurent F; Sætrom, Pål; Gemignani, Federica; Landi, Stefano; Schuster-Böckler, Benjamin; Bell, Douglas A; Bond, Gareth L

    2016-04-01

    Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.

  19. Pathways to genetic screening: Patient knowledges, patient practices. Annual report

    SciTech Connect

    1994-12-31

    This study is design to assess the impacts of the integration of genetic knowledge in to the life of high-risk family members. The social and cultural barriers and bridges that incorporation of genetic information will have on these families as well as how they use this genetic information to increase reproductive options and improve the quality of family life are a major focus of this work.

  20. Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways.

    PubMed

    Sicko, Robert J; Browne, Marilyn L; Rigler, Shannon L; Druschel, Charlotte M; Liu, Gang; Fan, Ruzong; Romitti, Paul A; Caggana, Michele; Kay, Denise M; Brody, Lawrence C; Mills, James L

    2016-01-01

    Ebstein anomaly (EA) is a rare heart defect in which the tricuspid valve is malformed and displaced. The tricuspid valve abnormalities can lead to backflow of blood from the right ventricle to the right atrium, preventing proper circulation of blood to the lungs. Although the etiology of EA is largely unresolved, increased prevalence of EA in those with a family history of congenital heart disease suggests EA has a genetic component. Copy number variants (CNVs) are a major source of genetic variation and have been implicated in a range of congenital heart defect phenotypes. We performed a systematic, genome-wide search for CNVs in 47 isolated EA cases using genotyping microarrays. In addition, we used a custom HaloPlex panel to sequence three known EA genes and 47 candidate EA genes. We identified 35 candidate CNVs in 24 (51%) EA cases. Rare sequence variants in genes associated with cardiomyopathy were identified in 11 (23%) EA cases. Two CNVs near the transcriptional repressor HEY1, a member of the NOTCH signaling pathway, were identified in three unrelated cases. All other candidate CNVs were each identified in a single case. At least 11 of 35 candidate CNVs include genes involved in myocardial development or function, including multiple genes in the BMP signaling pathway. We identified enrichment of gene sets involved in histone modification and cardiomyocyte differentiation, supporting the involvement of the developing myocardium in the etiology of EA. Gene set enrichment analysis also identified ribosomal RNA processing, a potentially novel pathway of altered cardiac development in EA. Our results suggest an altered myocardial program may contribute to abnormal tricuspid valve development in EA. Future studies should investigate abnormal differentiation of cardiomyocytes as a potential etiological factor in EA.

  1. Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

    PubMed Central

    Druschel, Charlotte M.; Fan, Ruzong; Caggana, Michele; Brody, Lawrence C.; Mills, James L.

    2016-01-01

    Ebstein anomaly (EA) is a rare heart defect in which the tricuspid valve is malformed and displaced. The tricuspid valve abnormalities can lead to backflow of blood from the right ventricle to the right atrium, preventing proper circulation of blood to the lungs. Although the etiology of EA is largely unresolved, increased prevalence of EA in those with a family history of congenital heart disease suggests EA has a genetic component. Copy number variants (CNVs) are a major source of genetic variation and have been implicated in a range of congenital heart defect phenotypes. We performed a systematic, genome-wide search for CNVs in 47 isolated EA cases using genotyping microarrays. In addition, we used a custom HaloPlex panel to sequence three known EA genes and 47 candidate EA genes. We identified 35 candidate CNVs in 24 (51%) EA cases. Rare sequence variants in genes associated with cardiomyopathy were identified in 11 (23%) EA cases. Two CNVs near the transcriptional repressor HEY1, a member of the NOTCH signaling pathway, were identified in three unrelated cases. All other candidate CNVs were each identified in a single case. At least 11 of 35 candidate CNVs include genes involved in myocardial development or function, including multiple genes in the BMP signaling pathway. We identified enrichment of gene sets involved in histone modification and cardiomyocyte differentiation, supporting the involvement of the developing myocardium in the etiology of EA. Gene set enrichment analysis also identified ribosomal RNA processing, a potentially novel pathway of altered cardiac development in EA. Our results suggest an altered myocardial program may contribute to abnormal tricuspid valve development in EA. Future studies should investigate abnormal differentiation of cardiomyocytes as a potential etiological factor in EA. PMID:27788187

  2. [Risk assessment of lead exposure from different intake pathways for children in Wuhan City].

    PubMed

    Hao, Han-Zhou; Chen, Tong-Bin; Wu, Ji-Liang; Lei, Mei; Tian, Hui; Zu, Wen-Pu; Zhong, Xue-Bin

    2012-06-01

    70 sampling points were set in Wuhan City to collect soil, dust, air and food samples. According to the U. S. EPA recommended childhood lead exposure parameters, U. S. EPA human exposure risk assessment method was used to assess the potential health risk of different pathway exposures of children in Wuhan City to lead. The results of calculation show: Wuhan urban children's daily lead exposure is 1.20 x 10(-3) mg x (kg x d)(-1). The digestive tract is the main way for children's exposure to lead, with the exposure of 1.04 x 10(-3) mg x (kg x d)(-1), followed by the respiratory route and dermal absorption route, the exposures were 0.153 x 10(-3) mg x (kg x d)(-1) and 8.56 x 10(-7) mg x (kg x d)(-1) respectively. Pathways of the digestive tract, ingestion of soil or dust lead exposure accounted for 52.0% of the total exposure, through the digestive tract of soil or dust ingestion is the main route of exposure. Monte-Carlo method was used to simulate the pathway in the digestive tract, the amount of lead exposure through ingestion of soil was 2. 48 x 10(-2) mg x d(-1). The probability that exceeded the PTDI (Provisional Tolerable Daily Intake) specified by JECFA (The Joint FAO/WHO Expert Committee on Food Additives) was 2.1%. The results of the risk assessment indicate that lead exposure risks from the digestive tract, respiratory tract, skin absorption are less than the maximum acceptable risk level 5.0 x 10(-5) respectively and the risk associated with skin absorption of lead is less than the negligible risk level 1 x 10(-8). Application of Kriging interpolation method, Wuhan City children lead exposure value on spatial distribution were obtained, and Qingshan district and Jiangan district have a high level of children lead exposure. The aggregate risk index of Wuhan City children lead exposure was yield by using the indicator Kriging.

  3. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  4. Genetic Variation in Dopamine Pathways Differentially Associated with Smoking Progression in Adolescence

    ERIC Educational Resources Information Center

    Laucht, Manfred; Becker, Katja; Frank, Josef; Schmidt, Martin H.; Esser, Gunter; Treutlein, Jens; Skowronek, Markus H.; Schumann, Gunter

    2008-01-01

    A study examines whether genetic variation in dopamine pathways differentially associate with smoking progression in adolescence. Results indicate the influence of specific dopamine genes in different stages of smoking progression in adolescents.

  5. Genetic abnormality of the visual pathways in a "white" tiger.

    PubMed

    Guillery, R W; Kaas, J H

    1973-06-22

    "White"tigers show an inherited reduction of pigment, produced by an autosomal recessive gene. The brain of one of these tigers shows an abnormality of the visual pathways similar to abnormalities that are associated with albinism in many other mammals. There is a close relationship between the reduced pigment formation, the pathway abnormality, and strabismus.

  6. Chemical form of selenium differentially influences DNA repair pathways following exposure to lead nitrate.

    PubMed

    McKelvey, Shauna M; Horgan, Karina A; Murphy, Richard A

    2015-01-01

    Lead, an environmental toxin is known to induce a broad range of physiological and biochemical dysfunctions in humans through a number of mechanisms including the deactivation of antioxidants thus leading to generation of reactive oxygen species (ROS) and subsequent DNA damage. Selenium on the other hand has been proven to play an important role in the protection of cells from free radical damage and oxidative stress, though its effects are thought to be form and dose dependent. As the liver is the primary organ required for metabolite detoxification, HepG2 cells were chosen to assess the protective effects of various selenium compounds following exposure to the genotoxic agent lead nitrate. Initially DNA damage was quantified using a comet assay, gene expression patterns associated with DNA damage and signalling were also examined using PCR arrays and the biological pathways which were most significantly affected by selenium were identified. Interestingly, the organic type selenium compounds (selenium yeast and selenomethionine) conferred protection against lead induced DNA damage in HepG2 cells; this is evident by reduction in the quantity of DNA present in the comet tail of cells cultured in their presence with lead. This trend also followed through the gene expression changes noted in DNA damage pathways analysed. These results were in contrast with those of inorganic sodium selenite which promoted lead induced DNA damage evident in both the comet assay results and the gene expression analysis. Over all this study provided valuable insights into the effects which various selenium compounds had on the DNA damage and signalling pathway indicating the potential for using organic forms of selenium such as selenium enriched yeast to protect against DNA damaging agents.

  7. De novo genetic engineering of the camalexin biosynthetic pathway.

    PubMed

    Møldrup, Morten E; Salomonsen, Bo; Geu-Flores, Fernando; Olsen, Carl E; Halkier, Barbara A

    2013-09-10

    Camalexin is a tryptophan-derived phytoalexin that is induced in the model plant Arabidopsis thaliana upon pathogen attack. Only few genes in the biosynthetic pathway of camalexin remain unidentified, however, investigation of candidate genes for these steps has proven particularly difficult partly because of redundancy in the genome of Arabidopsis. Here we describe metabolic engineering of the camalexin biosynthetic pathway in the transient Nicotiana benthamiana expression system. Camalexin accumulated in levels corresponding to what is seen in induced Arabidopsis thaliana. We have used this system to evaluate candidate genes suggested to be involved in the camalexin pathway. This has provided biochemical evidence for CYP71A12 conducting same reaction as CYP71A13 in the pathway. We discuss the prospects of using metabolic engineering of camalexin, both with respect to engineering plant defense and as a tool for screening yet unidentified candidate genes in the camalexin pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. Multiple Developmental Pathways Leading to a Single Morph: Monosulcate Pollen (Examples From the Asparagales)

    PubMed Central

    PENET, L.; NADOT, S.; RESSAYRE, A.; FORCHIONI, A.; DREYER, L.; GOUYON, P. H.

    2004-01-01

    • Background and Aims Early developmental events in microsporogenesis are known to play a role in pollen morphology: variation in cytokinesis type, cell wall formation, tetrad shape and aperture polarity are responsible for pollen aperture patterning. Despite the existence of other morphologies, monosulcate pollen is one of the most common aperture types in monocots, and is also considered as the ancestral condition in this group. It is known to occur from either a successive or a simultaneous cytokinesis. In the present study, the developmental sequence of microsporogenesis is investigated in several species of Asparagales that produce such monosulcate pollen, representing most families of this important monocot clade. • Methods The developmental pathway of microsporogenesis was investigated using light transmission and epifluorescence microscopy for all species studied. Confocal microscopy was used to confirm centripetal cell plate formation. • Key Results Microsporogenesis is diverse in Asparagales, and most variation is generally found between families. It is confirmed that the whole higher Asparagales clade has a very conserved microsporogenesis, with a successive cytokinesis and centrifugal cell plate formation. Centripetal cell wall formation is described in Tecophilaeaceae and Iridaceae, a feature that had so far only been reported for eudicots. • Conclusions Monosulcate pollen can be obtained from several developmental pathways, leading thus to homoplasy in the monosulcate character state. Monosulcate pollen should not therefore be considered as the ancestral state unless it is produced through the ancestral developmental pathway. The question about the ancestral developmental pathway leading to monosulcy remains open. PMID:15567807

  9. Academic provenance: Investigation of pathways that lead students into the geosciences

    NASA Astrophysics Data System (ADS)

    Houlton, Heather R.

    Pathways that lead students into the geosciences as a college major have not been fully explored in the current literature, despite the recent studies on the "geoscience pipeline model." Anecdotal evidence suggests low quality geoscience curriculum in K-12 education, lack of visibility of the discipline and lack of knowledge about geoscience careers contribute to low geoscience enrollments at universities. This study investigated the reasons why college students decided to major in the geosciences. Students' interests, experiences, motivations and desired future careers were examined to develop a pathway model. In addition, self-efficacy was used to inform pathway analyses, as it is an influential factor in academic major and career choice. These results and interpretations have strong implications for recruitment and retention in academia and industry. A semi-structured interview protocol was developed, which was informed by John Flanagan's critical incident theory. The responses to this interview were used to identify common experiences that diverse students shared for reasons they became geoscience majors. Researchers used self-efficacy theory by Alfred Bandura to assess students' pathways. Seventeen undergraduate geoscience majors from two U.S. Midwest research universities were sampled for cross-comparison and analysis. Qualitative analyses led to the development of six categorical steps for the geoscience pathway. The six pathway steps are: innate attributes/interest sources, pre-college critical incidents, college critical incidents, current/near future goals, expected career attributes and desired future careers. Although, how students traversed through each step was unique for individuals, similar patterns were identified between different populations in our participants: Natives, Immigrants and Refugees. In addition, critical incidents were found to act on behavior in two different ways: to support and confirm decision-making behavior (supportive critical

  10. Genetic heterogeneity in autism: From single gene to a pathway perspective.

    PubMed

    An, Joon Yong; Claudianos, Charles

    2016-09-01

    The extreme genetic heterogeneity of autism spectrum disorder (ASD) represents a major challenge. Recent advances in genetic screening and systems biology approaches have extended our knowledge of the genetic etiology of ASD. In this review, we discuss the paradigm shift from a single gene causation model to pathway perturbation model as a guide to better understand the pathophysiology of ASD. We discuss recent genetic findings obtained through next-generation sequencing (NGS) and examine various integrative analyses using systems biology and complex networks approaches that identify convergent patterns of genetic elements associated with ASD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Bioactive Lysophospholipids Generated by Hepatic Lipase Degradation of Lipoproteins Lead to Complement Activation via the Classical Pathway

    PubMed Central

    Ma, Wanchao; Paik, David C.; Barile, Gaetano R.

    2014-01-01

    Purpose. We determined bioactivity of lysophospholipids generated by degradation of the low-density (LDL), very low-density (VLDL), and high-density (HDL) lipoproteins with hepatic lipase (HL), cholesterol esterase (CE), and lipoprotein-associated phospholipase A2 (Lp-PLA2). Methods. The LDL, VLDL, and HDL were treated with HL, CE, and Lp-PLA2 after immobilization on plates, and complement activation studies were performed with diluted human serum. Complement component 3 (C3) fixation, a marker for complement activation, was determined with a monoclonal anti-human C3d antibody. Enzymatic properties of HL and CE were assayed with triglyceride and phosphatidylcholine substrates for triglyceride hydrolase and phospholipase A activities. The ARPE-19 cells were used for viability studies. Results. The HL degradation of human lipoproteins LDL, VLDL, or HDL results in the formation of modified lipoproteins that can activate the complement pathway. Complement activation is dose- and time-dependent upon HL and occurs via the classical pathway. Enzymatic studies suggest that the phospholipase A1 activity of HL generates complement-activating lysophospholipids. C-reactive protein (CRP), known to simultaneously interact with complement C1 and complement factor H (CFH), further enhances HL-induced complement activation. The lysophospholipids, 1-Palmitoyl-sn-glycero-3-phosphocholine and 1-Oleoyl-sn-glycero-3-phosphocholine, can be directly cytotoxic to ARPE-19 cells. Conclusions. The HL degradation of lipoproteins, known to accumulate in the outer retina and in drusen, can lead to the formation of bioactive lysophospholipids that can trigger complement activation and induce RPE cellular dysfunction. Given the known risk associations for age-related macular degeneration (AMD) with HL, CRP, and CFH, this study elucidates a possible damage pathway for age-related macular degeneration (AMD) in genetically predisposed individuals, that HL activity may lead to accumulation of

  12. Bioactive lysophospholipids generated by hepatic lipase degradation of lipoproteins lead to complement activation via the classical pathway.

    PubMed

    Ma, Wanchao; Paik, David C; Barile, Gaetano R

    2014-09-09

    We determined bioactivity of lysophospholipids generated by degradation of the low-density (LDL), very low-density (VLDL), and high-density (HDL) lipoproteins with hepatic lipase (HL), cholesterol esterase (CE), and lipoprotein-associated phospholipase A2 (Lp-PLA2). The LDL, VLDL, and HDL were treated with HL, CE, and Lp-PLA2 after immobilization on plates, and complement activation studies were performed with diluted human serum. Complement component 3 (C3) fixation, a marker for complement activation, was determined with a monoclonal anti-human C3d antibody. Enzymatic properties of HL and CE were assayed with triglyceride and phosphatidylcholine substrates for triglyceride hydrolase and phospholipase A activities. The ARPE-19 cells were used for viability studies. The HL degradation of human lipoproteins LDL, VLDL, or HDL results in the formation of modified lipoproteins that can activate the complement pathway. Complement activation is dose- and time-dependent upon HL and occurs via the classical pathway. Enzymatic studies suggest that the phospholipase A1 activity of HL generates complement-activating lysophospholipids. C-reactive protein (CRP), known to simultaneously interact with complement C1 and complement factor H (CFH), further enhances HL-induced complement activation. The lysophospholipids, 1-Palmitoyl-sn-glycero-3-phosphocholine and 1-Oleoyl-sn-glycero-3-phosphocholine, can be directly cytotoxic to ARPE-19 cells. The HL degradation of lipoproteins, known to accumulate in the outer retina and in drusen, can lead to the formation of bioactive lysophospholipids that can trigger complement activation and induce RPE cellular dysfunction. Given the known risk associations for age-related macular degeneration (AMD) with HL, CRP, and CFH, this study elucidates a possible damage pathway for age-related macular degeneration (AMD) in genetically predisposed individuals, that HL activity may lead to accumulation of lysophospholipids to initiate complement

  13. Molecular Genetic Characterization of Terreic Acid Pathway in Aspergillus terreus

    DOE PAGES

    Guo, Chun-Jun; Sun, Wei-wen; Bruno, Kenneth S.; ...

    2014-09-29

    Terreic acid is a natural product derived from 6-methylsalicylic acid (6-MSA). A compact gene cluster for its biosynthesis was characterized. Isolation of the intermediates and shunt products from the mutant strains, in combined with bioinformatic analyses, allowed us to propose a biosynthetic pathway for terreic acid. Lastly, defining the pathway and the genes involved will facilitate the engineering of this molecule with interesting antimicrobial and antitumor bioactivities.

  14. The genetic makeup of the Drosophila piRNA pathway.

    PubMed

    Handler, Dominik; Meixner, Katharina; Pizka, Manfred; Lauss, Kathrin; Schmied, Christopher; Gruber, Franz Sebastian; Brennecke, Julius

    2013-06-06

    The piRNA (PIWI-interacting RNA) pathway is a small RNA silencing system that acts in animal gonads and protects the genome against the deleterious influence of transposons. A major bottleneck in the field is the lack of comprehensive knowledge of the factors and molecular processes that constitute this pathway. We conducted an RNAi screen in Drosophila and identified ~50 genes that strongly impact the ovarian somatic piRNA pathway. Many identified genes fall into functional categories that indicate essential roles for mitochondrial metabolism, RNA export, the nuclear pore, transcription elongation, and chromatin regulation in the pathway. Follow-up studies on two factors demonstrate that components acting at distinct hierarchical levels of the pathway were identified. Finally, we define CG2183/Gasz as an essential primary piRNA biogenesis factor in somatic and germline cells. Based on the similarities between insect and vertebrate piRNA pathways, our results have far-reaching implications for the understanding of this conserved genome defense system. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. The Genetic Makeup of the Drosophila piRNA Pathway

    PubMed Central

    Handler, Dominik; Meixner, Katharina; Pizka, Manfred; Lauss, Kathrin; Schmied, Christopher; Gruber, Franz Sebastian; Brennecke, Julius

    2013-01-01

    Summary The piRNA (PIWI-interacting RNA) pathway is a small RNA silencing system that acts in animal gonads and protects the genome against the deleterious influence of transposons. A major bottleneck in the field is the lack of comprehensive knowledge of the factors and molecular processes that constitute this pathway. We conducted an RNAi screen in Drosophila and identified ∼50 genes that strongly impact the ovarian somatic piRNA pathway. Many identified genes fall into functional categories that indicate essential roles for mitochondrial metabolism, RNA export, the nuclear pore, transcription elongation, and chromatin regulation in the pathway. Follow-up studies on two factors demonstrate that components acting at distinct hierarchical levels of the pathway were identified. Finally, we define CG2183/Gasz as an essential primary piRNA biogenesis factor in somatic and germline cells. Based on the similarities between insect and vertebrate piRNA pathways, our results have far-reaching implications for the understanding of this conserved genome defense system. PMID:23665231

  16. Synonymous Mutations and Ribosome Stalling Can Lead to Altered Folding Pathways and Distinct Minima

    PubMed Central

    Tsai, Chung-Jung; Sauna, Zuben E.; Kimchi-Sarfaty, Chava; Ambudkar, Suresh V.; Gottesman, Michael M.; Nussinov, Ruth

    2008-01-01

    How can we understand a case where a given amino acid sequence folds into structurally and functionally distinct molecules? Synonymous single-nucleotide polymorphisms (SNPs) in the multidrug resistance 1 (MDR1 or ABCB1) gene involving frequent to rare codon substitutions lead to identical protein sequences. Remarkably these alternative sequences give a protein product with similar but different structures and functions. Here we propose that long-enough ribosomal pause time-scales may lead to alternate folding pathways and distinct minima on the folding free energy surface. While the conformational and functional differences between the native and alternate states may be minor, the MDR1 case illustrates that the barriers may nevertheless constitute sufficiently high hurdles in physiological time-scales, leading to kinetically trapped states with altered structures and functions. Different folding pathways leading to conformationally-similar trapped states may be due to swapping of (fairly symmetric) segments. Domain swapping is more likely in the no-pause case where the chain elongates and folds simulaneously; on the other hand, sufficiently long pause times between such segments may be expected to lessen the chances of swapping events. Here, we review the literature in this light. PMID:18722384

  17. Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways.

    PubMed

    Mattingsdal, Morten; Brown, Andrew Anand; Djurovic, Srdjan; Sønderby, Ida Elken; Server, Andres; Melle, Ingrid; Agartz, Ingrid; Hovig, Eivind; Jensen, Jimmy; Andreassen, Ole A

    2013-04-15

    Several lines of evidence suggest that common polygenic variation influences brain function in humans. Combining high-density genetic markers with brain imaging techniques is constricted by the practicalities of collecting sufficiently large brain imaging samples. Pathway analysis promises to leverage knowledge on function of genes to detect recurring signals of moderate effect. We adapt this approach, exploiting the deep information collected on brain function by fMRI methods, to identify molecular pathways containing genetic variants which influence brain activation during a commonly applied experiment based on a face matching task (n=246) which was developed to study neural processing of faces displaying negative emotions. Genetic markers moderately associated (p<10(-4)) with whole brain activation phenotypes constructed by applying principal components to contrast maps, were tested for pathway enrichment using permutation based methods. The most significant pathways are related to post NMDA receptor activation events, driven by genetic variants in calcium/calmodulin-dependent protein kinase II (CAMK2G, CAMK2D) and a calcium-regulated nucleotide exchange factor (RASGRF2) in which all are activated by intracellular calcium/calmodulin. The most significant effect of the combined polygenic model were localized to the left inferior frontal gyrus (p=1.03 × 10(-9)), a region primarily involved in semantic processing but also involved in processing negative emotions. These findings suggest that pathway analysis of GWAS results derived from principal component analysis of fMRI data is a promising method, to our knowledge, not previously described. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Mutations in ligands and receptors of the leptin-melanocortin pathway that lead to obesity.

    PubMed

    Farooqi, I Sadaf; O'Rahilly, Stephen

    2008-10-01

    Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes mellitus and certain cancers. The prevalence of obesity is increasing rapidly throughout the world and is now recognized as a major global public-health concern. Although the increased prevalence of obesity is undoubtedly driven by environmental factors, the evidence that inherited factors profoundly influence human fat mass is equally compelling. Twin and adoption studies indicate that up to 70% of the interindividual variance in fat mass is determined by genetic factors. Genetic strategies can, therefore, provide a useful tool with which to dissect the complex (and often heterogeneous) molecular and physiologic mechanisms involved in the regulation of body weight. In this Review, we have focused our attention on monogenic disorders, which primarily result in severe, early-onset obesity. The study of these genetic disorders has provided a framework for our understanding of the mechanisms involved in the regulation of body weight in humans and how these mechanisms are disrupted in obesity. The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight.

  19. t-BHQ Provides Protection against Lead Neurotoxicity via Nrf2/HO-1 Pathway

    PubMed Central

    Ye, Fang; Li, Xiaoyi; Li, Lili; Yuan, Jing; Chen, Jun

    2016-01-01

    The neurotoxicity of lead has been well established, and oxidative stress is strongly associated with lead-induced neurotoxicity. Nrf2 is important for protection against oxidative stress in many disease models. We applied t-BHQ, which is an Nrf2 activator, to investigate the possible role of Nrf2 in the protection against lead neurotoxicity. t-BHQ significantly attenuated the oxidative stress in developmental rats by decreasing MDA level, as well as by increasing SOD activity and GSH content, in the hippocampus and frontal cortex. Furthermore, neuronal apoptosis was detected by Nissl staining, and Bax expression was inhibited in the t-BHQ-treated group. Results showed that t-BHQ suppressed ROS production and caspase 3/7 activity but increased intracellular GSH content, in SH-SY5Y cells under lead exposure. Moreover, in vivo and in vitro, t-BHQ enhanced the nuclear translocation of Nrf2 and binding to ARE areas but did not induce Nrf2 transcription. These phenomena were confirmed using RT-PCR, EMSA, Western blot, and immunofluorescence analyses. Subsequent upregulation of the expression of HO-1, NQO1, and GCLC was observed. However, knockdown of Nrf2 or HO-1 adversely affected the protective effects of t-BHQ against lead toxicity in SH-SY5Y cells. Thus, t-BHQ can protect against lead neurotoxicity, depending on the Nrf2/HO-1 pathway. PMID:26798413

  20. Genetic Architectures of Quantitative Variation in RNA Editing Pathways.

    PubMed

    Gu, Tongjun; Gatti, Daniel M; Srivastava, Anuj; Snyder, Elizabeth M; Raghupathy, Narayanan; Simecek, Petr; Svenson, Karen L; Dotu, Ivan; Chuang, Jeffrey H; Keller, Mark P; Attie, Alan D; Braun, Robert E; Churchill, Gary A

    2016-02-01

    RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing. Copyright © 2016 by the Genetics Society of America.

  1. Lead

    MedlinePlus

    ... EPA United States Environmental Protection Agency Search Search Lead Contact Us Share Lead Poisoning is Preventable If your home was built ... to protect people from harmful lead exposures. Less Lead in Drinking Water = Better Health Learn about the ...

  2. Whole Genome Sequencing and Complete Genetic Analysis Reveals Novel Pathways to Glycopeptide Resistance in Staphylococcus aureus

    PubMed Central

    Renzoni, Adriana; Andrey, Diego O.; Jousselin, Ambre; Barras, Christine; Monod, Antoinette; Vaudaux, Pierre; Lew, Daniel; Kelley, William L.

    2011-01-01

    The precise mechanisms leading to the emergence of low-level glycopeptide resistance in Staphylococcus aureus are poorly understood. In this study, we used whole genome deep sequencing to detect differences between two isogenic strains: a parental strain and a stable derivative selected stepwise for survival on 4 µg/ml teicoplanin, but which grows at higher drug concentrations (MIC 8 µg/ml). We uncovered only three single nucleotide changes in the selected strain. Nonsense mutations occurred in stp1, encoding a serine/threonine phosphatase, and in yjbH, encoding a post-transcriptional negative regulator of the redox/thiol stress sensor and global transcriptional regulator, Spx. A missense mutation (G45R) occurred in the histidine kinase sensor of cell wall stress, VraS. Using genetic methods, all single, pairwise combinations, and a fully reconstructed triple mutant were evaluated for their contribution to low-level glycopeptide resistance. We found a synergistic cooperation between dual phospho-signalling systems and a subtle contribution from YjbH, suggesting the activation of oxidative stress defences via Spx. To our knowledge, this is the first genetic demonstration of multiple sensor and stress pathways contributing simultaneously to glycopeptide resistance development. The multifactorial nature of glycopeptide resistance in this strain suggests a complex reprogramming of cell physiology to survive in the face of drug challenge. PMID:21738716

  3. Elucidating the early signal transduction pathways leading to fetal brain injury in preterm birth.

    PubMed

    Elovitz, Michal A; Mrinalini, Conjeevaram; Sammel, Mary D

    2006-01-01

    Adverse neurologic outcome, including cerebral palsy, is a significant contributor to long-term morbidity in preterm neonates. However, the mechanisms leading to brain injury in the setting of a preterm birth are poorly understood. In the last decade, there has been a growing body of evidence correlating infection or inflammation with preterm birth. The presence of intrauterine inflammation significantly increases the risk for adverse neurologic outcome in the neonate. These studies were performed to elucidate the early signal transduction pathways activated in the fetal brain that may result in long-term neurologic injury. Using our mouse model of localized intrauterine inflammation, the activation of TH1/TH2 pathways in the placenta, fetus corpus, fetal liver, and fetal brain was investigated. Additional studies determined whether activation of TH1/TH2 pathways could promote cell death and alter glial development. Real-time PCR studies demonstrated that a robust TH1/TH2 response occurs rapidly in the fetal brain after exposure to intrauterine inflammation. The cytokine response in the fetus and placenta was not significantly correlated with the response in the fetal brain. Along with an immune response, cell death pathways were activated early in the fetal brain in response to intrauterine LPS. Implicating TH1/TH2 and cell death pathways in permanent brain injury are our findings of an increase in GFAP mRNA and protein as well as a loss of pro-oligodendrocytes. With increased understanding of the mechanisms by which inflammation promotes brain injury in the preterm neonate, identification of potential targets to limit adverse neonatal outcomes becomes possible.

  4. Genetic Architectures of Quantitative Variation in RNA Editing Pathways

    PubMed Central

    Gu, Tongjun; Gatti, Daniel M.; Srivastava, Anuj; Snyder, Elizabeth M.; Raghupathy, Narayanan; Simecek, Petr; Svenson, Karen L.; Dotu, Ivan; Chuang, Jeffrey H.; Keller, Mark P.; Attie, Alan D.; Braun, Robert E.; Churchill, Gary A.

    2016-01-01

    RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing. PMID:26614740

  5. New IBD genetics: common pathways with other diseases.

    PubMed

    Lees, C W; Barrett, J C; Parkes, M; Satsangi, J

    2011-12-01

    Complex disease genetics has been revolutionised in recent years by the advent of genome-wide association (GWA) studies. The chronic inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis have seen notable successes culminating in the discovery of 99 published susceptibility loci/genes (71 Crohn's disease; 47 ulcerative colitis) to date. Approximately one-third of loci described confer susceptibility to both Crohn's disease and ulcerative colitis. Amongst these are multiple genes involved in IL23/Th17 signalling (IL23R, IL12B, JAK2, TYK2 and STAT3), IL10, IL1R2, REL, CARD9, NKX2.3, ICOSLG, PRDM1, SMAD3 and ORMDL3. The evolving genetic architecture of IBD has furthered our understanding of disease pathogenesis. For Crohn's disease, defective processing of intracellular bacteria has become a central theme, following gene discoveries in autophagy and innate immunity (associations with NOD2, IRGM, ATG16L1 are specific to Crohn's disease). Genetic evidence has also demonstrated the importance of barrier function to the development of ulcerative colitis (HNF4A, LAMB1, CDH1 and GNA12). However, when the data are analysed in more detail, deeper themes emerge including the shared susceptibility seen with other diseases. Many immune-mediated diseases overlap in this respect, paralleling the reported epidemiological evidence. However, in several cases the reported shared susceptibility appears at odds with the clinical picture. Examples include both type 1 and type 2 diabetes mellitus. In this review we will detail the presently available data on the genetic overlap between IBD and other diseases. The discussion will be informed by the epidemiological data in the published literature and the implications for pathogenesis and therapy will be outlined. This arena will move forwards very quickly in the next few years. Ultimately, we anticipate that these genetic insights will transform the landscape of common complex diseases such as IBD.

  6. Genetic control of the alternative pathway of complement in humans and age-related macular degeneration.

    PubMed

    Hecker, Laura A; Edwards, Albert O; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H; Brown, William L; Charbel Issa, Peter; Scholl, Hendrik P; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E; Bailey, Kent R; Oppermann, Martin

    2010-01-01

    Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues.

  7. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network, and pathway analyses

    PubMed Central

    Kogelman, Lisette J. A.; Pant, Sameer D.; Fredholm, Merete; Kadarmideen, Haja N.

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH) and differentially wired (DW) networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g., NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g., metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic) obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways that underlie

  8. Systems genetics of obesity in an F2 pig model by genome-wide association, genetic network, and pathway analyses.

    PubMed

    Kogelman, Lisette J A; Pant, Sameer D; Fredholm, Merete; Kadarmideen, Haja N

    2014-01-01

    Obesity is a complex condition with world-wide exponentially rising prevalence rates, linked with severe diseases like Type 2 Diabetes. Economic and welfare consequences have led to a raised interest in a better understanding of the biological and genetic background. To date, whole genome investigations focusing on single genetic variants have achieved limited success, and the importance of including genetic interactions is becoming evident. Here, the aim was to perform an integrative genomic analysis in an F2 pig resource population that was constructed with an aim to maximize genetic variation of obesity-related phenotypes and genotyped using the 60K SNP chip. Firstly, Genome Wide Association (GWA) analysis was performed on the Obesity Index to locate candidate genomic regions that were further validated using combined Linkage Disequilibrium Linkage Analysis and investigated by evaluation of haplotype blocks. We built Weighted Interaction SNP Hub (WISH) and differentially wired (DW) networks using genotypic correlations amongst obesity-associated SNPs resulting from GWA analysis. GWA results and SNP modules detected by WISH and DW analyses were further investigated by functional enrichment analyses. The functional annotation of SNPs revealed several genes associated with obesity, e.g., NPC2 and OR4D10. Moreover, gene enrichment analyses identified several significantly associated pathways, over and above the GWA study results, that may influence obesity and obesity related diseases, e.g., metabolic processes. WISH networks based on genotypic correlations allowed further identification of various gene ontology terms and pathways related to obesity and related traits, which were not identified by the GWA study. In conclusion, this is the first study to develop a (genetic) obesity index and employ systems genetics in a porcine model to provide important insights into the complex genetic architecture associated with obesity and many biological pathways that underlie

  9. Genetic and Environmental Pathways in Type 1 Diabetes Complications

    DTIC Science & Technology

    2010-09-01

    active duty members of the military, their families and retired military personnel will potentially allow focused preventative treatment of at- risk...Ovington NR, Allen J, Adlem E, Leung HT, Wallace C, Howson JM, Guja C, Ionescu-Tîrgovişte C; Genetics of Type 1 Diabetes in Finland , Simmonds MJ, Heward...tools as well as in creation of new therapeutic treatments . Goal 1. PROJECT DESCRIPTION This application proposes to fine-map recognized Type 1

  10. Trigeminal Neuralgia Induced by Cobra Venom Leads to Cognitive Deficits Associated with Downregulation of CREB/BDNF Pathway.

    PubMed

    Zhang, Li; Ding, Xinli; Wu, Zhe; Qian, Xiaoyan; An, Jianxiong; Tian, Ming

    2017-02-01

    Chronic pain often results in cognitive impairment. Our previous study showed that trigeminal neuralgia induced by cobra venom leads to spatial learning and memory deficits, although the underlying mechanism remains unclear. However, recent evidence indicates that the c-AMP-responsive element binding protein (CREB)/brain derived neurotrophic factor (BDNF) pathway plays a critical role in various etiologies of cognitive deficits. Our aim was to explore the CREB/BDNF pathway to determine the molecular mechanisms involved in the pathogenesis of cognitive impairment caused by cobra venom-induced trigeminal neuralgia. A randomized, controlled animal study. Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University. Fifty male Sprague-Dawley rats were randomly divided into 3 groups: cobra venom group, sham group, and control group. Cobra venom or saline was injected into the sheath of the infraorbital nerve (ION), respectively. Video recordings and mechanical thresholds were used to analyze changes in behavioral activity 3 days before surgery and 4, 7, 14, 21, 28, and 56 days after surgery. Morris water maze tests were conducted at 4- and 8-week time points after surgery to evaluate spatial learning and memory. We also investigated expression changes of phosphorylated CREB (p-CREB) and BDNF in the hippocampus and prefrontal cortex (PFC) using western blotting and immunohistochemistry. Cobra venom-treated rats exhibited significant changes in face grooming, as well as exploratory and resting behaviors, compared with the control group and sham group (both P < 0.001). Rats in the cobra venom group exhibited slightly impaired acquisition (P < 0.05) without memory deficits (P > 0.05) in the first water maze protocol. In the second water maze test, rats in the cobra venom group exhibited spatial learning and memory deficits, with fewer platform site crossings during the probe trial (P < 0.05). Moreover, results showed decreased p-CREB and BDNF

  11. Actin-induced hyperactivation of the Ras signaling pathway leads to apoptosis in Saccharomyces cerevisiae.

    PubMed

    Gourlay, C W; Ayscough, K R

    2006-09-01

    Recent research has revealed a conserved role for the actin cytoskeleton in the regulation of aging and apoptosis among eukaryotes. Here we show that the stabilization of the actin cytoskeleton caused by deletion of Sla1p or End3p leads to hyperactivation of the Ras signaling pathway. The consequent rise in cyclic AMP (cAMP) levels leads to the loss of mitochondrial membrane potential, accumulation of reactive oxygen species (ROS), and cell death. We have established a mechanistic link between Ras signaling and actin by demonstrating that ROS production in actin-stabilized cells is dependent on the G-actin binding region of the cyclase-associated protein Srv2p/CAP. Furthermore, the artificial elevation of cAMP directly mimics the apoptotic phenotypes displayed by actin-stabilized cells. The effect of cAMP elevation in inducing actin-mediated apoptosis functions primarily through the Tpk3p subunit of protein kinase A. This pathway represents the first defined link between environmental sensing, actin remodeling, and apoptosis in Saccharomyces cerevisiae.

  12. Genetic findings in Parkinson's disease and translation into treatment: a leading role for mitochondria?

    PubMed Central

    Bogaerts, V; Theuns, J; van Broeckhoven, C

    2008-01-01

    Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder and in most patients its aetiology remains unknown. Molecular genetic studies in familial forms of the disease identified key proteins involved in PD pathogenesis, and support a major role for mitochondrial dysfunction, which is also of significant importance to the common sporadic forms of PD. While current treatments temporarily alleviate symptoms, they do not halt disease progression. Drugs that target the underlying pathways to PD pathogenesis, including mitochondrial dysfunction, therefore hold great promise for neuroprotection in PD. Here we summarize how the proteins identified through genetic research (α-synuclein, parkin, PINK1, DJ-1, LRRK2 and HTRA2) fit into and add to our current understanding of the role of mitochondrial dysfunction in PD. We highlight how these genetic findings provided us with suitable animal models and critically review how the gained insights will contribute to better therapies for PD. PMID:17680806

  13. Revisiting sesquiterpene biosynthetic pathways leading to santalene and its analogues: a comprehensive mechanistic study.

    PubMed

    Jindal, Garima; Sunoj, Raghavan B

    2012-10-21

    Santalene and bergamotene are the major olefinic sesquiterpenes responsible for the fragrance of sandalwood oil. Herein we report the details of density functional theory investigations on the biosynthetic pathway of this important class of terpenes. The mechanistic study has been found to be effective toward gaining significant new insight into different possibilities for the formation of the key intermediates involved in santalene and bergamotene biosynthesis. The stereoelectronic features of the transition states and intermediates for (i) ring closure of the initial bisabolyl cation, and (ii) skeletal rearrangements in the ensuing bicyclic carbocationic intermediates leading to (-)-epi-β-santalene, (-)-β-santalene, (-)-α-santalene, (+)-epi-β-santalene, exo-β-bergamotene, endo-β-bergamotene, exo-α-bergamotene, and endo-α-bergamotene are presented. Interesting structural features pertaining to certain new carbocationic intermediates (such as b) resulting from the ring closure of bisabolyl cation are discussed. Extensive conformational sampling of all key intermediates along the biosynthetic pathway offered new insight into the role of the isoprenyl side chain conformation in the formation of santalene and its analogues. Although the major bicyclic products in Santalum album appear to arise from the right or left handed helical form of farnesyl pyrophosphate (FPP), different alternatives for their formation are found to be energetically feasible. The interconversion of the exo and endo isomers of bisabolyl cation and a likely epimerization, both with interesting mechanistic implications, are presented. The exo to endo conversion is identified to be energetically more favorable than another pathway emanating from the left handed helical FPP. The role of pyrophosphate (OPP(-)) in the penultimate deprotonation step leading to olefinic sesquiterpenes is also examined.

  14. Associations of genetic risk scores based on adult adiposity pathways with childhood growth and adiposity measures.

    PubMed

    Monnereau, Claire; Vogelezang, Suzanne; Kruithof, Claudia J; Jaddoe, Vincent W V; Felix, Janine F

    2016-08-18

    Results from genome-wide association studies (GWAS) identified many loci and biological pathways that influence adult body mass index (BMI). We aimed to identify if biological pathways related to adult BMI also affect infant growth and childhood adiposity measures. We used data from a population-based prospective cohort study among 3,975 children with a mean age of 6 years. Genetic risk scores were constructed based on the 97 SNPs associated with adult BMI previously identified with GWAS and on 28 BMI related biological pathways based on subsets of these 97 SNPs. Outcomes were infant peak weight velocity, BMI at adiposity peak and age at adiposity peak, and childhood BMI, total fat mass percentage, android/gynoid fat ratio, and preperitoneal fat area. Analyses were performed using linear regression models. A higher overall adult BMI risk score was associated with infant BMI at adiposity peak and childhood BMI, total fat mass, android/gynoid fat ratio, and preperitoneal fat area (all p-values < 0.05). Analyses focused on specific biological pathways showed that the membrane proteins genetic risk score was associated with infant peak weight velocity, and the genetic risk scores related to neuronal developmental processes, hypothalamic processes, cyclicAMP, WNT-signaling, membrane proteins, monogenic obesity and/or energy homeostasis, glucose homeostasis, cell cycle, and muscle biology pathways were associated with childhood adiposity measures (all p-values <0.05). None of the pathways were associated with childhood preperitoneal fat area. A genetic risk score based on 97 SNPs related to adult BMI was associated with peak weight velocity during infancy and general and abdominal fat measurements at the age of 6 years. Risk scores based on genetic variants linked to specific biological pathways, including central nervous system and hypothalamic processes, influence body fat development from early life onwards.

  15. Genetic defects in folate and cobalamin pathways affecting the brain.

    PubMed

    Kirsch, Susanne H; Herrmann, Wolfgang; Obeid, Rima

    2013-01-01

    Folate and cobalamin are necessary for early brain development and function. Deficiency of folate or cobalamin during pregnancy can cause severe malformation in the central nervous system such as neural tube defects. After birth, folate and cobalamin deficiency can cause anemia, failure to thrive, recurrent infections, psychiatric and neurological symptoms. The folate and the homocysteine metabolic pathways interact at a central step where 5-methyltetrahydrofolate donates its methyl group to homocysteine to produce methionine and tetrahydrofolate. Methyl cobalamin and folate interact at this critical step. Both nutrients have a crucial role in DNA synthesis and in delivering S-adenosylmethionine, the universal methyl donor. Severe and mild inherited disorders in folate and cobalamin pathways have been described. The two groups of disorders share some similarities, but differ in the molecular mechanism, metabolic dysregulation, and disease management. This review summarizes selected disorders, including rare and common mutations that affect folate and cobalamin absorption, transport, or dependent enzymes. When the mutations are discovered early enough, many of the described disorders are easily treatable by B vitamin supplementation, which often prevents or reverses the manifestation of the disease. Therefore, the screening for mutations is recommended and should be carried out as early as possible: after occurrence of the first symptoms or when a certain constellations of the folate and cobalamin related markers are measured, such as elevated homocysteine and/or methylmalonic acid.

  16. Pathways to Understanding Ovarian Cancer, Epidemiology, Genetic Susceptibility, and Survival

    DTIC Science & Technology

    2011-05-01

    develop from the fallopian tubes while others develop from the ovarian surface epithelium through Mullerian inclusions or endometriosis implants...RAS and BRA F mutations leading to low grade serous and m ucinous carcinomas, 2) endometriosis implants or transformation into endometrioid... endometriosis (p for heterogeneity = 0.0002), w e observed significant associations only with dominant tumors. Interestingly, IUD use was associated with a

  17. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK Pathway

    PubMed Central

    Stevenson, David A.; Schill, Lisa; Schoyer, Lisa; Andresen, Brage S.; Bakker, Annette; Bayrak-Toydemir, Pinar; Burkitt-Wright, Emma; Chatfield, Kathryn; Elefteriou, Florent; Elgersma, Ype; Fisher, Michael J.; Franz, David; Gelb, Bruce D.; Goriely, Anne; Gripp, Karen W.; Hardan, Antonio Y.; Keppler-Noreuil, Kim M.; Kerr, Bronwyn; Korf, Bruce; Leoni, Chiara; McCormick, Frank; Plotkin, Scott R.; Rauen, Katherine A.; Reilly, Karlyne; Roberts, Amy; Sandler, Abby; Siegel, Dawn; Walsh, Karin; Widemann, Brigitte C.

    2016-01-01

    The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation–arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. PMID:27155140

  18. Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality.

    PubMed

    Russom, Christine L; LaLone, Carlie A; Villeneuve, Daniel L; Ankley, Gerald T

    2014-10-01

    Adverse outcome pathways (AOPs) are designed to describe linkages of key events within a biological pathway that result in an adverse outcome associated with chemical perturbation of a well-defined molecular initiating event. Risk assessors have traditionally relied on data from apical endpoints (e.g., mortality, growth, reproduction) to derive benchmark values for use in determining the potential adverse impacts of chemicals. One goal in building reliable and well-characterized AOPs is to identify relevant in vitro assays and/or in vivo biomarkers that could be used in screening the potential hazard of substances, thereby reducing costs and increasing the number of chemicals that can be evaluated in a timely fashion. The purpose of this review article is to build an AOP for substances with a molecular initiating event of acetylcholinesterase inhibition leading to acute mortality following guidance developed by the Organisation for Economic Cooperation and Development. In contrast to most other AOPs developed to date, in which coverage is for a relatively limited taxonomic group or life stage, this AOP is applicable to a wide range of species at multiple life stages. Furthermore, while development of most AOPs has relied on data for a few model chemicals, the AOP described in the present review captures information from a large number of studies with a diversity of organophosphate and carbamate insecticides. Published 2014 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.

  19. Human exposure pathways of heavy metals in a lead-zinc mining area, Jiangsu Province, China.

    PubMed

    Qu, Chang-Sheng; Ma, Zong-Wei; Yang, Jin; Liu, Yang; Bi, Jun; Huang, Lei

    2012-01-01

    Heavy metal pollution is becoming a serious issue in developing countries such as China, and the public is increasingly aware of its adverse health impacts in recent years. We assessed the potential health risks in a lead-zinc mining area and attempted to identify the key exposure pathways. We evaluated the spatial distributions of personal exposure using indigenous exposure factors and field monitoring results of water, soil, food, and indoor and outdoor air samples. The risks posed by 10 metals and the contribution of inhalation, ingestion and dermal contact pathways to these risks were estimated. Human hair samples were also analyzed to indicate the exposure level in the human body. Our results show that heavy metal pollution may pose high potential health risks to local residents, especially in the village closest to the mine (V1), mainly due to Pb, Cd and Hg. Correspondingly, the residents in V1 had higher Pb (8.14 mg/kg) levels in hair than those in the other two villages. Most of the estimated risks came from soil, the intake of self-produced vegetables and indoor air inhalation. This study highlights the importance of site-specific multipathway health risk assessments in studying heavy-metal exposures in China.

  20. Ecdysone Receptor Agonism Leading to Lethal Molting Disruption in Arthropods: Review and Adverse Outcome Pathway Development.

    PubMed

    Song, You; Villeneuve, Daniel L; Toyota, Kenji; Iguchi, Taisen; Tollefsen, Knut Erik

    2017-04-18

    Molting is critical for growth, development, reproduction, and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting chemicals (EDCs). Based on several known ED mechanisms, a wide range of pesticides has been developed to combat unwanted organisms in food production activities such as agriculture and aquaculture. Meanwhile, these chemicals may also pose hazards to nontarget species by causing molting defects, and thus potentially affecting the health of the ecosystems. The present review summarizes the available knowledge on molting-related endocrine regulation and chemically mediated disruption in arthropods (with special focus on insects and crustaceans), to identify research gaps and develop a mechanistic model for assessing environmental hazards of these compounds. Based on the review, multiple targets of EDCs in the molting processes were identified and the link between mode of action (MoA) and adverse effects characterized to inform future studies. An adverse outcome pathway (AOP) describing ecdysone receptor agonism leading to incomplete ecdysis associated mortality was developed according to the OECD guideline and subjected to weight of evidence considerations by evolved Bradford Hill Criteria. This review proposes the first invertebrate ED AOP and may serve as a knowledge foundation for future environmental studies and AOP development.

  1. Human Exposure Pathways of Heavy Metals in a Lead-Zinc Mining Area, Jiangsu Province, China

    PubMed Central

    Qu, Chang-Sheng; Ma, Zong-Wei; Yang, Jin; Liu, Yang; Bi, Jun; Huang, Lei

    2012-01-01

    Heavy metal pollution is becoming a serious issue in developing countries such as China, and the public is increasingly aware of its adverse health impacts in recent years. We assessed the potential health risks in a lead-zinc mining area and attempted to identify the key exposure pathways. We evaluated the spatial distributions of personal exposure using indigenous exposure factors and field monitoring results of water, soil, food, and indoor and outdoor air samples. The risks posed by 10 metals and the contribution of inhalation, ingestion and dermal contact pathways to these risks were estimated. Human hair samples were also analyzed to indicate the exposure level in the human body. Our results show that heavy metal pollution may pose high potential health risks to local residents, especially in the village closest to the mine (V1), mainly due to Pb, Cd and Hg. Correspondingly, the residents in V1 had higher Pb (8.14 mg/kg) levels in hair than those in the other two villages. Most of the estimated risks came from soil, the intake of self-produced vegetables and indoor air inhalation. This study highlights the importance of site-specific multipathway health risk assessments in studying heavy-metal exposures in China. PMID:23152752

  2. Endosomal Signaling of Epidermal Growth Factor Receptor Stimulates Signal Transduction Pathways Leading to Cell Survival

    PubMed Central

    Wang, Yi; Pennock, Steven; Chen, Xinmei; Wang, Zhixiang

    2002-01-01

    In spite of intensified efforts to understand cell signaling from endosomes, there is no direct evidence demonstrating that endosomal signaling is sufficient to activate signal transduction pathways and no evidence to demonstrate that endosomal signaling is able to produce a biological outcome. The lack of breakthrough is due in part to the lack of means to generate endosomal signals without plasma membrane signaling. In this paper, we report the establishment of a system to specifically activate epidermal growth factor (EGF) receptor (EGFR) when it endocytoses into endosomes. We treated cells with EGF in the presence of AG-1478, a specific EGFR tyrosine kinase inhibitor, and monensin, which blocks the recycling of EGFR. This treatment led to the internalization of nonactivated EGF-EGFR complexes into endosomes. The endosome-associated EGFR was then activated by removing AG-1478 and monensin. During this procedure we did not observe any surface EGFR phosphorylation. We also achieved specific activation of endosome-associated EGFR without using monensin. By using this system, we provided original evidence demonstrating that (i) the endosome can serve as a nucleation site for the formation of signaling complexes, (ii) endosomal EGFR signaling is sufficient to activate the major signaling pathways leading to cell proliferation and survival, and (iii) endosomal EGFR signaling is sufficient to suppress apoptosis induced by serum withdrawal. PMID:12242303

  3. HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis.

    PubMed

    Deng, Lin; Chen, Ming; Tanaka, Motofumi; Ku, Yonson; Itoh, Tomoo; Shoji, Ikuo; Hotta, Hak

    2015-09-01

    We previously reported that hepatitis C virus (HCV) infection induces Bax-triggered, mitochondrion-mediated apoptosis by using the HCV J6/JFH1 strain and Huh-7.5 cells. However, it was still unclear how HCV-induced Bax activation. In this study, we showed that the HCV-induced activation and mitochondrial accumulation of Bax were significantly attenuated by treatment with a general antioxidant, N-acetyl cysteine (NAC), or a specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, with the result suggesting that the reactive oxygen species (ROS)/JNK signalling pathway is upstream of Bax activation in HCV-induced apoptosis. We also demonstrated that HCV infection transcriptionally activated the gene for the pro-apoptotic protein Bim and the protein expression of three major splice variants of Bim (BimEL, BimL and BimS). The HCV-induced increase in the Bim mRNA and protein levels was significantly counteracted by treatment with NAC or SP600125, suggesting that the ROS/JNK signalling pathway is involved in Bim upregulation. Moreover, HCV infection led to a marked accumulation of Bim on the mitochondria to facilitate its interaction with Bax. On the other hand, downregulation of Bim by siRNA (small interfering RNA) significantly prevented HCV-mediated activation of Bax and caspase 3. Taken together, these observations suggest that HCV-induced ROS/JNK signalling transcriptionally activates Bim expression, which leads to Bax activation and apoptosis induction.

  4. Hypertrophic and Dilated Cardiomyopathy: Four Decades of Basic Research on Muscle Lead to Potential Therapeutic Approaches to These Devastating Genetic Diseases

    PubMed Central

    Spudich, James A.

    2014-01-01

    With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases. PMID:24655499

  5. Hypertrophic and dilated cardiomyopathy: four decades of basic research on muscle lead to potential therapeutic approaches to these devastating genetic diseases.

    PubMed

    Spudich, James A

    2014-03-18

    With the advent of technologies to obtain the complete sequence of the human genome in a cost-effective manner, this decade and those to come will see an exponential increase in our understanding of the underlying genetics that lead to human disease. And where we have a deep understanding of the biochemical and biophysical basis of the machineries and pathways involved in those genetic changes, there are great hopes for the development of modern therapeutics that specifically target the actual machinery and pathways altered by individual mutations. Prime examples of such a genetic disease are those classes of hypertrophic and dilated cardiomyopathy that result from single amino-acid substitutions in one of several of the proteins that make up the cardiac sarcomere or from the truncation of myosin binding protein C. Hypertrophic cardiomyopathy alone affects ∼1 in 500 individuals, and it is the leading cause of sudden cardiac death in young adults. Here I describe approaches to understand the molecular basis of the alterations in power output that result from these mutations. Small molecules binding to the mutant sarcomeric protein complex should be able to mitigate the effects of hypertrophic and dilated cardiomyopathy mutations at their sources, leading to possible new therapeutic approaches for these genetic diseases.

  6. Association Between Clinical Pathways Leading to Medical Management and Prognosis in Patients With NSTEACS.

    PubMed

    Bueno, Héctor; Pocock, Stuart; Medina, Jesús; Danchin, Nicolas; Annemans, Lieven; Licour, Muriel; Gregson, John; Vega, Ana María; van de Werf, Frans

    2017-10-01

    A large proportion of patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) are initially selected for medical management (MM) and do not undergo coronary revascularization during or immediately after the index event. The aim of this study was to explore the clinical pathways leading to MM in NSTEACS patients and their influence on prognosis. Patient characteristics, pathways leading to MM, and 2-year outcomes were recorded in a prospective cohort of 5591 NSTEACS patients enrolled in 555 hospitals in 20 countries across Europe and Latin America. Cox models were used to assess the impact of hospital management on postdischarge mortality. Medical management was the selected strategy in 2306 (41.2%) patients, of whom 669 (29%) had significant coronary artery disease (CAD), 451 (19.6%) had nonsignificant disease, and 1186 (51.4%) did not undergo coronary angiography. Medically managed patients were older and had higher risk features than revascularized patients. Two-year mortality was higher in medically managed patients than in revascularized patients (11.0% vs 4.4%; P < .001), with higher mortality rates in patients who did not undergo angiography (14.6%) and in those with significant CAD (9.3%). Risk-adjusted mortality was highest for patients who did not undergo angiography (HR = 1.81; 95%CI, 1.23-2.65), or were not revascularized in the presence of significant CAD (HR = 1.90; 95%CI, 1.23-2.95) compared with revascularized patients. Medically managed NSTEACS patients represent a heterogeneous population with distinct risk profiles and outcomes. These differences should be considered when designing future studies in this population. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  7. Pigmentation, pleiotropy, and genetic pathways in humans and mice

    SciTech Connect

    Barsh, G.S.

    1995-10-01

    Some of the most striking polymorphisms in human populations affect the color of our eyes, hair, or skin. Despite some simple lessons from high school biology (blue eyes are recessive; brown are dominant), the genetic basis of such phenotypic variability has, for the most part, eluded Mendelian description. A logical place to search for the keys to understanding common variation in human pigmentation are genes in which defects cause uncommon conditions such as albinism or piebaldism. The area under this lamppost has recently gotten larger, with two articles, one in this issue of the Journal, that describe the map position for Hermansky-Pudlak syndrome (HPS) and with the recent cloning of a gene that causes X-linked ocular albinism (OA1). In addition, a series of three recent articles in Cell demonstrate (1) that defects in the gene encoding the endothelin B (ET{sub B}) receptor cause hypopigmentation and Hirschsprung disease in a Mennonite population and the mouse mutation piebald(s) and (2) that a defect in the edn3 gene, which encodes one of the ligands for the ET{sub B} receptor, causes the lethal spotting (ls) mouse mutation. 47 refs., 1 fig.

  8. Genetic pathways of 'de novo' colorectal carcinomas with reference to fetal-type glycogen phosphorylase positive foci.

    PubMed

    Shiomori, Kenji; Shimada, Shinya; Marutsuka, Takashi; Hatayama, Ichiro; Ogawa, Michio

    2003-01-01

    'De novo' carcinogenesis has been advocated besides 'adenoma carcinoma sequence' as another dominant pathway leading to the colorectal carcinoma. Our previous study demonstrated that brain (fetal)-type glycogen phosphorylase (BGP) positive foci in the transitional mucosa (BGP foci) have frequent p53 mutations and that the distribution of BGP foci has a close relationship with the location of 'de novo' carcinoma. The aims of the present study were to investigate further genetic alterations in the BGP foci and to clarify the mechanism of 'de novo' carcinogenesis. Twenty-eight colorectal carcinomas with invasion into submucosa or superficial muscularis propria without any adenoma component expressing immunoreactive p53 protein were selected from 168 resected specimens. Investigations of the p53, K-ras and APC mutations was performed in the BGP foci, BGP negative colorectal mucosa and 'de novo' carcinoma using PCR-SSCP and DNA squencing. In all 28 cases, immunoreactive BGP was positive in the carcinomas and the BGP foci were observed sporadically in the mucosa adjacent to the carcinoma. No K-ras mutation was observed in either carcinoma or BGP foci in any of the cases. Mutations of p53 and APC were 14 (50.0%) and 9 (32.1%) in 'de novo' carcinomas, and 11 (39.3%) and 1 (3.6%) in BGP foci, respectively. Both p53 and APC mutations were detected in 8 and 1, p53 mutation alone in 6 and 10, APC mutation alone in 1 and 0 out of 28 carcinomas and BGP positive foci, respectively. These results suggest that the BGP foci may play a very important role in the 'de novo' colorectal carcinogenesis from the frequent genetic alterations of p53, and that there may be two major pathways, i.e., the p53-APC pathway and the p53 alone pathway, from the chain of genetic alterations between BGP foci and 'de novo' carcinoma.

  9. Uracil salvage pathway in Lactobacillus plantarum: Transcription and genetic studies.

    PubMed

    Arsène-Ploetze, Florence; Nicoloff, Hervé; Kammerer, Benoît; Martinussen, Jan; Bringel, Françoise

    2006-07-01

    The uracil salvage pathway in Lactobacillus plantarum was demonstrated to be dependent on the upp-pyrP gene cluster. PyrP was the only high-affinity uracil transporter since a pyrP mutant no longer incorporated low concentrations of radioactively labeled uracil and had increased resistance to the toxic uracil analogue 5-fluorouracil. The upp gene encoded a uracil phosphoribosyltransferase (UPRT) enzyme catalyzing the conversion of uracil and 5-phosphoribosyl-alpha-1-pyrophosphate to UMP and pyrophosphate. Analysis of mutants revealed that UPRT is a major cell supplier of UMP synthesized from uracil provided by preformed nucleic acid degradation. In a mutant selection study, seven independent upp mutants were isolated and all were found to excrete low amounts of pyrimidines to the growth medium. Pyrimidine-dependent transcription regulation of the biosynthetic pyrimidine pyrR1-B-C-Aa1-Ab1-D-F-E operon was impaired in the upp mutants. Despite the fact that upp and pyrP are positioned next to each other on the chromosome, they are not cotranscribed. Whereas pyrP is expressed as a monocistronic message, the upp gene is part of the lp_2376-glyA-upp operon. The lp_2376 gene encodes a putative protein that belongs to the conserved protein family of translation modulators such as Sua5, YciO, and YrdC. The glyA gene encodes a putative hydroxymethyltransferase involved in C1 unit charging of tetrahydrofolate, which is required in the biosynthesis of thymidylate, pantothenate, and purines. Unlike upp transcription, pyrP transcription is regulated by exogenous pyrimidine availability, most likely by the same mechanism of transcription attenuation as that of the pyr operon.

  10. Uracil Salvage Pathway in Lactobacillus plantarum: Transcription and Genetic Studies

    PubMed Central

    Arsène-Ploetze, Florence; Nicoloff, Hervé; Kammerer, Benoît; Martinussen, Jan; Bringel, Françoise

    2006-01-01

    The uracil salvage pathway in Lactobacillus plantarum was demonstrated to be dependent on the upp-pyrP gene cluster. PyrP was the only high-affinity uracil transporter since a pyrP mutant no longer incorporated low concentrations of radioactively labeled uracil and had increased resistance to the toxic uracil analogue 5-fluorouracil. The upp gene encoded a uracil phosphoribosyltransferase (UPRT) enzyme catalyzing the conversion of uracil and 5-phosphoribosyl-α-1-pyrophosphate to UMP and pyrophosphate. Analysis of mutants revealed that UPRT is a major cell supplier of UMP synthesized from uracil provided by preformed nucleic acid degradation. In a mutant selection study, seven independent upp mutants were isolated and all were found to excrete low amounts of pyrimidines to the growth medium. Pyrimidine-dependent transcription regulation of the biosynthetic pyrimidine pyrR1-B-C-Aa1-Ab1-D-F-E operon was impaired in the upp mutants. Despite the fact that upp and pyrP are positioned next to each other on the chromosome, they are not cotranscribed. Whereas pyrP is expressed as a monocistronic message, the upp gene is part of the lp_2376-glyA-upp operon. The lp_2376 gene encodes a putative protein that belongs to the conserved protein family of translation modulators such as Sua5, YciO, and YrdC. The glyA gene encodes a putative hydroxymethyltransferase involved in C1 unit charging of tetrahydrofolate, which is required in the biosynthesis of thymidylate, pantothenate, and purines. Unlike upp transcription, pyrP transcription is regulated by exogenous pyrimidine availability, most likely by the same mechanism of transcription attenuation as that of the pyr operon. PMID:16788187

  11. Pathways to Childhood Depressive Symptoms: The Role of Social, Cognitive, and Genetic Risk Factors

    ERIC Educational Resources Information Center

    Lau, Jennifer Y. F.; Rijsdijk, Fruhling; Gregory, Alice M.; McGuffin, Peter; Eley, Thalia C.

    2007-01-01

    Childhood depressive conditions have been explored from multiple theoretical approaches but with few empirical attempts to address the interrelationships among these different domains and their combined effects. In the present study, the authors examined different pathways through which social, cognitive, and genetic risk factors may be expressed…

  12. Pathways to Childhood Depressive Symptoms: The Role of Social, Cognitive, and Genetic Risk Factors

    ERIC Educational Resources Information Center

    Lau, Jennifer Y. F.; Rijsdijk, Fruhling; Gregory, Alice M.; McGuffin, Peter; Eley, Thalia C.

    2007-01-01

    Childhood depressive conditions have been explored from multiple theoretical approaches but with few empirical attempts to address the interrelationships among these different domains and their combined effects. In the present study, the authors examined different pathways through which social, cognitive, and genetic risk factors may be expressed…

  13. Genetic Identification of an Enzymatic Se(VI) Reduction Pathway

    NASA Astrophysics Data System (ADS)

    Yee, N.; Kobayashi, D. Y.

    2006-12-01

    Enterobacter cloacae is a biofilm-forming organism that colonizes the subterranean portions of plants. Because of its ability to catalyze the reduction of selenium oxyanions, this bacterium plays an important role in Se(0) biomineralization and Se cycling in soils. Identification of the genes that regulate selenate reductase activity is needed to elucidate the mechanisms employed by this organism to reduce Se(VI). However, the genes in E. cloacae involved in selenium reduction are currently unknown. In this study, transposon mutagenesis and direct cloning techniques were used to identify genetic regions in E. cloacae SLD1a-1 associated with selenate reductase activity. The mini-Tn5 transposon system was used to produce mutants that have lost the ability to reduce selenate. E. cloacae mutants and genomic library clones heterologously expressed in E. coli S17-1 were screened for activity on LB agar supplemented with sodium selenate. The rate of selenate reduction by the clones was measured in liquid minimal media, and the Se(0) minerals formed by the clones were examined using EXAFS, TEM, and XRD. The transposon mutagenesis experiments revealed that mutation of menaquinone biosynthesis genes inhibits selenate reduction. The direct cloning experiments showed that heterologous expression of the global anaerobic regulatory gene fnr from Enterobacter cloacae in the non Se-reducing strain E. coli S17-1 activated selenate reductase activity and the ability to precipitate Se(0) particles. Se(VI) reduction by E. coli S17-1 containing the fnr gene occurred at similar rates as E. cloacae and produced elemental selenium particles with identical morphologies and short range atomic order. These findings indicate that Se(VI) reduction by facultative anaerobes is regulated by anaerobic electron carriers and oxygen sensing transcription factors.

  14. THE ADVERSE OUTCOME PATHWAY (AOP) FRAMEWORK: A FRAMEWORK FOR ORGANIZING BIOLOGICAL KNOWLEDGE LEADING TO HEALTH RISKS.

    EPA Science Inventory

    An Adverse Outcome Pathway (AOP) represents the organization of current and newly acquired knowledge of biological pathways. These pathways contain a series of nodes (Key Events, KEs) that when sufficiently altered influence the next node on the pathway, beginning from an Molecul...

  15. Structured parenting of toddlers at high versus low genetic risk: two pathways to child problems.

    PubMed

    Leve, Leslie D; Harold, Gordon T; Ge, Xiaojia; Neiderhiser, Jenae M; Shaw, Daniel; Scaramella, Laura V; Reiss, David

    2009-11-01

    Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for psychopathology. The sample included 290 linked sets of adoptive families and birth mothers and 95 linked birth fathers. Genetic risk was assessed via birth mother and birth father psychopathology (anxiety, depression, antisociality, and drug use). Structured parenting was assessed via microsocial coding of adoptive mothers' behavior during a cleanup task. Toddler behavior problems were assessed with the Child Behavior Checklist. Controlling for temperamental risk at 9 months, there was an interaction between birth mother psychopathology and adoptive mothers' parenting on toddler behavior problems at 18 months. The interaction indicated two pathways to child problems: structured parenting was beneficial for toddlers at high genetic risk but was related to behavior problems for toddlers at low genetic risk. This crossover interaction pattern was replicated with birth father psychopathology as the index of genetic risk. The effects of structured parenting on toddler behavior problems varied as a function of genetic risk. Children at genetic risk might benefit from parenting interventions during toddlerhood that enhance structured parenting.

  16. Differing Patterns of Selection and Geospatial Genetic Diversity within Two Leading Plasmodium vivax Candidate Vaccine Antigens

    PubMed Central

    Parobek, Christian M.; Bailey, Jeffrey A.; Hathaway, Nicholas J.; Socheat, Duong; Rogers, William O.; Juliano, Jonathan J.

    2014-01-01

    Although Plasmodium vivax is a leading cause of malaria around the world, only a handful of vivax antigens are being studied for vaccine development. Here, we investigated genetic signatures of selection and geospatial genetic diversity of two leading vivax vaccine antigens – Plasmodium vivax merozoite surface protein 1 (pvmsp-1) and Plasmodium vivax circumsporozoite protein (pvcsp). Using scalable next-generation sequencing, we deep-sequenced amplicons of the 42 kDa region of pvmsp-1 (n = 44) and the complete gene of pvcsp (n = 47) from Cambodian isolates. These sequences were then compared with global parasite populations obtained from GenBank. Using a combination of statistical and phylogenetic methods to assess for selection and population structure, we found strong evidence of balancing selection in the 42 kDa region of pvmsp-1, which varied significantly over the length of the gene, consistent with immune-mediated selection. In pvcsp, the highly variable central repeat region also showed patterns consistent with immune selection, which were lacking outside the repeat. The patterns of selection seen in both genes differed from their P. falciparum orthologs. In addition, we found that, similar to merozoite antigens from P. falciparum malaria, genetic diversity of pvmsp-1 sequences showed no geographic clustering, while the non-merozoite antigen, pvcsp, showed strong geographic clustering. These findings suggest that while immune selection may act on both vivax vaccine candidate antigens, the geographic distribution of genetic variability differs greatly between these two genes. The selective forces driving this diversification could lead to antigen escape and vaccine failure. Better understanding the geographic distribution of genetic variability in vaccine candidate antigens will be key to designing and implementing efficacious vaccines. PMID:24743266

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

    PubMed Central

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

    2015-01-01

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

  18. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases.

    PubMed

    Stamp, Lisa K; Roberts, Rebecca L

    2011-10-01

    Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.

  19. Lead

    MedlinePlus

    ... are approximately half a million U.S. children ages 1-5 with blood lead levels above 5 micrograms per deciliter (µg/dL), the reference level at which CDC recommends public health actions be initiated. No safe blood lead level in children has been ...

  20. Codon sextets with leading role of serine create "ideal" symmetry classification scheme of the genetic code.

    PubMed

    Rosandić, Marija; Paar, Vladimir

    2014-06-10

    The standard classification scheme of the genetic code is organized for alphabetic ordering of nucleotides. Here we introduce the new, "ideal" classification scheme in compact form, for the first time generated by codon sextets encoding Ser, Arg and Leu amino acids. The new scheme creates the known purine/pyrimidine, codon-anticodon, and amino/keto type symmetries and a novel A+U rich/C+G rich symmetry. This scheme is built from "leading" and "nonleading" groups of 32 codons each. In the ensuing 4 × 16 scheme, based on trinucleotide quadruplets, Ser has a central role as initial generator. Six codons encoding Ser and six encoding Arg extend continuously along a linear array in the "leading" group, and together with four of six Leu codons uniquely define construction of the "leading" group. The remaining two Leu codons enable construction of the "nonleading" group. The "ideal" genetic code suggests the evolution of genetic code with serine as an initiator. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Genetic evidence for common pathways in human age-related diseases

    PubMed Central

    Johnson, Simon C; Dong, Xiao; Vijg, Jan; Suh, Yousin

    2015-01-01

    Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, translation, proteostasis, stress responses, and genome maintenance. Taking advantage of the vast amount of genetic data from the GWAS, our findings provide the first direct evidence that conserved pathways of aging simultaneously influence multiple age-related diseases in humans as has been demonstrated in model organisms. PMID:26077337

  2. Genetic evidence for common pathways in human age-related diseases.

    PubMed

    Johnson, Simon C; Dong, Xiao; Vijg, Jan; Suh, Yousin

    2015-10-01

    Aging is the single largest risk factor for chronic disease. Studies in model organisms have identified conserved pathways that modulate aging rate and the onset and progression of multiple age-related diseases, suggesting that common pathways of aging may influence age-related diseases in humans as well. To determine whether there is genetic evidence supporting the notion of common pathways underlying age-related diseases, we analyzed the genes and pathways found to be associated with five major categories of age-related disease using a total of 410 genomewide association studies (GWAS). While only a small number of genes are shared among all five disease categories, those found in at least three of the five major age-related disease categories are highly enriched for apoliprotein metabolism genes. We found that a more substantial number of gene ontology (GO) terms are shared among the 5 age-related disease categories and shared GO terms include canonical aging pathways identified in model organisms, such as nutrient-sensing signaling, translation, proteostasis, stress responses, and genome maintenance. Taking advantage of the vast amount of genetic data from the GWAS, our findings provide the first direct evidence that conserved pathways of aging simultaneously influence multiple age-related diseases in humans as has been demonstrated in model organisms. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  3. Type 2 Diabetes Mellitus: New Genetic Insights will Lead to New Therapeutics

    PubMed Central

    Wolfs, M.G.M; Hofker, M.H; Wijmenga, C; van Haeften, T.W.

    2009-01-01

    Type 2 diabetes is a disorder of dysregulated glucose homeostasis. Normal glucose homeostasis is a complex process involving several interacting mechanisms, such as insulin secretion, insulin sensitivity, glucose production, and glucose uptake. The dysregulation of one or more of these mechanisms due to environmental and/or genetic factors, can lead to a defective glucose homeostasis. Hyperglycemia is managed by augmenting insulin secretion and/or interaction with hepatic glucose production, as well as by decreasing dietary caloric intake and raising glucose metabolism through exercise. Although these interventions can delay disease progression and correct blood glucose levels, they are not able to cure the disease or stop its progression entirely. Better management of type 2 diabetes is sorely needed. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with type 2 diabetes through genome-wide association studies (GWAS). So far, genetic variants on 19 loci have been identified. Most of these loci contain or lie close to genes that were not previously linked to diabetes and they may thus harbor targets for new drugs. It is also hoped that further genetic studies will pave the way for predictive genetic screening. The newly discovered type 2 diabetes genes can be classified based on their presumed molecular function, and we discuss the relation between these gene classes and current treatments. We go on to consider whether the new genes provide opportunities for developing alternative drug therapies. PMID:19794883

  4. Applications of genetically-encoded biosensors for the construction and control of biosynthetic pathways.

    PubMed

    Michener, Joshua K; Thodey, Kate; Liang, Joe C; Smolke, Christina D

    2012-05-01

    Cells are filled with biosensors, molecular systems that measure the state of the cell and respond by regulating host processes. In much the same way that an engineer would monitor a chemical reactor, the cell uses these sensors to monitor changing intracellular environments and produce consistent behavior despite the variable environment. While natural systems derive a clear benefit from pathway regulation, past research efforts in engineering cellular metabolism have focused on introducing new pathways and removing existing pathway regulation. Synthetic biology is a rapidly growing field that focuses on the development of new tools that support the design, construction, and optimization of biological systems. Recent advances have been made in the design of genetically-encoded biosensors and the application of this class of molecular tools for optimizing and regulating heterologous pathways. Biosensors to cellular metabolites can be taken directly from natural systems, engineered from natural sensors, or constructed entirely in vitro. When linked to reporters, such as antibiotic resistance markers, these metabolite sensors can be used to report on pathway productivity, allowing high-throughput screening for pathway optimization. Future directions will focus on the application of biosensors to introduce feedback control into metabolic pathways, providing dynamic control strategies to increase the efficient use of cellular resources and pathway reliability.

  5. A Systems Genetics Approach Provides a Bridge from Discovered Genetic Variants to Biological Pathways in Rheumatoid Arthritis

    PubMed Central

    Nakaoka, Hirofumi; Cui, Tailin; Tajima, Atsushi; Oka, Akira; Mitsunaga, Shigeki; Kashiwase, Koichi; Homma, Yasuhiko; Sato, Shinji; Suzuki, Yasuo; Inoko, Hidetoshi; Inoue, Ituro

    2011-01-01

    Genome-wide association studies (GWAS) have yielded novel genetic loci underlying common diseases. We propose a systems genetics approach to utilize these discoveries for better understanding of the genetic architecture of rheumatoid arthritis (RA). Current evidence of genetic associations with RA was sought through PubMed and the NHGRI GWAS catalog. The associations of 15 single nucleotide polymorphisms and HLA-DRB1 alleles were confirmed in 1,287 cases and 1,500 controls of Japanese subjects. Among these, HLA-DRB1 alleles and eight SNPs showed significant associations and all but one of the variants had the same direction of effect as identified in the previous studies, indicating that the genetic risk factors underlying RA are shared across populations. By receiver operating characteristic curve analysis, the area under the curve (AUC) for the genetic risk score based on the selected variants was 68.4%. For seropositive RA patients only, the AUC improved to 70.9%, indicating good but suboptimal predictive ability. A simulation study shows that more than 200 additional loci with similar effect size as recent GWAS findings or 20 rare variants with intermediate effects are needed to achieve AUC = 80.0%. We performed the random walk with restart (RWR) algorithm to prioritize genes for future mapping studies. The performance of the algorithm was confirmed by leave-one-out cross-validation. The RWR algorithm pointed to ZAP70 in the first rank, in which mutation causes RA-like autoimmune arthritis in mice. By applying the hierarchical clustering method to a subnetwork comprising RA-associated genes and top-ranked genes by the RWR, we found three functional modules relevant to RA etiology: “leukocyte activation and differentiation”, “pattern-recognition receptor signaling pathway”, and “chemokines and their receptors”. These results suggest that the systems genetics approach is useful to find directions of future mapping strategies to illuminate

  6. A Hypothesis for Using Pathway Genetic Load Analysis for Understanding Complex Outcomes in Bilirubin Encephalopathy

    PubMed Central

    Riordan, Sean M.; Bittel, Douglas C.; Le Pichon, Jean-Baptiste; Gazzin, Silvia; Tiribelli, Claudio; Watchko, Jon F.; Wennberg, Richard P.; Shapiro, Steven M.

    2016-01-01

    Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60–80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. The lack of a monogenetic source for this risk of bilirubin neurotoxicity suggests that disease progression is dependent upon an overall decrease in the functionality of one or more essential genetically controlled metabolic pathways. In other words, a “load” is placed on key pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load (PGL) that affects the response to a specific insult has been previously reported as a PGL score. We hypothesize that the PGL score can be used to investigate whether increased susceptibility to bilirubin-induced CNS damage in neonates is due to a mutational load being placed on key genetic pathways important to the central nervous system's response to bilirubin neurotoxicity. We propose a modification of the PGL score method that replaces the use of a canonical pathway with custom gene lists organized into three tiers with descending levels of evidence combined with the utilization of single nucleotide polymorphism (SNP) causality prediction methods. The PGL score has the potential to explain the genetic background of complex bilirubin induced neurological disorders (BIND) such as kernicterus and could be the key to understanding ranges of outcome severity

  7. A Hypothesis for Using Pathway Genetic Load Analysis for Understanding Complex Outcomes in Bilirubin Encephalopathy.

    PubMed

    Riordan, Sean M; Bittel, Douglas C; Le Pichon, Jean-Baptiste; Gazzin, Silvia; Tiribelli, Claudio; Watchko, Jon F; Wennberg, Richard P; Shapiro, Steven M

    2016-01-01

    Genetic-based susceptibility to bilirubin neurotoxicity and chronic bilirubin encephalopathy (kernicterus) is still poorly understood. Neonatal jaundice affects 60-80% of newborns, and considerable effort goes into preventing this relatively benign condition from escalating into the development of kernicterus making the incidence of this potentially devastating condition very rare in more developed countries. The current understanding of the genetic background of kernicterus is largely comprised of mutations related to alterations of bilirubin production, elimination, or both. Less is known about mutations that may predispose or protect against CNS bilirubin neurotoxicity. The lack of a monogenetic source for this risk of bilirubin neurotoxicity suggests that disease progression is dependent upon an overall decrease in the functionality of one or more essential genetically controlled metabolic pathways. In other words, a "load" is placed on key pathways in the form of multiple genetic variants that combine to create a vulnerable phenotype. The idea of epistatic interactions creating a pathway genetic load (PGL) that affects the response to a specific insult has been previously reported as a PGL score. We hypothesize that the PGL score can be used to investigate whether increased susceptibility to bilirubin-induced CNS damage in neonates is due to a mutational load being placed on key genetic pathways important to the central nervous system's response to bilirubin neurotoxicity. We propose a modification of the PGL score method that replaces the use of a canonical pathway with custom gene lists organized into three tiers with descending levels of evidence combined with the utilization of single nucleotide polymorphism (SNP) causality prediction methods. The PGL score has the potential to explain the genetic background of complex bilirubin induced neurological disorders (BIND) such as kernicterus and could be the key to understanding ranges of outcome severity in

  8. Determination of informed choice and pathways leading to selection of the Environmental Studies major

    NASA Astrophysics Data System (ADS)

    Dierberger, Betsy S.

    The reasons why students select the Environmental Studies (ES) major at the University of Nebraska were investigated. A survey was used to determine factors of influence and career awareness as measures for making an informed choice in selection of a major. In addition, pathways of selection of the ES major were determined. Thirty-five students with ES majors and 14 faculty advisors completed the survey. Seven students participated in interviews. Student interviews were conducted to determine the "life-world" of the students during the decision making process leading to the selection of major. Interest in environmental issues, the challenge of solving environmental problems and a desire to make a difference in the environment were factors identified as positively influencing selection of this major. Environmental career attributes which influenced choice of major were variety of tasks and use of science skills. Faculty advisor perception of careers and advisor understanding of why students select the ES major were explored. Faculty advisors recommended selection of the ES major to students who demonstrated a clear interest in natural resources. Faculty advisors and students selected career categories appropriate to the ES curriculum indicating an awareness of career and job requirements. Informed choice was defined as evidence of student self-knowledge of interests, abilities and aptitudes and evidence of awareness of career opportunities in environmentally related areas. Students expressed self- knowledge of factors influential in major selection and career awareness. Therefore, the students did make informed decisions for selection of the ES major. Interview themes suggested three pathways for the selection of the ES major: (1) Direct Choice, (2) Focused Choice, and (3) Delayed Choice. Direct Choice occurs Men a student with ES interest selects the major and enrolls as a new student. Focused Choice occurs when students have life or school experiences that narrow

  9. Physician Scientist Research Pathway Leading to Certification by the American Board of Pathology.

    PubMed

    Weiss, Sharon W; Johnson, Rebecca L

    2016-01-01

    In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway. This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees.

  10. Signal transduction pathways leading to the production of IL-8 by human monocytes are differentially regulated by dexamethasone.

    PubMed Central

    Anttila, H S; Reitamo, S; Ceska, M; Hurme, M

    1992-01-01

    Previous studies have shown that IL-8 gene expression is enhanced by various stimuli, which induce different signal transduction pathways. A lipopolysaccharide (LPS)-induced pathway has been reported to be inhibited by glucocorticoids in monocytes. We have now examined the effect of dexamethasone on the LPS-induced and other signal transduction pathways leading to the production of IL-8 by human monocytes. Dexamethasone inhibited the production of IL-8 stimulated with a cyclic adenosine monophosphate analog or LPS. In contrast, dexamethasone had no significant effect on a phorbol ester (PMA)-stimulated IL-8 production. These results suggest that the signal transduction pathways leading to the production of IL-8 by human monocytes are differentially regulated by dexamethasone. PMID:1325308

  11. The Protective Effect of Gangliosides on Lead (Pb)-Induced Neurotoxicity Is Mediated by Autophagic Pathways

    PubMed Central

    Meng, Hongtao; Wang, Lan; He, Junhong; Wang, Zhufeng

    2016-01-01

    Lead (Pb) is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS) from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions. PMID:27023584

  12. The Protective Effect of Gangliosides on Lead (Pb)-Induced Neurotoxicity Is Mediated by Autophagic Pathways.

    PubMed

    Meng, Hongtao; Wang, Lan; He, Junhong; Wang, Zhufeng

    2016-03-25

    Lead (Pb) is a ubiquitous environmental and industrial pollutant and can affect intelligence development and the learning ability and memory of children. Therefore, necessary measures should be taken to protect the central nervous system (CNS) from Pb toxicity. Gangliosides are sialic acid-containing glycosphingolipids that are constituents of mammalian cell membranes and are more abundantly expressed in the CNS. Studies have shown that gangliosides constitute a useful tool in the attempt to promote functional recovery of CNS and can reverse Pb-induced impairments of synaptic plasticity in rats. However, the detailed mechanisms have yet to be fully understood. In our present study, we tried to investigate the role of gangliosides in Pb-induced injury in hippocampus neurons and to further confirm the detailed mechanism. Our results show that Pb-induced injuries in the spatial reference memory were associated with a reduction of cell viability and cell apoptosis, and treatment with gangliosides markedly ameliorated the Pb-induced injury by inhibition of apoptosis action. Gangliosides further attenuated Pb-induced the abnormal autophagic process by regulation of mTOR pathways. In summary, our study establishes the efficacy of gangliosides as neuroprotective agents and provides a strong rationale for further studies on the underlying mechanisms of their neuroprotective functions.

  13. Thermal fluctuations of immature SOD1 lead to separate folding and misfolding pathways

    PubMed Central

    Sekhar, Ashok; Rumfeldt, Jessica AO; Broom, Helen R; Doyle, Colleen M; Bouvignies, Guillaume; Meiering, Elizabeth M; Kay, Lewis E

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving cytotoxic conformations of Cu, Zn superoxide dismutase (SOD1). A major challenge in understanding ALS disease pathology has been the identification and atomic-level characterization of these conformers. Here, we use a combination of NMR methods to detect four distinct sparsely populated and transiently formed thermally accessible conformers in equilibrium with the native state of immature SOD1 (apoSOD12SH). Structural models of two of these establish that they possess features present in the mature dimeric protein. In contrast, the other two are non-native oligomers in which the native dimer interface and the electrostatic loop mediate the formation of aberrant intermolecular interactions. Our results show that apoSOD12SH has a rugged free energy landscape that codes for distinct kinetic pathways leading to either maturation or non-native association and provide a starting point for a detailed atomic-level understanding of the mechanisms of SOD1 oligomerization. DOI: http://dx.doi.org/10.7554/eLife.07296.001 PMID:26099300

  14. Genistein alleviates lead-induced neurotoxicity in vitro and in vivo: Involvement of multiple signaling pathways.

    PubMed

    Su, Peng; Zhang, Jianbin; Wang, Siwang; Aschner, Michael; Cao, Zipeng; Zhao, Fang; Wang, Diya; Chen, Jiangyuan; Luo, Wenjing

    2016-03-01

    Lead (Pb) is a ubiquitous environmental and industrial pollutant. It induces neurotoxicity and cell death by disrupting the pro- and anti-oxidative balance; however, the mechanisms of its toxicity have yet to be fully understood. The soy-derived isoflavonoid, genistein (GEN), was reported to possess neuroprotective and antioxidative properties. The present study investigated the molecular mechanisms of Pb-induced neurotoxicity in vivo and in vitro, addressing the efficacy of GEN in protecting against Pb-induced toxicity. Pb exposure was associated with reduction of cell viability and cell apoptosis, concomitant with reactive oxygen species (ROS) generation in vitro, and pre-treatment with GEN markedly ameliorated the Pb-induced oxidative injury by increasing the expression of key antioxidant enzymes and the antioxidant transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Next, PKC-α activation was found after Pb exposure in vitro and pretreatment with GEN attenuated Pb-induced ROS generation by PKC-α inhibition. MAPK-NF-κB activation triggered by Pb was also inhibited by GEN. In summary, our study establishes that GEN alleviates Pb-induced impairment in spatial memory, and reduces cell apoptosis caused by Pb exposure and GEN protects neurons from Pb-induced neurotoxicity by downstream activation of antioxidant and anti-apoptotic pathways via regulation of Nrf2 and MAPK-NF-κB signaling.

  15. Genetics pathway-based imaging approaches in Chinese Han population with Alzheimer's disease risk.

    PubMed

    Bai, Feng; Liao, Wei; Yue, Chunxian; Pu, Mengjia; Shi, Yongmei; Yu, Hui; Yuan, Yonggui; Geng, Leiyu; Zhang, Zhijun

    2016-01-01

    The tau hypothesis has been raised with regard to the pathophysiology of Alzheimer's disease (AD). Mild cognitive impairment (MCI) is associated with a high risk for developing AD. However, no study has directly examined the brain topological alterations based on combined effects of tau protein pathway genes in MCI population. Forty-three patients with MCI and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) in Chinese Han, and a tau protein pathway-based imaging approaches (7 candidate genes: 17 SNPs) were used to investigate changes in the topological organisation of brain activation associated with MCI. Impaired regional activation is related to tau protein pathway genes (5/7 candidate genes) in patients with MCI and likely in topologically convergent and divergent functional alterations patterns associated with genes, and combined effects of tau protein pathway genes disrupt the topological architecture of cortico-cerebellar loops. The associations between the loops and behaviours further suggest that tau protein pathway genes do play a significant role in non-episodic memory impairment. Tau pathway-based imaging approaches might strengthen the credibility in imaging genetic associations and generate pathway frameworks that might provide powerful new insights into the neural mechanisms that underlie MCI.

  16. Genetic demography at the leading edge of the distribution of a rabies virus vector.

    PubMed

    Piaggio, Antoinette J; Russell, Amy L; Osorio, Ignacio A; Jiménez Ramírez, Alejandro; Fischer, Justin W; Neuwald, Jennifer L; Tibbels, Annie E; Lecuona, Luis; McCracken, Gary F

    2017-07-01

    The common vampire bat, Desmodus rotundus, ranges from South America into northern Mexico in North America. This sanguivorous species of bat feeds primarily on medium to large-sized mammals and is known to rely on livestock as primary prey. Each year, there are hotspot areas of D. rotundus-specific rabies virus outbreaks that lead to the deaths of livestock and economic losses. Based on incidental captures in our study area, which is an area of high cattle mortality from D. rotundus transmitted rabies, it appears that D. rotundus are being caught regularly in areas and elevations where they previously were thought to be uncommon. Our goal was to investigate demographic processes and genetic diversity at the north eastern edge of the range of D. rotundus in Mexico. We generated control region sequences (441 bp) and 12-locus microsatellite genotypes for 602 individuals of D. rotundus. These data were analyzed using network analyses, Bayesian clustering approaches, and standard population genetic statistical analyses. Our results demonstrate panmixia across our sampling area with low genetic diversity, low population differentiation, loss of intermediate frequency alleles at microsatellite loci, and very low mtDNA haplotype diversity with all haplotypes being very closely related. Our study also revealed strong signals of population expansion. These results follow predictions from the leading-edge model of expanding populations and supports conclusions from another study that climate change may allow this species to find suitable habitat within the U.S. border.

  17. Pathway-Driven Approaches of Interaction between Oxidative Balance and Genetic Polymorphism on Metabolic Syndrome

    PubMed Central

    2017-01-01

    Despite evidences of association between basic redox biology and metabolic syndrome (MetS), few studies have evaluated indices that account for multiple oxidative effectors for MetS. Oxidative balance score (OBS) has indicated the role of oxidative stress in chronic disease pathophysiology. In this study, we evaluated OBS as an oxidative balance indicator for estimating risk of MetS with 6414 study participants. OBS is a multiple exogenous factor score for development of disease; therefore, we investigated interplay between oxidative balance and genetic variation for development of MetS focusing on biological pathways by using gene-set-enrichment analysis. As a result, participants in the highest quartile of OBS were less likely to be at risk for MetS than those in the lowest quartile. In addition, persons in the highest quartile of OBS had the lowest level of inflammatory markers including C-reactive protein and WBC. With GWAS-based pathway analysis, we found that VEGF signaling pathway, glutathione metabolism, and Rac-1 pathway were significantly enriched biological pathways involved with OBS on MetS. These findings suggested that mechanism of angiogenesis, oxidative stress, and inflammation can be involved in interaction between OBS and genetic variation on risk of MetS. PMID:28191276

  18. Versatile genetic assembly system (VEGAS) to assemble pathways for expression in S. cerevisiae.

    PubMed

    Mitchell, Leslie A; Chuang, James; Agmon, Neta; Khunsriraksakul, Chachrit; Phillips, Nick A; Cai, Yizhi; Truong, David M; Veerakumar, Ashan; Wang, Yuxuan; Mayorga, María; Blomquist, Paul; Sadda, Praneeth; Trueheart, Joshua; Boeke, Jef D

    2015-07-27

    We have developed a method for assembling genetic pathways for expression in Saccharomyces cerevisiae. Our pathway assembly method, called VEGAS (Versatile genetic assembly system), exploits the native capacity of S. cerevisiae to perform homologous recombination and efficiently join sequences with terminal homology. In the VEGAS workflow, terminal homology between adjacent pathway genes and the assembly vector is encoded by 'VEGAS adapter' (VA) sequences, which are orthogonal in sequence with respect to the yeast genome. Prior to pathway assembly by VEGAS in S. cerevisiae, each gene is assigned an appropriate pair of VAs and assembled using a previously described technique called yeast Golden Gate (yGG). Here we describe the application of yGG specifically to building transcription units for VEGAS assembly as well as the VEGAS methodology. We demonstrate the assembly of four-, five- and six-gene pathways by VEGAS to generate S. cerevisiae cells synthesizing β-carotene and violacein. Moreover, we demonstrate the capacity of yGG coupled to VEGAS for combinatorial assembly. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  19. Versatile genetic assembly system (VEGAS) to assemble pathways for expression in S. cerevisiae

    PubMed Central

    Mitchell, Leslie A.; Chuang, James; Agmon, Neta; Khunsriraksakul, Chachrit; Phillips, Nick A.; Cai, Yizhi; Truong, David M.; Veerakumar, Ashan; Wang, Yuxuan; Mayorga, María; Blomquist, Paul; Sadda, Praneeth; Trueheart, Joshua; Boeke, Jef D.

    2015-01-01

    We have developed a method for assembling genetic pathways for expression in Saccharomyces cerevisiae. Our pathway assembly method, called VEGAS (Versatile genetic assembly system), exploits the native capacity of S. cerevisiae to perform homologous recombination and efficiently join sequences with terminal homology. In the VEGAS workflow, terminal homology between adjacent pathway genes and the assembly vector is encoded by ‘VEGAS adapter’ (VA) sequences, which are orthogonal in sequence with respect to the yeast genome. Prior to pathway assembly by VEGAS in S. cerevisiae, each gene is assigned an appropriate pair of VAs and assembled using a previously described technique called yeast Golden Gate (yGG). Here we describe the application of yGG specifically to building transcription units for VEGAS assembly as well as the VEGAS methodology. We demonstrate the assembly of four-, five- and six-gene pathways by VEGAS to generate S. cerevisiae cells synthesizing β-carotene and violacein. Moreover, we demonstrate the capacity of yGG coupled to VEGAS for combinatorial assembly. PMID:25956652

  20. Building strong relationships between conservation genetics and primary industry leads to mutually beneficial genomic advances.

    PubMed

    Galla, Stephanie J; Buckley, Thomas R; Elshire, Rob; Hale, Marie L; Knapp, Michael; McCallum, John; Moraga, Roger; Santure, Anna W; Wilcox, Phillip; Steeves, Tammy E

    2016-11-01

    Several reviews in the past decade have heralded the benefits of embracing high-throughput sequencing technologies to inform conservation policy and the management of threatened species, but few have offered practical advice on how to expedite the transition from conservation genetics to conservation genomics. Here, we argue that an effective and efficient way to navigate this transition is to capitalize on emerging synergies between conservation genetics and primary industry (e.g., agriculture, fisheries, forestry and horticulture). Here, we demonstrate how building strong relationships between conservation geneticists and primary industry scientists is leading to mutually-beneficial outcomes for both disciplines. Based on our collective experience as collaborative New Zealand-based scientists, we also provide insight for forging these cross-sector relationships. © 2016 The Authors. Molecular Ecology Published by John Wiley & Sons Ltd.

  1. A Genetic and Pharmacological Analysis of Isoprenoid Pathway by LC-MS/MS in Fission Yeast

    PubMed Central

    Takami, Tomonori; Fang, Yue; Zhou, Xin; Jaiseng, Wurentuya; Ma, Yan; Kuno, Takayoshi

    2012-01-01

    Currently, statins are the only drugs acting on the mammalian isoprenoid pathway. The mammalian genes in this pathway are not easily amenable to genetic manipulation. Thus, it is difficult to study the effects of the inhibition of various enzymes on the intermediate and final products in the isoprenoid pathway. In fission yeast, antifungal compounds such as azoles and terbinafine are available as inhibitors of the pathway in addition to statins, and various isoprenoid pathway mutants are also available. Here in these mutants, treated with statins or antifungals, we quantified the final and intermediate products of the fission yeast isoprenoid pathway using liquid chromatography-mass spectrometry/mass spectrometry. In hmg1-1, a mutant of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), ergosterol (a final sterol product), and squalene (an intermediate pathway product), were decreased to approximately 80% and 10%, respectively, compared with that of wild-type cells. Consistently in wild-type cells, pravastatin, an HMGR inhibitor decreased ergosterol and squalene, and the effect was more pronounced on squalene. In hmg1-1 mutant and in wild-type cells treated with pravastatin, the decrease in the levels of farnesyl pyrophosphate and geranylgeranyl pyrophosphate respectively was larger than that of ergosterol but was smaller than that of squalene. In Δerg6 or Δsts1 cells, mutants of the genes involved in the last step of the pathway, ergosterol was not detected, and the changes of intermediate product levels were distinct from that of hmg1-1 mutant. Notably, in wild-type cells miconazole and terbinafine only slightly decreased ergosterol level. Altogether, these studies suggest that the pleiotropic phenotypes caused by the hmg1-1 mutation and pravastatin might be due to decreased levels of isoprenoid pyrophosphates or other isoprenoid pathway intermediate products rather than due to a decreased ergosterol level. PMID:23145048

  2. Genetic variants in IL-6/JAK/STAT3 pathway and the risk of CRC.

    PubMed

    Wang, Shuwei; Zhang, Weidong

    2016-05-01

    Interleukin (IL)-6 and the downstream Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway have previously been reported to be important in the development of colorectal cancer (CRC), and several studies have shown the relationship between the polymorphisms of related genes in this pathway with the risk of CRC. However, the findings of these related studies are inconsistent. Moreover, there has no systematic review and meta-analysis to evaluate the relationship between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility. Hence, we conducted a meta-analysis to explore the relationship between polymorphisms in IL-6/JAK/STAT3 pathway genes and CRC risk. Eighteen eligible studies with a total of 13,795 CRC cases and 18,043 controls were identified by searching PubMed, Web of Science, Embase, and the Cochrane Library databases for the period up to September 15, 2015. Odds ratios (ORs) and their 95 % confidence intervals (CIs) were used to calculate the strength of the association. Our results indicated that IL-6 genetic variants in allele additive model (OR = 1.05, 95 % CI = 1.00, 1.09) and JAK2 genetic variants (OR = 1.40, 95 % CI = 1.15, 1.65) in genotype recessive model were significantly associated with CRC risk. Moreover, the pooled data revealed that IL-6 rs1800795 polymorphism significantly increased the risk of CRC in allele additive model in Europe (OR = 1.07, 95 % CI = 1.01, 1.14). In conclusion, the present findings indicate that IL-6 and JAK2 genetic variants are associated with the increased risk of CRC while STAT3 genetic variants not. We need more well-designed clinical studies covering more countries and population to definitively establish the association between genetic variants in IL-6/JAK/STAT3 pathway and CRC susceptibility.

  3. Genetic Diversity Influences the Response of the Brain to Developmental Lead Exposure

    PubMed Central

    Schneider, Jay S.; Talsania, Keyur; Mettil, William; Anderson, David W.

    2014-01-01

    Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0, 250, or 750 ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of “Pb toxicity” genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning. PMID:24913800

  4. Genetic diversity influences the response of the brain to developmental lead exposure.

    PubMed

    Schneider, Jay S; Talsania, Keyur; Mettil, William; Anderson, David W

    2014-09-01

    Although extrinsic factors, such as nutritional status, and some intrinsic genetic factors may modify susceptibility to developmental lead (Pb) poisoning, no studies have specifically examined the influence of genetic background on outcomes from Pb exposure. In this study, we used gene microarray profiling to identify Pb-responsive genes in rats of different genetic backgrounds, including inbred (Fischer 344 (F344)) and outbred (Long Evans (LE), Sprague Dawley (SD)) strains, to investigate the role that genetic variation may play in influencing outcomes from developmental Pb exposure. Male and female animals received either perinatal (gestation through lactation) or postnatal (birth through weaning) exposure to Pb in food (0, 250, or 750 ppm). RNA was extracted from the hippocampus at day 55 and hybridized to Affymetrix Rat Gene 1.0 ST Arrays. There were significant strain-specific effects of Pb on the hippocampal transcriptome with 978 transcripts differentially expressed in LE rats across all experimental groups, 269 transcripts differentially expressed in F344 rats, and only 179 transcripts differentially expressed in SD rats. These results were not due to strain-related differences in brain accumulation of Pb. Further, no genes were consistently differentially regulated in all experimental conditions. There was no set of "Pb toxicity" genes that are a molecular signature for Pb neurotoxicity that transcended sex, exposure condition, and strain. These results demonstrate the influence that strain and genetic background play in modifying the brain's response to developmental Pb exposure and may have relevance for better understanding the molecular underpinnings of the lack of a neurobehavioral signature in childhood Pb poisoning. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  5. Pathway analysis of genetic factors associated with spontaneous preterm birth and pre-labor preterm rupture of membranes.

    PubMed

    Capece, Antonio; Vasieva, Olga; Meher, Shireen; Alfirevic, Zarko; Alfirevic, Ana

    2014-01-01

    Pre-term birth (PTB) remains the leading cause of infant mortality and morbidity. Its etiology is multifactorial, with a strong genetic component. Genetic predisposition for the two subtypes, spontaneous PTB with intact membranes (sPTB) and preterm prelabor rapture of membranes (PPROM), and differences between them, have not yet been systematically summarised. Our literature search identified 15 association studies conducted in 3,600 women on 2175 SNPs in 274 genes. We used Ingenuity software to impute gene pathways and networks related to sPTB and PPROM. Detailed insight in the defined functional ontologies clearly separated integrated datasets for sPTB and PPROM. Our analysis of upstream regulators of genes suggests that glucocorticoid receptor (NR3C1), peroxisome proliferator activated receptor γ (PPARG) and interferon regulating factor 3 (IRF3) may be sPTB specific. PPROM-specific genes may be regulated by estrogen receptor2 (ESR2) and signal transducer and activator of transcription (STAT1). The inflammatory transcription factor NFκB is linked to both sPTB and PPROM, however, their inflammatory response is distinctly different. Based on our analyses, we propose an autoimmune/hormonal regulation axis for sPTB, whilst pathways implicated in the etiology of PPROM include hematologic/coagulation function disorder, collagen metabolism, matrix degradation and local inflammation. Our hypothesis generating study has identified new candidate genes in the pathogenesis of PPROM and sPTB, which should be validated in large cohorts.

  6. Mutations in the HECT domain of NEDD4L lead to AKT/mTOR pathway deregulation and cause periventricular nodular heterotopia

    PubMed Central

    Ivanova, Ekaterina; Schmucker, Stéphane; Drouot, Nathalie; Clayton-Smith, Jill; Pagnamenta, Alistair T.; Metcalfe, Kay.A.; Isidor, Bertrand; Louvier, Ulrike Walther; Poduri, Annapurna; Taylor, Jenny C.; Tilly, Peggy; Poirier, Karine; Saillour, Yoann; Lebrun, Nicolas; Stemmelen, Tristan; Rudolf, Gabrielle; Muraca, Giuseppe; Saintpierre, Benjamin; Elmorjani, Adrienne; Moïse, Martin; Weirauch, Nathalie Bednarek; Guerrini, Renzo; Boland, Anne; Olaso, Robert; Masson, Cecile; Tripathy, Ratna; Keays, David; Beldjord, Cherif; Nguyen, Laurent; Godin, Juliette; Kini, Usha; Nischké, Patrick; Deleuze, Jean-François; Bahi-Buisson, Nadia; Sumara, Izabela; Hinckelmann, Maria-Victoria; Chelly, Jamel

    2016-01-01

    Neurodevelopmental disorders with periventricular nodular heterotopia (PNH) are etiologically heterogeneous, and their genetic causes remain in many cases unknown. Here we show that missense mutations in the HECT domain of the E3 ubiquitin ligase NEDD4L lead to PNH associated with toes syndactyly, cleft palate and neurodevelopmental delay. Cellular and expression data showed a sensitivity of PNH-associated mutants to proteasome degradation. Moreover, in utero electroporation approach showed that PNH-related mutants and excess of wild type (WT) NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin based experiments, revealed differential deregulation of pathways involved. Excess of WT NEDD4L leads to a disruption of Dab1 and mTORC1 pathways, while PNH-related mutations are associated with a deregulation of mTORC1 and AKT activities. Altogether, these data provide insights to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development. PMID:27694961

  7. Physician scientist research pathway leading to certification by the American Board of Pathology.

    PubMed

    Weiss, Sharon W; Johnson, Rebecca L

    2016-06-01

    In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway (PSRP). This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Variants in folate pathway genes as modulators of genetic instability and lung cancer risk.

    PubMed

    Piskac-Collier, Amanda L; Monroy, Claudia; Lopez, Mirtha S; Cortes, Andrea; Etzel, Carol J; Greisinger, Anthony J; Spitz, Margaret R; El-Zein, Randa A

    2011-01-01

    Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. © 2010 Wiley-Liss, Inc.

  9. Genetic variants in the inositol phosphate metabolism pathway and risk of different types of cancer.

    PubMed

    Tan, Juan; Yu, Chen-Yang; Wang, Zhen-Hua; Chen, Hao-Yan; Guan, Jian; Chen, Ying-Xuan; Fang, Jing-Yuan

    2015-02-16

    Members of the inositol phosphate metabolism pathway regulate cell proliferation, migration and phosphatidylinositol-3-kinase (PI3K)/Akt signaling, and are frequently dysregulated in cancer. Whether germline genetic variants in inositol phosphate metabolism pathway are associated with cancer risk remains to be clarified. We examined the association between inositol phosphate metabolism pathway genes and risk of eight types of cancer using data from genome-wide association studies. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-based associations were tested using the permutation-based adaptive rank-truncated product method. The overall inositol phosphate metabolism pathway was significantly associated with risk of lung cancer (P = 2.00 × 10(-4)), esophageal squamous cell carcinoma (P = 5.70 × 10(-3)), gastric cancer (P = 3.03 × 10(-2)) and renal cell carcinoma (P = 1.26 × 10(-2)), but not with pancreatic cancer (P = 1.40 × 10(-1)), breast cancer (P = 3.03 × 10(-1)), prostate cancer (P = 4.51 × 10(-1)), and bladder cancer (P = 6.30 × 10(-1)). Our results provide a link between inherited variation in the overall inositol phosphate metabolism pathway and several individual genes and cancer. Further studies will be needed to validate these positive findings, and to explore its mechanisms.

  10. Natural Genetic Variation Influences Protein Abundances in C. elegans Developmental Signalling Pathways

    PubMed Central

    Singh, Kapil Dev; Roschitzki, Bernd; Snoek, L. Basten; Grossmann, Jonas; Zheng, Xue; Elvin, Mark; Kamkina, Polina; Schrimpf, Sabine P.; Poulin, Gino B.; Kammenga, Jan E.; Hengartner, Michael O.

    2016-01-01

    Complex traits, including common disease-related traits, are affected by many different genes that function in multiple pathways and networks. The apoptosis, MAPK, Notch, and Wnt signalling pathways play important roles in development and disease progression. At the moment we have a poor understanding of how allelic variation affects gene expression in these pathways at the level of translation. Here we report the effect of natural genetic variation on transcript and protein abundance involved in developmental signalling pathways in Caenorhabditis elegans. We used selected reaction monitoring to analyse proteins from the abovementioned four pathways in a set of recombinant inbred lines (RILs) generated from the wild-type strains N2 (Bristol) and CB4856 (Hawaii) to enable quantitative trait locus (QTL) mapping. About half of the cases from the 44 genes tested showed a statistically significant change in protein abundance between various strains, most of these were however very weak (below 1.3-fold change). We detected a distant QTL on the left arm of chromosome II that affected protein abundance of the phosphatidylserine receptor protein PSR-1, and two separate QTLs that influenced embryonic and ionizing radiation-induced apoptosis on chromosome IV. Our results demonstrate that natural variation in C. elegans is sufficient to cause significant changes in signalling pathways both at the gene expression (transcript and protein abundance) and phenotypic levels. PMID:26985669

  11. Fungal Indole Alkaloid Biosynthesis: Genetic and Biochemical Investigation of Tryptoquialanine Pathway in Penicillium aethiopicum

    PubMed Central

    Gao, Xue; Chooi, Yit-Heng; Ames, Brian D.; Wang, Peng; Walsh, Christopher T.; Tang, Yi

    2011-01-01

    Tremorgenic mycotoxins are a group of indole alkaloids which include the quinazoline-containing tryptoquivaline 2 that are capable of eliciting intermittent or sustained tremors in vertebrate animals. The biosynthesis of this group of bioactive compounds, which are characterized by an acetylated quinazoline ring connected to a 6-5-5 imidazoindolone ring system via a 5-membered spirolactone, has remained uncharacterized. Here, we report the identification of a gene cluster (tqa) from P. aethiopicum that is involved in the biosynthesis of tryptoquialanine 1, which is structurally similar to 2. The pathway has been confirmed to go through an intermediate common to the fumiquinazoline pathway, fumiquinazoline F, which originates from a fungal trimodular nonribosomal peptide synthetase (NRPS). By systematically inactivating every biosynthetic gene in the cluster, followed by isolation and characterization of the intermediates, we were able to establish the biosynthetic sequence of the pathway. An unusual oxidative opening of the pyrazinone ring by an FAD-dependent berberine bridge enzyme-like oxidoreductase has been proposed based on genetic knockout studies. Notably, a 2-aminoisobutyric acid (AIB)-utilizing NRPS module has been identified and reconstituted in vitro, along with two putative enzymes of unknown functions that are involved in the synthesis of the unnatural amino acid by genetic analysis. This work provides new genetic and biochemical insights into the biosynthesis of this group of fungal alkaloids, including the tremorgens related to 2. PMID:21299212

  12. Fungal indole alkaloid biosynthesis: genetic and biochemical investigation of the tryptoquialanine pathway in Penicillium aethiopicum.

    PubMed

    Gao, Xue; Chooi, Yit-Heng; Ames, Brian D; Wang, Peng; Walsh, Christopher T; Tang, Yi

    2011-03-02

    Tremorgenic mycotoxins are a group of indole alkaloids which include the quinazoline-containing tryptoquivaline (2) that are capable of eliciting intermittent or sustained tremors in vertebrate animals. The biosynthesis of this group of bioactive compounds, which are characterized by an acetylated quinazoline ring connected to a 6-5-5 imidazoindolone ring system via a 5-membered spirolactone, has remained uncharacterized. Here, we report the identification of a gene cluster (tqa) from P. aethiopicum that is involved in the biosynthesis of tryptoquialanine (1), which is structurally similar to 2. The pathway has been confirmed to go through an intermediate common to the fumiquinazoline pathway, fumiquinazoline F, which originates from a fungal trimodular nonribosomal peptide synthetase (NRPS). By systematically inactivating every biosynthetic gene in the cluster, followed by isolation and characterization of the intermediates, we were able to establish the biosynthetic sequence of the pathway. An unusual oxidative opening of the pyrazinone ring by an FAD-dependent berberine bridge enzyme-like oxidoreductase has been proposed based on genetic knockout studies. Notably, a 2-aminoisobutyric acid (AIB)-utilizing NRPS module has been identified and reconstituted in vitro, along with two putative enzymes of unknown functions that are involved in the synthesis of the unnatural amino acid by genetic analysis. This work provides new genetic and biochemical insights into the biosynthesis of this group of fungal alkaloids, including the tremorgens related to 2.

  13. Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival

    PubMed Central

    Kong, Jinyu; Xu, Fangxiu; Qu, Jinli; Wang, Yu; Gao, Ming; Yu, Herbert; Qian, Biyun

    2015-01-01

    Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival. PMID:25544771

  14. A portable expression resource for engineering cross-species genetic circuits and pathways

    PubMed Central

    Kushwaha, Manish; Salis, Howard M.

    2015-01-01

    Genetic circuits and metabolic pathways can be reengineered to allow organisms to process signals and manufacture useful chemicals. However, their functions currently rely on organism-specific regulatory parts, fragmenting synthetic biology and metabolic engineering into host-specific domains. To unify efforts, here we have engineered a cross-species expression resource that enables circuits and pathways to reuse the same genetic parts, while functioning similarly across diverse organisms. Our engineered system combines mixed feedback control loops and cross-species translation signals to autonomously self-regulate expression of an orthogonal polymerase without host-specific promoters, achieving nontoxic and tuneable gene expression in diverse Gram-positive and Gram-negative bacteria. Combining 50 characterized system variants with mechanistic modelling, we show how the cross-species expression resource's dynamics, capacity and toxicity are controlled by the control loops' architecture and feedback strengths. We also demonstrate one application of the resource by reusing the same genetic parts to express a biosynthesis pathway in both model and non-model hosts. PMID:26184393

  15. Lead toxicity induces autophagy to protect against cell death through mTORC1 pathway in cardiofibroblasts.

    PubMed

    Sui, Li; Zhang, Rui-Hong; Zhang, Ping; Yun, Ke-Li; Zhang, Hong-Cai; Liu, Li; Hu, Ming-Xu

    2015-03-31

    Heavy metals, such as lead (Pb(2+)), are usually accumulated in human bodies and impair human's health. Lead is a metal with many recognized adverse health side effects and yet the molecular processes underlying lead toxicity are still poorly understood. In the present study, we proposed to investigate the effects of lead toxicity in cultured cardiofibroblasts. After lead treatment, cultured cardiofibroblasts showed severe endoplasmic reticulum (ER) stress. However, the lead-treated cardiofibroblasts were not dramatically apoptotic. Further, we found that these cells determined to undergo autophagy through inhibiting mammalian target of rapamycin complex 1 (mTORC1) pathway. Moreover, inhibition of autophagy by 3-methyladenine (3-MA) may dramatically enhance lead toxicity in cardiofibroblasts and cause cell death. Our data establish that lead toxicity induces cell stress in cardiofibroblasts and protective autophagy is activated by inhibition of mTORC1 pathway. These findings describe a mechanism by which lead toxicity may promote the autophagy of cardiofibroblasts cells, which protects cells from cell stress. Our findings provide evidence that autophagy may help cells to survive under ER stress conditions in cardiofibroblasts and may set up an effective therapeutic strategy for heavy metal toxicity.

  16. GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia

    PubMed Central

    Khanzada, Naveen S.; Butler, Merlin G.; Manzardo, Ann M.

    2017-01-01

    Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. PMID:28264500

  17. GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia.

    PubMed

    Khanzada, Naveen S; Butler, Merlin G; Manzardo, Ann M

    2017-02-28

    Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction.

  18. Forward and reverse genetics approaches to uncover metabolic aging pathways in Caenorhabditis elegans.

    PubMed

    Gao, Arwen W; Uit de Bos, Jelmi; Sterken, Mark G; Kammenga, Jan E; Smith, Reuben L; Houtkooper, Riekelt H

    2017-09-15

    The biological mechanisms of aging have been studied in depth and prominent findings in this field promote the development of new therapies for age-associated disorders. Various model organisms are used for research on aging; among these, the nematode Caenorhabditis elegans has been widely used and has provided valuable knowledge in determining the regulatory mechanisms driving the aging process. Many genes involved in lifespan regulation are associated with metabolic pathways and are influenced by genetic and environmental factors. In line with this, C. elegans provides a promising platform to study such gene by environment interactions, in either a reverse or forward genetics approach. In this review, we discuss longevity mechanisms related to metabolic networks that have been discovered in C. elegans. We also highlight the use of wild populations to study the complex genetic basis of natural variation for quantitative traits that mediate longevity. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  19. Axon regeneration pathways identified by systematic genetic screening in C. elegans.

    PubMed

    Chen, Lizhen; Wang, Zhiping; Ghosh-Roy, Anindya; Hubert, Thomas; Yan, Dong; O'Rourke, Sean; Bowerman, Bruce; Wu, Zilu; Jin, Yishi; Chisholm, Andrew D

    2011-09-22

    The mechanisms underlying the ability of axons to regrow after injury remain poorly explored at the molecular genetic level. We used a laser injury model in Caenorhabditis elegans mechanosensory neurons to screen 654 conserved genes for regulators of axonal regrowth. We uncover several functional clusters of genes that promote or repress regrowth, including genes classically known to affect axon guidance, membrane excitability, neurotransmission, and synaptic vesicle endocytosis. The conserved Arf Guanine nucleotide Exchange Factor (GEF), EFA-6, acts as an intrinsic inhibitor of regrowth. By combining genetics and in vivo imaging, we show that EFA-6 inhibits regrowth via microtubule dynamics, independent of its Arf GEF activity. Among newly identified regrowth inhibitors, only loss of function in EFA-6 partially bypasses the requirement for DLK-1 kinase. Identification of these pathways significantly expands our understanding of the genetic basis of axonal injury responses and repair.

  20. Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are designed to describe linkages of key events (KEs) within a biological pathway that result in an adverse outcome associated with chemical perturbation of a well-defined molecular initiating event (MIE). Risk assessors have traditionally relied ...

  1. Care pathways lead to better teamwork: results of a systematic review.

    PubMed

    Deneckere, Svin; Euwema, Martin; Van Herck, Pieter; Lodewijckx, Cathy; Panella, Massimiliano; Sermeus, Walter; Vanhaecht, Kris

    2012-07-01

    Care pathways are often said to promote interprofessional teamwork. As no systematic review on pathway effectiveness has ever focused on how care pathways promote teamwork, the objective of this review was to study this relationship. We performed an extensive search of electronic databases and identified 26 relevant studies. In our analysis of these studies we identified 20 team indicators and found that care pathways positively affected 17 of these indicators. Most frequently positive effects were found on staff knowledge, interprofessional documentation, team communication and team relations. However, the level of evidence was rather low. We found Level II evidence for improved interprofessional documentation. We also found Level II evidence for increased workload; improved actual versus planned team size; and improved continuity of care. The studies most frequently mentioned the need for a multidisciplinary approach and educational training sessions in order for pathways to be successful. The systematic review revealed that care pathways have the potential to support interprofessional teams in enhancing teamwork. Necessary conditions are a context that supports teamwork and including appropriate active pathway components that can mediate an effect on team processes. To achieve this, each care pathway requires a clearly defined team approach customized to the individual teams' needs.

  2. Development of an adverse outcome pathway for acetylcholinesterase inhibition leading to acute mortality

    EPA Science Inventory

    Adverse outcome pathways (AOPs) are designed to describe linkages of key events (KEs) within a biological pathway that result in an adverse outcome associated with chemical perturbation of a well-defined molecular initiating event (MIE). Risk assessors have traditionally relied ...

  3. Genetic analysis of interferon induced thyroiditis (IIT): evidence for a key role for MHC and apoptosis related genes and pathways.

    PubMed

    Hasham, Alia; Zhang, Weijia; Lotay, Vaneet; Haggerty, Shannon; Stefan, Mihaela; Concepcion, Erlinda; Dieterich, Douglas T; Tomer, Yaron

    2013-08-01

    Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.

  4. GENETIC ANALYSIS OF INTERFERON INDUCED THYROIDITIS (IIT): EVIDENCE FOR A KEY ROLE FOR MHC AND APOPTOSIS RELATED GENES AND PATHWAYS

    PubMed Central

    Hasham, Alia; Zhang, Weijia; Lotay, Vaneet; Haggerty, Shannon; Stefan, Mihaela; Concepcion, Erlinda; Dieterich, Douglas T.; Tomer, Yaron

    2013-01-01

    Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT. PMID:23683877

  5. Going and Passing through Community Colleges: Examining the Effectiveness of Project Lead The Way in STEM Pathways

    ERIC Educational Resources Information Center

    Starobin, Soko S.; Schenk, Tom, Jr.; Laanan, Frankie Santos; Rethwisch, David G.; Moeller, Darin

    2013-01-01

    Project Lead The Way (PLTW), which aims to create a seamless pathway from secondary education to college and career success in STEM fields, was first implemented in the state of Iowa in 2005. As a part of a statewide, longitudinal research in PLTW, this study explores the effectiveness of PLTW in college persistence by analyzing multiple data…

  6. Going and Passing through Community Colleges: Examining the Effectiveness of Project Lead The Way in STEM Pathways

    ERIC Educational Resources Information Center

    Starobin, Soko S.; Schenk, Tom, Jr.; Laanan, Frankie Santos; Rethwisch, David G.; Moeller, Darin

    2013-01-01

    Project Lead The Way (PLTW), which aims to create a seamless pathway from secondary education to college and career success in STEM fields, was first implemented in the state of Iowa in 2005. As a part of a statewide, longitudinal research in PLTW, this study explores the effectiveness of PLTW in college persistence by analyzing multiple data…

  7. Recent Advances in Human Genetics and Epigenetics of Adiposity: Pathway to Precision Medicine?

    PubMed

    Fall, Tove; Mendelson, Michael; Speliotes, Elizabeth K

    2017-05-01

    Obesity is a heritable trait that contributes to substantial global morbidity and mortality. Here, we summarize findings from the past decade of genetic and epigenetic research focused on unravelling the underpinnings of adiposity. More than 140 genetic regions now are known to influence adiposity traits. The genetics of general adiposity, as measured by body mass index, and that of abdominal obesity, as measured by waist-to-hip ratio, have distinct biological backgrounds. Gene expression associated with general adiposity is enriched in the nervous system. In contrast, genes associated with abdominal adiposity function in adipose tissue. Recent population-based epigenetic analyses have highlighted additional distinct loci. We discuss how associated genetic variants can lead to understanding causal mechanisms, and to disentangling reverse causation in epigenetic analyses. Discoveries emerging from population genomics are identifying new disease markers and potential novel drug targets to better define and combat obesity and related diseases. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Population Genetic Analysis Infers Migration Pathways of Phytophthora ramorum in US Nurseries

    PubMed Central

    Goss, Erica M.; Larsen, Meg; Chastagner, Gary A.; Givens, Donald R.; Grünwald, Niklaus J.

    2009-01-01

    Recently introduced, exotic plant pathogens may exhibit low genetic diversity and be limited to clonal reproduction. However, rapidly mutating molecular markers such as microsatellites can reveal genetic variation within these populations and be used to model putative migration patterns. Phytophthora ramorum is the exotic pathogen, discovered in the late 1990s, that is responsible for sudden oak death in California forests and ramorum blight of common ornamentals. The nursery trade has moved this pathogen from source populations on the West Coast to locations across the United States, thus risking introduction to other native forests. We examined the genetic diversity of P. ramorum in United States nurseries by microsatellite genotyping 279 isolates collected from 19 states between 2004 and 2007. Of the three known P. ramorum clonal lineages, the most common and genetically diverse lineage in the sample was NA1. Two eastward migration pathways were revealed in the clustering of NA1 isolates into two groups, one containing isolates from Connecticut, Oregon, and Washington and the other isolates from California and the remaining states. This finding is consistent with trace forward analyses conducted by the US Department of Agriculture's Animal and Plant Health Inspection Service. At the same time, genetic diversities in several states equaled those observed in California, Oregon, and Washington and two-thirds of multilocus genotypes exhibited limited geographic distributions, indicating that mutation was common during or subsequent to migration. Together, these data suggest that migration, rapid mutation, and genetic drift all play a role in structuring the genetic diversity of P. ramorum in US nurseries. This work demonstrates that fast-evolving genetic markers can be used to examine the evolutionary processes acting on recently introduced pathogens and to infer their putative migration patterns, thus showing promise for the application of forensics to plant

  9. Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

    PubMed

    Kreiner, Eskil; Waage, Johannes; Standl, Marie; Brix, Susanne; Pers, Tune H; Couto Alves, Alexessander; Warrington, Nicole M; Tiesler, Carla M T; Fuertes, Elaine; Franke, Lude; Hirschhorn, Joel N; James, Alan; Simpson, Angela; Tung, Joyce Y; Koppelman, Gerard H; Postma, Dirkje S; Pennell, Craig E; Jarvelin, Marjo-Riitta; Custovic, Adnan; Timpson, Nicholas; Ferreira, Manuel A; Strachan, David P; Henderson, John; Hinds, David; Bisgaard, Hans; Bønnelykke, Klaus

    2017-09-01

    The relationship between allergy and autoimmune disorders is complex and poorly understood. We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms. We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases. Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases. We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights

  10. An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation

    PubMed Central

    Xue, Jing; Ideraabdullah, Folami Y.

    2015-01-01

    In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate of key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators and many of the diet induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally-induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes, and toxicants that contribute to obesity and obesity-related phenotypes. PMID:27012616

  11. Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development

    EPA Science Inventory

    Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, s...

  12. Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

    PubMed Central

    Jones, Bridgette L.; Sherwin, Catherine M. T.; Liu, Xiaoxi; Dai, Hongying; Vyhlidal, Carrie A.

    2017-01-01

    Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) (n = 10) among genes (HDC, HNMT, ABP1, HRH1, HRH4) within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Results: Genotyping and HILD response profiles were completed for 163 children. ABP1 47 C/T, ABP1 4107, and HNMT-1639 C/Twere associated with Emax (ABP1 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, p = 0.04; ABP1 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, p = 0.005; HNMT-1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, p = 0.02). In a stratified analysis among African American children only, ABP1 and HNMT SNPs were also associated with PD response; HRH4 413 CC genotype was associated with lower Emax, p = 0.009. Conclusions: We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more

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

    PubMed Central

    Raponi, Mitch; Belly, Robert T; Karp, Judith E; Lancet, Jeffrey E; Atkins, David; Wang, Yixin

    2004-01-01

    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. PMID:15329151

  14. Experimental and kinetic study for lead removal via photosynthetic consortia using genetic algorithms to parameter estimation.

    PubMed

    Hernández-Melchor, Dulce Jazmín; López-Pérez, Pablo A; Carrillo-Vargas, Sergio; Alberto-Murrieta, Alvaro; González-Gómez, Evanibaldo; Camacho-Pérez, Beni

    2017-09-06

    This work presents an experimental-theoretical strategy for a batch process for lead removal by photosynthetic consortium, conformed by algae and bacteria. Photosynthetic consortium, isolated from a treatment plant wastewater of Tecamac (Mexico), was used as inoculum in bubble column photobioreactors. The consortium was used to evaluate the kinetics of lead removal at different initial concentrations of metal (15, 30, 40, 50, and 60 mgL(-1)), carried out in batch culture with a hydraulic residence time of 14 days using Bold's Basal mineral medium. The photobioreactor was operated under the following conditions: aeration of 0.5 vvm, 80 μmol m(-2) s(-1) of photon flux density and a photoperiod light/dark 12:12. After determining the best growth kinetics of biomass and metal removal, they were tested under different ratios (30 and 60%) of wastewater-culture medium. Additionally, the biomass growth (X), nitrogen consumption (N), chemical oxygen demand (COD), and metal removal (Pb) were quantified. Achieved lead removal was 97.4% when the initial lead concentration was up to 50 mgL(-1) using 60% of wastewater. Additionally, an unstructured-type mathematical model was developed to simulate COD, X, N, and lead removal. Furthermore, a comparison between the Levenberg-Marquardt (L-M) optimization approach and Genetic Algorithms (GA) was carried out for parameter estimation. Also, it was concluded that GA has a slightly better performance and possesses better convergence and computational time than L-M. Hence, the proposed method might be applied for parameter estimation of biological models and be used for the monitoring and control process.

  15. Identifying Genetic Variants for Heart Rate Variability in the Acetylcholine Pathway

    PubMed Central

    Riese, Harriëtte; Muñoz, Loretto M.; Hartman, Catharina A.; Ding, Xiuhua; Su, Shaoyong; Oldehinkel, Albertine J.; van Roon, Arie M.; van der Most, Peter J.; Lefrandt, Joop; Gansevoort, Ron T.; van der Harst, Pim; Verweij, Niek; Licht, Carmilla M. M.; Boomsma, Dorret I.; Hottenga, Jouke-Jan; Willemsen, Gonneke; Penninx, Brenda W. J. H.; Nolte, Ilja M.; de Geus, Eco J. C.; Wang, Xiaoling; Snieder, Harold

    2014-01-01

    Heart rate variability is an important risk factor for cardiovascular disease and all-cause mortality. The acetylcholine pathway plays a key role in explaining heart rate variability in humans. We assessed whether 443 genotyped and imputed common genetic variants in eight key genes (CHAT, SLC18A3, SLC5A7, CHRNB4, CHRNA3, CHRNA, CHRM2 and ACHE) of the acetylcholine pathway were associated with variation in an established measure of heart rate variability reflecting parasympathetic control of the heart rhythm, the root mean square of successive differences (RMSSD) of normal RR intervals. The association was studied in a two stage design in individuals of European descent. First, analyses were performed in a discovery sample of four cohorts (n = 3429, discovery stage). Second, findings were replicated in three independent cohorts (n = 3311, replication stage), and finally the two stages were combined in a meta-analysis (n = 6740). RMSSD data were obtained under resting conditions. After correction for multiple testing, none of the SNPs showed an association with RMSSD. In conclusion, no common genetic variants for heart rate variability were identified in the largest and most comprehensive candidate gene study on the acetylcholine pathway to date. Future gene finding efforts for RMSSD may want to focus on hypothesis free approaches such as the genome-wide association study. PMID:25384021

  16. Conserved Genetic Pathways Controlling the Development of the Diffuse Endocrine System in Vertebrates and Drosophila

    PubMed Central

    Hartenstein, Volker; Takashima, Shigeo; Adams, Katrina

    2014-01-01

    The midgut epithelium is formed by absorptive enterocytes, secretory cells and endocrine cells. Each of these lineages is derived from the pluripotent progenitors that constitute the embryonic endoderm; the mature midgut retains pools of self-renewing stem cells that continue to produce all lineages. Recent findings in vertebrates and Drosophila shed light on the genetic mechanism that specifies the fate of the different lineages. A pivotal role is played by the Notch signaling pathway that, in a manner that appears to be very similar to the way in which Notch signaling selects neural progenitors within the neurectoderm, distinguishes the fate of secretory/endocrine cells and enterocytes. Proneural genes encoding bHLH transcription factors are expressed and required in prospective endocrine cells; activation of the Notch pathways restricts the number of these cells and promotes enterocyte development. In this review we compare the development of the intestinal endocrine cells in vertebrates and insects and summarize recent findings dealing with genetic pathways controlling this cell type. PMID:20005229

  17. Characterizing genetic variation of adrenergic signalling pathways in Takotsubo (stress) cardiomyopathy exomes.

    PubMed

    Goodloe, Adele H; Evans, Jared M; Middha, Sumit; Prasad, Abhiram; Olson, Timothy M

    2014-09-01

    Exome sequencing was used to genotype comprehensively a Takotsubo (stress) cardiomyopathy (TC) cohort, enabling investigation of a vast 486 gene network for adrenergic signalling. Twenty-eight TC subjects, including a mother-daughter pair and five recurrent cases, underwent whole-exome sequencing. Frequencies of 17 common, functional adrenergic polymorphisms were statistically similar to those of population controls. Filtering for rare, predicted-deleterious, catecholamine/adrenergic signalling variants revealed heterozygosity in 55 genes in TC cases and 59 genes in healthy controls. Overall allele burden was similar and did not discriminate clinical variables among TC subjects, but gene identities were largely cohort specific, and TC cases were enriched for variants within functional domains (68% vs. 48%, P = 0.031). Two-thirds of TC cases carried more than one filtered adrenergic pathway variant, and 11 genes harboured a variant in ≥ 2 cases. The mother-daughter pair shared missense variants in highly conserved functional domains of ADH5, CACNG1, EPHA4, and PRKCA. An adrenergic pathway-independent analysis of the cohort exposed no common gene for TC. Overall, these data support genetic heterogeneity in TC susceptibility and a likely polygenic basis, conferring a cumulative effect on adrenergic pathway dysregulation in a subset of individual subjects. Study of larger cohorts and non-coding regulatory regions is warranted to define genetic risk factors for TC further. © 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.

  18. Conserved genetic pathways controlling the development of the diffuse endocrine system in vertebrates and Drosophila.

    PubMed

    Hartenstein, Volker; Takashima, Shigeo; Adams, Katrina L

    2010-05-01

    The midgut epithelium is formed by absorptive enterocytes, secretory cells and endocrine cells. Each of these lineages is derived from the pluripotent progenitors that constitute the embryonic endoderm; the mature midgut retains pools of self-renewing stem cells that continue to produce all lineages. Recent findings in vertebrates and Drosophila shed light on the genetic mechanism that specifies the fate of the different lineages. A pivotal role is played by the Notch signaling pathway that, in a manner that appears to be very similar to the way in which Notch signaling selects neural progenitors within the neurectoderm, distinguishes the fate of secretory/endocrine cells and enterocytes. Proneural genes encoding bHLH transcription factors are expressed and required in prospective endocrine cells; activation of the Notch pathways restricts the number of these cells and promotes enterocyte development. In this review we compare the development of the intestinal endocrine cells in vertebrates and insects and summarize recent findings dealing with genetic pathways controlling this cell type. Copyright 2009. Published by Elsevier Inc.

  19. Genetic polymorphisms in the metabolic pathway and non-Hodgkin lymphoma survival

    PubMed Central

    Han, Xuesong; Zheng, Tongzhang; Foss, Francine M.; Lan, Qing; Holford, Theodore R.; Rothman, Nathaniel; Ma, Shuangge; Zhang, Yawei

    2010-01-01

    Background Metabolic pathway enzymes, such as Cytochrome P450 (CYP), glutathione S-transferase (GST), and N-Acetyltransferases (NAT) are involved in activation and detoxification of environmental carcinogens as well as drug metabolism. We hypothesized that the genetic variations in such metabolic pathways may affect NHL prognosis and survival. Methodology/Principal Findings Follow-up information of 469 female NHL incident cases diagnosed during 1995-2000 in Connecticut were abstracted from Connecticut Tumor Registry in 2008; survival analyses were conducted using the Kaplan-Meier method, and hazard ratios (HR) were estimated by Cox Proportional Hazard models adjusting for demographic and tumor characteristics which were suggested by previous studies to be determinants of NHL survival. Our results identified nine SNPs from five metabolism genes (CYP2E1, GSTP1, GSTT1, NAT1 and NAT2) that were associated with NHL survival. Specifically, polymorphisms in NAT1 and NAT2 genes were associated with diffuse large B-cell lymphoma survival; polymorphisms in GSTT1 was associated with follicular lymphoma survival; and polymorphisms in CYP2E1, GSTP1 and NAT1 were associated with survival of chronic lymphocytic leukemia/small lymphocytic lymphoma. Conclusions/Significance Our study suggests that genetic polymorphisms in metabolic pathways may help improving the prediction of NHL survival and prognosis. PMID:20029944

  20. Why genetic modification of lignin leads to low-recalcitrance biomass

    DOE PAGES

    Carmona, Christopher; Langan, Paul; Smith, Jeremy C.; ...

    2014-11-11

    Genetic modification of plants via down-regulation of cinnamyl alcohol dehydrogenase leads to incorporation of aldehyde groups in the lignin polymer. Moreover, the resulting lignocellulosic biomass has increased bioethanol yield. However, a molecular-scale explanation of this finding is currently lacking. We perform molecular dynamics simulation of the copolymer with hemicellulose of wild type and the genetically modified lignin, in aqueous solution. We find that the non-covalent association with hemicellulose of lignin containing aldehyde groups is reduced compared to the wild-type. This phase separation may increase the cell wall porosity in the mutant plants, thus explaining their easier deconstruction to biofuels. Themore » thermodynamic origin of the reduced lignin-hemicellulose association is found to be a more favorable self-interaction energy and less favorable interaction with hemicellulose for the mutant lignin. Furthermore, reduced hydration water density fluctuations are found for the mutant lignin, implying a more hydrophobic lignin surface. Our results provide a detailed description of how aldehyde incorporation makes lignin more hydrophobic and reduces its association with hemicellulose, thus suggesting that increased lignin hydrophobicity may be an optimal characteristic required for improved biofuel production.« less

  1. Why genetic modification of lignin leads to low-recalcitrance biomass

    SciTech Connect

    Carmona, Christopher; Langan, Paul; Smith, Jeremy C.; Petridis, Loukas

    2014-11-11

    Genetic modification of plants via down-regulation of cinnamyl alcohol dehydrogenase leads to incorporation of aldehyde groups in the lignin polymer. Moreover, the resulting lignocellulosic biomass has increased bioethanol yield. However, a molecular-scale explanation of this finding is currently lacking. We perform molecular dynamics simulation of the copolymer with hemicellulose of wild type and the genetically modified lignin, in aqueous solution. We find that the non-covalent association with hemicellulose of lignin containing aldehyde groups is reduced compared to the wild-type. This phase separation may increase the cell wall porosity in the mutant plants, thus explaining their easier deconstruction to biofuels. The thermodynamic origin of the reduced lignin-hemicellulose association is found to be a more favorable self-interaction energy and less favorable interaction with hemicellulose for the mutant lignin. Furthermore, reduced hydration water density fluctuations are found for the mutant lignin, implying a more hydrophobic lignin surface. Our results provide a detailed description of how aldehyde incorporation makes lignin more hydrophobic and reduces its association with hemicellulose, thus suggesting that increased lignin hydrophobicity may be an optimal characteristic required for improved biofuel production.

  2. Long-term human exposure to lead from different media and intake pathways.

    PubMed

    Pizzol, Massimo; Thomsen, Marianne; Andersen, Mikael Skou

    2010-10-15

    Lead (Pb) is well known as an environmental pollutant: it can accumulate in various media, so actual lead exposure reflects both historical and present contaminations. Two main challenges then emerge: obtaining updated information to gain an overall picture of the sources of exposure, and predicting the resulting internal body exposure levels and effects that occur under long-term exposure conditions. In this paper, a modeling approach is used to meet these challenges with reference to Danish exposure conditions. Levels of lead content in various media have been coupled with data for lead intake and absorption in the human body, for both children and adults. An age-dependent biokinetic model allows then for determination of the blood lead levels resulting from chronic exposure. The study shows that the actual intake of lead is up to 27% of the Provisional Tolerable Daily Intake (PTDI) for children and around 8% for adults. It is confirmed that the critical route of exposure is via ingestion, accounting for 99% of total lead intake, while inhalation contributes only to 1% of total lead intake. The resulting lead levels in the blood after 2 years of exposure to actual contamination conditions have been estimated as up to 2.2μg/dl in children and almost 1μg/dl in adults. Impacts from lead can occur even at such levels. The role of historical and present sources to lead in the environment is discussed, and, for specific child and adult exposure scenarios, external-internal concentration relationships for the direct linkage between lead in environmental media and resulting concentrations of lead in blood are then presented. Copyright © 2010 Elsevier B.V. All rights reserved.

  3. An Ultra High-Throughput, Whole-Animal Screen for Small Molecule Modulators of a Specific Genetic Pathway in Caenorhabditis elegans

    PubMed Central

    Leung, Chi K.; Wang, Ying; Malany, Siobhan; Deonarine, Andrew; Nguyen, Kevin; Vasile, Stefan; Choe, Keith P.

    2013-01-01

    High-throughput screening (HTS) is a powerful approach to drug discovery, but many lead compounds are found to be unsuitable for use in vivo after initial screening. Screening in small animals like C. elegans can help avoid these problems, but this system has been limited to screens with low-throughput or no specific molecular target. We report the first in vivo 1536-well plate assay for a specific genetic pathway in C. elegans. Our assay measures induction of a gene regulated by SKN-1, a master regulator of detoxification genes. SKN-1 inhibitors will be used to study and potentially reverse multidrug resistance in parasitic nematodes. Screens of two small commercial libraries and the full Molecular Libraries Small Molecule Repository (MLSMR) of ∼364,000 compounds validate our platform for ultra HTS. Our platform overcomes current limitations of many whole-animal screens and can be widely adopted for other inducible genetic pathways in nematodes and humans. PMID:23637990

  4. New discoveries in schizophrenia genetics reveal neurobiological pathways: a review of recent findings

    PubMed Central

    Kotlar, Alex V.; Mercer, Kristina B.; Zwick, Michael E.; Mulle, Jennifer G.

    2015-01-01

    Schizophrenia research has undergone a recent transformation. By leveraging large sample sizes, genome-wide association studies of common genetic variants have approximately tripled the number of candidate genetic loci. Rare variant studies have identified copy number variants that are schizophrenia risk loci. Among these, the 3q29 microdeletion is now known to be the single largest schizophrenia risk factor. Next-generation sequencing studies are increasingly used for rare variant association testing, and have already facilitated identification of large effect alleles. Collectively, recent findings implicate voltage-gated calcium channel and cytoskeletal pathways in the pathogenesis of schizophrenia. Taken together, these results suggest the possibility of imminent breakthroughs in the molecular understanding of schizophrenia. PMID:26493318

  5. Pathway analysis to identify genetic variants associated with efficacy of adalimumab in rheumatoid arthritis.

    PubMed

    Eektimmerman, Frank; Swen, Jesse J; Böhringer, Stefan; Huizinga, Tom Wj; Kooloos, Wouter M; Allaart, Cornelia F; Guchelaar, Henk-Jan

    2017-07-01

    About 30% of rheumatoid arthritis patients have no clinical benefit from TNF inhibitors. Genome-wide association (GWA) and candidate gene studies tested several putative genetic variants for TNF inhibitor efficacy with inconclusive results. Therefore, this study applied a systematic pathway analysis. A total of 325 rheumatoid arthritis patients treated with adalimumab were genotyped for 223 SNPs. We tested the association between SNPs and European League Against Rheumatism response and remission at 14 weeks under the additive genetic model using logistic regression. A total of 3 SNPs located in CD40LG (rs1126535), TANK (rs1267067) and VEGFA (rs25648) showed association with both end points. TNFAIP3 (rs2230926) had the strongest effect related to European League Against Rheumatism response. This exploratory study suggests that TNFAIP3, CD40LG, TANK and VEGFA play a role in the response to adalimumab treatment.

  6. New discoveries in schizophrenia genetics reveal neurobiological pathways: A review of recent findings.

    PubMed

    Kotlar, Alex V; Mercer, Kristina B; Zwick, Michael E; Mulle, Jennifer G

    2015-12-01

    Schizophrenia research has undergone a recent transformation. By leveraging large sample sizes, genome-wide association studies of common genetic variants have approximately tripled the number of candidate genetic loci. Rare variant studies have identified copy number variants that are schizophrenia risk loci. Among these, the 3q29 microdeletion is now known to be the single largest schizophrenia risk factor. Next-generation sequencing studies are increasingly used for rare variant association testing, and have already facilitated identification of large effect alleles. Collectively, recent findings implicate voltage-gated calcium channel and cytoskeletal pathways in the pathogenesis of schizophrenia. Taken together, these results suggest the possibility of imminent breakthroughs in the molecular understanding of schizophrenia. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  7. Human high-altitude adaptation: forward genetics meets the HIF pathway

    PubMed Central

    Bigham, Abigail W.

    2014-01-01

    Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia. PMID:25319824

  8. Structural and Functional Characterization of a Caenorhabditis elegans Genetic Interaction Network within Pathways

    PubMed Central

    Boucher, Benjamin; Lee, Anna Y.; Hallett, Michael; Jenna, Sarah

    2016-01-01

    A genetic interaction (GI) is defined when the mutation of one gene modifies the phenotypic expression associated with the mutation of a second gene. Genome-wide efforts to map GIs in yeast revealed structural and functional properties of a GI network. This provided insights into the mechanisms underlying the robustness of yeast to genetic and environmental insults, and also into the link existing between genotype and phenotype. While a significant conservation of GIs and GI network structure has been reported between distant yeast species, such a conservation is not clear between unicellular and multicellular organisms. Structural and functional characterization of a GI network in these latter organisms is consequently of high interest. In this study, we present an in-depth characterization of ~1.5K GIs in the nematode Caenorhabditis elegans. We identify and characterize six distinct classes of GIs by examining a wide-range of structural and functional properties of genes and network, including co-expression, phenotypical manifestations, relationship with protein-protein interaction dense subnetworks (PDS) and pathways, molecular and biological functions, gene essentiality and pleiotropy. Our study shows that GI classes link genes within pathways and display distinctive properties, specifically towards PDS. It suggests a model in which pathways are composed of PDS-centric and PDS-independent GIs coordinating molecular machines through two specific classes of GIs involving pleiotropic and non-pleiotropic connectors. Our study provides the first in-depth characterization of a GI network within pathways of a multicellular organism. It also suggests a model to understand better how GIs control system robustness and evolution. PMID:26871911

  9. Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma

    PubMed Central

    Anvari, Sara; Vyhlidal, Carrie A.; Dai, Hongying

    2015-01-01

    Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7–18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease. PMID:25909280

  10. Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

    PubMed

    Anvari, Sara; Vyhlidal, Carrie A; Dai, Hongying; Jones, Bridgette L

    2015-12-01

    Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease.

  11. Unraveling the Genetic Basis of Aspirin Hypersensitivity in Asthma Beyond Arachidonate Pathways

    PubMed Central

    Park, Se-Min; Park, Jong Sook; Park, Hae-Sim

    2013-01-01

    Although aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with severe asthma, it remains widely under-diagnosed in the asthmatic population. Oral aspirin challenge is the best method of diagnosing AERD, but this is a time-consuming procedure with serious complications in some cases. Thus, development of non-invasive methods for easy diagnosis is necessary to prevent unexpected complications of aspirin use in susceptible patients. For the past decade, many studies have attempted to elucidate the genetic variants responsible for risk of AERD. Several approaches have been applied in these genetic studies. To date, a limited number of biologically plausible candidate genes in the arachidonate and immune and inflammatory pathways have been studied. Recently, a genome-wide association study was performed. In this review, the results of these studies are summarized, and their limitations discussed. In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity. Finally, perspectives on application of new genomic technologies are introduced; these will aid our understanding of the genetic pathogenesis of aspirin hypersensitivity in asthma. PMID:24003382

  12. Theoretical Study on Reaction Pathways Leading to CO and CO2 in the Pyrolysis of Resorcinol.

    PubMed

    Furutani, Yuki; Kudo, Shinji; Hayashi, Jun-Ichiro; Norinaga, Koyo

    2017-01-26

    Possible pathways for the pyrolysis of resorcinol with the formation of CO and CO2 as final products were proposed and evaluated using ab initio calculations. Our experimental study revealed that large quantities of CO2 are generated in the pyrolysis of 1,3-dihydroxybenzene (resorcinol), while the pyrolysis of the dihydroxybenzene isomers 1,2-dihydroxybenzene (catechol) and 1,4-dihydroxybenzene (hydroquinone) produces little CO2. The fate of oxygen atoms in catechol and hydroquinone was essentially the formation of CO. In the proposed pathways, the triplet ground state m-benzoquinone was generated initially from simultaneous cleavage of the two O-H bonds in resorcinol. Subsequently, the direct cleavage of a C-C bond of the m-benzoquinone diradical yields 2-oxidanylcyclopenta-2,4-dien-1-yl-methanone, which can be converted via two channels: release of CO from the aldehyde radical group and combination of the ketone radical and carbon atom in the aldehyde radical group to form the 6-oxabicyclo[3.2.0]hepta-2,4-dien-7-one, resulting in the release of CO2. Potential energy surfaces along the proposed reaction pathways were calculated employing the CBS-QB3 method, and the rate constants at the high-pressure limit were also evaluated based on transition-state theory to assess the feasibility of the proposed reaction pathways.

  13. Many pathways in laboratory evolution can lead to improved enzymes: how to escape from local minima.

    PubMed

    Gumulya, Yosephine; Sanchis, Joaquin; Reetz, Manfred T

    2012-05-07

    Directed evolution is a method to tune the properties of enzymes for use in organic chemistry and biotechnology, to study enzyme mechanisms, and to shed light on darwinian evolution in nature. In order to enhance its efficacy, iterative saturation mutagenesis (ISM) was implemented. This involves: 1) randomized mutation of appropriate sites of one or more residues; 2) screening of the initial mutant libraries for properties such as enzymatic rate, stereoselectivity, or thermal robustness; 3) use of the best hit in a given library as a template for saturation mutagenesis at the other sites; and 4) continuation of the process until the desired degree of enzyme improvement has been reached. Despite the success of a number of ISM-based studies, the question of the optimal choice of the many different possible pathways remains unanswered. Here we considered a complete 4-site ISM scheme. All 24 pathways were systematically explored, with the epoxide hydrolase from Aspergillus niger as the catalyst in the stereoselective hydrolytic kinetic resolution of a chiral epoxide. All 24 pathways were found to provide improved mutants with notably enhanced stereoselectivity. When a library failed to contain any hits, non-improved or even inferior mutants were used as templates in the continuation of the evolutionary pathway, thereby escaping from the local minimum. These observations have ramifications for directed evolution in general and for evolutionary biological studies in which protein engineering techniques are applied. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model.

    PubMed

    O'Neil, Derek; Mendez-Figueroa, Hector; Mistretta, Toni-Ann; Su, Chunliu; Lane, Robert H; Aagaard, Kjersti M

    2013-11-01

    In our primate model of maternal high fat diet exposure, we have described that fetal epigenomic modifications to the peripheral circadian Npas2 are associated with persistent alterations in fetal hepatic metabolism and non-alcoholic fatty liver. As the interaction of circadian response with metabolism is not well understood, we employed a murine knockout model to characterize the molecular mechanisms with which Npas2 reprograms the fetal hepatic metabolic response. cDNA was generated from Npas2-/- and +/+ (wild type) livers at day 2 (newborn) and at 25 weeks (adult) of life. Newborn samples were analyzed by exon array (n = 3/cohort). Independent pathway analysis software determined that the primary dysregulated pathway(s) in the Npas2-/- animals uniformly converged on lipid metabolism. Of particular interest, Ppargc1a, which integrates circadian and metabolism pathways, was significantly (p < .01) over expressed in newborn (1.7 fold) and adult (1.8 fold) Npas2-/- animals. These findings are consistent with an essential role for Npas2 in programming the peripheral circadian response and hepatic metabolism, which has not been previously described.

  15. PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON OF BRAIN AROMATASE IN FISH LEADING TO REPRODUCTIVE IMPAIRMENT

    EPA Science Inventory

    The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework p...

  16. PUTATIVE ADVERSE OUTCOME PATHWAY FOR INHIBITON OF BRAIN AROMATASE IN FISH LEADING TO REPRODUCTIVE IMPAIRMENT

    EPA Science Inventory

    The adverse outcome pathway (AOP) provides a framework for organizing knowledge to define links between a molecular initiating event (MIE) and an adverse outcome (AO) occurring at a higher level of biological organization, such as the individual or population. The AOP framework p...

  17. Prolonged exposure to FLT3 inhibitors leads to resistance via activation of parallel signaling pathways

    PubMed Central

    Piloto, Obdulio; Wright, Melissa; Brown, Patrick; Kim, Kyu-Tae; Levis, Mark; Small, Donald

    2007-01-01

    Continuous treatment of malignancies with tyrosine kinase inhibitors (TKIs) may select for resistant clones (ie, imatinib mesylate). To study resistance to TKIs targeting FLT3, a receptor tyrosine kinase that is frequently mutated in acute myelogenous leukemia (AML), we developed resistant human cell lines through prolonged coculture with FLT3 TKIs. FLT3 TKI-resistant cell lines and primary samples still exhibit inhibition of FLT3 phosphorylation on FLT3 TKI treatment. However, FLT3 TKI-resistant cell lines and primary samples often show continued activation of downstream PI3K/Akt and/or Ras/MEK/MAPK signaling pathways as well as continued expression of genes involved in FLT3-mediated cellular transformation. Inhibition of these signaling pathways restores partial sensitivity to FLT3 TKIs. Mutational screening of FLT3 TKI-resistant cell lines revealed activating N-Ras mutations in 2 cell lines that were not present in the parental FLT3 TKI-sensitive cell line. Taken together, these data indicate that FLT3 TKI-resistant cells most frequently become FLT3 independent because of activation of parallel signaling pathways that provide compensatory survival/proliferation signals when FLT3 is inhibited. Anti-FLT3 mAb treatment was still cytotoxic to FLT3 TKI-resistant clones. An approach combining FLT3 TKIs with anti-FLT3 antibodies and/or inhibitors of important pathways downstream of FLT3 may reduce the chances of developing resistance. PMID:17047150

  18. Common genetic heterogeneity of human interleukin-37 leads to functional variance.

    PubMed

    Yan, Jingjing; Zhang, Yuling; Cheng, Shimeng; Kang, Bin; Peng, Jinbiao; Zhang, Xiaodan; Yuan, Meichun; Chu, Wenqi; Zhang, Wen; Shen, Jiayin; Zhang, Shuye

    2017-09-01

    Interleukin-37 (IL-37) is an inhibitory member of the IL-1 family of cytokines. We previously found that balanced selection maintains common variations of the human IL37 gene. However, the functional consequences of this selection have yet to be validated. Here, using cells expressing exogenous IL-37 variants, including IL-37 Ref and IL-37 Var1 and Var2, we found that the three variants of IL-37 exhibited different immunoregulatory potencies in response to immune stimulation. The protein level of IL-37 Var2 was found to be significantly less than that of IL-37 Ref or Var1, despite the comparable mRNA levels of all three variants. Further study showed that IL-37 Var2 was rapidly degraded by a proteasome-dependent mechanism mediated by enhanced polyubiquitination, leading to a transient upregulation of IL-37 Var2 after immune stimulation. Finally, when ectopically expressed in cells, human IL-37 Var2 exerted less inhibition on proinflammatory cytokine production than did other IL-37 variants. Conversely, purified extracellular IL-37 variant proteins demonstrated comparable inhibitory abilities in vitro. In conclusion, our study reveals that common genetic variants of IL37 lead to different immune-inhibitory potencies, primarily as a result of differences in IL-37 protein stability, suggesting the possible involvement of these variants in various human diseases.

  19. Automated Lead Optimization of MMP-12 Inhibitors Using a Genetic Algorithm.

    PubMed

    Pickett, Stephen D; Green, Darren V S; Hunt, David L; Pardoe, David A; Hughes, Ian

    2011-01-13

    Traditional lead optimization projects involve long synthesis and testing cycles, favoring extensive structure-activity relationship (SAR) analysis and molecular design steps, in an attempt to limit the number of cycles that a project must run to optimize a development candidate. Microfluidic-based chemistry and biology platforms, with cycle times of minutes rather than weeks, lend themselves to unattended autonomous operation. The bottleneck in the lead optimization process is therefore shifted from synthesis or test to SAR analysis and design. As such, the way is open to an algorithm-directed process, without the need for detailed user data analysis. Here, we present results of two synthesis and screening experiments, undertaken using traditional methodology, to validate a genetic algorithm optimization process for future application to a microfluidic system. The algorithm has several novel features that are important for the intended application. For example, it is robust to missing data and can suggest compounds for retest to ensure reliability of optimization. The algorithm is first validated on a retrospective analysis of an in-house library embedded in a larger virtual array of presumed inactive compounds. In a second, prospective experiment with MMP-12 as the target protein, 140 compounds are submitted for synthesis over 10 cycles of optimization. Comparison is made to the results from the full combinatorial library that was synthesized manually and tested independently. The results show that compounds selected by the algorithm are heavily biased toward the more active regions of the library, while the algorithm is robust to both missing data (compounds where synthesis failed) and inactive compounds. This publication places the full combinatorial library and biological data into the public domain with the intention of advancing research into algorithm-directed lead optimization methods.

  20. An assessment of molecular pathways of obesity susceptible to nutrient, toxicant and genetically induced epigenetic perturbation.

    PubMed

    Xue, Jing; Ideraabdullah, Folami Y

    2016-04-01

    In recent years, the etiology of human disease has greatly improved with the inclusion of epigenetic mechanisms, in particular as a common link between environment and disease. However, for most diseases we lack a detailed interpretation of the epigenetic regulatory pathways perturbed by environment and causal mechanisms. Here, we focus on recent findings elucidating nutrient-related epigenetic changes linked to obesity. We highlight studies demonstrating that obesity is a complex disease linked to disruption of epigenetically regulated metabolic pathways in the brain, adipose tissue and liver. These pathways regulate (1) homeostatic and hedonic eating behaviors, (2) adipocyte differentiation and fat accumulation, and (3) energy expenditure. By compiling these data, we illustrate that obesity-related phenotypes are repeatedly linked to disruption of critical epigenetic mechanisms that regulate key metabolic genes. These data are supported by genetic mutation of key epigenetic regulators, and many of the diet-induced epigenetic mechanisms of obesity are also perturbed by exposure to environmental toxicants. Identifying similarly perturbed epigenetic mechanisms in multiple experimental models of obesity strengthens the translational applications of these findings. We also discuss many of the ongoing challenges to understanding the role of environmentally induced epigenetic pathways in obesity and suggest future studies to elucidate these roles. This assessment illustrates our current understanding of molecular pathways of obesity that are susceptible to environmental perturbation via epigenetic mechanisms. Thus, it lays the groundwork for dissecting the complex interactions between diet, genes and toxicants that contribute to obesity and obesity-related phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

    PubMed

    Ehret, Georg B; Munroe, Patricia B; Rice, Kenneth M; Bochud, Murielle; Johnson, Andrew D; Chasman, Daniel I; Smith, Albert V; Tobin, Martin D; Verwoert, Germaine C; Hwang, Shih-Jen; Pihur, Vasyl; Vollenweider, Peter; O'Reilly, Paul F; Amin, Najaf; Bragg-Gresham, Jennifer L; Teumer, Alexander; Glazer, Nicole L; Launer, Lenore; Zhao, Jing Hua; Aulchenko, Yurii; Heath, Simon; Sõber, Siim; Parsa, Afshin; Luan, Jian'an; Arora, Pankaj; Dehghan, Abbas; Zhang, Feng; Lucas, Gavin; Hicks, Andrew A; Jackson, Anne U; Peden, John F; Tanaka, Toshiko; Wild, Sarah H; Rudan, Igor; Igl, Wilmar; Milaneschi, Yuri; Parker, Alex N; Fava, Cristiano; Chambers, John C; Fox, Ervin R; Kumari, Meena; Go, Min Jin; van der Harst, Pim; Kao, Wen Hong Linda; Sjögren, Marketa; Vinay, D G; Alexander, Myriam; Tabara, Yasuharu; Shaw-Hawkins, Sue; Whincup, Peter H; Liu, Yongmei; Shi, Gang; Kuusisto, Johanna; Tayo, Bamidele; Seielstad, Mark; Sim, Xueling; Nguyen, Khanh-Dung Hoang; Lehtimäki, Terho; Matullo, Giuseppe; Wu, Ying; Gaunt, Tom R; Onland-Moret, N Charlotte; Cooper, Matthew N; Platou, Carl G P; Org, Elin; Hardy, Rebecca; Dahgam, Santosh; Palmen, Jutta; Vitart, Veronique; Braund, Peter S; Kuznetsova, Tatiana; Uiterwaal, Cuno S P M; Adeyemo, Adebowale; Palmas, Walter; Campbell, Harry; Ludwig, Barbara; Tomaszewski, Maciej; Tzoulaki, Ioanna; Palmer, Nicholette D; Aspelund, Thor; Garcia, Melissa; Chang, Yen-Pei C; O'Connell, Jeffrey R; Steinle, Nanette I; Grobbee, Diederick E; Arking, Dan E; Kardia, Sharon L; Morrison, Alanna C; Hernandez, Dena; Najjar, Samer; McArdle, Wendy L; Hadley, David; Brown, Morris J; Connell, John M; Hingorani, Aroon D; Day, Ian N M; Lawlor, Debbie A; Beilby, John P; Lawrence, Robert W; Clarke, Robert; Hopewell, Jemma C; Ongen, Halit; Dreisbach, Albert W; Li, Yali; Young, J Hunter; Bis, Joshua C; Kähönen, Mika; Viikari, Jorma; Adair, Linda S; Lee, Nanette R; Chen, Ming-Huei; Olden, Matthias; Pattaro, Cristian; Bolton, Judith A Hoffman; Köttgen, Anna; Bergmann, Sven; Mooser, Vincent; Chaturvedi, Nish; Frayling, Timothy M; Islam, Muhammad; Jafar, Tazeen H; Erdmann, Jeanette; Kulkarni, Smita R; Bornstein, Stefan R; Grässler, Jürgen; Groop, Leif; Voight, Benjamin F; Kettunen, Johannes; Howard, Philip; Taylor, Andrew; Guarrera, Simonetta; Ricceri, Fulvio; Emilsson, Valur; Plump, Andrew; Barroso, Inês; Khaw, Kay-Tee; Weder, Alan B; Hunt, Steven C; Sun, Yan V; Bergman, Richard N; Collins, Francis S; Bonnycastle, Lori L; Scott, Laura J; Stringham, Heather M; Peltonen, Leena; Perola, Markus; Vartiainen, Erkki; Brand, Stefan-Martin; Staessen, Jan A; Wang, Thomas J; Burton, Paul R; Soler Artigas, Maria; Dong, Yanbin; Snieder, Harold; Wang, Xiaoling; Zhu, Haidong; Lohman, Kurt K; Rudock, Megan E; Heckbert, Susan R; Smith, Nicholas L; Wiggins, Kerri L; Doumatey, Ayo; Shriner, Daniel; Veldre, Gudrun; Viigimaa, Margus; Kinra, Sanjay; Prabhakaran, Dorairaj; Tripathy, Vikal; Langefeld, Carl D; Rosengren, Annika; Thelle, Dag S; Corsi, Anna Maria; Singleton, Andrew; Forrester, Terrence; Hilton, Gina; McKenzie, Colin A; Salako, Tunde; Iwai, Naoharu; Kita, Yoshikuni; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ueshima, Hirotsugu; Umemura, Satoshi; Eyheramendy, Susana; Meitinger, Thomas; Wichmann, H-Erich; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Scott, James; Sehmi, Joban S; Zhang, Weihua; Hedblad, Bo; Nilsson, Peter; Smith, George Davey; Wong, Andrew; Narisu, Narisu; Stančáková, Alena; Raffel, Leslie J; Yao, Jie; Kathiresan, Sekar; O'Donnell, Christopher J; Schwartz, Stephen M; Ikram, M Arfan; Longstreth, W T; Mosley, Thomas H; Seshadri, Sudha; Shrine, Nick R G; Wain, Louise V; Morken, Mario A; Swift, Amy J; Laitinen, Jaana; Prokopenko, Inga; Zitting, Paavo; Cooper, Jackie A; Humphries, Steve E; Danesh, John; Rasheed, Asif; Goel, Anuj; Hamsten, Anders; Watkins, Hugh; Bakker, Stephan J L; van Gilst, Wiek H; Janipalli, Charles S; Mani, K Radha; Yajnik, Chittaranjan S; Hofman, Albert; Mattace-Raso, Francesco U S; Oostra, Ben A; Demirkan, Ayse; Isaacs, Aaron; Rivadeneira, Fernando; Lakatta, Edward G; Orru, Marco; Scuteri, Angelo; Ala-Korpela, Mika; Kangas, Antti J; Lyytikäinen, Leo-Pekka; Soininen, Pasi; Tukiainen, Taru; Würtz, Peter; Ong, Rick Twee-Hee; Dörr, Marcus; Kroemer, Heyo K; Völker, Uwe; Völzke, Henry; Galan, Pilar; Hercberg, Serge; Lathrop, Mark; Zelenika, Diana; Deloukas, Panos; Mangino, Massimo; Spector, Tim D; Zhai, Guangju; Meschia, James F; Nalls, Michael A; Sharma, Pankaj; Terzic, Janos; Kumar, M V Kranthi; Denniff, Matthew; Zukowska-Szczechowska, Ewa; Wagenknecht, Lynne E; Fowkes, F Gerald R; Charchar, Fadi J; Schwarz, Peter E H; Hayward, Caroline; Guo, Xiuqing; Rotimi, Charles; Bots, Michiel L; Brand, Eva; Samani, Nilesh J; Polasek, Ozren; Talmud, Philippa J; Nyberg, Fredrik; Kuh, Diana; Laan, Maris; Hveem, Kristian; Palmer, Lyle J; van der Schouw, Yvonne T; Casas, Juan P; Mohlke, Karen L; Vineis, Paolo; Raitakari, Olli; Ganesh, Santhi K; Wong, Tien Y; Tai, E Shyong; Cooper, Richard S; Laakso, Markku; Rao, Dabeeru C; Harris, Tamara B; Morris, Richard W; Dominiczak, Anna F; Kivimaki, Mika; Marmot, Michael G; Miki, Tetsuro; Saleheen, Danish; Chandak, Giriraj R; Coresh, Josef; Navis, Gerjan; Salomaa, Veikko; Han, Bok-Ghee; Zhu, Xiaofeng; Kooner, Jaspal S; Melander, Olle; Ridker, Paul M; Bandinelli, Stefania; Gyllensten, Ulf B; Wright, Alan F; Wilson, James F; Ferrucci, Luigi; Farrall, Martin; Tuomilehto, Jaakko; Pramstaller, Peter P; Elosua, Roberto; Soranzo, Nicole; Sijbrands, Eric J G; Altshuler, David; Loos, Ruth J F; Shuldiner, Alan R; Gieger, Christian; Meneton, Pierre; Uitterlinden, Andre G; Wareham, Nicholas J; Gudnason, Vilmundur; Rotter, Jerome I; Rettig, Rainer; Uda, Manuela; Strachan, David P; Witteman, Jacqueline C M; Hartikainen, Anna-Liisa; Beckmann, Jacques S; Boerwinkle, Eric; Vasan, Ramachandran S; Boehnke, Michael; Larson, Martin G; Järvelin, Marjo-Riitta; Psaty, Bruce M; Abecasis, Gonçalo R; Chakravarti, Aravinda; Elliott, Paul; van Duijn, Cornelia M; Newton-Cheh, Christopher; Levy, Daniel; Caulfield, Mark J; Johnson, Toby

    2011-09-11

    Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

  2. Genetic Variants in Novel Pathways Influence Blood Pressure and Cardiovascular Disease Risk

    PubMed Central

    2011-01-01

    Blood pressure (BP) is a heritable trait1 influenced by multiple biological pathways and is responsive to environmental stimuli. Over one billion people worldwide have hypertension (BP ≥140 mm Hg systolic [SBP] or ≥90 mm Hg diastolic [DBP])2. Even small increments in BP are associated with increased risk of cardiovascular events3. This genome-wide association study of SBP and DBP, which used a multi-stage design in 200,000 individuals of European descent, identified 16 novel loci: six of these loci contain genes previously known or suspected to regulate BP (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other 10 provide new clues to BP physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke, and coronary artery disease, but not kidney disease or kidney function. We also observed associations with BP in East Asian, South Asian, and African ancestry individuals. Our findings provide new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention. PMID:21909115

  3. The Genetic Link between Parkinson's Disease and the Kynurenine Pathway Is Still Missing

    PubMed Central

    Török, Nóra; Török, Rita; Szolnoki, Zoltán; Somogyvári, Ferenc; Klivényi, Péter; Vécsei, László

    2015-01-01

    Background. There is substantial evidence that the kynurenine pathway (KP) plays a role in the normal physiology of the brain and is involved in the pathology of neurodegenerative disorders such as Huntington's disease and Parkinson's disease (PD). Objective. We set out to investigate the potential roles in PD of single nucleotide polymorphisms (SNPs) from one of the key enzymes of the KP, kynurenine 3-monooxygenase (KMO). Methods. 105 unrelated, clinically definitive PD patients and 131 healthy controls were enrolled to investigate the possible effects of the different alleles of KMO. Fluorescently labeled TaqMan probes were used for allele discrimination. Results. None of the four investigated SNPs proved to be associated with PD or influenced the age at onset of the disease. Conclusions. The genetic link between the KP and PD is still missing. The investigated SNPs presumably do not appear to influence the function of KMO and probably do not contain binding sites for regulatory proteins of relevance in PD. This is the first study to assess the genetic background behind the biochemical alterations of the kynurenine pathway in PD, directing the attention to this previously unexamined field. PMID:25785227

  4. Comparison of LAIR-1 genetic pathways in murine vs human internal organs.

    PubMed

    Sun, Shuqiu; Jiao, Yan; Wei, Wei; Postlethwaite, Arnold E; Gu, Weikuan; Sun, Dianjun

    2014-11-15

    Growing evidence suggests that defective expression or dysfunction of LAIR-1, a novel immunoinhibitory receptor for collagen, is closely associated with some autoimmune diseases, cancers, as well as viral infections. We analyzed the variation of LAIR-1 genetic pathways in murine versus human internal organs, including the lung and brain. The results showed that, under physiological conditions, LAIR-1 links more closely to the common genes in mouse than in human, which poses tissue specificity. It means that mice experimental data in relation to the role of LAIR-1 immune regulation may be overestimated when applied to assess human conditions. Moreover, we found that the in vivo interaction of LAIR-1 with LAIR-2 rarely occurs, implying that the species difference in LAIR-1 genetic pathways could not be primarily attributed to the existence of human LAIR-2. In summary, this study opens the door for insight into LAIR-1 functions inside the human body, and raises concern as to extrapolative credibility of the murine model in biomedical research.

  5. Genetic Variation Within Adrenergic Pathways Determines In Vivo Effects of Presynaptic Stimulation in Humans

    PubMed Central

    Fung, Maple M.; Nguyen, Carie; Mehtani, Parag; Salem, Rany M.; Perez, Brandon; Thomas, Brenda; Das, Madhusudan; Schork, Nicholas J.; Mahata, Sushil K.; Ziegler, Michael G.; O’Connor, Daniel T.

    2009-01-01

    Background Catecholamines govern stress blood pressure responses. Catecholaminergic responses may be partially genetic and contribute to the complex heritability of hypertension. Methods and Results To evaluate catecholaminergic responses without systemic counterregulation, we infused graded concentrations of tyramine, an indirect presynaptic norepinephrine releaser, into dorsal hand veins of 49 normotensive men and women of 5 ethnicities. Vascular responses were coupled to common (minor allele frequency >10%) single-nucleotide polymorphisms at adrenergic target loci within presynaptic pathways. Significance was set at P<0.003 after Bonferroni correction. Generalized analysis of molecular variance (GAMOVA) was performed to determine whether genetic admixture contributed to results. Venoconstriction progressed to 47% with increasing concentrations of tyramine (0.129 to 25.8 mmol/L; P<0.001). Family history of hypertension (P<0.001) and female sex (P=0.02) predicted blunted tyramine responses. Two genetic loci significantly predicted vascular response: chromogranin B, which encodes a protein that catalyzes catecholamine vesicle formation (CHGB, exon 4, Glu348Glu; P=0.002), and cytochrome b-561 (CYB561, intron 1, C719G; P<0.001), an electron shuttle for catecholamine synthesis. Stepwise regression suggested important effects for the CHGB locus, with polymorphisms for the vacuolar-ATPase β-subunit (ATP6V1B1, exon 1, Ile30Thr) and flavin-containing monooxygenase-3 (FMO3, exon 3, Lys158Glu, P=0.002). GAMOVA did not show a significant relationship between overall genetic profile and hand-vein constriction (P=0.29), which indicates that population stratification did not contribute to this phenotype. Conclusions Locally infused tyramine produced dose-dependent pressor responses, predicted by family history of hypertension, sex, and genetic variants at loci, particularly CHGB, that encode the biosynthesis, storage, and metabolism of catecholamines. Such variants may

  6. Chemical Pathways Connecting Lead(II) Iodide and Perovskite via Polymeric Plumbate(II) Fiber.

    PubMed

    Guo, Yunlong; Shoyama, Kazutaka; Sato, Wataru; Matsuo, Yutaka; Inoue, Kento; Harano, Koji; Liu, Chao; Tanaka, Hideyuki; Nakamura, Eiichi

    2015-12-23

    Despite tremendous progress in optoelectronic devices using lead perovskite (CH3NH3(+)PbI3(-)), there has been a paucity of mechanistic information on how photoactive micron-sized crystals of lead perovskite grow from a mixture of a layered crystal of lead(II) iodide and methylammonium iodide mediated by a polar solvent, DMSO or DMF. We report here that the whole process of the lead perovskite synthesis consists of a series of equilibria driven by reversible solvent participation involving a polymeric strip of plumbate(II) oligomer as a key intermediate. A significant finding includes quick decomposition of perovskite crystal upon exposure to DMSO or DMF at room temperature, where the solvent molecules act as a base to remove acidic ammonium iodide from the perovskite crystal. This observation accounts for the difficulty in controlling perovskite solar cell fabrication. Overall, the polar solvent is indispensible first to degrade a 2-D sheet of crystals of lead(II) iodide into 1-D fibrous intermediates and then to promote Oswald ripening of perovskite crystals. The detailed chemical information provided here will help to rationalize the photovoltaic device studies that have so far remained empirical and to open a new venue to a developing field of microscale lead perovskite devices, as illustrated by fabrication of photovoltaic devices and photodetectors.

  7. Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

    PubMed Central

    2012-01-01

    Background Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. Methods To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry. Results Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. Conclusions Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in

  8. Biotechnology of polyketides: New breath of life for the novel antibiotic genetic pathways discovery through metagenomics

    PubMed Central

    Gomes, Elisângela Soares; Schuch, Viviane; de Macedo Lemos, Eliana Gertrudes

    2013-01-01

    The discovery of secondary metabolites produced by microorganisms (e.g., penicillin in 1928) and the beginning of their industrial application (1940) opened new doors to what has been the main medication source for the treatment of infectious diseases and tumors. In fact, approximately 80 years after the discovery of the first antibiotic compound, and despite all of the warnings about the failure of the “goose that laid the golden egg,” the potential of this wealth is still inexorable: simply adjust the focus from “micro” to “nano”, that means changing the look from microorganisms to nanograms of DNA. Then, the search for new drugs, driven by genetic engineering combined with metagenomic strategies, shows us a way to bypass the barriers imposed by methodologies limited to isolation and culturing. However, we are far from solving the problem of supplying new molecules that are effective against the plasticity of multi- or pan-drug-resistant pathogens. Although the first advances in genetic engineering date back to 1990, there is still a lack of high-throughput methods to speed up the screening of new genes and design new molecules by recombination of pathways. In addition, it is necessary an increase in the variety of heterologous hosts and improvements throughout the full drug discovery pipeline. Among numerous studies focused on this subject, those on polyketide antibiotics stand out for the large technical-scientific efforts that established novel solutions for the transfer/engineering of major metabolic pathways using transposons and other episomes, overcoming one of the main methodological constraints for the heterologous expression of major pathways. In silico prediction analysis of three-dimensional enzymatic structures and advances in sequencing technologies have expanded access to the metabolic potential of microorganisms. PMID:24688489

  9. Biotechnology of polyketides: new breath of life for the novel antibiotic genetic pathways discovery through metagenomics.

    PubMed

    Gomes, Elisângela Soares; Schuch, Viviane; de Macedo Lemos, Eliana Gertrudes

    2013-12-01

    The discovery of secondary metabolites produced by microorganisms (e.g., penicillin in 1928) and the beginning of their industrial application (1940) opened new doors to what has been the main medication source for the treatment of infectious diseases and tumors. In fact, approximately 80 years after the discovery of the first antibiotic compound, and despite all of the warnings about the failure of the "goose that laid the golden egg," the potential of this wealth is still inexorable: simply adjust the focus from "micro" to "nano", that means changing the look from microorganisms to nanograms of DNA. Then, the search for new drugs, driven by genetic engineering combined with metagenomic strategies, shows us a way to bypass the barriers imposed by methodologies limited to isolation and culturing. However, we are far from solving the problem of supplying new molecules that are effective against the plasticity of multi- or pan-drug-resistant pathogens. Although the first advances in genetic engineering date back to 1990, there is still a lack of high-throughput methods to speed up the screening of new genes and design new molecules by recombination of pathways. In addition, it is necessary an increase in the variety of heterologous hosts and improvements throughout the full drug discovery pipeline. Among numerous studies focused on this subject, those on polyketide antibiotics stand out for the large technical-scientific efforts that established novel solutions for the transfer/engineering of major metabolic pathways using transposons and other episomes, overcoming one of the main methodological constraints for the heterologous expression of major pathways. In silico prediction analysis of three-dimensional enzymatic structures and advances in sequencing technologies have expanded access to the metabolic potential of microorganisms.

  10. Genetic variants in endotoxin signalling pathway, domestic endotoxin exposure and asthma exacerbations.

    PubMed

    Kljaic-Bukvic, Blazenka; Blekic, Mario; Aberle, Neda; Curtin, John A; Hankinson, Jenny; Semic-Jusufagic, Aida; Belgrave, Danielle; Simpson, Angela; Custovic, Adnan

    2014-10-01

    We investigated the interaction between genetic variants in endotoxin signalling pathway and domestic endotoxin exposure in relation to asthma presence, and amongst children with asthma, we explored the association of these genetic variants and endotoxin exposure with hospital admissions due to asthma exacerbations. In a case-control study, we analysed data from 824 children (417 asthmatics, 407 controls; age 5-18 yr). Amongst asthmatics, we extracted data on hospitalization for asthma exacerbation from medical records. Endotoxin exposure was measured in dust samples collected from homes. We included 26 single-nucleotide polymorphisms (SNPs) in the final analysis (5 CD14, 7LY96 and 14 TLR4). Two variants remained significantly associated with hospital admissions with asthma exacerbations after correction for multiple testing: for CD14 SNP rs5744455, carriers of T allele had decreased risk of repeated hospital admissions compared with homozygotes for C allele [OR (95% CI), 0.42 (0.25-0.88), p = 0.01, False Discovery Rate (FDR) p = 0.02]; for LY96 SNP rs17226566, C-allele carriers were at a lower risk of hospital admissions compared with T-allele homozygotes [0.59 (0.38-0.90), p = 0.01, FDR p = 0.04]. We observed two interactions between SNPs in CD14 and LY96 with environmental endotoxin exposure in relation to hospital admissions due to asthma exacerbation which remained significant after correction for multiple testing (CD14 SNPs rs2915863 and LY96 SNP rs17226566). Amongst children with asthma, genetic variants in CD14 and LY96 may increase the risk of hospital admissions with acute exacerbations. Polymorphisms in endotoxin pathway interact with domestic endotoxin exposure in further modification of the risk of hospitalization. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Genetic immunization based on the ubiquitin-fusion degradation pathway against Trypanosoma cruzi

    SciTech Connect

    Chou, Bin; Hiromatsu, Kenji; Hisaeda, Hajime; Duan, Xuefeng; Imai, Takashi; Murata, Shigeo; Tanaka, Keiji; Himeno, Kunisuke

    2010-02-12

    Cytotoxic CD8{sup +} T cells are particularly important to the development of protective immunity against the intracellular protozoan parasite, Trypanosoma cruzi, the etiological agent of Chagas disease. We have developed a new effective strategy of genetic immunization by activating CD8{sup +} T cells through the ubiquitin-fusion degradation (UFD) pathway. We constructed expression plasmids encoding the amastigote surface protein-2 (ASP-2) of T. cruzi. To induce the UFD pathway, a chimeric gene encoding ubiquitin fused to ASP-2 (pUB-ASP-2) was constructed. Mice immunized with pUB-ASP-2 presented lower parasitemia and longer survival period, compared with mice immunized with pASP-2 alone. Depletion of CD8{sup +} T cells abolished protection against T. cruzi in mice immunized with pUB-ASP-2 while depletion of CD4{sup +} T cells did not influence the effective immunity. Mice deficient in LMP2 or LMP7, subunits of immunoproteasomes, were not able to develop protective immunity induced. These results suggest that ubiquitin-fused antigens expressed in antigen-presenting cells were effectively degraded via the UFD pathway, and subsequently activated CD8{sup +} T cells. Consequently, immunization with pUB-ASP-2 was able to induce potent protective immunity against infection of T. cruzi.

  12. Phenotypic categorization of genetic skin diseases reveals new relations between phenotypes, genes and pathways

    PubMed Central

    Sadreyev, Ruslan I.; Feramisco, Jamison D.; Tsao, Hensin; Grishin, Nick V.

    2009-01-01

    Motivation: Systematic analysis of connection between proteins, their cellular function and phenotypic manifestations in disease is a central problem of biological and clinical research. The solution to this problem requires the development of new approaches to link the rapidly growing dataset of gene–disease associations with the many complex and overlapping phenotypes of human disease. Results: We analyze genetic skin disorders and suggest a manually designed set of elementary phenotypes whose combinations define diseases as points in a multidimensional space, providing a basis for phenotypic disease clustering. Placing the known gene–disease associations in the context of this space reveals new patterns that suggest previously unknown functional links between proteins, signaling pathways and disease phenotypes. For example, analysis of telangiectasias (spider vein diseases) reveals a previously unrecognized interplay between the TGF-β signaling pathway and pentose phosphate pathway. This interaction may mediate glucose-dependent regulation of TGF-β signaling, providing a clue to the known association between angiopathies and diabetes and implying new gene candidates for mutational analysis and drug targeting. Contact: grishin@chop.swmed.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:19744994

  13. BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes.

    PubMed

    Zhang, Qihong; Seo, Seongjin; Bugge, Kevin; Stone, Edwin M; Sheffield, Val C

    2012-05-01

    There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet-Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7(-/-) mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect.

  14. The Independent Acquisition of Plant Root Nitrogen-Fixing Symbiosis in Fabids Recruited the Same Genetic Pathway for Nodule Organogenesis

    PubMed Central

    Svistoonoff, Sergio; Benabdoun, Faiza Meriem; Nambiar-Veetil, Mathish; Imanishi, Leandro; Vaissayre, Virginie; Cesari, Stella; Diagne, Nathalie; Hocher, Valérie; de Billy, Françoise; Bonneau, Jocelyne; Wall, Luis; Ykhlef, Nadia; Rosenberg, Charles; Bogusz, Didier; Franche, Claudine; Gherbi, Hassen

    2013-01-01

    Only species belonging to the Fabid clade, limited to four classes and ten families of Angiosperms, are able to form nitrogen-fixing root nodule symbioses (RNS) with soil bacteria. This concerns plants of the legume family (Fabaceae) and Parasponia (Cannabaceae) associated with the Gram-negative proteobacteria collectively called rhizobia and actinorhizal plants associated with the Gram-positive actinomycetes of the genus Frankia. Calcium and calmodulin-dependent protein kinase (CCaMK) is a key component of the common signaling pathway leading to both rhizobial and arbuscular mycorrhizal symbioses (AM) and plays a central role in cross-signaling between root nodule organogenesis and infection processes. Here, we show that CCaMK is also needed for successful actinorhiza formation and interaction with AM fungi in the actinorhizal tree Casuarina glauca and is also able to restore both nodulation and AM symbioses in a Medicago truncatula ccamk mutant. Besides, we expressed auto-active CgCCaMK lacking the auto-inhibitory/CaM domain in two actinorhizal species: C. glauca (Casuarinaceae), which develops an intracellular infection pathway, and Discaria trinervis (Rhamnaceae) which is characterized by an ancestral intercellular infection mechanism. In both species, we found induction of nodulation independent of Frankia similar to response to the activation of CCaMK in the rhizobia-legume symbiosis and conclude that the regulation of actinorhiza organogenesis is conserved regardless of the infection mode. It has been suggested that rhizobial and actinorhizal symbioses originated from a common ancestor with several independent evolutionary origins. Our findings are consistent with the recruitment of a similar genetic pathway governing rhizobial and Frankia nodule organogenesis. PMID:23741336

  15. The independent acquisition of plant root nitrogen-fixing symbiosis in Fabids recruited the same genetic pathway for nodule organogenesis.

    PubMed

    Svistoonoff, Sergio; Benabdoun, Faiza Meriem; Nambiar-Veetil, Mathish; Imanishi, Leandro; Vaissayre, Virginie; Cesari, Stella; Diagne, Nathalie; Hocher, Valérie; de Billy, Françoise; Bonneau, Jocelyne; Wall, Luis; Ykhlef, Nadia; Rosenberg, Charles; Bogusz, Didier; Franche, Claudine; Gherbi, Hassen

    2013-01-01

    Only species belonging to the Fabid clade, limited to four classes and ten families of Angiosperms, are able to form nitrogen-fixing root nodule symbioses (RNS) with soil bacteria. This concerns plants of the legume family (Fabaceae) and Parasponia (Cannabaceae) associated with the Gram-negative proteobacteria collectively called rhizobia and actinorhizal plants associated with the Gram-positive actinomycetes of the genus Frankia. Calcium and calmodulin-dependent protein kinase (CCaMK) is a key component of the common signaling pathway leading to both rhizobial and arbuscular mycorrhizal symbioses (AM) and plays a central role in cross-signaling between root nodule organogenesis and infection processes. Here, we show that CCaMK is also needed for successful actinorhiza formation and interaction with AM fungi in the actinorhizal tree Casuarina glauca and is also able to restore both nodulation and AM symbioses in a Medicago truncatula ccamk mutant. Besides, we expressed auto-active CgCCaMK lacking the auto-inhibitory/CaM domain in two actinorhizal species: C. glauca (Casuarinaceae), which develops an intracellular infection pathway, and Discaria trinervis (Rhamnaceae) which is characterized by an ancestral intercellular infection mechanism. In both species, we found induction of nodulation independent of Frankia similar to response to the activation of CCaMK in the rhizobia-legume symbiosis and conclude that the regulation of actinorhiza organogenesis is conserved regardless of the infection mode. It has been suggested that rhizobial and actinorhizal symbioses originated from a common ancestor with several independent evolutionary origins. Our findings are consistent with the recruitment of a similar genetic pathway governing rhizobial and Frankia nodule organogenesis.

  16. Genotype-environment interactions reveal causal pathways that mediate genetic effects on phenotype.

    PubMed

    Gagneur, Julien; Stegle, Oliver; Zhu, Chenchen; Jakob, Petra; Tekkedil, Manu M; Aiyar, Raeka S; Schuon, Ann-Kathrin; Pe'er, Dana; Steinmetz, Lars M

    2013-01-01

    Unraveling the molecular processes that lead from genotype to phenotype is crucial for the understanding and effective treatment of genetic diseases. Knowledge of the causative genetic defect most often does not enable treatment; therefore, causal intermediates between genotype and phenotype constitute valuable candidates for molecular intervention points that can be therapeutically targeted. Mapping genetic determinants of gene expression levels (also known as expression quantitative trait loci or eQTL studies) is frequently used for this purpose, yet distinguishing causation from correlation remains a significant challenge. Here, we address this challenge using extensive, multi-environment gene expression and fitness profiling of hundreds of genetically diverse yeast strains, in order to identify truly causal intermediate genes that condition fitness in a given environment. Using functional genomics assays, we show that the predictive power of eQTL studies for inferring causal intermediate genes is poor unless performed across multiple environments. Surprisingly, although the effects of genotype on fitness depended strongly on environment, causal intermediates could be most reliably predicted from genetic effects on expression present in all environments. Our results indicate a mechanism explaining this apparent paradox, whereby immediate molecular consequences of genetic variation are shared across environments, and environment-dependent phenotypic effects result from downstream integration of environmental signals. We developed a statistical model to predict causal intermediates that leverages this insight, yielding over 400 transcripts, for the majority of which we experimentally validated their role in conditioning fitness. Our findings have implications for the design and analysis of clinical omics studies aimed at discovering personalized targets for molecular intervention, suggesting that inferring causation in a single cellular context can benefit from

  17. Between destiny and disease: genetics and molecular pathways of human central nervous system aging

    PubMed Central

    Glorioso, Christin; Sibille, Etienne

    2010-01-01

    Aging of the human brain is associated with “normal” functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human postmortem brain microarray studies, which we hypothesize, point to a potential genetically-controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches. PMID:21130140

  18. Genetic interplay between human longevity and metabolic pathways - a large-scale eQTL study.

    PubMed

    Häsler, Robert; Venkatesh, Geetha; Tan, Qihua; Flachsbart, Friederike; Sinha, Anupam; Rosenstiel, Philip; Lieb, Wolfgang; Schreiber, Stefan; Christensen, Kaare; Christiansen, Lene; Nebel, Almut

    2017-08-01

    Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study (eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years. Our eQTL-based approach revealed for the first time that human longevity is associated with a depletion of metabolic pathways in a genotype-dependent and independent manner. Further analyses indicated that 20% of the differentially expressed genes are influenced by genetic variants in cis. The subsequent study of twins showed that the transcriptional activity of a third of the differentially regulated genes is heritable. These findings suggest that longevity-associated biological processes such as altered metabolism are, to a certain extent, also the driving force of longevity rather than just a consequence of old age. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  19. Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway.

    PubMed

    Long, Miao; Liu, Yi; Cao, Yu; Wang, Nan; Dang, Meng; He, Jianbin

    2016-10-21

    Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress-related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of

  20. Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway

    PubMed Central

    Long, Miao; Liu, Yi; Cao, Yu; Wang, Nan; Dang, Meng; He, Jianbin

    2016-01-01

    Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress-related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of

  1. MYH biallelic mutation can inactivate the two genetic pathways of colorectal cancer by APC or MLH1 transversions.

    PubMed

    Lefevre, Jérémie H; Colas, Chrystelle; Coulet, Florence; Bonilla, Carolina; Mourra, Najat; Flejou, Jean-Francois; Tiret, Emmanuel; Bodmer, Walter; Soubrier, Florent; Parc, Yann

    2010-12-01

    MYH associated polyposis is a hereditary syndrome responsible for early colorectal cancer with a distinct genetic pathway from the Familial Adenomatous Polyposis or the Hereditary Non Polyposis Colorectal Cancer syndrome. We have studied a family with three members bearing a biallelic mutation in MYH at c.1185_1186dup. One patient who developed colon cancer had loss of expression of MLH1 on tumoral tissue and microsatellite instability (MSI) phenotype. Analysis of MLH1 based on his blood sample revealed no germline mutation or large genomic deletion. No methylation of the promoter was identified in tumoral DNA. No transversion mutations were identified in APC or KRAS in tumor DNA of this patient. Loss of expression of MLH1 was due to a transversion in intron 7 at position +5 (c.588 + 5G > T) leading to a complete deletion of exon 7 at the RNA level. This observation demonstrates that MLH1 can be a target of MYH transversions leading to MSI phenotype.

  2. Effects of Lead Exposure and Genetic Polymorphisms on ALAD and GPx Activities in Brazilian Battery Workers.

    PubMed

    da Cunha Martins, Airton; Mazzaron Barcelos, Gustavo Rafael; Jacob Ferreira, Anna Laura Bechara; de Souza, Marilesia Ferreira; de Syllos Cólus, Ilce Mara; Antunes, Lusânia Maria Greggi; Bastos Paoliello, Monica Maria; Adeyemi, Joseph A; Barbosa, Fernando

    2015-01-01

    Lead (Pb) is a toxic metal that is widely used by metallurgical industries such as car battery recycling. Exposure to the metal may modify the redox status of the cells and consequently result in changes in activities of important enzymes such as delta-aminolevulinic acid dehydratase (ALAD) and glutathione peroxidase (GPx). Similarly, genetic polymorphisms may modulate the activities of enzymes related to detoxification processes of the metal and may modify Pb body burden. Therefore, the aims of the present study were (i) to evaluate the correlation between blood lead levels (BLL) and activities of the enzymes ALAD and GPx, and (ii) to determine whether activities of these enzymes may be influenced by polymorphisms in ALAD and GPx genes in Brazilian automotive battery workers chronically exposed to Pb, as well as the effects of these polymorphisms on BLL. Our study included 257 participants; BLL were determined by inductively couple plasma-mass spectrometry (ICP-MS), and the activities of the enzymes ALAD and GPx were quantified spectrophotometrically; and genotyping of ALAD (rs1800435) and GPx-1 (rs1800668) polymorphisms was performed by TaqMan assays (real-time polymerase chain reaction, RT-PCR). Significant negative correlations were found between BLL and ALAD activity. Subjects who carried at least one polymorphic allele for ALAD gene displayed markedly lower ALAD activities, while no significant effect was observed regarding GPx-1 polymorphism and activity of the same enzyme. Further, ALAD and GPx-1 polymorphisms exerted no marked influence on BLL. Taken together, our results showed that BLL affected ALAD but not GPx activities, and these were not modulated by polymorphisms in ALAD and GPx gene. Further, the rs1800435 SNP showed a tendency to modulate ALAD activity, while the rs1800668 SNP did not modulate GPx activity in Brazilian automotive battery workers exposed to Pb.

  3. fDWI Evaluation of Hypothalamic Appetite Regulation Pathways in Mice Genetically Deficient in Leptin or Neuropeptide Y.

    PubMed

    Lizarbe, Blanca; López-Larrubia, Pilar; Cerdán, Sebastián

    2015-12-01

    We evaluate the contribution of leptin-dependent anorexigenic pathways and neuropeptide Y (NPY)-dependent orexigenic pathways to the changes in hypothalamic water diffusion parameters observed in vivo by functional diffusion weighted MRI (fDWI). Mice genetically deficient in leptin (B6.V-Lep (ob) /J) or NPY (129S-Npy (tm1Rpa) /J) and the corresponding wild-type controls, were subjected to sequential isocaloric feeding, fasting and recovery regimes. Non-invasive fDWI measurements were performed under these conditions, and complemented with parallel determinations of food and water consumption, respiratory exchange ratio (RER), locomotor activity and endocrine profiles. Control mice showed significant increases in hypothalamic water diffusion parameters upon fasting, returning to normal values in the recovery period. Leptin deficient mice depicted permanently increased water diffusion parameters under all feeding conditions as compared to wild type controls, without important changes upon fasting or recovery. These results paralleled sustained increases in food and water intake, significantly augmented body weight, and decreased RER values or locomotor activity, thus configuring an obese phenotype. NPY-deficient mice showed significantly reduced increases (or even slight decreases) in the water diffusion parameters upon fasting as compared to wild type controls, paralleled by decreased food and water intake during the recovery period. In conclusion, leptin deficiency results in sustained orexigenic stimulation, leading to increased water diffusion parameters, while NPY deficiency lead to reduced orexigenic stimulation and water diffusion parameters. Diffusion changes are proposed to reflect net astrocytic volume changes induced by the balance between the orexigenic and anorexigenic firings of AgRP/NPY and POMC/CART neurons, respectively. Together, our results suggest that fDWI provides an adequate tool to investigate hypothalamic appetite disorders.

  4. Saccharomyces Cerevisiae Pac2 Functions with Cin1, 2 and 4 in a Pathway Leading to Normal Microtubule Stability

    PubMed Central

    Hoyt, M. A.; Macke, J. P.; Roberts, B. T.; Geiser, J. R.

    1997-01-01

    The products of the Saccharomyces cerevisiae CIN1, CIN2 and CIN4 genes participate in a nonessential pathway required for normal microtubule function. In this article, we demonstrate that the product of PAC2 also functions in this pathway. PAC2 deletion mutants displayed phenotypes and genetic interactions similar to those caused by cin1Δ, cin2Δ and cin4Δ. These include cold-sensitive microtubule structures and sensitivity to the microtubule depolymerizing agent benomyl. Involvement in a common functional pathway is indicated by the observation that all double mutant combinations are viable and no more affected than any single mutant. In addition, extra copies of CIN1 were found to suppress the benomyl sensitivity of pac2Δ, cin2Δ and cin4Δ, but not that caused by other mutations that affect microtubule function. Cin1p and Pac2p were found to be related in sequence to mammalian proteins that aid in the folding of β-tubulin into an assembly-competent state. Alleles of CIN1 were identified that could suppress the benomyl sensitivity of cin4-4 in a highly specific fashion. Our findings suggest that the guanine nucleotide-binding Cin4p interacts with Cin1p and regulates its tubulin folding activity. PMID:9215891

  5. Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids.

    PubMed

    Kondo, Natsuki; Ohno, Yusuke; Yamagata, Maki; Obara, Takashi; Seki, Naoya; Kitamura, Takuya; Naganuma, Tatsuro; Kihara, Akio

    2014-10-27

    The long-chain base phytosphingosine is a component of sphingolipids and exists in yeast, plants and some mammalian tissues. Phytosphingosine is unique in that it possesses an additional hydroxyl group compared with other long-chain bases. However, its metabolism is unknown. Here we show that phytosphingosine is metabolized to odd-numbered fatty acids and is incorporated into glycerophospholipids both in yeast and mammalian cells. Disruption of the yeast gene encoding long-chain base 1-phosphate lyase, which catalyzes the committed step in the metabolism of phytosphingosine to glycerophospholipids, causes an ~40% reduction in the level of phosphatidylcholines that contain a C15 fatty acid. We also find that 2-hydroxypalmitic acid is an intermediate of the phytosphingosine metabolic pathway. Furthermore, we show that the yeast MPO1 gene, whose product belongs to a large, conserved protein family of unknown function, is involved in phytosphingosine metabolism. Our findings provide insights into fatty acid diversity and identify a pathway by which hydroxyl group-containing lipids are metabolized.

  6. Genetic analysis for cognitive flexibility in Trail Making Test in attention deficit hyperactivity disorder patients from SNP, gene to pathway.

    PubMed

    Zhang, Kunlin; Fan, Zili; Wang, Yufeng; Faraone, Stephen V; Yang, Li; Chang, Suhua

    2017-10-03

    Investigation of the genetic basis of endophenotype and analysis the pathways with multiple genes of small effects might increase the understanding of the genetic basis of attention deficit hyperactivity disorder (ADHD). Here we aimed to explore the genetic basis of cognitive flexibility in ADHD at SNP, gene and pathway level. The Trail-Making Test (TMT) was used to test the cognitive flexibility of 788 ADHD patients. A genome-wide association analysis of cognitive flexibility was conducted for 644,166 single nucleotide polymorphisms (SNPs). The top SNP rs2049161 (P = 5.08e-7) involved gene DLGAP1 and the top gene CADPS2 in the gene-based analysis obtained much literature evidence to be associated with psychiatric disorders. Gene expression and network analysis showed their contribution to cognition function. The interval enrichment analysis highlighted potential contribution of 'adenylate cyclase activity' and ADCY2 to cognitive flexibility. Candidate pathway-based analysis for all SNPs found glutamate system, neurite outgrowth and noradrenergic system related pathways were significantly associated with cognitive flexibility (FDR < 0.05), among which the neurite outgrowth pathway was also associated with ADHD symptoms. This study provides evidence for the genes and pathways associated with cognitive flexibility and facilitate the uncovering of the genetic basis of ADHD.

  7. Arsenic alters vascular smooth muscle cell focal adhesion complexes leading to activation of FAK-src mediated pathways

    SciTech Connect

    Pysher, Michele D. Chen, Qin M.; Vaillancourt, Richard R.

    2008-09-01

    Chronic exposure to arsenic has been linked to tumorigenesis, cardiovascular disease, hypertension, atherosclerosis, and peripheral vascular disease; however, the molecular mechanisms underlying its pathological effects remain elusive. In this study, we investigated arsenic-induced alteration of focal adhesion protein complexes in normal, primary vascular smooth muscle cells. We demonstrate that exposure to environmentally relevant concentrations of arsenic (50 ppb As{sup 3+}) can alter focal adhesion protein co-association leading to activation of downstream pathways. Co-associated proteins were identified and quantitated via co-immunoprecipitation, SDS-PAGE, and Western blot analysis followed by scanning densitometry. Activation of MAPK pathways in total cell lysates was evaluated using phosphor-specific antibodies. In our model, arsenic treatment caused a sustained increase in FAK-src association and activation, and induced the formation of unique signaling complexes (beginning after 3-hour As{sup 3+} exposure and continuing throughout the 12-hour time course studied). The effects of these alterations were manifested as chronic stimulation of downstream PAK, ERK and JNK pathways. Past studies have demonstrated that these pathways are involved in cellular survival, growth, proliferation, and migration in VSMCs.

  8. Genetic Disruption of the Copulatory Plug in Mice Leads to Severely Reduced Fertility

    PubMed Central

    Dean, Matthew D.

    2013-01-01

    Seminal fluid proteins affect fertility at multiple stages in reproduction. In many species, a male's ejaculate coagulates to form a copulatory plug. Although taxonomically widespread, the molecular details of plug formation remain poorly understood, limiting our ability to manipulate the structure and understand its role in reproduction. Here I show that male mice knockouts for transglutaminase IV (Tgm4) fail to form a copulatory plug, demonstrating that this gene is necessary for plug formation and lending a powerful new genetic tool to begin characterizing plug function. Tgm4 knockout males show normal sperm count, sperm motility, and reproductive morphology. However, very little of their ejaculate migrates into the female's reproductive tract, suggesting the plug prevents ejaculate leakage. Poor ejaculate migration leads to a reduction in the proportion of oocytes fertilized. However, Tgm4 knockout males fertilized between 3–11 oocytes, which should be adequate for a normal litter. Nevertheless, females mated to Tgm4 knockout males for approximately 14 days were significantly less likely to give birth to a litter compared to females mated to wild-type males. Therefore, it appears that the plug also affects post-fertilization events such as implantation and/or gestation. This study shows that a gene influencing the viscosity of seminal fluid has a major influence on male fertility. PMID:23341775

  9. Overview of the Cancer Genetics and Pathway Curation tasks of BioNLP Shared Task 2013

    PubMed Central

    2015-01-01

    Background Since their introduction in 2009, the BioNLP Shared Task events have been instrumental in advancing the development of methods and resources for the automatic extraction of information from the biomedical literature. In this paper, we present the Cancer Genetics (CG) and Pathway Curation (PC) tasks, two event extraction tasks introduced in the BioNLP Shared Task 2013. The CG task focuses on cancer, emphasizing the extraction of physiological and pathological processes at various levels of biological organization, and the PC task targets reactions relevant to the development of biomolecular pathway models, defining its extraction targets on the basis of established pathway representations and ontologies. Results Six groups participated in the CG task and two groups in the PC task, together applying a wide range of extraction approaches including both established state-of-the-art systems and newly introduced extraction methods. The best-performing systems achieved F-scores of 55% on the CG task and 53% on the PC task, demonstrating a level of performance comparable to the best results achieved in similar previously proposed tasks. Conclusions The results indicate that existing event extraction technology can generalize to meet the novel challenges represented by the CG and PC task settings, suggesting that extraction methods are capable of supporting the construction of knowledge bases on the molecular mechanisms of cancer and the curation of biomolecular pathway models. The CG and PC tasks continue as open challenges for all interested parties, with data, tools and resources available from the shared task homepage. PMID:26202570

  10. Genetic Profiling of the Isoprenoid and Sterol Biosynthesis Pathway Genes of Trypanosoma cruzi

    PubMed Central

    Cosentino, Raúl O.; Agüero, Fernán

    2014-01-01

    In Trypanosoma cruzi the isoprenoid and sterol biosynthesis pathways are validated targets for chemotherapeutic intervention. In this work we present a study of the genetic diversity observed in genes from these pathways. Using a number of bioinformatic strategies, we first identified genes that were missing and/or were truncated in the T. cruzi genome. Based on this analysis we obtained the complete sequence of the ortholog of the yeast ERG26 gene and identified a non-orthologous homolog of the yeast ERG25 gene (sterol methyl oxidase, SMO), and we propose that the orthologs of ERG25 have been lost in trypanosomes (but not in Leishmanias). Next, starting from a set of 16 T. cruzi strains representative of all extant evolutionary lineages, we amplified and sequenced ∼24 Kbp from 22 genes, identifying a total of 975 SNPs or fixed differences, of which 28% represent non-synonymous changes. We observed genes with a density of substitutions ranging from those close to the average (∼2.5/100 bp) to some showing a high number of changes (11.4/100 bp, for the putative lathosterol oxidase gene). All the genes of the pathway are under apparent purifying selection, but genes coding for the sterol C14-demethylase, the HMG-CoA synthase, and the HMG-CoA reductase have the lowest density of missense SNPs in the panel. Other genes (TcPMK, TcSMO-like) have a relatively high density of non-synonymous SNPs (2.5 and 1.9 every 100 bp, respectively). However, none of the non-synonymous changes identified affect a catalytic or ligand binding site residue. A comparative analysis of the corresponding genes from African trypanosomes and Leishmania shows similar levels of apparent selection for each gene. This information will be essential for future drug development studies focused on this pathway. PMID:24828104

  11. Host genetic variation in mucosal immunity pathways influences the upper airway microbiome.

    PubMed

    Igartua, Catherine; Davenport, Emily R; Gilad, Yoav; Nicolae, Dan L; Pinto, Jayant; Ober, Carole

    2017-02-01

    The degree to which host genetic variation can modulate microbial communities in humans remains an open question. Here, we performed a genetic mapping study of the microbiome in two accessible upper airway sites, the nasopharynx and the nasal vestibule, during two seasons in 144 adult members of a founder population of European decent. We estimated the relative abundances (RAs) of genus level bacteria from 16S rRNA gene sequences and examined associations with 148,653 genetic variants (linkage disequilibrium [LD] r (2) < 0.5) selected from among all common variants discovered in genome sequences in this population. We identified 37 microbiome quantitative trait loci (mbQTLs) that showed evidence of association with the RAs of 22 genera (q < 0.05) and were enriched for genes in mucosal immunity pathways. The most significant association was between the RA of Dermacoccus (phylum Actinobacteria) and a variant 8 kb upstream of TINCR (rs117042385; p = 1.61 × 10(-8); q = 0.002), a long non-coding RNA that binds to peptidoglycan recognition protein 3 (PGLYRP3) mRNA, a gene encoding a known antimicrobial protein. A second association was between a missense variant in PGLYRP4 (rs3006458) and the RA of an unclassified genus of family Micrococcaceae (phylum Actinobacteria) (p = 5.10 × 10(-7); q = 0.032). Our findings provide evidence of host genetic influences on upper airway microbial composition in humans and implicate mucosal immunity genes in this relationship.

  12. Evidence of Multi-step Nucleation Leading to Various Crystallization Pathways from an Fe-O-Al Melt

    PubMed Central

    Wang, G. C.; Wang, Q.; Li, S. L.; Ai, X. G.; Fan, C. G.

    2014-01-01

    The crystallization process from a solution begins with nucleation, which determines the structure and size of the resulting crystals. Further understanding of multi-pathway crystallizations from solution through two-step nucleation mechanisms is needed. This study uses density functional theory to probe the thermodynamic properties of alumina clusters at high temperature and reveals the thermodynamic relationship between these clusters and the saturation levels of dissolved oxygen and aluminum in an Fe–O–Al melt. Based on the thermodynamics of cluster formation and the experimental evidence for both excess oxygen in the Fe-O-Al melt and for alumina with a polycrystalline structure in solidified iron, we demonstrate that the appearance of various types of clusters that depends on the saturation ratio determines the nucleation steps that lead to the various crystallization pathways. Such mechanisms may also be important in nucleation and crystallization from solution. PMID:24866413

  13. Mesenchymal chemotaxis requires selective inactivation of myosin II at the leading edge via a noncanonical PLCγ/PKCα pathway.

    PubMed

    Asokan, Sreeja B; Johnson, Heath E; Rahman, Anisur; King, Samantha J; Rotty, Jeremy D; Lebedeva, Irina P; Haugh, Jason M; Bear, James E

    2014-12-22

    Chemotaxis, migration toward soluble chemical cues, is critical for processes such as wound healing and immune surveillance and is exhibited by various cell types, from rapidly migrating leukocytes to slow-moving mesenchymal cells. To study mesenchymal chemotaxis, we observed cell migration in microfluidic chambers that generate stable gradients of platelet-derived growth factor (PDGF). Surprisingly, we found that pathways implicated in amoeboid chemotaxis, such as PI3K and mammalian target of rapamycin signaling, are dispensable for PDGF chemotaxis. Instead, we find that local inactivation of Myosin IIA, through a noncanonical Ser1/2 phosphorylation of the regulatory light chain, is essential. This site is phosphorylated by PKCα, which is activated by an intracellular gradient of diacylglycerol generated by PLCγ. Using a combination of live imaging and gradients of activators/inhibitors in the microfluidic chambers, we demonstrate that this signaling pathway and subsequent inhibition of Myosin II activity at the leading edge are required for mesenchymal chemotaxis.

  14. Heterotrimeric G Proteins and Apoptosis: Intersecting Signaling Pathways Leading to Context Dependent Phenotypes

    PubMed Central

    Yanamadala, Vijay; Negoro, Hideyuki; Denker, Bradley M.

    2010-01-01

    Apoptosis, a programmed cell death mechanism, is a fundamental process during the normal development and somatic maintenance of all multicellular organisms and thus is highly conserved and tightly regulated through numerous signaling pathways. Apoptosis is of particular clinical importance as its dysregulation contributes significantly to numerous human diseases, primarily through changes in the expression and activation of key apoptotic regulators. Each of the four families of heterotrimeric G proteins (Gs, Gi/o, Gq/11 and G12/13) has been implicated in numerous cellular signaling processes, including proliferation, transformation, migration, differentiation, and apoptosis. Heterotrimeric G protein signaling is an important but not widely studied mechanism regulating apoptosis. G protein Signaling and Apoptosis broadly cover two large bodies of literature and share numerous signaling pathways. Examination of the intersection between these two areas is the focus of this review. Several studies have implicated signaling through each of the four heterotrimeric G protein families to regulate apoptosis within numerous disease contexts, but the mechanism(s) are not well defined. Each G protein family has been shown to stimulate and/or inhibit apoptosis in a context-dependent fashion through regulating numerous downstream effectors including the Bcl-2 family, NF-κB, PI3 Kinase, MAP Kinases, and small GTPases. These cell-type specific and G protein coupled receptor dependent effects have led to a complex body of literature of G protein regulation of apoptosis. Here, we review the literature and summarize apoptotic signaling through each of the four heterotrimeric G protein families (and the relevant G protein coupled receptors), and discuss limitations and future directions for research on regulating apoptosis through G protein coupled mechanisms. Continued investigation in this field is essential for the identification of important targets for pharmacological

  15. Identification of Biochemical Pathways Associated with Lead Tolerance and Detoxification in Chrysopogon zizanioides L. Nash (Vetiver) by Metabolic Profiling.

    PubMed

    Pidatala, Venkataramana R; Li, Kefeng; Sarkar, Dibyendu; Ramakrishna, Wusirika; Datta, Rupali

    2016-03-01

    Lead (Pb) is a major urban pollutant, due to deteriorating lead-based paint in houses built before 1978. Phytoremediation is an inexpensive and effective technique for remediation of Pb-contaminated homes. Vetiver (Chrysopogon zizanioides), a noninvasive, fast-growing grass with high biomass, can tolerate and accumulate large quantities of Pb in its tissues. Lead is known to induce phytochelatins and antioxidative enzymes in vetiver; however, the overall impact of Pb stress on metabolic pathways of vetiver is unknown. In the current study, vetiver plants were treated with different concentrations of Pb in a hydroponic setup. Metabolites were extracted and analyzed using LC/MS/MS. Multivariate analysis of metabolites in both root and shoot tissue showed tremendous induction in key metabolic pathways including sugar metabolism, amino acid metabolism, and an increase in production of osmoprotectants, such as betaine and polyols, and metal-chelating organic acids. The data obtained provide a comprehensive insight into the overall stress response mechanisms in vetiver.

  16. An integrative systems genetics approach reveals potential causal genes and pathways related to obesity.

    PubMed

    Kogelman, Lisette J A; Zhernakova, Daria V; Westra, Harm-Jan; Cirera, Susanna; Fredholm, Merete; Franke, Lude; Kadarmideen, Haja N

    2015-10-20

    Obesity is a multi-factorial health problem in which genetic factors play an important role. Limited results have been obtained in single-gene studies using either genomic or transcriptomic data. RNA sequencing technology has shown its potential in gaining accurate knowledge about the transcriptome, and may reveal novel genes affecting complex diseases. Integration of genomic and transcriptomic variation (expression quantitative trait loci [eQTL] mapping) has identified causal variants that affect complex diseases. We integrated transcriptomic data from adipose tissue and genomic data from a porcine model to investigate the mechanisms involved in obesity using a systems genetics approach. Using a selective gene expression profiling approach, we selected 36 animals based on a previously created genomic Obesity Index for RNA sequencing of subcutaneous adipose tissue. Differential expression analysis was performed using the Obesity Index as a continuous variable in a linear model. eQTL mapping was then performed to integrate 60 K porcine SNP chip data with the RNA sequencing data. Results were restricted based on genome-wide significant single nucleotide polymorphisms, detected differentially expressed genes, and previously detected co-expressed gene modules. Further data integration was performed by detecting co-expression patterns among eQTLs and integration with protein data. Differential expression analysis of RNA sequencing data revealed 458 differentially expressed genes. The eQTL mapping resulted in 987 cis-eQTLs and 73 trans-eQTLs (false discovery rate < 0.05), of which the cis-eQTLs were associated with metabolic pathways. We reduced the eQTL search space by focusing on differentially expressed and co-expressed genes and disease-associated single nucleotide polymorphisms to detect obesity-related genes and pathways. Building a co-expression network using eQTLs resulted in the detection of a module strongly associated with lipid pathways. Furthermore, we

  17. Emerging pathways in genetic Parkinson's disease: Potential role of ceramide metabolism in Lewy body disease.

    PubMed

    Bras, Jose; Singleton, Andrew; Cookson, Mark R; Hardy, John

    2008-12-01

    Heterozygous loss-of-function mutations at the glucosecerebrosidase locus have recently been shown to be a potent risk factor for Lewy body disease. Based on this observation, we have re-evaluated the likelihood that the different PARK loci (defined using clinical criteria for disease) may be misleading attempts to find common pathways to pathogenesis. Rather, we suggest, grouping the different loci which lead to different Lewy body disease may be more revealing. Doing this, we suggest that several of the genes involved in disparate Lewy body diseases impinge on ceramide metabolism and we suggest that this may be a common theme for pathogenesis.

  18. Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia.

    PubMed

    Pedersen-Bjergaard, J; Pedersen, M; Roulston, D; Philip, P

    1995-11-01

    Development of myelodysplasia (MDS) with subsequent progression to acute myeloid leukemia (AML) is an example of the multistep process of malignant transformation in which each step often relates to genetic abnormalities that can be directly seen as chromosomal aberrations. Therapy-related MDS and AML (t-MDS and t-AML) may serve as an ideal model for a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is often diagnosed early due to a close patient follow-up. The cytogenetic characteristics at diagnosis were studied in 137 consecutive cases of t-MDS and t-AML, including 22 new cases, and correlated with the clinical characteristics and the course of the disease. Balanced translocations to chromosome bands 11q23 and 21q22 represent primary steps in pathways leading directly to overt t-AML. Specific chromosomal deletions or losses, on the other hand, represent primary or secondary events in alternative pathways leading to t-MDS with potential for subsequent transformation to overt t-AML. Loss of a whole chromosome 7 (-7) or deletion of its long arm (7q-) and deletion of the long arm of a chromosome 5 (5q-) were the most frequent primary abnormalities significantly related to t-MDS. Loss of a whole chromosome 5 (-5) was also a primary event, but surprisingly, was observed equally in t-MDS and in t-AML. Deletion of chromosome 13, including bands q13q14, was another less common primary aberration of t-MDS. Except for -7 and del(13q), these primary aberrations were most often observed together with secondary abnormalities. These included balanced aberrations involving band 3q26 and various deletions of chromosome 3, a gain of a whole chromosome 8, deletions of the short arm or loss of chromosomes 12 and 17, loss of a whole chromosome 18, and deletions of the short arm of chromosome 21. Deletions or loss or chromosomes 5 and 7 were significantly associated with previous therapy with

  19. Assembly Pathway of Hepatitis B Core Virus-like Particles from Genetically Fused Dimers*

    PubMed Central

    Holmes, Kris; Shepherd, Dale A.; Ashcroft, Alison E.; Whelan, Mike; Rowlands, David J.; Stonehouse, Nicola J.

    2015-01-01

    Macromolecular complexes are responsible for many key biological processes. However, in most cases details of the assembly/disassembly of such complexes are unknown at the molecular level, as the low abundance and transient nature of assembly intermediates make analysis challenging. The assembly of virus capsids is an example of such a process. The hepatitis B virus capsid (core) can be composed of either 90 or 120 dimers of coat protein. Previous studies have proposed a trimer of dimers as an important intermediate species in assembly, acting to nucleate further assembly by dimer addition. Using novel genetically-fused coat protein dimers, we have been able to trap higher-order assembly intermediates and to demonstrate for the first time that both dimeric and trimeric complexes are on pathway to virus-like particle (capsid) formation. PMID:25953902

  20. Genetic analysis of photoreceptor action pathways in Arabidopsis thaliana. Progress report

    SciTech Connect

    Not Available

    1991-12-31

    The specific strategies and long-term goals of this proposal remain intact relative to the original proposal. We continue to isolate and characterize photomorphogenic mutants of Arabidopsis thaliana. The molecular and biochemical characterization of one of these mutants, det1, has led to one publication of original data and to one Society for Experimental Biology Symposium paper (see below). The phenotype of a second mutant, det2, has also been studied during this funding period. In addition, we have continued work on a general strategy to isolate mutations in trans-acting regulatory factors that mediate light-regulated gene expression, and have identified several potentially interesting regulatory mutants. In the third funding period, we will concentrate on the genetical, biochemical, and molecular characterization of these new mutants. Construction of double mutants between the new mutants and the previously characterized morphological mutants should allow us to construct a pathway for light-regulated seedling development in Arabidopsis.

  1. [Genetic code: codon bases--the symbols of amino acid synthesis and catabolism pathways].

    PubMed

    Konyshev, V A

    1983-01-01

    The correlations between genetic codes of amino acids and pathways of synthesis and catabolism of carbon backbone of amino acids are considered. Codes of amino acids which are synthesized from oxoacids of glycolysis, the Krebs cycle and glyoxalic cycle via transamination without any additional chemical reactions, are initiated with guanine (alanine, glutamic and aspartic acids, glycine). Codons of amino acids which are formed on the branches of glycolysis at the level of compounds with three carbon atoms, begin with uracil (phenylalanine, serine, leucine, tyrosine, cysteine, tryptophan). Codes of amino acids formed from aspartate begin with adenine (methionine, isoleucine, threonine, asparagine, lysine, serine), while those of the amino acids formed from the compounds with five carbon atoms (glutamic acid and phosphoribosyl pyrophosphate) begin with cytosine (arginine, proline, glutamine, histidine). The second letter of codons is linked to catabolic pathways of amino acids: most of amino acids entering glycolysis and the Krebs cycle through even-numbered carbon compounds, have adenine and uracil at the second position of codes (A-U type); most of amino acids entering the glycolysis and the Krebs cycle via odd-numbered carbon compounds, have codons with guanine and cytidine at the second position (G-C type). The usage of purine and pyrimidine as the third letter of weak codones in most of amino acids is linked to the enthropy of amino acid formation. A hypothesis claiming that the linear genetic code was assembled from the purine and pyrimidine derivatives which have acted as participants of primitive control of amino acid synthesis and catabolism, is suggested.

  2. Intergenerational pathways leading to foster care placement of foster care alumni’s children

    PubMed Central

    Beadnell, Blair; Pecora, Peter J.

    2014-01-01

    This study examined a path model that postulated intergenerational relationships between biological parent psychosocial functioning and foster care alumni mental health, economic status, and social support; and from these to the likelihood of children of foster care alumni being placed in foster care. The sample included 742 adults who spent time in foster care as children with a private foster care agency and who reported having at least one biological child. A full pathway was found between poorer father’s functioning to greater alumni depression, which was in turn associated with negative social support, and then a greater likelihood of child out of home placement. Other parent to alumni paths were that poorer father functioning was associated with alumni anxiety and PTSD, and poorer mother’s mental health was associated with PTSD; however, anxiety and PTSD were not implicated as precursors of foster care placement of the child. Findings support the need for increased practice and policy support to address the mental health needs of parents of children in or at risk of foster care, as well as the children themselves, as family history may have a lasting influence on quality of life, even when children are raised apart from biological parents. PMID:25729315

  3. Isoprenoid biosynthesis in bacteria: a novel pathway for the early steps leading to isopentenyl diphosphate.

    PubMed

    Rohmer, M; Knani, M; Simonin, P; Sutter, B; Sahm, H

    1993-10-15

    Incorporation of 13C-labelled glucose, acetate, pyruvate or erythrose allowed the determination of the origin of the carbon atoms of triterpenoids of the hopane series and/or of the ubiquinones from several bacteria (Zymomonas mobilis, Methylobacterium fujisawaense, Escherichia coli and Alicyclobacillus acidoterrestris) confirmed our earlier results obtained by incorporation of 13C-labelled acetate into the hopanoids of other bacteria and led to the identification of a novel biosynthetic route for the early steps of isoprenoid biosynthesis. The C5 framework of isoprenic units results most probably (i) from the condensation of a C2 unit derived from pyruvate decarboxylation (e.g. thiamine-activated acetaldehyde) on the C-2 carbonyl group of a triose phosphate derivative issued probably from dihydroxyacetone phosphate and not from pyruvate and (ii) from a transposition step. Although this hypothetical biosynthetic pathway resembles that of L-valine biosynthesis, this amino acid or its C5 precursors could be excluded as intermediates in the formation of isoprenic units.

  4. Intergenerational pathways leading to foster care placement of foster care alumni's children.

    PubMed

    Jackson Foster, Lovie J; Beadnell, Blair; Pecora, Peter J

    2015-02-01

    This study examined a path model that postulated intergenerational relationships between biological parent psychosocial functioning and foster care alumni mental health, economic status, and social support; and from these to the likelihood of children of foster care alumni being placed in foster care. The sample included 742 adults who spent time in foster care as children with a private foster care agency and who reported having at least one biological child. A full pathway was found between poorer father's functioning to greater alumni depression, which was in turn associated with negative social support, and then a greater likelihood of child out of home placement. Other parent to alumni paths were that poorer father functioning was associated with alumni anxiety and PTSD, and poorer mother's mental health was associated with PTSD; however, anxiety and PTSD were not implicated as precursors of foster care placement of the child. Findings support the need for increased practice and policy support to address the mental health needs of parents of children in or at risk of foster care, as well as the children themselves, as family history may have a lasting influence on quality of life, even when children are raised apart from biological parents.

  5. Cytochrome P450 promiscuity leads to a bifurcating biosynthetic pathway for tanshinones.

    PubMed

    Guo, Juan; Ma, Xiaohui; Cai, Yuan; Ma, Ying; Zhan, Zhilai; Zhou, Yongjin J; Liu, Wujun; Guan, Mengxin; Yang, Jian; Cui, Guanghong; Kang, Liping; Yang, Lei; Shen, Ye; Tang, Jinfu; Lin, Huixin; Ma, Xiaojing; Jin, Baolong; Liu, Zhenming; Peters, Reuben J; Zhao, Zongbao K; Huang, Luqi

    2016-04-01

    Cytochromes P450 (CYPs) play a key role in generating the structural diversity of terpenoids, the largest group of plant natural products. However, functional characterization of CYPs has been challenging because of the expansive families found in plant genomes, diverse reactivity and inaccessibility of their substrates and products. Here we present the characterization of two CYPs, CYP76AH3 and CYP76AK1, which act sequentially to form a bifurcating pathway for the biosynthesis of tanshinones, the oxygenated diterpenoids from the Chinese medicinal plant Danshen (Salvia miltiorrhiza). These CYPs had similar transcription profiles to that of the known gene responsible for tanshinone production in elicited Danshen hairy roots. Biochemical and RNA interference studies demonstrated that both CYPs are promiscuous. CYP76AH3 oxidizes ferruginol at two different carbon centers, and CYP76AK1 hydroxylates C-20 of two of the resulting intermediates. Together, these convert ferruginol into 11,20-dihydroxy ferruginol and 11,20-dihydroxy sugiol en route to tanshinones. Moreover, we demonstrated the utility of these CYPs by engineering yeast for heterologous production of six oxygenated diterpenoids, which in turn enabled structural characterization of three novel compounds produced by CYP-mediated oxidation. Our results highlight the incorporation of multiple CYPs into diterpenoid metabolic engineering, and a continuing trend of CYP promiscuity generating complex networks in terpenoid biosynthesis. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  6. Cytochrome P450 promiscuity leads to a bifurcating biosynthetic pathway for tanshinones

    PubMed Central

    Guo, Juan; Ma, Xiaohui; Cai, Yuan; Ma, Ying; Zhan, Zhilai; Zhou, Yongjin J; Liu, Wujun; Guan, Mengxin; Yang, Jian; Cui, Guanghong; Kang, Liping; Yang, Lei; Shen, Ye; Tang, Jinfu; Lin, Huixin; Ma, Xiaojing; Jin, Baolong; Liu, Zhenming; Peters, Reuben J.; Zhao, Zongbao K.; Huang, Luqi

    2016-01-01

    Summary Cytochromes P450 (CYPs) play key role in generating the structural diversity of terpenoids, the largest group of plant natural products. However, functional characterization of CYPs has been challenging because of the expansive families found in plant genomes, diverse reactivity and inaccessibility of their substrates and products.Here we present the characterization of two CYPs, CYP76AH3 and CYP76AK1, that act sequentially to form a bifurcating pathway for the biosynthesis of tanshinones, the oxygenated diterpenoids from the Chinese medicinal plant Danshen.These CYPs had similar transcription profiles to that of the known gene responsible for tanshinone production in elicited Danshen hairy roots. Biochemical and RNA interference studies demonstrated that both CYPs are promiscuous. CYP76AH3 oxidizes ferruginol at two different carbon centers, and CYP76AK1 hydroxylates C-20 of two of the resulting intermediates. Together, these convert ferruginol into 11,20-dihydroxy ferruginol and 11,20-dihydroxy sugiol en route to tanshinones. Moreover, we demonstrate the utility of these CYPs by engineering yeast for heterologous production of six oxygenated diterpenoids, which in turn enabled structural characterization of three novel compounds produced by CYP-mediated oxidation.Our results highlight the incorporation of multiple CYPs in diterpenoids metabolic engineering, and a continuing trend of CYPs promiscuity generating complex networks in terpenoid biosynthesis. PMID:26682704

  7. Pathways Leading to Phosphorylation of P450c17 and to the Posttranslational Regulation of Androgen Biosynthesis

    PubMed Central

    Tee, Meng Kian; Dong, Qing; Miller, Walter L.

    2008-01-01

    Cytochrome P450c17 (P450c17) is the single enzyme that catalyzes steroid 17α-hydroxylase and 17,20 lyase activities and hence is the crucial decision-making step that determines the class of steroid made in a steroidogenic cell. Although both activities are catalyzed on a single active site, the ratio of these activities is regulated by posttranslational events. Serine phosphorylation of P450c17 increases 17,20 lyase activity by increasing the enzyme’s affinity for its redox partner, P450 oxidoreductase. We searched for the relevant kinase(s) that phosphorylates P450c17 by microarray studies and by testing of kinase inhibitors. Microarrays show that 145 of the 278 known serine/threonine kinases are expressed in human adrenal NCI-H295A cells, only six of which were induced more than 2-fold by treatment with 8-Br-cAMP. Key components of the ERK1/2 and MAPK/ERK kinase (MEK)1/2 pathways, which have been implicated in the insulin resistance of PCOS, were not found in NCI-H295A cells, implying that these pathways do not participate in P450c17 phosphorylation. Treatment with various kinase inhibitors that probe the protein kinase A/phosphatidylinositol 3-kinase/Akt pathway and the calcium/calmodulin/MAPK kinase pathway had no effect on the ratio of 17,20 lyase activity to 17α-hydroxylase activity, appearing to eliminate these pathways as candidates leading to the phosphorylation of P450c17. Two inhibitors that target the Rho-associated, coiled-coil containing protein kinase (ROCK)/Rho pathway suppressed 17,20 lyase activity and P450c17 phosphorylation, both in NCI-H295A cells and in COS-1 cells transfected with a P450c17 expression vector. ROCK1 phosphorylated P450c17 in vitro, but that phosphorylation did not affect 17,20 lyase activity. We conclude that members of the ROCK/Rho pathway act upstream from the kinase that phosphorylates P450c17 in a fashion that augments 17,20 lyase activity, possibly acting to catalyze a priming phosphorylation. PMID:18187541

  8. Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration.

    PubMed

    Chen, Qi; Peto, Charles A; Shelton, G Diane; Mizisin, Andrew; Sawchenko, Paul E; Schubert, David

    2009-01-07

    Axonal dysfunction is the major phenotypic change in many neurodegenerative diseases, but the processes underlying this impairment are not clear. Modifier of cell adhesion (MOCA) is a presenilin binding protein that functions as a guanine nucleotide exchange factor for Rac1. The loss of MOCA in mice leads to axonal degeneration and causes sensorimotor impairments by decreasing cofilin phosphorylation and altering its upstream signaling partners LIM kinase and p21-activated kinase, an enzyme directly downstream of Rac1. The dystrophic axons found in MOCA-deficient mice are associated with abnormal aggregates of neurofilament protein, the disorganization of the axonal cytoskeleton, and the accumulation of autophagic vacuoles and polyubiquitinated proteins. Furthermore, MOCA deficiency causes an alteration in the actin cytoskeleton and the formation of cofilin-containing rod-like structures. The dystrophic axons show functional abnormalities, including impaired axonal transport. These findings demonstrate that MOCA is required for maintaining the functional integrity of axons and define a model for the steps leading to axonal degeneration.

  9. Phenylpropanoid pathway metabolites promote tolerance response of lupine roots to lead stress.

    PubMed

    Izbiańska, Karolina; Arasimowicz-Jelonek, Magdalena; Deckert, Joanna

    2014-12-01

    Over the past decade, there has been increasing interest in the role of phenolic compounds, especially flavonoids in plants in response to heavy metal stress. In this study, it was found that treatment of yellow lupine (Lupinus luteus L.) with Pb (150mg/l Pb(NO3)2) increased flavonoid contents in both cotyledons (by ca. 67%) and roots (by ca. 54%). Moreover, seedling roots preincubated with flavonoid extracts, derived from Pb-treated lupine cotyledons, exhibited enhanced tolerance to the heavy metal. Flavonoid preincubated lupine seedlings, growing for 48h in the presence of Pb(NO3)2, showed mitigated symptoms of lead stress, which was manifested by a significant increase in the root length and its biomass. Additionally, in seedlings pretreated with the natural flavonoid preparations an impressive rise of the antioxidant capacity was observed. Simultaneously, root cells exhibited reduced accumulation of both H2O2 and O2(-), which was associated with the decreased TBARS content and the number of dying cells under Pb stress. Taken together, accumulation of flavonoids could be an effective event in the plant׳s spectrum of defense responses to heavy metal stress, and the protective role of flavonoids against heavy metals might be associated with their ability to scavenge reactive oxygen species overproduced under lead stress. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Oral azathioprine leads to higher incorporation of 6-thioguanine in DNA of skin than liver: the protective role of the Keap1/Nrf2/ARE pathway.

    PubMed

    Kalra, Sukirti; Zhang, Ying; Knatko, Elena V; Finlayson, Stewart; Yamamoto, Masayuki; Dinkova-Kostova, Albena T

    2011-10-01

    Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to UVA radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacologic activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA and protects 6-thioguanine-treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4, an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy.

  11. Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway

    PubMed Central

    Kalra, Sukirti; Zhang, Ying; Knatko, Elena V.; Finlayson, Stewart; Yamamoto, Masayuki; Dinkova-Kostova, Albena T.

    2011-01-01

    Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to ultraviolet A (UVA) radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacological activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA, and protects 6-thioguanine-treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4 (MRP4), an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy. PMID:21803983

  12. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

    PubMed

    Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H; Johnson, Andrew D; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B; Nolte, Ilja M; van der Most, Peter J; Wright, Alan F; Shuldiner, Alan R; Morrison, Alanna C; Hofman, Albert; Smith, Albert V; Dreisbach, Albert W; Franke, Andre; Uitterlinden, Andre G; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I; Ponte, Belen; Oostra, Ben A; Paulweber, Bernhard; Krämer, Bernhard K; Mitchell, Braxton D; Buckley, Brendan M; Peralta, Carmen A; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N; Shaffer, Christian M; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J; Holliday, Elizabeth G; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B; Navis, Gerjan J; Curhan, Gary C; Ehret, George B; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K; Kramer, Holly; Lin, Honghuang; Leach, I Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M; Kolcic, Ivana; Persico, Ivana; Jukema, J Wouter; Wilson, James F; Felix, Janine F; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M; Gaspoz, Jean-Michel; Smith, Jennifer A; Faul, Jessica D; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N; Attia, John; Whitfield, John B; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C; Karjalainen, Juha; Fernandes, Jyotika K; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L; Lohman, Kurt; Portas, Laura; Launer, Lenore J; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K; Sale, Michele M; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B; Ridker, Paul M; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H; Kovacs, Peter; Wild, Philipp S; Froguel, Philippe; Rettig, Rainer; Mägi, Reedik; Biffar, Reiner; Schmidt, Reinhold; Middelberg, Rita P S; Carroll, Robert J; Penninx, Brenda W; Scott, Rodney J; Katz, Ronit; Sedaghat, Sanaz; Wild, Sarah H; Kardia, Sharon L R; Ulivi, Sheila; Hwang, Shih-Jen; Enroth, Stefan; Kloiber, Stefan; Trompet, Stella; Stengel, Benedicte; Hancock, Stephen J; Turner, Stephen T; Rosas, Sylvia E; Stracke, Sylvia; Harris, Tamara B; Zeller, Tanja; Zemunik, Tatijana; Lehtimäki, Terho; Illig, Thomas; Aspelund, Thor; Nikopensius, Tiit; Esko, Tonu; Tanaka, Toshiko; Gyllensten, Ulf; Völker, Uwe; Emilsson, Valur; Vitart, Veronique; Aalto, Ville; Gudnason, Vilmundur; Chouraki, Vincent; Chen, Wei-Min; Igl, Wilmar; März, Winfried; Koenig, Wolfgang; Lieb, Wolfgang; Loos, Ruth J F; Liu, Yongmei; Snieder, Harold; Pramstaller, Peter P; Parsa, Afshin; O'Connell, Jeffrey R; Susztak, Katalin; Hamet, Pavel; Tremblay, Johanne; de Boer, Ian H; Böger, Carsten A; Goessling, Wolfram; Chasman, Daniel I; Köttgen, Anna; Kao, W H Linda; Fox, Caroline S

    2016-01-21

    Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

  13. Genetic polymorphisms in the catechol estrogen metabolism pathway and breast cancer risk

    PubMed Central

    Reding, Kerryn W.; Weiss, Noel S.; Chen, Chu; Li, Christopher I.; Carlson, Christopher S.; Wilkerson, Hui-Wen; Farin, Federico M.; Thummel, Kenneth E.; Daling, Janet R.; Malone, Kathleen E.

    2009-01-01

    Background This study investigated whether single nucleotide polymorphisms (SNPs) in genes within the catechol estrogen metabolism pathway altered the risk of breast cancer alone or in combination, as well as whether menopausal hormone therapy (HT) modified the effect of these SNPs on breast cancer risk. Methods In a population-based case-control study of breast cancer, 891 cases and 878 controls were genotyped for six functional SNPs in the COMT, CYP1B1, GSTM1, GSTP1, and GSTT1 genes. Results Women homozygous with the T allele in CYP1B1*2 (Ser119; rs1056827) were at 1.69 (95% confidence interval [CI]: 1.17–2.46) times the risk of women homozygous with the G allele; women homozygous with the G allele in GSTP1 (Val105; rs1695) were at 0.73 (95% CI: 0.54–0.99) times the risk of breast cancer compared to women homozygous with the A allele. No other SNPs tested were associated with breast cancer to any appreciable degree. Potential gene-gene and gene-HT interactions were investigated. Conclusion With the exception of GSTP1 and possibly CYP1B1*2, our findings do not provide support for the role of genetic variation in the catechol estrogen metabolism pathway and breast cancer risk in post-menopausal women. PMID:19383894

  14. A conserved genetic pathway determines inflorescence architecture in Arabidopsis and rice.

    PubMed

    Liu, Chang; Teo, Zhi Wei Norman; Bi, Yang; Song, Shiyong; Xi, Wanyan; Yang, Xiaobei; Yin, Zhongchao; Yu, Hao

    2013-03-25

    The spatiotemporal architecture of inflorescences that bear flowers determines plant reproductive success by affecting fruit set and plant interaction with pollinators. The inflorescence architecture that displays great diversity across flowering plants depends on developmental decisions at inflorescence meristems. Here we report a key conserved genetic pathway determining inflorescence architecture in Arabidopsis thaliana and Oryza sativa (rice). In Arabidopsis, four MADS-box genes, SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1, SHORT VEGETATIVE PHASE, AGAMOUS-LIKE 24, and SEPALLATA 4 act redundantly and directly to suppress TERMINAL FLOWER1 (TFL1) in emerging floral meristems. This is indispensable for the well-known function of APETALA1 in specifying floral meristems and is coupled with a conformational change in chromosome looping at the TFL1 locus. Similarly, we demonstrate that the orthologs of these MADS-box genes in rice determine panicle branching by regulating TFL1-like genes. Our findings reveal a conserved regulatory pathway that determines inflorescence architecture in flowering plants. Copyright © 2013 Elsevier Inc. All rights reserved.

  15. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

    PubMed Central

    Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H.; Johnson, Andrew D.; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F.; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B.; Nolte, Ilja M.; van der Most, Peter J.; Wright, Alan F.; Shuldiner, Alan R.; Morrison, Alanna C.; Hofman, Albert; Smith, Albert V.; Dreisbach, Albert W.; Franke, Andre; Uitterlinden, Andre G.; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I.; Ponte, Belen; Oostra, Ben A.; Paulweber, Bernhard; Krämer, Bernhard K.; Mitchell, Braxton D.; Buckley, Brendan M.; Peralta, Carmen A.; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N.; Shaffer, Christian M.; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M.; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S.; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J.; Holliday, Elizabeth G.; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P.; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B.; Navis, Gerjan J.; Curhan, Gary C.; Ehret, George B.; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W.; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K.; Kramer, Holly; Lin, Honghuang; Leach, I. Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M.; Kolcic, Ivana; Persico, Ivana; Jukema, J. Wouter; Wilson, James F.; Felix, Janine F.; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M.; Gaspoz, Jean-Michel; Smith, Jennifer A.; Faul, Jessica D.; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N.; Attia, John; Whitfield, John B.; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C.; Karjalainen, Juha; Fernandes, Jyotika K.; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L.; Lohman, Kurt; Portas, Laura; Launer, Lenore J.; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M.; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E.; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C.; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A.; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K.; Sale, Michele M.; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G.; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H.; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B.; Ridker, Paul M.; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H.; Abecasis, Goncalo R.; Adair, Linda S.; Alexander, Myriam; Altshuler, David; Amin, Najaf; Arking, Dan E.; Arora, Pankaj; Aulchenko, Yurii; Bakker, Stephan J. L.; Bandinelli, Stefania; Barroso, Ines; Beckmann, Jacques S.; Beilby, John P.; Bergman, Richard N.; Bergmann, Sven; Bis, Joshua C.; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Bots, Michiel L.; Bragg-Gresham, Jennifer L.; Brand, Stefan-Martin; Brand, Eva; Braund, Peter S.; Brown, Morris J.; Burton, Paul R.; Casas, Juan P.; Caulfield, Mark J.; Chakravarti, Aravinda; Chambers, John C.; Chandak, Giriraj R.; Chang, Yen-Pei C.; Charchar, Fadi J.; Chaturvedi, Nish; Shin Cho, Yoon; Clarke, Robert; Collins, Francis S.; Collins, Rory; Connell, John M.; Cooper, Jackie A.; Cooper, Matthew N.; Cooper, Richard S.; Corsi, Anna Maria; Dörr, Marcus; Dahgam, Santosh; Danesh, John; Smith, George Davey; Day, Ian N. M.; Deloukas, Panos; Denniff, Matthew; Dominiczak, Anna F.; Dong, Yanbin; Doumatey, Ayo; Elliott, Paul; Elosua, Roberto; Erdmann, Jeanette; Eyheramendy, Susana; Farrall, Martin; Fava, Cristiano; Forrester, Terrence; Fowkes, F. Gerald R.; Fox, Ervin R.; Frayling, Timothy M.; Galan, Pilar; Ganesh, Santhi K.; Garcia, Melissa; Gaunt, Tom R.; Glazer, Nicole L.; Go, Min Jin; Goel, Anuj; Grässler, Jürgen; Grobbee, Diederick E.; Groop, Leif; Guarrera, Simonetta; Guo, Xiuqing; Hadley, David; Hamsten, Anders; Han, Bok-Ghee; Hardy, Rebecca; Hartikainen, Anna-Liisa; Heath, Simon; Heckbert, Susan R.; Hedblad, Bo; Hercberg, Serge; Hernandez, Dena; Hicks, Andrew A.; Hilton, Gina; Hingorani, Aroon D.; Bolton, Judith A Hoffman; Hopewell, Jemma C.; Howard, Philip; Humphries, Steve E.; Hunt, Steven C.; Hveem, Kristian; Ikram, M. Arfan; Islam, Muhammad; Iwai, Naoharu; Jarvelin, Marjo-Riitta; Jackson, Anne U.; Jafar, Tazeen H.; Janipalli, Charles S.; Johnson, Toby; Kathiresan, Sekar; Khaw, Kay-Tee; Kim, Hyung-Lae; Kinra, Sanjay; Kita, Yoshikuni; Kivimaki, Mika; Kooner, Jaspal S.; Kumar, M. J. Kranthi; Kuh, Diana; Kulkarni, Smita R.; Kumari, Meena; Kuusisto, Johanna; Kuznetsova, Tatiana; Laakso, Markku; Laan, Maris; Laitinen, Jaana; Lakatta, Edward G.; Langefeld, Carl D.; Larson, Martin G.; Lathrop, Mark; Lawlor, Debbie A.; Lawrence, Robert W.; Lee, Jong-Young; Lee, Nanette R.; Levy, Daniel; Li, Yali; Longstreth, Will T.; Luan, Jian'an; Lucas, Gavin; Ludwig, Barbara; Mangino, Massimo; Mani, K. Radha; Marmot, Michael G.; Mattace-Raso, Francesco U. S.; Matullo, Giuseppe; McArdle, Wendy L.; McKenzie, Colin A.; Meitinger, Thomas; Melander, Olle; Meneton, Pierre; Meschia, James F.; Miki, Tetsuro; Milaneschi, Yuri; Mohlke, Karen L.; Mooser, Vincent; Morken, Mario A.; Morris, Richard W.; Mosley, Thomas H.; Najjar, Samer; Narisu, Narisu; Newton-Cheh, Christopher; Nguyen, Khanh-Dung Hoang; Nilsson, Peter; Nyberg, Fredrik; O'Donnell, Christopher J.; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ong, RickTwee-Hee; Ongen, Halit; Onland-Moret, N. Charlotte; O'Reilly, Paul F.; Org, Elin; Orru, Marco; Palmas, Walter; Palmen, Jutta; Palmer, Lyle J.; Palmer, Nicholette D.; Parker, Alex N.; Peden, John F.; Peltonen, Leena; Perola, Markus; Pihur, Vasyl; Platou, Carl G. P.; Plump, Andrew; Prabhakaran, Dorairajan; Psaty, Bruce M.; Raffel, Leslie J.; Rao, Dabeeru C.; Rasheed, Asif; Ricceri, Fulvio; Rice, Kenneth M.; Rosengren, Annika; Rotter, Jerome I.; Rudock, Megan E.; Sõber, Siim; Salako, Tunde; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J.; Schwartz, Steven M.; Schwarz, Peter E. H.; Scott, Laura J.; Scott, James; Scuteri, Angelo; Sehmi, Joban S.; Seielstad, Mark; Seshadri, Sudha; Sharma, Pankaj; Shaw-Hawkins, Sue; Shi, Gang; Shrine, Nick R. G.; Sijbrands, Eric J. G.; Sim, Xueling; Singleton, Andrew; Sjögren, Marketa; Smith, Nicholas L.; Artigas, Maria Soler; Spector, Tim D.; Staessen, Jan A.; Stancakova, Alena; Steinle, Nanette I.; Strachan, David P.; Stringham, Heather M.; Sun, Yan V.; Swift, Amy J.; Tabara, Yasuharu; Tai, E-Shyong; Talmud, Philippa J.; Taylor, Andrew; Terzic, Janos; Thelle, Dag S.; Tobin, Martin D.; Tomaszewski, Maciej; Tripathy, Vikal; Tuomilehto, Jaakko; Tzoulaki, Ioanna; Uda, Manuela; Ueshima, Hirotsugu; Uiterwaal, Cuno S. P. M.; Umemura, Satoshi; van der Harst, Pim; van der Schouw, Yvonne T.; van Gilst, Wiek H.; Vartiainen, Erkki; Vasan, Ramachandran S.; Veldre, Gudrun; Verwoert, Germaine C.; Viigimaa, Margus; Vinay, D. G.; Vineis, Paolo; Voight, Benjamin F.; Vollenweider, Peter; Wagenknecht, Lynne E.; Wain, Louise V.; Wang, Xiaoling; Wang, Thomas J.; Wareham, Nicholas J.; Watkins, Hugh; Weder, Alan B.; Whincup, Peter H.; Wiggins, Kerri L.; Witteman, Jacqueline C. M.; Wong, Andrew; Wu, Ying; Yajnik, Chittaranjan S.; Yao, Jie; Young, J. H.; Zelenika, Diana; Zhai, Guangju; Zhang, Weihua; Zhang, Feng; Zhao, Jing Hua; Zhu, Haidong; Zhu, Xiaofeng; Zitting, Paavo; Zukowska-Szczechowska, Ewa; Okada, Yukinori; Wu, Jer-Yuarn; Gu, Dongfeng; Takeuchi, Fumihiko; Takahashi, Atsushi; Maeda, Shiro; Tsunoda, Tatsuhiko; Chen, Peng; Lim, Su-Chi; Wong, Tien-Yin; Liu, Jianjun; Young, Terri L.; Aung, Tin; Teo, Yik-Ying; Kim, Young Jin; Kang, Daehee; Chen, Chien-Hsiun; Tsai, Fuu-Jen; Chang, Li-Ching; Fann, S. -J. Cathy; Mei, Hao; Hixson, James E.; Chen, Shufeng; Katsuya, Tomohiro; Isono, Masato; Albrecht, Eva; Yamamoto, Kazuhiko; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki; Kato, Norihiro; He, Jiang; Chen, Yuan-Tsong; Tanaka, Toshihiro; Reilly, Muredach P; Schunkert, Heribert; Assimes, Themistocles L.; Hall, Alistair; Hengstenberg, Christian; König, Inke R.; Laaksonen, Reijo; McPherson, Ruth; Thompson, John R.; Thorsteinsdottir, Unnur; Ziegler, Andreas; Absher, Devin; Chen, Li; Cupples13, L. Adrienne; Halperin, Eran; Li, Mingyao; Musunuru, Kiran; Preuss, Michael; Schillert, Arne; Thorleifsson, Gudmar; Wells, George A.; Holm, Hilma; Roberts, Robert; Stewart, Alexandre F. R.; Fortmann, Stephen; Go, Alan; Hlatky, Mark; Iribarren, Carlos; Knowles, Joshua; Myers, Richard; Quertermous, Thomas; Sidney, Steven; Risch, Neil; Tang, Hua; Blankenberg, Stefan; Schnabel, Renate; Sinning, Christoph; Lackner, Karl J.; Tiret, Laurence; Nicaud, Viviane; Cambien, Francois; Bickel, Christoph; Rupprecht, Hans J.; Perret, Claire; Proust, Carole; Münzel, Thomas F.; Barbalic, Maja; Chen, Ida Yii-Der; Demissie-Banjaw, Serkalem; Folsom, Aaron; Lumley, Thomas; Marciante, Kristin; Taylor, Kent D.; Volcik, Kelly; Gretarsdottir, Solveig; Gulcher, Jeffrey R.; Kong, Augustine; Stefansson, Kari; Thorgeirsson, Gudmundur; Andersen, Karl; Fischer, Marcus; Grosshennig, Anika; Linsel-Nitschke, Patrick; Stark, Klaus; Schreiber, Stefan; Aherrahrou, Zouhair; Bruse, Petra; Doering, Angela; Klopp, Norman; Diemert, Patrick; Loley, Christina; Medack, Anja; Nahrstedt, Janja; Peters, Annette; Wagner, Arnika K.; Willenborg, Christina; Böhm, Bernhard O.; Dobnig, Harald; Grammer, Tanja B.; Hoffmann, Michael M.; Meinitzer, Andreas; Winkelmann, Bernhard R.; Pilz, Stefan; Renner, Wilfried; Scharnagl, Hubert; Stojakovic, Tatjana; Tomaschitz, Andreas; Winkler, Karl; Guiducci, Candace; Burtt, Noel; Gabriel, Stacey B.; Dandona, Sonny; Jarinova, Olga; Qu, Liming; Wilensky, Robert; Matthai, William; Hakonarson, Hakon H.; Devaney, Joe; Burnett, Mary Susan; Pichard, Augusto D.; Kent, Kenneth M.; Satler, Lowell; Lindsay, Joseph M.; Waksman, Ron; Knouff, Christopher W.; Waterworth, Dawn M.; Walker, Max C.; Epstein, Stephen E.; Rader, Daniel J.; Nelson, Christopher P.; Wright, Benjamin J.; Balmforth, Anthony J.; Ball, Stephen G.; Loehr, Laura R.; Rosamond, Wayne D.; Benjamin, Emelia; Haritunians, Talin; Couper, David; Murabito, Joanne; Wang, Ying A.; Stricker, Bruno H.; Chang, Patricia P.; Willerson, James T.; Felix, Stephan B.; Watzinger, Norbert; Aragam, Jayashri; Zweiker, Robert; Lind, Lars; Rodeheffer, Richard J.; Greiser, Karin Halina; Deckers, Jaap W.; Stritzke, Jan; Ingelsson, Erik; Kullo, Iftikhar; Haerting, Johannes; Reffelmann, Thorsten; Redfield, Margaret M.; Werdan, Karl; Mitchell, Gary F.; Arnett, Donna K.; Gottdiener, John S.; Blettner, Maria; Friedrich, Nele; Kovacs, Peter; Wild, Philipp S.; Froguel, Philippe; Rettig, Rainer; Mägi, Reedik; Biffar, Reiner; Schmidt, Reinhold; Middelberg, Rita P. S.; Carroll, Robert J.; Penninx, Brenda W.; Scott, Rodney J.; Katz, Ronit; Sedaghat, Sanaz; Wild, Sarah H.; Kardia, Sharon L. R.; Ulivi, Sheila; Hwang, Shih-Jen; Enroth, Stefan; Kloiber, Stefan; Trompet, Stella; Stengel, Benedicte; Hancock, Stephen J.; Turner, Stephen T.; Rosas, Sylvia E.; Stracke, Sylvia; Harris, Tamara B.; Zeller, Tanja; Zemunik, Tatijana; Lehtimäki, Terho; Illig, Thomas; Aspelund, Thor; Nikopensius, Tiit; Esko, Tonu; Tanaka, Toshiko; Gyllensten, Ulf; Völker, Uwe; Emilsson, Valur; Vitart, Veronique; Aalto, Ville; Gudnason, Vilmundur; Chouraki, Vincent; Chen, Wei-Min; Igl, Wilmar; März, Winfried; Koenig, Wolfgang; Lieb, Wolfgang; Loos, Ruth J. F.; Liu, Yongmei; Snieder, Harold; Pramstaller, Peter P.; Parsa, Afshin; O'Connell, Jeffrey R.; Susztak, Katalin; Hamet, Pavel; Tremblay, Johanne; de Boer, Ian H.; Böger, Carsten A.; Goessling, Wolfram; Chasman, Daniel I.; Köttgen, Anna; Kao, W. H. Linda; Fox, Caroline S.

    2016-01-01

    Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. PMID:26831199

  16. Genetic Analysis of Benzothiophene Biodesulfurization Pathway of Gordonia terrae Strain C-6

    PubMed Central

    Lian, Kehui; Zhang, Yue; Tian, Huimei; Ji, Kaihua; Li, Guoqiang

    2013-01-01

    Sulfur can be removed from benzothiophene (BT) by some bacteria without breaking carbon-carbon bonds. However, a clear mechanism for BT desulfurization and its genetic components have not been reported in literatures so far. In this study, we used comparative transcriptomics to study differential expression of genes in Gordonia terrae C-6 cultured with BT or sodium sulfate as the sole source of sulfur. We found that 135 genes were up-regulated with BT relative to sodium sulfate as the sole sulfur source. Many of these genes encode flavin-dependent monooxygenases, alkane sulfonate monooxygenases and desulfinase, which perform similar functions to those involved in the 4S pathway of dibenzothiophene (DBT) biodesulfurization. Three of the genes were found to be located in the same operon, designated bdsABC. Cell extracts of pET28a-bdsABC transfected E. coli Rosetta (DE3) converted BT to a phenolic compound, identified as o-hydroxystyrene. These results advance our understanding of enzymes involved in the BT biodesulfurization pathway. PMID:24367657

  17. Combinatorial genetic transformation of cereals and the creation of metabolic libraries for the carotenoid pathway.

    PubMed

    Farre, Gemma; Naqvi, Shaista; Sanahuja, Georgina; Bai, Chao; Zorrilla-López, Uxue; Rivera, Sol M; Canela, Ramon; Sandman, Gerhard; Twyman, Richard M; Capell, Teresa; Zhu, Changfu; Christou, Paul

    2012-01-01

    Combinatorial nuclear transformation is used to generate populations of transgenic plants containing random selections from a collection of input transgenes. This is a useful approach because it provides the means to test different combinations of genes without the need for separate transformation experiments, allowing the comprehensive analysis of metabolic pathways and other genetic systems requiring the coordinated expression of multiple genes. The principle of combinatorial nuclear transformation is demonstrated in this chapter through protocols developed in our laboratory that allow combinations of genes encoding enzymes in the carotenoid biosynthesis pathway to be introduced into rice and a white-endosperm variety of corn. These allow the accumulation of carotenoids to be screened initially by the colour of the endosperm, which ranges from white through various shades of yellow and orange depending on the types and quantities of carotenoids present. The protocols cover the preparation of DNA-coated metal particles, the transformation of corn and rice plants by particle bombardment, the regeneration of transgenic plants, the extraction of carotenoids from plant tissues, and their analysis by high-performance liquid chromatography.

  18. Novel adverse outcome pathways revealed by chemical genetics in a developing marine fish

    PubMed Central

    Sørhus, Elin; Incardona, John P; Furmanek, Tomasz; Goetz, Giles W; Scholz, Nathaniel L; Meier, Sonnich; Edvardsen, Rolf B; Jentoft, Sissel

    2017-01-01

    Crude oil spills are a worldwide ocean conservation threat. Fish are particularly vulnerable to the oiling of spawning habitats, and crude oil causes severe abnormalities in embryos and larvae. However, the underlying mechanisms for these developmental defects are not well understood. Here, we explore the transcriptional basis for four discrete crude oil injury phenotypes in the early life stages of the commercially important Atlantic haddock (Melanogrammus aeglefinus). These include defects in (1) cardiac form and function, (2) craniofacial development, (3) ionoregulation and fluid balance, and (4) cholesterol synthesis and homeostasis. Our findings suggest a key role for intracellular calcium cycling and excitation-transcription coupling in the dysregulation of heart and jaw morphogenesis. Moreover, the disruption of ionoregulatory pathways sheds new light on buoyancy control in marine fish embryos. Overall, our chemical-genetic approach identifies initiating events for distinct adverse outcome pathways and novel roles for individual genes in fundamental developmental processes. DOI: http://dx.doi.org/10.7554/eLife.20707.001 PMID:28117666

  19. Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility

    PubMed Central

    Fahmideh, Maral Adel; Lavebratt, Catharina; Schüz, Joachim; Röösli, Martin; Tynes, Tore; Grotzer, Michael A.; Johansen, Christoffer; Kuehni, Claudia E; Lannering, Birgitta; Prochazka, Michaela; Schmidt, Lisbeth S; Feychting, Maria

    2016-01-01

    Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk. The study is based on the largest series of PBT cases to date. Saliva DNA from 245 cases and 489 controls, aged 7–19 years at diagnosis/reference date, was genotyped for 68 SNPs. Data were analyzed using unconditional logistic regression. The results showed EGFRrs730437 and EGFRrs11506105 may decrease susceptibility to PBTs, whereas ERCC1rs3212986 may increase risk of these tumors. Moreover, stratified analyses indicated CHAF1Ars243341, CHAF1Ars2992, and XRCC1rs25487 were associated with a decreased risk of astrocytoma subtype. Furthermore, an increased risk of non-astrocytoma subtype associated with EGFRrs9642393, EME1rs12450550, ATMrs170548, and GLTSCRrs1035938 as well as a decreased risk of this subtype associated with XRCC4rs7721416 and XRCC4rs2662242 were detected. This study indicates SNPs in EGFR, ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4 may be associated with the risk of PBTs. Therefore, cell cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways. PMID:27613841

  20. Perinatal lead exposure affects nitric oxide and cyclooxygenase pathways in aorta of weaned rats.

    PubMed

    Grizzo, Larissa Tercilia; Cordellini, Sandra

    2008-05-01

    Perinatal Pb exposure may modulate arterial tone through nitric oxide (NO) and cyclooxygenase products. To investigate this, Wistar dams received 1000 ppm of Pb or sodium acetate (control) in drinking water during pregnancy and lactation. Curves were constructed in phenylephrine-precontracted intact and/or denuded rings of thoracic aortas of weaned (23-day-old) male pups from their responses to N(omega)-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) and ACh in the absence or presence of indomethacin (10(-5)M, cyclooxygenase inhibitor) or L-NAME (3 x 10(-7)M and 3 x 10(-4)M). Blood lead concentration and systolic blood pressure (SBP) were higher in intoxicated than control pups (blood lead microg/dl: control < 3.0, Pb 58.7 +/- 6.5*; SBP mmHg: control 111.4 +/- 2.3, Pb 135.5 +/- 2.4*). In L-NAME-treated rings maximal responses increased in Pb-exposed rats, and were higher in intact than in denuded aortas (contraction [% of phenylephrine] intact: control 184.3 +/- 23.7, Pb 289.1 +/- 18.3*; denuded: control 125.1 +/- 4.5, Pb 154.8 +/- 13.3*). ACh-induced relaxation in intact aortas from Pb-exposed rats presented rightward shift in L-NAME presence (EC50 x 10(-7)M: control 1.32 [0.33-5.18], Pb 4.88 [3.56-6.69]*) but moved left under indomethacin (EC50 x 10(-7)M: control 8.95 [3.47-23.07], Pb 0.97 [0.38-2.43]*). *p < 0.05 significant relative to the respective control; N = 7-9. Endothelium removal abolished ACh-induced relaxation. Perinatal Pb exposure caused hypertension associated with alterations in the production and/or release of basal and stimulated endothelium-derived relaxing factors-NO and constricting cyclooxygenase products. These findings may help explain the contribution of NO and cyclooxygenase products to the etiology and/or maintenance of Pb-induced hypertension and could ultimately lead to therapeutic advantages in plumbism.

  1. Identification of downstream genetic pathways of Tbx1 in the second heart field

    PubMed Central

    Liao, Jun; Aggarwal, Vimla S.; Nowotschin, Sonja; Bondarev, Alexei; Lipner, Shari; Morrow, Bernice E.

    2008-01-01

    Tbx1, a T-box transcription factor, and an important gene for velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) in humans, causes outflow tract (OFT) heart defects when inactivated in the mouse. Tbx1 is expressed in the second heart field (SHF) and is required in this tissue for OFT development. To identify Tbx1 regulated genetic pathways in the SHF, we performed gene expression profiling of the caudal pharyngeal region in Tbx1-/- and wild type embryos. Isl1, a key marker for the SHF, as well as Hod and Nkx2-6, were downregulated in Tbx1-/- mutants, while genes required for cardiac morphogenesis, such as Raldh2, Gata4, and Tbx5, as well as a subset of muscle contractile genes, signifying myocardial differentiation, were ectopically expressed. Pan-mesodermal ablation of Tbx1 resulted in similar gene expression changes, suggesting cell-autonomous roles of Tbx1 in regulating these genes. Opposite expression changes concomitant with SHF-derived cardiac defects occurred in TBX1 gain-of-function mutants, indicating that appropriate levels of Tbx1 are required for heart development. When taken together, our studies show that Tbx1 acts upstream in a genetic network that positively regulates SHF cell proliferation and negatively regulates differentiation, cell-autonomously in the caudal pharyngeal region. PMID:18328475

  2. Genetic polymorphisms in DNA repair and oxidative stress pathways associated with malignant melanoma susceptibility.

    PubMed

    Ibarrola-Villava, Maider; Peña-Chilet, Maria; Fernandez, Lara P; Aviles, Jose A; Mayor, Matias; Martin-Gonzalez, Manuel; Gomez-Fernandez, Cristina; Casado, Beatriz; Lazaro, Pablo; Lluch, Ana; Benitez, Javier; Lozoya, Rafael; Boldo, Enrique; Pizarro, Angel; Martinez-Cadenas, Conrado; Ribas, Gloria

    2011-11-01

    Base excision repair (BER) and nucleotide excision repair (NER) pathways eliminate a wide variety of DNA damage, including UV photoproducts. The ability of each individual to repair DNA damage following different causes might explain at least in part the variability in cancer susceptibility. Moreover, inflammatory response to UV exposure may further contribute to skin carcinogenesis by oxidative stress mechanisms. Single nucleotide polymorphisms in genes encoding various DNA-repair enzymes and oxidative stress factors may be candidate low-penetrance variants with a role in susceptibility to different cancers, particularly in those with aetiologies linked to environmental exposure, such as malignant melanoma (MM). In this case-control study, 684 Spanish sporadic MM patients and 406 cancer-free control subjects were included and the role of 46 polymorphisms belonging to 16 BER and NER genes as well as 11 genes involved in oxidative stress processes were investigated. One polymorphism was identified to be individually associated with MM in the Spanish population. The variant was found in the NOS1 oxidative stress gene (rs2682826; p-value=0.01). These results suggest a putative role of oxidative stress processes in the genetic predisposition to melanoma. To the authors' knowledge, this is the largest DNA repair-related SNP study in melanoma risk conducted in the Spanish population up to now. Furthermore, it also represents a comprehensive genetic study of several oxidative stress polymorphisms tested in relation to MM susceptibility. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Identification of downstream genetic pathways of Tbx1 in the second heart field.

    PubMed

    Liao, Jun; Aggarwal, Vimla S; Nowotschin, Sonja; Bondarev, Alexei; Lipner, Shari; Morrow, Bernice E

    2008-04-15

    Tbx1, a T-box transcription factor, and an important gene for velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) in humans, causes outflow tract (OFT) heart defects when inactivated in the mouse. Tbx1 is expressed in the second heart field (SHF) and is required in this tissue for OFT development. To identify Tbx1 regulated genetic pathways in the SHF, we performed gene expression profiling of the caudal pharyngeal region in Tbx1(-/-) and wild type embryos. Isl1, a key marker for the SHF, as well as Hod and Nkx2-6, were downregulated in Tbx1(-/-) mutants, while genes required for cardiac morphogenesis, such as Raldh2, Gata4, and Tbx5, as well as a subset of muscle contractile genes, signifying myocardial differentiation, were ectopically expressed. Pan-mesodermal ablation of Tbx1 resulted in similar gene expression changes, suggesting cell-autonomous roles of Tbx1 in regulating these genes. Opposite expression changes concomitant with SHF-derived cardiac defects occurred in TBX1 gain-of-function mutants, indicating that appropriate levels of Tbx1 are required for heart development. When taken together, our studies show that Tbx1 acts upstream in a genetic network that positively regulates SHF cell proliferation and negatively regulates differentiation, cell-autonomously in the caudal pharyngeal region.

  4. The genetics of heterotopic ossification: insight into the bone remodeling pathway.

    PubMed

    Mitchell, Erika J; Canter, Jeffrey; Norris, Patrick; Jenkins, Judith; Morris, John

    2010-09-01

    Heterotopic Ossification (HO) is a significant complication after trauma occurring in 12% to 25% of fractures. Although clinical predictors have been studied to determine the likelihood of developing HO, the results have been inconsistent. This study examines genetic predictors of the HO phenotype to identify the "at-risk" patient and increase the understanding of the genetic contribution to the formation of HO. We examined the frequency of 61 single nucleotide polymorphisms (SNPs) in 1095 consecutive trauma patients with fractures. Radiographic studies of these patients were examined for HO in follow-up. Ten percent of the patients in the study demonstrated radiographic evidence of HO. Multivariate logistic regression was used to analyze each SNP independently while adjusting for severity of injury (as measured by the Trauma and Injury Severity Score). Three SNPs (beta2-adrenergic receptor, toll-like receptor 4, complement factor H) were identified that were associated with an increased or decreased frequency of HO. The less common polymorphism of the beta2-adrenergic receptor gene was associated with increased risk of HO. For toll-like receptor 4 and complement factor H, the less common polymorphism was associated with a decreased risk of HO. The SNPs identified as predictors of HO formation are representative of the adrenergic system, immune system, and the alternative complement system. This represents the interplay of multiple pathways that affect bone remodeling, aberrations of which may be found in the genome.

  5. Epigenetic and genetic deregulation in cancer target distinct signaling pathway domains

    PubMed Central

    Gao, Yang; Teschendorff, Andrew E.

    2017-01-01

    Cancer is characterized by both genetic and epigenetic alterations. While cancer driver mutations and copy-number alterations have been studied at a systems-level, relatively little is known about the systems-level patterns exhibited by their epigenetic counterparts. Here we perform a pan-cancer wide systems-level analysis, mapping candidate cancer-driver DNA methylation (DNAm) alterations onto a human interactome. We demonstrate that functional DNAm alterations in cancer tend to map to nodes of lower connectivity and inter-connectivity, compared to the corresponding alterations at the genomic level. We find that epigenetic alterations are relatively over-represented in extracellular and transmembrane signaling domains, whereas cancer genes undergoing amplification or deletion tend to be enriched within the intracellular domain. A pan-cancer wide meta-analysis identifies WNT and chemokine signaling, as two key pathways where epigenetic deregulation preferentially targets extracellular components. We further pinpoint specific chemokine ligands/receptors whose epigenetic deregulation associates with key epigenetic enzymes, representing potential targets for epigenetic therapy. Our results suggest that epigenetic deregulation in cancer not only targets tissue-specific transcription factors, but also modulates signaling within the extra-cellular domain, providing novel system-level insight into the potential distinctive role of genetic and epigenetic alterations in cancer. PMID:27899617

  6. Genetic and expression analysis of cattle identifies candidate genes in pathways responding to Trypanosoma congolense infection

    PubMed Central

    Noyes, Harry; Brass, Andy; Obara, Isaiah; Anderson, Susan; Archibald, Alan L.; Bradley, Dan G.; Fisher, Paul; Freeman, Abigail; Gibson, John; Gicheru, Michael; Hall, Laurence; Hanotte, Olivier; Hulme, Helen; McKeever, Declan; Murray, Caitriona; Oh, Sung Jung; Tate, Catriona; Smith, Ken; Tapio, Miika; Wambugu, John; Williams, Diana J.; Agaba, Morris; Kemp, Stephen J.

    2011-01-01

    African bovine trypanosomiasis caused by Trypanosoma sp., is a major constraint on cattle productivity in sub-Saharan Africa. Some African Bos taurus breeds are highly tolerant of infection, but the potentially more productive Bos indicus zebu breeds are much more susceptible. Zebu cattle are well adapted for plowing and haulage, and increasing their tolerance of trypanosomiasis could have a major impact on crop cultivation as well as dairy and beef production. We used three strategies to obtain short lists of candidate genes within QTL that were previously shown to regulate response to infection. We analyzed the transcriptomes of trypanotolerant N'Dama and susceptible Boran cattle after infection with Trypanosoma congolense. We sequenced EST libraries from these two breeds to identify polymorphisms that might underlie previously identified quantitative trait loci (QTL), and we assessed QTL regions and candidate loci for evidence of selective sweeps. The scan of the EST sequences identified a previously undescribed polymorphism in ARHGAP15 in the Bta2 trypanotolerance QTL. The polymorphism affects gene function in vitro and could contribute to the observed differences in expression of the MAPK pathway in vivo. The expression data showed that TLR and MAPK pathways responded to infection, and the former contained TICAM1, which is within a QTL on Bta7. Genetic analyses showed that selective sweeps had occurred at TICAM1 and ARHGAP15 loci in African taurine cattle, making them strong candidates for the genes underlying the QTL. Candidate QTL genes were identified in other QTL by their expression profile and the pathways in which they participate. PMID:21593421

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

    PubMed Central

    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

  8. Genetic Characterization of the Galactitol Utilization Pathway of Salmonella enterica Serovar Typhimurium.

    PubMed

    Nolle, Nicoletta; Felsl, Angela; Heermann, Ralf; Fuchs, Thilo M

    2017-02-15

    Galactitol degradation by salmonellae remains underinvestigated, although this metabolic capability contributes to growth in animals (R. R. Chaudhuri et al., PLoS Genet 9:e1003456, 2013, https://doi.org/10.1371/journal.pgen.1003456). The genes responsible for this metabolic capability are part of a 9.6-kb gene cluster that spans from gatY to gatR (STM3253 to STM3262) and encodes a phosphotransferase system, four enzymes, and a transporter of the major facilitator superfamily. Genome comparison revealed the presence of this genetic determinant in nearly all Salmonella strains. The generation time of Salmonella enterica serovar Typhimurium strain ST4/74 was higher in minimal medium with galactitol than with glucose. Knockout of STM3254 and gatC resulted in a growth-deficient phenotype of S Typhimurium, with galactitol as the sole carbon source. Partial deletion of gatR strongly reduced the lag phase of growth with galactitol, whereas strains overproducing GatR exhibited a near-zero growth phenotype. Luciferase reporter assays demonstrated strong induction of the gatY and gatZ promoters, which control all genes of this cluster except gatR, in the presence of galactitol but not glucose. Purified GatR bound to these two main gat gene cluster promoters as well as to its own promoter, demonstrating that this autoregulated repressor controls galactitol degradation. Surface plasmon resonance spectroscopy revealed distinct binding properties of GatR toward the three promoters, resulting in a model of differential gat gene expression. The cyclic AMP receptor protein (CRP) bound these promoters with similarly high affinities, and a mutant lacking crp showed severe growth attenuation, demonstrating that galactitol utilization is subject to catabolite repression. Here, we provide the first genetic characterization of galactitol degradation in Salmonella, revealing novel insights into the regulation of this dissimilatory pathway.

  9. Dispersal pathways and genetic differentiation among worldwide populations of the invasive weed Centaurea solstitialis L. (Asteraceae).

    PubMed

    Eriksen, Renée L; Hierro, José L; Eren, Özkan; Andonian, Krikor; Török, Katalin; Becerra, Pablo I; Montesinos, Daniel; Khetsuriani, Liana; Diaconu, Alecu; Kesseli, Rick

    2014-01-01

    The natural history of introduced species is often unclear due to a lack of historical records. Even when historical information is readily available, important factors of the invasions such as genetic bottlenecks, hybridization, historical relationships among populations and adaptive changes are left unknown. In this study, we developed a set of nuclear, simple sequence repeat markers and used these to characterize the genetic diversity and population structure among native (Eurasian) and non-native (North and South American) populations of Centaurea solstitialis L., (yellow starthistle). We used these data to test hypotheses about the invasion pathways of the species that were based on historical and geographical records, and we make inferences about historical relationships among populations and demographic processes following invasion. We confirm that the center of diversity and the native range of the species is likely the eastern Mediterranean region in the vicinity of Turkey. From this region, the species likely proceeded to colonize other parts of Europe and Asia via a slow, stepwise range expansion. Spanish populations were the primary source of seed to invade South America via human-mediated events, as was evident from historical records, but populations from the eastern Mediterranean region were also important. North American populations were largely derived from South America, but had secondary contributors. We suggest that the introduction history of non-native populations from disparate parts of the native range have allowed not just one, but multiple opportunities first in South America then again in North America for the creation of novel genotypes via intraspecific hybridization. We propose that multiple intraspecific hybridization events may have created especially potent conditions for the selection of a noxious invader, and may explain differences in genetic patterns among North and South America populations, inferred differences in demographic

  10. Dispersal Pathways and Genetic Differentiation among Worldwide Populations of the Invasive Weed Centaurea solstitialis L. (Asteraceae)

    PubMed Central

    Eriksen, Renée L.; Hierro, José L.; Eren, Özkan; Andonian, Krikor; Török, Katalin; Becerra, Pablo I.; Montesinos, Daniel; Khetsuriani, Liana; Diaconu, Alecu; Kesseli, Rick

    2014-01-01

    The natural history of introduced species is often unclear due to a lack of historical records. Even when historical information is readily available, important factors of the invasions such as genetic bottlenecks, hybridization, historical relationships among populations and adaptive changes are left unknown. In this study, we developed a set of nuclear, simple sequence repeat markers and used these to characterize the genetic diversity and population structure among native (Eurasian) and non-native (North and South American) populations of Centaurea solstitialis L., (yellow starthistle). We used these data to test hypotheses about the invasion pathways of the species that were based on historical and geographical records, and we make inferences about historical relationships among populations and demographic processes following invasion. We confirm that the center of diversity and the native range of the species is likely the eastern Mediterranean region in the vicinity of Turkey. From this region, the species likely proceeded to colonize other parts of Europe and Asia via a slow, stepwise range expansion. Spanish populations were the primary source of seed to invade South America via human-mediated events, as was evident from historical records, but populations from the eastern Mediterranean region were also important. North American populations were largely derived from South America, but had secondary contributors. We suggest that the introduction history of non-native populations from disparate parts of the native range have allowed not just one, but multiple opportunities first in South America then again in North America for the creation of novel genotypes via intraspecific hybridization. We propose that multiple intraspecific hybridization events may have created especially potent conditions for the selection of a noxious invader, and may explain differences in genetic patterns among North and South America populations, inferred differences in demographic

  11. Interrogating causal pathways linking genetic variants, small molecule metabolites, and circulating lipids

    PubMed Central

    2014-01-01

    Background Emerging technologies based on mass spectrometry or nuclear magnetic resonance enable the monitoring of hundreds of small metabolites from tissues or body fluids. Profiling of metabolites can help elucidate causal pathways linking established genetic variants to known disease risk factors such as blood lipid traits. Methods We applied statistical methodology to dissect causal relationships between single nucleotide polymorphisms, metabolite concentrations, and serum lipid traits, focusing on 95 genetic loci reproducibly associated with the four main serum lipids (total-, low-density lipoprotein-, and high-density lipoprotein- cholesterol and triglycerides). The dataset used included 2,973 individuals from two independent population-based cohorts with data for 151 small molecule metabolites and four main serum lipids. Three statistical approaches, namely conditional analysis, Mendelian randomization, and structural equation modeling, were compared to investigate causal relationship at sets of a single nucleotide polymorphism, a metabolite, and a lipid trait associated with one another. Results A subset of three lipid-associated loci (FADS1, GCKR, and LPA) have a statistically significant association with at least one main lipid and one metabolite concentration in our data, defining a total of 38 cross-associated sets of a single nucleotide polymorphism, a metabolite and a lipid trait. Structural equation modeling provided sufficient discrimination to indicate that the association of a single nucleotide polymorphism with a lipid trait was mediated through a metabolite at 15 of the 38 sets, and involving variants at the FADS1 and GCKR loci. Conclusions These data provide a framework for evaluating the causal role of components of the metabolome (or other intermediate factors) in mediating the association between established genetic variants and diseases or traits. PMID:24678845

  12. Impaired dynamin 2 function leads to increased AP-1 transcriptional activity through the JNK/c-Jun pathway.

    PubMed

    Szymanska, Ewelina; Skowronek, Agnieszka; Miaczynska, Marta

    2016-01-01

    Activation of AP-1 transcription factors, composed of the Jun and Fos proteins, regulates cellular fates, such as proliferation, differentiation or apoptosis. Among other stimuli, the AP-1 pathway can be initiated by extracellular ligands, such as growth factors or cytokines, which undergo internalization in complex with their receptors. Endocytosis has been implicated in the regulation of several signaling pathways; however its possible impact on AP-1 signaling remains unknown. Here we show that inhibition of dynamin 2 (Dyn2), a major regulator of endocytic internalization, strongly stimulates the AP-1 pathway. Specifically, expression of a dominant-negative Dyn2 K44A mutant increases the total levels of c-Jun, its phosphorylation on Ser63/73 and transcription of AP-1 target genes. Interestingly, DNM2 mutations implicated in human neurological disorders exhibit similar effects on AP-1 signaling. Mechanistically, Dyn2 K44A induces AP-1 by increasing phosphorylation of several receptor tyrosine kinases. Their activation is required to initiate a Src- and JNK-dependent signaling cascade converging on c-Jun and stimulating expression of AP-1 target genes. Cumulatively, our data uncover a link between the Dyn2 function and JNK signaling which leads to AP-1 induction.

  13. Is the 12-lead electrocardiogram during antidromic circus movement tachycardia helpful in predicting the ablation site in atriofascicular pathways?

    PubMed

    Sternick, Eduardo Back; Lokhandwala, Yash; Bohora, Shomu; Timmermans, Carl; Martins, Priscila Reis; Dias, Liana Valadão; Correia, Frederico Soares; Wellens, Hein J J

    2014-11-01

    Unlike in the Wolff-Parkinson-White syndrome, there has been no systematic study on the role of the pre-excitation pattern in predicting the ablation site in patients with atriofascicular (AF) pathways. We assessed in a large cohort the value of the 12-lead electrocardiogram (ECG) during antidromic tachycardia (ADT) to predict the site of ablation. Forty-five patients were studied, 23 males (51%), mean age of 27 ± 12 years with 46 AF pathways and 48 ADT using the AF pathway for A-V conduction. Inclusion required induction of a sustained ADT and successful ablation. Ablation site was assessed during LAO 45° projection and clockwise classified as hours in posteroseptal, posterolateral, lateral, anterolateral, and anteroseptal tricuspid annulus as follows: 05:00-07:00, >07:00-08:00, >08:00-09:00, >09:00-11:00, and >11:00-13:00 o'clock. The QRS axis was assessed during ADT and classified as normal (>+15°), horizontal (+15° to -30°), and superior (<-30°). During ADT axis was superior (-57° ± 10°) in 15 (31%), horizontal (-11° ± 14°) in 22 (46%), and normal (+45° ± 16°) in 11 (23%) patients. The correct ablation site did not differ between the different groups of QRS axis. QRS width during ADT was narrower in patients with a normal when compared with a horizontal and leftward axis (127 ± 14 vs. 145 ± 12 ms, P < 0.0001), and the V-H interval was shorter (4 ± 3 ms vs. 19 ± 22 ms, P = 0.03). There was no correlation between the AF pathway ablation site and the QRS axis during ADT. The 12-lead ECG during maximal pre-excitation does not predict the proper site of tricuspid annulus ablation in patients with A-V conduction over an AF pathway. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  14. Genetic association and epistatic interaction of the interleukin-10 signaling pathway in pediatric inflammatory bowel disease

    PubMed Central

    Lin, Zhenwu; Wang, Zhong; Hegarty, John P; Lin, Tony R; Wang, Yunhua; Deiling, Sue; Wu, Rongling; Thomas, Neal J; Floros, Joanna

    2017-01-01

    AIM To study the genetic association and epistatic interaction of the interleukin (IL)-10 and IL-10/STAT3 pathways in pediatric inflammatory bowel disease (IBD). METHODS A total of 159 pediatric inflammatory IBD patients (Crohn’s disease, n = 136; ulcerative colitis, n = 23) and 129 matched controls were studied for genetic association of selected single nucleotide polymorphisms (SNPs) of the IL-10 gene and the genes IL10RA, IL10RB, STAT3, and HO1, from the IL-10/STAT3 signaling pathway. As interactions between SNPs from different loci may significantly affect the associated risk for disease, additive (a) and dominant (d) modeling of SNP interactions was also performed to examine high-order epistasis between combinations of the individual SNPs. RESULTS The results showed that IL-10 rs304496 was associated with pediatric IBD (P = 0.022), but no association was found for two other IL-10 SNPs, rs1800872 and rs2034498, or for SNPs in genes IL10RA, IL10RB, STAT3, and HO1. However, analysis of epistatic interaction among these genes showed significant interactions: (1) between two IL-10 SNPs rs1800872 and rs3024496 (additive-additive P = 0.00015, Bonferroni P value (Bp) = 0.003); (2) between IL-10RB rs2834167 and HO1 rs2071746 (dominant-additive, P = 0.0018, Bp = 0.039); and (3) among IL-10 rs1800872, IL10RB rs2834167, and HO1 rs2071746 (additive-dominant-additive, P = 0.00015, Bp = 0.005), as well as weak interactions among IL-10 rs1800872, IL-10 rs3024496, and IL-10RA (additive-additive-additive, P = 0.003; Bp = 0.099), and among IL10RA, IL10RB, and HO1 genes (additive-dominant-additive, P = 0.008, Bp = 0.287). CONCLUSION These results indicate that both the IL-10 gene itself, and through epistatic interaction with genes within the IL-10/STAT3 signaling pathway, contribute to the risk of pediatric IBD. PMID:28785144

  15. Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk.

    PubMed

    Chen, Meng; Cassidy, Adrian; Gu, Jian; Delclos, George L; Zhen, Fan; Yang, Hushan; Hildebrandt, Michelle A T; Lin, Jie; Ye, Yuanqing; Chamberlain, Robert M; Dinney, Colin P; Wu, Xifeng

    2009-12-01

    Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24-2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35-3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19-2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31-3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70-0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09-1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33-3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.

  16. QM/MM studies reveal pathways leading to the quenching of the formation of thymine dimer photoproduct by flanking bases.

    PubMed

    Lee, Wook; Matsika, Spiridoula

    2015-04-21

    It is known that the formation of the photochemical product of thymine-thymine cyclobutane pyrimidine dimer (TT-CPD) formed upon UV excitation in DNA is significantly affected by the nature of the flanking bases, and that the oxidation potential of the flanking base correlates with the quenching of TT-CPD formation. However, the electronic details of this correlation have remained controversial. The quenching of thymine dimer formation exerted by flanking bases was suggested to be driven by both conformational and electronic effects. In the present study, we examine both of these effects using umbrella sampling and a quantum mechanical/molecular mechanical (QM/MM) approach for selected model systems. Our results demonstrate that a charge transfer (CT) state between the flanking base and the adjacent thymine base can provide a decay pathway for the population to escape from dimer formation, which eventually leads to the formation of an exciplex. The QM/MM vertical excitation energies also reveal that the oxidation potential of flanking bases correlates with the energy level of the CT state, thereby determining whether the CT state intersects with the state that can lead to dimer formation. The consistency between these results and experimentally obtained dimer formation rates implies that the quenching of dimer formation is mainly attributed to the decay pathway via the CT state. The present results further underline the importance of the electronic effects in quenching.

  17. Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents

    PubMed Central

    Imokawa, Genji; Ishida, Koichi

    2014-01-01

    Few anti-pigmenting agents have been designed and developed according to their known hyperpigmentation mechanisms and corresponding intracellular signaling cascades. Most anti-pigmenting agents developed so far are mechanistically involved in the interruption of constitutional melanogenic mechanisms by which skin color is maintained at a normal and unstimulated level. Thus, owing to the difficulty of confining topical application to a specific hyperpigmented skin area, potent anti-pigmenting agents capable of attenuating the natural unstimulated pigmentation process have the risk of leading to hypopigmentation. Since intracellular signaling pathways within melanocytes do not function substantially in maintaining normal skin color and are activated only by environmental stimuli such as UV radiation, specifically down-regulating the activation of melanogenesis to the constitutive level would be an appropriate strategy to develop new potent anti-pigmenting agents with a low risk of hypopigmentation. In this article, we review the hyperpigmentation mechanisms and intracellular signaling pathways that lead to the stimulation of melanogenesis. We also discuss a screening and evaluation system to select candidates for new anti-melanogenic substances by focusing on inhibitors of endothelin-1 or stem cell factor-triggered intracellular signaling cascades. From this viewpoint, we show that extracts of the herbs Withania somnifera and Melia toosendan and the natural chemicals Withaferin A and Astaxanthin are new candidates for potent anti-pigmenting substances that avoid the risk of hypopigmentation. PMID:24823877

  18. Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes.

    PubMed

    Cirillo, Federica; Resmini, Giulia; Ghiroldi, Andrea; Piccoli, Marco; Bergante, Sonia; Tettamanti, Guido; Anastasia, Luigi

    2017-02-10

    Regeneration of skeletal muscle is a complex process that requires the activation of quiescent adult stem cells, called satellite cells, which are resident in hypoxic niches in the tissue. Hypoxia has been recognized as a key factor to maintain stem cells in an undifferentiated state. Herein we report that hypoxia plays a fundamental role also in activating myogenesis. In particular, we found that the activation of the hypoxia-inducible factor (HIF)-1α under hypoxia, in murine skeletal myoblasts, leads to activation of MyoD through the noncanonical Wnt/β-catenin pathway. Moreover, chemical inhibition of HIF-1α activity significantly reduces differentiation, thus confirming its crucial role in the process. Furthermore, hypoxia-preconditioned myoblasts, once induced to differentiate under normoxic conditions, tend to form hypertrophic myotubes. These results support the notion that hypoxia plays a pivotal role in activating the regeneration process by directly inducing myogenesis through HIF-1α. Although preliminary, these findings may suggest new perspective for novel therapeutic targets in the treatment of several muscle diseases.-Cirillo, F., Resmini, G., Ghiroldi, A., Piccoli, M., Bergante, S., Tettamanti, G., Anastasia, L. Activation of the hypoxia-inducible factor 1α promotes myogenesis through the noncanonical Wnt pathway, leading to hypertrophic myotubes.

  19. Heme Utilization by Pathogenic Bacteria: Not All Pathways Lead to Biliverdin

    PubMed Central

    2015-01-01

    converted to biliverdin under hydrolytic conditions. The differences between heme oxygenation by the canonical and noncanonical HOs and coupled oxidation will be discussed in the context of the stabilization of the reactive FeIII–OOH intermediate and regioselective heme hydroxylation. Thus, in the determination of heme oxygenase activity in vitro, it is important to ensure that the reaction proceeds through successive oxygenation steps. We further suggest that when bacterial heme degradation is being characterized, a systems biology approach combining genetics, mechanistic enzymology, and metabolite profiling should be undertaken. PMID:24873177

  20. rugose (rg), a Drosophila A kinase anchor protein, is required for retinal pattern formation and interacts genetically with multiple signaling pathways.

    PubMed Central

    Shamloula, Hoda K; Mbogho, Mkajuma P; Pimentel, Angel C; Chrzanowska-Lightowlers, Zosia M A; Hyatt, Vanneta; Okano, Hideyuki; Venkatesh, Tadmiri R

    2002-01-01

    In the developing Drosophila eye, cell fate determination and pattern formation are directed by cell-cell interactions mediated by signal transduction cascades. Mutations at the rugose locus (rg) result in a rough eye phenotype due to a disorganized retina and aberrant cone cell differentiation, which leads to reduction or complete loss of cone cells. The cone cell phenotype is sensitive to the level of rugose gene function. Molecular analyses show that rugose encodes a Drosophila A kinase anchor protein (DAKAP 550). Genetic interaction studies show that rugose interacts with the components of the EGFR- and Notch-mediated signaling pathways. Our results suggest that rg is required for correct retinal pattern formation and may function in cell fate determination through its interactions with the EGFR and Notch signaling pathways. PMID:12072466

  1. Genome-wide search for genetic modulators in gene regulatory pathways: weighted window-based peak identification algorithm.

    PubMed

    Lee, Eunjee; Kim, Kyunga; Park, Taesung

    2011-06-01

    Genome-wide gene expression and genotype data have been integratively analyzed in expression quantitative trait loci (eQTL) studies to elucidate the genetics of gene transcription. Most eQTL analyses have focused on identifying polymorphic genetic variants that influence the expression levels of individual genes, and such analyses may have limitations in explaining gene regulatory pathways that are likely to involve multiple genes and their genetic and/or non-genetic modulators. We have developed a novel two-step method for identifying potential genetic modulators of transcription processes for multiple genes in a biological pathway. We proposed a new weighted window-based peak identification algorithm to improve the detection of genetic modulators for individual genes and employed a Poisson-based test to search for master genetic modulators of multiple genes. Here, we have illustrated this two-step approach by analyzing the gene expression data in the Centre d'Etude du Polymorphisme Humain (CEPH) lymphoblast cells and single nucleotide polymorphism chip data.

  2. Sources, sinks, and exposure pathways of lead in urban garden soil.

    PubMed

    Clark, Heather F; Brabander, Daniel J; Erdil, Rachel M

    2006-01-01

    The chemistry of Pb in urban soil must be understood in order to limit human exposure to Pb in soil and produce and to implement remediation schemes. In inner-city gardens where Pb contamination is prevalent and financial resources are limited, it is critical to identify the variables that control Pb bioavailability. Field-portable X-ray fluorescence was used to measure Pb in 103 urban gardens in Roxbury and Dorchester, MA, and 88% were found to contain Pb above the USEPA reportable limit of 400 mug g(-1). Phosphorus, iron, loss on ignition, and pH data were collected, Pb-bearing phases were identified by X-ray diffraction, and Pb isotopes were measured using inductively coupled plasma mass spectrometry. Four test crops were grown both in situ and in Roxbury soil in a greenhouse, and plant tissue was analyzed for Pb uptake by polarized energy-dispersive X-ray fluorescence. Variation at the neighborhood scale in soil mineralogical and chemical characteristics suggests that the bioavailable fraction of Pb in gardens is site specific. Based on Pb isotope analysis, two historical Pb sources appear to dominate the inventory of Pb in Roxbury gardens: leaded gasoline ((207) Pb/(206) Pb = 0.827) and Pb-based paint ((207)Pb/(206) Pb = 0.867). Nearly 70% of the samples analyzed can be isotopically described by mixing these two end members, with Pb-based paint contributing 40 to 80% of the mass balance. A simplified urban human exposure model suggests that the consumption of produce from urban gardens is equivalent to approximately 10 to 25% of children's daily exposure from tap water. Furthermore, analysis of over 60 samples of plant tissue from the four test species suggests that in these urban gardens unamended phytoremediation is an inadequate tool for decreasing soil Pb.

  3. Genetic variants in the mTOR pathway and breast cancer risk in African American women.

    PubMed

    Cheng, Ting-Yuan David; Ambrosone, Christine B; Hong, Chi-Chen; Lunetta, Kathryn L; Liu, Song; Hu, Qiang; Yao, Song; Sucheston-Campbell, Lara; Bandera, Elisa V; Ruiz-Narváez, Edward A; Haddad, Stephen; Troester, Melissa A; Haiman, Christopher A; Bensen, Jeannette T; Olshan, Andrew F; Palmer, Julie R; Rosenberg, Lynn

    2016-01-01

    The phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (mTOR) pathway has been implicated in breast carcinogenesis. However, there has been no large-scale investigation of genetic variants in the mTOR pathway and breast cancer risk. We examined 28847 single-nucleotide polymorphisms (SNPs) in 61 mTOR pathway genes in the African American Breast Cancer Epidemiology and Risk consortium of 3663 cases [1983 estrogen receptor-positive (ER+) and 1098 ER-negative (ER-)] and 4687 controls. Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10773 SNPs that were not highly correlated (r (2) < 0.8), and SNP-level analyses were conducted with logistic regression. Among genes that were prioritized (nominal P < 0.05, ARTP tests), associations were observed for intronic SNPs TSC2 rs181088346 [odds ratio (OR) of each copy of variant allele = 0.77, 95% confidence interval (CI) = 0.65-0.88 for all breast cancer] and BRAF rs114729114 (OR = 1.53, 95% CI = 1.24-1.91 for all breast cancer and OR = 2.03, 95% CI = 1.50-2.76 for ER- tumors). For ER- tumors, intronic SNPs PGF rs11542848 (OR = 1.38, 95% CI = 1.15-1.66) and rs61759375 (OR = 1.34, 95% CI = 1.14-1.57) and MAPK3 rs78564187 (OR = 1.26, 95% CI = 1.11-1.43) were associated with increased risk. These SNPs were significant at a gene-wide level (Bonferroni-corrected P < 0.05). The variant allele of RPS6KB2 rs35363135, a synonymous coding SNP, was more likely to be observed in ER- than ER+ tumors (OR = 1.18, 95% CI = 1.05-1.31, gene-wide Bonferroni-corrected P = 0.06). In conclusion, specific mTOR pathway genes are potentially important to breast cancer risk and to the ER negativity in African American women. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Genetic Variation in ACE-related pathways associated with Sudden Cardiac Arrest Risk

    PubMed Central

    Sotoodehnia, Nona; Li, Guo; Johnson, Catherine O.; Lemaitre, Rozenn N.; Rice, Kenneth M.; Rea, Thomas D.; Siscovick, David S.

    2009-01-01

    Background Angiotensin converting enzyme (ACE)-related pathways influence arrhythmias and sudden cardiac arrest (SCA) risk. Objective We investigated whether genetic variation in ACE-related pathways are associated with SCA risk. Because these pathways are sex-dependent and influenced by estrogen, we examined these genotype-SCA associations in the full study population, and tested for interaction with gender. Methods In a population-based case-control study set in King County WA, we genotyped 211 SCA cases (mean age 59, 80% male) and 730 age- and gender-matched controls of European descent for 47 single nucleotide polymorphisms (SNPs) in eight genes (ACE, AGT, REN, AGTR1, AGTR2, ACE2, KNG1, BDKRB2). We examined association of SNPs and haplotypes with SCA risk using logistic regression. Results AGTR1 SNP rs1492099 (allele frequency=15%) was associated with decreased SCA risk (OR=0.62, 95%CI=0.4–0.9). Haplotype variation in AGTR2 was associated with SCA risk (global haplotype test p=0.001), with haplotype 2 (allele frequency=27%) associated with increased risk (OR=1.26, 95%CI=1.1–1.5). There was interaction with gender on SCA risk for variation in KNG1 (interaction p-value range=0.0004–0.017 for 6/8 SNPs). KNG1 SNP rs710448 (allele frequency=42%) was associated with decreased risk (OR=0.44, 95%CI=0.3–0.8) among women but not men. Other SNPs and haplotypes in the eight genes examined were not associated with SCA risk after multiple testing correction. Conclusions Variation in AGTR1 and AGTR2 are associated with SCA risk in a population-based case-control study. There was evidence of interaction with gender on SCA risk for variation in KNG1. Our findings, if replicated, suggest that variation in genes in ACE-related pathways influence SCA risk. PMID:19716087

  5. Genetic variants in the mTOR pathway and breast cancer risk in African American women

    PubMed Central

    Cheng, Ting-Yuan David; Ambrosone, Christine B.; Hong, Chi-Chen; Lunetta, Kathryn L.; Liu, Song; Hu, Qiang; Yao, Song; Sucheston-Campbell, Lara; Bandera, Elisa V.; Ruiz-Narváez, Edward A.; Haddad, Stephen; Troester, Melissa A.; Haiman, Christopher A.; Bensen, Jeannette T.; Olshan, Andrew F.; Palmer, Julie R.; Rosenberg, Lynn

    2016-01-01

    The phosphatidylinositol 3-kinase–AKT–mammalian target of rapamycin (mTOR) pathway has been implicated in breast carcinogenesis. However, there has been no large-scale investigation of genetic variants in the mTOR pathway and breast cancer risk. We examined 28847 single-nucleotide polymorphisms (SNPs) in 61 mTOR pathway genes in the African American Breast Cancer Epidemiology and Risk consortium of 3663 cases [1983 estrogen receptor-positive (ER+) and 1098 ER-negative (ER−)] and 4687 controls. Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10773 SNPs that were not highly correlated (r 2 < 0.8), and SNP-level analyses were conducted with logistic regression. Among genes that were prioritized (nominal P < 0.05, ARTP tests), associations were observed for intronic SNPs TSC2 rs181088346 [odds ratio (OR) of each copy of variant allele = 0.77, 95% confidence interval (CI) = 0.65–0.88 for all breast cancer] and BRAF rs114729114 (OR = 1.53, 95% CI = 1.24–1.91 for all breast cancer and OR = 2.03, 95% CI = 1.50–2.76 for ER− tumors). For ER− tumors, intronic SNPs PGF rs11542848 (OR = 1.38, 95% CI = 1.15–1.66) and rs61759375 (OR = 1.34, 95% CI = 1.14–1.57) and MAPK3 rs78564187 (OR = 1.26, 95% CI = 1.11–1.43) were associated with increased risk. These SNPs were significant at a gene-wide level (Bonferroni-corrected P < 0.05). The variant allele of RPS6KB2 rs35363135, a synonymous coding SNP, was more likely to be observed in ER− than ER+ tumors (OR = 1.18, 95% CI = 1.05–1.31, gene-wide Bonferroni-corrected P = 0.06). In conclusion, specific mTOR pathway genes are potentially important to breast cancer risk and to the ER negativity in African American women. PMID:26577839

  6. How can advances in epilepsy genetics lead to better treatments and cures?

    PubMed

    Guerrini, Renzo; Noebels, Jeffrey

    2014-01-01

    Advances in genetic analysis are fundamentally changing our understanding of the causes of epilepsy, and promise to add more precision to diagnosis and management of the clinical disorder. Single gene mutations that appear among more complex patterns of genomic variation can now be readily defined. As each mutation is identified, its predicted effects can now be validated in neurons derived from the patient's own stem cells, allowing a more precise understanding of the cellular defect. Parallel breakthroughs in genetic engineering now allow the creation of developmental experimental models bearing mutations identical to the human disorder. These models enable investigators to carry out detailed exploration of the downstream effects of the defective gene on the developing nervous system, and a framework for pursuing new therapeutic target discovery. Once these genetic strategies are combined with interdisciplinary technological advances in bioinformatics, imaging, and drug development, the promise of delivering clinical cures for some genetic epilepsies will be within our reach.

  7. Natal philopatry does not lead to population genetic differentiation in Buller's albatross (Thalassarche bulleri bulleri).

    PubMed

    van Bekkum, Margo; Sagar, Paul M; Stahl, Jean-Claude; Chambers, Geoffrey K

    2006-01-01

    Genetic variability in the only two existing populations of Buller's albatross (Thalassarche bulleri bulleri) was assessed using six polymorphic microsatellite loci. Large biological samples were obtained from both the Snares (n = 99) and the Solander Islands (n = 27). Several measures of genetic differentiation including F(ST) and R(ST) and a principal coordinates analysis (PCO) suggest a complete absence of genetic structure between three breeding colonies on the Snares Islands, and between them and one breeding colony on the Solander Islands. Mark/recapture studies of recently banded albatross chicks on the Snares found high natal philopatry in T. b. bulleri, but the microsatellite DNA data suggest that sufficient gene flow still occurs between all four breeding colonies to maintain a genetically homogeneous population overall.

  8. Cultural transmission of tool use combined with habitat specializations leads to fine-scale genetic structure in bottlenose dolphins.

    PubMed

    Kopps, Anna M; Ackermann, Corinne Y; Sherwin, William B; Allen, Simon J; Bejder, Lars; Krützen, Michael

    2014-05-07

    Socially learned behaviours leading to genetic population structure have rarely been described outside humans. Here, we provide evidence of fine-scale genetic structure that has probably arisen based on socially transmitted behaviours in bottlenose dolphins (Tursiops sp.) in western Shark Bay, Western Australia. We argue that vertical social transmission in different habitats has led to significant geographical genetic structure of mitochondrial DNA (mtDNA) haplotypes. Dolphins with mtDNA haplotypes E or F are found predominantly in deep (more than 10 m) channel habitat, while dolphins with a third haplotype (H) are found predominantly in shallow habitat (less than 10 m), indicating a strong haplotype-habitat correlation. Some dolphins in the deep habitat engage in a foraging strategy using tools. These 'sponging' dolphins are members of one matriline, carrying haplotype E. This pattern is consistent with what had been demonstrated previously at another research site in Shark Bay, where vertical social transmission of sponging had been shown using multiple lines of evidence. Using an individual-based model, we found support that in western Shark Bay, socially transmitted specializations may have led to the observed genetic structure. The reported genetic structure appears to present an example of cultural hitchhiking of mtDNA haplotypes on socially transmitted foraging strategies, suggesting that, as in humans, genetic structure can be shaped through cultural transmission.

  9. Cultural transmission of tool use combined with habitat specializations leads to fine-scale genetic structure in bottlenose dolphins

    PubMed Central

    Kopps, Anna M.; Ackermann, Corinne Y.; Sherwin, William B.; Allen, Simon J.; Bejder, Lars; Krützen, Michael

    2014-01-01

    Socially learned behaviours leading to genetic population structure have rarely been described outside humans. Here, we provide evidence of fine-scale genetic structure that has probably arisen based on socially transmitted behaviours in bottlenose dolphins (Tursiops sp.) in western Shark Bay, Western Australia. We argue that vertical social transmission in different habitats has led to significant geographical genetic structure of mitochondrial DNA (mtDNA) haplotypes. Dolphins with mtDNA haplotypes E or F are found predominantly in deep (more than 10 m) channel habitat, while dolphins with a third haplotype (H) are found predominantly in shallow habitat (less than 10 m), indicating a strong haplotype–habitat correlation. Some dolphins in the deep habitat engage in a foraging strategy using tools. These ‘sponging’ dolphins are members of one matriline, carrying haplotype E. This pattern is consistent with what had been demonstrated previously at another research site in Shark Bay, where vertical social transmission of sponging had been shown using multiple lines of evidence. Using an individual-based model, we found support that in western Shark Bay, socially transmitted specializations may have led to the observed genetic structure. The reported genetic structure appears to present an example of cultural hitchhiking of mtDNA haplotypes on socially transmitted foraging strategies, suggesting that, as in humans, genetic structure can be shaped through cultural transmission. PMID:24648223

  10. Puerarin protects rat kidney from lead-induced apoptosis by modulating the PI3K/Akt/eNOS pathway

    SciTech Connect

    Liu, Chan-Min; Ma, Jie-Qiong; Sun, Yun-Zhi

    2012-02-01

    Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. However, its protective effects against lead (Pb) induced injury in kidney have not been clarified. The aim of the present study was to investigate the effects of puerarin on renal oxidative stress and apoptosis in rats exposed to Pb. Wistar rats were exposed to lead acetate in the drinking water (500 mg Pb/l) with or without puerarin co-administration (100, 200, 300 and 400 mg PU/kg intragastrically once daily) for 75 days. Our data showed that puerarin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of kidney damage (serum urea, uric acid and creatinine) and histopathological analysis. Moreover, Pb-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of intracellular reduced glutathione (GSH) level in kidney, were suppressed by treatment with puerarin. Furthermore, TUNEL assay showed that Pb-induced apoptosis in rat kidney was significantly inhibited by puerarin. In exploring the underlying mechanisms of puerarin action, we found that activities of caspase-3 were markedly inhibited by the treatment of puerarin in the kidney of Pb-treated rats. Puerarin increased phosphorylated Akt, phosphorylated eNOS and NO levels in kidney, which in turn inactivated pro-apoptotic signaling events including inhibition of mitochondria cytochrome c release and restoration of the balance between pro- and anti-apoptotic Bcl-2 proteins in kidney of Pb-treated rats. In conclusion, these results suggested that the inhibition of Pb-induced apoptosis by puerarin is due at least in part to its antioxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway. Highlights: ► Puerarin prevented lead-induced nephrototoxicity. ► Puerarin reduced lead-induced increase in ROS and TBARS production

  11. Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions

    PubMed Central

    Barthold, Julia Spencer; Wang, Yanping; Kolon, Thomas F.; Kollin, Claude; Nordenskjöld, Agneta; Olivant Fisher, Alicia; Figueroa, T. Ernesto; BaniHani, Ahmad H.; Hagerty, Jennifer A.; Gonzaléz, Ricardo; Noh, Paul H.; Chiavacci, Rosetta M.; Harden, Kisha R.; Abrams, Debra J.; Kim, Cecilia E.; Li, Jin; Hakonarson, Hakon; Devoto, Marcella

    2015-01-01

    STUDY QUESTION What are the genetic loci that increase susceptibility to nonsyndromic cryptorchidism, or undescended testis? SUMMARY ANSWER A genome-wide association study (GWAS) suggests that susceptibility to cryptorchidism is heterogeneous, with a subset of suggestive signals linked to cytoskeleton-dependent functions and syndromic forms of the disease. WHAT IS KNOWN ALREADY Population studies suggest moderate genetic risk of cryptorchidism and possible maternal and environmental contributions to risk. Previous candidate gene analyses have failed to identify a major associated locus, although variants in insulin-like 3 (INSL3), relaxin/insulin-like family peptide receptor 2 (RXFP2) and other hormonal pathway genes may increase risk in a small percentage of patients. STUDY DESIGN, SIZE, DURATION This is a case–control GWAS of 844 boys with nonsyndromic cryptorchidism and 2718 control subjects without syndromes or genital anomalies, all of European ancestry. PARTICIPANTS/MATERIALS, SETTING, METHODS All boys with cryptorchidism were diagnosed and treated by a pediatric specialist. In the discovery phase, DNA was extracted from tissue or blood samples and genotyping performed using the Illumina HumanHap550 and Human610-Quad (Group 1) or OmniExpress (Group 2) platform. We imputed genotypes genome-wide, and combined single marker association results in meta-analyses for all cases and for secondary subphenotype analyses based on testis position, laterality and age, and defined genome-wide significance as P = 7 × 10−9 to correct for multiple testing. Selected markers were genotyped in an independent replication group of European cases (n = 298) and controls (n = 324). We used several bioinformatics tools to analyze top (P < 10−5) and suggestive (P < 10−3) signals for significant enrichment of signaling pathways, cellular functions and custom gene lists after multiple testing correction. MAIN RESULTS AND THE ROLE OF CHANCE In the full analysis, we identified 20

  12. Genetic Polymorphisms in Estrogen Metabolic Pathway Associated with Risks of Alzheimer's Disease: Evidence from a Southern Chinese Population.

    PubMed

    Chen, Lu Hua; Fan, Yan Hui; Kao, Patrick Yu Ping; Ho, Deborah Tip Yin; Ha, Joyce Cheuk Tung; Chu, Leung Wing; Song, You-Qiang

    2017-02-01

    To investigate whether genetic variations on the estrogen metabolic pathway would be associated with risk of Alzheimer's disease (AD). Cross-sectional study. Individuals were recruited at the Memory Clinic, Queen Mary Hospital, Hong Kong. Chinese individuals with (n = 426) and without (n = 350) AD. All subjects underwent a standardized cognitive assessment and genotyping of four candidate genes on the estrogen metabolic pathway (estrogen receptor α gene (ESR1), estrogen receptor β gene (ESR2), cytochrome P450 19A1 gene (CYP19A1), cytochrome P450 11A1 gene (CYP11A1)). Apart from consistent results showing an association between apolipoprotein (APO)E and AD, strong evidence of disease associations were found for polymorphisms in ESR2 and CYP11A1 based on the entire data set. For ESR2, significant protective effects were found for A alleles of rs4986938 (permuted P = .02) and rs867443 (permuted P = .02). For CYP11A1, significant risk effects were found for G alleles of rs11638442 (permuted P = .03) and rs11632698 (permuted P = .03). Stratifying subjects according to APOE ε4 status, their genetic effects continued to be significant in the APOE ε4-negative subgroup. Associations between CYP11A1 polymorphisms (rs2279357, rs2073475) and risk of AD were detected in women but not men. Further gene-level analysis confirmed the above association between ESR2 and CYP11A1, and pathway-level analysis highlighted the genetic effect of the estrogen metabolic pathway on disease susceptibility (permuted pathway-level P = .03). Consistent with previous biological findings for sex steroid hormones in the central nervous system, genetic alterations on the estrogen metabolic pathway were revealed in the Chinese population. Confirmation of these present findings in an independent population is warranted to elucidate disease pathogenesis and to explore the potential of hormone therapy in the treatment of AD. © 2017, Copyright the Authors Journal compilation © 2017, The American

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

    SciTech Connect

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

    2016-10-05

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

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

    DOE PAGES

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

    2016-10-05

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

  15. Genetic variants in vitamin D signaling pathways and risk of gestational diabetes mellitus.

    PubMed

    Shi, Aiwu; Wen, Juan; Liu, Guangquan; Liu, Heng; Fu, Ziyi; Zhou, Jing; Zhu, Yao; Liu, Yaoqiu; Guo, Xirong; Xu, Jianguo

    2016-10-18

    Vitamin D (VD) deficiency during pregnancy has been repeatedly linked to an increased gestational diabetes mellitus (GDM) risk. We sought to determine the influences of genetic variants in vitamin D signaling pathways on the risk of GDM. In this study, we genotyped 15 single nucleotide polymorphisms (SNPs) within 8 representative genes (CYP27A1, CYP27B1, CYP24A1, VDR, RXRA, RXRB, RXRG and GC) of the vitamin D signaling pathways in a case-control study with 964 GDM cases and 1,021 controls using the Sequenom MassARRAY iPLEX platform. Logistic regression analyses in additive model showed that GC rs16847024 C>T, RXRG rs17429130 G>C and RXRA rs4917356 T>C were significantly associated with the increased risk of GDM (adjusted OR = 1.31, 95% CI = 1.10-1.58 for rs16847024; adjusted OR = 1.28, 95% CI = 1.04-1.57 for rs17429130; adjusted OR = 1.28, 95% CI = 1.06-1.54 for rs4917356). And GDM risk significantly increased with the increasing number of variant alleles of the three SNPs in a dose-dependent manner (P for trend < 0.001). Moreover, the combined effect of the three SNPs on GDM occurrence was more prominent in older women (age > 30). Further interactive analyses also detected a significantly multiplicative interaction between the combined variant alleles and age on GDM risk (P = 0.035). Together, these findings indicate that GC rs16847024, RXRG rs17429130 and RXRA rs4917356 were candidate susceptibility markers for GDM in Chinese females. Further validation studies with different ethnic background and biological function analyses were needed.

  16. Final Technical Report: Genetic and Molecular Analysis of a new control pathway in assimilate partitioning.

    SciTech Connect

    Bush, Daniel, R.

    2009-03-10

    Assimilate partitioning refers to the systemic distribution of photoassimilate from sites of primary assimilation (source tissue) to import-dependent tissues and organs (sinks). One of the defining questions in this area is how plants balance source productivity with sink demand. We discovered a sucrose-sensing signal transduction pathway that controls the activity of BvSUT1, a proton-sucrose symporter in sugar beet leaf tissue. Sucrose symporters are responsible for sucrose accumulation in the phloem of many plants and, therefore, they mediate the pivotal step in the long-distance transport of photoassimilate to non-photosynthetic tissues, such as roots and seed. We previously showed that sucrose transport activity is directly proportional to the transcription rate of BvSUT1 and that symporter mRNA and protein have high rates of turnover with half-lives on the order of 2 h. We further demonstrated that symporter transcription is regulated by sucrose levels in the leaf and that sucrose-dependent regulation of BvSUT1 transcription is mediated, at least in part, by a protein phosphorylation relay pathway. The goal of the experiments during this current grant were to use genetic and molecular approaches to identify essential components of this vital regulatory system. The initial objectives were to: (1) to characterize Arabidopsis mutants we've isolated that are resistant to growth inhibition by sucrose analogues that are recognized by the sucrose-sensor, (2) to screen for loss of function mutants in BvSUT1-promoter:luciferase transgenic plants that no longer respond to sucrose accumulation in the leaf using non-destructive visualization of luciferase activity, (3) to use gel mobility-shift assays and nuclease protection experiments to identify cis elements in the symporter promoter and DNA-binding proteins that are involved in sucrose regulation of symporter expression.

  17. Common genetic variants in metabolism and detoxification pathways and the risk of papillary thyroid cancer

    PubMed Central

    Aschebrook-Kilfoy, Briseis; Neta, Gila; Brenner, Alina V; Hutchinson, Amy; Pfeiffer, Ruth M; Sturgis, Erich M; Xu, Li; Wheeler, William; Doody, Michele M; Chanock, Stephen J; Sigurdson, Alice J

    2012-01-01

    Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (Ptrend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (Pgene interaction) were evaluated by combining Ptrend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (Ptrend≤0.01) and seven genes/regions (Pregion<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (Pgene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (Pgene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings. PMID:22389382

  18. Genetic analysis of a transcriptional activation pathway by using hepatoma cell variants.

    PubMed Central

    Bulla, G A; Fournier, R E

    1994-01-01

    A hierarchy of liver-enriched transcription factors plays an important role in activating expression of many hepatic genes. In particular, hepatocyte nuclear factor 4 (HNF-4) is a major activator of the gene encoding HNF-1, and HNF-1 itself activates expression of more than 20 liver genes. To dissect this activation pathway genetically, we prepared somatic cell variants that were deficient in expression of the liver-specific alpha 1-antitrypsin (alpha 1AT) gene, which requires both HNF-1 and HNF-4 for high-level gene activity. This was accomplished in two steps. First, hepatoma transfectants that stably expressed two selectable markers under alpha 1AT promoter control were prepared; second, variant sublines that could no longer express either transgene were isolated by direct selection. In this report, we demonstrate that the variants contain defects in the HNF-4/HNF-1 activation pathway. These defects functioned in trans, as expression of many liver genes was affected, but the variant phenotypes were recessive to wild type in somatic cell hybrids. Three different variant classes could be discriminated by their phenotypic responses to ectopic expression of either HNF-4 or HNF-1. Two variant clones appeared specifically deficient in HNF-4 expression, as transfection with an HNF-4 expression cassette fully restored their hepatic phenotypes. Another line activated HNF-1 in response to forced HNF-4 expression, but activation of downstream genes failed to occur. One clone was unresponsive to either HNF-1 or HNF-4. Using the variants, we demonstrate further that the chromosomal genes encoding alpha 1AT, aldolase B, and alpha-fibrinogen display strict requirements for HNF-1 activation in vivo, while other liver genes were unaffected by the presence or absence of HNF-1 or HNF-4. We also provide evidence for the existence of an autoregulatory loop in which HNF-1 regulates its own expression through activation of HNF-4. Images PMID:7935424

  19. Further genetic evidence suggesting a role for the RhoGTPase-RhoGEF pathway in osteoporosis.

    PubMed

    Mullin, Ben H; Prince, Richard L; Mamotte, Cyril; Spector, Tim D; Hart, Deborah J; Dudbridge, Frank; Wilson, Scott G

    2009-08-01

    Osteoporosis is a highly heritable trait that appears to be influenced by multiple genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p21 as a quantitative trait locus for BMD. We have previously published evidence suggesting that the ARHGEF3 gene from this region is associated with BMD in women. The product of this gene activates the RHOA GTPase, the gene for which is also located within this region. The aim of this study was to evaluate the influence of genetic polymorphism in RHOA on bone density in women. Sequence variation within the RHOA gene region was determined using 9 single nucleotide polymorphisms (SNPs) in a discovery cohort of 769 female sibs. Of the 9 SNPs, one was found to be monomorphic with the others representing 3 distinct linkage disequilibrium (LD) blocks. Using FBAT software, significant associations were found between two of these LD blocks and BMD Z-score of the spine and hip (P=0.001-0.036). The LD block tagged by the SNP rs17595772 showed maximal association, with the more common G allele at rs17595772 associated with decreased BMD Z-score. Genotyping for rs17595772 in a replication cohort of 780 postmenopausal women confirmed an association with BMD Z-score (P=0.002-0.036). Again, the G allele was found to be associated with a reduced hip and spine BMD Z-score. These results support the implication of the RhoGTPase-RhoGEF pathway in osteoporosis, and suggest that one or more genes in this pathway may be responsible for the linkage observed between 3p14-p21 and BMD.

  20. Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma.

    PubMed

    Lin, Yuan; Chahal, Harvind S; Wu, Wenting; Cho, Hyunje G; Ransohoff, Katherine J; Song, Fengju; Tang, Jean Y; Sarin, Kavita Y; Han, Jiali

    2017-09-01

    DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10(-6) ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10(-6) and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10(-6) ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis. © 2017 UICC.

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

    SciTech Connect

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

    2016-10-05

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

  2. Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway

    PubMed Central

    Sakai, Eiji; Fukuyo, Masaki; Ohata, Ken; Matsusaka, Keisuke; Doi, Noriteru; Mano, Yasunobu; Takane, Kiyoko; Abe, Hiroyuki; Yagi, Koichi; Matsuhashi, Nobuyuki; Fukushima, Junichi; Fukayama, Masashi; Akagi, Kiwamu; Aburatani, Hiroyuki; Nakajima, Atsushi

    2015-01-01

    To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway. PMID:26510091

  3. Comparison of Metabolic Pathways in Escherichia coli by Using Genetic Algorithms

    PubMed Central

    Ortegon, Patricia; Poot-Hernández, Augusto C.; Perez-Rueda, Ernesto; Rodriguez-Vazquez, Katya

    2015-01-01

    In order to understand how cellular metabolism has taken its modern form, the conservation and variations between metabolic pathways were evaluated by using a genetic algorithm (GA). The GA approach considered information on the complete metabolism of the bacterium Escherichia coli K-12, as deposited in the KEGG database, and the enzymes belonging to a particular pathway were transformed into enzymatic step sequences by using the breadth-first search algorithm. These sequences represent contiguous enzymes linked to each other, based on their catalytic activities as they are encoded in the Enzyme Commission numbers. In a posterior step, these sequences were compared using a GA in an all-against-all (pairwise comparisons) approach. Individual reactions were chosen based on their measure of fitness to act as parents of offspring, which constitute the new generation. The sequences compared were used to construct a similarity matrix (of fitness values) that was then considered to be clustered by using a k-medoids algorithm. A total of 34 clusters of conserved reactions were obtained, and their sequences were finally aligned with a multiple-sequence alignment GA optimized to align all the reaction sequences included in each group or cluster. From these comparisons, maps associated with the metabolism of similar compounds also contained similar enzymatic step sequences, reinforcing the Patchwork Model for the evolution of metabolism in E. coli K-12, an observation that can be expanded to other organisms, for which there is metabolism information. Finally, our mapping of these reactions is discussed, with illustrations from a particular case. PMID:25973143

  4. Comparison of Metabolic Pathways in Escherichia coli by Using Genetic Algorithms.

    PubMed

    Ortegon, Patricia; Poot-Hernández, Augusto C; Perez-Rueda, Ernesto; Rodriguez-Vazquez, Katya

    2015-01-01

    In order to understand how cellular metabolism has taken its modern form, the conservation and variations between metabolic pathways were evaluated by using a genetic algorithm (GA). The GA approach considered information on the complete metabolism of the bacterium Escherichia coli K-12, as deposited in the KEGG database, and the enzymes belonging to a particular pathway were transformed into enzymatic step sequences by using the breadth-first search algorithm. These sequences represent contiguous enzymes linked to each other, based on their catalytic activities as they are encoded in the Enzyme Commission numbers. In a posterior step, these sequences were compared using a GA in an all-against-all (pairwise comparisons) approach. Individual reactions were chosen based on their measure of fitness to act as parents of offspring, which constitute the new generation. The sequences compared were used to construct a similarity matrix (of fitness values) that was then considered to be clustered by using a k-medoids algorithm. A total of 34 clusters of conserved reactions were obtained, and their sequences were finally aligned with a multiple-sequence alignment GA optimized to align all the reaction sequences included in each group or cluster. From these comparisons, maps associated with the metabolism of similar compounds also contained similar enzymatic step sequences, reinforcing the Patchwork Model for the evolution of metabolism in E. coli K-12, an observation that can be expanded to other organisms, for which there is metabolism information. Finally, our mapping of these reactions is discussed, with illustrations from a particular case.

  5. Hodgkin disease risk: role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes.

    PubMed

    Monroy, Claudia M; Cortes, Andrea C; Lopez, Mirtha S; D'Amelio, Anthony M; Etzel, Carol J; Younes, Anas; Strom, Sara S; El-Zein, Randa A

    2011-01-01

    Inflammation is a critical component of cancer development. The clinical and pathological features of Hodgkin disease (HD) reflect an abnormal immunity that results from cytokines secreted by Reed-Sternberg cells and the surrounding tumor. Numerous studies have reported the association between genetic polymorphisms in cytokine genes and the susceptibility to different hematologic cancers. However, the effects of such SNPs on modulating HD risk have not yet been investigated. We hypothesized that gene-gene interactions between candidate genes in the anti- and pro-inflammatory pathways carrying suspicious polymorphisms may contribute to susceptibility to HD. To test this hypothesis, we conducted a study on 200 HD cases and 220 controls to assess associations between HD risk and 38 functional SNPs in inflammatory genes. We evaluated potential gene-gene interactions using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction, and classification and regression tree (CART) approaches. We observed that, in combination, allelic variants in the COX2, IL18, ILR4, and IL10 genes modify the risk for developing HD. Moreover, the cumulative genetic risk score (CGRS) revealed a significant trend where the risk for developing HD increases as the number of adverse alleles in the cytokine genes increase. These findings support the notion that epigenetic-interactions between these cytokines may influence pathogenesis of HD modulating the proliferation of regulatory T cells. In this way, the innate and adaptative immune responses may be altered and defy their usual functions in the host anti-tumor response. Our study is the first to report the association between polymorphisms in inflammation genes and HD susceptibility risk. © 2010 Wiley-Liss, Inc.

  6. Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk

    PubMed Central

    Barry, Kathryn Hughes; Koutros, Stella; Andreotti, Gabriella; Sandler, Dale P.; Burdette, Laurie A.; Yeager, Meredith; Beane Freeman, Laura E.; Lubin, Jay H.; Zheng, Tongzhang; Alavanja, Michael C.R.; Berndt, Sonja I.

    2012-01-01

    Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case–control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65–5.39; Pinteract = 3.6 × 10−4; FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r2 = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31–3.10 for rs11744596; Pinteract = 7.2 × 10−4; FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk. PMID:22102698

  7. VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis

    PubMed Central

    Avidan, Nili; Le Panse, Rozen; Harbo, Hanne F; Bernasconi, Pia; Poulas, Konstantinos; Ginzburg, Elizabeta; Cavalcante, Paola; Colleoni, Lara; Baggi, Fulvio; Antozzi, Carlo; Truffault, Frédérique; Horn-Saban, Shirley; Pöschel, Simone; Zagoriti, Zoi; Maniaol, Angelina; Lie, Benedicte A; Bernard, Isabelle; Saoudi, Abdelhadi; Illes, Zsolt; Casasnovas Pons, Carlos; Melms, Arthur; Tzartos, Socrates; Willcox, Nicholas; Kostera-Pruszczyk, Anna; Tallaksen, Chantal; Mantegazza, Renato; Berrih-Aknin, Sonia; Miller, Ariel

    2014-01-01

    Objective To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy. Methods Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA-DRA and TNF-α loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG. PMID:25356403

  8. Randomized BioBrick assembly: a novel DNA assembly method for randomizing and optimizing genetic circuits and metabolic pathways.

    PubMed

    Sleight, Sean C; Sauro, Herbert M

    2013-09-20

    The optimization of genetic circuits and metabolic pathways often involves constructing various iterations of the same construct or using directed evolution to achieve the desired function. Alternatively, a method that randomizes individual parts in the same assembly reaction could be used for optimization by allowing for the ability to screen large numbers of individual clones expressing randomized circuits or pathways for optimal function. Here we describe a new assembly method to randomize genetic circuits and metabolic pathways from modular DNA fragments derived from PCR-amplified BioBricks. As a proof-of-principle for this method, we successfully assembled CMY (Cyan-Magenta-Yellow) three-gene circuits using Gibson Assembly that express CFP, RFP, and YFP with independently randomized promoters, ribosome binding sites, transcriptional terminators, and all parts randomized simultaneously. Sequencing results from 24 CMY circuits with various parts randomized show that 20/24 circuits are distinct and expression varies over a 200-fold range above background levels. We then adapted this method to randomize the same parts with enzyme coding sequences from the lycopene biosynthesis pathway instead of fluorescent proteins, designed to independently express each enzyme in the pathway from a different promoter. Lycopene production is improved using this randomization method by about 30% relative to the highest polycistronic-expressing pathway. These results demonstrate the potential of generating nearly 20,000 unique circuit or pathway combinations when three parts are permutated at each position in a three-gene circuit or pathway, and the methodology can likely be adapted to other circuits and pathways to maximize products of interest.

  9. The microtubule-associated molecular pathways may be genetically disrupted in patients with Bipolar Disorder. Insights from the molecular cascades.

    PubMed

    Drago, Antonio; Crisafulli, Concetta; Sidoti, Antonina; Calabrò, Marco; Serretti, Alessandro

    2016-01-15

    Bipolar Disorder is a severe disease characterized by pathological mood swings from major depressive episodes to manic ones and vice versa. The biological underpinnings of Bipolar Disorder have yet to be defined. As a consequence, pharmacological treatments are suboptimal. In the present paper we test the hypothesis that the molecular pathways involved with the direct targets of lithium, hold significantly more genetic variations associated with BD. A molecular pathway approach finds its rationale in the polygenic nature of the disease. The pathways were tested in a sample of ∼ 7,000 patients and controls. Data are available from the public NIMH database. The definition of the pathways was conducted according to the National Cancer Institute (http://pid.nci.nih.gov/). As a result, 3 out of the 18 tested pathways related to lithium action resisted the permutation analysis and were found to be associated with BD. These pathways were related to Reelin, Integrins and Aurora. A pool of genes selected from the ones linked with the above pathways was further investigated in order to identify the fine molecular mechanics shared by our significant pathways and also their link with lithium mechanism of action. The data obtained point out to a possible involvement of microtubule-related mechanics. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway.

    PubMed

    Rizzo, Angela; Salvati, Erica; Porru, Manuela; D'Angelo, Carmen; Stevens, Malcolm F; D'Incalci, Maurizio; Leonetti, Carlo; Gilson, Eric; Zupi, Gabriella; Biroccio, Annamaria

    2009-09-01

    Functional telomeres are required to maintain the replicative ability of cancer cells and represent putative targets for G-quadruplex (G4) ligands. Here, we show that the pentacyclic acridinium salt RHPS4, one of the most effective and selective G4 ligands, triggers damages in cells traversing S phase by interfering with telomere replication. Indeed, we found that RHPS4 markedly reduced BrdU incorporation at telomeres and altered the dynamic association of the telomeric proteins TRF1, TRF2 and POT1, leading to chromosome aberrations such as telomere fusions and telomere doublets. Analysis of the molecular damage pathway revealed that RHPS4 induced an ATR-dependent ATM signaling that plays a functional role in the cellular response to RHPS4 treatment. We propose that RHPS4, by stabilizing G4 DNA at telomeres, impairs fork progression and/or telomere processing resulting in telomere dysfunction and activation of a replication stress response pathway. The detailed understanding of the molecular mode of action of this class of compounds makes them attractive tools to understand telomere biology and provides the basis for a rational use of G4 ligands for the therapy of cancer.

  11. Born to Lead? A Twin Design and Genetic Association Study of Leadership Role Occupancy*

    PubMed Central

    De Neve, Jan-Emmanuel; Mikhaylov, Slava; Dawes, Christopher T.; Christakis, Nicholas A.; Fowler, James H.

    2013-01-01

    We address leadership emergence and the possibility that there is a partially innate predisposition to occupy a leadership role. Employing twin design methods on data from the National Longitudinal Study of Adolescent Health, we estimate the heritability of leadership role occupancy at 24%. Twin studies do not point to specific genes or neurological processes that might be involved. We therefore also conduct association analysis on the available genetic markers. The results show that leadership role occupancy is associated with rs4950, a single nucleotide polymorphism (SNP) residing on a neuronal acetylcholine receptor gene (CHRNB3). We replicate this family-based genetic association result on an independent sample in the Framingham Heart Study. This is the first study to identify a specific genotype associated with the tendency to occupy a leadership position. The results suggest that what determines whether an individual occupies a leadership position is the complex product of genetic and environmental influences; with a particular role for rs4950. PMID:23459689

  12. Genetic alterations leading to increases in internal potassium concentrations are detrimental for DNA integrity in Saccharomyces cerevisiae.

    PubMed

    Merchan, Stephanie; Pedelini, Leda; Hueso, Guillem; Calzada, Arturo; Serrano, Ramón; Yenush, Lynne

    2011-02-01

    We have investigated the effects of alterations in potassium homeostasis on cell cycle progression and genome stability in Saccharomyces cerevisiae. Yeast strains lacking the PPZ1 and PPZ2 phosphatase genes, which aberrantly accumulate potassium, are sensitive to agents causing replicative stress or DNA damage and present a cell cycle delay in the G(1) /S phase. A synthetic slow growth phenotype was identified in a subset of DNA repair mutants upon inhibition of Ppz activity. Moreover, we observe that this slow growth phenotype observed in cdc7(ts) mutants with reduced Ppz activity is reverted by disrupting the TRK1 potassium transporter gene. As over-expression of a mammalian potassium transporter leads to similar phenotypes, we conclude that these defects can be attributed to potassium accumulation. As we reported previously, internal potassium accumulation activates the Slt2 MAP kinase pathway. We show that the removal of SLT2 in ppz1 ppz2 mutants ameliorates sensitivity to agents causing replication stress and DNA damage, whereas over-activation of the pathway leads to similar cell cycle-related defects. Taken together, these results are consistent with inappropriate potassium accumulation reducing DNA replication efficiency, negatively influencing DNA integrity and leading to the requirement of mismatch repair, the MRX complex, or homologous recombination pathways for normal growth. © 2010 The Authors. Journal compilation © 2010 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

  13. Pathways and barriers to genetic testing and screening: Molecular genetics meets the high-risk family. Final report

    SciTech Connect

    Duster, T.

    1998-11-01

    The proliferation of genetic screening and testing is requiring increasing numbers of Americans to integrate genetic knowledge and interventions into their family life and personal experience. This study examines the social processes that occur as families at risk for two of the most common autosomal recessive diseases, sickle cell disease (SC) and cystic fibrosis (CF), encounter genetic testing. Each of these diseases is found primarily in a different ethnic/racial group (CF in Americans of North European descent and SC in Americans of West African descent). This has permitted them to have a certain additional lens on the role of culture in integrating genetic testing into family life and reproductive planning. A third type of genetic disorder, the thalassemias was added to the sample in order to extent the comparative frame and to include other ethnic and racial groups.

  14. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

    PubMed Central

    Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

    2016-01-01

    Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma. PMID:25961939

  15. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis.

    PubMed

    Moriarity, Branden S; Otto, George M; Rahrmann, Eric P; Rathe, Susan K; Wolf, Natalie K; Weg, Madison T; Manlove, Luke A; LaRue, Rebecca S; Temiz, Nuri A; Molyneux, Sam D; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L; Scott, Milcah C; Forster, Colleen L; Modiano, Jaime F; Khanna, Chand; Hewitt, Stephen M; Khokha, Rama; Yang, Yi; Gorlick, Richard; Dyer, Michael A; Largaespada, David A

    2015-06-01

    Osteosarcomas are sarcomas of the bone, derived from osteoblasts or their precursors, with a high propensity to metastasize. Osteosarcoma is associated with massive genomic instability, making it problematic to identify driver genes using human tumors or prototypical mouse models, many of which involve loss of Trp53 function. To identify the genes driving osteosarcoma development and metastasis, we performed a Sleeping Beauty (SB) transposon-based forward genetic screen in mice with and without somatic loss of Trp53. Common insertion site (CIS) analysis of 119 primary tumors and 134 metastatic nodules identified 232 sites associated with osteosarcoma development and 43 sites associated with metastasis, respectively. Analysis of CIS-associated genes identified numerous known and new osteosarcoma-associated genes enriched in the ErbB, PI3K-AKT-mTOR and MAPK signaling pathways. Lastly, we identified several oncogenes involved in axon guidance, including Sema4d and Sema6d, which we functionally validated as oncogenes in human osteosarcoma.

  16. Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'.

    PubMed

    Bystrykh, Leonid; Weersing, Ellen; Dontje, Bert; Sutton, Sue; Pletcher, Mathew T; Wiltshire, Tim; Su, Andrew I; Vellenga, Edo; Wang, Jintao; Manly, Kenneth F; Lu, Lu; Chesler, Elissa J; Alberts, Rudi; Jansen, Ritsert C; Williams, Robert W; Cooke, Michael P; de Haan, Gerald

    2005-03-01

    We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.

  17. Genetic approach identifies distinct asthma pathways in overweight vs normal weight children.

    PubMed

    Butsch Kovacic, M; Martin, L J; Biagini Myers, J M; He, H; Lindsey, M; Mersha, T B; Khurana Hershey, G K

    2015-08-01

    The pathogenesis of asthma in the context of excess body weight may be distinct from asthma that develops in normal weight children. The study's objective was to explore the biology of asthma in the context of obesity and normal weight status using genetic methodologies. Associations between asthma and SNPs in 49 genes were assessed, as well as, interactions between SNPs and overweight status in child participants of the Greater Cincinnati Pediatric Clinic Repository. Asthma was significantly associated with weight (OR = 1.38; P = 0.037). The number of genes and the magnitude of their associations with asthma were notably greater when considering overweight children alone vs normal weight and overweight children together. When considering weight, distinct sets of asthma-associated genes were observed, many times with opposing effects. We demonstrated that the underlying heterogeneity of asthma is likely due in part to distinct pathogenetic pathways that depend on preceding/comorbid overweight and/or allergy. It is therefore important to consider both obesity and asthma when conducting studies of asthma.

  18. Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer.

    PubMed

    Young, Jonathan H; Peyton, Michael; Seok Kim, Hyun; McMillan, Elizabeth; Minna, John D; White, Michael A; Marcotte, Edward M

    2016-05-01

    Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets. Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel. The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper marcotte@icmb.utexas.edu or jon.young@utexas.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  19. Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice.

    PubMed

    Chan, Aubrey C; Drakos, Stavros G; Ruiz, Oscar E; Smith, Alexandra C H; Gibson, Christopher C; Ling, Jing; Passi, Samuel F; Stratman, Amber N; Sacharidou, Anastasia; Revelo, M Patricia; Grossmann, Allie H; Diakos, Nikolaos A; Davis, George E; Metzstein, Mark M; Whitehead, Kevin J; Li, Dean Y

    2011-05-01

    Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krev1 interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Krit1. PDCD10 bound to germinal center kinase III (GCKIII) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcd10 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity.

  20. Maternal hyperglycemia activates an ASK1-FoxO3a-caspase 8 pathway that leads to embryonic neural tube defects.

    PubMed

    Yang, Peixin; Li, Xuezheng; Xu, Cheng; Eckert, Richard L; Reece, E Albert; Zielke, Horst Ronald; Wang, Fang

    2013-08-27

    Neural tube defects result from failure to completely close neural tubes during development. Maternal diabetes is a substantial risk factor for neural tube defects, and available evidence suggests that the mechanism that links hyperglycemia to neural tube defects involves oxidative stress and apoptosis. We demonstrated that maternal hyperglycemia correlated with activation of the apoptosis signal-regulating kinase 1 (ASK1) in the developing neural tube, and Ask1 gene deletion was associated with reduced neuroepithelial cell apoptosis and development of neural tube defects. ASK1 activation stimulated the activity of the transcription factor FoxO3a, which increased the abundance of the apoptosis-promoting adaptor protein TRADD, leading to activation of caspase 8. Hyperglycemia-induced apoptosis and the development of neural tube defects were reduced with genetic ablation of either FoxO3a or Casp8 or inhibition of ASK1 by thioredoxin. Examination of human neural tissues affected by neural tube defects revealed increased activation or abundance of ASK1, FoxO3a, TRADD, and caspase 8. Thus, activation of an ASK1-FoxO3a-TRADD-caspase 8 pathway participates in the development of neural tube defects, which could be prevented by inhibiting intermediates in this cascade.

  1. Genetic Factors That Might Lead to Different Responses in Individuals Exposed to Perchlorate

    PubMed Central

    Scinicariello, Franco; Murray, H. Edward; Smith, Lester; Wilbur, Sharon; Fowler, Bruce A.

    2005-01-01

    Perchlorate has been detected in groundwater in many parts of the United States, and recent detection in vegetable and dairy food products indicates that contamination by perchlorate is more widespread than previously thought. Perchlorate is a competitive inhibitor of the sodium iodide symporter, the thyroid cell–surface protein responsible for transporting iodide from the plasma into the thyroid. An estimated 4.3% of the U.S. population is subclinically hypothyroid, and 6.9% of pregnant women may have low iodine intake. Congenital hypothyroidism affects 1 in 3,000 to 1 in 4,000 infants, and 15% of these cases have been attributed to genetic defects. Our objective in this review is to identify genetic biomarkers that would help define subpopulations sensitive to environmental perchlorate exposure. We review the literature to identify genetic defects involved in the iodination process of the thyroid hormone synthesis, particularly defects in iodide transport from circulation into the thyroid cell, defects in iodide transport from the thyroid cell to the follicular lumen (Pendred syndrome), and defects of iodide organification. Furthermore, we summarize relevant studies of perchlorate in humans. Because of perchlorate inhibition of iodide uptake, it is biologically plausible that chronic ingestion of perchlorate through contaminated sources may cause some degree of iodine discharge in populations that are genetically susceptible to defects in the iodination process of the thyroid hormone synthesis, thus deteriorating their conditions. We conclude that future studies linking human disease and environmental perchlorate exposure should consider the genetic makeup of the participants, actual perchlorate exposure levels, and individual iodine intake/excretion levels. PMID:16263499

  2. Genetic factors that might lead to different responses in individuals exposed to perchlorate.

    PubMed

    Scinicariello, Franco; Murray, H Edward; Smith, Lester; Wilbur, Sharon; Fowler, Bruce A

    2005-11-01

    Perchlorate has been detected in groundwater in many parts of the United States, and recent detection in vegetable and dairy food products indicates that contamination by perchlorate is more widespread than previously thought. Perchlorate is a competitive inhibitor of the sodium iodide symporter, the thyroid cell-surface protein responsible for transporting iodide from the plasma into the thyroid. An estimated 4.3% of the U.S. population is subclinically hypothyroid, and 6.9% of pregnant women may have low iodine intake. Congenital hypothyroidism affects 1 in 3,000 to 1 in 4,000 infants, and 15% of these cases have been attributed to genetic defects. Our objective in this review is to identify genetic biomarkers that would help define subpopulations sensitive to environmental perchlorate exposure. We review the literature to identify genetic defects involved in the iodination process of the thyroid hormone synthesis, particularly defects in iodide transport from circulation into the thyroid cell, defects in iodide transport from the thyroid cell to the follicular lumen (Pendred syndrome), and defects of iodide organification. Furthermore, we summarize relevant studies of perchlorate in humans. Because of perchlorate inhibition of iodide uptake, it is biologically plausible that chronic ingestion of perchlorate through contaminated sources may cause some degree of iodine discharge in populations that are genetically susceptible to defects in the iodination process of the thyroid hormone synthesis, thus deteriorating their conditions. We conclude that future studies linking human disease and environmental perchlorate exposure should consider the genetic makeup of the participants, actual perchlorate exposure levels, and individual iodine intake/excretion levels.

  3. Endogenous TRPV1 stimulation leads to the activation of the inositol phospholipid pathway necessary for sustained Ca(2+) oscillations.

    PubMed

    Pecze, László; Blum, Walter; Henzi, Thomas; Schwaller, Beat

    2016-12-01

    Sensory neuron subpopulations as well as breast and prostate cancer cells express functional transient receptor potential vanilloid type 1 (TRPV1) ion channels; however little is known how TRPV1 activation leads to biological responses. Agonist-induced activation of TRPV1 resulted in specific spatiotemporal patterns of cytoplasmic Ca(2+) signals in breast and prostate cancer-derived cells. Capsaicin (CAPS; 50μM) evoked intracellular Ca(2+) oscillations and/or intercellular Ca(2+) waves in all cell lines. As evidenced in prostate cancer Du 145 cells, oscillations were largely dependent on the expression of functional TRPV1 channels in the plasma membrane, phospholipase C activation and on the presence of extracellular Ca(2+) ions. Concomitant oscillations of the mitochondrial matrix Ca(2+) concentration resulted in mitochondria energization evidenced by increased ATP production. CAPS-induced Ca(2+) oscillations also occurred in a subset of sensory neurons, yet already at lower CAPS concentrations (1μM). Stimulation of ectopically expressed TRPV1 channels in CAPS-insensitive NIH-3T3 cells didn't provoke CAPS-triggered Ca(2+) oscillations; rather it resulted in low-magnitude, long-lasting elevations of the cytosolic Ca(2+) concentration. This indicates that sole TRPV1 activation is not sufficient to generate Ca(2+) oscillations. Instead the initial TRPV1-mediated signal leads to the activation of the inositol phospholipid pathway. This in turn suffices to generate a biologically relevant frequency-modulated Ca(2+) signal.

  4. Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma.

    PubMed

    Zhang, Mingfeng; Liang, Liming; Morar, Nilesh; Dixon, Anna L; Lathrop, G Mark; Ding, Jun; Moffatt, Miriam F; Cookson, William O C; Kraft, Peter; Qureshi, Abrar A; Han, Jiali

    2012-04-01

    Genome-wide association studies (GWASs) have primarily focused on marginal effects for individual markers and have incorporated external functional information only after identifying robust statistical associations. We applied a new approach combining the genetics of gene expression and functional classification of genes to the GWAS of basal cell carcinoma (BCC) to identify potential biological pathways associated with BCC. We first identified 322,324 expression-associated single-nucleotide polymorphisms (eSNPs) from two existing GWASs of global gene expression in lymphoblastoid cell lines (n = 955), and evaluated the association of these functionally annotated SNPs with BCC among 2,045 BCC cases and 6,013 controls in Caucasians. We then grouped them into 99 KEGG pathways for pathway analysis and identified two pathways associated with BCC with p value <0.05 and false discovery rate (FDR) <0.5: the autoimmune thyroid disease pathway (mainly HLA class I and II antigens, p < 0.001, FDR = 0.24) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway (p = 0.02, FDR = 0.49). Seventy-nine (25.7%) out of 307 significant eSNPs in the JAK-STAT pathway were associated with BCC risk (p < 0.05) in an independent replication set of 278 BCC cases and 1,262 controls. In addition, the association of JAK-STAT signaling pathway was marginally validated using 16,691 eSNPs identified from 110 normal skin samples (p = 0.08). Based on the evidence of biological functions of the JAK-STAT pathway on oncogenesis, it is plausible that this pathway is involved in BCC pathogenesis.

  5. No evidence that genetic variation in the myeloid-derived suppressor cell pathway influences ovarian cancer survival

    PubMed Central

    Sucheston-Campbell, Lara E.; Cannioto, Rikki; Clay, Alyssa I.; Etter, John Lewis; Eng, Kevin H.; Liu, Song; Battaglia, Sebastiano; Hu, Qiang; Szender, J. Brian; Minlikeeva, Albina; Joseph, Janine M.; Mayor, Paul; Abrams, Scott I.; Segal, Brahm H.; Wallace, Paul K.; Soh, Kah Teong; Zsiros, Emese; Anton-Culver, Hoda; Bandera, Elisa V.; Beckmann, Matthias W.; Berchuck, Andrew; Bjorge, Line; Bruegl, Amanda; Campbell, Ian; Campbell, Shawn Patrice; Chenevix-Trench, Georgia; Cramer, Daniel W.; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Diergaarde, Brenda; Doerk, Thilo; Doherty, Jennifer A.; du Bois, Andreas; Eccles, Diana; Engelholm, Svend Aage; Fasching, Peter A.; Gayther, Simon; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind M.; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemmanns, Peter; Høgdall, Claus; Høgdall, Estrid; Huzarski, Tomasz; Jensen, Allan; Johnatty, Sharon E.; Jung, Audrey; Karlan, Beth Y.; Klapdor, Reudiger; Kluz, Tomasz; Konopka, Bożena; Kjær, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lester, Jenny; Lubiński, Jan; Levine, Douglas A.; Lundvall, Lene; McGuire, Valerie; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Ness, Roberta; Orsulic, Sandra; Paul, Jim; Pearce, Celeste Leigh; Pejovic, Tanja; Pharoah, Paul; Ramus, Susan J.; Rothstein, Joseph; Rossing, Mary Anne; Rübner, Matthias; Schildkraut, Joellen M.; Schmalfeldt, Barbara; Schwaab, Ira; Siddiqui, Nadeem; Sieh, Weiva; Sobiczewski, Piotr; Song, Honglin; Terry, Kathryn L.; Van Nieuwenhuysen, Els; Vanderstichele, Adriaan; Vergote, Ignace; Walsh, Christine; Webb, Penny; Wentzensen, Nicolas; Whittemore, Alice; Wu, Anna H.; Ziogas, Argyrios; Odunsi, Kunle; Chang-Claude, Jenny; Goode, Ellen L.; Moysich, Kirsten B.

    2017-01-01

    Background The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immune suppressive/pro-tumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be one prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association study (VEGAS) and the Admixture Likelihood method (AML), were used to test gene and pathway associations with survival. Results We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (p<3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact Common inherited variation in genes relevant to MDSCs were not associated with survival in women diagnosed with invasive EOC. PMID:27677730

  6. No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival.

    PubMed

    Sucheston-Campbell, Lara E; Cannioto, Rikki; Clay, Alyssa I; Etter, John Lewis; Eng, Kevin H; Liu, Song; Battaglia, Sebastiano; Hu, Qiang; Szender, J Brian; Minlikeeva, Albina; Joseph, Janine M; Mayor, Paul; Abrams, Scott I; Segal, Brahm H; Wallace, Paul K; Soh, Kah Teong; Zsiros, Emese; Anton-Culver, Hoda; Bandera, Elisa V; Beckmann, Matthias W; Berchuck, Andrew; Bjorge, Line; Bruegl, Amanda; Campbell, Ian G; Campbell, Shawn Patrice; Chenevix-Trench, Georgia; Cramer, Daniel W; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Diergaarde, Brenda; Doerk, Thilo; Doherty, Jennifer A; du Bois, Andreas; Eccles, Diana; Engelholm, Svend Aage; Fasching, Peter A; Gayther, Simon A; Gentry-Maharaj, Aleksandra; Glasspool, Rosalind M; Goodman, Marc T; Gronwald, Jacek; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemmanns, Peter; Høgdall, Claus; Høgdall, Estrid V S; Huzarski, Tomasz; Jensen, Allan; Johnatty, Sharon E; Jung, Audrey; Karlan, Beth Y; Klapdor, Reudiger; Kluz, Tomasz; Konopka, Bożena; Kjær, Susanne Krüger; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lester, Jenny; Lubiński, Jan; Levine, Douglas A; Lundvall, Lene; McGuire, Valerie; McNeish, Iain A; Menon, Usha; Modugno, Francesmary; Ness, Roberta B; Orsulic, Sandra; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pharoah, Paul; Ramus, Susan J; Rothstein, Joseph; Rossing, Mary Anne; Rübner, Matthias; Schildkraut, Joellen M; Schmalfeldt, Barbara; Schwaab, Ira; Siddiqui, Nadeem; Sieh, Weiva; Sobiczewski, Piotr; Song, Honglin; Terry, Kathryn L; Van Nieuwenhuysen, Els; Vanderstichele, Adriaan; Vergote, Ignace; Walsh, Christine S; Webb, Penelope M; Wentzensen, Nicolas; Whittemore, Alice S; Wu, Anna H; Ziogas, Argyrios; Odunsi, Kunle; Chang-Claude, Jenny; Goode, Ellen L; Moysich, Kirsten B

    2017-03-01

    Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10(-5)), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. Harnessing biodiesel-producing microbes: from genetic engineering of lipase to metabolic engineering of fatty acid biosynthetic pathway.

    PubMed

    Yan, Jinyong; Yan, Yunjun; Madzak, Catherine; Han, Bingnan

    2017-02-01

    Microbial production routes, notably whole-cell lipase-mediated biotransformation and fatty-acids-derived biosynthesis, offer new opportunities for synthesizing biodiesel. They compare favorably to immobilized lipase and chemically catalyzed processes. Genetically modified whole-cell lipase-mediated in vitro route, together with in vivo and ex vivo microbial biosynthesis routes, constitutes emerging and rapidly developing research areas for effective production of biodiesel. This review presents recent advances in customizing microorganisms for producing biodiesel, via genetic engineering of lipases and metabolic engineering (including system regulation) of fatty-acids-derived pathways. Microbial hosts used include Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris and Aspergillus oryzae. These microbial cells can be genetically modified to produce lipases under different forms: intracellularly expressed, secreted or surface-displayed. They can be metabolically redesigned and systematically regulated to obtain balanced biodiesel-producing cells, as highlighted in this study. Such genetically or metabolically modified microbial cells can support not only in vitro biotransformation of various common oil feedstocks to biodiesel, but also de novo biosynthesis of biodiesel from glucose, glycerol or even cellulosic biomass. We believe that the genetically tractable oleaginous yeast Yarrowia lipolytica could be developed to an effective biodiesel-producing microbial cell factory. For this purpose, we propose several engineered pathways, based on lipase and wax ester synthase, in this promising oleaginous host.

  8. Genetic variation in the parasympathetic signaling pathway in patients with reflex syncope.

    PubMed

    Holmegard, H N; Benn, M; Mehlsen, J; Haunsø, S

    2013-01-30

    Reflex syncope is defined by a self-terminating transient loss of consciousness associated with an exaggerated response of the vagal reflexes upon orthostatic challenges. A hereditary component has previously been suggested. We hypothesized that variations in genes encoding proteins mediating the vagal signaling in the heart may be involved in reflex syncope pathogenesis. We systematically resequenced the entire coding regions and flanking intron sequences in 5 genes in the cardiac post-synaptic parasympathetic signaling pathway [muscarinic acetylcholine receptor M2 (CHRM2); G-protein beta-1 subunit (GNB1); G-protein gamma-2 subunit (GNG2); potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); and potassium inwardly rectifying channel, subfamily J, member 5 (KCNJ5)] in 74 patients with well-characterized reflex syncope of either cardioinhibitory [Vasovagal Syncope International Study (VASIS-IIB), N = 38] or vasodepressor (VASIS-III, N = 36) type. We identified 2 novel genetic variants (CHRM2 c.1114C>G and GNG2 c.87+34G>A) and several known variants (GNB1: c.267+14G>A, c.267+19C>T, and c.738C>T; KCNJ3: c.119A>G, c.591C>T, c.1038T>C, and c.1494T>C; KCNJ5: c. 171T>C, c.810T>G, c.834T>C, c.844C>G, c.938+7C>T, and c.938-10G>A). The minor allele frequency of the KCNJ5 c.938+7C>T variant was significantly lower in patients than in the control group (0.014 versus 0.089, P = 0.001), and the frequency of heterozygosity and homozygosity was lower in cardioinhibitory patients compared to controls. Genetic variations in genes responsible for the vagal signaling in the heart, including CHRM2, GNB1, GNG2, KCNJ3, and KCNJ5, are not major contributors to the pathogenesis of reflex syncope of vasodepressor or cardioinhibitory types.

  9. National Human Exposure Assessment Survey: analysis of exposure pathways and routes for arsenic and lead in EPA Region 5.

    PubMed

    Clayton, C A; Pellizzari, E D; Quackenboss, J J

    2002-01-01

    The National Human Exposure Assessment Survey (NHEXAS) Phase I field study conducted in EPA Region 5 (Great Lakes Area) provides extensive exposure data on a representative sample of approximately 250 residents of the region. Associated environmental media and biomarker (blood, urine) concentration data were also obtained for the study participants to aid in understanding of the relationships of exposures to both contaminant pathways and doses. Besides fulfilling the primary NHEXAS objectives, the NHEXAS data provided an opportunity to explore secondary usages, such as examining pathway to route of exposure relationships. A generic type of structural equation model was used to define the anticipated relationships among the various data types for both arsenic (As) and lead (Pb). Since, by design, only a few participants provided data for all sample types, implementing this model required that some media concentrations (outdoor air and soil) be imputed for subjects with missing information by using measurements collected in the same geographic area and time period. The model, and associated pairwise correlations, generally revealed significant but weak associations among the concentrations, exposures, and doses; the strongest associations occurred for the various air measurements (indoor versus outdoor and personal). The generally weak associations were thought to be partly due to the absence of complete coverage of nonresidential environmental media and to nonsynchronization of relevant measurement times and integration periods of collection across the various sample types. In general, relationships between the NHEXAS questionnaire data and the various concentration, exposure, and body-burden measures were also weak. The model results and the modeling exercise suggest several ways for optimizing the design of future exposure assessment studies that are aimed at supporting structural modeling activities.

  10. Accumulation, elimination, sequestration, and genetic variation of lead (Pb(2+)) loads within and between generations of Drosophila melanogaster.

    PubMed

    Peterson, Elizabeth K; Wilson, Diane T; Possidente, Bernard; McDaniel, Phillip; Morley, Eric J; Possidente, Debra; Hollocher, Kurt T; Ruden, Douglas M; Hirsch, Helmut V B

    2017-08-01

    We examined accumulation, sequestration, elimination, and genetic variation for lead (Pb) loads within and between generations of Drosophila melanogaster. Flies were reared in control or leaded medium at various doses and tested for their Pb loads at different stages of development (larvae, eclosion, newly-eclosed adults, and mature adults). Pb loads were tested using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). We found that D. melanogaster readily accumulated Pb throughout their lifespan and the levels of accumulation increased with Pb exposure in the medium. Wandering third-instar larvae accumulated more Pb than mature adults; this phenomenon may be due to elimination of Pb in the pupal cases during eclosion and/or depuration in adults post-eclosion. The accumulated Pb in mature adults was not transferred to F1 mature adult offspring. Using a set of recombinant inbred strains, we identified a quantitative trait locus for adult Pb loads and found that genetic variation accounted for 34% of the variance in Pb load. We concluded that D. melanogaster is a useful model organism for evaluating changes in Pb loads during development, as well as between generations. Furthermore, we found that genetic factors can influence Pb loads; this provides an essential foundation for evaluating phenotypic variation induced by the toxic effects of Pb. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

    PubMed Central

    Purrington, Kristen S.; Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A.; Fasching, Peter A.; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E.; Mulligan, Anna Marie; Knight, Julia A.; Tchatchou, Sandrine; Reed, Malcolm W.R.; Cross, Simon S.; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B.; Hartmann, Arndt; Beckmann, Matthias W.; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E.; Ambrosone, Christine B.; Labrèche, France; Goldberg, Mark S.; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H.M.; Martens, John W.M.; Kriege, Mieke; Figueroa, Jonine D.; Chanock, Stephen J.; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J.; Gerty, Susan M.; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L.; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J.; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M.; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L.; Hopper, John L.; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M.; Giles, Graham G.; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D.P.; Easton, Douglas; Pankratz, V. Shane; Slager, Susan; Vachon, Celine M.; Couch, Fergus J.

    2014-01-01

    Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer. PMID:24927736

  12. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways

    PubMed Central

    Lenz, Georg; Wright, George W.; Emre, N. C. Tolga; Kohlhammer, Holger; Dave, Sandeep S.; Davis, R. Eric; Carty, Shannon; Lam, Lloyd T.; Shaffer, A. L.; Xiao, Wenming; Powell, John; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Connors, Joseph M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Rimsza, Lisa M.; Fisher, Richard I.; Weisenburger, Dennis D.; Chan, Wing C.; Staudt, Louis M.

    2008-01-01

    Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways. PMID:18765795

  13. Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk.

    PubMed

    Wu, I-Chen; Zhao, Yang; Zhai, Rihong; Liu, Chen-yu; Chen, Feng; Ter-Minassian, Monica; Asomaning, Kofi; Su, Li; Heist, Rebecca S; Kulke, Matthew H; Liu, Geoffrey; Christiani, David C

    2011-04-01

    How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene-environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene-environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08-2.58 times [interaction odds ratio (ORi)=2.08-2.58, adjusted P-value (Padj)=0.02-0.04]. Compared with patients carrying ≤1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi=1.89, Padj=0.016) or ≥3 (ORi=4.30, Padj<0.0001) risk genotypes. Compared with cases with ≤1 risk genotype, smoking-associated EA risk increased by 3.15 times when ≥2 risk genotypes were present (ORi=3.15, Padj<0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development.

  14. Interactions between genetic polymorphisms in the apoptotic pathway and environmental factors on esophageal adenocarcinoma risk

    PubMed Central

    Wu, I-Chen; Zhao, Yang; Zhai, Rihong; Liu, Chen-yu.; Chen, Feng; Ter-Minassian, Monica; Asomaning, Kofi; Su, Li; Heist, Rebecca S.; Kulke, Matthew H.; Liu, Geoffrey; Christiani, David C.

    2011-01-01

    How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene–environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene–environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08–2.58 times [interaction odds ratio (ORi) = 2.08–2.58, adjusted P-value (Padj) = 0.02–0.04]. Compared with patients carrying ≤1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi = 1.89, Padj = 0.016) or ≥3 (ORi = 4.30, Padj < 0.0001) risk genotypes. Compared with cases with ≤1 risk genotype, smoking-associated EA risk increased by 3.15 times when ≥2 risk genotypes were present (ORi = 3.15, Padj < 0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development. PMID:21212151

  15. Genetic Variation in Base Excision Repair Pathway Genes, Pesticide Exposure, and Prostate Cancer Risk

    PubMed Central

    Koutros, Stella; Berndt, Sonja I.; Andreotti, Gabriella; Hoppin, Jane A.; Sandler, Dale P.; Burdette, Laurie A.; Yeager, Meredith; Freeman, Laura E. Beane; Lubin, Jay H.; Ma, Xiaomei; Zheng, Tongzhang; Alavanja, Michael C.R.

    2011-01-01

    Background: Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage. Objectives: Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case–control study of white Agricultural Health Study (AHS) pesticide applicators. Methods: We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach. Results: The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (pinteract) = 9.3 × 10–6; FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2. Conclusions: Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide

  16. Association between common genetic variants in the opioid pathway and smoking behaviors in Chinese men.

    PubMed

    Fang, Juan; Wang, Xiaohong; He, Bei

    2014-01-21

    There is biological evidence that the brain opioidergic system plays a critical role in the addictive properties of nicotine. The purpose of the present study was to examine the associations of single nucleotide polymorphisms (SNPs) in the genes encoding mu-opioid receptor (MOR) and the MOR-interacting proteins (including OPRM1, ARRB2, and HINT1) with smoking behaviors in Chinese men. A total of 284 subjects (including current and ex-smokers) were recruited. Special questionnaires were used to assess smoking behaviors including age of smoking initiation, daily cigarette consumption, and Fagerström test for nicotine dependence (FTND) score. Participant samples were genotyped for six SNPs in the opioid pathway genes: rs1799971 in OPRM1, rs1045280, rs2036657 and rs3786047 in ARRB2, rs3852209 and rs2278060 in HINT1. Linear and logistic regression models were used to determine single-locus and haplotype-based association analyses. There was no significant association between any of SNPs analyzed and smoking behaviors. Logistic regression analyses under dominant, recessive, and additive models showed no significant associations of the six SNPs with smoking status (current vs. ex-smokers). After adjustment for age at enrollment and smoking initiation age, HINT1 rs3852209 was significantly associated with smoking status with an OR of 0.54 (95% CI, 0.31-0.95; P = 0.03) under dominant inheritance model. No haplotypes in ARRB2 or HINT1 were related to smoking status. The present study indicates no significant association between common genetic variations in MOR and MOR-interacting proteins and smoking behaviors in Chinese men, and gives suggestive evidence that HINT1 rs3852209 may be related to smoking status. The findings require confirmation from further studies in additional larger samples.

  17. Association between Common Genetic Variants in the Opioid Pathway and Smoking Behaviors in Chinese Men

    PubMed Central

    2014-01-01

    Background There is biological evidence that the brain opioidergic system plays a critical role in the addictive properties of nicotine. The purpose of the present study was to examine the associations of single nucleotide polymorphisms (SNPs) in the genes encoding mu-opioid receptor (MOR) and the MOR-interacting proteins (including OPRM1, ARRB2, and HINT1) with smoking behaviors in Chinese men. Methods A total of 284 subjects (including current and ex-smokers) were recruited. Special questionnaires were used to assess smoking behaviors including age of smoking initiation, daily cigarette consumption, and Fagerström test for nicotine dependence (FTND) score. Participant samples were genotyped for six SNPs in the opioid pathway genes: rs1799971 in OPRM1, rs1045280, rs2036657 and rs3786047 in ARRB2, rs3852209 and rs2278060 in HINT1. Linear and logistic regression models were used to determine single-locus and haplotype-based association analyses. Results There was no significant association between any of SNPs analyzed and smoking behaviors. Logistic regression analyses under dominant, recessive, and additive models showed no significant associations of the six SNPs with smoking status (current vs. ex-smokers). After adjustment for age at enrollment and smoking initiation age, HINT1 rs3852209 was significantly associated with smoking status with an OR of 0.54 (95% CI, 0.31-0.95; P = 0.03) under dominant inheritance model. No haplotypes in ARRB2 or HINT1 were related to smoking status. Conclusions The present study indicates no significant association between common genetic variations in MOR and MOR-interacting proteins and smoking behaviors in Chinese men, and gives suggestive evidence that HINT1 rs3852209 may be related to smoking status. The findings require confirmation from further studies in additional larger samples. PMID:24447405

  18. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

    PubMed

    Purrington, Kristen S; Slettedahl, Seth; Bolla, Manjeet K; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E; Andrulis, Irene L; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A; Fasching, Peter A; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E; Mulligan, Anna Marie; Knight, Julia A; Tchatchou, Sandrine; Reed, Malcolm W R; Cross, Simon S; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B; Hartmann, Arndt; Beckmann, Matthias W; Hartikainen, Jaana M; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E; Ambrosone, Christine B; Labrèche, France; Goldberg, Mark S; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S; Apicella, Carmel; Southey, Melissa C; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A E M; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H M; Martens, John W M; Kriege, Mieke; Figueroa, Jonine D; Chanock, Stephen J; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J; Gerty, Susan M; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L; Hopper, John L; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M; Giles, Graham G; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D P; Easton, Douglas; Pankratz, V Shane; Slager, Susan; Vachon, Celine M; Couch, Fergus J

    2014-11-15

    Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

  19. Genetic variants in chromatin-remodeling pathway associated with lung cancer risk in a Chinese population.

    PubMed

    Geng, Liguo; Zhu, Meng; Wang, Yuzhuo; Cheng, Yang; Liu, Jia; Shen, Wei; Li, Zhihua; Zhang, Jiahui; Wang, Cheng; Jin, Guangfu; Ma, Hongxia; Shen, Hongbing; Hu, Zhibin; Dai, Juncheng

    2016-08-10

    Chromatin remodeling complexes utilize the energy of ATP hydrolysis to remodel nucleosomes and have essential roles in transcriptional modulation. Increasing evidences indicate that these complexes directly interact with numerous proteins and regulate the formation of cancer. However, few studies reported the association of polymorphisms in chromatin remodeling genes and lung cancer. We hypothesized that variants in critical genes of chromatin remodeling pathway might contribute to the susceptibility of lung cancer. To validate this hypothesis, we systematically screened 40 polymorphisms in six key chromatin remodeling genes (SMARCA5, SMARCC2, SMARCD2, ARID1A, NR3C1 and SATB1) and evaluated them with a case-control study including 1341 cases and 1982 controls. Logistic regression revealed that four variants in NR3C1 and SATB1 were significantly associated with lung cancer risk after false discovery rate (FDR) correction [For NR3C1, rs9324921: odds ratio (OR)=1.23, P for FDR=0.029; rs12521436: OR=0.85, P for FDR=0.040; rs4912913: OR=1.17, P for FDR=0.040; For SATB1, rs6808523: OR=1.33, P for FDR=0.040]. Combing analysis presented a significant allele-dosage tendency for the number of risk alleles and lung cancer risk (Ptrend<0.001). Moreover, expression quantitative trait loci (eQTL) analysis revealed that these two genes were differently expressed between lung tumor and adjacent normal tissues in the database of The Cancer Genome Atlas (TCGA) (P=0.009 for rs6808523). These findings suggested that genetic variants in key chromatin remodeling genes may contribute to lung cancer risk in Chinese population. Further large and well-designed studies are warranted to validate our results.

  20. Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus.

    PubMed

    Rupasree, Yedluri; Naushad, Shaik Mohammad; Rajasekhar, Liza; Kutala, Vijay Kumar

    2013-10-01

    In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 ml, m2 and m4 variants (D': 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 ml variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L x GSTT1 null x GSTM1 null (p < 0.0001) and also between the phase II and I variants i.e. COMT H108L x GSTTI null x CYP1A1 ml x CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to ml and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE.

  1. Structured Parenting of Toddlers at High versus Low Genetic Risk: Two Pathways to Child Problems

    ERIC Educational Resources Information Center

    Leve, Leslie D.; Harold, Gordon T.; Ge, Xiaojia; Neiderhiser, Jenae M.; Shaw, Daniel; Scaramella, Laura V.; Reiss, David

    2009-01-01

    Objective: Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for…

  2. Structured Parenting of Toddlers at High versus Low Genetic Risk: Two Pathways to Child Problems

    ERIC Educational Resources Information Center

    Leve, Leslie D.; Harold, Gordon T.; Ge, Xiaojia; Neiderhiser, Jenae M.; Shaw, Daniel; Scaramella, Laura V.; Reiss, David

    2009-01-01

    Objective: Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for…

  3. Can Genetic Analysis of Putative Blood Alzheimer's Disease Biomarkers Lead to Identification of Susceptibility Loci?

    PubMed

    Barber, Robert C; Phillips, Nicole R; Tilson, Jeffrey L; Huebinger, Ryan M; Shewale, Shantanu J; Koenig, Jessica L; Mitchel, Jeffrey S; O'Bryant, Sid E; Waring, Stephen C; Diaz-Arrastia, Ramon; Chasse, Scott; Wilhelmsen, Kirk C

    2015-01-01

    Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ≤1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel

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

    PubMed

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

    2017-01-20

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

  5. Budd-Chiari syndrome: combination of genetic defects and the use of oral contraceptives leading to hypercoagulability.

    PubMed

    Minnema, M C; Janssen, H L; Niermeijer, P; de Man, R A

    2000-09-01

    A young female, who had been in excellent health and had used third-generation oral contraceptives, was admitted to hospital because of abdominal pain and ascites. Budd-Chiari syndrome (BCS) was diagnosed by radiographic and histological examination. Tests for myeloproliferative disease, deficiency of coagulation inhibitors and paroxysmal nocturnal haemoglobinuria were negative. DNA investigation showed a double heterozygous defect: the Arg506Gln mutation in the factor V gene (factor V Leiden) and G20210A nucleotide substitution in the prothrombin gene. This double defect was also found in the patient's father, who had never experienced an episode of venous thromboembolism. Genetic and acquired thrombogenic risk factors are being detected increasingly in patients with BCS. With the discovery of new genetic defects leading to hypercoagulabiulity an increasing number of patients with serious thrombotic manifestations, such as BCS, will exhibit concurrence of hereditary and acquired risk factors for thrombosis.

  6. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity

    PubMed Central

    Pirmohamed, Munir; Ostrov, David A.; Park, B. Kevin

    2015-01-01

    Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide-binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions. PMID:26254050

  7. Intraguild predation leads to genetically based character shifts in the threespine stickleback.

    PubMed

    Miller, Sara E; Metcalf, Daniel; Schluter, Dolph

    2015-12-01

    Intraguild predation is a common ecological interaction that occurs when a species preys upon another species with which it competes. The interaction is potentially a mechanism of divergence between intraguild prey (IG-prey) populations, but it is unknown if cases of character shifts in IG-prey are an environmental or evolutionary response. We investigated the genetic basis and inducibility of character shifts in threespine stickleback from lakes with and without prickly sculpin, a benthic intraguild predator (IG-predator). Wild populations of stickleback sympatric with sculpin repeatedly show greater defensive armor and water column height preference. We laboratory-raised stickleback from lakes with and without sculpin, as well as marine stickleback, and found that differences between populations in armor, body shape, and behavior persisted in a common garden. Within the common garden, we raised stickleback half-families from multiple populations in the presence and absence of sculpin. Although the presence of sculpin induced trait changes in the marine stickleback, we did not observe an induced response in the freshwater stickleback. Behavioral and morphological trait differences between freshwater populations thus have a genetic basis and suggest an evolutionary response to intraguild predation.

  8. New genetic findings lead the way to a better understanding of fundamental mechanisms of drug hypersensitivity.

    PubMed

    Pirmohamed, Munir; Ostrov, David A; Park, B Kevin

    2015-08-01

    Drug hypersensitivity reactions are an important clinical problem for both health care and industry. Recent advances in genetics have identified a number of HLA alleles associated with a range of these adverse reactions predominantly affecting the skin but also other organs, such as the liver. The associations between abacavir hypersensitivity and HLA-B*57:01 and carbamazepine-induced Stevens-Johnson syndrome and HLA-B*15:02 have been implemented in clinical practice. There are many different mechanisms proposed in the pathogenesis of drug hypersensitivity reactions, including the hapten hypothesis, direct binding to T-cell receptors (the pharmacologic interaction hypothesis), and peptide-binding displacement. A problem with all the hypotheses is that they are largely based on in vitro findings, with little direct in vivo evidence. Although most studies have focused on individual mechanisms, it is perhaps more important to consider them all as being complementary, potentially occurring at the same time with the same drug in the same patient. This might at least partly account for the heterogeneity of the immune response seen in different patients. There is a need to develop novel methodologies to evaluate how the in vitro mechanisms relate to the in vivo situation and how the highly consistent genetic findings with different HLA alleles can be more consistently used for both prediction and prevention of these serious adverse reactions.

  9. Brain imaging genetics in ADHD and beyond - mapping pathways from gene to disorder at different levels of complexity.

    PubMed

    Klein, Marieke; Onnink, Marten; van Donkelaar, Marjolein; Wolfers, Thomas; Harich, Benjamin; Shi, Yan; Dammers, Janneke; Arias-Va Squez, Alejandro; Hoogman, Martine; Franke, Barbara

    2017-01-31

    Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.

  10. The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway

    PubMed Central

    Ciura, Sorana; Sellier, Chantal; Campanari, Maria-Letizia; Charlet-Berguerand, Nicolas; Kabashi, Edor

    2016-01-01

    ABSTRACT The most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is repeat expansion of a hexanucleotide sequence (GGGGCC) within the C9orf72 genomic sequence. To elucidate the functional role of C9orf72 in disease pathogenesis, we identified certain molecular interactors of this factor. We determined that C9orf72 exists in a complex with SMCR8 and WDR41 and that this complex acts as a GDP/GTP exchange factor for RAB8 and RAB39, 2 RAB GTPases involved in macroautophagy/autophagy. Consequently, C9orf72 depletion in neuronal cultures leads to accumulation of unresolved aggregates of SQSTM1/p62 and phosphorylated TARDBP/TDP-43. However, C9orf72 reduction does not lead to major neuronal toxicity, suggesting that a second stress may be required to induce neuronal cell death. An intermediate size of polyglutamine repeats within ATXN2 is an important genetic modifier of ALS-FTD. We found that coexpression of intermediate polyglutamine repeats (30Q) of ATXN2 combined with C9orf72 depletion increases the aggregation of ATXN2 and neuronal toxicity. These results were confirmed in zebrafish embryos where partial C9orf72 knockdown along with intermediate (but not normal) repeat expansions in ATXN2 causes locomotion deficits and abnormal axonal projections from spinal motor neurons. These results demonstrate that C9orf72 plays an important role in the autophagy pathway while genetically interacting with another major genetic risk factor, ATXN2, to contribute to ALS-FTD pathogenesis. PMID:27245636

  11. Reciprocal subsidies and food web pathways leading to chum salmon fry in a temperate marine-terrestrial ecotone.

    PubMed

    Romanuk, Tamara N; Levings, Colin D

    2010-04-08

    Stable isotope analysis was used to determine the relative proportions of terrestrial and marine subsidies of carbon to invertebrates along a tidal gradient (low-intertidal, mid-intertidal, high-intertidal, supralittoral) and to determine the relative importance of terrestrial carbon in food web pathways leading to chum salmon fry Oncorhynchus keta (Walbaum) in Howe Sound, British Columbia. We found a clear gradient in the proportion of terrestrially derived carbon along the tidal gradient ranging from 68% across all invertebrate taxa in the supralittoral to 25% in the high-intertidal, 20% in the mid-intertidal, and 12% in the low-intertidal. Stable isotope values of chum salmon fry indicated carbon contributions from both terrestrial and marine sources, with terrestrially derived carbon ranging from 12.8 to 61.5% in the muscle tissue of chum salmon fry (mean 30%). Our results provide evidence for reciprocal subsidies of marine and terrestrially derived carbon on beaches in the estuary and suggest that the vegetated supralittoral is an important trophic link in supplying terrestrial carbon to nearshore food webs.

  12. Evolution of a novel pathway leading to dolutegravir resistance in a patient harbouring N155H and multiclass drug resistance.

    PubMed

    Hardy, Isabelle; Brenner, Bluma; Quashie, Peter; Thomas, Réjean; Petropoulos, Christos; Huang, Wei; Moisi, Daniela; Wainberg, Mark A; Roger, Michel

    2015-02-01

    Dolutegravir has been recently approved for treatment-naive and -experienced HIV-infected subjects, including integrase inhibitor (INI)-experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure. Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations. Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations. Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155H raltegravir mutation. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

    PubMed Central

    Polanowski, Rebecca; Dunman, Paul M.; Medina-Bielski, Sara; Lane, Michelle; Rott, Marc; Lipker, Lauren; Wescott, Amy; Monte, Aaron; Baumann, Douglas D.; Witzigmann, Christopher M.; Mikel, Cassandra

    2017-01-01

    The mechanism of action for a new lead stilbene compound coded SK-03-92 with bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) is unknown. To gain insight into the killing process, transcriptional profiling was performed on SK-03-92 treated vs. untreated S. aureus. Fourteen genes were upregulated and 38 genes downregulated by SK-03-92 treatment. Genes involved in sortase A production, protein metabolism, and transcriptional regulation were upregulated, whereas genes encoding transporters, purine synthesis proteins, and a putative two-component system (SACOL2360 (MW2284) and SACOL2361 (MW2285)) were downregulated by SK-03-92 treatment. Quantitative real-time polymerase chain reaction analyses validated upregulation of srtA and tdk as well as downregulation of the MW2284/MW2285 and purine biosynthesis genes in the drug-treated population. A quantitative real-time polymerase chain reaction analysis of MW2284 and MW2285 mutants compared to wild-type cells demonstrated that the srtA gene was upregulated by both putative two-component regulatory gene mutants compared to the wild-type strain. Using a transcription profiling technique, we have identified several cellular pathways regulated by SK-03-92 treatment, including a putative two-component system that may regulate srtA and other genes that could be tied to the SK-03-92 mechanism of action, biofilm formation, and drug persisters. PMID:28892020

  14. Reciprocal Subsidies and Food Web Pathways Leading to Chum Salmon Fry in a Temperate Marine-Terrestrial Ecotone

    PubMed Central

    Romanuk, Tamara N.; Levings, Colin D.

    2010-01-01

    Stable isotope analysis was used to determine the relative proportions of terrestrial and marine subsidies of carbon to invertebrates along a tidal gradient (low-intertidal, mid-intertidal, high-intertidal, supralittoral) and to determine the relative importance of terrestrial carbon in food web pathways leading to chum salmon fry Oncorhynchus keta (Walbaum) in Howe Sound, British Columbia. We found a clear gradient in the proportion of terrestrially derived carbon along the tidal gradient ranging from 68% across all invertebrate taxa in the supralittoral to 25% in the high-intertidal, 20% in the mid-intertidal, and 12% in the low-intertidal. Stable isotope values of chum salmon fry indicated carbon contributions from both terrestrial and marine sources, with terrestrially derived carbon ranging from 12.8 to 61.5% in the muscle tissue of chum salmon fry (mean 30%). Our results provide evidence for reciprocal subsidies of marine and terrestrially derived carbon on beaches in the estuary and suggest that the vegetated supralittoral is an important trophic link in supplying terrestrial carbon to nearshore food webs. PMID:20386705

  15. Direct observation of kinetic traps associated with structural transformations leading to multiple pathways of S-layer assembly.

    PubMed

    Shin, Seong-Ho; Chung, Sungwook; Sanii, Babak; Comolli, Luis R; Bertozzi, Carolyn R; De Yoreo, James J

    2012-08-07

    The concept of a folding funnel with kinetic traps describes folding of individual proteins. Using in situ Atomic Force Microscopy to investigate S-layer assembly on mica, we show this concept is equally valid during self-assembly of proteins into extended matrices. We find the S-layer-on-mica system possesses a kinetic trap associated with conformational differences between a long-lived transient state and the final stable state. Both ordered tetrameric states emerge from clusters of the monomer phase, however, they then track along two different pathways. One leads directly to the final low-energy state and the other to the kinetic trap. Over time, the trapped state transforms into the stable state. By analyzing the time and temperature dependencies of formation and transformation we find that the energy barriers to formation of the two states differ by only 0.7 kT, but once the high-energy state forms, the barrier to transformation to the low-energy state is 25 kT. Thus the transient state exhibits the characteristics of a kinetic trap in a folding funnel.

  16. Genetic engineering of the complete carotenoid pathway towards enhanced astaxanthin formation in Xanthophyllomyces dendrorhous starting from a high-yield mutant.

    PubMed

    Gassel, Sören; Breitenbach, Jürgen; Sandmann, Gerhard

    2014-01-01

    The yeast Xanthophyllomyces dendrorhous is one of the rare organisms which can synthesize the commercially interesting carotenoid astaxanthin. However, astaxanthin yield in wild-type and also in classical mutants is still too low for an attractive bioprocess. Therefore, we combined classical mutagenesis with genetic engineering of the complete pathway covering improved precursor supply for carotenogenesis, enhanced metabolite flow into the pathway, and efficient conversion of intermediates into the desired end product astaxanthin. We also constructed new transformation plasmids for the stepwise expression of the genes of 3-hydroxymethyl-3-glutaryl coenzyme A reductase, geranylgeranyl pyrophosphate synthase, phytoene synthase/lycopene cyclase, and astaxanthin synthase. Starting from two mutants with a 15-fold higher astaxanthin, we obtained transformants with an additional 6-fold increase in the final step of pathway engineering. Thus, a maximum astaxanthin content of almost 9 mg per g dry weight was reached in shaking cultures. Under optimized fermenter conditions, astaxanthin production with these engineered transformants should be comparable to Haematococcus pluvialis, the leading commercial producer of natural astaxanthin.

  17. Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.

    PubMed

    Disney, Matthew D

    2013-12-01

    RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA.

  18. Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts

    PubMed Central

    Disney, Matthew D.

    2013-01-01

    RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. PMID:23939337

  19. Modified natural clinoptilolite detoxifies small mammal's organism loaded with lead II: genetic, cell, and physiological effects.

    PubMed

    Topashka-Ancheva, Margarita; Beltcheva, Michaela; Metcheva, Roumiana; Rojas, J Antonio Heredia; Rodriguez-De la Fuente, Abraham O; Gerasimova, Tsvetelina; Rodríguez-Flores, Laura E; Teodorova, Svetla E

    2012-06-01

    The detoxification capacity of the clinoptilolite modification KLS-10-MA used as food additive in small mammals, chronically lead-exposed, was proven for the first time. The modified clinoptilolite was prepared based on natural Bulgarian clinoptilolite deposits. As a powder, it was mechanically mixed at 12.5% concentration with the conventional forage for small rodents. Lead in the form of aqueous solution of Pb(NO(3))(2) was diluted in the drinking water. In the ecotoxicological experiment covering 90 days, imprinting control region laboratory mice were used. They were allocated into four groups: group 1, (control): animals fed with conventional food for small rodents and water; group 2: animals fed with conventional food + clinosorbent KLS-10-MA and water; group 3: animals fed with conventional food and water + Pb(NO(3))(2); and group 4: animals fed with conventional food + KLS-10-MA and water + Pb(NO(3))(2). A group of non-exposed healthy animals was fed with conventional forage mixed with KLS-10-MA to prove eventual toxicity of the sorbent and influence on growth performance. The changes in the chromosome structure, mitotic index, erythrocyte form, erythropoiesis, and body weight gain were recorded. On day 90, the following relations were established: Pb-exposed and clinoptilolite-supplemented mice exhibited 2.3-fold lower chromosome aberrations frequency, 2.5-fold higher mitotic index, and 1.5-fold higher percentage normal erythrocytes 1.3-fold higher body weight compared to Pb-exposed and unsupplemented animals. The obtained data showed that the sorbent is practically non-toxic. The results of the present study encourage a further elaboration of a reliable drug based on the tested substance in the cases of chronic lead intoxication.

  20. The reverse cholesterol transport pathway improves understanding of genetic networks for fat deposition and muscle growth in beef cattle.

    PubMed

    Daniels, Tyler F; Wu, Xiao-Lin; Pan, Zengxiang; Michal, Jennifer J; Wright, Raymond W; Killinger, Karen M; MacNeil, Michael D; Jiang, Zhihua

    2010-12-03

    In the present study, thirteen genes involved in the reverse cholesterol transport (RCT) pathway were investigated for their associations with three fat depositions, eight fatty acid compositions and two growth-related phenotypes in a Wagyu x Limousin reference population, including 6 F(1) bulls, 113 F(1) dams, and 246 F(2) progeny. A total of 37 amplicons were used to screen single nucleotide polymorphisms (SNPs) on 6 F(1) bulls. Among 36 SNPs detected in 11 of these 13 genes, 19 were selected for genotyping by the Sequenom assay design on all F(2) progeny. Single-marker analysis revealed seven SNPs in ATP binding cassette A1, apolipoproteins A1, B and E, phospholipid transfer protein and paraoxinase 1 genes significantly associated with nine phenotypes (P<0.05). Previously, we reported genetic networks associated with 19 complex phenotypes based on a total of 138 genetic polymorphisms derived from 71 known functional genes. Therefore, after Bonferroni correction, these significant (adjusted P<0.05) and suggestive (adjusted P<0.10) associations were then used to identify genetic networks related to the RCT pathway. Multiple-marker analysis suggested possible genetic networks involving the RCT pathway for kidney-pelvic-heart fat percentage, rib-eye area, and subcutaneous fat depth phenotypes with markers derived from paraoxinase 1, apolipoproteins A1 and E, respectively. The present study confirmed that genes involved in cholesterol homeostasis are useful targets for investigating obesity in humans as well as for improving meat quality phenotypes in a livestock production.

  1. Adolescent stress leads to glutamatergic disturbance through dopaminergic abnormalities in the prefrontal cortex of genetically vulnerable mice.

    PubMed

    Matsumoto, Yurie; Niwa, Minae; Mouri, Akihiro; Noda, Yukihiro; Fukushima, Takeshi; Ozaki, Norio; Nabeshima, Toshitaka

    2017-07-29

    Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia. In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc). We report that late adolescent stress in combination with Disrupted-in-Schizophrenia 1 (DISC1) genetic risk elicited alterations in glutamatergic neurons in the PFc, such as increased expression of glutamate transporters, decreased extracellular levels of glutamate, decreased concentration of d-serine, and impaired activation of NMDA-Ca(2+)/calmodulin kinase II signaling. These changes resulted in behavioral deficits in locomotor activity, forced swim, social interaction, and novelty preference tests. The glutamatergic alterations in the PFc were prevented if the animals were treated with an atypical antipsychotic drug clozapine and a dopamine D1 agonist SKF81297, which suggests that the activation of dopaminergic neurons is involved in the regulation of the glutamatergic system. Our results suggest that adolescent stress combined with dopaminergic abnormalities in the PFc of genetically vulnerable mice induces glutamatergic disturbances, which leads to behavioral deficits in the young adult stage.

  2. Meta-analysis of genetic and environmental Parkinson's disease models reveals a common role of mitochondrial protection pathways.

    PubMed

    Soreq, Lilach; Ben-Shaul, Yoram; Israel, Zvi; Bergman, Hagai; Soreq, Hermona

    2012-03-01

    Both genetic and environmental factors trigger risks of and protection from Parkinson's disease, the second most common neurodegenerative syndrome, but possible inter-relationships between these risk and protection processes were not yet explored. By examining gene expression changes in the brains of mice under multiple treatments that increase or attenuate PD symptoms we detected underlying disease and protection-associated genes and pathways. In search for potential links between these different genes and pathways, we conducted meta-analysis on 131 brain region transcriptomes from mice over-expressing native or mutated α-synuclein (SNCA) with or without the protective HSP70 chaperone, or exposed to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with or without the protective acetylcholinesterase (AChE-R) variant. All these models showed shared risk-inducible and protection-suppressible transcript modifications. Self-organized map (SOM) classification revealed risk- and protection-associated alterations in nuclear and mitochondrial metal ion-regulated transcripts, respectively; Gene Ontology based analysis validated these pathways. To complement this approach, and identify potential outcome damages, we further searched for shared functional enrichments in the lists of genes detected in young SNCA mutant or in old SNCA mutants and MPTP-exposed mice. This post-hoc functional analysis identified early-onset changes in Parkinsonian, immune and alternative splicing pathways which shifted into late-onset or exposure-associated NFkB-mediated neuro-inflammation. Our study suggests metal ions-mediated cross-talk between nuclear and mitochondrial pathways by both environmental and genetic risk and protective factors involved in Parkinson's disease, which eventually culminates in neuro-inflammation. Together, these findings offer new insights and novel targets for therapeutic interference with the gene-environment interactions underlying

  3. Genetic variants in Hippo pathway genes YAP1, TEAD1 and TEAD4 are associated with melanoma-specific survival.

    PubMed

    Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Wei, Qingyi

    2015-08-01

    Cutaneous melanoma (CM) is the most lethal form of skin cancers. The Hippo pathway controls cell migration, development and sizes of the organs in diverse species, and deregulation of this pathway may affect CM progression and prognosis. Therefore, we hypothesized that genetic variants of Hippo pathway genes might predict survival of CM patients. We used the genotyping data of 1,115 common single nucleotide polymorphisms (SNPs) in the 12 pathway core genes (i.e., MST1, MST2, SAV1, LATS1, LATS2, MOB1A, MOB1B, YAP1, TEAD1, TEAD2, TEAD3 and TEAD4) from the dataset of our previously published CM genome-wide association study and comprehensively analyzed their associations with CM-specific survival (CSS) in 858 CM patients by using the Kaplan-Meier analyses and Cox proportional hazards regression models. We found a predictive role of YAP1 rs11225163 CC, TEAD1 rs7944031 AG+GG and TEAD4 rs1990330 CA+AA in the prognosis of CM. In addition, patients with an increasing number of unfavorable genotypes (NUG) had a markedly increased risk of death. After incorporating NUG in the model with clinical variables, the new model showed a significantly improved discriminatory ability to classify CSS (AUC increased from 82.03% to 84.56%). Our findings suggest that genetic variants of Hippo pathway genes, particularly YAP1 rs11225163, TEAD1 rs7944031 and TEAD4 rs1990330, may independently or jointly modulate survival of CM patients. Additional large, prospective studies are needed to validate these findings. © 2015 UICC.

  4. Genetic variants in Hippo pathway genes YAP1, TEAD1 and TEAD4 are associated with melanoma-specific survival

    PubMed Central

    Yuan, Hua; Liu, Hongliang; Liu, Zhensheng; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Wei, Qingyi

    2015-01-01

    Cutaneous melanoma (CM) is the most lethal form of skin cancers. The Hippo pathway controls cell migration, development and sizes of the organs in diverse species, and deregulation of this pathway may affect CM progression and prognosis. Therefore, we hypothesized that genetic variants of Hippo pathway genes might predict survival of CM patients. We used the genotyping data of 1,115 common single nucleotide polymorphisms (SNPs) in the 12 pathway core genes (i.e., MST1, MST2, SAV1, LATS1, LATS2, MOB1A, MOB1B, YAP1, TEAD1, TEAD2, TEAD3, and TEAD4) from the dataset of our previously published CM genome-wide association study and comprehensively analyzed their associations with CM-specific survival (CSS) in 858 CM patients by using the Kaplan-Meier analyses and Cox proportional hazards regression models. We found a predictive role of YAP1 rs11225163 CC, TEAD1 rs7944031 AG+GG, and TEAD4 rs1990330 CA+AA in the prognosis of CM. In addition, patients with an increasing number of unfavorable genotypes (NUG) had a markedly increased risk of death. After incorporating NUG in the model with clinical variables, the new model showed a significantly improved discriminatory ability to classify CSS (AUC increased from 82.03% to 84.56%). Our findings suggest that genetic variants of Hippo pathway genes, particularly YAP1 rs11225163, TEAD1 rs7944031 and TEAD4 rs1990330, may independently or jointly modulate survival of CM patients. Additional large, prospective studies are needed to validate these findings. PMID:25628125

  5. Using the Drosophila Melanogaster Genetics Reference Panel to Identify Toxicity Pathways for Toluene

    EPA Science Inventory

    Mechanistic information is needed to link effects of chemicals at molecular targets in high­ throughput screening assays to adverse outcomes in whole organisms. This study was designed to use the Drosophila Genetic Reference Panel (DGRP), a set of genetically well...

  6. Population genetic analysis infers mMigration pathways of Phytophthora ramorum in US nurseries

    Treesearch

    Erica M. Goss; Meg Larsen; Gary A. Chastagner; Donald R. Givens; Niklaus J. Grünwald; Barbara Jane Howlett

    2009-01-01

    Recently introduced, exotic plant pathogens may exhibit low genetic diversity and be limited to clonal reproduction. However, rapidly mutating molecular markers such as microsatellites can reveal genetic variation within these populations and be used to model putative migration patterns. Phytophthora ramorum is the exotic pathogen, discovered in...

  7. Using the Drosophila Melanogaster Genetics Reference Panel to Identify Toxicity Pathways for Toluene

    EPA Science Inventory

    Mechanistic information is needed to link effects of chemicals at molecular targets in high­ throughput screening assays to adverse outcomes in whole organisms. This study was designed to use the Drosophila Genetic Reference Panel (DGRP), a set of genetically well...

  8. Automated workflow-based exploitation of pathway databases provides new insights into genetic associations of metabolite profiles

    PubMed Central

    2013-01-01

    Background Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) that associate with clinical phenotypes, but these SNPs usually explain just a small part of the heritability and have relatively modest effect sizes. In contrast, SNPs that associate with metabolite levels generally explain a higher percentage of the genetic variation and demonstrate larger effect sizes. Still, the discovery of SNPs associated with metabolite levels is challenging since testing all metabolites measured in typical metabolomics studies with all SNPs comes with a severe multiple testing penalty. We have developed an automated workflow approach that utilizes prior knowledge of biochemical pathways present in databases like KEGG and BioCyc to generate a smaller SNP set relevant to the metabolite. This paper explores the opportunities and challenges in the analysis of GWAS of metabolomic phenotypes and provides novel insights into the genetic basis of metabolic variation through the re-analysis of published GWAS datasets. Results Re-analysis of the published GWAS dataset from Illig et al. (Nature Genetics, 2010) using a pathway-based workflow (http://www.myexperiment.org/packs/319.html), confirmed previously identified hits and identified a new locus of human metabolic individuality, associating Aldehyde dehydrogenase family1 L1 (ALDH1L1) with serine/glycine ratios in blood. Replication in an independent GWAS dataset of phospholipids (Demirkan et al., PLoS Genetics, 2012) identified two novel loci supported by additional literature evidence: GPAM (Glycerol-3 phosphate acyltransferase) and CBS (Cystathionine beta-synthase). In addition, the workflow approach provided novel insight into the affected pathways and relevance of some of these gene-metabolite pairs in disease development and progression. Conclusions We demonstrate the utility of automated exploitation of background knowledge present in pathway databases for the analysis of GWAS

  9. Candidate genetic pathways for attention-deficit/hyperactivity disorder (ADHD) show association to hyperactive/impulsive symptoms in children with ADHD.

    PubMed

    Bralten, Janita; Franke, Barbara; Waldman, Irwin; Rommelse, Nanda; Hartman, Catharina; Asherson, Philip; Banaschewski, Tobias; Ebstein, Richard P; Gill, Michael; Miranda, Ana; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph A; Oosterlaan, Jaap; Sonuga-Barke, Edmund; Steinhausen, Hans-Christoph; Faraone, Stephen V; Buitelaar, Jan K; Arias-Vásquez, Alejandro

    2013-11-01

    Because multiple genes with small effect sizes are assumed to play a role in attention-deficit/hyperactivity disorder (ADHD) etiology, considering multiple variants within the same analysis likely increases the total explained phenotypic variance, thereby boosting the power of genetic studies. This study investigated whether pathway-based analysis could bring scientists closer to unraveling the biology of ADHD. The pathway was described as a predefined gene selection based on a well-established database or literature data. Common genetic variants in pathways involved in dopamine/norepinephrine and serotonin neurotransmission and genes involved in neuritic outgrowth were investigated in cases from the International Multicentre ADHD Genetics (IMAGE) study. Multivariable analysis was performed to combine the effects of single genetic variants within the pathway genes. Phenotypes were DSM-IV symptom counts for inattention and hyperactivity/impulsivity (n = 871) and symptom severity measured with the Conners Parent (n = 930) and Teacher (n = 916) Rating Scales. Summing genetic effects of common genetic variants within the pathways showed a significant association with hyperactive/impulsive symptoms ((p)empirical = .007) but not with inattentive symptoms ((p)empirical = .73). Analysis of parent-rated Conners hyperactive/impulsive symptom scores validated this result ((p)empirical = .0018). Teacher-rated Conners scores were not associated. Post hoc analyses showed a significant contribution of all pathways to the hyperactive/impulsive symptom domain (dopamine/norepinephrine, (p)empirical = .0004; serotonin, (p)empirical = .0149; neuritic outgrowth, (p)empirical = .0452). The present analysis shows an association between common variants in 3 genetic pathways and the hyperactive/impulsive component of ADHD. This study demonstrates that pathway-based association analyses, using quantitative measurements of ADHD symptom domains, can increase the power of genetic analyses to

  10. The Functional Genetics of Handedness and Language Lateralization: Insights from Gene Ontology, Pathway and Disease Association Analyses.

    PubMed

    Schmitz, Judith; Lor, Stephanie; Klose, Rena; Güntürkün, Onur; Ocklenburg, Sebastian

    2017-01-01

    Handedness and language lateralization are partially determined by genetic influences. It has been estimated that at least 40 (and potentially more) possibly interacting genes may influence the ontogenesis of hemispheric asymmetries. Recently, it has been suggested that analyzing the genetics of hemispheric asymmetries on the level of gene ontology sets, rather than at the level of individual genes, might be more informative for understanding the underlying functional cascades. Here, we performed gene ontology, pathway and disease association analyses on genes that have previously been associated with handedness and language lateralization. Significant gene ontology sets for handedness were anatomical structure development, pattern specification (especially asymmetry formation) and biological regulation. Pathway analysis highlighted the importance of the TGF-beta signaling pathway for handedness ontogenesis. Significant gene ontology sets for language lateralization were responses to different stimuli, nervous system development, transport, signaling, and biological regulation. Despite the fact that some authors assume that handedness and language lateralization share a common ontogenetic basis, gene ontology sets barely overlap between phenotypes. Compared to genes involved in handedness, which mostly contribute to structural development, genes involved in language lateralization rather contribute to activity-dependent cognitive processes. Disease association analysis revealed associations of genes involved in handedness with diseases affecting the whole body, while genes involved in language lateralization were specifically engaged in mental and neurological diseases. These findings further support the idea that handedness and language lateralization are ontogenetically independent, complex phenotypes.

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

    PubMed

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

    2016-01-01

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

  12. Genetic variations in the VEGF pathway as prognostic factors in metastatic colorectal cancer patients treated with oxaliplatin-based chemotherapy.

    PubMed

    Paré-Brunet, L; Sebio, A; Salazar, J; Berenguer-Llergo, A; Río, E; Barnadas, A; Baiget, M; Páez, D

    2015-10-01

    Angiogenesis is a significant biological mechanism in the progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF), its receptors and signaling effectors have a central role in tumor-induced angiogenesis. Genetic variation in the VEGF pathway may impact on tumor angiogenesis and, hence, on clinical cancer outcomes. This study evaluates the influence of common genetic variations within the VEGF pathway in the clinical outcomes of 172 metastatic colorectal cancer (mCRC) patients treated with first-line oxaliplatin/5-fluorouracil chemotherapy. A total of 27 single-nucleotide polymorphisms (SNPs) in 16 genes in the VEGF-dependent angionenesis process were genotyped using a dynamic array on the BioMark™ system. After assessing the KRAS mutational status, we found that four SNPs located in three genes (KISS1, KRAS and VEGFR2) were associated with progression-free survival. Five SNPs in three genes (ITGAV, KRAS and VEGFR2) correlated with overall survival. The gene-gene interactions identified in the survival tree analysis support the importance of VEGFR2 rs2071559 and KISS1 rs71745629 in modulating these outcomes. This study provides evidence that functional germline polymorphisms in the VEGF pathway may help to predict outcome in mCRC patients who undergo oxaliplatin/5-fluorouracil chemotherapy.

  13. A Tbx1-Six1/Eya1-Fgf8 genetic pathway controls mammalian cardiovascular and craniofacial morphogenesis.

    PubMed

    Guo, Chaoshe; Sun, Ye; Zhou, Bin; Adam, Rosalyn M; Li, XiaoKun; Pu, William T; Morrow, Bernice E; Moon, Anne; Li, Xue

    2011-04-01

    Shared molecular programs govern the formation of heart and head during mammalian embryogenesis. Development of both structures is disrupted in human chromosomal microdeletion of 22q11.2 (del22q11), which causes DiGeorge syndrome (DGS) and velo-cardio-facial syndrome (VCFS). Here, we have identified a genetic pathway involving the Six1/Eya1 transcription complex that regulates cardiovascular and craniofacial development. We demonstrate that murine mutation of both Six1 and Eya1 recapitulated most features of human del22q11 syndromes, including craniofacial, cardiac outflow tract, and aortic arch malformations. The mutant phenotypes were attributable in part to a reduction of fibroblast growth factor 8 (Fgf8), which was shown to be a direct downstream effector of Six1 and Eya1. Furthermore, we showed that Six1 and Eya1 genetically interacted with Fgf8 and the critical del22q11 gene T-box transcription factor 1 (Tbx1) in mice. Together, these findings reveal a Tbx1-Six1/Eya1-Fgf8 genetic pathway that is crucial for mammalian cardiocraniofacial morphogenesis and provide insights into the pathogenesis of human del22q11 syndromes.

  14. Novel bioassay for the discovery of inhibitors of the 2-C-Methyl-D-Erythritol 4-Phosphate (MEP) and terpenoid pathways leading to carotenoid biosynthesis

    USDA-ARS?s Scientific Manuscript database

    The 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway leads to the synthesis of isopentenyl-phosphate (IPP) in plastids. It is a major branch point providing precursors for the synthesis of carotenoids, tocopherols, plastoquinone and the phytyl chain of chlorophylls, as well as the hormones abscisi...

  15. p38 mitogen-activated protein kinase-dependent and -independent intracellular signal transduction pathways leading to apoptosis in human neutrophils.

    PubMed

    Frasch, S C; Nick, J A; Fadok, V A; Bratton, D L; Worthen, G S; Henson, P M

    1998-04-03

    Human neutrophils undergo apoptosis spontaneously when cultured in vitro; however, the signal transduction pathways involved remain largely unknown. In some cell types, c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase (MAPK) have been implicated in the pathways leading to stress-induced apoptosis. In this study, we begin to define two pathways leading to apoptosis in the neutrophil induced either by stress stimuli (UV, hyperosmolarity, sphingosine) or by anti-Fas antibody or overnight culture in vitro (spontaneous apoptosis). Apoptosis induced by stress stimuli activated p38 MAPK, and apoptosis was inhibited by the specific p38 MAPK inhibitor, 6-(4-Fluorophenyl)-2.3-dihydro-5-(4-puridinyl)imidazo(2, 1-beta)thiazole dihydrochloride. Furthermore, differentiation of HL-60 cells toward the neutrophil phenotype resulted in a loss in c-Jun NH2-terminal kinase activation with concomitant acquisition of formylmethionylleucylphenylalanine-stimulatable and stress-inducible p38 MAPK activity as well as apoptosis blockade by the p38 MAPK inhibitor. In contrast, anti-Fas-induced or spontaneous apoptosis occurred independent of p38 MAPK activation and was not blocked by the inhibitor. Both pathways appear to utilize member(s) of the caspase family, since pretreatment with either Val-Ala-Asp-fluoromethyl ketone or Asp-Glu-Val-Asp-fluoromethyl ketone inhibited apoptosis induced by each of the stimuli. We propose the presence of at least two pathways leading to apoptosis in human neutrophils, a stress-activated pathway that is dependent on p38 MAPK activation and an anti-FAS/spontaneous pathway that is p38 MAPK-independent.

  16. Estimating P-coverage of biosynthetic pathways in DNA libraries and screening by genetic selection: biotin biosynthesis in the marine microorganism Chromohalobacter.

    PubMed

    Kim, Eun Jin; Angell, Scott; Janes, Jeff; Watanabe, Coran M H

    2008-06-01

    Traditional approaches to natural product discovery involve cell-based screening of natural product extracts followed by compound isolation and characterization. Their importance notwithstanding, continued mining leads to depletion of natural resources and the reisolation of previously identified metabolites. Metagenomic strategies aimed at localizing the biosynthetic cluster genes and expressing them in surrogate hosts offers one possible alternative. A fundamental question that naturally arises when pursuing such a strategy is, how large must the genomic library be to effectively represent the genome of an organism(s) and the biosynthetic gene clusters they harbor? Such an issue is certainly augmented in the absence of expensive robotics to expedite colony picking and/or screening of clones. We have developed an algorism, named BPC (biosynthetic pathway coverage), supported by molecular simulations to deduce the number of BAC clones required to achieve proper coverage of the genome and their respective biosynthetic pathways. The strategy has been applied to the construction of a large-insert BAC library from a marine microorganism, Hon6 (isolated from Honokohau, Maui) thought to represent a new species. The genomic library is constructed with a BAC yeast shuttle vector pClasper lacZ paving the way for the culturing of libraries in both prokaryotic and eukaryotic hosts. Flow cytometric methods are utilized to estimate the genome size of the organism and BPC implemented to assess P-coverage or percent coverage. A genetic selection strategy is illustrated, applications of which could expedite screening efforts in the identification and localization of biosynthetic pathways from marine microbial consortia, offering a powerful complement to genome sequencing and degenerate probe strategies. Implementing this approach, we report on the biotin biosynthetic pathway from the marine microorganism Hon6.

  17. A role for Drosophila Cyclin J in oogenesis revealed by genetic interactions with the piRNA pathway.

    PubMed

    Atikukke, Govindaraja; Albosta, Paul; Zhang, Huamei; Finley, Russell L

    2014-08-01

    Cyclin J (CycJ) is a poorly characterized member of the Cyclin superfamily of cyclin-dependent kinase regulators, many of which regulate the cell cycle or transcription. Although CycJ is conserved in metazoans its cellular function has not been identified and no mutant defects have been described. In Drosophila, CycJ transcript is present primarily in ovaries and very early embryos, suggesting a role in one or both of these tissues. The CycJ gene (CycJ) lies immediately downstream of armitage (armi), a gene involved in the Piwi-associated RNA (piRNA) pathways that are required for silencing transposons in the germline and adjacent somatic cells. Mutations in armi result in oogenesis defects but a role for CycJ in oogenesis has not been defined. Here we assessed oogenesis in CycJ mutants in the presence or absence of mutations in armi or other piRNA pathway genes. CycJ null ovaries appeared normal, indicating that CycJ is not essential for oogenesis under normal conditions. In contrast, armi null ovaries produced only two egg chambers per ovariole and the eggs had severe axis specification defects, as observed previously for armi and other piRNA pathway mutants. Surprisingly, the CycJ armi double mutant failed to produce any mature eggs. The double null ovaries generally had only one egg chamber per ovariole and the egg chambers frequently contained an overabundance of differentiated germline cells. Production of these compound egg chambers could be suppressed with CycJ transgenes but not with mutations in the checkpoint gene mnk, which suppress oogenesis defects in armi mutants. The CycJ null showed similar genetic interactions with the germline and somatic piRNA pathway gene piwi, and to a lesser extent with aubergine (aub), a member of the germline-specific piRNA pathway. The strong genetic interactions between CycJ and piRNA pathway genes reveal a role for CycJ in early oogenesis. Our results suggest that CycJ is required to regulate egg chamber production or

  18. A role for Drosophila Cyclin J in oogenesis revealed by genetic interactions with the piRNA pathway

    PubMed Central

    Atikukke, Govindaraja; Albosta, Paul; Zhang, Huamei; Finley, Russell L.

    2014-01-01

    Cyclin J (CycJ) is a poorly characterized member of the Cyclin superfamily of cyclin-dependent kinase regulators, many of which regulate the cell cycle or transcription. Although CycJ is conserved in metazoans its cellular function has not been identified and no mutant defects have been described. In Drosophila, CycJ transcript is present primarily in ovaries and very early embryos, suggesting a role in one or both of these tissues. The CycJ gene (CycJ) lies immediately downstream of armitage (armi), a gene involved in the Piwi-associated RNA (piRNA) pathways that are required for silencing transposons in the germline and adjacent somatic cells. Mutations in armi result in oogenesis defects but a role for CycJ in oogenesis has not been defined. Here we assessed oogenesis in CycJ mutants in the presence or absence of mutations in armi or other piRNA pathway genes. CycJ null ovaries appeared normal, indicating that CycJ is not essential for oogenesis under normal conditions. In contrast, armi null ovaries produced only two egg chambers per ovariole and the eggs had severe axis specification defects, as observed previously for armi and other piRNA pathway mutants. Surprisingly, the CycJ armi double mutant failed to produce any mature eggs. The double null ovaries generally had only one egg chamber per ovariole and the egg chambers frequently contained an overabundance of differentiated germline cells. Production of these compound egg chambers could be suppressed with CycJ transgenes but not with mutations in the checkpoint gene mnk, which suppress oogenesis defects in armi mutants. The CycJ null showed similar genetic interactions with the germline and somatic piRNA pathway gene piwi, and to a lesser extent with aubergine (aub), a member of the germline-specific piRNA pathway. The strong genetic interactions between CycJ and piRNA pathway genes reveal a role for CycJ in early oogenesis. Our results suggest that CycJ is required to regulate egg chamber production or

  19. Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium.

    PubMed

    Yao, Song; Haddad, Stephen A; Hu, Qiang; Liu, Song; Lunetta, Kathryn L; Ruiz-Narvaez, Edward A; Hong, Chi-Chen; Zhu, Qianqian; Sucheston-Campbell, Lara; Cheng, Ting-Yuan David; Bensen, Jeannette T; Johnson, Candace S; Trump, Donald L; Haiman, Christopher A; Olshan, Andrew F; Palmer, Julie R; Ambrosone, Christine B

    2016-05-01

    Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER- breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER- cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 × 10(-5), gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 × 10(-4), corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes.

  20. Genetic variations in vitamin D-related pathways and breast cancer risk in African American women in the AMBER consortium

    PubMed Central

    Yao, Song; Haddad, Stephen A.; Hu, Qiang; Liu, Song; Lunetta, Kathryn L.; Ruiz-Narvaez, Edward A.; Hong, Chi-Chen; Zhu, Qianqian; Sucheston-Campbell, Lara; Cheng, Ting-Yuan David; Bensen, Jeannette T.; Johnson, Candace S.; Trump, Donald L.; Haiman, Christopher A.; Olshan, Andrew F.; Palmer, Julie R.; Ambrosone, Christine B.

    2016-01-01

    Studies of genetic variations in vitamin D-related pathways and breast cancer risk have been conducted mostly in populations of European ancestry, and only sparsely in African Americans (AA), who are known for a high prevalence of vitamin D deficiency. We analyzed 24,445 germline variants in 63 genes from vitamin D-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, including 3,663 breast cancer cases and 4,687 controls. Odds ratios (OR) were derived from logistic regression models for overall breast cancer, by estrogen receptor (ER) status (1,983 ER positive and 1,098 ER negative), and for case-only analyses of ER status. None of the three vitamin D-related pathways were associated with breast cancer risk overall or by ER status. Gene-level analyses identified associations with risk for several genes at a nominal p ≤ 0.05, particularly for ER− breast cancer, including rs4647707 in DDB2. In case-only analyses, vitamin D metabolism and signaling pathways were associated with ER− cancer (pathway-level p = 0.02), driven by a single gene CASR (gene-level p = 0.001). The top SNP in CASR was rs112594756 (p = 7 × 10−5, gene-wide corrected p = 0.01), followed by a second signal from a nearby SNP rs6799828 (p = 1 × 10−4, corrected p = 0.03). In summary, several variants in vitamin D pathways were associated with breast cancer risk in AA women. In addition, CASR may be related to tumor ER status, supporting a role of vitamin D or calcium in modifying breast cancer phenotypes. PMID:26650177

  1. The third international meeting on genetic disorders in the RAS/MAPK pathway: towards a therapeutic approach.

    PubMed

    Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D; Gripp, Karen W; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum A; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A; Roberts, Amy; Silva, Alcino J; Sittampalam, Sitta G; Zhang, Chao; Schoyer, Lisa

    2015-08-01

    "The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach" was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion.

  2. The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

    PubMed Central

    Korf, Bruce; Ahmadian, Reza; Allanson, Judith; Aoki, Yoko; Bakker, Annette; Wright, Emma Burkitt; Denger, Brian; Elgersma, Ype; Gelb, Bruce D.; Gripp, Karen W.; Kerr, Bronwyn; Kontaridis, Maria; Lazaro, Conxi; Linardic, Corinne; Lozano, Reymundo; MacRae, Calum A.; Messiaen, Ludwine; Mulero-Navarro, Sonia; Neel, Benjamin; Plotkin, Scott; Rauen, Katherine A.; Roberts, Amy; Silva, Alcino J.; Sittampalam, Sitta G.; Zhang, Chao; Schoyer, Lisa

    2015-01-01

    “The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach” was held at the Renaissance Orlando at SeaWorld Hotel (August 2–4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion. PMID:25900621

  3. Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay

    PubMed Central

    Pendergast, Julie S.; Allen, Melissa J.; Leu, Roberta M.; Johnson, Carl Hirschie; Elsea, Sarah H.; Malow, Beth A.

    2014-01-01

    Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with comorbid expression of sleep onset delay. We evaluated variation in two melatonin pathway genes, acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2). We observed higher frequencies than currently reported (p < 0.04) for variants evidenced to decrease ASMT expression and related to decreased CYP1A2 enzyme activity (p ≤ 0.0007). We detected a relationship between genotypes in ASMT and CYP1A2 (r2 = 0.63). Our results indicate that expression of sleep onset delay relates to melatonin pathway genes. PMID:25059483

  4. Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life

    PubMed Central

    Wong, J. Tze-Fei; Ng, Siu-Kin; Mat, Wai-Kin; Hu, Taobo; Xue, Hong

    2016-01-01

    The origins of the components of genetic coding are examined in the present study. Genetic information arose from replicator induction by metabolite in accordance with the metabolic expansion law. Messenger RNA and transfer RNA stemmed from a template for binding the aminoacyl-RNA synthetase ribozymes employed to synthesize peptide prosthetic groups on RNAs in the Peptidated RNA World. Coevolution of the genetic code with amino acid biosynthesis generated tRNA paralogs that identify a last universal common ancestor (LUCA) of extant life close to Methanopyrus, which in turn points to archaeal tRNA introns as the most primitive introns and the anticodon usage of Methanopyrus as an ancient mode of wobble. The prediction of the coevolution theory of the genetic code that the code should be a mutable code has led to the isolation of optional and mandatory synthetic life forms with altered protein alphabets. PMID:26999216

  5. Genetic LRRK2 Models of Parkinson’s Disease: Dissecting Pathogenic pathway and Exploring Clinical Application

    PubMed Central

    Yue, Zhenyu; Lachenmayer, M. Lenard

    2011-01-01

    Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). Understanding LRRK2 biology and pathophysiology is central to the elucidation of PD etiology and development of disease intervention. Recently a number of genetic mouse models of LRRK2 have been reported utilizing different genetic approaches. Some similarities in PD-related pathology emerge in these genetic models, despite lack of substantial neuropathology and clinical syndromes of PD. The systematic characterization of these models has begun to shed light on LRRK2 biology and pathophysiology and is expected to offer the identification and validation of drug targets. In this review, we summarize the progress of genetic LRRK2 mouse models and discuss their utility in understanding much needed knowledge regarding early stage (pre-symptomatic) disease progression, identifying drug targets, and exploring the potential in aiding compound screening focused on inhibitors of kinase activity of LRRK2. PMID:21538530

  6. Coevolution Theory of the Genetic Code at Age Forty: Pathway to Translation and Synthetic Life.

    PubMed

    Wong, J Tze-Fei; Ng, Siu-Kin; Mat, Wai-Kin; Hu, Taobo; Xue, Hong

    2016-03-16

    The origins of the components of genetic coding are examined in the present study. Genetic information arose from replicator induction by metabolite in accordance with the metabolic expansion law. Messenger RNA and transfer RNA stemmed from a template for binding the aminoacyl-RNA synthetase ribozymes employed to synthesize peptide prosthetic groups on RNAs in the Peptidated RNA World. Coevolution of the genetic code with amino acid biosynthesis generated tRNA paralogs that identify a last universal common ancestor (LUCA) of extant life close to Methanopyrus, which in turn points to archaeal tRNA introns as the most primitive introns and the anticodon usage of Methanopyrus as an ancient mode of wobble. The prediction of the coevolution theory of the genetic code that the code should be a mutable code has led to the isolation of optional and mandatory synthetic life forms with altered protein alphabets.

  7. Pathways of expansion and multiple introductions illustrated by large genetic differentiation among worldwide populations of the southern house mosquito.

    PubMed

    Fonseca, Dina M; Smith, Julie L; Wilkerson, Richard C; Fleischer, Robert C

    2006-02-01

    The southern house mosquito Culex quinquefasciatus is a principal vector of human lymphatic filariasis, several encephalitides (including West Nile virus), avian malaria, and poxvirus, but its importance as a vector varies considerably among regions. This species has spread with humans and is ubiquitous in tropical urban and suburban environments. This was the first mosquito to reach Hawaii and we performed a worldwide genetic survey using micro-satellite loci to identify its source. Our analyses showed divergent Old World and New World genetic signatures in Cx. quinquefasciatus with further distinctions between east and west African, Asian, and Pacific populations that correlate with the epidemiology of human filariasis. We found that in Hawaii south Pacific mosquitoes have largely replaced the original New World introduction of Cx. quinquefasciatus, consistent with their reported expansion to higher elevations. We hypothesize worldwide pathways of expansion of this disease vector.

  8. The Central Role of KNG1 Gene as a Genetic Determinant of Coagulation Pathway-Related Traits: Exploring Metaphenotypes

    PubMed Central

    Massanet, Raimon; Martinez-Perez, Angel; Ziyatdinov, Andrey; Martin-Fernandez, Laura; Souto, Juan Carlos; Perera, Alexandre; Soria, José Manuel

    2016-01-01

    Traditional genetic studies of single traits may be unable to detect the pleiotropic effects involved in complex diseases. To detect the correlation that exists between several phenotypes involved in the same biological process, we introduce an original methodology to analyze sets of correlated phenotypes involved in the coagulation cascade in genome-wide association studies. The methodology consists of a two-stage process. First, we define new phenotypic meta-variables (linear combinations of the original phenotypes), named metaphenotypes, by applying Independent Component Analysis for the multivariate analysis of correlated phenotypes (i.e. the levels of coagulation pathway–related proteins). The resulting metaphenotypes integrate the information regarding the underlying biological process (i.e. thrombus/clot formation). Secondly, we take advantage of a family based Genome Wide Association Study to identify genetic elements influencing these metaphenotypes and consequently thrombosis risk. Our study utilized data from the GAIT Project (Genetic Analysis of Idiopathic Thrombophilia). We obtained 15 metaphenotypes, which showed significant heritabilities, ranging from 0.2 to 0.7. These results indicate the importance of genetic factors in the variability of these traits. We found 4 metaphenotypes that showed significant associations with SNPs. The most relevant were those mapped in a region near the HRG, FETUB and KNG1 genes. Our results are provocative since they show that the KNG1 locus plays a central role as a genetic determinant of the entire coagulation pathway and thrombus/clot formation. Integrating data from multiple correlated measurements through metaphenotypes is a promising approach to elucidate the hidden genetic mechanisms underlying complex diseases. PMID:28005926

  9. Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.

    PubMed

    de Sanctis, L; Giachero, F; Mantovani, G; Weber, G; Salerno, M; Baroncelli, G I; Elli, M F; Matarazzo, P; Wasniewska, M; Mazzanti, L; Scirè, G; Tessaris, D

    2016-11-21

    Genetic and epigenetic alterations in the GNAS locus are responsible for the Gsα protein dysfunctions causing Pseudohypoparathyroidism (PHP) type Ia/c and Ib, respectively. For these heterogeneous diseases characterized by multiple hormone resistances and Albright's Hereditary Osteodystrophy (AHO) the current classification results inadequate because of the clinical overlap between molecular subtypes and a standard clinical approach is still missing. In the present paper several members of the Study Group Endocrine diseases due to altered function of Gsα protein of the Italian Society of Pediatric Endocrinology and Diabetology (ISPED) have reviewed and updated the clinical-molecular data of the largest case series of (epi)/genetically characterized AHO/PHP patients; they then produced a common healthcare pathway for patients with these disorders. The molecular analysis of the GNAS gene and locus identified the causal alteration in 74 subjects (46 genetic and 28 epigenetic mutations). The clinical data at the diagnosis and their evolution during up to 15 years follow-up were collected using two different cards. In patients with genetic mutations the growth impairment worsen during the time, while obesity prevalence decreases; subcutaneous ossifications seem specific for this group. Brachydactyly has been detected in half of the subjects with epigenetic alterations, in which the disease overts later in life, often with symptomatic hypocalcaemia, and also early TSH and GHRH resistances have been recorded. A dedicated healthcare pathway addressing all these aspects in a systematic way would improve the clinical management, allowing an earlier recognition of some PHP features, the optimization of their medical treatment and a better clinical-oriented molecular analysis. Furthermore, standardized follow-up data would provide new insight into less known aspects.

  10. Lack of myotubularin (MTM1) leads to muscle hypotrophy through unbalanced regulation of the autophagy and ubiquitin-proteasome pathways.

    PubMed

    Al-Qusairi, Lama; Prokic, Ivana; Amoasii, Leonela; Kretz, Christine; Messaddeq, Nadia; Mandel, Jean-Louis; Laporte, Jocelyn

    2013-08-01

    Mutations in the phosphoinositide phosphatase myotubularin (MTM1) results in X-linked myotubular/centronuclear myopathy (XLMTM), characterized by a severe decrease in muscle mass and strength in patients and murine models. However, the molecular mechanism involved in the muscle hypotrophy is unclear. Here we show that the IGF1R/Akt pathway is affected in Mtm1-deficient murine muscles, characterized by an increase in IGF1 receptor and Akt levels in both the presymptomatic and symptomatic phases. Moreover, up-regulation of atrogenes was observed in the presymptomatic phase of the myopathy, supporting overactivation of the ubiquitin-proteasome pathway. In parallel, the autophagy machinery was affected as indicated by the increase in the number of autophagosomes and of autophagy markers, such as LC3 and P62. However, phosphorylation of FOXO3a and mTOR were abnormal at late but not at early stages of the disease, suggesting that myotubularin acts both upstream in the IGF1R/Akt pathway and downstream on the balance between the autophagy and ubiquitin-proteasome pathways in vivo. Adeno-associated virus-mediated delivery of Mtm1 into Mtm1-null muscles rescued muscle mass and normalized the expression levels of IGF1 receptor, the ubiquitin-proteasome pathway, and autophagy markers. These data support the hypothesis that the unbalanced regulation of the ubiquitin proteasome pathway and the autophagy machinery is a primary cause of the XLMTM pathogenesis.

  11. Genetics

    MedlinePlus

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

  12. [Genetic engineering of microbial metabolic pathway for production of advanced biodiesel].

    PubMed

    Fu, Ai-Si; Liu, Ran; Zhu, Jing; Liu, Tian-Gang

    2011-10-01

    Biodiesel is a renewable biofuel and alternative diesel, but the first generation of biodiesel, which has many defects in properties and in production methods, mainly comes from the chemical transesterification of triglyceride from plant oil. With the fast development in the field of synthetic biology and metabolic engineer-ing, the researchers can choose suitable microbes and engineer its metabolic pathways, such as fatty acid bio-synthesis pathway and isoprenoid biosynthesis pathway, to directly produce the second generation of advanced biodiesel---long chain hydrocarbons, which have better properties and quality using the newest biotechnology techniques. In this review, we summarized the research progress about microbial production of advanced bio-diesel and also pointed the deficiencies and future direction in this new field.

  13. Gustatory neural pathways revealed by genetic tracing from taste receptor cells.

    PubMed

    Matsumoto, Ichiro

    2013-01-01

    Taste receptor cells encounter chemicals in foods and transmit this information to the gustatory neurons, which convey it further to the gustatory relay nuclei in the lower brainstem. Characterizing neurons involved in the transmission of gustatory information in the peripheral and central nervous systems helps us better understand how we perceive and discriminate tastes. However, it is difficult to anatomically identify them. Using cell-type-specific promoters/enhancers and a transneuronal tracer, we generated transgenic mice to visualize neurons in the gustatory neural pathways. We observed the tracer in the neurons of cranial sensory ganglia and the nucleus of the solitary tract in the medulla where gustatory neurons project. The tracer was also distributed in the reticular formation and several motor nuclei in the medulla that have not been recognized as gustatory ascending pathways. These transgenic mice revealed gustatory relay neurons in the known gustatory ascending pathway and an unexpected, thus presumably novel, neural circuit of gustatory system.

  14. Gustatory Neural Pathways Revealed by Genetic Tracing from Taste Receptor Cells

    PubMed Central

    Matsumoto, Ichiro

    2013-01-01

    Taste receptor cells encounter chemicals in foods and transmit this information to the gustatory neurons, which convey it further to the gustatory relay nuclei in the lower brainstem. Characterizing neurons involved in the transmission of gustatory information in the peripheral and central nervous systems helps us better understand how we perceive and discriminate tastes. However, it is difficult to anatomically identify them. Using cell-type-specific promoters/enhancers and a transneuronal tracer, we generated transgenic mice to visualize neurons in the gustatory neural pathways. We observed the tracer in the neurons of cranial sensory ganglia and the nucleus of the solitary tract in the medulla where gustatory neurons project. The tracer was also distributed in the reticular formation and several motor nuclei in the medulla that have not been recognized as gustatory ascending pathways. These transgenic mice revealed gustatory relay neurons in the known gustatory ascending pathway and an unexpected, thus presumably novel, neural circuit of gustatory system. PMID:23832339

  15. Lead induces the expression of endoplasmic reticulum chaperones GRP78 and GRP94 in vascular endothelial cells via the JNK-AP-1 pathway.

    PubMed

    Shinkai, Yasuhiro; Yamamoto, Chika; Kaji, Toshiyuki

    2010-04-01

    Lead, a ubiquitous heavy metal, is an important industrial and environmental pollutant that can target the vascular endothelium. To clarify the effects of lead on the unfolded protein response (UPR) and their significance in cytotoxicity, we examined the expression and function of endoplasmic reticulum (ER) chaperones glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94) in vascular endothelial cells. We used bovine aortic endothelial cells as an in vitro model of the vascular endothelium. Exposure of vascular endothelial cells to lead nitrate resulted in a marked induction of GRP78 and GRP94 messenger RNA levels. In response to lead, the expression of GRP78 and GRP94 proteins also significantly increased in a dose- and time-dependent manner. In addition, small interfering RNA (siRNA)-mediated knockdown of GRP78 significantly enhanced lead-induced cytotoxicity. Compared with other metal(loid)s, including cadmium chloride, zinc sulfate, copper sulfate, and sodium arsenite, lead nitrate was found to be the most potent metal to induce these chaperones in endothelial cells. In the examined UPR pathways, lead increased the phosphorylation of inositol-requiring enzyme 1 (IRE1) and c-jun N-terminal kinase (JNK). Interestingly, the lead-induced upregulation of GRP78 and GRP94 was almost completely blocked by the JNK inhibitor SP600125 or activator protein-1 (AP-1) inhibitor curcumin. Taken together, these results suggest that lead induces ER stress, but the induction of GRP78 and GRP94 expression via the JNK-AP-1 pathway functions as a defense mechanism against lead-induced cytotoxicity in vascular endothelial cells.

  16. Novel Bioassay for the Discovery of Inhibitors of the 2-C-Methyl-D-erythritol 4-Phosphate (MEP) and Terpenoid Pathways Leading to Carotenoid Biosynthesis

    PubMed Central

    Corniani, Natália; Velini, Edivaldo D.; Silva, Ferdinando M. L.; Nanayakkara, N. P. Dhammika; Witschel, Matthias; Dayan, Franck E.

    2014-01-01

    The 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway leads to the synthesis of isopentenyl diphosphate in plastids. It is a major branch point providing precursors for the synthesis of carotenoids, tocopherols, plastoquinone and the phytyl chain of chlorophylls, as well as the hormones abscisic acid and gibberellins. Consequently, disruption of this pathway is harmful to plants. We developed an in vivo bioassay that can measure the carbon flow through the carotenoid pathway. Leaf cuttings are incubated in the presence of a phytoene desaturase inhibitor to induce phytoene accumulation. Any compound reducing the level of phytoene accumulation is likely to interfere with either one of the steps in the MEP pathway or the synthesis of geranylgeranyl diphosphate. This concept was tested with known inhibitors of steps of the MEP pathway. The specificity of this in vivo bioassay was also verified by testing representative herbicides known to target processes outside of the MEP and carotenoid pathways. This assay enables the rapid screen of new inhibitors of enzymes preceding the synthesis of phytoene, though there are some limitations related to the non-specific effect of some inhibitors on this assay. PMID:25077957

  17. Novel bioassay for the discovery of inhibitors of the 2-C-methyl-D-erythritol 4-phosphate (MEP) and terpenoid pathways leading to carotenoid biosynthesis.

    PubMed

    Corniani, Natália; Velini, Edivaldo D; Silva, Ferdinando M L; Nanayakkara, N P Dhammika; Witschel, Matthias; Dayan, Franck E

    2014-01-01

    The 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway leads to the synthesis of isopentenyl diphosphate in plastids. It is a major branch point providing precursors for the synthesis of carotenoids, tocopherols, plastoquinone and the phytyl chain of chlorophylls, as well as the hormones abscisic acid and gibberellins. Consequently, disruption of this pathway is harmful to plants. We developed an in vivo bioassay that can measure the carbon flow through the carotenoid pathway. Leaf cuttings are incubated in the presence of a phytoene desaturase inhibitor to induce phytoene accumulation. Any compound reducing the level of phytoene accumulation is likely to interfere with either one of the steps in the MEP pathway or the synthesis of geranylgeranyl diphosphate. This concept was tested with known inhibitors of steps of the MEP pathway. The specificity of this in vivo bioassay was also verified by testing representative herbicides known to target processes outside of the MEP and carotenoid pathways. This assay enables the rapid screen of new inhibitors of enzymes preceding the synthesis of phytoene, though there are some limitations related to the non-specific effect of some inhibitors on this assay.

  18. Genetic deletion of Rnd3 results in aqueductal stenosis leading to hydrocephalus through up-regulation of Notch signaling.

    PubMed

    Lin, Xi; Liu, Baohui; Yang, Xiangsheng; Yue, Xiaojing; Diao, Lixia; Wang, Jing; Chang, Jiang

    2013-05-14

    Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, is involved in the regulation of cell actin cytoskeleton dynamics, cell migration, and proliferation through the Rho kinase-dependent signaling pathway. We report a role of Rnd3 in the pathogenesis of hydrocephalus disorder. Mice with Rnd3 genetic deletion developed severe obstructive hydrocephalus with enlargement of the lateral and third ventricles, but not of the fourth ventricles. The cerebral aqueducts in Rnd3-null mice were partially or completely blocked by the overgrowth of ependymal epithelia. We examined the molecular mechanism contributing to this Rnd3-deficiency-mediated hydrocephalus and found that Rnd3 is a regulator of Notch signaling. Rnd3 deficiency, through either gene deletion or siRNA knockdown, resulted in a decrease in Notch intracellular domain (NICD) protein degradation. However, there was no correlated change in mRNA change, which in turn led to an increase in NICD protein levels. Immunoprecipitation analysis demonstrated that Rnd3 and NICD physically interacted, and that down-regulation of Rnd3 attenuated NICD protein ubiquitination. This eventually enhanced Notch signaling activity and promoted aberrant growth of aqueduct ependymal cells, resulting in aqueduct stenosis and the development of congenital hydrocephalus. Inhibition of Notch activity rescued the hydrocephalus disorder in the mutant animals.

  19. Genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway as potential risk factors of menopausal hot flashes

    PubMed Central

    ZIV-GAL, Ayelet; GALLICCHIO, Lisa; MILLER, Susan R.; ZACUR, Howard A.; FLAWS, Jodi A.

    2012-01-01

    Objective To determine if genetic polymorphisms in the aryl hydrocarbon receptor signaling pathway are associated with menopausal hot flashes via hormone levels. Study design Women (n=639) aged 45–54 years completed a study survey and provided blood for genetic and hormone analyses. The associations were analyzed using multivariable logistic regression and generalized linear models. Results Women carrying CYP1B1 (rs1800440) GG genotype had 3-fold greater odds of experiencing hot flashes for ≥1 year compared to the AA genotype [adjusted odds ratio (aOR): 3.05 (1.12–8.25)]. Adding serum estradiol concentrations to the confounder-adjusted model resulted in a non-significant association [aOR: 2.59 (0.91–7.18)]. Carriers of both CYP1B1 (rs1800440) G and CYP1B1 (rs1058636) G alleles had higher odds of experiencing hot flashes for ≥1 year compared to women homozygous for the major alleles [aOR: 1.77 (1.06–2.96)], even after adjustment for serum estradiol. Conclusion CYP1B1 is associated with menopausal hot flashes v