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Sample records for pathways linking socioeconomic

  1. Neurobiological Pathways Linking Socioeconomic Position and Health

    PubMed Central

    Gianaros, Peter J.; Manuck, Stephen B.

    2010-01-01

    Across individuals, risk for poor health varies inversely with socioeconomic position (SEP). The pathways by which SEP affects health have been viewed from many epidemiological perspectives. Central to these perspectives is the notion that socioeconomic health disparities arise from an interplay between nested, recursive, and cumulative environmental, social, familial, psychological, behavioral, and physiological processes that unfold over the life span. Epidemiological perspectives on socioeconomic health disparities, however, have not yet formally integrated emerging findings from neuropharmacological, molecular genetic, and neuroimaging studies demonstrating that indicators of SEP relate to patterns of brain neurotransmission, brain morphology, and brain functionality implicated in the etiology of chronic medical conditions and psychological disorders. Here, we survey these emerging findings and consider how future neurobiological studies in this area can enhance our understanding of the pathways by which different dimensions of SEP become embodied by the brain to influence health throughout life. PMID:20498294

  2. Pathways Linking Socioeconomic Status and Postpartum Smoking Relapse

    PubMed Central

    Businelle, Michael S.; Kendzor, Darla E.; Reitzel, Lorraine R.; Vidrine, Jennifer Irvin; Castro, Yessenia; Mullen, Patricia Dolan; Velasquez, Mary M.; Cofta-Woerpel, Ludmila; Cinciripini, Paul M.; Greisinger, Anthony J.; Wetter, David W.

    2012-01-01

    Background Low socioeconomic status (SES) exacerbates the high rate of smoking relapse in women following childbirth. Purpose This study examined multiple models of potential mechanisms linking SES and postpartum smoking relapse among women who quit smoking due to pregnancy. Methods Participants were 251 women enrolled in a randomized clinical trial of a new postpartum smoking relapse prevention intervention. Four models of the prepartum mechanisms linking SES and postpartum smoking relapse were evaluated using a latent variable modeling approach. Results Each of the hypothesized models were a good fit for the data. As hypothesized, SES indirectly influenced postpartum smoking relapse through increased prepartum negative affect/stress, reduced sense of agency, and increased craving for cigarettes. However, the model that included craving as the sole final pathway between SES and relapse demonstrated superior fit when compared with all other models. Conclusions Findings have implications for future interventions that aim to reduce postpartum relapse. PMID:23086590

  3. Psychological Perspectives on Pathways Linking Socioeconomic Status and Physical Health

    PubMed Central

    Matthews, Karen A.; Gallo, Linda C.

    2011-01-01

    Low socioeconomic status (SES) is a reliable correlate of poor physical health. Rather than treat SES as a covariate, health psychology has increasingly focused on the psychobiological pathways that inform understanding why SES is related to physical health. This review assesses the status of research that has examined stress and its associated distress, and social and personal resources as pathways. It highlights work on biomarkers and biological pathways related to SES that can serve as intermediate outcomes in future studies. Recent emphasis on the accumulation of psychobiological risks across the life course is summarized and represents an important direction for future research. Studies that test pathways from SES to candidate psychosocial pathways to health outcomes are few in number but promising. Future research should test integrated models rather than taking piecemeal approaches to evidence. Much work remains to be done, but the questions are of great health significance. PMID:20636127

  4. Pathways linking socioeconomic status to obesity through depression and lifestyle factors among young US adults

    PubMed Central

    Beydoun, May A.; Wang, Youfa

    2009-01-01

    Obesity and depression are two diseases of major public health importance. While both correlate with each other, potential pathways involving depression that would link socioeconomic status (SES) to lifestyle factors and obesity have not been systematically examined using nationally representative data. Using rich data on 2,217 US young adults aged 20–39 years from the 1999–2004 National Health and Nutrition Surveys (NHANES) and multivariate linear and logistic regression models, we examined associations between major depressive disorder (MDD), dietary intake, physical activity (PA), and measured body mass index (BMI) controlling for socio-demographic factors. Further, structural equations models (SEM) were fit to test pathway explaining SES disparities in BMI through MDD and lifestyle factors. Recent prevalence of MDD was lower among young US men than women (6.4% vs 9.2%) although their prevalence of obesity was similar (21.2% vs 22.7%). Among women, MDD was associated with higher BMI and inversely associated with PA, but not among men. MDD was specifically associated with increased risk of morbid obesity (BMI≥40) among women (OR: 2.88 (1.32, 6.30)). Using SEM, a main pathway linking SES to BMI among women was that linking SES → food insecurity → MDD → PA → BMI. A main pathway linking MDD to BMI in both genders was that going through PA rather than overall dietary quality. Gender and ethnic differences existed underlying how MDD, SES and lifestyle factors were associated with adiposity. Future prospective studies are needed to examine potential mechanisms using physiological markers of depression, lifestyle and obesity. PMID:19853306

  5. Adolescent smoking and tertiary education: opposing pathways linking socio-economic background to alcohol consumption.

    PubMed

    Green, Michael J; Leyland, Alastair H; Sweeting, Helen; Benzeval, Michaela

    2016-08-01

    If socio-economic disadvantage is associated with more adolescent smoking, but less participation in tertiary education, and smoking and tertiary education are both associated with heavier drinking, these may represent opposing pathways to heavy drinking. This paper examines contextual variation in the magnitude and direction of these associations. Comparing cohort studies. United Kingdom. Participants were from the 1958 National Child Development Study (NCDS58; n = 15 672), the British birth cohort study (BCS70; n = 12 735) and the West of Scotland Twenty-07 1970s cohort (T07; n = 1515). Participants self-reported daily smoking and weekly drinking in adolescence (age 16 years) and heavy drinking (> 14/21 units in past week) in early adulthood (ages 22-26 years). Parental occupational class (manual versus non-manual) indicated socio-economic background. Education beyond age 18 was coded as tertiary. Models were adjusted for parental smoking and drinking, family structure and adolescent psychiatric distress. Respondents from a manual class were more likely to smoke and less likely to enter tertiary education (e.g. in NCDS58, probit coefficients were 0.201 and -0.765, respectively; P < 0.001 for both) than respondents from a non-manual class. Adolescent smokers were more likely to drink weekly in adolescence (0.346; P < 0.001) and more likely to drink heavily in early adulthood (0.178; P < 0.001) than adolescent non-smokers. Respondents who participated in tertiary education were more likely to drink heavily in early adulthood (0.110 for males, 0.182 for females; P < 0.001 for both) than respondents with no tertiary education. With some variation in magnitude, these associations were consistent across all three cohorts. In Britain, young adults are more likely to drink heavily both if they smoke and participate in tertiary education (college and university) despite socio-economic background being associated in opposite directions with these risk

  6. Biopsychosocial pathways linking subjective socioeconomic disadvantage to glycemic control in youths with type I diabetes.

    PubMed

    Zilioli, Samuele; Ellis, Deborah A; Carré, Justin M; Slatcher, Richard B

    2017-04-01

    Older adolescent and young adults (OAYA) with type 1 diabetes (T1D) living in contexts of socio-economic disadvantage (SED) suffer disproportionately from poor glycemic control and related health complications. Although SED may convey a variety of risks, it may exacerbate diabetes-related stress levels, which in turn may account for observed disparities in health outcomes. The primary goal of the present study was to investigate the relationship between subjective SED, diabetes-related perceived stress, and diurnal cortisol secretion in urban OAYA with T1D. A secondary goal was to determine if cortisol was related to measures of blood glucose (HbA1c and mean blood glucose). Analyses were conducted among OAYA ages 17-20 years (n=61) affected by T1D, who provided daily saliva samples for four days, measures of glycemic control (i.e., HbA1c and mean blood glucose assessed via Continuous Glucose Monitor), and completed psychosocial questionnaires. We found that subjective SED was associated with a flatter diurnal cortisol rhythm via diabetes-related stress. Flattened cortisol rhythm was, in turn, associated with higher levels of HbA1c, but not with mean blood glucose assessed via Continuous Glucose Monitor. These results represent some of the first empirical evidence on how distal social factors (i.e., subjective SED) and proximal psychological processes (diabetes-related perceived stress) are connected to condition-relevant biological mechanisms (i.e., elevated HbA1c), via broad biological pathways implicated in health (i.e., flatter cortisol slope).

  7. Ethnic Variations of Pathways Linking Socioeconomic Status, Parenting, and Preacademic Skills in a Nationally Representative Sample

    ERIC Educational Resources Information Center

    Iruka, Iheoma U.; Dotterer, Aryn M.; Pungello, Elizabeth P.

    2014-01-01

    Research Findings: Grounded in the investment model and informed by the integrative theory of the study of minority children, this study used the Early Childhood Longitudinal Study-Birth Cohort data set, a nationally representative sample of young children, to investigate whether the association between socioeconomic status (family income and…

  8. Ethnic Variations of Pathways Linking Socioeconomic Status, Parenting, and Preacademic Skills in a Nationally Representative Sample

    ERIC Educational Resources Information Center

    Iruka, Iheoma U.; Dotterer, Aryn M.; Pungello, Elizabeth P.

    2014-01-01

    Research Findings: Grounded in the investment model and informed by the integrative theory of the study of minority children, this study used the Early Childhood Longitudinal Study-Birth Cohort data set, a nationally representative sample of young children, to investigate whether the association between socioeconomic status (family income and…

  9. Forecasting civil conflict along the shared socioeconomic pathways

    NASA Astrophysics Data System (ADS)

    Hegre, Håvard; Buhaug, Halvard; Calvin, Katherine V.; Nordkvelle, Jonas; Waldhoff, Stephanie T.; Gilmore, Elisabeth

    2016-05-01

    Climate change and armed civil conflict are both linked to socioeconomic development, although conditions that facilitate peace may not necessarily facilitate mitigation and adaptation to climate change. While economic growth lowers the risk of conflict, it is generally associated with increased greenhouse gas emissions and costs of climate mitigation policies. This study investigates the links between growth, climate change, and conflict by simulating future civil conflict using new scenario data for five alternative socioeconomic pathways with different mitigation and adaptation assumptions, known as the shared socioeconomic pathways (SSPs). We develop a statistical model of the historical effect of key socioeconomic variables on country-specific conflict incidence, 1960-2013. We then forecast the annual incidence of conflict, 2014-2100, along the five SSPs. We find that SSPs with high investments in broad societal development are associated with the largest reduction in conflict risk. This is most pronounced for the least developed countries—poverty alleviation and human capital investments in poor countries are much more effective instruments to attain global peace and stability than further improvements to wealthier economies. Moreover, the SSP that describes a sustainability pathway, which poses the lowest climate change challenges, is as conducive to global peace as the conventional development pathway.

  10. Socioeconomic Disparities and Health: Impacts and Pathways

    PubMed Central

    Kondo, Naoki

    2012-01-01

    Growing socioeconomic disparity is a global concern, as it could affect population health. The author and colleagues have investigated the health impacts of socioeconomic disparities as well as the pathways that underlie those disparities. Our meta-analysis found that a large population has risks of mortality and poor self-rated health that are attributable to income inequality. The study results also suggested the existence of threshold effects (ie, a threshold of income inequality over which the adverse impacts on health increase), period effects (ie, the potential for larger impacts in later years, specifically after the 1990s), and lag effects between income inequality and health outcomes. Our other studies using Japanese national representative survey data and a large-scale cohort study of Japanese older adults (AGES cohort) support the relative deprivation hypothesis, namely, that invidious social comparisons arising from relative deprivation in an unequal society adversely affect health. A study with a natural experiment design found that the socioeconomic gradient in self-rated health might actually have become shallower after the 1997–98 economic crisis in Japan, due to smaller health improvements among middle-class white-collar workers and middle/upper-income workers. In conclusion, income inequality might have adverse impacts on individual health, and psychosocial stress due to relative deprivation may partially explain those impacts. Any study of the effects of macroeconomic fluctuations on health disparities should also consider multiple potential pathways, including expanding income inequality, changes in the labor market, and erosion of social capital. Further studies are needed to attain a better understanding of the social determinants of health in a rapidly changing society. PMID:22156290

  11. Socioeconomic disparities and health: impacts and pathways.

    PubMed

    Kondo, Naoki

    2012-01-01

    Growing socioeconomic disparity is a global concern, as it could affect population health. The author and colleagues have investigated the health impacts of socioeconomic disparities as well as the pathways that underlie those disparities. Our meta-analysis found that a large population has risks of mortality and poor self-rated health that are attributable to income inequality. The study results also suggested the existence of threshold effects (ie, a threshold of income inequality over which the adverse impacts on health increase), period effects (ie, the potential for larger impacts in later years, specifically after the 1990s), and lag effects between income inequality and health outcomes. Our other studies using Japanese national representative survey data and a large-scale cohort study of Japanese older adults (AGES cohort) support the relative deprivation hypothesis, namely, that invidious social comparisons arising from relative deprivation in an unequal society adversely affect health. A study with a natural experiment design found that the socioeconomic gradient in self-rated health might actually have become shallower after the 1997-98 economic crisis in Japan, due to smaller health improvements among middle-class white-collar workers and middle/upper-income workers. In conclusion, income inequality might have adverse impacts on individual health, and psychosocial stress due to relative deprivation may partially explain those impacts. Any study of the effects of macroeconomic fluctuations on health disparities should also consider multiple potential pathways, including expanding income inequality, changes in the labor market, and erosion of social capital. Further studies are needed to attain a better understanding of the social determinants of health in a rapidly changing society.

  12. Scenarios Based on Shared Socioeconomic Pathway Assumptions

    NASA Astrophysics Data System (ADS)

    Edmonds, J.

    2013-12-01

    A set of new scenarios is being developed by the international scientific community as part of a larger program that was articulated in Moss, et al. (2009), published in Nature. A long series of meetings including climate researchers drawn from the climate modeling, impacts, adaptation and vulnerability (IAV) and integrated assessment modeling (IAM) communities have led to the development of a set of five Shared Socioeconomic Pathways (SSPs), which define the state of human and natural societies at a macro scale over the course of the 21st century without regard to climate mitigation or change. SSPs were designed to explore a range of possible futures consistent with greater or lesser challenges to mitigation and challenges to adaptation. They include a narrative storyline and a set of quantified measures--e.g. demographic and economic profiles--that define the high-level state of society as it evolves over the 21st century under the assumption of no significant climate feedback. SSPs can be used to develop quantitative scenarios of human Earth systems using IAMs. IAMs produce information about greenhouse gas emissions, energy systems, the economy, agriculture and land use. Each set of SSPs will have a different human Earth system realization for each IAM. Five groups from the IAM community have begun to explore the implications of SSP assumptions for emissions, energy, economy, agriculture and land use. We report the quantitative results of initial experiments from those groups. A major goal of the Moss, et al. strategy was to enable the use of CMIP5 climate model ensemble products for IAV research. CMIP5 climate scenarios used four Representative Concentration Pathway (RCP) scenarios, defined in terms of radiative forcing in the year 2100: 2.6, 4.5, 6.0, and 8.5 Wm-2. There is no reason to believe that the SSPs will generate year 2100 levels of radiative forcing that correspond to the four RCP levels, though it is important that at least one SSP produce a

  13. Biological ageing: a fundamental, biological link between socio-economic status and health?

    PubMed

    Adams, Jean M; White, Martin

    2004-09-01

    Socio-economic differences in health appear to be universal but the precise pathways that link socio-economic status and health remain unclear. Differential exposure to specific risk and protective factors are often cited as, at least, partial explanations of socio-economic differences in health. However, risk factors are culturally specific and risk factor-specific models of socio-economic differences in health may be inadequate: as soon as prevailing risk factors change, so too must associated explanations of socio-economic differences in health. An alternative, risk factor-independent, model of socio-economic differences in health proposes that fundamental pathways to health and disease exist and that risk and protective factors act by feeding into these pathways. We propose that biological ageing is one such fundamental pathway to health, disease and, thus, socio-economic differences in health. Biological ageing is the progressive decline in physiological ability to meet demands, that occurs over time. It is due to the accumulation of damage at the cellular level and the rate of biological ageing is determined by both environmental and genetic factors. There is increasing evidence that many known disease risk and protective factors influence the rate of cellular damage accumulation and hence biological ageing and that the pathogenesis of some important diseases is related to biological ageing. We discuss these issues and hypothesize that socio-economic differences in health are partly a result of poor people ageing faster than rich people due to the unhealthy environments to which they are exposed.

  14. The need for and use of socio-economic scenarios for climate change analysis: A new approach based on shared socio-economic pathways

    SciTech Connect

    Kriegler, Elmar; O'Neill, Brian; Hallegatte, Stephane; Kram, Tom; Lempert, Rob; Moss, Richard H.; Wilbanks, Thomas

    2012-10-01

    A new set of socioeconomic scenarios (Shared Socioeconomic Pathways) are described that provide a set of global narratives and socio-economic pathways to pair with climate model scenarios developed using the new Representative Concentration Pathways.

  15. Pathways between Socioeconomic Status and Modifiable Risk Factors Among African American Smokers

    PubMed Central

    Kendzor, Darla E.; Businelle, Michael S.; Mazas, Carlos A.; Cofta-Woerpel, Ludmila M.; Reitzel, Lorraine R.; Vidrine, Jennifer Irvin; Li, Yisheng; Costello, Tracy J.; Cinciripini, Paul M.; Ahluwalia, Jasjit S.; Wetter, David W.

    2010-01-01

    Although socioeconomic status is a major contributing factor to health disparities, the mechanisms through which socioeconomic status influences health remain unclear. The purpose of the present study was to evaluate an a priori conceptual model of the pathways between socioeconomic status and modifiable health risk factors in a sample of 399 African Americans seeking smoking cessation treatment. A latent variable modeling approach was utilized to characterize the interrelationships among socioeconomic status, neighborhood disadvantage, social support, negative affect/perceived stress, and three specific modifiable risk factors (i.e., overweight/obesity, insufficient physical activity, at-risk drinking). Findings indicated that neighborhood disadvantage, social support, and negative affect/perceived stress function as pathways linking socioeconomic status and modifiable risk factors among African American smokers, and negative affect/perceived stress appears to play a key mediating role. Policy, community, and individual-level interventions may attenuate the impact of socioeconomic status on health by targeting intermediate psychosocial, environmental, and behavioral pathways. PMID:19757014

  16. Future air pollution in the Shared Socio-economic Pathways

    SciTech Connect

    Rao, Shilpa; Klimont, Zbigniew; Smith, Steven J.; Van Dingenen, Rita; Dentener, Frank; Bouwman, Lex; Riahi, Keywan; Amann, Markus; Bodirsky, Benjamin Leon; van Vuuren, Detlef P.; Reis, Lara Aleluia; Calvin, Katherine; Drouet, Laurent; Fricko, Oliver; Fujimori, Shinichiro; Gernaat, David; Havlik, Petr; Harmsen, Mathijs; Hasegawa, Tomoko; Heyes, Chris; Hilaire, Jérôme; Luderer, Gunnar; Masui, Toshihiko; Stehfest, Elke; Strefler, Jessica; van der Sluis, Sietske; Tavoni, Massimo

    2016-07-15

    Emissions of air pollutants such as sulfur and nitrogen oxides and particulates have significant health impacts as well as effects on natural and anthropogenic ecosystems. These same emissions also can change atmospheric chemistry and the planetary energy balance, thereby impacting global and regional climate. Long-term scenarios for air pollutant emissions are needed as inputs to global climate and chemistry models, and for analysis linking air pollutant impacts across sectors. In this paper we present methodology and results for air pollutant emissions in Shared Socioeconomic Pathways (SSP) scenarios. We first present a set of three air pollution narratives that describe high, central, and low pollution control ambitions over the 21st century. These narratives are then translated into quantitative guidance for use in integrated assessment models. We provide an overview of pollutant emission trajectories under the SSP scenarios. Pollutant emissions in these scenarios cover a wider range than the scenarios used in previous international climate model comparisons. Furthermore, the SSP scenarios provide the opportunity to access a more comprehensive range of future global and regional air quality outcomes.

  17. Future Air Pollution in the Shared Socio-Economic Pathways

    SciTech Connect

    Rao, Shilpa; Klimont, Zbigniew; Smith, Steven J.; van Dingenen, Rita; Dentener, Frank; Bouwman, Lex; Riahi, Keywan; Amann, Markus; Bodirsky, Benjamin; Van Vuuren, Detlef; Reis, Lara; Calvin, Katherine V.; Drouet, Laurent; Fricko, Oliver; Fujimori, Shinichiro; Gernaat, David; Havlik, Petr; Harmsen, Mathijs; Hasegawa, Tomoko; Heyes, Chris; Hilaire, Jerome; Luderer, Gunnar; Masui, Toshihiko; Stehfest, Eike; Strefler, Jessica; van der Sluis, Sietske; Tavoni, Massimo

    2017-01-01

    Emissions of air pollutants such as sulfur and nitrogen oxides and particulates have significant health impacts as well as effects on natural and anthropogenic ecosystems. These same emissions also can change atmospheric chemistry and the planetary energy balance, thereby impacting global and regional climate. Long-term scenarios for air pollutant emissions are needed as inputs to global climate and chemistry models, and for analysis linking air pollutant impacts across sectors. In this paper we present methodology and results for air pollutant emissions in Shared Socioeconomic Pathways (SSP) scenarios. We first present a set of three air pollution narratives that describe high, central, and low pollution control ambitions over the 21st century. These narratives are then translated into quantitative guidance for use in integrated assessment models. We provide an overview of pollutant emission trajectories under the SSP scenarios. Pollutant emissions in these scenarios cover a wider range than the scenarios used in previous international climate model comparisons. The SSP scenarios provide the opportunity to access a more comprehensive range of future global and regional air quality outcomes.

  18. Future air pollution in the Shared Socio-economic Pathways

    DOE PAGES

    Rao, Shilpa; Klimont, Zbigniew; Smith, Steven J.; ...

    2016-07-15

    Emissions of air pollutants such as sulfur and nitrogen oxides and particulates have significant health impacts as well as effects on natural and anthropogenic ecosystems. These same emissions also can change atmospheric chemistry and the planetary energy balance, thereby impacting global and regional climate. Long-term scenarios for air pollutant emissions are needed as inputs to global climate and chemistry models, and for analysis linking air pollutant impacts across sectors. In this paper we present methodology and results for air pollutant emissions in Shared Socioeconomic Pathways (SSP) scenarios. We first present a set of three air pollution narratives that describe high,more » central, and low pollution control ambitions over the 21st century. These narratives are then translated into quantitative guidance for use in integrated assessment models. We provide an overview of pollutant emission trajectories under the SSP scenarios. Pollutant emissions in these scenarios cover a wider range than the scenarios used in previous international climate model comparisons. Furthermore, the SSP scenarios provide the opportunity to access a more comprehensive range of future global and regional air quality outcomes.« less

  19. 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.

  20. Stress and resource pathways connecting early socioeconomic adversity to young adults' physical health risk.

    PubMed

    Wickrama, Kandauda K A S; Lee, Tae Kyoung; O'Neal, Catherine Walker; Kwon, Josephine A

    2015-05-01

    Although research has established the impact of early stress, including stressful life contexts, and early resources, such as educational attainment, on various adolescent health outcomes, previous research has not adequately investigated "integrative models" incorporating both stress and resource mediational pathways to explain how early socioeconomic adversity impacts physical health outcomes, particularly in early life stages. Data on early childhood/adolescent stress and socioeconomic resources as well as biomarkers indicating physical health status in young adulthood were collected from 11,798 respondents (54 % female) over a 13-year period from youth participating in the National Study of Adolescent Health (Add Health). Physical health risk in young adulthood was measured using a composite index of nine regulatory biomarkers of cardiovascular and metabolic systems. Heterogeneity in stress and socioeconomic resource pathways was assessed using latent class analysis to identify clusters, or classes, of stress and socioeconomic resource trajectories. The influence of early socioeconomic adversity on young adults' physical health risk, as measured by biomarkers, was estimated, and the role of stress and socioeconomic resource trajectory classes as linking mechanisms was assessed. There was evidence for the influence of early socioeconomic adversity on young adults' physical health risk directly and indirectly through stress and socioeconomic resource trajectory classes over the early life course. These findings suggest that health models should be broadened to incorporate both stress and resource experiences simultaneously. Furthermore, these findings have prevention and intervention implications, including the importance of early socioeconomic adversity and key intervention points for "turning" the trajectories of at-risk youth.

  1. How does childhood socioeconomic hardship affect reproductive strategy? Pathways of development

    PubMed Central

    Pearce, Mark S.; Sear, Rebecca

    2015-01-01

    Objectives In high‐income populations, evidence suggests that socioeconomic disadvantage early in life is correlated with reproductive strategy. Children growing up in unfavorable rearing environments tend to experience earlier sexual maturity and first births. Earlier first births may be associated with higher fertility, but links between socioeconomic disadvantage and larger family size have rarely been tested. The pathways through which early disadvantage influences reproduction are unknown. We test whether physiological factors link childhood adversity to age at first birth and total children. Methods Using data from the Newcastle Thousand Families Study, a 1947 British birth cohort, we developed path models to identify possible physiological traits linking childhood socioeconomic status, and poor housing standards, to two reproductive outcomes: age at first birth and total children. We explored birth weight, weight gain after birth, childhood illnesses, body mass index at age 9, age at menarche, and adult height as possible mediators. Results We found direct, negative effects of socioeconomic status (SES) and housing on age at first birth, and of housing on fertility. Although we found links between childhood disadvantage and menarche and height, neither of these were significantly correlated with either reproductive outcome. Age at first birth completely mediates the relationship between childhood adversity and total fertility, which we believe has not been empirically demonstrated before. Conclusions While there are some links between childhood adversity and child health, we find little evidence that physiological pathways, such as child health and growth, link early childhood adversity to reproductive outcomes in this relatively well‐nourished population. Am. J. Hum. Biol. 28:356–363, 2016. © 2015 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc. PMID:26407916

  2. How does childhood socioeconomic hardship affect reproductive strategy? Pathways of development.

    PubMed

    Sheppard, Paula; Pearce, Mark S; Sear, Rebecca

    2016-05-01

    In high-income populations, evidence suggests that socioeconomic disadvantage early in life is correlated with reproductive strategy. Children growing up in unfavorable rearing environments tend to experience earlier sexual maturity and first births. Earlier first births may be associated with higher fertility, but links between socioeconomic disadvantage and larger family size have rarely been tested. The pathways through which early disadvantage influences reproduction are unknown. We test whether physiological factors link childhood adversity to age at first birth and total children. Using data from the Newcastle Thousand Families Study, a 1947 British birth cohort, we developed path models to identify possible physiological traits linking childhood socioeconomic status, and poor housing standards, to two reproductive outcomes: age at first birth and total children. We explored birth weight, weight gain after birth, childhood illnesses, body mass index at age 9, age at menarche, and adult height as possible mediators. We found direct, negative effects of socioeconomic status (SES) and housing on age at first birth, and of housing on fertility. Although we found links between childhood disadvantage and menarche and height, neither of these were significantly correlated with either reproductive outcome. Age at first birth completely mediates the relationship between childhood adversity and total fertility, which we believe has not been empirically demonstrated before. While there are some links between childhood adversity and child health, we find little evidence that physiological pathways, such as child health and growth, link early childhood adversity to reproductive outcomes in this relatively well-nourished population. Am. J. Hum. Biol. 28:356-363, 2016. © 2015 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc. © 2015 The Authors American Journal of Human Biology Published by Wiley Periodicals, Inc.

  3. Family Socioeconomic Status and Academic Achievement among Korean Adolescents: Linking Mechanisms of Family Processes and Adolescents' Time Use

    ERIC Educational Resources Information Center

    Bae, Dayoung; Wickrama, K. A. S.

    2015-01-01

    This study examined pathways through which family socioeconomic status may influence adolescents' academic achievement. We focused on parental monitoring and adolescents' after-school time-use patterns as linking mechanisms. Participants were 441 twelve- to fourteen-year-old Korean adolescents who participated in the Korea Welfare Panel Study.…

  4. Family Socioeconomic Status and Academic Achievement among Korean Adolescents: Linking Mechanisms of Family Processes and Adolescents' Time Use

    ERIC Educational Resources Information Center

    Bae, Dayoung; Wickrama, K. A. S.

    2015-01-01

    This study examined pathways through which family socioeconomic status may influence adolescents' academic achievement. We focused on parental monitoring and adolescents' after-school time-use patterns as linking mechanisms. Participants were 441 twelve- to fourteen-year-old Korean adolescents who participated in the Korea Welfare Panel Study.…

  5. Racial and Socioeconomic Differences Manifest in Process Measure Adherence for Enhanced Recovery After Surgery Pathway.

    PubMed

    Leeds, Ira L; Alimi, Yewande; Hobson, Deborah R; Efron, Jonathan E; Wick, Elizabeth C; Haut, Elliott R; Johnston, Fabian M

    2017-10-01

    quality improvement purposes. Differences in outcomes by race and socioeconomic status did not arise following implementation of an enhanced recovery pathway. Differences in process measures by population subgroups highlight differences in care that require further investigation. See Video Abstract at http://links.lww.com/DCR/A386.

  6. Antisocial and human capital pathways to socioeconomic exclusion: A 42-year prospective study.

    PubMed

    Savolainen, Jukka; Mason, W Alex; Lyyra, Anna-Liisa; Pulkkinen, Lea; Kokko, Katja

    2017-08-01

    Nordic welfare states have been very successful at reducing poverty and inequality among their citizens. However, the presence of a strong social safety net in these countries has not solved the problem of socioeconomic exclusion, manifesting in such outcomes as chronic unemployment and welfare dependency. In an effort to understand this phenomenon, the current study builds on the assumption that psychological risk factors emerge as important determinants of socioeconomic disadvantage in an environment where ascribed characteristics have less impact on educational and occupational attainment. Using data from Finland, this research examined a life course model linking childhood differences in cognitive skills and antisocial propensity to midlife socioeconomic exclusion. The Jyväskylä Longitudinal Study of Personality and Social Development (n = 369) follows individuals from age 8 (b. 1959) through age 50. Evidence from a structural equation model found support for key theoretical predictions: (a) human capital and antisocial pathways contributed independently to socioeconomic exclusion; (b) the effect of childhood psychological factors on midlife socioeconomic exclusion was mediated by adolescent and adult life course outcomes; and (c) the human capital and antisocial domains intersected such that antisocial children struggled in school as adolescents, which contributed to their persistence in crime and deviance in adulthood-a behavioral pattern that directly increased the risk of socioeconomic exclusion in midlife. In short, the findings suggest that early emerging differences in cognitive ability and antisociality set in motion a process of negative life outcomes with enduring consequences for socioeconomic well-being. The results are discussed from the perspective of sociohistorical context and public policy. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  7. Data on fossil fuel availability for Shared Socioeconomic Pathways.

    PubMed

    Bauer, Nico; Hilaire, Jérôme; Brecha, Robert J; Edmonds, Jae; Jiang, Kejun; Kriegler, Elmar; Rogner, Hans-Holger; Sferra, Fabio

    2017-02-01

    The data files contain the assumptions and results for the construction of cumulative availability curves for coal, oil and gas for the five Shared Socioeconomic Pathways. The files include the maximum availability (also known as cumulative extraction cost curves) and the assumptions that are applied to construct the SSPs. The data is differentiated into twenty regions. The resulting cumulative availability curves are plotted and the aggregate data as well as cumulative availability curves are compared across SSPs. The methodology, the data sources and the assumptions are documented in a related article (N. Bauer, J. Hilaire, R.J. Brecha, J. Edmonds, K. Jiang, E. Kriegler, H.-H. Rogner, F. Sferra, 2016) [1] under DOI: http://dx.doi.org/10.1016/j.energy.2016.05.088.

  8. How Many Pathways Underlie Socioeconomic Differences in the Development of Cognition and Achievement?

    PubMed

    Tucker-Drob, Elliot M

    2013-06-01

    Children whose parents have higher education enjoy greater age-linked gains in cognitive abilities and academic achievement. Different researchers have typically focused on different outcomes, and the extent to which parental education relates to multiple child outcomes via a single developmental pathway has received little empirical attention. This issue was examined by applying common factor structural equation models to a large (N = 4,810) nationally representative sample of kindergarten through 12(th) grade children, who were measured on 6 distinct cognitive abilities and 5 distinct forms of knowledge and academic achievement. Results indicated that a single pathway accounted for the relations between parental education and age differences in children's cognitive abilities. However, additional unique pathways were necessary to account for the relations between parental education and age differences in academic knowledge and mathematics. These results suggest that while socioeconomic differences are largely manifest in global aspects of cognitive development, they have incremental relations with some forms of academic achievement.

  9. Multiple Pathways Linking Racism to Health Outcomes

    PubMed Central

    Harrell, Camara Jules P.; Burford, Tanisha I.; Cage, Brandi N.; Nelson, Travette McNair; Shearon, Sheronda; Thompson, Adrian; Green, Steven

    2012-01-01

    This commentary discusses advances in the conceptual understanding of racism and selected research findings in the social neurosciences. The traditional stress and coping model holds that racism constitutes a source of aversive experiences that, when perceived by the individual, eventually lead to poor health outcomes. Current evidence points to additional psychophysiological pathways linking facets of racist environments with physiological reactions that contribute to disease. The alternative pathways emphasize prenatal experiences, subcortical emotional neural circuits, conscious and preconscious emotion regulation, perseverative cognitions, and negative affective states stemming from racist cognitive schemata. Recognition of these pathways challenges change agents to use an array of cognitive and self-controlling interventions in mitigating racism’s impact. Additionally, it charges policy makers to develop strategies that eliminate deep-seated structural aspects of racism in society. PMID:22518195

  10. kpath: integration of metabolic pathway linked data

    PubMed Central

    Navas-Delgado, Ismael; García-Godoy, María Jesús; López-Camacho, Esteban; Rybinski, Maciej; Reyes-Palomares, Armando; Medina, Miguel Ángel; Aldana-Montes, José F.

    2015-01-01

    In the last few years, the Life Sciences domain has experienced a rapid growth in the amount of available biological databases. The heterogeneity of these databases makes data integration a challenging issue. Some integration challenges are locating resources, relationships, data formats, synonyms or ambiguity. The Linked Data approach partially solves the heterogeneity problems by introducing a uniform data representation model. Linked Data refers to a set of best practices for publishing and connecting structured data on the Web. This article introduces kpath, a database that integrates information related to metabolic pathways. kpath also provides a navigational interface that enables not only the browsing, but also the deep use of the integrated data to build metabolic networks based on existing disperse knowledge. This user interface has been used to showcase relationships that can be inferred from the information available in several public databases. Database URL: The public Linked Data repository can be queried at http://sparql.kpath.khaos.uma.es using the graph URI “www.khaos.uma.es/metabolic-pathways-app”. The GUI providing navigational access to kpath database is available at http://browser.kpath.khaos.uma.es. PMID:26055101

  11. Pathways from childhood abuse and other adversities to adult health risks: The role of adult socioeconomic conditions.

    PubMed

    Font, Sarah A; Maguire-Jack, Kathryn

    2016-01-01

    Adverse childhood experiences (ACEs), including child abuse, have been linked with poor health outcomes in adulthood. The mechanisms that explain these relations are less understood. This study assesses whether associations of ACEs and health risks are mediated by adult socioeconomic conditions, and whether these pathways are different for maltreatment than for other types of adversities. Using the Behavioral Risk Factor Surveillance System 2012 survey (N=29,229), we employ structural equation modeling to (1) estimate associations of the number and type of ACEs with five health risks-depression, obesity, tobacco use, binge drinking, and self-reported sub-optimal health; and (2) assess whether adult socioeconomic conditions-marriage, divorce and separation, educational attainment, income and insurance status-mediate those associations. Findings suggest both direct and indirect associations between ACEs and health risks. At high numbers of ACEs, 15-20% of the association between number of ACEs and adult health risks was attributable to socioeconomic conditions. Associations of three ACEs (exposure to domestic violence, parental divorce, and residing with a person who was incarcerated) with health risks were nearly entirely explained by socioeconomic conditions in adulthood. However, child physical, emotional, and sexual abuse were significantly associated with several adult health risks, beyond the effects of other adversities, and socioeconomic conditions explained only a small portion of these associations. These findings suggest that the pathways to poor adult health differ by types of ACEs, and that childhood abuse is more likely than other adversities to have a direct impact.

  12. Pathways from Childhood Abuse and Other Adversities to Adult Health Risks: The Role of Adult Socioeconomic Conditions

    PubMed Central

    Maguire-Jack, Kathryn

    2015-01-01

    Adverse Childhood Experiences (ACEs), including child abuse, have been linked with poor health outcomes in adulthood. The mechanisms that explain these relations are less understood. This study assesses whether associations of ACEs and health risks are mediated by adult socioeconomic conditions, and whether these pathways are different for maltreatment than for other types of adversities. Using the Behavioral Risk Factor Surveillance System 2012 survey (N=29,229), we employ structural equation modeling to (1) estimate associations of the number and type of ACEs with five health risks – depression, obesity, tobacco use, binge drinking, and self-reported sub-optimal health; and (2) assess whether adult socioeconomic conditions— marriage, divorce and separation, educational attainment, income and insurance status—mediate those associations. Findings suggest both direct and indirect associations between ACEs and health risks. At high numbers of ACEs, 15–20% of the association between number of ACEs and adult health risks was attributable to socioeconomic conditions. Associations of three ACEs (exposure to domestic violence, parental divorce, and residing with a person who was incarcerated) with health risks were nearly entirely explained by socioeconomic conditions in adulthood. However, child physical, emotional and sexual abuse were significantly associated with several adult health risks, beyond the effects of other adversities, and socioeconomic conditions explained only a small portion of these associations. These findings suggest that the pathways to poor adult health differ by types of ACEs, and that childhood abuse is more likely than other adversities to have a direct impact. PMID:26059537

  13. kpath: integration of metabolic pathway linked data.

    PubMed

    Navas-Delgado, Ismael; García-Godoy, María Jesús; López-Camacho, Esteban; Rybinski, Maciej; Reyes-Palomares, Armando; Medina, Miguel Ángel; Aldana-Montes, José F

    2015-01-01

    In the last few years, the Life Sciences domain has experienced a rapid growth in the amount of available biological databases. The heterogeneity of these databases makes data integration a challenging issue. Some integration challenges are locating resources, relationships, data formats, synonyms or ambiguity. The Linked Data approach partially solves the heterogeneity problems by introducing a uniform data representation model. Linked Data refers to a set of best practices for publishing and connecting structured data on the Web. This article introduces kpath, a database that integrates information related to metabolic pathways. kpath also provides a navigational interface that enables not only the browsing, but also the deep use of the integrated data to build metabolic networks based on existing disperse knowledge. This user interface has been used to showcase relationships that can be inferred from the information available in several public databases.

  14. How Many Pathways Underlie Socioeconomic Differences in the Development of Cognition and Achievement?

    PubMed Central

    Tucker-Drob, Elliot M.

    2013-01-01

    Children whose parents have higher education enjoy greater age-linked gains in cognitive abilities and academic achievement. Different researchers have typically focused on different outcomes, and the extent to which parental education relates to multiple child outcomes via a single developmental pathway has received little empirical attention. This issue was examined by applying common factor structural equation models to a large (N = 4,810) nationally representative sample of kindergarten through 12th grade children, who were measured on 6 distinct cognitive abilities and 5 distinct forms of knowledge and academic achievement. Results indicated that a single pathway accounted for the relations between parental education and age differences in children’s cognitive abilities. However, additional unique pathways were necessary to account for the relations between parental education and age differences in academic knowledge and mathematics. These results suggest that while socioeconomic differences are largely manifest in global aspects of cognitive development, they have incremental relations with some forms of academic achievement. PMID:23710118

  15. Water scarcity under various socio-economic pathways and its potential effects on food production in the Yellow River basin

    NASA Astrophysics Data System (ADS)

    Yin, Yuanyuan; Tang, Qiuhong; Liu, Xingcai; Zhang, Xuejun

    2017-02-01

    Increasing population and socio-economic development have put great pressure on water resources of the Yellow River (YR) basin. The anticipated climate and socio-economic changes may further increase water stress. Many studies have investigated the changes in renewable water resources under various climate change scenarios, but few have considered the joint pressure from both climate change and socio-economic development. In this study, we assess water scarcity under various socio-economic pathways with emphasis on the impact of water scarcity on food production. The water demands in the 21st century are estimated based on the newly developed shared socio-economic pathways (SSPs) and renewable water supply is estimated using the climate projections under the Representative Concentration Pathway (RCP) 8.5 scenario. The assessment predicts that the renewable water resources would decrease slightly then increase. The domestic and industrial water withdrawals are projected to increase in the next a few decades and then remain at the high level or decrease slightly during the 21st century. The increase in water withdrawals will put the middle and lower reaches in a condition of severe water scarcity beginning in the next a few decades. If 40 % of the renewable water resources were used to sustain ecosystems, a portion of irrigated land would have to be converted to rain-fed agriculture, which would lead to a 2-11 % reduction in food production. This study highlights the links between water, food and ecosystems in a changing environment and suggests that trade-offs should be considered when developing regional adaptation strategies.

  16. Cascading events in linked ecological and socioeconomic systems

    USGS Publications Warehouse

    Peters, Debra P. C.; Sala, O.E.; Allen, C.D.; Covich, A.; Brunson, M.

    2007-01-01

    Cascading events that start at small spatial scales and propagate non-linearly through time to influence larger areas often have major impacts on ecosystem goods and services. Events such as wildfires and hurricanes are increasing in frequency and magnitude as systems become more connected through globalization processes. We need to improve our understanding of these events in order to predict their occurrence, minimize potential impacts, and allow for strategic recovery. Here, we synthesize information about cascading events in systems located throughout the Americas. We discuss a variety of examples of cascading events that share a common feature: they are often driven by linked ecological and human processes across scales. In this era of globalization, we recommend studies that explicitly examine connections across scales and examine the role of connectivity among non-contiguous as well as contiguous areas. ?? The Ecological Society of America.

  17. Socioeconomic Risk Moderates the Link between Household Chaos and Maternal Executive Function

    PubMed Central

    Deater-Deckard, Kirby; Chen, Nan; Wang, Zhe; Bell, Martha Ann

    2012-01-01

    We examined the link between household chaos (i.e., noise, clutter, disarray, lack of routines) and maternal executive function (i.e., effortful regulation of attention and memory), and whether it varied as a function of socioeconomic risk (i.e., single parenthood, lower mother and father educational attainment, housing situation, and father unemployment). We hypothesized that: 1) higher levels of household chaos would be linked with poorer maternal executive function, even when controlling for other measures of cognitive functioning (e.g., verbal ability), and 2) this link would be strongest in the most socioeconomically distressed or lowest-socioeconomic status households. The diverse sample included 153 mothers from urban and rural areas who completed a questionnaire and a battery of cognitive executive function tasks and a verbal ability task in the laboratory. Results were mixed for hypothesis 1, and consistent with hypothesis 2. Two-thirds of the variance overlapped between household chaos and maternal executive function, but only in families with high levels of socioeconomic risk. This pattern was not found for chaos and maternal verbal ability, suggesting that the potentially deleterious effects of household chaos may be specific to maternal executive function. The findings implicate household chaos as a powerful statistical predictor of maternal executive function in socioeconomically distressed contexts. PMID:22563703

  18. Gender differences in the link between childhood socioeconomic conditions and heart attack risk in adulthood.

    PubMed

    Hamil-Luker, Jenifer; O'Rand, Angela M

    2007-02-01

    A growing body of evidence shows that childhood socioeconomic status (SES) is predictive of disease risk in later life, with those from the most disadvantaged backgrounds more likely to experience poor adult-health outcomes. Most of these studies, however are based on middle-aged male populations and pay insufficient attention to the pathways between childhood risks and specific adult disorders. This article examines gender differences in the link between childhood SES and heart attack risk trajectories and the mechanisms by which early environments affect future disease risk. By using methods that model both latent and path-specific influences, we identify heterogeneity in early life conditions and human, social, and health capital in adulthood that contribute to diverse heart attack risk trajectories between and among men and women as they age into their 60s and 70s. We find that key risk factors for heart attack operate differently for men and women. For men, childhood SES does not differentiate those at low, increasing, and high risk for heart attack. In contrast, women who grew up without a father and/or under adverse economic conditions are the most likely to experience elevated risk for heart attack, even after we adjust for the unequal distribution of working and living conditions, social relationships, access to health care, and adult lifestyle behaviors that influence health outcomes.

  19. Uncertainty in Socioeconomic Pathways and Their Implications for Climate Forcing and Analysis—the Shared Socioeconomic Scenarios (SSPs)

    NASA Astrophysics Data System (ADS)

    Edmonds, J.

    2014-12-01

    The Representative Concentration Pathways (RCPs; Moss, et al., 2010; van Vuuren, et al., 2011) were designed to span the range of anthropogenic climate forcing that existed in the literature. While these scenarios serve to reflect uncertainty in the domain of climate forcing, they are far less useful in exploring the range of potential future socioeconomic developments that might be experienced, and which might form the background from which climate forcing might emerge and against which climate impacts and adaptation might be experienced. A set of "Shared Socioeconomic Pathways" (SSPs) have been proposed, Ebi, et al., (2015), to address this deficiency. This architecture is being implemented in quantitative scenarios of human energy, economic, and land systems by researchers. This presentation provides an update on community quantitative implementation of the SSPs. References: Ebi, Kristie L., Stephane Hallegatte, Tom Kram, Nigel W. Arnell, Timothy R. Carter, Jae Edmonds, Elmar Kriegler, et al., A new scenario framework for climate change research: background, process, and future directions, Climatic Change (2014) 122:363-372. DOI 10.1007/s10584-013-0912-3 Moss, Richard H., Jae A. Edmonds, Kathy A. Hibbard, Martin R. Manning, Steven K. Rose, Detlef P. Van Vuuren, Timothy R. Carter et al. "The next generation of scenarios for climate change research and assessment." Nature 463, no. 7282 (2010): 747-756. Van Vuuren, Detlef P., Jae Edmonds, Mikiko Kainuma, Keywan Riahi, Allison Thomson, Kathy Hibbard, George C. Hurtt et al. "The representative concentration pathways: an overview." Climatic Change 109 (2011): 5-31.

  20. Enhancing the Quantitative Representation of Socioeconomic Conditions in the Shared Socio-economic Pathways (SSPs) using the International Futures Model

    NASA Astrophysics Data System (ADS)

    Rothman, D. S.; Siraj, A.; Hughes, B.

    2013-12-01

    The international research community is currently in the process of developing new scenarios for climate change research. One component of these scenarios are the Shared Socio-economic Pathways (SSPs), which describe a set of possible future socioeconomic conditions. These are presented in narrative storylines with associated quantitative drivers. The core quantitative drivers include total population, average GDP per capita, educational attainment, and urbanization at the global, regional, and national levels. At the same time there have been calls, particularly by the IAV community, for the SSPs to include additional quantitative information on other key social factors, such as income inequality, governance, health, and access to key infrastructures, which are discussed in the narratives. The International Futures system (IFs), based at the Pardee Center at the University of Denver, is able to provide forecasts of many of these indicators. IFs cannot use the SSP drivers as exogenous inputs, but we are able to create development pathways that closely reproduce the core quantitative drivers defined by the different SSPs, as well as incorporating assumptions on other key driving factors described in the qualitative narratives. In this paper, we present forecasts for additional quantitative indicators based upon the implementation of the SSP development pathways in IFs. These results will be of value to many researchers.

  1. Pathways in heart failure disease management across socioeconomic spectra.

    PubMed

    Hebert, Kathy; Gogichaishvili, Ilia; Gopie, Stephanie; Arcement, Lee

    2011-12-01

    Caring for heart failure patients with a low socioeconomic status presents a unique set of challenges for health care providers. Heart failure disease management programs can integrate the use of teaching DVDs to overcome deficiencies in health literacy and take advantage of the Wal-Mart/Target $4 dollar medication program to provide life-saving medical therapy. In addition, open discussions with the patient and family regarding the costs of medications and the reality of what they can afford to pay monthly on a long term basis can guide the physician to prescribing medications by prioritizing use with a focus on evidence-based data for the medications with the highest mortality reduction. Finally, connecting inpatient visits to outpatient visits through the use of electronic medical records systems can facilitate avoidance of unnecessary repeat lab and diagnostic testing.

  2. Certification Criteria for Linked Learning Pathways

    ERIC Educational Resources Information Center

    ConnectEd: The California Center for College and Career, 2010

    2010-01-01

    Pathways offer a promising strategy for transforming high schools and improving student outcomes. However, to achieve these desired results, pathways must be of high quality. To guide sites in planning and implementing such pathways, a design team of experts developed the criteria outlined in this document. Sites can choose to go through a…

  3. A multi-scale framework to link remotely sensed metrics with socioeconomic data

    NASA Astrophysics Data System (ADS)

    Watmough, Gary; Svenning, Jens-Christian; Palm, Cheryl; Sullivan, Clare; Danylo, Olha; McCallum, Ian

    2017-04-01

    There is increasing interest in the use of remotely sensed satellite data for estimating human poverty as it can bridge data gaps that prevent fine scale monitoring of development goals across large areas. The ways in which metrics derived from satellite imagery are linked with socioeconomic data are crucial for accurate estimation of poverty. Yet, to date, approaches in the literature linking satellite metrics with socioeconomic data are poorly characterized. Typically, approaches use a GIS approach such as circular buffer zones around a village or household or an administrative boundary such as a district or census enumeration area. These polygons are then used to extract environmental data from satellite imagery and related to the socioeconomic data in statistical analyses. The use of a single polygon to link environment and socioeconomic data is inappropriate in coupled human-natural systems as processes operate over multiple scales. Human interactions with the environment occur at multiple levels from individual (household) access to agricultural plots adjacent to homes, to communal access to common pool resources (CPR) such as forests at the village level. Here, we present a multi-scale framework that explicitly considers how people use the landscape. The framework is presented along with a case study example in Kenya. The multi-scale approach could enhance the modelling of human-environment interactions which will have important consequences for monitoring the sustainable development goals for human livelihoods and biodiversity conservation.

  4. Extending the Shared Socioeconomic Pathways for sub-national impacts, adaptation, and vulnerability studies

    SciTech Connect

    Absar, Syeda Mariya; Preston, Benjamin L.

    2015-05-25

    The exploration of alternative socioeconomic futures is an important aspect of understanding the potential consequences of climate change. While socioeconomic scenarios are common and, at times essential, tools for the impact, adaptation and vulnerability and integrated assessment modeling research communities, their approaches to scenario development have historically been quite distinct. However, increasing convergence of impact, adaptation and vulnerability and integrated assessment modeling research in terms of scales of analysis suggests there may be value in the development of a common framework for socioeconomic scenarios. The Shared Socioeconomic Pathways represents an opportunity for the development of such a common framework. However, the scales at which these global storylines have been developed are largely incommensurate with the sub-national scales at which impact, adaptation and vulnerability, and increasingly integrated assessment modeling, studies are conducted. Our objective for this study was to develop sub-national and sectoral extensions of the global SSP storylines in order to identify future socioeconomic challenges for adaptation for the U.S. Southeast. A set of nested qualitative socioeconomic storyline elements, integrated storylines, and accompanying quantitative indicators were developed through an application of the Factor-Actor-Sector framework. Finally, in addition to revealing challenges and opportunities associated with the use of the SSPs as a basis for more refined scenario development, this study generated sub-national storyline elements and storylines that can subsequently be used to explore the implications of alternative subnational socioeconomic futures for the assessment of climate change impacts and adaptation.

  5. Socioeconomic Status and the Health of Youth: A Multilevel, Multidomain Approach to Conceptualizing Pathways

    ERIC Educational Resources Information Center

    Schreier, Hannah M. C.; Chen, Edith

    2013-01-01

    Previous research has clearly established associations between low socioeconomic status (SES) and poor youth physical health outcomes. This article provides an overview of the main pathways through which low SES environments come to influence youth health. We focus on 2 prevalent chronic health problems in youth today, asthma and obesity. We…

  6. Socio-Economic Background, Senior Secondary Mathematics, and Post-Secondary Pathways

    ERIC Educational Resources Information Center

    Yeoh, Eng; Leigh-Lancaster, David

    2010-01-01

    The relationship between socio-economic background and completion of senior secondary mathematics study leading to various post-schooling pathways has been an area of keen interest to researchers, school systems and policy makers for some time. This paper briefly considers some aspects of this relationship using recent Victorian data relating to…

  7. Socioeconomic Status and the Health of Youth: A Multilevel, Multidomain Approach to Conceptualizing Pathways

    ERIC Educational Resources Information Center

    Schreier, Hannah M. C.; Chen, Edith

    2013-01-01

    Previous research has clearly established associations between low socioeconomic status (SES) and poor youth physical health outcomes. This article provides an overview of the main pathways through which low SES environments come to influence youth health. We focus on 2 prevalent chronic health problems in youth today, asthma and obesity. We…

  8. Rubric for Linked Learning Pathway Certification

    ERIC Educational Resources Information Center

    LaPlante, Arlene; Stearns, Roman

    2010-01-01

    This rubric was created to help pathway teams as they work together to develop and improve a comprehensive program of study. Specifically, the rubric can serve as a tool for: (1) Visioning; (2) Self-assessment; (3) Planning; and (4) Quality review. ConnectEd designed this rubric to be used in coordination with the Certification Criteria for Linked…

  9. Rubric for Linked Learning Pathway Certification

    ERIC Educational Resources Information Center

    LaPlante, Arlene; Stearns, Roman

    2010-01-01

    This rubric was created to help pathway teams as they work together to develop and improve a comprehensive program of study. Specifically, the rubric can serve as a tool for: (1) Visioning; (2) Self-assessment; (3) Planning; and (4) Quality review. ConnectEd designed this rubric to be used in coordination with the Certification Criteria for Linked…

  10. Extending the Shared Socioeconomic Pathways for sub-national impacts, adaptation, and vulnerability studies

    DOE PAGES

    Absar, Syeda Mariya; Preston, Benjamin L.

    2015-05-25

    The exploration of alternative socioeconomic futures is an important aspect of understanding the potential consequences of climate change. While socioeconomic scenarios are common and, at times essential, tools for the impact, adaptation and vulnerability and integrated assessment modeling research communities, their approaches to scenario development have historically been quite distinct. However, increasing convergence of impact, adaptation and vulnerability and integrated assessment modeling research in terms of scales of analysis suggests there may be value in the development of a common framework for socioeconomic scenarios. The Shared Socioeconomic Pathways represents an opportunity for the development of such a common framework. However,more » the scales at which these global storylines have been developed are largely incommensurate with the sub-national scales at which impact, adaptation and vulnerability, and increasingly integrated assessment modeling, studies are conducted. Our objective for this study was to develop sub-national and sectoral extensions of the global SSP storylines in order to identify future socioeconomic challenges for adaptation for the U.S. Southeast. A set of nested qualitative socioeconomic storyline elements, integrated storylines, and accompanying quantitative indicators were developed through an application of the Factor-Actor-Sector framework. Finally, in addition to revealing challenges and opportunities associated with the use of the SSPs as a basis for more refined scenario development, this study generated sub-national storyline elements and storylines that can subsequently be used to explore the implications of alternative subnational socioeconomic futures for the assessment of climate change impacts and adaptation.« less

  11. The Pathways Between Socioeconomic Status and Adolescent Outcomes: A Systematic Review.

    PubMed

    Devenish, Bethany; Hooley, Merrilyn; Mellor, David

    2017-03-01

    Socioeconomic status (SES) is a significant risk factor for negative adolescent development outcomes. Identifying the pathways between SES and these outcomes may inform interventions for adolescents from this demographic. We conducted a systematic literature review of eight databases for studies investigating pathways between SES and adolescent psychosocial outcomes. A total of 59 articles met inclusion criteria. Significant risk factors identified include economic stress, chaos in the home, and violence in the community. These risk factors appear to be mediated through parent depression, conflict between parents, parenting practices, and adolescent resilience. Interventions focusing on the identified risk factors are recommended.

  12. PIKfyve Regulation of Endosome-Linked Pathways

    PubMed Central

    de Lartigue, Jane; Polson, Hannah; Feldman, Morri; Shokat, Kevan; Tooze, Sharon A; Urbé, Sylvie; Clague, Michael J

    2009-01-01

    The phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of PtdIns(3,5)P2, that has been implicated in various trafficking events associated with the endocytic pathway. We have now directly compared the effects of siRNA-mediated knockdown of PIKfyve in HeLa cells with a specific pharmacological inhibitor of enzyme activity. Both approaches induce changes in the distribution of CI-M6PR and trans-Golgi network (TGN)-46 proteins, which cycles between endosomes and TGN, leading to their accumulation in dispersed punctae, whilst the TGN marker golgin-245 retains a perinuclear disposition. Trafficking of CD8-CI-M6PR (retromer-dependent) and CD8-Furin (retromer-independent) chimeras from the cell surface to the TGN is delayed following drug administration, as is the transport of the Shiga toxin B-subunit. siRNA knockdown of PIKfyve produced no defect in epidermal growth factor receptor (EGFR) degradation, unless combined with knockdown of its activator molecule Vac14, suggesting that a low threshold of PtdIns(3,5)P2 is necessary and sufficient for this pathway. Accordingly pharmacological inhibition of PIKfyve results in a profound block to the lysosomal degradation of activated epidermal growth factor (EGF) and Met receptors. Immunofluorescence revealed EGF receptors to be trapped in the interior of a swollen endosomal compartment. In cells starved of amino acids, PIKfyve inhibition leads to the accumulation of the lipidated form of GFP-LC3, a marker of autophagosomal structures, which can be visualized as fluorescent punctae. We suggest that PIKfyve inhibition may render the late endosome/lysosome compartment refractory to fusion with both autophagosomes and with EGFR-containing multivesicular bodies. PMID:19582903

  13. A hybrid framework for assessing socioeconomic drought: Linking climate variability, local resilience, and demand

    NASA Astrophysics Data System (ADS)

    Mehran, Ali; Mazdiyasni, Omid; AghaKouchak, Amir

    2015-08-01

    Socioeconomic drought broadly refers to conditions whereby the water supply cannot satisfy the demand. Most previous studies describe droughts based on large-scale meteorological/hydrologic conditions, ignoring the demand and local resilience to cope with climate variability. Reservoirs provide resilience against climatic extremes and play a key role in water supply and demand management. Here we outline a unique multivariate approach as a measure of socioeconomic drought, termed Multivariate Standardized Reliability and Resilience Index (MSRRI). The model combines information on the inflow and reservoir storage relative to the demand. MSRRI combines (I) a "top-down" approach that focuses on processes/phenomena that cannot be simply controlled or altered by decision makers, such as climate change and variability, and (II) a "bottom-up" methodology that represents the local resilience and societal capacity to respond or adapt to droughts. MSRRI is based on a nonparametric multivariate distribution function that links inflow-demand reliability indicator to water storage resilience indicator. These indicators are used to assess socioeconomic drought during the Australian Millennium drought (1998-2010) and the 2011-2014 California drought. The results show that MSRRI is superior to univariate indices because it captures both early onset and persistence of water stress over time. The suggested framework can be applied to both individual reservoirs and a group of reservoirs in a region, and it is consistent with the currently available standardized drought indicators. MSRRI provides complementary information on socioeconomic drought development and recovery based on reservoir storage and demand that cannot be achieved from the commonly used drought indicators.

  14. Pathways between Socioeconomic Disadvantage and Childhood Growth in the Scottish Longitudinal Study, 1991–2001

    PubMed Central

    Silverwood, Richard J.; Williamson, Lee; Grundy, Emily M.; De Stavola, Bianca L.

    2016-01-01

    Socioeconomically disadvantaged children are more likely to be of shorter stature and overweight, leading to greater risk of obesity in adulthood. Disentangling the mediatory pathways between socioeconomic disadvantage and childhood size may help in the development of appropriate policies aimed at reducing these health inequalities. We aimed to elucidate the putative mediatory role of birth weight using a representative sample of the Scottish population born 1991–2001 (n = 16,628). Estimated height and overweight/obesity at age 4.5 years were related to three measures of socioeconomic disadvantage (mother’s education, Scottish Index of Multiple Deprivation, synthetic weekly income). Mediation was examined using two approaches: a ‘traditional’ mediation analysis and a counterfactual-based mediation analysis. Both analyses identified a negative effect of each measure of socioeconomic disadvantage on height, mediated to some extent by birth weight, and a positive ‘direct effect’ of mother’s education and Scottish Index of Multiple Deprivation on overweight/obesity, which was partly counterbalanced by a negative ‘indirect effect’. The extent of mediation estimated when adopting the traditional approach was greater than when adopting the counterfactual-based approach because of inappropriate handling of intermediate confounding in the former. Our findings suggest that higher birth weight in more disadvantaged groups is associated with reduced social inequalities in height but also with increased inequalities in overweight/obesity. PMID:27736963

  15. Pathways between Socioeconomic Disadvantage and Childhood Growth in the Scottish Longitudinal Study, 1991-2001.

    PubMed

    Silverwood, Richard J; Williamson, Lee; Grundy, Emily M; De Stavola, Bianca L

    2016-01-01

    Socioeconomically disadvantaged children are more likely to be of shorter stature and overweight, leading to greater risk of obesity in adulthood. Disentangling the mediatory pathways between socioeconomic disadvantage and childhood size may help in the development of appropriate policies aimed at reducing these health inequalities. We aimed to elucidate the putative mediatory role of birth weight using a representative sample of the Scottish population born 1991-2001 (n = 16,628). Estimated height and overweight/obesity at age 4.5 years were related to three measures of socioeconomic disadvantage (mother's education, Scottish Index of Multiple Deprivation, synthetic weekly income). Mediation was examined using two approaches: a 'traditional' mediation analysis and a counterfactual-based mediation analysis. Both analyses identified a negative effect of each measure of socioeconomic disadvantage on height, mediated to some extent by birth weight, and a positive 'direct effect' of mother's education and Scottish Index of Multiple Deprivation on overweight/obesity, which was partly counterbalanced by a negative 'indirect effect'. The extent of mediation estimated when adopting the traditional approach was greater than when adopting the counterfactual-based approach because of inappropriate handling of intermediate confounding in the former. Our findings suggest that higher birth weight in more disadvantaged groups is associated with reduced social inequalities in height but also with increased inequalities in overweight/obesity.

  16. A systematic review of the relationships between social capital and socioeconomic inequalities in health: a contribution to understanding the psychosocial pathway of health inequalities

    PubMed Central

    2013-01-01

    Introduction Recent research on health inequalities moves beyond illustrating the importance of psychosocial factors for health to a more in-depth study of the specific psychosocial pathways involved. Social capital is a concept that captures both a buffer function of the social environment on health, as well as potential negative effects arising from social inequality and exclusion. This systematic review assesses the current evidence, and identifies gaps in knowledge, on the associations and interactions between social capital and socioeconomic inequalities in health. Methods Through this systematic review we identified studies on the interactions between social capital and socioeconomic inequalities in health published before July 2012. Results The literature search resulted in 618 studies after removal of duplicates, of which 60 studies were eligible for analysis. Self-reported measures of health were most frequently used, together with different bonding, bridging and linking components of social capital. A large majority, 56 studies, confirmed a correlation between social capital and socioeconomic inequalities in health. Twelve studies reported that social capital might buffer negative health effects of low socioeconomic status and five studies concluded that social capital has a stronger positive effect on health for people with a lower socioeconomic status. Conclusions There is evidence for both a buffer effect and a dependency effect of social capital on socioeconomic inequalities in health, although the studies that assess these interactions are limited in number. More evidence is needed, as identified hypotheses have implications for community action and for action on the structural causes of social inequalities. PMID:23870068

  17. Accelerated ageing and renal dysfunction links lower socioeconomic status and dietary phosphate intake

    PubMed Central

    McClelland, Ruth; Christensen, Kelly; Mohammed, Suhaib; McGuinness, Dagmara; Cooney, Josephine; Bakshi, Andisheh; Demou, Evangelia; MacDonald, Ewan; Caslake, Muriel; Stenvinkel, Peter; Shiels, Paul G.

    2016-01-01

    Background We have sought to explore the impact of dietary Pi intake on human age related health in the pSoBid cohort (n=666) to explain the disparity between health and deprivation status in this cohort. As hyperphosphataemia is a driver of accelerated ageing in rodent models of progeria we tested whether variation in Pi levels in man associate with measures of biological ageing and health. Results We observed significant relationships between serum Pi levels and markers of biological age (telomere length (p=0.040) and DNA methylation content (p=0.028), gender and chronological age (p=0.032). When analyses were adjusted for socio-economic status and nutritional factors, associations were observed between accelerated biological ageing (telomere length, genomic methylation content) and dietary derived Pi levels among the most deprived males, directly related to the frequency of red meat consumption. Conclusions Accelerated ageing is associated with high serum Pi levels and frequency of red meat consumption. Our data provide evidence for a mechanistic link between high intake of Pi and age-related morbidities tied to socio-economic status. PMID:27132985

  18. Adolescent depression linked to socioeconomic status? Molecular approaches for revealing premorbid risk factors.

    PubMed

    Uddin, Monica; Jansen, Stefan; Telzer, Eva H

    2017-03-01

    The means by which social environmental exposures influence risk of mental disorders is a persistent and still open question. A key candidate mechanism for the biologic mediation of environmental effects involves epigenetic factors, which regulate gene function without altering underlying DNA sequence. Recent work has shown that environmental exposures such as childhood abuse, family history of mental disorder, and low socioeconomic status (SES) associate with differential DNA methylation (5mC) - a relatively stable, but modifiable, epigenetic factor. However, the longitudinal relation among SES, 5mC, brain function, and risk of depression remains to be elucidated. Here, we briefly review literature relevant to these associations and discuss recent findings that, for the first time, prospectively demonstrate sequential links between low SES, changes in 5mC, changes in brain function, and risk of depression in a cohort of adolescents.

  19. Visionmaker NYC: A bottom-up approach to finding shared socioeconomic pathways in New York City

    NASA Astrophysics Data System (ADS)

    Sanderson, E. W.; Fisher, K.; Giampieri, M.; Barr, J.; Meixler, M.; Allred, S. B.; Bunting-Howarth, K. E.; DuBois, B.; Parris, A. S.

    2015-12-01

    Visionmaker NYC is a free, public participatory, bottom-up web application to develop and share climate mitigation and adaptation strategies for New York City neighborhoods. The goal is to develop shared socioeconomic pathways by allowing a broad swath of community members - from schoolchildren to architects and developers to the general public - to input their concepts for a desired future. Visions are comprised of climate scenarios, lifestyle choices, and ecosystem arrangements, where ecosystems are broadly defined to include built ecosystems (e.g. apartment buildings, single family homes, etc.), transportation infrastructure (e.g. highways, connector roads, sidewalks), and natural land cover types (e.g. wetlands, forests, estuary.) Metrics of water flows, carbon cycling, biodiversity patterns, and population are estimated for the user's vision, for the same neighborhood today, and for that neighborhood as it existed in the pre-development state, based on the Welikia Project (welikia.org.) Users can keep visions private, share them with self-defined groups of other users, or distribute them publicly. Users can also propose "challenges" - specific desired states of metrics for specific parts of the city - and others can post visions in response. Visionmaker contributes by combining scenario planning, scientific modelling, and social media to create new, wide-open possibilities for discussion, collaboration, and imagination regarding future, shared socioeconomic pathways.

  20. How Many Pathways Underlie Socioeconomic Differences in the Development of Cognition and Achievement?

    ERIC Educational Resources Information Center

    Tucker-Drob, Elliot M.

    2013-01-01

    Children whose parents are more highly educated enjoy greater age-linked gains in cognitive abilities and academic achievement. Different researchers have typically focused on different outcomes, and the extent to which parental education relates to multiple child outcomes via a single developmental pathway has received little empirical attention.…

  1. Adolescent Overweight and Obesity: Links to Socioeconomic Status and Fruit and Vegetable Intakes.

    PubMed

    You, Jihyun; Choo, Jina

    2016-03-09

    Whether adolescent overweight/obesity is linked to socioeconomic status (SES) and fruit and vegetable (F/V) intakes has not been confirmed. We aimed to determine whether there is an association between SES and adolescent overweight/obesity and to test the mediating effect of F/V intakes. This cross-sectional study included the data of 63,111 adolescents extracted from the 2013 Korea Youth Risk Behavior Web-based Survey. Overweight/obesity was defined as a body mass index ≥ 85th percentile, while F/V intakes were categorized as high (recommended levels: ≥ 1 fruit serving and ≥ 3 vegetable servings per day) versus low. Among girls, low SES (beta = 0.50, p < 0.001) and F/V intakes (beta = -0.17, p = 0.038) were both significantly associated with overweight/obesity; the former association was significantly mediated by F/V intakes (Sobel test: z = 2.00, p = 0.046). Among boys, neither SES nor F/V intakes was significantly associated with overweight/obesity. Adolescent overweight/obesity was significantly linked to low SES and F/V intakes among girls only; low SES indirectly increased the risk of overweight/obesity via low F/V intakes. Therefore, promoting F/V intakes for socially disadvantaged girls should be prioritized as a population-based strategy for preventing adolescent overweight/obesity in South Korea.

  2. Adolescent Overweight and Obesity: Links to Socioeconomic Status and Fruit and Vegetable Intakes

    PubMed Central

    You, Jihyun; Choo, Jina

    2016-01-01

    Whether adolescent overweight/obesity is linked to socioeconomic status (SES) and fruit and vegetable (F/V) intakes has not been confirmed. We aimed to determine whether there is an association between SES and adolescent overweight/obesity and to test the mediating effect of F/V intakes. This cross-sectional study included the data of 63,111 adolescents extracted from the 2013 Korea Youth Risk Behavior Web-based Survey. Overweight/obesity was defined as a body mass index ≥ 85th percentile, while F/V intakes were categorized as high (recommended levels: ≥1 fruit serving and ≥3 vegetable servings per day) versus low. Among girls, low SES (beta = 0.50, p < 0.001) and F/V intakes (beta = −0.17, p = 0.038) were both significantly associated with overweight/obesity; the former association was significantly mediated by F/V intakes (Sobel test: z = 2.00, p = 0.046). Among boys, neither SES nor F/V intakes was significantly associated with overweight/obesity. Adolescent overweight/obesity was significantly linked to low SES and F/V intakes among girls only; low SES indirectly increased the risk of overweight/obesity via low F/V intakes. Therefore, promoting F/V intakes for socially disadvantaged girls should be prioritized as a population-based strategy for preventing adolescent overweight/obesity in South Korea. PMID:27005654

  3. Shared Socio-Economic Pathways of the Energy Sector – Quantifying the Narratives

    SciTech Connect

    Bauer, Nico; Calvin, Katherine; Emmerling, Johannes; Fricko, Oliver; Fujimori, Shinichiro; Hilaire, Jérôme; Eom, Jiyong; Krey, Volker; Kriegler, Elmar; Mouratiadou, Ioanna; Sytze de Boer, Harmen; van den Berg, Maarten; Carrara, Samuel; Daioglou, Vassilis; Drouet, Laurent; Edmonds, James E.; Gernaat, David; Havlik, Petr; Johnson, Nils; Klein, David; Kyle, Page; Marangoni, Giacomo; Masui, Toshihiko; Pietzcker, Robert C.; Strubegger, Manfred; Wise, Marshall; Riahi, Keywan; van Vuuren, Detlef P.

    2016-08-23

    Energy is crucial for supporting basic human needs, development and well-being. The future evolution of the scale and character of the energy system will be fundamentally shaped by socioeconomic conditions and drivers, available energy resources, technologies of energy supply and transformation, and end-use energy demand. However, because energy-related activities are significant sources of greenhouse gas (GHG) emissions and other environmental and social externalities, energy system development will also be influenced by social acceptance and strategic policy choices. All of these uncertainties have important implications for many aspects of economic and environmental sustainability, and climate change in particular. In the Shared-Socioeconomic Pathway (SSP) framework these uncertainties are structured into five narratives, arranged according to the challenges to climate change mitigation and adaptation. In this study we explore future energy sector developments across the five SSPs using Integrated Assessment Models (IAMs), and we also provide summary output and analysis for selected scenarios of global emissions mitigation policies. The mitigation challenge strongly corresponds with global baseline energy sector growth over the 21st century, which varies between 40% and 230% depending on final energy consumer behavior, technological improvements, resource availability and policies. The future baseline CO2-emission range is even larger, as the most energy-intensive SSP also incorporates a comparatively high share of carbon-intensive fossil fuels, and vice versa. Inter-regional disparities in the SSPs are consistent with the underlying socioeconomic assumptions; these differences are particularly strong in the SSPs with large adaptation challenges, which have little inter-regional convergence in long-term income and final energy demand levels. The scenarios presented do not include feedbacks of climate change on energy sector development. The energy

  4. Eco-Health Linkages: evidence base and socio-economic considerations for linking ecosystem goods and services to human health

    EPA Science Inventory

    Ecosystem goods and services (EGS) are thought to play a role in protecting human health, but the empirical evidence directly linking EGS to human health outcomes is limited, and our ability to detect Eco-Health linkages is confounded by socio-economic factors. These limitations ...

  5. Eco-Health Linkages: evidence base and socio-economic considerations for linking ecosystem goods and services to human health

    EPA Science Inventory

    Ecosystem goods and services (EGS) are thought to play a role in protecting human health, but the empirical evidence directly linking EGS to human health outcomes is limited, and our ability to detect Eco-Health linkages is confounded by socio-economic factors. These limitations ...

  6. Reactive nitrogen losses from China's food system for the shared socioeconomic pathways (SSPs).

    PubMed

    Wang, Mengru; Kroeze, Carolien; Strokal, Maryna; Ma, Lin

    2017-12-15

    Food production in China has been changing fast as a result of socio-economic development. This resulted in an increased use of nitrogen (N) in food production, and also to increased reactive nitrogen (Nr) losses to the environment, causing nitrogen pollution. Our study is the first to quantify future Nr losses from China's food system for the Shared Socio-economic Pathways (SSPs). We show that Nr losses differ largely among SSPs. We first qualitatively described the five SSP storylines for China with a focus on food production and consumption. Next, we interpreted these SSP scenarios quantitatively for 2030 and 2050, using the NUFER (NUtrient Flows in Food chains, Environment and Resources use) model to project the Nr losses from China's food system. The results indicate that Nr losses from future food system in China are relatively low for SSP1 and SSP2, and relatively high for SSP3 and SSP4. In SSP5 Nr losses from China's food system are projected to be slightly lower than the level of today. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Causal pathways linking Farm to School to childhood obesity prevention.

    PubMed

    Joshi, Anupama; Ratcliffe, Michelle M

    2012-08-01

    Farm to School programs are rapidly gaining attention as a potential strategy for preventing childhood obesity; however, the causal linkages between Farm to School activities and health outcomes are not well documented. To capitalize on the increased interest in and momentum for Farm to School, researchers and practitioners need to move from developing and implementing evidence informed programs and policies to ones that are evidence-based. The purpose of this article is to outline a framework for facilitating an evidence base for Farm to School programs and policies through a systematic and coordinated approach. Employing the concepts of causal pathways, the authors introduce a proposed framework for organizing and systematically testing out multiple hypotheses (or potential causal links) for how, why, and under what conditions Farm to School Inputs and Activities may result in what Outputs, Effects, and Impacts. Using the causal pathways framework may help develop and test competing hypotheses, identify multicausality, strength, and interactions of causes, and discern the difference between catalysts and causes. In this article, we introduce causal pathways, present menus of potential independent and dependent variables from which to create and test causal pathways linking Farm to School interventions and their role in preventing childhood obesity, discuss their applicability to Farm to School research and practice, and outline proposed next steps for developing a coordinated research framework for Farm to School programs.

  8. Scenarios for the risk of hunger in the twenty-first century using Shared Socioeconomic Pathways

    NASA Astrophysics Data System (ADS)

    Hasegawa, Tomoko; Fujimori, Shinichiro; Takahashi, Kiyoshi; Masui, Toshihiko

    2015-01-01

    Shared socioeconomic pathways (SSPs) are being developed internationally for cross-sectoral assessments of climate change impacts, adaptation, and mitigation. These are five scenarios that include both qualitative and quantitative information for mitigation and adaptation challenges to climate change. In this study, we quantified scenarios for the risk of hunger in the 21st century using SSPs, and clarified elements that influence future hunger risk. There were two primary findings: (1) risk of hunger in the 21st-century greatly differed among five SSPs; and (2) population growth, improvement in the equality of food distribution within a country, and increases in food consumption mainly driven by income growth greatly influenced future hunger risk and were important elements in its long-term assessment.

  9. The Shared Socioeconomic Pathways and their energy, land use, and greenhouse gas emissions implications: An overview

    DOE PAGES

    Riahi, Keywan; van Vuuren, Detlef P.; Kriegler, Elmar; ...

    2017-09-09

    This study presents the overview of the Shared Socioeconomic Pathways (SSPs) and their energy, land use, and emissions implications. The SSPs are part of a new scenario framework, established by the climate change research community in order to facilitate the integrated analysis of future climate impacts, vulnerabilities, adaptation, and mitigation. The pathways were developed over the last years as a joint community effort and describe plausible major global developments that together would lead in the future to different challenges for mitigation and adaptation to climate change. The SSPs are based on five narratives describing alternative socio-economic developments, including sustainable development,more » regional rivalry, inequality, fossil-fueled development, and middle-of-the-road development. The long-term demographic and economic projections of the SSPs depict a wide uncertainty range consistent with the scenario literature. A multi-model approach was used for the elaboration of the energy, land-use and the emissions trajectories of SSP-based scenarios. The baseline scenarios lead to global energy consumption of 400–1200 EJ in 2100, and feature vastly different land-use dynamics, ranging from a possible reduction in cropland area up to a massive expansion by more than 700 million hectares by 2100. The associated annual CO2 emissions of the baseline scenarios range from about 25 GtCO2 to more than 120 GtCO2 per year by 2100. With respect to mitigation, we find that associated costs strongly depend on three factors: (1) the policy assumptions, (2) the socio-economic narrative, and (3) the stringency of the target. The carbon price for reaching the target of 2.6 W/m2 that is consistent with a temperature change limit of 2 °C, differs in our analysis thus by about a factor of three across the SSP marker scenarios. Moreover, many models could not reach this target from the SSPs with high mitigation challenges. While the SSPs were designed to represent

  10. A Framework for Developing Indicators Linking Socio-Economic and Ecological Impacts of Water Funds

    NASA Astrophysics Data System (ADS)

    Bremer, L.; Game, E.; Calvache, A.; Moreno, P.; Morales, A.; Rivera, B.; Rodriguez, L. M.

    2014-12-01

    Growing interest in the equity and sustainability of water funds and other investment in watershed services programs has spurred interest in evaluation of program impacts on ecosystem services and human well-being. Yet, programs often lack a systematic framework to select indicators that are both important to stakeholders and relevant to hypothesized program impact. To fill this gap, we developed a participatory indicator selection methodology and piloted it in Fondo Agua por La Vida y la Sostenibilidad in the East Cauca Valley Colombia. We started by linking program activities to anticipated ecological and socio-economic impacts through stakeholder developed results chains. Using results chains as the framework, we constructed fuzzy cognitive models to explore the relative impact of program activities on social and ecological attributes. To prioritize indicators to monitor, we combined our fuzzy modelling results with an assessment of the perceived importance of different attributes for stakeholders in the water fund. We used the selected indicators to design a monitoring program that will allow the water fund to track and communicate its impact over the long-term.

  11. BID links ferroptosis to mitochondrial cell death pathways.

    PubMed

    Neitemeier, Sandra; Jelinek, Anja; Laino, Vincenzo; Hoffmann, Lena; Eisenbach, Ina; Eying, Roman; Ganjam, Goutham K; Dolga, Amalia M; Oppermann, Sina; Culmsee, Carsten

    2017-03-09

    Ferroptosis has been defined as an oxidative and iron-dependent pathway of regulated cell death that is distinct from caspase-dependent apoptosis and established pathways of death receptor-mediated regulated necrosis. While emerging evidence linked features of ferroptosis induced e.g. by erastin-mediated inhibition of the Xc(-) system or inhibition of glutathione peroxidase 4 (Gpx4) to an increasing number of oxidative cell death paradigms in cancer cells, neurons or kidney cells, the biochemical pathways of oxidative cell death remained largely unclear. In particular, the role of mitochondrial damage in paradigms of ferroptosis needs further investigation. In the present study, we find that erastin-induced ferroptosis in neuronal cells was accompanied by BID transactivation to mitochondria, loss of mitochondrial membrane potential, enhanced mitochondrial fragmentation and reduced ATP levels. These hallmarks of mitochondrial demise are also established features of oxytosis, a paradigm of cell death induced by Xc(-) inhibition by millimolar concentrations of glutamate. Bid knockout using CRISPR/Cas9 approaches preserved mitochondrial integrity and function, and mediated neuroprotective effects against both, ferroptosis and oxytosis. Furthermore, the BID-inhibitor BI-6c9 inhibited erastin-induced ferroptosis, and, in turn, the ferroptosis inhibitors ferrostatin-1 and liproxstatin-1 prevented mitochondrial dysfunction and cell death in the paradigm of oxytosis. These findings show that mitochondrial transactivation of BID links ferroptosis to mitochondrial damage as the final execution step in this paradigm of oxidative cell death.

  12. Alternative futures for societal change: The Shared Socio-Economic Pathways (SSPs) (Invited)

    NASA Astrophysics Data System (ADS)

    O'Neill, B. C.

    2013-12-01

    Deciding how best to respond to the challenge of climate change requires anticipating not only how climate might change in the future, but how society might change as well. Changes in population and economic growth, innovation, technological development, governance, culture, and lifestyle all will affect the energy use and land use that drive climate change, as well as society's capacity to reduce emissions or adapt to climate change impacts. Developing a set of alternative scenarios for societal development is one way to capture and explore the uncertainty in future conditions. The climate change research community has produced a new set of five such scenarios, called Shared Socio-Economic Pathways (SSPs), that is intended to underpin scientific studies, assessments, and policy dialogues for the next decade or more. The SSPs include both qualitative narratives and quantitative projections of key elements such as population, economic growth, urbanization, and educational attainment. They are designed to span a wide range of future conditions in terms of the challenges they present to both adaptation and mitigation. The SSPs are one component of a larger scenario framework which also includes a set of radiative forcing pathways and climate model simulations based on them. Alternative climate futures will be integrated with the alternative societal futures represented by the SSPs to investigate climate change impacts as well as mitigation and adaptation response options.

  13. A Quantative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population Dynamics

    EPA Science Inventory

    A Quantitative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population DynamicsAn adverse outcome pathway (AOP) is a qualitative description linking a molecular initiating event (MIE) with measureable key events leading to an adverse outcome (AO). ...

  14. A Quantative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population Dynamics

    EPA Science Inventory

    A Quantitative Adverse Outcome Pathway Linking Aromatase Inhibition in Fathead Minnows with Population DynamicsAn adverse outcome pathway (AOP) is a qualitative description linking a molecular initiating event (MIE) with measureable key events leading to an adverse outcome (AO). ...

  15. Modeling global yield growth of major crops under multiple socioeconomic pathways

    NASA Astrophysics Data System (ADS)

    Iizumi, T.; Kim, W.; Zhihong, S.; Nishimori, M.

    2016-12-01

    Global gridded crop models (GGCMs) are a key tool in deriving global food security scenarios under climate change. However, it is difficult for GGCMs to reproduce the reported yield growth patterns—rapid growth, yield stagnation and yield collapse. Here, we propose a set of parameterizations for GGCMs to capture the contributions to yield from technological improvements at the national and multi-decadal scales. These include country annual per capita gross domestic product (GDP)-based parameterizations for the nitrogen application rate and crop tolerance to stresses associated with high temperature, low temperature, water deficit and water excess. Using a GGCM combined with the parameterizations, we present global 140-year (1961-2100) yield growth simulations for maize, soybean, rice and wheat under multiple shared socioeconomic pathways (SSPs) and no climate change. The model reproduces the major characteristics of reported global and country yield growth patterns over the 1961-2013 period. Under the most rapid developmental pathway SSP5, the simulated global yields for 2091-2100, relative to 2001-2010, are the highest (1.21-1.82 times as high, with variations across the crops), followed by SSP1 (1.14-1.56 times as high), SSP2 (1.12-1.49 times as high), SSP4 (1.08-1.38 times as high) and SSP3 (1.08-1.36 times as high). Future country yield growth varies substantially by income level as well as by crop and by SSP. These yield pathways offer a new baseline for addressing the interdisciplinary questions related to global agricultural development, food security and climate change.

  16. Shared Socio-Economic Pathways of the Energy Sector – Quantifying the Narratives

    DOE PAGES

    Bauer, Nico; Calvin, Katherine; Emmerling, Johannes; ...

    2016-08-23

    Energy is crucial for supporting basic human needs, development and well-being. The future evolution of the scale and character of the energy system will be fundamentally shaped by socioeconomic conditions and drivers, available energy resources, technologies of energy supply and transformation, and end-use energy demand. However, because energy-related activities are significant sources of greenhouse gas (GHG) emissions and other environmental and social externalities, energy system development will also be influenced by social acceptance and strategic policy choices. All of these uncertainties have important implications for many aspects of economic and environmental sustainability, and climate change in particular. In the Shared-Socioeconomicmore » Pathway (SSP) framework these uncertainties are structured into five narratives, arranged according to the challenges to climate change mitigation and adaptation. In this study we explore future energy sector developments across the five SSPs using Integrated Assessment Models (IAMs), and we also provide summary output and analysis for selected scenarios of global emissions mitigation policies. The mitigation challenge strongly corresponds with global baseline energy sector growth over the 21st century, which varies between 40% and 230% depending on final energy consumer behavior, technological improvements, resource availability and policies. The future baseline CO2-emission range is even larger, as the most energy-intensive SSP also incorporates a comparatively high share of carbon-intensive fossil fuels, and vice versa. Inter-regional disparities in the SSPs are consistent with the underlying socioeconomic assumptions; these differences are particularly strong in the SSPs with large adaptation challenges, which have little inter-regional convergence in long-term income and final energy demand levels. The scenarios presented do not include feedbacks of climate change on energy sector development. The energy sector

  17. Extended Shared Socioeconomic Pathways for Coastal Impact Assessment: Spatial Coastal Population Scenarios

    NASA Astrophysics Data System (ADS)

    Merkens, Jan-Ludolf; Reimann, Lena; Hinkel, Jochen; Vafeidis, Athanasios T.

    2016-04-01

    This work extends the Shared Socioeconomic Pathways (SSPs) by developing spatial projections of global coastal population distribution for the five basic SSPs. Based on a series of coastal migration drivers, which were identified from existing literature, we develop coastal narratives for the five basic SSPs (SSP1-5). These narratives account for differences in coastal versus inland population development in urban and rural areas. To spatially distribute population we use the International Institute for Applied Systems Analysis (IIASA) national population and urbanisation projections and employ country-specific growth rates which differ for coastal and inland as well as for urban and rural regions. These rates are derived from spatial analysis of historical population data. We then adjust these rates for each SSP based on the coastal narratives. The resulting global population grids depict the projected distribution of coastal population for each SSP, until the end of the 21st century, at a spatial resolution of 30 arc seconds. These grids exhibit a three- to four-fold increase in coastal population compared to the basic SSPs. Across all SSPs, except for SSP3, coastal population peaks by the middle of the 21st century and declines afterwards. In SSP3 the coastal population grows continuously until 2100. Compared to the base year 2000 the coastal population increases considerably in all SSPs. The extended SSPs are intended to be utilised in Impact, Adaptation and Vulnerability (IAV) assessments as they allow for improved analysis of exposure to sea-level rise and coastal flooding under different physical and socioeconomic scenarios.

  18. Exploring pathways linking greenspace to health: Theoretical and methodological guidance.

    PubMed

    Markevych, Iana; Schoierer, Julia; Hartig, Terry; Chudnovsky, Alexandra; Hystad, Perry; Dzhambov, Angel M; de Vries, Sjerp; Triguero-Mas, Margarita; Brauer, Michael; Nieuwenhuijsen, Mark J; Lupp, Gerd; Richardson, Elizabeth A; Astell-Burt, Thomas; Dimitrova, Donka; Feng, Xiaoqi; Sadeh, Maya; Standl, Marie; Heinrich, Joachim; Fuertes, Elaine

    2017-10-01

    In a rapidly urbanizing world, many people have little contact with natural environments, which may affect health and well-being. Existing reviews generally conclude that residential greenspace is beneficial to health. However, the processes generating these benefits and how they can be best promoted remain unclear. During an Expert Workshop held in September 2016, the evidence linking greenspace and health was reviewed from a transdisciplinary standpoint, with a particular focus on potential underlying biopsychosocial pathways and how these can be explored and organized to support policy-relevant population health research. Potential pathways linking greenspace to health are here presented in three domains, which emphasize three general functions of greenspace: reducing harm (e.g. reducing exposure to air pollution, noise and heat), restoring capacities (e.g. attention restoration and physiological stress recovery) and building capacities (e.g. encouraging physical activity and facilitating social cohesion). Interrelations between among the three domains are also noted. Among several recommendations, future studies should: use greenspace and behavioural measures that are relevant to hypothesized pathways; include assessment of presence, access and use of greenspace; use longitudinal, interventional and (quasi)experimental study designs to assess causation; and include low and middle income countries given their absence in the existing literature. Cultural, climatic, geographic and other contextual factors also need further consideration. While the existing evidence affirms beneficial impacts of greenspace on health, much remains to be learned about the specific pathways and functional form of such relationships, and how these may vary by context, population groups and health outcomes. This Report provides guidance for further epidemiological research with the goal of creating new evidence upon which to develop policy recommendations. Copyright © 2017 Elsevier Inc

  19. Cumulative structural disadvantage and racial health disparities: the pathways of childhood socioeconomic influence.

    PubMed

    Pais, Jeremy

    2014-10-01

    Cumulative structural disadvantage theory posits two major sources of endogenous selection in shaping racial health disparities: a race-based version of the theory anticipates a racially distinct selection process, whereas a social class-based version anticipates a racially similar process. To operationalize cumulative structural disadvantage, this study uses data from the 1979 National Longitudinal Survey of Youth in a Latent Class Analysis that demographically profiles health impairment trajectories. This analysis is used to examine the nature of selection as it relates to racial differences in the development of health impairments that are significant enough to hinder one's ability to work. The results provide no direct support for the race-based version of cumulative structural disadvantage theory. Instead, two key findings support the social class-based version of cumulative disadvantage theory. First, the functional form of the different health trajectories are invariant for whites and blacks, suggesting more racial similarly in the developmental process than anticipated by the race-based version of the theory. The extent of the racial disparity in the prevalences across the health impairment trajectories is, however, significant and noteworthy: nearly one-third of blacks (28 %) in the United States experience some form of impairment during their prime working years compared with 18.8 % of whites. Second, racial differences in childhood background mediate this racial health disparity through the indirect pathway of occupational attainment and through the direct pathway of early-life exposure to health-adverse environments. Thus, the selection of individuals into different health trajectories, based largely on childhood socioeconomic background, helps explain racial disparities in the development of health impairments.

  20. Sensitivity of projected long-term CO2 emissions across the Shared Socioeconomic Pathways

    NASA Astrophysics Data System (ADS)

    Marangoni, G.; Tavoni, M.; Bosetti, V.; Borgonovo, E.; Capros, P.; Fricko, O.; Gernaat, D. E. H. J.; Guivarch, C.; Havlik, P.; Huppmann, D.; Johnson, N.; Karkatsoulis, P.; Keppo, I.; Krey, V.; Ó Broin, E.; Price, J.; van Vuuren, D. P.

    2017-01-01

    Scenarios showing future greenhouse gas emissions are needed to estimate climate impacts and the mitigation efforts required for climate stabilization. Recently, the Shared Socioeconomic Pathways (SSPs) have been introduced to describe alternative social, economic and technical narratives, spanning a wide range of plausible futures in terms of challenges to mitigation and adaptation. Thus far the key drivers of the uncertainty in emissions projections have not been robustly disentangled. Here we assess the sensitivities of future CO2 emissions to key drivers characterizing the SSPs. We use six state-of-the-art integrated assessment models with different structural characteristics, and study the impact of five families of parameters, related to population, income, energy efficiency, fossil fuel availability, and low-carbon energy technology development. A recently developed sensitivity analysis algorithm allows us to parsimoniously compute both the direct and interaction effects of each of these drivers on cumulative emissions. The study reveals that the SSP assumptions about energy intensity and economic growth are the most important determinants of future CO2 emissions from energy combustion, both with and without a climate policy. Interaction terms between parameters are shown to be important determinants of the total sensitivities.

  1. Pathways from childhood intelligence and socioeconomic status to late-life cardiovascular disease risk.

    PubMed

    Hagger-Johnson, Gareth; Mõttus, René; Craig, Leone C A; Starr, John M; Deary, Ian J

    2012-07-01

    C-reactive protein (CRP) is an acute-phase marker of systemic inflammation and considered an established risk marker for cardiovascular disease (CVD) in old age. Previous studies have suggested that low childhood intelligence, lower socioeconomic status (SES) in childhood or in later life, unhealthy behaviors, poor wellbeing, and high body mass index (BMI) are associated with inflammation. Life course models that simultaneously incorporate all these risk factors can explain how CVD risks accumulate over time, from childhood to old age. Using the data from 1,091 Scottish adults (Lothian Birth Cohort Study, 1936), a path model was constructed to predict CRP at age 70 from concurrent health behaviors, self-perceived quality of life, and BMI and adulthood SES as mediating variables, and from parental SES and childhood intelligence as distal risk factors. A well-fitting path model (CFI = .92, SRMR = .05) demonstrated significant indirect effects from childhood intelligence and parental social class to inflammation via BMI, health behaviors and quality of life (all ps < .05). Low childhood intelligence, unhealthy behaviors, and higher BMI were also direct predictors of CRP. The life course model illustrated how CVD risks may accumulate over time, beginning in childhood and being both direct and transmitted indirectly via low adult SES, unhealthy behaviors, impaired quality of life, and high BMI. Knowledge on the childhood risk factors and their pathways to poor health can be used to identify high-risk individuals for more intensive and tailored behavior change interventions, and to develop effective public health policies.

  2. Investigating the evolution of Shared Socioeconomic Pathways with a large number of scenarios

    NASA Astrophysics Data System (ADS)

    Schweizer, V. J.; Guivarch, C.; Rozenberg, J.

    2013-12-01

    The new scenario framework for climate change research includes alternative possible trends for socioeconomic development called Shared Socioeconomic Pathways (SSPs). The SSPs bear some similarities to other scenarios used for global change research, but they also have important differences. Like the IPCC Special Report on Emissions Scenarios or the Millennium Ecosystem Assessment, SSPs are defined by a scenario logic consisting of two axes. However, these axes define SSPs with respect to their location in an outcome space for challenges to mitigation and to adaptation rather than by their drivers. Open questions for the SSPs include what their drivers are and how the time dimension could be interpreted with the outcomes space. We present a new analytical approach for addressing both questions by studying large numbers of scenarios produced by an integrated assessment model, IMACLIM-R. We systematically generated 432 scenarios and used the SSP framework to classify them by typology. We then analyzed them dynamically, tracing their evolution through the SSP challenges space at annual time steps over the period 2010-2090. Through this approach, we found that many scenarios do not remain fixed to a particular SSP domain; they drift from one domain to another. In papers describing the framework for new scenarios, SSPs are envisioned as hypothetical (counter-factual) reference scenarios that remain fixed in one domain over some time period of interest. However, we conclude that it may be important to also research scenarios that shift across SSP domains. This is relevant for another open question, which is what scenarios are important to explore given their consequences. Through a data mining technique, we uncovered prominent drivers for scenarios that shift across SSP domains. Scenarios with different challenges for adaptation and mitigation (that is, mitigation and adaptation challenges that are not co-varying) were found to be the least stable, and the following

  3. Brain-Body Pathways Linking Psychological Stress and Physical Health.

    PubMed

    Gianaros, Peter J; Wager, Tor D

    2015-08-01

    Psychological stress is thought to arise from appraisal processes that ascribe threat-related meaning to experiences that tax or exceed our coping ability. Neuroimaging research indicates that these appraisal processes originate in brain systems that also control physiological stress reactions in the body. Separate lines of research in health psychology and behavioral medicine indicate that these physiological stress reactions confer risk for physical disease. Accordingly, integrative research that cuts across historically separated disciplines may help to define the brain-body pathways linking psychological stress to physical health. We describe recent studies aimed at this goal, focusing on studies of the brain bases of stressor-evoked cardiovascular system reactions and heart disease risk. We also outline an interpretive framework for these studies, as well as needs for next-generation models and metrics to better understand how the brain encodes and embodies stress in relation to health.

  4. Brain-Body Pathways Linking Psychological Stress and Physical Health

    PubMed Central

    Gianaros, Peter J.; Wager, Tor D.

    2015-01-01

    Psychological stress is thought to arise from appraisal processes that ascribe threat-related meaning to experiences that tax or exceed our coping ability. Neuroimaging research indicates that these appraisal processes originate in brain systems that also control physiological stress reactions in the body. Separate lines of research in health psychology and behavioral medicine indicate that these physiological stress reactions confer risk for physical disease. Accordingly, integrative research that cuts across historically separated disciplines may help to define the brain-body pathways linking psychological stress to physical health. We describe recent studies aimed at this goal, focusing on studies of the brain bases of stressor-evoked cardiovascular system reactions and heart disease risk. We also outline an interpretive framework for these studies, as well as needs for next-generation models and metrics to better understand how the brain encodes and embodies stress in relation to health. PMID:26279608

  5. Socioeconomic position and depression in South African adults with long-term health conditions: a longitudinal study of causal pathways.

    PubMed

    Elwell-Sutton, T; Folb, N; Clark, A; Fairall, L R; Lund, C; Bachmann, M O

    2017-08-14

    There is convincing evidence that lower socioeconomic position is associated with increased risk of mental disorders. However, the mechanisms involved are not well understood. This study aims to elucidate the causal pathways between socioeconomic position and depression symptoms in South African adults. Two possible causal theories are examined: social causation, which suggests that poor socioeconomic conditions cause mental ill health; and social drift, which suggests that those with poor mental health are more likely to drift into poor socioeconomic circumstances. The study used longitudinal and cross-sectional observational data on 3904 adults, from a randomised trial carried out in 38 primary health care clinics between 2011 and 2012. Structural equation models and counterfactual mediation analyses were used to examine causal pathways in two directions. First, we examined social causation pathways, with language (a proxy for racial or ethnic category) being treated as an exposure, while education, unemployment, income and depression were treated as sequential mediators and outcomes. Second, social drift was explored with depression treated as a potential influence on health-related quality of life, job loss and, finally, income. The results suggest that the effects of language on depression at baseline, and on changes in depression during follow-up, were mediated through education and income but not through unemployment. Adverse effects of unemployment and job loss on depression appeared to be mostly mediated through income. The effect of depression on decreasing income appeared to be mediated by job loss. These results suggest that both social causation and social selection processes operate concurrently. This raises the possibility that people could get trapped in a vicious cycle in which poor socioeconomic conditions lead to depression, which, in turn, can cause further damage to their economic prospects. This study also suggests that modifiable factors such

  6. Television and the behaviour of adolescents: does socio-economic status moderate the link?

    PubMed

    Chowhan, James; Stewart, Jennifer M

    2007-10-01

    This paper examines the relationship between adolescent behaviour, television viewing and family socio-economic status (SES) using the Canadian National Longitudinal Survey of Children and Youth (NLSCY). The effect of television viewing on adolescents' behaviour, ranging from pro-social to aggressive, and whether this effect is moderated by family socio-economic status is investigated. An adolescent fixed effects model is used to estimate the effect of television viewing on behaviour. The results indicate that the effect of television viewing varies between males and females. Family SES has a role in the effect of television on adolescents' behaviour, although the results do not distinguish between the two proposed hypotheses.

  7. Socioeconomic Status and the Health of Youth: A Multi-level, Multi-domain Approach to Conceptualizing Pathways

    PubMed Central

    Schreier, Hannah M. C.; Chen, Edith

    2012-01-01

    Previous research has clearly established associations between low socioeconomic status (SES) and poor youth physical health outcomes. This article provides an overview of the main pathways through which low SES environments come to influence youth health. We focus on two of the most prevalent chronic health problems in youth today, asthma and obesity. We review and propose a model that encompasses (1) multiple levels of influence, including the neighborhood, family and person level, (2) both social and physical domains in the environment, and finally (3) dynamic relationships between these factors. A synthesis of existing research and our proposed model draw attention to the notion of adverse physical and social exposures in youth’s neighborhood environments altering family characteristics and youth psychosocial and behavioral profiles, thereby increasing youth’s risk for health problems. We also note the importance of acknowledging reciprocal influences across levels and domains (e.g., between family and child) that create self-perpetuating patterns of influence that further accentuate the impact of these factors on youth health. Finally, we document that factors across levels can interact (e.g., environmental pollution levels with child stress) to create unique, synergistic effects on youth health. Our model stresses the importance of evaluating influences on youth’s physical health not in isolation but in the context of the broader social and physical environments in which youth live. Understanding the complex relationships between the factors that link low SES to youth’s long-term health trajectories is necessary for the creation and implementation of successful interventions and policies to ultimately reduce health disparities. PMID:22845752

  8. Gridded population projections for the coastal zone under the Shared Socioeconomic Pathways

    NASA Astrophysics Data System (ADS)

    Merkens, Jan-Ludolf; Reimann, Lena; Hinkel, Jochen; Vafeidis, Athanasios T.

    2016-10-01

    Existing quantifications of the Shared Socioeconomic Pathways (SSP) used for climate impact assessment do not account for subnational population dynamics such as coastward-migration that can be critical for coastal impact assessment. This paper extends the SSPs by developing spatial projections of global coastal population distribution for the five basic SSPs. Based on a series of coastal migration drivers we develop coastal narratives for each SSP. These narratives account for differences in coastal and inland population developments in urban and rural areas. To spatially distribute population, we use the International Institute for Applied Systems Analysis (IIASA) national population and urbanisation projections and employ country-specific growth rates, which differ for coastal and inland as well as for urban and rural regions, to project coastal population for each SSP. These rates are derived from spatial analysis of historical population data and adjusted for each SSP based on the coastal narratives. Our results show that, compared to the year 2000 (638 million), the population living in the Low Elevated Coastal Zone (LECZ) increases by 58% to 71% until 2050 and exceeds one billion in all SSPs. By the end of the 21st century, global coastal population declines to 830-907 million in all SSPs except for SSP3, where coastal population growth continues and reaches 1.184 billion. Overall, the population living in the LECZ is higher by 85 to 239 million compared to the original IIASA projections. Asia expects the highest absolute growth (238-303 million), Africa the highest relative growth (153% to 218%). Our results highlight regions where high coastal population growth is expected and will therefore face an increased exposure to coastal flooding.

  9. Socioeconomic status and social support following illicit drug use: causal pathways or common liability?

    PubMed

    Bergen, Sarah E; Gardner, Charles O; Aggen, Steven H; Kendler, Kenneth S

    2008-06-01

    The negative social attributes associated with drug use and abuse/dependence may arise as a result of shared genetic or environmental factors rather than through causal pathways. To evaluate this possibility, structured interviews were conducted for 3969 male and female twins from the Mid-Atlantic Twin Registry and evaluations of their socioeconomic status (SES), social interactions, and use of drugs were obtained. Drug involvement was categorized as never used, tried, or met criteria for abuse or dependence. A co-twin control design was implemented using hierarchical linear modeling to assess whether twins who used drugs experienced lower SES and social support than non-using co-twins. Poorer social functioning in the drug-exposed twin is consistent with a causal relationship, while similar functioning in the drug exposed versus naive twins imply shared genetic or common environmental factors. Use of drugs was not significantly related to any SES measures. However, education and job status appear to share genetic influences with drug abuse/dependence. Lower income was not related to abuse/dependence of drugs. Negative interactions with friends and relatives share genetic factors with use of drugs, but the escalation from trying drugs to abusing them appears to generate discord between the abuser and friends and relatives in a causal fashion. These results indicate that presumptive causal influences of drug abuse/dependence on low SES may actually be mediated by shared genes. Drug use and social discord also appear to have shared genetic factors, but increased levels of drug involvement seem to causally influence social interactions.

  10. Spatially explicit global population scenarios consistent with the Shared Socioeconomic Pathways

    NASA Astrophysics Data System (ADS)

    Jones, B.; O'Neill, B. C.

    2016-08-01

    The projected size and spatial distribution of the future population are important drivers of global change and key determinants of exposure and vulnerability to hazards. Spatial demographic projections are widely used as inputs to spatial projections of land use, energy use, and emissions, as well as to assessments of the impacts of extreme events, sea level rise, and other climate-related outcomes. To date, however, there are very few global-scale, spatially explicit population projections, and those that do exist are often based on simple scaling or trend extrapolation. Here we present a new set of global, spatially explicit population scenarios that are consistent with the new Shared Socioeconomic Pathways (SSPs) developed to facilitate global change research. We use a parameterized gravity-based downscaling model to produce projections of spatial population change that are quantitatively consistent with national population and urbanization projections for the SSPs and qualitatively consistent with assumptions in the SSP narratives regarding spatial development patterns. We show that the five SSPs lead to substantially different spatial population outcomes at the continental, national, and sub-national scale. In general, grid cell-level outcomes are most influenced by national-level population change, second by urbanization rate, and third by assumptions about the spatial style of development. However, the relative importance of these factors is a function of the magnitude of the projected change in total population and urbanization for each country and across SSPs. We also demonstrate variation in outcomes considering the example of population existing in a low-elevation coastal zone under alternative scenarios.

  11. Spatially explicit global population scenarios consistent with the Shared Socioeconomic Pathways

    DOE PAGES

    Jones, B.; O’Neill, B. C.

    2016-07-29

    Here we report that the projected size and spatial distribution of the future population are important drivers of global change and key determinants of exposure and vulnerability to hazards. Spatial demographic projections are widely used as inputs to spatial projections of land use, energy use, and emissions, as well as to assessments of the impacts of extreme events, sea level rise, and other climate-related outcomes. To date, however, there are very few global-scale, spatially explicit population projections, and those that do exist are often based on simple scaling or trend extrapolation. Here we present a new set of global, spatiallymore » explicit population scenarios that are consistent with the new Shared Socioeconomic Pathways (SSPs) developed to facilitate global change research. We use a parameterized gravity-based downscaling model to produce projections of spatial population change that are quantitatively consistent with national population and urbanization projections for the SSPs and qualitatively consistent with assumptions in the SSP narratives regarding spatial development patterns. We show that the five SSPs lead to substantially different spatial population outcomes at the continental, national, and sub-national scale. In general, grid cell-level outcomes are most influenced by national-level population change, second by urbanization rate, and third by assumptions about the spatial style of development. However, the relative importance of these factors is a function of the magnitude of the projected change in total population and urbanization for each country and across SSPs. We also demonstrate variation in outcomes considering the example of population existing in a low-elevation coastal zone under alternative scenarios.« less

  12. Building Links between Early Socioeconomic Status, Cognitive Ability, and Math and Science Achievement

    ERIC Educational Resources Information Center

    Blums, Angela; Belsky, Jay; Grimm, Kevin; Chen, Zhe

    2017-01-01

    The present study examined whether and how socioeconomic status (SES) predicts school achievement in science, technology, engineering, and math (STEM) using structural equation modeling and data from the National Institute of Child Health and Human Development Study of Child Care and Youth Development. The present inquiry addresses gaps in…

  13. Building Links between Early Socioeconomic Status, Cognitive Ability, and Math and Science Achievement

    ERIC Educational Resources Information Center

    Blums, Angela; Belsky, Jay; Grimm, Kevin; Chen, Zhe

    2017-01-01

    The present study examined whether and how socioeconomic status (SES) predicts school achievement in science, technology, engineering, and math (STEM) using structural equation modeling and data from the National Institute of Child Health and Human Development Study of Child Care and Youth Development. The present inquiry addresses gaps in…

  14. Linking Socioeconomic Status to Social Cognitive Career Theory Factors: A Partial Least Squares Path Modeling Analysis

    ERIC Educational Resources Information Center

    Huang, Jie-Tsuen; Hsieh, Hui-Hsien

    2011-01-01

    The purpose of this study was to investigate the contributions of socioeconomic status (SES) in predicting social cognitive career theory (SCCT) factors. Data were collected from 738 college students in Taiwan. The results of the partial least squares (PLS) analyses indicated that SES significantly predicted career decision self-efficacy (CDSE);…

  15. Epigenetic pathways through which experiences become linked with biology

    PubMed Central

    McGowan, Patrick O.; Roth, Tania L.

    2015-01-01

    This article highlights the defining principles, progress, and future directions in epigenetics research in relation to this special issue. Exciting studies in the fields of neuroscience, psychology, and psychiatry have provided new insights into the epigenetic factors (e.g. DNA methylation) that are responsive to environmental input and serve as biological pathways in behavioral development. Here we highlight the experimental evidence, mainly from animal models, that factors such as psychosocial stress and environmental adversity can become encoded within epigenetic factors with functional consequences for brain plasticity and behavior. We also highlight evidence that epigenetic marking of genes in one generation can have consequences for future generations (i.e. inherited), and work with humans linking epigenetics, cognitive dysfunction, and psychiatric disorder. Though epigenetics has offered more of a beginning than an answer to the centuries-old nature-nurture debate, continued research is certain to yield substantial information regarding biological determinants of CNS changes and behavior with relevance for the study of developmental psychopathology. PMID:25997776

  16. Evolutionary bursts in Euphorbia (Euphorbiaceae) are linked with photosynthetic pathway.

    PubMed

    Horn, James W; Xi, Zhenxiang; Riina, Ricarda; Peirson, Jess A; Yang, Ya; Dorsey, Brian L; Berry, Paul E; Davis, Charles C; Wurdack, Kenneth J

    2014-12-01

    The mid-Cenozoic decline of atmospheric CO2 levels that promoted global climate change was critical to shaping contemporary arid ecosystems. Within angiosperms, two CO2 -concentrating mechanisms (CCMs)-crassulacean acid metabolism (CAM) and C4 -evolved from the C3 photosynthetic pathway, enabling more efficient whole-plant function in such environments. Many angiosperm clades with CCMs are thought to have diversified rapidly due to Miocene aridification, but links between this climate change, CCM evolution, and increased net diversification rates (r) remain to be further understood. Euphorbia (∼2000 species) includes a diversity of CAM-using stem succulents, plus a single species-rich C4 subclade. We used ancestral state reconstructions with a dated molecular phylogeny to reveal that CCMs independently evolved 17-22 times in Euphorbia, principally from the Miocene onwards. Analyses assessing among-lineage variation in r identified eight Euphorbia subclades with significantly increased r, six of which have a close temporal relationship with a lineage-corresponding CCM origin. Our trait-dependent diversification analysis indicated that r of Euphorbia CCM lineages is approximately threefold greater than C3 lineages. Overall, these results suggest that CCM evolution in Euphorbia was likely an adaptive strategy that enabled the occupation of increased arid niche space accompanying Miocene expansion of arid ecosystems. These opportunities evidently facilitated recent, replicated bursts of diversification in Euphorbia. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  17. Antisocial and Human Capital Pathways to Socioeconomic Exclusion: A 42-Year Prospective Study

    ERIC Educational Resources Information Center

    Savolainen, Jukka; Mason, W. Alex; Lyyra, Anna-Liisa; Pulkkinen, Lea; Kokko, Katja

    2017-01-01

    Nordic welfare states have been very successful at reducing poverty and inequality among their citizens. However, the presence of a strong social safety net in these countries has not solved the problem of "socioeconomic exclusion", manifesting in such outcomes as chronic unemployment and welfare dependency. In an effort to understand…

  18. Genetic link between family socioeconomic status and children's educational achievement estimated from genome-wide SNPs.

    PubMed

    Krapohl, E; Plomin, R

    2016-03-01

    One of the best predictors of children's educational achievement is their family's socioeconomic status (SES), but the degree to which this association is genetically mediated remains unclear. For 3000 UK-representative unrelated children we found that genome-wide single-nucleotide polymorphisms could explain a third of the variance of scores on an age-16 UK national examination of educational achievement and half of the correlation between their scores and family SES. Moreover, genome-wide polygenic scores based on a previously published genome-wide association meta-analysis of total number of years in education accounted for ~3.0% variance in educational achievement and ~2.5% in family SES. This study provides the first molecular evidence for substantial genetic influence on differences in children's educational achievement and its association with family SES.

  19. Night-time lights: A global, long term look at links to socio-economic trends

    PubMed Central

    Zavala-Araiza, Daniel; Wagner, Gernot

    2017-01-01

    We use a parallelized spatial analytics platform to process the twenty-one year totality of the longest-running time series of night-time lights data—the Defense Meteorological Satellite Program (DMSP) dataset—surpassing the narrower scope of prior studies to assess changes in area lit of countries globally. Doing so allows a retrospective look at the global, long-term relationships between night-time lights and a series of socio-economic indicators. We find the strongest correlations with electricity consumption, CO2 emissions, and GDP, followed by population, CH4 emissions, N2O emissions, poverty (inverse) and F-gas emissions. Relating area lit to electricity consumption shows that while a basic linear model provides a good statistical fit, regional and temporal trends are found to have a significant impact. PMID:28346500

  20. Genetic link between family socioeconomic status and children's educational achievement estimated from genome-wide SNPs

    PubMed Central

    Krapohl, E; Plomin, R

    2016-01-01

    One of the best predictors of children's educational achievement is their family's socioeconomic status (SES), but the degree to which this association is genetically mediated remains unclear. For 3000 UK-representative unrelated children we found that genome-wide single-nucleotide polymorphisms could explain a third of the variance of scores on an age-16 UK national examination of educational achievement and half of the correlation between their scores and family SES. Moreover, genome-wide polygenic scores based on a previously published genome-wide association meta-analysis of total number of years in education accounted for ~3.0% variance in educational achievement and ~2.5% in family SES. This study provides the first molecular evidence for substantial genetic influence on differences in children's educational achievement and its association with family SES. PMID:25754083

  1. Enduring links from childhood mathematics and reading achievement to adult socioeconomic status.

    PubMed

    Ritchie, Stuart J; Bates, Timothy C

    2013-07-01

    Understanding the determinants of socioeconomic status (SES) is an important economic and social goal. Several major influences on SES are known, yet much of the variance in SES remains unexplained. In a large, population-representative sample from the United Kingdom, we tested the effects of mathematics and reading achievement at age 7 on attained SES by age 42. Mathematics and reading ability both had substantial positive associations with adult SES, above and beyond the effects of SES at birth, and with other important factors, such as intelligence. Achievement in mathematics and reading was also significantly associated with intelligence scores, academic motivation, and duration of education. These findings suggest effects of improved early mathematics and reading on SES attainment across the life span.

  2. An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents

    PubMed Central

    Swartz, Johnna R.

    2016-01-01

    Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step towards developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear if differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging, and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status predict changes in risk-related brain function. Specifically, we find that lower socioeconomic status during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention amongst high-risk individuals. PMID:27217150

  3. Global Inequalities in Cervical Cancer Incidence and Mortality are Linked to Deprivation, Low Socioeconomic Status, and Human Development

    PubMed Central

    Singh, Gopal K.; Azuine, Romuladus E.; Siahpush, Mohammad

    2012-01-01

    Objectives This study examined global inequalities in cervical cancer incidence and mortality rates as a function of cross-national variations in the Human Development Index (HDI), socioeconomic factors, Gender Inequality Index (GII), and healthcare expenditure. Methods Age-adjusted incidence and mortality rates were calculated for women in 184 countries using the 2008 GLOBOCAN database, and incidence and mortality trends were analyzed using the WHO cancer mortality database. Log-linear regression was used to model annual trends, while OLS and Poisson regression models were used to estimate the impact of socioeconomic and human development factors on incidence and mortality rates. Results Cervical cancer incidence and mortality rates varied widely, with many African countries such as Guinea, Zambia, Comoros, Tanzania, and Malawi having at least 10-to-20-fold higher rates than several West Asian, Middle East, and European countries, including Iran, Saudi Arabia, Syria, Egypt, and Switzerland. HDI, GII, poverty rate, health expenditure per capita, urbanization, and literacy rate were all significantly related to cervical cancer incidence and mortality, with HDI and poverty rate each explaining >52% of the global variance in mortality. Both incidence and mortality rates increased in relation to lower human development and higher gender inequality levels. A 0.2 unit increase in HDI was associated with a 20% decrease in cervical cancer risk and a 33% decrease in cervical cancer mortality risk. The risk of a cervical cancer diagnosis increased by 24% and of cervical cancer death by 42% for a 0.2 unit increase in GII. Higher health expenditure levels were independently associated with decreased incidence and mortality risks. Conclusions and Public Health Implications Global inequalities in cervical cancer are clearly linked to disparities in human development, social inequality, and living standards. Reductions in cervical cancer rates are achievable by reducing

  4. Socio-economic factors related to moral reasoning in childhood and adolescence: the missing link between brain and behavior.

    PubMed

    Caravita, Simona C S; Giardino, Simona; Lenzi, Leonardo; Salvaterra, Mariaelena; Antonietti, Alessandro

    2012-01-01

    Neuroscientific and psychological research on moral development has until now developed independently, referring to distinct theoretical models, contents, and methods. In particular, the influence of socio-economic and cultural factors on morality has been broadly investigated by psychologists but as yet has not been investigated by neuroscientists. The value of bridging these two areas both theoretically and methodologically has, however, been suggested. This study aims at providing a first connection between neuroscientific and psychological literature on morality by investigating whether socio-economic dimensions, i.e., living socio-geographic/economic area, immigrant status and socio-economic status (SES), affect moral reasoning as operationalized in moral domain theory (a seminal approach in psychological studies on morality) and in Greene et al. (2001) perspective (one of the main approaches in neuroethics research). Participants were 81 primary school (M = 8.98 years; SD = 0.39), 72 middle school (M = 12.14 years; SD = 0.61), and 73 high school (M = 15.10 years; SD = 0.38) students from rural and urban areas. Participants' immigrant status (native vs. immigrant) and family SES level were recorded. Moral reasoning was assessed by means of a series of personal and impersonal dilemmas based on Greene et al. (2001) neuroimaging experiment and a series of moral and socio-conventional rule dilemmas based on the moral domain theory. Living socio-geographic/economic area, immigrant status and SES mainly affected evaluations of moral and, to a higher extent, socio-conventional dilemmas, but had no impact on judgment of personal and impersonal dilemmas. Results are mainly discussed from the angle of possible theoretical links and suggestions emerging for studies on moral reasoning in the frameworks of neuroscience and psychology.

  5. Socio-economic factors related to moral reasoning in childhood and adolescence: the missing link between brain and behavior

    PubMed Central

    Caravita, Simona C. S.; Giardino, Simona; Lenzi, Leonardo; Salvaterra, Mariaelena; Antonietti, Alessandro

    2012-01-01

    Neuroscientific and psychological research on moral development has until now developed independently, referring to distinct theoretical models, contents, and methods. In particular, the influence of socio-economic and cultural factors on morality has been broadly investigated by psychologists but as yet has not been investigated by neuroscientists. The value of bridging these two areas both theoretically and methodologically has, however, been suggested. This study aims at providing a first connection between neuroscientific and psychological literature on morality by investigating whether socio-economic dimensions, i.e., living socio-geographic/economic area, immigrant status and socio-economic status (SES), affect moral reasoning as operationalized in moral domain theory (a seminal approach in psychological studies on morality) and in Greene et al. (2001) perspective (one of the main approaches in neuroethics research). Participants were 81 primary school (M = 8.98 years; SD = 0.39), 72 middle school (M = 12.14 years; SD = 0.61), and 73 high school (M = 15.10 years; SD = 0.38) students from rural and urban areas. Participants' immigrant status (native vs. immigrant) and family SES level were recorded. Moral reasoning was assessed by means of a series of personal and impersonal dilemmas based on Greene et al. (2001) neuroimaging experiment and a series of moral and socio-conventional rule dilemmas based on the moral domain theory. Living socio-geographic/economic area, immigrant status and SES mainly affected evaluations of moral and, to a higher extent, socio-conventional dilemmas, but had no impact on judgment of personal and impersonal dilemmas. Results are mainly discussed from the angle of possible theoretical links and suggestions emerging for studies on moral reasoning in the frameworks of neuroscience and psychology. PMID:23015787

  6. FLOOD MANAGEMENT: A CASE STUDY TO LINK SOCIO-ECONOMIC AND ENVIRONMENTAL POLICY

    EPA Science Inventory

    Human living standards are inextricably linked through the economy to the integrity of the natural resources from which they are derived. The complex trade-offs needed to shape sustainable living standards will require a much greater ability to predict the consequences of public...

  7. FLOOD MANAGEMENT: A CASE STUDY TO LINK SOCIO-ECONOMIC AND ENVIRONMENTAL POLICY

    EPA Science Inventory

    Human living standards are inextricably linked through the economy to the integrity of the natural resources from which they are derived. The complex trade-offs needed to shape sustainable living standards will require a much greater ability to predict the consequences of public...

  8. Links between Socio-Economic Circumstances and Changes in Smoking Behavior in the Mexican Population: 2002–2010

    PubMed Central

    Beltrán-Sánchez, HIRAM; Thomas, DUNCAN; Teruel, GRACIELA; Wheaton, FELICIA; Crimmins, EILEEN M.

    2013-01-01

    While deleterious consequences of smoking on health have been widely publicized, in many developing countries, smoking prevalence is high and increasing. Little is known about the dynamics underlying changes in smoking behavior. This paper examines socio-economic and demographic characteristics associated with smoking initiation and quitting in Mexico between 2002 and 2010. In addition to the influences of age, gender, education, household economic resources and location of residence, changes in marital status, living arrangements and health status are examined. Drawing data from the Mexican Family Life Survey, a rich population-based longitudinal study of individuals, smoking behavior of individuals in 2002 is compared with their behavior in 2010. Logistic models are used to examine socio-demographic and health factors that are associated with initiating and quitting smoking. There are three main findings. First, part of the relationship between education and smoking reflects the role of economic resources. Second, associations of smoking with education and economic resources differ for females and males. Third, there is considerable heterogeneity in the factors linked to smoking behavior in Mexico indicating that the smoking epidemic may be at different stages in different population subgroups. Mexico has recently implemented fiscal policies and public health campaigns aimed at reducing smoking prevalence and discouraging smoking initiation. These programs are likely to be more effective if they target particular socio-economic and demographic sub-groups. PMID:23888371

  9. Prematurity, Birth Weight, and Socioeconomic Status Are Linked to Atypical Diurnal Hypothalamic-Pituitary-Adrenal Axis Activity in Young Adults.

    PubMed

    Winchester, Suzy Barcelos; Sullivan, Mary C; Roberts, Mary B; Granger, Douglas A

    2016-02-01

    In a prospective, case-controlled longitudinal design, 180 preterm and fullterm infants who had been enrolled at birth participated in a comprehensive assessment battery at age 23. Of these, 149 young adults, 34 formerly full-term and 115 formerly preterm (22 healthy preterm, 48 with medical complications, 21 with neurological complications, and 24 small for gestational age) donated five saliva samples from a single day that were assayed for cortisol to assess diurnal variation of the hypothalamic-pituitary-adrenal (HPA) axis. Analyses were conducted to determine whether prematurity category, birth weight, and socioeconomic status were associated with differences in HPA axis function. Pre- and perinatal circumstances associated with prematurity influenced the activity of this environmentally sensitive physiological system. Results are consistent with the theory of Developmental Origins of Health and Disease and highlight a possible mechanism for the link between prematurity and health disparities later in life.

  10. Parenting of divorced mothers as a link between social status and boys' academic outcomes: unpacking the effects of socioeconomic status.

    PubMed

    DeGarmo, D S; Forgatch, M S; Martinez, C R

    1999-01-01

    Socialization theories posit parenting practices as mechanisms linking socioeconomic status (SES) and children's academic outcomes. A mediational parenting model was tested examining separate effects of maternal education, occupation, and income for a sample of 238 divorced or recently separated mothers of 6- to 9-year-old sons. For the SEM path models, each indicator of SES was associated with better parenting, and parenting in turn had indirect effects on achievement through home skill-building activities and school behavior. The direct effect of maternal education on achievement was mediated by home skill-building activities, the direct effect of maternal occupation on achievement was not mediated, and income measures had no direct effects on achievement. These findings underscore the importance of unpacking the effects of SES and the relevance of effective parenting practices as a protective factor in the home and school environment for young boys' school success during postdivorce adjustment.

  11. Pathways to a Four-Year Degree: Determinants of Degree Completion among Socioeconomically Disadvantaged Students.

    ERIC Educational Resources Information Center

    Cabrera, Alberto F.; Burkum, Kurt R.; La Nasa, Steven M.

    The High School Sophomore Cohort of 1980 followed nine different pathways to a 4-year college degree. These paths were formed by a combination of different levels of academic preparation secured in high school and the first type of postsecondary institution attended. The pathway most likely to lead to a 4-year degree is one defined by acquiring…

  12. 5-HTTLPR polymorphism is linked to neural mechanisms of selective attention in preschoolers from lower socioeconomic status backgrounds.

    PubMed

    Isbell, Elif; Stevens, Courtney; Hampton Wray, Amanda; Bell, Theodore; Neville, Helen J

    2016-12-01

    While a growing body of research has identified experiential factors associated with differences in selective attention, relatively little is known about the contribution of genetic factors to the skill of sustained selective attention, especially in early childhood. Here, we assessed the association between the serotonin transporter linked polymorphic region (5-HTTLPR) genotypes and the neural mechanisms of selective attention in young children from lower socioeconomic status (SES) backgrounds. Event-related potentials (ERPs) were recorded during a dichotic listening task from 121 children (76 females, aged 40-67 months), who were also genotyped for the short and long allele of 5-HTTLPR. The effect of selective attention was measured as the difference in ERP mean amplitudes elicited by identical probe stimuli embedded in stories when they were attended versus unattended. Compared to children homozygous for the long allele, children who carried at least one copy of the short allele showed larger effects of selective attention on neural processing. These findings link the short allele of the 5-HTTLPR to enhanced neural mechanisms of selective attention and lay the groundwork for future studies of gene-by-environment interactions in the context of key cognitive skills. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. A Missing Link for California's Pathways Movement: CTE Instructional Staff

    ERIC Educational Resources Information Center

    Lundy-Wagner, Valerie

    2016-01-01

    Recently, the State of California committed nearly one billion dollars to the development of career and technical education (CTE) pathways that lead to locally relevant, high-growth, high-demand careers. This investment represents a pivot from relatively disjointed approaches to CTE in high schools and community colleges, and reflects an…

  14. Framework for Developing a System of Linked Learning Pathways

    ERIC Educational Resources Information Center

    Stearns, Roman

    2010-01-01

    This Framework is intended for use by school districts and their community partners as they plan and adopt systems of quality pathways. The Critical Elements that make up the Framework are intended to deepen and clarify the district's thinking about how to build the infrastructure that supports the design, implementation, and sustainability of a…

  15. Framework for Developing a System of Linked Learning Pathways

    ERIC Educational Resources Information Center

    Stearns, Roman

    2010-01-01

    This Framework is intended for use by school districts and their community partners as they plan and adopt systems of quality pathways. The Critical Elements that make up the Framework are intended to deepen and clarify the district's thinking about how to build the infrastructure that supports the design, implementation, and sustainability of a…

  16. Central role of the brain in stress and adaptation: Links to socioeconomic status, health, and disease

    PubMed Central

    McEwen, Bruce S.; Gianaros, Peter J.

    2010-01-01

    The brain is the key organ of stress reactivity, coping, and recovery processes. Within the brain, a distributed neural circuitry determines what is threatening and thus stressful to the individual. Instrumental brain systems of this circuitry include the hippocampus, amygdala, and areas of the prefrontal cortex. Together, these systems regulate physiological and behavioral stress processes, which can be adaptive in the short-term and maladaptive in the long-term. Importantly, such stress processes arise from bidirectional patterns of communication between the brain and the autonomic, cardiovascular, and immune systems via neural and endocrine mechanisms underpinning cognition, experience, and behavior. In one respect, these bidirectional stress mechanisms are protective in that they promote short-term adaptation (allostasis). In another respect, however, these stress mechanisms can lead to a long-term dysregulation of allostasis in that they promote maladaptive wear-and-tear on the body and brain under chronically stressful conditions (allostatic load), compromising stress resiliency and health. This review focuses specifically on the links between stress-related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load. PMID:20201874

  17. Socio-economic inequalities in stage at diagnosis, and in time intervals on the lung cancer pathway from first symptom to treatment: systematic review and meta-analysis.

    PubMed

    Forrest, Lynne F; Sowden, Sarah; Rubin, Greg; White, Martin; Adams, Jean

    2017-05-01

    Cancer diagnosis at an early stage increases the chance of curative treatment and of survival. It has been suggested that delays on the pathway from first symptom to diagnosis and treatment may be socio-economically patterned, and contribute to socio-economic differences in receipt of treatment and in cancer survival. This review aimed to assess the published evidence for socio-economic inequalities in stage at diagnosis of lung cancer, and in the length of time spent on the lung cancer pathway. MEDLINE, EMBASE and CINAHL databases were searched to locate cohort studies of adults with a primary diagnosis of lung cancer, where the outcome was stage at diagnosis or the length of time spent within an interval on the care pathway, or a suitable proxy measure, analysed according to a measure of socio-economic position. Meta-analysis was undertaken when there were studies available with suitable data. Of the 461 records screened, 39 papers were included in the review (20 from the UK) and seven in a final meta-analysis for stage at diagnosis. There was no evidence of socio-economic inequalities in late stage at diagnosis in the most, compared with the least, deprived group (OR=1.04, 95% CI=0.92 to 1.19). No socio-economic inequalities in the patient interval or in time from diagnosis to treatment were found. Socio-economic inequalities in stage at diagnosis are thought to be an important explanatory factor for survival inequalities in cancer. However, socio-economic inequalities in stage at diagnosis were not found in a meta-analysis for lung cancer. CRD42014007145. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. Linking multiple pathogenic pathways in Alzheimer’s disease

    PubMed Central

    Bou Khalil, Rami; Khoury, Elie; Koussa, Salam

    2016-01-01

    Alzheimer’s disease (AD) is a chronic neurodegenerative disorder presenting as progressive cognitive decline with dementia that does not, to this day, benefit from any disease-modifying drug. Multiple etiologic pathways have been explored and demonstrate promising solutions. For example, iron ion chelators, such as deferoxamine, are a potential therapeutic solution around which future studies are being directed. Another promising domain is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD to prove that all these mechanisms converge onto the same cascade of neuroinflammatory events. This common pathway is initiated by the presence of vascular risk factors that induce brain tissue hypoxia, which leads to endothelial cell activation. However, the ensuing hypoxia stimulates the production and release of reactive oxygen species and pro-inflammatory proteins. Furthermore, the endothelial activation may become excessive and dysfunctional in predisposed individuals, leading to thrombin activation and iron ion decompartmentalization. The oxidative stress that results from these modifications in the neurovascular unit will eventually lead to neuronal and glial cell death, ultimately leading to the development of AD. Hence, future research in this field should focus on conducting trials with combinations of potentially efficient treatments, such as the combination of intranasal deferoxamine and direct thrombin inhibitors. PMID:27354962

  19. A global water scarcity assessment under Shared Socio-economic Pathways - Part 2: Water availability and scarcity

    NASA Astrophysics Data System (ADS)

    Hanasaki, N.; Fujimori, S.; Yamamoto, T.; Yoshikawa, S.; Masaki, Y.; Hijioka, Y.; Kainuma, M.; Kanamori, Y.; Masui, T.; Takahashi, K.; Kanae, S.

    2013-07-01

    A global water scarcity assessment for the 21st century was conducted under the latest socio-economic scenario for global change studies, namely Shared Socio-economic Pathways (SSPs). SSPs depict five global situations with substantially different socio-economic conditions. In the accompanying paper, a water use scenario compatible with the SSPs was developed. This scenario considers not only quantitative socio-economic factors such as population and electricity production but also qualitative ones such as the degree of technological change and overall environmental consciousness. In this paper, water availability and water scarcity were assessed using a global hydrological model called H08. H08 simulates both the natural water cycle and major human activities such as water abstraction and reservoir operation. It simulates water availability and use at daily time intervals at a spatial resolution of 0.5° × 0.5°. A series of global hydrological simulations were conducted under the SSPs, taking into account different climate policy options and the results of climate models. Water scarcity was assessed using an index termed the Cumulative Abstraction to Demand ratio, which is expressed as the accumulation of daily water abstraction from a river divided by the daily consumption-based potential water demand. This index can be used to express whether renewable water resources are available from rivers when required. The results suggested that by 2071-2100 the population living under severely water-stressed conditions for SSP1-5 will reach 2588-2793 × 106 (39-42% of total population), 3966-4298 × 106 (46-50%), 5334-5643 × 106 (52-55%), 3427-3786 × 106 (40-45%), 3164-3379 × 106 (46-49%) respectively, if climate policies are not adopted. Even in SSP1 (the scenario with least change in water use and climate) global water scarcity increases considerably, as compared to the present-day. This is mainly due to the growth in population and economic activity in developing

  20. A global water scarcity assessment under shared socio-economic pathways - Part 2: Water availability and scarcity

    NASA Astrophysics Data System (ADS)

    Hanasaki, N.; Fujimori, S.; Yamamoto, T.; Yoshikawa, S.; Masaki, Y.; Hijioka, Y.; Kainuma, M.; Kanamori, Y.; Masui, T.; Takahashi, K.; Kanae, S.

    2012-12-01

    A global water scarcity assessment for the 21st century was conducted under the latest socio-economic scenario for global change studies, namely Shared Socio-economic Pathways (SSPs). SSPs depict five global situations with substantially different socio-economic conditions. In the accompanying paper, a water use scenario compatible with the SSPs was developed. This scenario considers not only quantitative socio-economic factors such as population and electricity production but also qualitative ones such as the degree of technological change and overall environmental consciousness. In this paper, water availability and water scarcity were assessed using a global hydrological model called H08. H08 simulates both the natural water cycle and major human activities such as water withdrawal and reservoir operation. It simulates water availability and use at daily time intervals at a spatial resolution of 0.5° × 0.5°. A series of global hydrological simulations were conducted under the SSPs, taking into account different climate policy options and the results of climate models. Water scarcity was assessed using an index termed the Cumulative Withdrawal to Demand ratio, which is expressed as the accumulation of daily water withdrawal from a river over the potential daily water consumption demand. This index can be used to express whether renewable water resources are available from rivers when required. The results suggested that by 2071-2100 the population living under severely water stressed conditions for SSP1-5 will reach 2588-2793 × 106 (39-42% of total population), 3966-4298 × 106 (46-50%), 5334-5643 × 106 (52-55%), 3427-3786 × 106 (40-45%), 3164-3379 × 106 (46-49%), respectively, if climate policies are not adopted. Even in SSP1 (the scenario with least change in water use and climate) global water scarcity increases considerably, as compared to the present day. This is mainly due to the growth in population and economic activity in developing countries, and

  1. Building a Linked Learning Pathway: A Guide for Transforming High Schools for College and Career Success

    ERIC Educational Resources Information Center

    Atterbury, Rob

    2014-01-01

    This guide provides an overview of a more robust online guide and toolkit available through ConnectEd Studios. It supplies a glimpse of the sequence of steps involved in creating a new Linked Learning pathway. This publication can help coaches, district leadership, and pathway teams gain an understanding of the overall process of designing and…

  2. An epigenetic mechanism links socioeconomic status to changes in depression-related brain function in high-risk adolescents.

    PubMed

    Swartz, Johnna R; Hariri, Ahmad R; Williamson, Douglas E

    2017-02-01

    Identifying biological mechanisms through which the experience of adversity emerges as individual risk for mental illness is an important step toward developing strategies for personalized treatment and, ultimately, prevention. Preclinical studies have identified epigenetic modification of gene expression as one such mechanism. Recent clinical studies have suggested that epigenetic modification, particularly methylation of gene regulatory regions, also acts to shape human brain function associated with risk for mental illness. However, it is not yet clear whether differential gene methylation as a function of adversity contributes to the emergence of individual risk for mental illness. Using prospective longitudinal epigenetic, neuroimaging and behavioral data from 132 adolescents, we demonstrate that changes in gene methylation associated with lower socioeconomic status (SES) predict changes in risk-related brain function. Specifically, we find that lower SES during adolescence is associated with an increase in methylation of the proximal promoter of the serotonin transporter gene, which predicts greater increases in threat-related amygdala reactivity. We subsequently demonstrate that greater increases in amygdala reactivity moderate the association between a positive family history for depression and the later manifestation of depressive symptoms. These initial results suggest a specific biological mechanism through which adversity contributes to altered brain function, which in turn moderates the emergence of general liability as individual risk for mental illness. If replicated, this prospective pathway may represent a novel target biomarker for intervention and prevention among high-risk individuals.

  3. Mediating pathways in the socio-economic gradient of child development

    PubMed Central

    Attanasio, Orazio; Grantham-McGregor, Sally

    2016-01-01

    Research has previously shown a gap of near 0.5 of a standard deviation (SD) in cognition and language development between the top and bottom household wealth quartile in children aged 6–42 months in a large representative sample of low- and middle-income families in Bogota, using the Bayley Scales of Infant and Toddler Development. The gaps in fine motor and socio-emotional development were about half that size. Developmental deficits increased with age. The current study explored the associations amongst child development, household socio-economic status (SES), and a set of potential mediating variables—parental characteristics, child biomedical factors, and the quality of the home environment—in this sample. We ran mediation tests to quantify the contribution of these variables to the SES gap, and explored the role of age as a moderator. Parental education, particularly maternal education, and the quality of the home environment mediated the SES gap in all outcomes examined. Height-for-age mediated a small amount of the deficit in language scales only. More educated mothers provided better home stimulation than less educated mothers and the home environment partly mediated the effect of maternal education. These results suggested that in interventions aimed at promoting child development, those focusing on the quality of the home environment should be effective. PMID:27885311

  4. Equitable Access by Design. A Conceptual Framework for Integrated Student Supports within Linked Learning Pathways

    ERIC Educational Resources Information Center

    de Velasco, Jorge Ruiz; Newman, Elizabeth; Borsato, Graciela

    2016-01-01

    This report proposes a conceptual framework for defining and implementing a system of integrated student supports that provides equitable access to college and career readiness via Linked Learning pathways in high schools. The framework emphasizes the central commitment of the Linked Learning approach to challenge prevailing norms of…

  5. Pathways between childhood/adolescent adversity, adolescent socioeconomic status, and long-term cardiovascular disease risk in young adulthood.

    PubMed

    Doom, Jenalee R; Mason, Susan M; Suglia, Shakira F; Clark, Cari Jo

    2017-09-01

    The current study investigated mediators between childhood/adolescent adversities (e.g., dating violence, maltreatment, homelessness, and parental death), low socioeconomic status (SES) during adolescence, and cardiovascular disease (CVD) risk in young adulthood. The purpose of these analyses was to understand whether SES during adolescence and childhood/adolescent adversities affect CVD risk through similar pathways, including maternal relationship quality, health behaviors, financial stress, medical/dental care, educational attainment, sleep problems, and depressive symptoms. Using the National Longitudinal Study of Adolescent to Adult Health (N = 14,493), which has followed US adolescents (Wave 1; M = 15.9 years) through early adulthood (Wave 4; M = 28.9 years), associations were examined between childhood/adolescent adversity and SES to 30-year CVD risk in young adulthood. The outcome was a Framingham-based prediction model of CVD risk that included age, sex, body mass index, smoking, systolic blood pressure, diabetes, and antihypertensive medication use at Wave 4. Path analysis was used to examine paths through the adolescent maternal relationship to young adult mediators of CVD risk. Childhood/adolescent adversity significantly predicted greater adult CVD risk through the following pathways: maternal relationship, health behaviors, financial stress, lack of medical/dental care, and educational attainment; but not through depressive symptoms or sleep problems. Lower SES during adolescence significantly predicted greater adult CVD risk through the following pathways: health behaviors, financial stress, lack of medical/dental care, and educational attainment, but not maternal relationship, depressive symptoms, or sleep problems. Childhood/adolescent adversities and SES affected CVD risk in young adulthood through both similar and unique pathways that may inform interventions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Promoter RNA links transcriptional regulation of inflammatory pathway genes

    PubMed Central

    Matsui, Masayuki; Chu, Yongjun; Zhang, Huiying; Gagnon, Keith T.; Shaikh, Sarfraz; Kuchimanchi, Satya; Manoharan, Muthiah; Corey, David R.; Janowski, Bethany A.

    2013-01-01

    Although many long non-coding RNAs (lncRNAs) have been discovered, their function and their association with RNAi factors in the nucleus have remained obscure. Here, we identify RNA transcripts that overlap the cyclooxygenase-2 (COX-2) promoter and contain two adjacent binding sites for an endogenous miRNA, miR-589. We find that miR-589 binds the promoter RNA and activates COX-2 transcription. In addition to miR-589, fully complementary duplex RNAs that target the COX-2 promoter transcript activate COX-2 transcription. Activation by small RNA requires RNAi factors argonaute-2 (AGO2) and GW182, but does not require AGO2-mediated cleavage of the promoter RNA. Instead, the promoter RNA functions as a scaffold. Binding of AGO2 protein/small RNA complexes to the promoter RNA triggers gene activation. Gene looping allows interactions between the promoters of COX-2 and phospholipase A2 (PLA2G4A), an adjacent pro-inflammatory pathway gene that produces arachidonic acid, the substrate for COX-2 protein. miR-589 and fully complementary small RNAs regulate both COX-2 and PLA2G4A gene expression, revealing an unexpected connection between key steps of the eicosanoid signaling pathway. The work demonstrates the potential for RNA to coordinate locus-dependent assembly of related genes to form functional operons through cis-looping. PMID:23999091

  7. Adolescent work intensity, school performance, and substance use: links vary by race/ethnicity and socioeconomic status.

    PubMed

    Bachman, Jerald G; Staff, Jeremy; O'Malley, Patrick M; Freedman-Doan, Peter

    2013-11-01

    High school students who spend long hours in paid employment during the school year are at increased risk of lower grades and higher substance use, although questions remain about whether these linkages reflect causation or prior differences (selection effects). Questions also remain about whether such associations vary by socioeconomic status (SES) and race/ethnicity. This study examines those questions using nationally representative data from two decades (1991-2010) of annual Monitoring the Future surveys involving about 600,000 students in 10th and 12th grades. White students are consistently more likely than minority students to hold paid employment during the school year. Among White and Asian American students, paid work intensity is negatively related to parental education and grade point averages (GPA) and is positively related to substance use. Also among Whites and Asian Americans, students with the most highly educated parents show the strongest negative relations between work intensity and GPA, whereas the links are weaker for those with less educated parents (i.e., lower SES levels). All of these relations are less evident for Hispanic students and still less evident for African American students. It thus appears that any costs possibly attributable to long hours of student work are most severe for those who are most advantaged--White or Asian American students with highly educated parents. Working long hours is linked with fewer disadvantages among Hispanic students and especially among African American students. Youth employment dropped in 2008-2010, but the relations described above have shown little change over two decades.

  8. Understanding how low-socioeconomic status households cope with health shocks: An analysis of multi-sector linked data.

    PubMed

    Leonard, Tammy; Hughes, Amy E; Pruitt, Sandi L

    2017-01-01

    Low-socioeconomic status (SES) households have little income or wealth to buffer against the negative impacts of an adverse health event (health shock) among adult household members. However, these households may employ a variety of other coping strategies such as receiving help from family, friends, and social services. Administrative data from a non-profit food distribution center, electronic medical record (EMR) data from a safety-net healthcare system, and publicly available residential appraisal data were linked to provide insight into these coping strategies. Three broad types of coping strategies were examined: changes in household structure, residential mobility, and utilization of social services. Of 3,235 households, 20.2% had at least one adult member who experienced a health shock. These households were more likely to gain additional adult household members and employed household members, were more likely to move residence and to move distances greater than one mile, and were less likely to visit the food distribution center after the shock.

  9. Cellular and molecular pathways linking inflammation and cancer.

    PubMed

    Porta, Chiara; Larghi, Paola; Rimoldi, Monica; Totaro, Maria Grazia; Allavena, Paola; Mantovani, Alberto; Sica, Antonio

    2009-01-01

    Several experimental and epidemiological evidence indicate that, irrespective of the trigger for the development (chronic infection/inflammation or genetic alteration), a "smouldering" inflammation is associated with the most of, if not all, tumours and supports their progression. Several evidence have highlighted that tumours promote a constant influx of myelomonocytic cells that express inflammatory mediators supporting pro-tumoral functions. Myelomonocytic cells are key orchestrators of cancer-related inflammation associated with proliferation and survival of malignant cells, subversion of adaptive immune response, angiogenesis, stroma remodelling and metastasis formation. Although the connection between inflammation and cancer is unequivocal the mechanistic basis of such association are largely unknown. Recent advances in the understanding of the cellular and molecular pathways involved in cancer-related inflammation as well as their potential relevance as diagnostic, prognostic and therapeutic targets are herein discussed.

  10. Common developmental pathways link tooth shape to regeneration

    PubMed Central

    Fraser, Gareth J.; Bloomquist, Ryan F.; Streelman, J. Todd

    2013-01-01

    In many non-mammalian vertebrates, adult dentitions result from cyclical rounds of tooth regeneration wherein simple unicuspid teeth are replaced by more complex forms. Therefore and by contrast to mammalian models, the numerical majority of vertebrate teeth develop shape during the process of replacement. Here, we exploit the dental diversity of Lake Malawi cichlid fishes to ask how vertebrates generally replace their dentition and in turn how this process acts to influence resulting tooth morphologies. First, we used immunohistochemistry to chart organogenesis of continually replacing cichlid teeth and discovered an epithelial down-growth that initiates the replacement cycle via a labial proliferation bias. Next, we identified sets of co-expressed genes from common pathways active during de novo, lifelong tooth replacement and tooth morphogenesis. Of note, we found two distinct epithelial cell populations, expressing markers of dental competence and cell potency, which may be responsible for tooth regeneration. Related gene sets were simultaneously active in putative signaling centers associated with the differentiation of replacement teeth with complex shapes. Finally, we manipulated targeted pathways (BMP, FGF, Hh, Notch, Wnt/β-catenin) in vivo with small molecules and demonstrated dose-dependent effects on both tooth replacement and tooth shape. Our data suggest that the processes of tooth regeneration and tooth shape morphogenesis are integrated via a common set of molecular signals. This linkage has subsequently been lost or decoupled in mammalian dentitions where complex tooth shapes develop in first generation dentitions that lack the capacity for lifelong replacement. Our dissection of the molecular mechanics of vertebrate tooth replacement coupled to complex shape pinpoints aspects of odontogenesis that might be re-evolved in the lab to solve problems in regenerative dentistry. PMID:23422830

  11. Common developmental pathways link tooth shape to regeneration.

    PubMed

    Fraser, Gareth J; Bloomquist, Ryan F; Streelman, J Todd

    2013-05-15

    In many non-mammalian vertebrates, adult dentitions result from cyclical rounds of tooth regeneration wherein simple unicuspid teeth are replaced by more complex forms. Therefore and by contrast to mammalian models, the numerical majority of vertebrate teeth develop shape during the process of replacement. Here, we exploit the dental diversity of Lake Malawi cichlid fishes to ask how vertebrates generally replace their dentition and in turn how this process acts to influence resulting tooth morphologies. First, we used immunohistochemistry to chart organogenesis of continually replacing cichlid teeth and discovered an epithelial down-growth that initiates the replacement cycle via a labial proliferation bias. Next, we identified sets of co-expressed genes from common pathways active during de novo, lifelong tooth replacement and tooth morphogenesis. Of note, we found two distinct epithelial cell populations, expressing markers of dental competence and cell potency, which may be responsible for tooth regeneration. Related gene sets were simultaneously active in putative signaling centers associated with the differentiation of replacement teeth with complex shapes. Finally, we manipulated targeted pathways (BMP, FGF, Hh, Notch, Wnt/β-catenin) in vivo with small molecules and demonstrated dose-dependent effects on both tooth replacement and tooth shape. Our data suggest that the processes of tooth regeneration and tooth shape morphogenesis are integrated via a common set of molecular signals. This linkage has subsequently been lost or decoupled in mammalian dentitions where complex tooth shapes develop in first generation dentitions that lack the capacity for lifelong replacement. Our dissection of the molecular mechanics of vertebrate tooth replacement coupled to complex shape pinpoints aspects of odontogenesis that might be re-evolved in the lab to solve problems in regenerative dentistry. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

    PubMed Central

    Siebzehnrubl, Florian A; Silver, Daniel J; Tugertimur, Bugra; Deleyrolle, Loic P; Siebzehnrubl, Dorit; Sarkisian, Matthew R; Devers, Kelly G; Yachnis, Antony T; Kupper, Marius D; Neal, Daniel; Nabilsi, Nancy H; Kladde, Michael P; Suslov, Oleg; Brabletz, Simone; Brabletz, Thomas; Reynolds, Brent A; Steindler, Dennis A

    2013-01-01

    Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors. Glioblastoma have a poor prognosis, mainly due to infiltrating and therapy resistant cells leading to cancer recurrence. Here, tumor formation, invasion and resistance are not independent but intertwined processes regulated by the EMT activator ZEB1. PMID:23818228

  13. Linking Family Economic Hardship to Early Childhood Health: An Investigation of Mediating Pathways.

    PubMed

    Hsu, Hui-Chin; Wickrama, Kandauda A S

    2015-12-01

    The underlying mechanisms through which family economic adversity influences child health are less understood. Taking a process-oriented approach, this study examined maternal mental health and investment in children, child health insurance, and child healthcare as mediators linking family economic hardship (FEH) to child health. A structural equation modeling was applied to test the hypothesized mediating model. After adjustment for sociodemographic risk factors, results revealed: (1) a significant direct path linking FEH to poor child health (effect size = .372), and (2) six significant mediating pathways (total effect size = .089). In two mediating pathways, exposures to FEH undermined mothers' mental health: in the first pathway poor maternal mental health led to decreased parental investment, which, in turn, contributed to poor child health, whereas in the second pathway the adverse effect of poor maternal mental health was cascaded through child unmet healthcare need, which resulted in poor child health. One pathway involved child insurance status, where the effect of FEH increased the likelihood to be uninsured, which led to unmet healthcare need, and, in turn, to poor health. Three pathways involved preventive care: in one pathway FEH contributed to poor preventive care, which led to unmet healthcare need and then to poor health; in the other two pathways where poor preventive care respectively gave rise to decreased investment in children or poor maternal mental health, which further contributed to poor child health. Results suggest that the association between FEH and children's health is mediated by multiple pathways.

  14. Socio-economic inequalities in patient, primary care, referral, diagnostic, and treatment intervals on the lung cancer care pathway: protocol for a systematic review and meta-analysis.

    PubMed

    Forrest, Lynne F; Sowden, Sarah; Rubin, Greg; White, Martin; Adams, Jean

    2014-03-25

    Early diagnosis and treatment of cancer is thought to be important for improving survival. Longer time between the onset of cancer symptoms and receipt of treatment may help explain the poorer survival of UK cancer patients compared to that in other countries.Socio-economic inequalities in receipt of, and time to, treatment may contribute to socio-economic differences in cancer survival. Socio-economic inequalities in receipt of lung cancer treatment have been shown in a recent systematic review. However, no systematic review of the evidence for socio-economic inequalities in time to presentation (patient interval), time to first investigation (primary care interval), time to secondary care investigation (referral interval), time to diagnosis (diagnostic interval), and time to treatment (treatment interval) has been conducted.This review aims to assess the published and grey literature evidence for socio-economic inequalities in the length of time spent on the lung cancer diagnostic and treatment pathway, examining interim intervals on the pathway where inequalities might occur. Systematic methods will be used to identify relevant studies, assess study eligibility for inclusion, and evaluate study quality. The online databases of MEDLINE, EMBASE, and CINAHL will be searched to locate cohort studies of adults with a primary diagnosis of lung cancer; where the outcome is mean or median time to the interval endpoint (or a suitable proxy measure of this), or the likelihood of longer or shorter time to the endpoint; analysed by a measure of socio-economic position. Meta-analysis will be conducted if there are sufficient studies available with suitable data. This review will systematically determine if there are socio-economic inequalities in time from symptom onset to treatment for lung cancer. If such inequalities are present, our review evidence will help inform the development of interventions to reduce the time to diagnosis and treatment, ultimately helping to

  15. Integrating Environmental and Socio-Economic Indicators of a Linked Catchment-Coastal System Using Variable Environmental Intensity

    NASA Astrophysics Data System (ADS)

    Dymond, John R.; Davie, Tim J. A.; Fenemor, Andrew D.; Ekanayake, Jagath C.; Knight, Ben R.; Cole, Anthony O.; de Oca Munguia, Oscar Montes; Allen, Will J.; Young, Roger G.; Basher, Les R.; Dresser, Marc; Batstone, Chris J.

    2010-09-01

    Can we develop land use policy that balances the conflicting views of stakeholders in a catchment while moving toward long term sustainability? Adaptive management provides a strategy for this whereby measures of catchment performance are compared against performance goals in order to progressively improve policy. However, the feedback loop of adaptive management is often slow and irreversible impacts may result before policy has been adapted. In contrast, integrated modelling of future land use policy provides rapid feedback and potentially improves the chance of avoiding unwanted collapse events. Replacing measures of catchment performance with modelled catchment performance has usually required the dynamic linking of many models, both biophysical and socio-economic—and this requires much effort in software development. As an alternative, we propose the use of variable environmental intensity (defined as the ratio of environmental impact over economic output) in a loose coupling of models to provide a sufficient level of integration while avoiding significant effort required for software development. This model construct was applied to the Motueka Catchment of New Zealand where several biophysical (riverine water quantity, sediment, E. coli faecal bacteria, trout numbers, nitrogen transport, marine productivity) models, a socio-economic (gross output, gross margin, job numbers) model, and an agent-based model were linked. An extreme set of land use scenarios (historic, present, and intensive) were applied to this modelling framework. Results suggest that the catchment is presently in a near optimal land use configuration that is unlikely to benefit from further intensification. This would quickly put stress on water quantity (at low flow) and water quality ( E. coli). To date, this model evaluation is based on a theoretical test that explores the logical implications of intensification at an unlikely extreme in order to assess the implications of likely growth

  16. Linking hydrology of traditional irrigation canals and socio-economic aspects of agricultural water use around Mt. Kilimanjaro

    NASA Astrophysics Data System (ADS)

    Kimaro, Jerome; Scharsich, Valeska; Huwe, Bernd; Bogner, Christina

    2017-04-01

    Traditional irrigation network around Mt. Kilimanjaro has been an important resource for both ecosystem functioning and agricultural production. However, a number of irrigation furrows can no longer maintain their discharge throughout the year and their future sustainability is uncertain. The actual efforts to improve the water supply were unsuccessful. We attribute this failure to a lack of information about the actual causes and extent of the problem. We suppose that there is a strong link between the socio-economic aspects like institutional and community management of the furrows and conflicts about water use. Therefore, we conducted a study to determine the relationship between current hydrological patterns and socio-economic aspects of agricultural water use. We measured discharge at 11 locations along an altitudinal gradient on the southern slopes of Mt. Kilimanjaro. Additionally, we conducted focus group discussions with participants from 15 villages and key informants interviews (n = 15). We found that the mean discharge did not differ significantly between dry and rainy seasons (ANOVA, p = 0.17). The overall discharge pattern indicated that furrows located in lower altitude had higher mean monthly discharge rate of 65 l s-1 compared to 11.5 l s-1 at the source area of the canals. This is due to the convergence of canals downstream. 41% of furrows were seasonal, 22% dry and only 37% perennial. Despite of a seemingly better water resource availability downstream, water conflicts are a major challenge across the whole mountain communities. Key informants and group discussions reported poor management of water on the district level. The Rural Moshi and Hai District Councils operate on a top down approach that give less power to the local water management committees. However, the latter have been an important part of the traditional management system for decades. Since 1990, the district authorities are using 65% of springs from the catchment to abstract water

  17. Testing pathways linking exposure to community violence and sexual behaviors among African American youth.

    PubMed

    Voisin, Dexter R; Hotton, Anna L; Neilands, Torsten B

    2014-09-01

    Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61% females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors.

  18. Testing Pathways Linking Exposure to Community Violence and Sexual Behaviors Among African American Youth

    PubMed Central

    Hotton, Anna L.; Neilands, Torsten B.

    2014-01-01

    Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61 % females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors. PMID:24327295

  19. The Effect of Linked Learning Certified Pathways on Selected Student Outcomes

    ERIC Educational Resources Information Center

    Fitzgerald, Robert; Ottem, Randolph; Hufford, Justine

    2016-01-01

    This report examines outcomes for grade-12 students in academic years (AY) 2010-11, 2011-12, and 2012-13 who were enrolled in a Linked Learning certified pathway (LLCP) in California. Outcomes include student engagement in learning, measured by high school attendance and discipline events, as well as college readiness and postsecondary enrollment.…

  20. How socioeconomic inequalities impact pathways of care for coronary artery disease among elderly patients: study protocol for a qualitative longitudinal study

    PubMed Central

    Schröder, Sara L; Fink, Astrid; Schumann, Nadine; Moor, Irene; Plehn, Alexander; Richter, Matthias

    2015-01-01

    Introduction Several studies have identified that socioeconomic inequalities in coronary artery disease (CAD) morbidity and mortality lead to a disadvantage in patients with low socioeconomic status (SES). International studies have shown that socioeconomic inequalities also exist in terms of access, utilisation and quality of cardiac care. The aim of this qualitative study is to provide information on the impact of socioeconomic inequalities on the pathway of care for CAD, and to establish which factors lead to socioeconomic inequality of care to form and expand existing scientific theories. Methods and analysis A longitudinal qualitative study with 48 patients with CAD, aged 60–80 years, is being conducted. Patients have been recruited consecutively at the University Hospital in Halle/Saale, Germany, and will be followed for a period of 6 months. Patients are interviewed two times face-to-face using semistructured interviews. Data are transcribed and analysed based on grounded theory. Ethics and dissemination Only participants who have been informed and who have signed a declaration of consent have been included in the study. The study complies rigorously with data protection legislation. Approval of the Ethical Review Committee at the Martin-Luther University Halle-Wittenberg, Germany was obtained. The results of the study will be presented at several congresses, and will be published in high-quality peer-reviewed international journals. Trial registration number This study has been registered with the German Clinical Trials Register and assigned DRKS00007839. PMID:26553827

  1. Relational pathways between socioeconomic position and cardiovascular risk in a multiethnic urban sample: complexities and their implications for improving health in economically disadvantaged populations.

    PubMed

    Schulz, A J; House, J S; Israel, B A; Mentz, G; Dvonch, J T; Miranda, P Y; Kannan, S; Koch, M

    2008-07-01

    The study was designed to provide evidence of a cascade effect linking socioeconomic position to anthropometric indicators of cardiovascular disease (CVD) risk through effects on psychosocial stress, psychological distress and health-related behaviours, and consider implications for disease prevention and health promotion. A cross-sectional stratified two-stage probability sample of occupied housing units in three areas of Detroit, Michigan, was used in the study. 919 adults aged > or =25 years completed the survey (mean age 46.3; 53% annual household income <$20 000; 57% non-Hispanic black, 22% Latino, 19% non-Hispanic white). Variables included self-report (eg, psychosocial stress, depressive symptoms, health behaviours) and anthropometric measurements (eg, waist circumference, height, weight). The main outcome variables were depressive symptoms, smoking status, physical activity, body mass index and waist circumference. Income was inversely associated with depressive symptoms, likelihood of current smoking, physical inactivity and waist circumference. These relationships were partly or fully mediated by psychosocial stress. A suppressor effect of current smoking on the relationship between depressive symptoms and waist circumference was found. Independent effects of psychosocial stress and psychological distress on current smoking and waist circumference were found, above and beyond the mediated pathways. The results suggest that relatively modest improvements in the income of economically disadvantaged people can set in motion a cascade of effects, simultaneously reducing exposure to stressful life conditions, improving mental well-being, increasing health-promoting behaviours and reducing anthropometric risks associated with CVD. Such interventions offer important opportunities to improve population health and reduce health disparities.

  2. Linking Strengths: Identifying and Exploring Protective Factor Clusters in Academically Resilient Low-Socioeconomic Urban Students of Color

    ERIC Educational Resources Information Center

    Morales, Erik E.

    2010-01-01

    Based on data from qualitative interviews with 50 high-achieving low-socioeconomic students of color, two "clusters" of important and symbiotic protective factors are identified and explored. Each cluster consists of a series of interrelated protective factors identified by the participants as crucial to their statistically exceptional academic…

  3. Adolescent Work Intensity, School Performance, and Substance Use: Links Vary by Race/Ethnicity and Socioeconomic Status

    ERIC Educational Resources Information Center

    Bachman, Jerald G.; Staff, Jeremy; O'Malley, Patrick M.; Freedman-Doan, Peter

    2013-01-01

    High school students who spend long hours in paid employment during the school year are at increased risk of lower grades and higher substance use, although questions remain about whether these linkages reflect causation or prior differences (selection effects). Questions also remain about whether such associations vary by socioeconomic status…

  4. Linking Strengths: Identifying and Exploring Protective Factor Clusters in Academically Resilient Low-Socioeconomic Urban Students of Color

    ERIC Educational Resources Information Center

    Morales, Erik E.

    2010-01-01

    Based on data from qualitative interviews with 50 high-achieving low-socioeconomic students of color, two "clusters" of important and symbiotic protective factors are identified and explored. Each cluster consists of a series of interrelated protective factors identified by the participants as crucial to their statistically exceptional academic…

  5. Parallel Driving and Modulatory Pathways Link the Prefrontal Cortex and Thalamus

    PubMed Central

    Zikopoulos, Basilis; Barbas, Helen

    2007-01-01

    Pathways linking the thalamus and cortex mediate our daily shifts from states of attention to quiet rest, or sleep, yet little is known about their architecture in high-order neural systems associated with cognition, emotion and action. We provide novel evidence for neurochemical and synaptic specificity of two complementary circuits linking one such system, the prefrontal cortex with the ventral anterior thalamic nucleus in primates. One circuit originated from the neurochemical group of parvalbumin-positive thalamic neurons and projected focally through large terminals to the middle cortical layers, resembling ‘drivers’ in sensory pathways. Parvalbumin thalamic neurons, in turn, were innervated by small ‘modulatory’ type cortical terminals, forming asymmetric (presumed excitatory) synapses at thalamic sites enriched with the specialized metabotropic glutamate receptors. A second circuit had a complementary organization: it originated from the neurochemical group of calbindin-positive thalamic neurons and terminated through small ‘modulatory’ terminals over long distances in the superficial prefrontal layers. Calbindin thalamic neurons, in turn, were innervated by prefrontal axons through small and large terminals that formed asymmetric synapses preferentially at sites with ionotropic glutamate receptors, consistent with a driving pathway. The largely parallel thalamo-cortical pathways terminated among distinct and laminar-specific neurochemical classes of inhibitory neurons that differ markedly in inhibitory control. The balance of activation of these parallel circuits that link a high-order association cortex with the thalamus may allow shifts to different states of consciousness, in processes that are disrupted in psychiatric diseases. PMID:17786219

  6. Axonal Pathways Linked to Therapeutic and Nontherapeutic Outcomes During Psychiatric Deep Brain Stimulation

    PubMed Central

    Lujan, J. Luis; Chaturvedi, Ashutosh; Malone, Donald A.; Rezai, Ali R.; Machado, Andre G.; McIntyre, Cameron C.

    2016-01-01

    Objective The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS. Experimental design Our approach combined clinical data, diffusion tensor tractography, and computer models of patient-specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment-resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS). Principal observations Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders. Conclusions Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices. PMID:21520343

  7. Two alanine aminotranferases link mitochondrial glycolate oxidation to the major photorespiratory pathway in Arabidopsis and rice.

    PubMed

    Niessen, Markus; Krause, Katrin; Horst, Ina; Staebler, Norma; Klaus, Stephanie; Gaertner, Stefanie; Kebeish, Rashad; Araujo, Wagner L; Fernie, Alisdair R; Peterhansel, Christoph

    2012-04-01

    The major photorespiratory pathway in higher plants is distributed over chloroplasts, mitochondria, and peroxisomes. In this pathway, glycolate oxidation takes place in peroxisomes. It was previously suggested that a mitochondrial glycolate dehydrogenase (GlcDH) that was conserved from green algae lacking leaf-type peroxisomes contributes to photorespiration in Arabidopsis thaliana. Here, the identification of two Arabidopsis mitochondrial alanine:glyoxylate aminotransferases (ALAATs) that link glycolate oxidation to glycine formation are described. By this reaction, the mitochondrial side pathway produces glycine from glyoxylate that can be used in the glycine decarboxylase (GCD) reaction of the major pathway. RNA interference (RNAi) suppression of mitochondrial ALAAT did not result in major changes in metabolite pools under standard conditions or enhanced photorespiratroy flux, respectively. However, RNAi lines showed reduced photorespiratory CO(2) release and a lower CO(2) compensation point. Mitochondria isolated from RNAi lines are incapable of converting glycolate to CO(2), whereas simultaneous overexpression of GlcDH and ALAATs in transiently transformed tobacco leaves enhances glycolate conversion. Furthermore, analyses of rice mitochondria suggest that the side pathway for glycolate oxidation and glycine formation is conserved in monocotyledoneous plants. It is concluded that the photorespiratory pathway from green algae has been functionally conserved in higher plants.

  8. Pathways to Hazardous Drinking Among Racially and Socioeconomically Diverse Lesbian Women: Sexual Minority Stress, Rumination, Social Isolation, and Drinking to Cope

    PubMed Central

    Lewis, Robin J.; Mason, Tyler B.; Winstead, Barbara A.; Gaskins, Melissa; Irons, Lance B.

    2016-01-01

    Lesbian women engage in more hazardous drinking than heterosexual women yet we know relatively little about what explains this disparity. In the present study, race, socioeconomic status, minority stress, general psychological processes and distress were examined as pathways to hazardous drinking among young (18-35 years) Black and non-Hispanic White lesbian women. We used the psychological mediation framework adaptation of minority stress theory and the reserve capacity model as theoretical underpinnings of the conceptual model in the current study. Self-identified lesbian participants (N= 867) completed a one-time online survey that assessed race, socioeconomic status, perceived sexual minority discrimination, proximal minority stress (concealment, internalized homophobia, lack of connection to lesbian community), rumination, social isolation, psychological distress, drinking to cope, and hazardous drinking. Cross-sectional results demonstrated that being Black was associated with hazardous drinking via sequential mediators of rumination, psychological distress, and drinking to cope. Socioeconomic status was associated with hazardous drinking via sequential mediators of sexual minority discrimination, proximal minority stress, rumination, social isolation, psychological distress, and drinking to cope. Understanding these pathways can aid researchers and clinicians studying and working with lesbians who are at risk for hazardous drinking. PMID:28138208

  9. Pathways to Hazardous Drinking Among Racially and Socioeconomically Diverse Lesbian Women: Sexual Minority Stress, Rumination, Social Isolation, and Drinking to Cope.

    PubMed

    Lewis, Robin J; Mason, Tyler B; Winstead, Barbara A; Gaskins, Melissa; Irons, Lance B

    2016-01-01

    Lesbian women engage in more hazardous drinking than heterosexual women yet we know relatively little about what explains this disparity. In the present study, race, socioeconomic status, minority stress, general psychological processes and distress were examined as pathways to hazardous drinking among young (18-35 years) Black and non-Hispanic White lesbian women. We used the psychological mediation framework adaptation of minority stress theory and the reserve capacity model as theoretical underpinnings of the conceptual model in the current study. Self-identified lesbian participants (N= 867) completed a one-time online survey that assessed race, socioeconomic status, perceived sexual minority discrimination, proximal minority stress (concealment, internalized homophobia, lack of connection to lesbian community), rumination, social isolation, psychological distress, drinking to cope, and hazardous drinking. Cross-sectional results demonstrated that being Black was associated with hazardous drinking via sequential mediators of rumination, psychological distress, and drinking to cope. Socioeconomic status was associated with hazardous drinking via sequential mediators of sexual minority discrimination, proximal minority stress, rumination, social isolation, psychological distress, and drinking to cope. Understanding these pathways can aid researchers and clinicians studying and working with lesbians who are at risk for hazardous drinking.

  10. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase

    PubMed Central

    Christmas, David M; Potokar, JP; Davies, Simon JC

    2011-01-01

    This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3-dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway. PMID:21792309

  11. Biochemical evidence for an alternate pathway in N-linked glycoprotein biosynthesis

    PubMed Central

    Larkin, Angelyn; Chang, Michelle M.; Whitworth, Garrett E.; Imperiali, Barbara

    2013-01-01

    Asparagine-linked glycosylation is a complex protein modification conserved among all three domains of life. Herein we report the in vitro analysis of N-linked glycosylation from the methanogenic archaeon Methanococcus voltae. Using a suite of synthetic and semisynthetic substrates, we show that AglK initiates N-linked glycosylation in M. voltae through the formation of α-linked dolichyl monophosphate N-acetylglucosamine (Dol-P-GlcNAc), which contrasts with the polyprenyl-diphosphate intermediates that feature in both eukaryotes and bacteria. Intriguingly, AglK exhibits high sequence homology to dolichyl-phosphate β-glucosyltransferases, including Alg5 in eukaryotes, suggesting a common evolutionary origin. The combined action of the first two enzymes, AglK and AglC, afforded an α-linked Dol-P-glycan that serves as a competent substrate for the archaeal oligosaccharyl transferase AglB. These studies provide the first biochemical evidence revealing that despite the apparent similarity of the overall pathways, there are actually two general strategies to achieve N-linked glycoproteins across the domains of life. PMID:23624439

  12. Intergenerational Pathways Linking Childhood Sexual Abuse to HIV Risk Among Women

    PubMed Central

    Cavanaugh, Courtenay E.; Classen, Catherine C.

    2009-01-01

    Childhood sexual abuse is prevalent among women and it has been linked to a number of problems affecting women's health and functioning including women's parenting practices. Another body of literature has linked specific maternal parenting practices to daughters’ HIV risk, including mother-daughter sex communication, monitoring/knowledge about daughters’ activities, mother-daughter relationship quality, attitudes towards sex, and modeling of sexual values. This paper reviews and links these two bodies of literature to indicate how maternal histories of childhood sexual abuse may compromise mothers’ parenting practices, which may in turn impact daughters’ HIV risk. We also build upon Malow and colleagues’ model (2006) of the associations between childhood sexual abuse and HIV risk to present a model indicating potential intergenerational pathways between childhood sexual abuse and HIV risk among women. The literature supporting this model and gaps in the literature are described. PMID:19333846

  13. How socioeconomic inequalities impact pathways of care for coronary artery disease among elderly patients: study protocol for a qualitative longitudinal study.

    PubMed

    Schröder, Sara L; Fink, Astrid; Schumann, Nadine; Moor, Irene; Plehn, Alexander; Richter, Matthias

    2015-11-09

    Several studies have identified that socioeconomic inequalities in coronary artery disease (CAD) morbidity and mortality lead to a disadvantage in patients with low socioeconomic status (SES). International studies have shown that socioeconomic inequalities also exist in terms of access, utilisation and quality of cardiac care. The aim of this qualitative study is to provide information on the impact of socioeconomic inequalities on the pathway of care for CAD, and to establish which factors lead to socioeconomic inequality of care to form and expand existing scientific theories. A longitudinal qualitative study with 48 patients with CAD, aged 60-80 years, is being conducted. Patients have been recruited consecutively at the University Hospital in Halle/Saale, Germany, and will be followed for a period of 6 months. Patients are interviewed two times face-to-face using semistructured interviews. Data are transcribed and analysed based on grounded theory. Only participants who have been informed and who have signed a declaration of consent have been included in the study. The study complies rigorously with data protection legislation. Approval of the Ethical Review Committee at the Martin-Luther University Halle-Wittenberg, Germany was obtained. The results of the study will be presented at several congresses, and will be published in high-quality peer-reviewed international journals. This study has been registered with the German Clinical Trials Register and assigned DRKS00007839. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  14. Physiological links among alternative electron transport pathways that reduce and oxidize plastoquinone in Arabidopsis.

    PubMed

    Okegawa, Yuki; Kobayashi, Yoshichika; Shikanai, Toshiharu

    2010-08-01

    In addition to linear electron transport from water to NADP(+) , alternative electron transport pathways are believed to regulate photosynthesis. In the two routes of photosystem I (PSI) cyclic electron transport, electrons are recycled from the stromal reducing pool to plastoquinone (PQ), generating additional ΔpH (proton gradient across thylakoid membranes). Plastid terminal oxidase (PTOX) accepts electrons from PQ and transfers them to oxygen to produce water. Although both electron transport pathways share the PQ pool, it is unclear whether they interact in vivo. To investigate the physiological link between PSI cyclic electron transport-dependent PQ reduction and PTOX-dependent PQ oxidation, we characterized mutants defective in both functions. Impairment of PSI cyclic electron transport suppressed leaf variegation in the Arabidopsis immutans (im) mutant, which is defective in PTOX. The im variegation was more effectively suppressed in the pgr5 mutant, which is defective in the main pathway of PSI cyclic electron transport, than in the crr2-2 mutant, which is defective in the minor pathway. In contrast to this chloroplast development phenotype, the im defect alleviated the growth phenotype of the crr2-2 pgr5 double mutant. This was accompanied by partial suppression of stromal over-reduction and restricted linear electron transport. We discuss the function of the alternative electron transport pathways in both chloroplast development and photosynthesis in mature leaves. © 2010 The Authors. Journal compilation © 2010 Blackwell Publishing Ltd.

  15. Towards precision medicine: discovering novel gynecological cancer biomarkers and pathways using linked data.

    PubMed

    Jha, Alokkumar; Khan, Yasar; Mehdi, Muntazir; Karim, Md Rezaul; Mehmood, Qaiser; Zappa, Achille; Rebholz-Schuhmann, Dietrich; Sahay, Ratnesh

    2017-09-19

    Next Generation Sequencing (NGS) is playing a key role in therapeutic decision making for the cancer prognosis and treatment. The NGS technologies are producing a massive amount of sequencing datasets. Often, these datasets are published from the isolated and different sequencing facilities. Consequently, the process of sharing and aggregating multisite sequencing datasets are thwarted by issues such as the need to discover relevant data from different sources, built scalable repositories, the automation of data linkage, the volume of the data, efficient querying mechanism, and information rich intuitive visualisation. We present an approach to link and query different sequencing datasets (TCGA, COSMIC, REACTOME, KEGG and GO) to indicate risks for four cancer types - Ovarian Serous Cystadenocarcinoma (OV), Uterine Corpus Endometrial Carcinoma (UCEC), Uterine Carcinosarcoma (UCS), Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) - covering the 16 healthy tissue-specific genes from Illumina Human Body Map 2.0. The differentially expressed genes from Illumina Human Body Map 2.0 are analysed together with the gene expressions reported in COSMIC and TCGA repositories leading to the discover of potential biomarkers for a tissue-specific cancer. We analyse the tissue expression of genes, copy number variation (CNV), somatic mutation, and promoter methylation to identify associated pathways and find novel biomarkers. We discovered twenty (20) mutated genes and three (3) potential pathways causing promoter changes in different gynaecological cancer types. We propose a data-interlinked platform called BIOOPENER that glues together heterogeneous cancer and biomedical repositories. The key approach is to find correspondences (or data links) among genetic, cellular and molecular features across isolated cancer datasets giving insight into cancer progression from normal to diseased tissues. The proposed BIOOPENER platform enriches mutations by filling in

  16. City-Specific Spatiotemporal Infant and Neonatal Mortality Clusters: Links with Socioeconomic and Air Pollution Spatial Patterns in France

    PubMed Central

    Padilla, Cindy M.; Kihal-Talantikit, Wahida; Vieira, Verónica M.; Deguen, Séverine

    2016-01-01

    Infant and neonatal mortality indicators are known to vary geographically, possibly as a result of socioeconomic and environmental inequalities. To better understand how these factors contribute to spatial and temporal patterns, we conducted a French ecological study comparing two time periods between 2002 and 2009 for three (purposefully distinct) Metropolitan Areas (MAs) and the city of Paris, using the French census block of parental residence as the geographic unit of analysis. We identified areas of excess risk and assessed the role of neighborhood deprivation and average nitrogen dioxide concentrations using generalized additive models to generate maps smoothed on longitude and latitude. Comparison of the two time periods indicated that statistically significant areas of elevated infant and neonatal mortality shifted northwards for the city of Paris, are present only in the earlier time period for Lille MA, only in the later time period for Lyon MA, and decrease over time for Marseille MA. These city-specific geographic patterns in neonatal and infant mortality are largely explained by socioeconomic and environmental inequalities. Spatial analysis can be a useful tool for understanding how risk factors contribute to disparities in health outcomes ranging from infant mortality to infectious disease—a leading cause of infant mortality. PMID:27338439

  17. City-Specific Spatiotemporal Infant and Neonatal Mortality Clusters: Links with Socioeconomic and Air Pollution Spatial Patterns in France.

    PubMed

    Padilla, Cindy M; Kihal-Talantikit, Wahida; Vieira, Verónica M; Deguen, Séverine

    2016-06-22

    Infant and neonatal mortality indicators are known to vary geographically, possibly as a result of socioeconomic and environmental inequalities. To better understand how these factors contribute to spatial and temporal patterns, we conducted a French ecological study comparing two time periods between 2002 and 2009 for three (purposefully distinct) Metropolitan Areas (MAs) and the city of Paris, using the French census block of parental residence as the geographic unit of analysis. We identified areas of excess risk and assessed the role of neighborhood deprivation and average nitrogen dioxide concentrations using generalized additive models to generate maps smoothed on longitude and latitude. Comparison of the two time periods indicated that statistically significant areas of elevated infant and neonatal mortality shifted northwards for the city of Paris, are present only in the earlier time period for Lille MA, only in the later time period for Lyon MA, and decrease over time for Marseille MA. These city-specific geographic patterns in neonatal and infant mortality are largely explained by socioeconomic and environmental inequalities. Spatial analysis can be a useful tool for understanding how risk factors contribute to disparities in health outcomes ranging from infant mortality to infectious disease-a leading cause of infant mortality.

  18. Integrated Basin-Scale Modelling and Assessment: Lessons and Challenges in Linking Biophysical and Socioeconomic Sciences for Enhancing Sustainability Outcomes

    NASA Astrophysics Data System (ADS)

    Jakeman, A. J.; Croke, B. F.; Letcher, R. A.; Newham, L. T.; Norton, J. P.

    2004-12-01

    Integrated Assessment (IA) and Integrated Scenario Modelling (ISM) are being increasingly used to assess sustainability options and, in particular, the effects of policy changes, land use management, climate forcing and other uncontrollable drivers on a wide range of river basin outcomes. IA and ISM are processes that invoke the necessary range of biophysical and socioeconomic disciplines and embrace stakeholder involvement as an essential ingredient. The authors report on their IA studies in Australian and Asian river basins. They illustrate a range of modelling frameworks and tools that were used to perform the assessments, engage the relevant interest groups and promote systems understanding and social learning. The studies cover a range of issues and policies including poverty alleviation, industrial investments, infrastructure provision, erosion and sedimentation, water supply allocation, and ecological protection. The positive impacts of these studies are presented, as well as the lessons learnt and the challenges for modellers and disciplinary experts in advancing the reputation and performance of integrated assessment exercises.

  19. Modeling the pathways linking childhood hyperactivity and substance use disorder in young adulthood.

    PubMed

    Tarter, Ralph E; Kirisci, Levent; Feske, Ulrike; Vanyukov, Michael

    2007-06-01

    This study modeled direct and mediated pathways linking childhood hyperactivity and substance use disorder (SUD). Boys (n = 112) were administered the revised Drug Use Screening Inventory at age 12-14 years and the Structured Clinical Interview for DSM-IV at age 22 years. Six newly derived scales having established heritability were conceptually organized into internalizing and externalizing pathways to SUD emanating from childhood hyperactivity. Hyperactivity directly predicts SUD. Neuroticism, conduct problems, and their respective manifestations of social withdrawal and school problems mediated the association between hyperactivity and SUD. Hyperactivity also predicted neuroticism that, in turn, predicted low self-esteem leading to social withdrawal and SUD. These results indicate that hyperactivity is a diathesis for both internalizing and externalizing disturbances that, in turn, portend differential expression of psychosocial maladjustment presaging SUD.

  20. Planarian Hh signaling regulates regeneration polarity and links Hh pathway evolution to cilia.

    PubMed

    Rink, Jochen C; Gurley, Kyle A; Elliott, Sarah A; Sánchez Alvarado, Alejandro

    2009-12-04

    The Hedgehog (Hh) signaling pathway plays multiple essential roles during metazoan development, homeostasis, and disease. Although core protein components are highly conserved, the variations in Hh signal transduction mechanisms exhibited by existing model systems (Drosophila, fish, and mammals) are difficult to understand. We characterized the Hh pathway in planarians. Hh signaling is essential for establishing the anterior/posterior axis during regeneration by modulating wnt expression. Moreover, RNA interference methods to reduce signal transduction proteins Cos2/Kif27/Kif7, Fused, or Iguana do not result in detectable Hh signaling defects; however, these proteins are essential for planarian ciliogenesis. Our study expands the understanding of Hh signaling in the animal kingdom and suggests an ancestral mechanistic link between Hh signaling and the function of cilia.

  1. The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.

    PubMed

    Knipscheer, Puck; Räschle, Markus; Smogorzewska, Agata; Enoiu, Milica; Ho, The Vinh; Schärer, Orlando D; Elledge, Stephen J; Walter, Johannes C

    2009-12-18

    Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.

  2. The tor pathway regulates gene expression by linking nutrient sensing to histone acetylation.

    PubMed

    Rohde, John R; Cardenas, Maria E

    2003-01-01

    The Tor pathway mediates cell growth in response to nutrient availability, in part by inducing ribosomal protein (RP) gene expression via an unknown mechanism. Expression of RP genes coincides with recruitment of the Esa1 histone acetylase to RP gene promoters. We show that inhibition of Tor with rapamycin releases Esa1 from RP gene promoters and leads to histone H4 deacetylation without affecting promoter occupancy by Rap1 and Abf1. Genetic and biochemical evidence identifies Rpd3 as the major histone deacetylase responsible for reversing histone H4 acetylation at RP gene promoters in response to Tor inhibition by rapamycin or nutrient limitation. Our results illustrate that the Tor pathway links nutrient sensing with histone acetylation to control RP gene expression and cell growth.

  3. Linking Biosynthetic Gene Clusters to their Metabolites via Pathway-Targeted Molecular Networking

    PubMed Central

    Trautman, Eric P.; Crawford, Jason M.

    2016-01-01

    The connection of microbial biosynthetic gene clusters to the small molecule metabolites they encode is central to the discovery and characterization of new metabolic pathways with ecological and pharmacological potential. With increasing microbial genome sequence information being deposited into publicly available databases, it is clear that microbes have the coding capacity for many more biologically active small molecules than previously realized. Of increasing interest are the small molecules encoded by the human microbiome, as these metabolites likely mediate a variety of currently uncharacterized human-microbe interactions that influence health and disease. In this mini-review, we describe the ongoing biosynthetic, structural, and functional characterizations of the genotoxic colibactin pathway in gut bacteria as a thematic example of linking biosynthetic gene clusters to their metabolites. We also highlight other natural products that are produced through analogous biosynthetic logic and comment on some current disconnects between bioinformatics predictions and experimental structural characterizations. Lastly, we describe the use of pathway-targeted molecular networking as a tool to characterize secondary metabolic pathways within complex metabolomes and to aid in downstream metabolite structural elucidation efforts. PMID:26456470

  4. Hydrodynamics selects the pathway for displacive transformations in DNA-linked colloidal crystallites.

    PubMed

    Jenkins, Ian C; Casey, Marie T; McGinley, James T; Crocker, John C; Sinno, Talid

    2014-04-01

    The degree to which DNA-linked particle crystals, particularly those composed of micrometer-scale colloids, are able to dynamically evolve or whether they are kinetically arrested after formation remains poorly understood. Here, we study a recently observed displacive transformation in colloidal binary superlattice crystals, whereby a body-centered cubic to face-centered cubic transformation is found to proceed spontaneously under some annealing conditions. Using a comprehensive suite of computer simulation tools, we develop a framework for analyzing the many displacive transformation pathways corresponding to distinct, but energetically degenerate, random hexagonal close-packed end states. Due to the short-ranged, spherically symmetric nature of the particle interactions the pathways are all barrierless, suggesting that all end states should be equally likely. Instead, we find that hydrodynamic correlations between particles result in anisotropic mobility along the various possible displacive pathways, strongly selecting for pathways that lead to the fcc-CuAu-I configuration, explaining recent experimental observations. This finding may provide clues for discovering new approaches for controlling structure in this emerging class of materials.

  5. The Role of Parenting in Linking Family Socioeconomic Disadvantage to Physical Activity in Adolescence and Young Adulthood

    ERIC Educational Resources Information Center

    Lee, Hedwig

    2014-01-01

    Parents play an important role in influencing adolescent health behaviors and parenting practices may be an important pathway through which social disadvantage influences adolescent health behaviors that can persist into adulthood. This analysis uses the National Longitudinal Study of Adolescent Health to examine how parenting practices mediate…

  6. The Role of Parenting in Linking Family Socioeconomic Disadvantage to Physical Activity in Adolescence and Young Adulthood

    ERIC Educational Resources Information Center

    Lee, Hedwig

    2014-01-01

    Parents play an important role in influencing adolescent health behaviors and parenting practices may be an important pathway through which social disadvantage influences adolescent health behaviors that can persist into adulthood. This analysis uses the National Longitudinal Study of Adolescent Health to examine how parenting practices mediate…

  7. Utility of linking primary care electronic medical records with Canadian census data to study the determinants of chronic disease: an example based on socioeconomic status and obesity.

    PubMed

    Biro, Suzanne; Williamson, Tyler; Leggett, Jannet Ann; Barber, David; Morkem, Rachael; Moore, Kieran; Belanger, Paul; Mosley, Brian; Janssen, Ian

    2016-03-11

    Electronic medical records (EMRs) used in primary care contain a breadth of data that can be used in public health research. Patient data from EMRs could be linked with other data sources, such as a postal code linkage with Census data, to obtain additional information on environmental determinants of health. While promising, successful linkages between primary care EMRs with geographic measures is limited due to ethics review board concerns. This study tested the feasibility of extracting full postal code from primary care EMRs and linking this with area-level measures of the environment to demonstrate how such a linkage could be used to examine the determinants of disease. The association between obesity and area-level deprivation was used as an example to illustrate inequalities of obesity in adults. The analysis included EMRs of 7153 patients aged 20 years and older who visited a single, primary care site in 2011. Extracted patient information included demographics (date of birth, sex, postal code) and weight status (height, weight). Information extraction and management procedures were designed to mitigate the risk of individual re-identification when extracting full postal code from source EMRs. Based on patients' postal codes, area-based deprivation indexes were created using the smallest area unit used in Canadian censuses. Descriptive statistics and socioeconomic disparity summary measures of linked census and adult patients were calculated. The data extraction of full postal code met technological requirements for rendering health information extracted from local EMRs into anonymized data. The prevalence of obesity was 31.6 %. There was variation of obesity between deprivation quintiles; adults in the most deprived areas were 35 % more likely to be obese compared with adults in the least deprived areas (Chi-Square = 20.24(1), p < 0.0001). Maps depicting spatial representation of regional deprivation and obesity were created to highlight high

  8. Genome-Scale Networks Link Neurodegenerative Disease Genes to α-Synuclein through Specific Molecular Pathways.

    PubMed

    Khurana, Vikram; Peng, Jian; Chung, Chee Yeun; Auluck, Pavan K; Fanning, Saranna; Tardiff, Daniel F; Bartels, Theresa; Koeva, Martina; Eichhorn, Stephen W; Benyamini, Hadar; Lou, Yali; Nutter-Upham, Andy; Baru, Valeriya; Freyzon, Yelena; Tuncbag, Nurcan; Costanzo, Michael; San Luis, Bryan-Joseph; Schöndorf, David C; Barrasa, M Inmaculada; Ehsani, Sepehr; Sanjana, Neville; Zhong, Quan; Gasser, Thomas; Bartel, David P; Vidal, Marc; Deleidi, Michela; Boone, Charles; Fraenkel, Ernest; Berger, Bonnie; Lindquist, Susan

    2017-02-22

    Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To "humanize" this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology. TransposeNet linked α-syn to multiple parkinsonism genes and druggable targets through perturbed protein trafficking and ER quality control as well as mRNA metabolism and translation. A calcium signaling hub linked these processes to perturbed mitochondrial quality control and function, metal ion transport, transcriptional regulation, and signal transduction. Parkinsonism gene interaction profiles spatially opposed in the network (ATP13A2/PARK9 and VPS35/PARK17) were highly distinct, and network relationships for specific genes (LRRK2/PARK8, ATXN2, and EIF4G1/PARK18) were confirmed in patient induced pluripotent stem cell (iPSC)-derived neurons. This cross-species platform connected diverse neurodegenerative genes to proteinopathy through specific mechanisms and may facilitate patient stratification for targeted therapy.

  9. High CO2 Primes Plant Biotic Stress Defences through Redox-Linked Pathways1[OPEN

    PubMed Central

    2016-01-01

    Industrial activities have caused tropospheric CO2 concentrations to increase over the last two centuries, a trend that is predicted to continue for at least the next several decades. Here, we report that growth of plants in a CO2-enriched environment activates responses that are central to defense against pathogenic attack. Salicylic acid accumulation was triggered by high-growth CO2 in Arabidopsis (Arabidopsis thaliana) and other plants such as bean (Phaseolus vulgaris). A detailed analysis in Arabidopsis revealed that elevated CO2 primes multiple defense pathways, leading to increased resistance to bacterial and fungal challenge. Analysis of gene-specific mutants provided no evidence that activation of plant defense pathways by high CO2 was caused by stomatal closure. Rather, the activation is partly linked to metabolic effects involving redox signaling. In support of this, genetic modification of redox components (glutathione contents and NADPH-generating enzymes) prevents full priming of the salicylic acid pathway and associated resistance by high CO2. The data point to a particularly influential role for the nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase, a cytosolic enzyme whose role in plants remains unclear. Our observations add new information on relationships between high CO2 and oxidative signaling and provide novel insight into plant stress responses in conditions of increased CO2. PMID:27578552

  10. Dominant Enhancers of Egfr in Drosophila Melanogaster: Genetic Links between the Notch and Egfr Signaling Pathways

    PubMed Central

    Price, J. V.; Savenye, E. D.; Lum, D.; Breitkreutz, A.

    1997-01-01

    The Drosophila epidermal growth factor receptor (EGFR) is a key component of a complex signaling pathway that participates in multiple developmental processes. We have performed an F(1) screen for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, we have recovered mutations in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the E(Egfr)s we have identified show dominant interactions in transheterozygous combinations with each other and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and EGFR signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro revealed that reductions in Egfr activity enhanced both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles led to the formation of ectopic compound eyes in a dosage sensitive manner. Our findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context. PMID:9383058

  11. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

    PubMed Central

    Rodilla, Verónica; Villanueva, Alberto; Obrador-Hevia, Antonia; Robert-Moreno, Àlex; Fernández-Majada, Vanessa; Grilli, Andrea; López-Bigas, Nuria; Bellora, Nicolás; Albà, M. Mar; Torres, Ferran; Duñach, Mireia; Sanjuan, Xavier; Gonzalez, Sara; Gridley, Thomas; Capella, Gabriel; Bigas, Anna; Espinosa, Lluís

    2009-01-01

    Notch has been linked to β-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/β-catenin (down-regulated when blocking Wnt/β-catenin) that are directly regulated by Notch (repressed by γ-secretase inhibitors and up-regulated by active Notch1 in the absence of β-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through β-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/β-catenin pathway in tumors implanted s.c. in nude mice. Crossing APCMin/+ with Jagged1+/Δ mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear β-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by β-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways. PMID:19325125

  12. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.

    PubMed

    Rodilla, Verónica; Villanueva, Alberto; Obrador-Hevia, Antonia; Robert-Moreno, Alex; Fernández-Majada, Vanessa; Grilli, Andrea; López-Bigas, Nuria; Bellora, Nicolás; Albà, M Mar; Torres, Ferran; Duñach, Mireia; Sanjuan, Xavier; Gonzalez, Sara; Gridley, Thomas; Capella, Gabriel; Bigas, Anna; Espinosa, Lluís

    2009-04-14

    Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.

  13. The TEA transcription factor Tec1 links TOR and MAPK pathways to coordinate yeast development.

    PubMed

    Brückner, Stefan; Kern, Sandra; Birke, Raphael; Saugar, Irene; Ulrich, Helle D; Mösch, Hans-Ulrich

    2011-10-01

    In Saccharomyces cerevisiae, the TEA transcription factor Tec1 controls several developmental programs in response to nutrients and pheromones. Tec1 is targeted by the pheromone-responsive Fus3/Kss1 mitogen-activated protein kinase (MAPK) cascade, which destabilizes the transcription factor to ensure efficient mating of sexual partner cells. The regulation of Tec1 by signaling pathways that control cell division and development in response to nutrients, however, is not known. Here, we show that Tec1 protein stability is under control of the nutrient-sensitive target of rapamycin complex 1 (TORC1) signaling pathway via the Tip41-Tap42-Sit4 branch. We further show that degradation of Tec1 upon inhibition of TORC1 by rapamycin does not involve polyubiquitylation and appears to be proteasome independent. However, rapamycin-induced Tec1 degradation depends on the HECT ubiquitin ligase Rsp5, which physically interacts with Tec1 via conserved PxY motives. We further demonstrate that rapamycin and mating pheromone control Tec1 protein stability through distinct mechanisms by targeting different domains of the transcription factor. Finally, we show that Tec1 is a positive regulator of yeast chronological lifespan (CLS), a known TORC1-regulated process. Our findings indicate that in yeast, Tec1 links TORC1 and MAPK signaling pathways to coordinate control of cellular development in response to different stimuli.

  14. IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance.

    PubMed

    Lee, Dung-Fang; Kuo, Hsu-Ping; Chen, Chun-Te; Wei, Yongkun; Chou, Chao-Kai; Hung, Jen-Yu; Yen, Chia-Jui; Hung, Mien-Chie

    2008-11-01

    The proinflammatory cytokine TNFalpha is one of the factors that links obesity-derived chronic inflammation with insulin resistance. Activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation and the inhibition of IRS1 by mTOR and its downstream effector, S6K1. It remains elusive that whether the mTOR pathway has a role in TNFalpha-mediated insulin resistance. In the present study, we demonstrated that TNFalpha-IKKbeta-mediated inactivation of TSC1 resulted in increasing phosphorylation of IRS1 serine 307 and serine 636/639, impaired insulin-induced glucose uptake, tyrosine phosphorylation of IRS1, and the association between IRS1 and PI3K p85. Furthermore, a higher expression of pIKKbeta (S181), pTSC1(S511), and pS6(S240/244) was found in livers obtained from both C57BL/6J mice on a high-fat diet and B6.V-Lepob/J mice. Collectively, dysregulation of the TSC1/ TSC2/mTOR signaling pathway by IKKbeta is a common molecular switch for both cancer pathogenesis and diet- and obesity-induced insulin resistance.

  15. High CO2 Primes Plant Biotic Stress Defences through Redox-Linked Pathways.

    PubMed

    Mhamdi, Amna; Noctor, Graham

    2016-10-01

    Industrial activities have caused tropospheric CO2 concentrations to increase over the last two centuries, a trend that is predicted to continue for at least the next several decades. Here, we report that growth of plants in a CO2-enriched environment activates responses that are central to defense against pathogenic attack. Salicylic acid accumulation was triggered by high-growth CO2 in Arabidopsis (Arabidopsis thaliana) and other plants such as bean (Phaseolus vulgaris). A detailed analysis in Arabidopsis revealed that elevated CO2 primes multiple defense pathways, leading to increased resistance to bacterial and fungal challenge. Analysis of gene-specific mutants provided no evidence that activation of plant defense pathways by high CO2 was caused by stomatal closure. Rather, the activation is partly linked to metabolic effects involving redox signaling. In support of this, genetic modification of redox components (glutathione contents and NADPH-generating enzymes) prevents full priming of the salicylic acid pathway and associated resistance by high CO2 The data point to a particularly influential role for the nonphosphorylating glyceraldehyde-3-phosphate dehydrogenase, a cytosolic enzyme whose role in plants remains unclear. Our observations add new information on relationships between high CO2 and oxidative signaling and provide novel insight into plant stress responses in conditions of increased CO2. © 2016 American Society of Plant Biologists. All Rights Reserved.

  16. A spatial analysis of variations in health access: linking geography, socio-economic status and access perceptions

    PubMed Central

    2011-01-01

    Background This paper analyses the relationship between public perceptions of access to general practitioners (GPs) surgeries and hospitals against health status, car ownership and geographic distance. In so doing it explores the different dimensions associated with facility access and accessibility. Methods Data on difficulties experienced in accessing health services, respondent health status and car ownership were collected through an attitudes survey. Road distances to the nearest service were calculated for each respondent using a GIS. Difficulty was related to geographic distance, health status and car ownership using logistic generalized linear models. A Geographically Weighted Regression (GWR) was used to explore the spatial non-stationarity in the results. Results Respondent long term illness, reported bad health and non-car ownership were found to be significant predictors of difficulty in accessing GPs and hospitals. Geographic distance was not a significant predictor of difficulty in accessing hospitals but was for GPs. GWR identified the spatial (local) variation in these global relationships indicating locations where the predictive strength of the independent variables was higher or lower than the global trend. The impacts of bad health and non-car ownership on the difficulties experienced in accessing health services varied spatially across the study area, whilst the impacts of geographic distance did not. Conclusions Difficulty in accessing different health facilities was found to be significantly related to health status and car ownership, whilst the impact of geographic distance depends on the service in question. GWR showed how these relationships were varied across the study area. This study demonstrates that the notion of access is a multi-dimensional concept, whose composition varies with location, according to the facility being considered and the health and socio-economic status of the individual concerned. PMID:21787394

  17. Linking the Fragile X mental retardation protein to the lipoxygenase pathway.

    PubMed

    Beaulieu, Marc-Alexandre

    2013-03-01

    Fragile X mental retardation is caused by the absence of the FMRP (fragile X mental retardation protein) a RNA-binding protein encoded by the Fmr1 gene. Despite the large number of studies about this syndrome, it is still unclear how the absence of FMRP affects the physiology of the nervous system. It has been reported however that the brain of the Fmr1-KO mouse shows altered membrane protein and lipid oxidation. There is also indirect evidence that FMRP may be involved in a negative feedback mechanism with metabotropic glutamate receptors (mGluRs). In this article, we will discuss several lines of evidences which tend to prove that the lipoxygenase pathway might be the missing link between FMRP and mGluRs.

  18. Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

    PubMed Central

    Balsam, A; Sexton, F; Borges, M; Ingbar, S H

    1983-01-01

    Studies were performed to elucidate the nature of the pathway of hepatic thyroxine (T4) metabolism that is activated by inhibitors of liver catalase. For this purpose, the metabolism of T4 in homogenates of rat liver was monitored with T4 labeled with 125I either at the 5'-position of the outer-ring (125I-beta-T4) or uniformly in both the outer and inner rings (125I-U-T4). In homogenates incubated with 125I-beta-T4 in an atmosphere of O2, the catalase inhibitor aminotriazole greatly enhanced T4 degradation, promoting the formation of large proportions of 125I-labeled iodide (125I-I-) and chromatographically immobile origin material (125I-OM), but only a minute proportion of 125I-labeled 3,5,3'-triiodothyronine (125I-T3) (T3 neogenesis). In an atmosphere of N2, in contrast, homogenates produced much larger proportions of 125I-T3, and aminotriazole had no effect. In incubations with 125I-U-T4, under aerobic conditions, control homogenates degraded T4 slowly; formation of 125I-labeled 3,5-diiodotyrosine (125I-DIT) was seen only occasionally and in minute proportions. However, in homogenates incubated under O2, but not N2, aminotriazole consistently elicited the formation of large proportions of 125I-DIT, indicating that the ether link of T4 was being cleaved by an O2-dependent process. Formation of 125I-DIT in the presence of aminotriazole and O2 was markedly inhibited by the substrates of peroxidase, aminoantipyrine, and guaiacol. GSH greatly attenuated the increase in DIT formation induced by aminotriazole, whereas the sulfhydryl inhibitor N-ethylmaleimide (NEM) activated the DIT-generating pathway, even in the absence of aminotriazole. Activation of the in vitro formation of 125I-DIT from 125I-U-T4 was also produced by the in vivo administration of aminotriazole or bacterial endotoxin, an agent that reduces hepatic catalase activity. Studies with 125I-DIT as substrate revealed it to be rapidly deiodinated by liver homogenates under aerobic conditions. Recovery of

  19. Molecular pathways linking non-shivering thermogenesis and obesity: focusing on brown adipose tissue development.

    PubMed

    Valente, Angelica; Jamurtas, Athanasios Z; Koutedakis, Yiannis; Flouris, Andreas D

    2015-02-01

    An increase in energy intake and/or a decrease in energy expenditure lead to fat storage, causing overweight and obesity phenotypes. The objective of this review was to analyse, for the first time using a systematic approach, all published evidence from the past 8 years regarding the molecular pathways linking non-shivering thermogenesis and obesity in mammals, focusing on mechanisms involved in brown adipose tissue development. Two major databases were scanned from 2006 to 2013 using 'brown adipose tissue' AND 'uncoupling protein-1' AND 'mammalian thermoregulation' AND 'obesity' as key words. A total of 61 articles were retrieved using the search criteria. The available research used knockout methodologies, various substances, molecules and agonist treatments, or different temperature and diet conditions, to assess the molecular pathways linking non-shivering thermogenesis and obesity. By integrating the results of the evaluated animal and human studies, our analysis identified specific molecules that enhance non-shivering thermogenesis and metabolism by: (i) stimulating 'brite' (brown-like) cell development in white adipose tissue; (ii) increasing uncoupling protein-1 expression in brite adipocytes; and (iii) augmenting brown and/or brite adipose tissue mass. The latter can be also increased through low temperature, hibernation and/or molecules involved in brown adipocyte differentiation. Cold stimuli and/or certain molecules activate uncoupling protein-1 in the existing brown adipocytes, thus increasing total energy expenditure by a magnitude proportional to the number of available brown adipocytes. Future research should address the interplay between body mass, brown adipose tissue mass, as well as the main molecules involved in brite cell development.

  20. Genotype link with extreme antisocial behavior: the contribution of cognitive pathways.

    PubMed

    Langley, Kate; Heron, Jon; O'Donovan, Michael C; Owen, Michael J; Thapar, Anita

    2010-12-01

    genotype but may not lie on the risk pathway to antisocial behavior. The findings demonstrate the importance of testing links between genotype, intermediate phenotype, and clinical outcome in the same sample to identify potential risk pathways.

  1. 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

  2. Mouse MAELSTROM: the link between meiotic silencing of unsynapsed chromatin and microRNA pathway?

    PubMed

    Costa, Yael; Speed, Robert M; Gautier, Philippe; Semple, Colin A; Maratou, Klio; Turner, James M A; Cooke, Howard J

    2006-08-01

    Meiotic silencing of unsynapsed chromatin (MSUC) is a key mechanism in spermatogenesis and a model system to study the dynamics of gene silencing. Here we show that MAEL, the ortholog of Drosophila's high mobility group box protein Maelstrom, is associated not only with the silenced XY body, but also with unsynapsed autosomes. Characterization of MAEL revealed that it interacts directly with the chromatin remodeler SNF5/INI1 and chromatin-associated protein SIN3B, which we also find localized to the XY body. This is the first time that a chromatin remodeler has been shown to associate with whole chromosomes. In addition, we show that MAEL is a component of the mouse meiotic nuage and its haploid cell counterpart, the chromatoid body. This is a site of accumulation of RNA and RNA processing enzymes, including proteins involved in the microRNA (miRNA) pathway. Furthermore, in the nuage, MAEL is present in a complex with germ cell specific MVH, an RNA helicase and Argonaute family members, MILI and MIWI. The presence of MAEL in these critical compartments of male germ cells and its interactions provide a link suggesting the involvement of the miRNA pathway in MSUC.

  3. Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

    PubMed

    Georgin-Lavialle, S; Moura, D S; Salvador, A; Chauvet-Gelinier, J-C; Launay, J-M; Damaj, G; Côté, F; Soucié, E; Chandesris, M-O; Barète, S; Grandpeix-Guyodo, C; Bachmeyer, C; Alyanakian, M-A; Aouba, A; Lortholary, O; Dubreuil, P; Teyssier, J-R; Trojak, B; Haffen, E; Vandel, P; Bonin, B; Hermine, O; Gaillard, R

    2016-11-01

    Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

  4. Spin-selective charge transport pathways through p-oligophenylene-linked donor-bridge-acceptor molecules.

    PubMed

    Scott, Amy M; Miura, Tomoaki; Ricks, Annie Butler; Dance, Zachary E X; Giacobbe, Emilie M; Colvin, Michael T; Wasielewski, Michael R

    2009-12-09

    A series of donor-bridge-acceptor (D-B-A) triads have been synthesized in which the donor, 3,5-dimethyl-4-(9-anthracenyl)julolidine (DMJ-An), and the acceptor, naphthalene-1,8:4,5-bis(dicarboximide) (NI), are linked by p-oligophenylene (Ph(n)) bridging units (n = 1-5). Photoexcitation of DMJ-An produces DMJ(+*)-An(-*) quantitatively, so that An(-*) acts as a high potential electron donor, which rapidly transfers an electron to NI yielding a long-lived spin-coherent radical ion pair (DMJ(+*)-An-Ph(n)-NI(-*)). The charge transfer properties of 1-5 have been studied using transient absorption spectroscopy, magnetic field effects (MFEs) on radical pair and triplet yields, and time-resolved electron paramagnetic resonance (TREPR) spectroscopy. The charge separation (CS) and recombination (CR) reactions exhibit exponential distance dependencies with damping coefficients of beta = 0.35 A(-1) and 0.34 A(-1), respectively. Based on these data, a change in mechanism from superexchange to hopping was not observed for either process in this system. However, the CR reaction is spin-selective and produces the singlet ground state and both (3*)An and (3*)NI. A kinetic analysis of the MFE data shows that superexchange dominates both pathways with beta = 0.48 A(-1) for the singlet CR pathway and beta = 0.35 A(-1) for the triplet CR pathway. MFEs and TREPR experiments were used to measure the spin-spin exchange interaction, 2J, which is directly related to the electronic coupling matrix element for CR, V(CR)(2). The magnitude of 2J also shows an exponential distance dependence with a damping coefficient alpha = 0.36 A(-1), which agrees with the beta values obtained from the distance dependence for triplet CR. These results were analyzed in terms of the bridge molecular orbitals that participate in the charge transport mechanism.

  5. A cortical-subcortical syntax pathway linking Broca's area and the striatum.

    PubMed

    Teichmann, Marc; Rosso, Charlotte; Martini, Jean-Baptiste; Bloch, Isabelle; Brugières, Pierre; Duffau, Hugues; Lehéricy, Stéphane; Bachoud-Lévi, Anne-Catherine

    2015-06-01

    Combinatorial syntax has been shown to be underpinned by cortical key regions such as Broca's area and temporal cortices, and by subcortical structures such as the striatum. The cortical regions are connected via several cortico-to-cortical tracts impacting syntactic processing (e.g., the arcuate) but it remains unclear whether and how the striatum can be integrated into this cortex-centered syntax network. Here, we used a systematic stepwise approach to investigate the existence and syntactic function of an additional deep Broca-striatum pathway. We first asked 15 healthy controls and 12 patients with frontal/striatal lesions to perform three syntax tests. The results obtained were subjected to voxel-based lesion-symptom mapping (VLSM) to provide an anatomo-functional approximation of the pathway. The significant VLSM clusters were then overlapped with the probability maps of four cortico-cortical language tracts generated for 12 healthy participants (arcuate, extreme capsule fiber system, uncinate, aslant), including a probabilistic Broca-striatum tract. Finally, we carried out quantitative analyses of the relationship between the lesion load along the tracts and syntactic processing, by calculating tract-lesion overlap for each patient and analyzing the correlation with syntactic data. Our findings revealed a Broca-striatum tract linking BA45 with the left caudate head and overlapping with VLSM voxel clusters relating to complex syntax. The lesion load values for this tract were correlated with complex syntax scores, whereas no such correlation was observed for the other tracts. These results extend current syntax-network models, by adding a deep "Broca-caudate pathway," and are consistent with functional accounts of frontostriatal circuits. © 2015 Wiley Periodicals, Inc.

  6. Pathways linking drug use and labour market trajectories: the role of catastrophic events.

    PubMed

    Richardson, Lindsey; Small, Will; Kerr, Thomas

    2016-01-01

    People affected by substance use disorders often experience sub-optimal employment outcomes. The role of drug use in processes that produce and entrench labour market precarity among people who inject drugs (PWID) have not, however, been fully described. We recruited 22 PWID from ongoing prospective cohort studies in Vancouver, Canada, with whom we conducted semi-structured retrospective interviews and then employed a thematic analysis that drew on concepts from life course theory to explore the mechanisms and pathways linking drug use and labour market trajectories. The participants' narratives identified processes corresponding to causation, whereby suboptimal employment outcomes led to harmful drug use; direct selection, where impairment, health complications or drug-seeking activities selected individuals out of employment; and indirect selection, where external factors, such as catastrophic events, marked the initiation or intensification of substance use concurrent with sudden changes in capacities for employment. Catastrophic events linking negative transitions in both drug use and labour market trajectories were of primary importance, demarcating critical initiation and transitional events in individual risk trajectories. These results challenge conventional assumptions about the primacy of drug use in determining employment outcomes among PWID and suggest the importance of multidimensional support to mitigate the initiation, accumulation and entrenchment of labour market and drug-related disadvantage.

  7. Slm35 links mitochondrial stress response and longevity through TOR signaling pathway

    PubMed Central

    Jose, L. Aguilar-Lopez; Laboy, Raymond; Fabiola, Jaimes-Miranda; Garay, Erika; Alexander, DeLuna; Funes, Soledad

    2016-01-01

    In most eukaryotic cells mitochondria are essential organelles involved in a great variety of cellular functions. One of the physiological processes linked to mitochondria is aging, a gradual process of damage accumulation that eventually promotes cell death. Aging depends on a balance between mitochondrial biogenesis, function and degradation. It has been previously shown that Tor1, Sch9 and Ras2 are activated in response to nutrient availability and regulate cell growth and division. A deficiency in any of these genes promotes lifespan extension and cell protection during oxidative and heat shock stress. In this work we report that in Saccharomyces cerevisiae, the uncharacterized mitochondrial protein Slm35 is functionally linked with the TOR signaling pathway. A Δtor1Δslm35 strain shows a severe decrease in lifespan and is unable to contend with oxidative and heat shock stresses. Specifically, this mutant shows decreased catalase activity indicating a misregulation of ROS scavenging mechanisms. In this study we show that Slm35 is also relevant for mitochondrial network dynamics and mitophagy. The results presented here suggest that Slm35 plays an important role connecting mitochondrial function with cytosolic responses and cell adaptation to stress and aging. PMID:27922823

  8. XPF-ERCC1 participates in the Fanconi anemia pathway of cross-link repair.

    PubMed

    Bhagwat, Nikhil; Olsen, Anna L; Wang, Anderson T; Hanada, Katsuhiro; Stuckert, Patricia; Kanaar, Roland; D'Andrea, Alan; Niedernhofer, Laura J; McHugh, Peter J

    2009-12-01

    Interstrand cross-links (ICLs) prevent DNA strand separation and, therefore, transcription and replication, making them extremely cytotoxic. The precise mechanism by which ICLs are removed from mammalian genomes largely remains elusive. Genetic evidence implicates ATR, the Fanconi anemia proteins, proteins required for homologous recombination, translesion synthesis, and at least two endonucleases, MUS81-EME1 and XPF-ERCC1. ICLs cause replication-dependent DNA double-strand breaks (DSBs), and MUS81-EME1 facilitates DSB formation. The subsequent repair of these DSBs occurs via homologous recombination after the ICL is unhooked by XPF-ERCC1. Here, we examined the effect of the loss of either nuclease on FANCD2 monoubiquitination to determine if the nucleolytic processing of ICLs is required for the activation of the Fanconi anemia pathway. FANCD2 was monoubiquitinated in Mus81(-/-), Ercc1(-/-), and XPF-deficient human, mouse, and hamster cells exposed to cross-linking agents. However, the monoubiquitinated form of FANCD2 persisted longer in XPF-ERCC1-deficient cells than in wild-type cells. Moreover, the levels of chromatin-bound FANCD2 were dramatically reduced and the number of ICL-induced FANCD2 foci significantly lower in XPF-ERCC1-deficient cells. These data demonstrate that the unhooking of an ICL by XPF-ERCC1 is necessary for the stable localization of FANCD2 to the chromatin and subsequent homologous recombination-mediated DSB repair.

  9. Slm35 links mitochondrial stress response and longevity through TOR signaling pathway.

    PubMed

    Aguilar-Lopez, Jose L; Laboy, Raymond; Jaimes-Miranda, Fabiola; Garay, Erika; DeLuna, Alexander; Funes, Soledad

    2016-12-02

    In most eukaryotic cells mitochondria are essential organelles involved in a great variety of cellular functions. One of the physiological processes linked to mitochondria is aging, a gradual process of damage accumulation that eventually promotes cell death. Aging depends on a balance between mitochondrial biogenesis, function and degradation. It has been previously shown that Tor1, Sch9 and Ras2 are activated in response to nutrient availability and regulate cell growth and division. A deficiency in any of these genes promotes lifespan extension and cell protection during oxidative and heat shock stress. In this work we report that in Saccharomyces cerevisiae, the uncharacterized mitochondrial protein Slm35 is functionally linked with the TOR signaling pathway. A Δtor1Δslm35 strain shows a severe decrease in lifespan and is unable to contend with oxidative and heat shock stresses. Specifically, this mutant shows decreased catalase activity indicating a misregulation of ROS scavenging mechanisms. In this study we show that Slm35 is also relevant for mitochondrial network dynamics and mitophagy. The results presented here suggest that Slm35 plays an important role connecting mitochondrial function with cytosolic responses and cell adaptation to stress and aging.

  10. Pathways linking drug use and labour market trajectories: the role of catastrophic events

    PubMed Central

    Richardson, Lindsey; Small, Will; Kerr, Thomas

    2015-01-01

    People affected by substance use disorders often experience sub-optimal employment outcomes. The role of drug use in processes that produce and entrench labour market precarity among people who inject drugs (PWID) have not, however, been fully described. We recruited 22 PWID from ongoing prospective cohort studies in Vancouver, Canada and conducted semi-structured retrospective interviews and employed a thematic analysis that draws on concepts from life course theory to explore mechanisms and pathways linking drug use and labour market trajectories. Narratives identified processes corresponding to: causation, whereby suboptimal employment outcomes led to harmful drug use; direct selection, where impairment, health complications or drug seeking activities selected individuals out of employment; and indirect selection, where external factors, such as catastrophic events, marked the initiation or intensification of substance use concurrent with sudden changes in capacities for employment. Catastrophic events linking negative transitions in both drug use and labour market trajectories were of primary importance, demarcating critical initiation and transitional events in individual risk trajectories. These results challenge conventional assumptions about the primacy of drug use in determining employment outcomes among PWID, and suggest the importance of multi-dimensional supports to mitigate the initiation, accumulation and entrenchment of labour market and drug-related disadvantage. PMID:26358407

  11. Impact of asthma on educational attainment in a socioeconomically deprived population: a study linking health, education and social care datasets.

    PubMed

    Sturdy, Pat; Bremner, Stephen; Harper, Gill; Mayhew, Les; Eldridge, Sandra; Eversley, John; Sheikh, Aziz; Hunter, Susan; Boomla, Kambiz; Feder, Gene; Prescott, Keith; Griffiths, Chris

    2012-01-01

    Asthma has the potential to adversely affect children's school examination performance, and hence longer term life chances. Asthma morbidity is especially high amongst UK ethnic minority children and those experiencing social adversity, populations which also have poor educational outcomes. We tested the hypothesis that asthma adversely affects performance in national school examinations in a large cohort from an area of ethnic diversity and social deprivation. With a novel method (using patient and address-matching algorithms) we linked administrative and clinical data for 2002-2005 for children in east London aged 5-14 years to contemporaneous education and social care datasets. We modelled children's performance in school examinations in relation to socio-demographic and clinical variables. The dataset captured examination performance for 12,136 children who sat at least one national examination at Key Stages 1-3. For illustration, estimates are presented as percentage changes in Key Stage 2 results. Having asthma was associated with a 1.1% increase in examination scores (95%CI 0.4 to 1.7)%,p = 0.02. Worse scores were associated with Bangladeshi ethnicity -1.3%(-2.5 to -0.1)%,p = 0.03; special educational need -14.6%(-15.7 to -13.5)%,p = 0.02; mental health problems -2.5%(-4.1 to -0.9)%,p = 0.003, and social adversity: living in a smoking household -1.2(-1.7 to -0.6)%,p<0.001; living in social housing -0.8%(-1.3 to -0.2)% p = 0.01, and entitlement to free school meals -0.8%(-1.5 to -0.1)%,p<0.001. Social adversity and ethnicity, but not asthma, are associated with poorer performance in national school examinations. Policies to improve educational attainment in socially deprived areas should focus on these factors.

  12. Elevated C-Reactive Protein in Children from Risky Neighborhoods: Evidence for a Stress Pathway Linking Neighborhoods and Inflammation in Children

    PubMed Central

    Broyles, Stephanie T.; Staiano, Amanda E.; Drazba, Kathryn T.; Gupta, Alok K.; Sothern, Melinda; Katzmarzyk, Peter T.

    2012-01-01

    Background Childhood socioeconomic status is linked to adult cardiovascular disease and disease risk. One proposed pathway involves inflammation due to exposure to a stress-inducing neighborhood environment. Whether CRP, a marker of systemic inflammation, is associated with stressful neighborhood conditions among children is unknown. Methods and Results The sample included 385 children 5–18 years of age from 255 households and 101 census tracts. Multilevel logistic regression analyses compared children and adolescents with CRP levels >3 mg/L to those with levels ≤3 mg/L across neighborhood environments. Among children living in neighborhoods (census tracts) in the upper tertile of poverty or crime, 18.6% had elevated CRP levels, in contrast to 7.9% of children living in neighborhoods with lower levels of poverty and crime. Children from neighborhoods with the highest levels of either crime or poverty had 2.7 (95% CI: 1.2–6.2) times the odds of having elevated CRP levels when compared to children from other neighborhoods, independent of adiposity, demographic and behavioral differences. Conclusions Children living in neighborhoods with high levels of poverty or crime had elevated CRP levels compared to children from other neighborhoods. This result is consistent with a psychosocial pathway favoring early development of cardiovascular risk that involves chronic stress from exposure to socially- and physically-disordered neighborhoods characteristic of poverty. PMID:23049799

  13. Adults with X-linked agammaglobulinemia: impact of disease on daily lives, quality of life, educational and socioeconomic status, knowledge of inheritance, and reproductive attitudes.

    PubMed

    Winkelstein, Jerry A; Conley, Mary Ellen; James, Cynthia; Howard, Vanessa; Boyle, John

    2008-09-01

    Since many children with X-linked agammaglobulinemia (XLA) can now be expected to reach adulthood, knowledge of the status of adults with XLA would be of importance to the patients, their families, and the physicians caring for these patients. We performed the current study in adults with XLA to examine the impact of XLA on their daily lives and quality of life, their educational and socioeconomic status, their knowledge of the inheritance of their disorder, and their reproductive attitudes. Physicians who had entered adult patients with XLA in a national registry were asked to pass on a survey instrument to their patients. The patients then filled out the survey instrument and returned it directly to the investigators. Adults with XLA were hospitalized more frequently and missed more work and/or school than did the general United States population. However, their quality of life was comparable to that of the general United States population. They achieved a higher level of education and had a higher income than did the general United States population. Their knowledge of the inheritance of their disease was excellent. Sixty percent of them would not exercise any reproductive planning options as a result of their disease. The results of the current study suggest that although the disease impacts the daily lives of adults with XLA, they still become productive members of society and excel in many areas.

  14. Klotho dysfunction: A pathway linking the aging process to bipolar disorder?

    PubMed

    Barbosa, Izabela Guimarães; Rocha, Natalia Pessoa; Alpak, Gokay; Vieira, Erica Leandro Marciano; Huguet, Rodrigo Barreto; Rocha, Fabio Lopes; de Oliveira Diniz, Breno Satler; Teixeira, Antonio Lucio

    2017-08-11

    Although accelerated aging profile has been described in bipolar disorder (BD), the biology linking BD and aging is still largely unknown. Reduced levels and/or activity of a protein named Klotho is associated with decreased life span, premature aging and occurrence of age-related diseases. Therefore, this study was designed to evaluate plasma levels of Klotho in BD patients and controls. Forty patients with type 1 BD and 30 controls were enrolled in this study. After clinical evaluation, peripheral blood samples were drawn and plasma levels of Klotho were measured using enzyme-linked immunosorbent assay. Patients with BD and controls presented similar age and sex distribution. The mean ± SD length of illness was 24.00 ± 12.75 years. BD patients presented increased frequency of clinical comorbidities in comparison with controls, mainly arterial hypertension, diabetes mellitus, and hypothyroidism. Both patients with BD in remission and in mania exhibited increased plasma levels of Klotho in comparison with controls. There was no significant difference between patients in mania and patients in remission regarding the levels of Klotho. Klotho-related pathway is altered in BD. Contrary to our original hypothesis, our sample of patients with BD presented increased plasma levels of Klotho in comparison with controls. Elevated levels of Klotho in long-term BD patients may be associated with the disorder progression. Further studies are needed to better understand the role of Klotho in BD and other mood disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Genomic ancestry and the social pathways leading to major depression in adulthood: the mediating effect of socioeconomic position and discrimination.

    PubMed

    Loret de Mola, Christian; Hartwig, Fernando Pires; Gonçalves, Helen; Quevedo, Luciana de Avila; Pinheiro, Ricardo; Gigante, Denise Petrucci; Motta, Janaína Vieira Dos Santos; Pereira, Alexandre C; Barros, Fernando C; Horta, Bernardo Lessa

    2016-09-05

    Evidence suggests that there is an association between ethnicity/skin color and depression; however, many contextual and individual variables, like sense of discrimination and socioeconomic position (SEP), might influence the direction of this association. We assessed the association between African ancestry and major depression among young adults that have been followed-up since birth in a Southern Brazilian city, and the mediating effect of SEP and discrimination. In 1982, all hospital deliveries in Pelotas (Southern Brazil) were identified; liveborns were examined and their mothers interviewed (n = 5914). In 2012-13, at 30 years of age, we used the Mini International Neuropsychiatric Interview (MINI) for major depression diagnosis. In addition, DNA samples were genotyped for approximately 2.5 million single nucleotide polymorphisms (SNPs) using Illumina (CA, USA) HumanOmni2.5-8v1 array. Genomic ancestry estimation was based on approximately 370 000 single nucleotide polymorphisms (SNPs) mutually available for the Pelotas cohort and selected samples (used as reference panels) of the HapMap and Human Genome Diversity (HGDP). We estimated prevalence ratios (PR) using Poisson regression models and evaluated the association between percentage of African ancestry and major depression. We used G-computation for mediation analysis. At 30 years, 3576 individuals were evaluated for major depression (prevalence = 7.9 %). Only individuals in the highest SEP, who had a percentage of African ancestry between >5-30 % and >30 % had a prevalence of major depression 2.16 (PR = 2.16 95 % CI [1.05-4.45]) and 2.74 (PR = 2.74 95 % CI [1.06-7.06]) times higher, than those with 5 % or less, respectively. Among these subjects, sense of discrimination by skin color, captured 84 % of the association between African ancestry and major depression. SEP is an important effect modifier of the positive association between African ancestry and major depression. In addition

  16. Investigating the benefits of scene linking for a pathway HMD: from laboratory flight experiments to flight tests

    NASA Astrophysics Data System (ADS)

    Schmerwitz, Sven; Többen, Helmut; Lorenz, Bernd; Iijima, Tomoko; Kuritz-Kaiser, Anthea

    2006-05-01

    Pathway-in-the-sky displays enable pilots to accurately fly difficult trajectories. However, these displays may drive pilots' attention to the aircraft guidance task at the expense of other tasks particularly when the pathway display is located head-down. A pathway HUD may be a viable solution to overcome this disadvantage. Moreover, the pathway may mitigate the perceptual segregation between the static near domain and the dynamic far domain and hence, may improve attention switching between both sources. In order to more comprehensively overcome the perceptual near-to-far domain disconnect alphanumeric symbols could be attached to the pathway leading to a HUD design concept called 'scene-linking'. Two studies are presented that investigated this concept. The first study used a simplified laboratory flight experiment. Pilots (N=14) flew a curved trajectory through mountainous terrain and had to detect display events (discrete changes in a command speed indicator to be matched with current speed) and outside scene events (hostile SAM station on ground). The speed indicators were presented in superposition to the scenery either in fixed position or scene-linked to the pathway. Outside scene event detection was found improved with scene linking, however, flight-path tracking was markedly deteriorated. In the second study a scene-linked pathway concept was implemented on a monocular retinal scanning HMD and tested in real flights on a Do228 involving 5 test pilots. The flight test mainly focused at usability issues of the display in combination with an optical head tracker. Visual and instrument departure and approach tasks were evaluated comparing HMD navigation with standard instrument or terrestrial navigation. The study revealed limitations of the HMD regarding its see-through capability, field of view, weight and wearing comfort that showed to have a strong influence on pilot acceptance rather than rebutting the approach of the display concept as such.

  17. Review of X-linked syndromes with arthrogryposis or early contractures-aid to diagnosis and pathway identification.

    PubMed

    Hunter, Jesse M; Kiefer, Jeff; Balak, Christopher D; Jooma, Sonya; Ahearn, Mary Ellen; Hall, Judith G; Baumbach-Reardon, Lisa

    2015-05-01

    The following is a review of 50 X-linked syndromes and conditions associated with either arthrogryposis or other types of early contractures. These entities are categorized as those with known responsible gene mutations, those which are definitely X-linked, but the responsible gene has not been identified, and those suspected from family history to be X-linked. Several important ontology pathways for known disease genes have been identified and are discussed in relevance to clinical characteristics. Tables are included which help to identify distinguishing clinical features of each of the conditions. © 2015 Wiley Periodicals, Inc.

  18. The alexithymic brain: the neural pathways linking alexithymia to physical disorders.

    PubMed

    Kano, Michiko; Fukudo, Shin

    2013-01-09

    Alexithymia is a personality trait characterized by difficulties in identifying and describing feelings and is associated with psychiatric and psychosomatic disorders. The mechanisms underlying the link between emotional dysregulation and psychosomatic disorders are unclear. Recent progress in neuroimaging has provided important information regarding emotional experience in alexithymia. We have conducted three brain imaging studies on alexithymia, which we describe herein. This article considers the role of emotion in the development of physical symptoms and discusses a possible pathway that we have identified in our neuroimaging studies linking alexithymia with psychosomatic disorders. In terms of socio-affective processing, alexithymics demonstrate lower reactivity in brain regions associated with emotion. Many studies have reported reduced activation in limbic areas (e.g., cingulate cortex, anterior insula, amygdala) and the prefrontal cortex when alexithymics attempt to feel other people's feelings or retrieve their own emotional episodes, compared to nonalexithymics. With respect to primitive emotional reactions such as the response to pain, alexithymics show amplified activity in areas considered to be involved in physical sensation. In addition to greater hormonal arousal responses in alexithymics during visceral pain, increased activity has been reported in the insula, anterior cingulate cortex, and midbrain. Moreover, in complex social situations, alexithymics may not be able to use feelings to guide their behavior appropriately. The Iowa gambling task (IGT) was developed to assess decision-making processes based on emotion-guided evaluation. When alexithymics perform the IGT, they fail to learn an advantageous decision-making strategy and show reduced activity in the medial prefrontal cortex, a key area for successful performance of the IGT, and increased activity in the caudate, a region associated with impulsive choice. The neural machinery in

  19. Impact of service redesign on the socioeconomic inequity in revascularisation rates for patients with acute myocardial infarction: a natural experiment and electronic record-linked cohort study

    PubMed Central

    Evans, Lloyd W; van Woerden, Hugo; Fone, David

    2016-01-01

    Aim To investigate the impact of service redesign in the provision of revascularisation procedures on the historical socioeconomic inequity in revascularisation rates for patients with acute myocardial infarction (AMI). Design Natural experiment and retrospective cohort study using linked data sets in the Secure Anonymised Information Linkage databank. Non-randomised intervention An increase in the capacity of revascularisation procedures and service redesign in the provision of revascularisation in late 2011 to early 2012. Setting South Wales cardiac network, Census 2011 population 1 359 051 aged 35 years and over. Participants 9128 participants admitted to an NHS hospital with a first AMI between 1 January 2010 and 30 June 2013, with 6-months follow-up. Main outcome measure Hazard ratios (HRs) for the time to revascularisation for deprivation quintiles, age, gender, comorbidities, rural–urban classification and revascularisation facilities of admitting hospital. Results In the preintervention period, there was a statistically significant decreased adjusted risk of revascularisation for participants in the most deprived quintile compared to the least deprived quintile (HR 0.80; 95% CI 0.69 to 0.92, p=0.002). In the postintervention period, the increase in revascularisation rates was statistically significant in all quintiles, and there was no longer any statistically significant difference in the adjusted revascularisation risk between the most and the least deprived quintile (HR 1.04; 95% CI 0.89 to 1.20, p<0.649). However, inequity persisted for those aged 75 years and over (HR 0.40; 95% CI 0.35 to 0.46, p<0.001) and women (HR 0.77; 95% CI 0.70 to 0.86, p<0.001). Conclusions Socioeconomic inequity of access to revascularisation was no longer apparent following redesign of revascularisation services in the south Wales cardiac network, although inequity persisted for women and those aged 75+ years. Increasing the capacity of revascularisation did not

  20. The link between the PDL1 costimulatory pathway and Th17 in fetomaternal tolerance.

    PubMed

    D'Addio, Francesca; Riella, Leonardo V; Mfarrej, Bechara G; Chabtini, Lola; Adams, La Tonya; Yeung, Melissa; Yagita, Hideo; Azuma, Miyuki; Sayegh, Mohamed H; Guleria, Indira

    2011-11-01

    Fetomaternal tolerance has been shown to depend both on regulatory T cells (Tregs) and negative signals from the PD1-PDL1 costimulatory pathway. More recently, IL-17-producing T cells (Th17) have been recognized as a barrier in inducing tolerance in transplantation. In this study, we investigate the mechanisms of PDL1-mediated regulation of fetomaternal tolerance using an alloantigen-specific CD4(+) TCR transgenic mouse model system (ABM-tg mouse). PDL1 blockade led to an increase in embryo resorption and a reduction in litter size. This was associated with a decrease in Tregs, leading to a lower Treg/effector T cell ratio. Moreover, PDL1 blockade inhibited Ag-specific alloreactive T cell apoptosis and induced apoptosis of Tregs and a shift toward higher frequency of Th17 cells, breaking fetomaternal tolerance. These Th17 cells arose predominantly from CD4(+)Foxp3(-) cells, rather than from conversion of Tregs. Locally in the placenta, similar decrease in regulatory and apoptotic markers was observed by real-time PCR. Neutralization of IL-17 abrogated the anti-PDL1 effect on fetal survival rate and restored Treg numbers. Finally, the adoptive transfer of Tregs was also able to improve fetal survival in the setting of PDL1 blockade. This is to our knowledge the first report using an alloantigen-specific model that establishes a link between PDL1, Th17 cells, and fetomaternal tolerance.

  1. Links between topography, moisture fluxes pathways and precipitation over South America

    NASA Astrophysics Data System (ADS)

    Saurral, Ramiro Ignacio; Camilloni, Inés Angela; Ambrizzi, Tércio

    2015-08-01

    The Andes Cordillera plays a role in driving moisture and heat from tropical onto subtropical South America. It forces the development of a lee-side trough that covers most of western Argentina and a low-level jet that maximizes over Paraguay, eastern Bolivia and northern Argentina and is tightly linked to precipitation variability over much of central and southeastern South America. Its steep slopes and the large zonal gradients in topography between the Equator and 40°S are misrepresented in climate simulations using Global Climate Models (GCM) with resolutions coarser than about 100 km, since they naturally have a poor representation of the Andes and related circulation features. This paper analyses the impact of varying artificially the altitude of the Andes Cordillera in a GCM as well as increasing the horizontal resolution to study how these variations determine moisture fluxes and precipitation over selected regions of South America. Results show that the height of the Andes is crucial in shaping moisture fluxes pathways onto subtropical South America all year long. In particular, the low-level jet is only simulated when the Andes heights are doubled. At the same time, the relationship between the Andes shape and the location of the Bolivian High in summer is also discussed. In terms of precipitation, the lowest bias in the simulations is achieved when the horizontal resolution is increased, while in particular near the Andes foothills the simulated annual rainfall is largely determined by the Mountains shape.

  2. Links between topography, moisture fluxes pathways and precipitation over South America

    NASA Astrophysics Data System (ADS)

    Saurral, Ramiro Ignacio; Camilloni, Inés Angela; Ambrizzi, Tércio

    2014-08-01

    The Andes Cordillera plays a role in driving moisture and heat from tropical onto subtropical South America. It forces the development of a lee-side trough that covers most of western Argentina and a low-level jet that maximizes over Paraguay, eastern Bolivia and northern Argentina and is tightly linked to precipitation variability over much of central and southeastern South America. Its steep slopes and the large zonal gradients in topography between the Equator and 40°S are misrepresented in climate simulations using Global Climate Models (GCM) with resolutions coarser than about 100 km, since they naturally have a poor representation of the Andes and related circulation features. This paper analyses the impact of varying artificially the altitude of the Andes Cordillera in a GCM as well as increasing the horizontal resolution to study how these variations determine moisture fluxes and precipitation over selected regions of South America. Results show that the height of the Andes is crucial in shaping moisture fluxes pathways onto subtropical South America all year long. In particular, the low-level jet is only simulated when the Andes heights are doubled. At the same time, the relationship between the Andes shape and the location of the Bolivian High in summer is also discussed. In terms of precipitation, the lowest bias in the simulations is achieved when the horizontal resolution is increased, while in particular near the Andes foothills the simulated annual rainfall is largely determined by the Mountains shape.

  3. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides.

    PubMed

    Gallardo, Gilbert; Schlüter, Oliver M; Südhof, Thomas C

    2008-03-01

    Pathogenic aggregates of alpha-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing alpha-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, alpha-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of alpha-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by alpha-synuclein and suppressed the accumulation of Abeta. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.

  4. Electrification pathways for Kenya–linking spatial electrification analysis and medium to long term energy planning

    NASA Astrophysics Data System (ADS)

    Moksnes, Nandi; Korkovelos, Alexandros; Mentis, Dimitrios; Howells, Mark

    2017-09-01

    In September 2015 UN announced 17 Sustainable Development goals (SDG) from which goal number 7 envisions universal access to modern energy services for all by 2030. In Kenya only about 46% of the population currently has access to electricity. This paper analyses hypothetical scenarios, and selected implications, investigating pathways that would allow the country to reach its electrification targets by 2030. Two modelling tools were used for the purposes of this study, namely OnSSET and OSeMOSYS. The tools were soft-linked in order to capture both the spatial and temporal dynamics of their nature. Two electricity demand scenarios were developed representing low and high end user consumption goals respectively. Indicatively, results show that geothermal, coal, hydro and natural gas would consist the optimal energy mix for the centralized national grid. However, in the case of the low demand scenario a high penetration of stand-alone systems is evident in the country, reaching out to approximately 47% of the electrified population. Increasing end user consumption leads to a shift in the optimal technology mix, with higher penetration of mini-grid technologies and grid extension.

  5. 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

  6. Neurocognitive development in socioeconomic context: Multiple mechanisms and implications for measuring socioeconomic status.

    PubMed

    Ursache, Alexandra; Noble, Kimberly G

    2016-01-01

    Socioeconomic status (SES) has been linked to functioning across a variety of neurocognitive domains including language, memory, executive functioning, and social-emotional processing. We review these findings and discuss the ways in which socioeconomic context may shape neural processes such that these skills are supported by different neurobiological pathways in children from lower versus higher SES backgrounds. Moreover, we consider the mechanisms by which SES may be related to specific neurocognitive functions. Specifically, we focus on linguistic exposure and stress as two main pathways through which SES could influence neurocognitive processes and shape relations between the neural and behavioral levels of functioning. Finally, suggestions for conceptualizing and measuring SES in future work are offered.

  7. Neurocognitive development in socioeconomic context: multiple mechanisms and implications for measuring socioeconomic status

    PubMed Central

    Ursache, Alexandra; Noble, Kimberly G.

    2015-01-01

    Socioeconomic status (SES) has been linked to functioning across a variety of neurocognitive domains including language, memory, executive functioning, and social-emotional processing. We review these findings and discuss the ways in which socioeconomic context may shape neural processes such that these skills are supported by different neurobiological pathways in children from lower versus high SES backgrounds. Moreover we consider the mechanisms by which SES may be related to specific neurocognitive functions. Specifically, we focus on linguistic exposure and stress as two main pathways through which SES could influence neurocognitive processes and shape relations between the neural and behavioral levels of functioning. Finally, suggestions for conceptualizing and measuring SES in future work are offered. PMID:26681619

  8. Long genes and genes with multiple splice variants are enriched in pathways linked to cancer and other multigenic diseases.

    PubMed

    Sahakyan, Aleksandr B; Balasubramanian, Shankar

    2016-03-12

    The role of random mutations and genetic errors in defining the etiology of cancer and other multigenic diseases has recently received much attention. With the view that complex genes should be particularly vulnerable to such events, here we explore the link between the simple properties of the human genes, such as transcript length, number of splice variants, exon/intron composition, and their involvement in the pathways linked to cancer and other multigenic diseases. We reveal a substantial enrichment of cancer pathways with long genes and genes that have multiple splice variants. Although the latter two factors are interdependent, we show that the overall gene length and splicing complexity increase in cancer pathways in a partially decoupled manner. Our systematic survey for the pathways enriched with top lengthy genes and with genes that have multiple splice variants reveal, along with cancer pathways, the pathways involved in various neuronal processes, cardiomyopathies and type II diabetes. We outline a correlation between the gene length and the number of somatic mutations. Our work is a step forward in the assessment of the role of simple gene characteristics in cancer and a wider range of multigenic diseases. We demonstrate a significant accumulation of long genes and genes with multiple splice variants in pathways of multigenic diseases that have already been associated with de novo mutations. Unlike the cancer pathways, we note that the pathways of neuronal processes, cardiomyopathies and type II diabetes contain genes long enough for topoisomerase-dependent gene expression to also be a potential contributing factor in the emergence of pathologies, should topoisomerases become impaired.

  9. Family support and ease of access link socio-economic status and sports club membership in adolescent girls: a mediation study

    PubMed Central

    2013-01-01

    Background Much research has been conducted into the determinants of physical activity (PA) participation among adolescent girls. However, the more specific question of what are the determinants of particular forms of PA participation, such as the link between participation through a sports club, has not been investigated. Accordingly, the aim of this study was to investigate the relationships between participation in a sports club and socio-economic status (SES), access to facilities, and family and peer support, for female adolescents. Methods A survey of 732 female adolescent school students (521 metropolitan, 211 non-metropolitan; 489 Year 7, 243 Year 11) was conducted. The survey included demographic information (living arrangements, ethnicity indicators, and indicators of SES such as parental education and employment status and locality); access to facilities; and family and peer support (travel, encouragement, watching, praise, joint participation). For each characteristic, sports club participants and non-participants were compared using chi-square tests. Multiple mediation analyses were used to investigate the role of access, family and peer support in the link between SES and sport participation. Results There were significant associations (p<0.05) between sports club participation and: all demographic characteristics; all measures of family and peer support; and access to sport-related facilities. Highest levels of participation were associated with monolingual Australian-born families, with two parents, at least one of whom was well-educated, with both parents employed, and high levels of parental assistance, engagement and support. Participation in club sport among both younger and older adolescent girls was significantly positively associated with the SES of both their neighbourhoods and their households, particularly in metropolitan areas. These associations were most strongly mediated by family support and by access to facilities. Conclusions To

  10. Family support and ease of access link socio-economic status and sports club membership in adolescent girls: a mediation study.

    PubMed

    Eime, Rochelle M; Harvey, Jack T; Craike, Melinda J; Symons, Caroline M; Payne, Warren R

    2013-04-25

    Much research has been conducted into the determinants of physical activity (PA) participation among adolescent girls. However, the more specific question of what are the determinants of particular forms of PA participation, such as the link between participation through a sports club, has not been investigated. Accordingly, the aim of this study was to investigate the relationships between participation in a sports club and socio-economic status (SES), access to facilities, and family and peer support, for female adolescents. A survey of 732 female adolescent school students (521 metropolitan, 211 non-metropolitan; 489 Year 7, 243 Year 11) was conducted. The survey included demographic information (living arrangements, ethnicity indicators, and indicators of SES such as parental education and employment status and locality); access to facilities; and family and peer support (travel, encouragement, watching, praise, joint participation). For each characteristic, sports club participants and non-participants were compared using chi-square tests. Multiple mediation analyses were used to investigate the role of access, family and peer support in the link between SES and sport participation. There were significant associations (p<0.05) between sports club participation and: all demographic characteristics; all measures of family and peer support; and access to sport-related facilities. Highest levels of participation were associated with monolingual Australian-born families, with two parents, at least one of whom was well-educated, with both parents employed, and high levels of parental assistance, engagement and support. Participation in club sport among both younger and older adolescent girls was significantly positively associated with the SES of both their neighbourhoods and their households, particularly in metropolitan areas. These associations were most strongly mediated by family support and by access to facilities. To facilitate and promote greater

  11. Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

    PubMed Central

    García-Jérez, Andrea; Luengo, Alicia; Carracedo, Julia; Ramírez-Chamond, Rafael; Rodriguez-Puyol, Diego; Rodriguez-Puyol, Manuel; Calleros, Laura

    2015-01-01

    Patients with chronic kidney disease (CKD) have a higher risk of developing cardiovascular diseases. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which, mostly protein-bound compounds such as indoxyl sulfate (IS) and p-cresyl sulphate, having poor clearance by conventional dialysis, induce endothelial toxicity. However, the molecular mechanism by which uraemic toxins regulate early stages of endothelial dysfunction remains unclear. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity. In this study, we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. First, we show that incubation of EA.hy926 cells with human uraemic serum from CKD patients upregulates ILK activity. This ILK activation also occurs when the cells are exposed to IS (25–100 μg ml−1), p-cresol (10–100 μg ml−1) or both combined, compared to human serum control. Next, we observed that high doses of both toxins together induce a slight decrease in cell proliferation and increase apoptosis and reactive oxygen species production. Interestingly, these toxic effects displayed a strong increase when the ILK protein is knocked down by small interfering RNA, even at low doses of uraemic toxins. Abrogation of AKT has demonstrated the ILK/AKT signalling pathway involved in these processes. This study has demonstrated the implication of ILK in the protection against endothelial cell damage induced by uraemic toxins, a molecular mechanism that could play a protective role in the early stages of endothelial dysfunction observed in uraemic patients. PMID:25398526

  12. cAMP-dependent proteolysis of GATA-6 is linked to JNK-signaling pathway

    SciTech Connect

    Ushijima, Hironori; Maeda, Masatomo

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer A JNK inhibitor SP600125 inhibited cAMP-dependent proteolysis of GATA-6. Black-Right-Pointing-Pointer Effect of a JNK activator anisomycin on the proteolysis was examined. Black-Right-Pointing-Pointer Anisomycin stimulated the export of nuclear GATA-6 into the cytoplasm. Black-Right-Pointing-Pointer JNK activated the CRM1 mediated nuclear export of GATA-6. Black-Right-Pointing-Pointer JNK further stimulated slowly the degradation of GATA-6 by cytoplasmic proteasomes. -- Abstract: A JNK inhibitor SP600125 inhibited cAMP-dependent proteolysis of GATA-6 by proteasomes around its IC50. We further examined the effects of SP600125 on the degradation of GATA-6 in detail, since an activator of JNK (anisomycin) is available. Interestingly, anisomycin immediately stimulated the export of nuclear GATA-6 into the cytoplasm, and then the cytoplasmic content of GATA-6 decreased slowly through degradation by proteasomes. Such an effect of anisomycin was inhibited by SP600125, indicating that the observed phenomenon might be linked to the JNK signaling pathway. The inhibitory effect of SP600125 could not be ascribed to the inhibition of PKA, since phosphorylation of CREB occurred in the presence of dbcAMP and SP600125. The nuclear export of GATA-6 was inhibited by leptomycin B, suggesting that CRM1-mediated export could be activated by anisomycin. Furthermore, it seems likely that the JNK activated by anisomycin may stimulate not only the nuclear export of GATA-6 through CRM1 but also the degradation of GATA-6 by cytoplasmic proteasomes. In contrast, A-kinase might activate only the latter process through JNK.

  13. 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

  14. Pathways linking health literacy, health beliefs, and cognition to medication adherence in older adults with asthma.

    PubMed

    Soones, Tacara N; Lin, Jenny L; Wolf, Michael S; O'Conor, Rachel; Martynenko, Melissa; Wisnivesky, Juan P; Federman, Alex D

    2017-03-01

    Limited health literacy is associated with low adherence to asthma controller medications among older adults. We sought to describe the causal pathway linking health literacy to medication adherence by modeling asthma illness and medication beliefs as mediators. We recruited adults aged 60 years and older with asthma from hospital and community practices in New York, New York, and Chicago, Illinois. We measured health literacy and medication adherence using the Short Test of Functional Health Literacy in Adults and the Medication Adherence Rating Scale, respectively. We used validated instruments to assess asthma illness and medication beliefs. We assessed cognition using a cognitive battery. Using structural equation modeling, we modeled illness and medication beliefs as mediators of the relationship between health literacy and adherence while controlling for cognition. Our study included 433 patients with a mean age of 67 ± 6.8 years. The sample had 84% women, 31% non-Hispanic blacks, and 39% Hispanics. The 36% of patients with limited health literacy were more likely to have misconceptions about asthma (P < .001) and asthma medications (P < .001). Health literacy had a direct effect (β = 0.089; P < .001) as well as an indirect effect on adherence mediated by medications concerns (β = 0.033; P = .002). Neither medication necessity (β = 0.044; P = .138) nor illness beliefs (β = 0.007; P = .143) demonstrated a mediational role between health literacy and adherence. Interventions designed to improve asthma controller medication adherence in older adults may be enhanced by addressing concerns about medications in addition to using communication strategies appropriate for populations with limited health literacy and cognitive impairments. Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  15. The human core of the shared socioeconomic pathways: Population scenarios by age, sex and level of education for all countries to 2100.

    PubMed

    Kc, Samir; Lutz, Wolfgang

    2017-01-01

    This paper applies the methods of multi-dimensional mathematical demography to project national populations based on alternative assumptions on future, fertility, mortality, migration and educational transitions that correspond to the five shared socioeconomic pathways (SSP) storylines. In doing so it goes a significant step beyond past population scenarios in the IPCC context which considered only total population size. By differentiating the human population not only by age and sex-as is conventionally done in demographic projections-but also by different levels of educational attainment the most fundamental aspects of human development and social change are being explicitly addressed through modeling the changing composition of populations by these three important individual characteristics. The scenarios have been defined in a collaborative effort of the international Integrated Assessment Modeling community with the medium scenario following that of a major new effort by the Wittgenstein Centre for Demography and Global Human Capital (IIASA, OEAW, WU) involving over 550 experts from around the world. As a result, in terms of total world population size the trajectories resulting from the five SSPs stay very close to each other until around 2030 and by the middle of the century already a visible differentiation appears with the range between the highest (SSP3) and the lowest (SSP1) trajectories spanning 1.5 billion. The range opens up much more with the SSP3 reaching 12.6 billion in 2100 and SSP1 falling to 6.9 billion which is lower than today's world population.

  16. Deregulated tryptophan-kynurenine pathway is linked to inflammation, oxidative stress, and immune activation pathway in cardiovascular diseases

    PubMed Central

    Wang, Qiongxin; Liu, Danxia; Song, Ping; Zou, Ming-Hui

    2016-01-01

    The kynurenine (Kyn) pathway is the major route for tryptophan (Trp) metabolism, and it contributes to several fundamental biological processes. Trp is constitutively oxidized by tryptophan 2, 3-dioxygenase in liver cells. In other cell types, it is catalyzed by an alternative inducible indoleamine-pyrrole 2, 3-dioxygenase (IDO) under certain pathophysiological conditions, which consequently increases the formation of Kyn metabolites. IDO is up-regulated in response to inflammatory conditions as a novel marker of immune activation in early atherosclerosis. Besides, IDO and the IDO-related pathway are important mediators of the immunoinflammatory responses in advanced atherosclerosis. In particular, Kyn, 3-hydroxykynurenine, and quinolinic acid are positively associated with inflammation, oxidative stress (SOX), endothelial dysfunction, and carotid artery intima-media thickness values in end-stage renal disease patients. Moreover, IDO is a potential novel contributor to vessel relaxation and metabolism in systemic infections, which is also activated in acute severe heart attacks. The Kyn pathway plays a key role in the increased prevalence of cardiovascular disease by regulating inflammation, SOX, and immune activation. PMID:25961549

  17. Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs

    PubMed Central

    Venkova, Larisa; Aliper, Alexander; Suntsova, Maria; Kholodenko, Roman; Shepelin, Denis; Borisov, Nicolas; Malakhova, Galina; Vasilov, Raif; Roumiantsev, Sergey; Zhavoronkov, Alex; Buzdin, Anton

    2015-01-01

    Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs. In this study, we compared the experimental data obtained in our laboratory and in the Genomics of Drug Sensitivity in Cancer (GDS) project for testing response to anticancer drugs and transcriptomes of various human cell lines. The microarray-based profiling of transcriptomes was performed for the cell lines before the addition of drugs to the medium, and experimental growth inhibition curves were built for each drug, featuring characteristic IC50 values. We assayed here four target drugs - Pazopanib, Sorafenib, Sunitinib and Temsirolimus, and 238 different cell lines, of which 11 were profiled in our laboratory and 227 - in GDS project. Using the OncoFinder-processed transcriptomic data on ∼600 molecular pathways, we identified pathways showing significant correlation between pathway activation strength (PAS) and IC50 values for these drugs. Correlations reflect relationships between response to drug and pathway activation features. We intersected the results and found molecular pathways significantly correlated in both our assay and GDS project. For most of these pathways, we generated molecular models of their interaction with known molecular target(s) of the respective drugs. For the first time, our study uncovered mechanisms underlying cancer cell response to drugs at the high-throughput molecular interactomic level. PMID:26317900

  18. Neisseria gonorrhoeae O-linked pilin glycosylation: functional analyses define both the biosynthetic pathway and glycan structure

    PubMed Central

    Aas, Finn Erik; Vik, Åshild; Vedde, John; Koomey, Michael; Egge-Jacobsen, Wolfgang

    2007-01-01

    Neisseria gonorrhoeae expresses an O-linked protein glycosylation pathway that targets PilE, the major pilin subunit protein of the Type IV pilus colonization factor. Efforts to define glycan structure and thus the functions of pilin glycosylation (Pgl) components at the molecular level have been hindered by the lack of sensitive methodologies. Here, we utilized a ‘top-down’ mass spectrometric approach to characterize glycan status using intact pilin protein from isogenic mutants. These structural data enabled us to directly infer the function of six components required for pilin glycosylation and to define the glycan repertoire of strain N400. Additionally, we found that the N. gonorrhoeae pilin glycan is O-acetylated, and identified an enzyme essential for this unique modification. We also identified the N. gonorrhoeae pilin oligosaccharyltransferase using bioinformatics and confirmed its role in pilin glycosylation by directed mutagenesis. Finally, we examined the effects of expressing the PglA glycosyltransferase from the Campylobacter jejuni N-linked glycosylation system that adds N-acetylgalactosamine onto undecaprenylpyrophosphate-linked bacillosamine. The results indicate that the C. jejuni and N. gonorrhoeae pathways can interact in the synthesis of O-linked di- and trisaccharides, and therefore provide the first experimental evidence that biosynthesis of the N. gonorrhoeae pilin glycan involves a lipid-linked oligosaccharide precursor. Together, these findings underpin more detailed studies of pilin glycosylation biology in both N. gonorrhoeae and N. meningitidis, and demonstrate how components of bacterial O- and N-linked pathways can be combined in novel glycoengineering strategies. PMID:17608667

  19. Emerging evidence of a link between the polycystins and the mTOR pathways.

    PubMed

    Boletta, Alessandra

    2009-10-28

    Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by the formation of renal cysts. This disease can be caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC-1) and -2 (PC-2), respectively.PC-1 is a large plasma membrane receptor involved in the regulation of several biological functions and signaling pathways, and PC-2 is a calcium channel of the TRP family. The two proteins associate in a complex to prevent cyst formation, but the precise mechanism(s) involved remain largely unknown.This review will focus on recent advances in our understanding of the functions of polycystins and their role in signal transduction.Increased activity of the mammalian target of rapamycin (mTOR) kinase has been observed in cysts found in ADPKD tissues. Rapamycin has been shown to have beneficial effects in rodent models of polycystic kidney disease, prompting the initiation of pilot clinical trials with human patients. Furthermore, a direct role for PC-1 in the regulation of cell growth (size) via mTOR has recently been demonstrated.Major advancements in the study of mTOR biology have highlighted that this kinase exists in association with two different complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTORC1 complex regulates cell growth (size), proliferation, translation and autophagy, and mTORC2 regulates the actin cytoskeleton and apoptosis. Interestingly, mTORC2 has been shown to contain the kinase responsible for the phosphorylation of Akt at Serine 473. Previous studies have shown that PC-1 controls the PI 3-kinase/Akt cascade to regulate apoptosis and the actin cytoskeleton, suggesting that this receptor might regulate mTOR at several levels.This review aims to discuss three different, inter-related themes emerging from the literature: (i) studies performed in our and other laboratories collectively suggest that PC-1 might be able to differentially regulate the two mTOR complexes; (ii) several

  20. Socioeconomic environment

    SciTech Connect

    1995-10-01

    This portion of the Energy vision 2020 draft report discusses the socioeconomic environment of the Tennessee Valley region. It describes the region and mentions geographical factors, current economy, the agricultural sector, and future trends in the economy of the region.

  1. Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia.

    PubMed

    Penny, Morgan K; Finco, Isabella; Hammer, Gary D

    2017-04-15

    The adrenal cortex is a dynamic tissue responsible for the synthesis of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens in humans. Advances have been made in understanding the role of adrenocortical stem/progenitor cell populations in cortex homeostasis and self-renewal. Recently, large molecular profiling studies of adrenocortical carcinoma (ACC) have given insights into proteins and signaling pathways involved in normal tissue homeostasis that become dysregulated in cancer. These data provide an impetus to examine the cellular pathways implicated in adrenocortical disease and study connections, or lack thereof, between adrenal homeostasis and tumorigenesis, with a particular focus on stem and progenitor cell pathways. In this review, we discuss evidence for stem/progenitor cells in the adrenal cortex, proteins and signaling pathways that may regulate these cells, and the role these proteins play in pathologic and neoplastic conditions. In turn, we also examine common perturbations in adrenocortical tumors (ACT) and how these proteins and pathways may be involved in adrenal homeostasis.

  2. The Association of Attention Deficit Hyperactivity Disorder with Socioeconomic Disadvantage: Alternative Explanations and Evidence

    ERIC Educational Resources Information Center

    Russell, Ginny; Ford, Tamsin; Rosenberg, Rachel; Kelly, Susan

    2014-01-01

    Background: Studies throughout Northern Europe, the United States and Australia have found an association between childhood attention deficit hyperactivity disorder (ADHD) and family socioeconomic disadvantage. We report further evidence for the association and review potential causal pathways that might explain the link. Methods: Secondary…

  3. The Association of Attention Deficit Hyperactivity Disorder with Socioeconomic Disadvantage: Alternative Explanations and Evidence

    ERIC Educational Resources Information Center

    Russell, Ginny; Ford, Tamsin; Rosenberg, Rachel; Kelly, Susan

    2014-01-01

    Background: Studies throughout Northern Europe, the United States and Australia have found an association between childhood attention deficit hyperactivity disorder (ADHD) and family socioeconomic disadvantage. We report further evidence for the association and review potential causal pathways that might explain the link. Methods: Secondary…

  4. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway.

    PubMed

    Lee, Dung-Fang; Kuo, Hsu-Ping; Chen, Chun-Te; Hsu, Jung-Mao; Chou, Chao-Kai; Wei, Yongkun; Sun, Hui-Lung; Li, Long-Yuan; Ping, Bo; Huang, Wei-Chien; He, Xianghuo; Hung, Jen-Yu; Lai, Chien-Chen; Ding, Qingqing; Su, Jen-Liang; Yang, Jer-Yen; Sahin, Aysegul A; Hortobagyi, Gabriel N; Tsai, Fuu-Jen; Tsai, Chang-Hai; Hung, Mien-Chie

    2007-08-10

    TNFalpha has recently emerged as a regulator linking inflammation to cancer pathogenesis, but the detailed cellular and molecular mechanisms underlying this link remain to be elucidated. The tuberous sclerosis 1 (TSC1)/TSC2 tumor suppressor complex serves as a repressor of the mTOR pathway, and disruption of TSC1/TSC2 complex function may contribute to tumorigenesis. Here we show that IKKbeta, a major downstream kinase in the TNFalpha signaling pathway, physically interacts with and phosphorylates TSC1 at Ser487 and Ser511, resulting in suppression of TSC1. The IKKbeta-mediated TSC1 suppression activates the mTOR pathway, enhances angiogenesis, and results in tumor development. We further find that expression of activated IKKbeta is associated with TSC1 Ser511 phosphorylation and VEGF production in multiple tumor types and correlates with poor clinical outcome of breast cancer patients. Our findings identify a pathway that is critical for inflammation-mediated tumor angiogenesis and may provide a target for clinical intervention in human cancer.

  5. Education as a social pathway from parental socioeconomic position to depression in late adolescence and early adulthood: a Finnish population-based register study.

    PubMed

    Korhonen, Kaarina; Remes, Hanna; Martikainen, Pekka

    2017-01-01

    There is inconsistent evidence for social differentials in the risk of depression in youth, and little is known about how education at this age influences the risk. We assess how parental socioeconomic position (SEP) and education predict depression from late adolescence to early adulthood, a time of major educational transitions. We followed a nationally representative 20 % sample of Finnish adolescents born in 1986-1990 (n = 60,829) over two educational transitory stages at the age of 17-19 and 20-23 covering the years 2003-2011. We identified incident depression using health care register data. We estimated the risk of depression by parental SEP and personal education using Cox regression, adjusting for family structure, parental depression and the individual's own psychiatric history. Lower parental income was associated with up to a twofold risk of depression. This effect was almost fully attributable to other parental characteristics or mediated by the individual's own education. Educational differences in risk were attenuated following adjustment for prior psychiatric history. Adjusted for all covariates, not being in education increased the risk up to 2.5-fold compared to being enrolled in general upper secondary school at the age of 17-19 and in tertiary education at the age of 20-23. Vocationally oriented women experienced a 20 % higher risk than their academically oriented counterparts in both age groups. Education constitutes a social pathway from parental SEP to the risk of depression in youth, whereby educational differences previously shown in adults are observed already before the establishment of adulthood SEP.

  6. The ABA-INSENSITIVE-4 (ABI4) transcription factor links redox, hormone and sugar signaling pathways.

    PubMed

    Foyer, Christine H; Kerchev, Pavel I; Hancock, Robert D

    2012-02-01

    The cellular reduction-oxidation (redox) hub processes information from metabolism and the environment and so regulates plant growth and defense through integration with the hormone signaling network. One key pathway of redox control involves interactions with ABSCISIC ACID (ABA). Accumulating evidence suggests that the ABA-INSENSITIVE-4 (ABI4) transcription factor plays a key role in transmitting information concerning the abundance of ascorbate and hence the ability of cells to buffer oxidative challenges. ABI4 is required for the ascorbate-dependent control of growth, a process that involves enhancement of salicylic acid (SA) signaling and inhibition of jasmonic acid (JA) signaling pathways. Low redox buffering capacity reinforces SA- JA- interactions through the mediation of ABA and ABI4 to fine-tune plant growth and defense in relation to metabolic cues and environmental challenges. Moreover, ABI4-mediated pathways of sugar sensitivity are also responsive to the abundance of ascorbate, providing evidence of overlap between redox and sugar signaling pathways.

  7. Adverse outcome pathways linked to population models as a methodology for investigating effects of chemical stressors

    EPA Science Inventory

    In addressing the complexity and toxicity of chemical contaminants in Great Lakes ecosystems, we describe an approach to link chemically induced alterations in molecular and biochemical endpoints to adverse outcomes in whole organisms and populations. Analysis of population impac...

  8. Adverse outcome pathways linked to population models as a methodology for investigating effects of chemical stressors

    EPA Science Inventory

    In addressing the complexity and toxicity of chemical contaminants in Great Lakes ecosystems, we describe an approach to link chemically induced alterations in molecular and biochemical endpoints to adverse outcomes in whole organisms and populations. Analysis of population impac...

  9. Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk

    PubMed Central

    Wright, Carrie; Calhoun, Vince D.; Ehrlich, Stefan; Wang, Lei; Turner, Jessica A.; Bizzozero, Nora I. Perrone-

    2015-01-01

    Background: A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function. Methods: In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University. Results: Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort. Conclusions: These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases. PMID:25941532

  10. Exploring Links to Unorganized and Organized Physical Activity during Adolescence: The Role of Gender, Socioeconomic Status, Weight Status, and Enjoyment of Physical Education

    ERIC Educational Resources Information Center

    Bengoechea, Enrique Garcia; Sabiston, Catherine M.; Ahmed, Rashid; Farnoush, Michelle

    2010-01-01

    There is limited research on participation context in studies of physical activity correlates during adolescence. Using an ecological approach, this study explored the association of gender, socioeconomic status (SES), weight status, and physical education enjoyment with participation in organized and unorganized physical activity contexts in a…

  11. The Contours of Inequality: The Links between Socio-Economic Status of Students and Other Variables at the University of Johannesburg

    ERIC Educational Resources Information Center

    van Zyl, André

    2016-01-01

    The low level of student success in South Africa is an intractable problem, with levels of success differing between the various groups that make up South African society. One of the major constraints influencing student success involves the socio-economic status (SES) of newly entering students. In the South African context, with its very high…

  12. Exploring Links to Unorganized and Organized Physical Activity during Adolescence: The Role of Gender, Socioeconomic Status, Weight Status, and Enjoyment of Physical Education

    ERIC Educational Resources Information Center

    Bengoechea, Enrique Garcia; Sabiston, Catherine M.; Ahmed, Rashid; Farnoush, Michelle

    2010-01-01

    There is limited research on participation context in studies of physical activity correlates during adolescence. Using an ecological approach, this study explored the association of gender, socioeconomic status (SES), weight status, and physical education enjoyment with participation in organized and unorganized physical activity contexts in a…

  13. The role of the TOR pathway in mediating the link between nutrition and longevity.

    PubMed

    Lushchak, Oleh; Strilbytska, Olha; Piskovatska, Veronika; Storey, Kenneth B; Koliada, Alexander; Vaiserman, Alexander

    2017-06-01

    The target of rapamycin (TOR) pathway integrates signals from extracellular and intracellular agents, such as growth factors, nutrients, mediators of energy balance, oxygen availability and other environmental cues. It allows the regulation of multiple cellular processes including protein and lipid synthesis, ribosome biogenesis, autophagy and metabolic processes. Being conserved across different phyla, TOR regulates longevity of various organisms in response to dietary conditions. In this review we described the main components of the TOR pathway and its upstream effectors and downstream processes in relation to aging. The potential contribution of the TOR pathway in lifespan-extending effects of varied dietary interventions, and the anti-aging drugs rapamycin and metformin direct or indirect regulation of TOR activity in yeasts, worms, flies and mammals are also discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Ozone and Trace Gas Trends in the UK and Links to Changing Air Mass Pathways

    NASA Astrophysics Data System (ADS)

    Fleming, Z.; Monks, P. S.; Reeves, C.; Bohnenstengel, S.

    2014-12-01

    Trace gas measurements from UK measurement sites on the North Sea coast and in central London reveal a complicated relationship between NO2, CO, hydrocarbons and ozone. Due to the location of the sites, they receive air masses from the UK, Europe, the North sea, Scandinavia and the Arctic and Atlantic Seas and any seasonality is hard to discern. The transport pathway of air masses that can change on an hourly timescale clearly influences the trace gas levels. Investigations into how the transport pathways have changed over the years, using the NAME dispersion model try to elucidate whether it is the 'where' (transport pathway) or the 'what' (trace gas emissions) that is leading to the ozone trends recorded over the past few years.

  15. Regulation of the protein glycosylation pathway in yeast: structural control of N-linked oligosaccharide elongation

    SciTech Connect

    Gopal, P.K.; Ballou, C.E.

    1987-12-01

    The yeast Saccharomyces cerevisiae X2180 strain with the mnn1 mnn2 mnn9 mutations, all of which affect mannoprotein glycosylation, synthesizes N-linked oligosaccharides. Membrane fractions from the mnn1 mnn2 and mnn1 mnn2 mnn9 mutants are equally effective in catalyzing transfer from GDP-(/sup 3/H)mannose to add mannose in both ..cap alpha..1 ..-->.. 2 and ..cap alpha..1 ..-->.. 6 linkages to an oligosaccharide. Neither membrane preparation can utilize the homologous mnn1 mnn2 mnn9 oligosaccharide as an acceptor. Thus, addition of the ..cap alpha..1 ..-->.. 2-linked mannose side chain to the terminal ..cap alpha..1 ..-->.. 6-linked mannose in oligosaccharides of the mnn9 mutant inhibits the elongation reaction and may serve as an important structural control of mannoprotein glycosylation. The mnn9 mutation also increases the transit time for invertase secretion, meaning that this mutation could affect the processing machinery in the Golgi apparatus.

  16. Structure of mycobacterial maltokinase, the missing link in the essential GlgE-pathway

    PubMed Central

    Fraga, Joana; Maranha, Ana; Mendes, Vitor; Pereira, Pedro José Barbosa; Empadinhas, Nuno; Macedo-Ribeiro, Sandra

    2015-01-01

    A novel four-step pathway identified recently in mycobacteria channels trehalose to glycogen synthesis and is also likely involved in the biosynthesis of two other crucial polymers: intracellular methylglucose lipopolysaccharides and exposed capsular glucan. The structures of three of the intervening enzymes - GlgB, GlgE, and TreS - were recently reported, providing the first templates for rational drug design. Here we describe the structural characterization of the fourth enzyme of the pathway, mycobacterial maltokinase (Mak), uncovering a eukaryotic-like kinase (ELK) fold, similar to methylthioribose kinases and aminoglycoside phosphotransferases. The 1.15 Å structure of Mak in complex with a non-hydrolysable ATP analog reveals subtle structural rearrangements upon nucleotide binding in the cleft between the N- and the C-terminal lobes. Remarkably, this new family of ELKs has a novel N-terminal domain topologically resembling the cystatin family of protease inhibitors. By interfacing with and restraining the mobility of the phosphate-binding region of the N-terminal lobe, Mak's unusual N-terminal domain might regulate its phosphotransfer activity and represents the most likely anchoring point for TreS, the upstream enzyme in the pathway. By completing the gallery of atomic-detail models of an essential pathway, this structure opens new avenues for the rational design of alternative anti-tubercular compounds. PMID:25619172

  17. Developmental Pathways Linking Externalizing Symptoms, Internalizing Symptoms, and Academic Competence to Adolescent Substance Use

    ERIC Educational Resources Information Center

    Englund, Michelle M.; Siebenbruner, Jessica

    2012-01-01

    This study extends previous research investigating the developmental pathways predicting adolescent alcohol and marijuana use by examining the cascading effects of externalizing and internalizing symptoms and academic competence in the prediction of use and level of use of these substances in adolescence. Participants (N = 191) were drawn from a…

  18. Linking Social Change and Developmental Change: Shifting Pathways of Human Development

    ERIC Educational Resources Information Center

    Greenfield, Patricia M.

    2009-01-01

    P. M. Greenfield's new theory of social change and human development aims to show how changing sociodemographic ecologies alter cultural values and learning environments and thereby shift developmental pathways. Worldwide sociodemographic trends include movement from rural residence, informal education at home, subsistence economy, and…

  19. Developmental Pathways Linking Externalizing Symptoms, Internalizing Symptoms, and Academic Competence to Adolescent Substance Use

    ERIC Educational Resources Information Center

    Englund, Michelle M.; Siebenbruner, Jessica

    2012-01-01

    This study extends previous research investigating the developmental pathways predicting adolescent alcohol and marijuana use by examining the cascading effects of externalizing and internalizing symptoms and academic competence in the prediction of use and level of use of these substances in adolescence. Participants (N = 191) were drawn from a…

  20. Gremlin Activates the Smad Pathway Linked to Epithelial Mesenchymal Transdifferentiation in Cultured Tubular Epithelial Cells

    PubMed Central

    Rodrigues-Diez, Raquel; Rodrigues-Diez, Raúl R.; Lavoz, Carolina; Carvajal, Gisselle; Droguett, Alejandra; Garcia-Redondo, Ana B.; Rodriguez, Isabel; Ortiz, Alberto; Egido, Jesús; Mezzano, Sergio; Ruiz-Ortega, Marta

    2014-01-01

    Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming growth factor-β (TGF-β). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial cells we have recently described that Gremlin induces EMT and acts as a downstream TGF-β mediator. Our aim was to investigate whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2) with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and Smad-dependent gene transcription). The blockade of TGF-β, by a neutralizing antibody against active TGF-β, did not modify Gremlin-induced early Smad activation. These data show that Gremlin directly, by a TGF-β independent process, activates the Smad pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF-β production and caused a sustained Smad activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation, diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF-β neutralization also diminished Gremlin-induced EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGF-β. PMID:24949470

  1. miRnalyze: an interactive database linking tool to unlock intuitive microRNA regulation of cell signaling pathways.

    PubMed

    Subhra Das, Sankha; James, Mithun; Paul, Sandip; Chakravorty, Nishant

    2017-01-01

    The various pathophysiological processes occurring in living systems are known to be orchestrated by delicate interplays and cross-talks between different genes and their regulators. Among the various regulators of genes, there is a class of small non-coding RNA molecules known as microRNAs. Although, the relative simplicity of miRNAs and their ability to modulate cellular processes make them attractive therapeutic candidates, their presence in large numbers make it challenging for experimental researchers to interpret the intricacies of the molecular processes they regulate. Most of the existing bioinformatic tools fail to address these challenges. Here, we present a new web resource 'miRnalyze' that has been specifically designed to directly identify the putative regulation of cell signaling pathways by miRNAs. The tool integrates miRNA-target predictions with signaling cascade members by utilizing TargetScanHuman 7.1 miRNA-target prediction tool and the KEGG pathway database, and thus provides researchers with in-depth insights into modulation of signal transduction pathways by miRNAs. miRnalyze is capable of identifying common miRNAs targeting more than one gene in the same signaling pathway-a feature that further increases the probability of modulating the pathway and downstream reactions when using miRNA modulators. Additionally, miRnalyze can sort miRNAs according to the seed-match types and TargetScan Context ++ score, thus providing a hierarchical list of most valuable miRNAs. Furthermore, in order to provide users with comprehensive information regarding miRNAs, genes and pathways, miRnalyze also links to expression data of miRNAs (miRmine) and genes (TiGER) and proteome abundance (PaxDb) data. To validate the capability of the tool, we have documented the correlation of miRnalyze's prediction with experimental confirmation studies. http://www.mirnalyze.in.

  2. Rare Genomic Variants Link Bipolar Disorder with Anxiety Disorders to CREB-Regulated Intracellular Signaling Pathways.

    PubMed

    Kerner, Berit; Rao, Aliz R; Christensen, Bryce; Dandekar, Sugandha; Yourshaw, Michael; Nelson, Stanley F

    2013-01-01

    Bipolar disorder is a common, complex, and severe psychiatric disorder with cyclical disturbances of mood and a high suicide rate. Here, we describe a family with four siblings, three affected females and one unaffected male. The disease course was characterized by early-onset bipolar disorder and co-morbid anxiety spectrum disorders that followed the onset of bipolar disorder. Genetic risk factors were suggested by the early onset of the disease, the severe disease course, including multiple suicide attempts, and lack of adverse prenatal or early life events. In particular, drug and alcohol abuse did not contribute to the disease onset. Exome sequencing identified very rare, heterozygous, and likely protein-damaging variants in eight brain-expressed genes: IQUB, JMJD1C, GADD45A, GOLGB1, PLSCR5, VRK2, MESDC2, and FGGY. The variants were shared among all three affected family members but absent in the unaffected sibling and in more than 200 controls. The genes encode proteins with significant regulatory roles in the ERK/MAPK and CREB-regulated intracellular signaling pathways. These pathways are central to neuronal and synaptic plasticity, cognition, affect regulation and response to chronic stress. In addition, proteins in these pathways are the target of commonly used mood-stabilizing drugs, such as tricyclic antidepressants, lithium, and valproic acid. The combination of multiple rare, damaging mutations in these central pathways could lead to reduced resilience and increased vulnerability to stressful life events. Our results support a new model for psychiatric disorders, in which multiple rare, damaging mutations in genes functionally related to a common signaling pathway contribute to the manifestation of bipolar disorder.

  3. Caenorhabditis elegans POLQ-1 and HEL-308 function in two distinct DNA interstrand cross-link repair pathways.

    PubMed

    Muzzini, Diego M; Plevani, Paolo; Boulton, Simon J; Cassata, Giuseppe; Marini, Federica

    2008-06-01

    DNA interstrand cross-links (ICLs) are highly cytotoxic DNA lesions hindering DNA replication and transcription. Whereas in bacteria and yeast the molecular mechanisms involved in ICL repair are genetically well dissected, the scenario in multicellular organisms remains unclear. Here, we report that the two new mus308 genes, polq-1 and hel-308 are involved in ICL repair in Caenorhabditis elegans. After treatment with ICL agents, a decrease in survival and an increase in checkpoint-induced cell-cycle arrest and apoptosis of germ cells is observed in mutants of both genes. Although sensitive to ICL agents and to a minor extent to IR, cytological and epistatic analyses suggest that polq-1 and hel-308 are involved in different DNA repair pathways. While hel-308 functions in a Fanconi anemia-dependent pathway, polq-1 has a role in a novel distinct and brc-1 (CeBRCA1)-dependent ICL repair process in metazoans.

  4. A single transcription factor regulates evolutionarily diverse but functionally linked metabolic pathways in response to nutrient availability.

    PubMed

    Schmid, Amy K; Reiss, David J; Pan, Min; Koide, Tie; Baliga, Nitin S

    2009-01-01

    During evolution, enzyme-coding genes are acquired and/or replaced through lateral gene transfer and compiled into metabolic pathways. Gene regulatory networks evolve to fine tune biochemical fluxes through such metabolic pathways, enabling organisms to acclimate to nutrient fluctuations in a competitive environment. Here, we demonstrate that a single TrmB family transcription factor in Halobacterium salinarum NRC-1 globally coordinates functionally linked enzymes of diverse phylogeny in response to changes in carbon source availability. Specifically, during nutritional limitation, TrmB binds a cis-regulatory element to activate or repress 113 promoters of genes encoding enzymes in diverse metabolic pathways. By this mechanism, TrmB coordinates the expression of glycolysis, TCA cycle, and amino-acid biosynthesis pathways with the biosynthesis of their cognate cofactors (e.g. purine and thiamine). Notably, the TrmB-regulated metabolic network includes enzyme-coding genes that are uniquely archaeal as well as those that are conserved across all three domains of life. Simultaneous analysis of metabolic and gene regulatory network architectures suggests an ongoing process of co-evolution in which TrmB integrates the expression of metabolic enzyme-coding genes of diverse origins.

  5. A single transcription factor regulates evolutionarily diverse but functionally linked metabolic pathways in response to nutrient availability

    PubMed Central

    Schmid, Amy K; Reiss, David J; Pan, Min; Koide, Tie; Baliga, Nitin S

    2009-01-01

    During evolution, enzyme-coding genes are acquired and/or replaced through lateral gene transfer and compiled into metabolic pathways. Gene regulatory networks evolve to fine tune biochemical fluxes through such metabolic pathways, enabling organisms to acclimate to nutrient fluctuations in a competitive environment. Here, we demonstrate that a single TrmB family transcription factor in Halobacterium salinarum NRC-1 globally coordinates functionally linked enzymes of diverse phylogeny in response to changes in carbon source availability. Specifically, during nutritional limitation, TrmB binds a cis-regulatory element to activate or repress 113 promoters of genes encoding enzymes in diverse metabolic pathways. By this mechanism, TrmB coordinates the expression of glycolysis, TCA cycle, and amino-acid biosynthesis pathways with the biosynthesis of their cognate cofactors (e.g. purine and thiamine). Notably, the TrmB-regulated metabolic network includes enzyme-coding genes that are uniquely archaeal as well as those that are conserved across all three domains of life. Simultaneous analysis of metabolic and gene regulatory network architectures suggests an ongoing process of co-evolution in which TrmB integrates the expression of metabolic enzyme-coding genes of diverse origins. PMID:19536205

  6. PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways.

    PubMed

    Xiong, Xiaoxing; Xie, Rong; Zhang, Hongfei; Gu, Lijuan; Xie, Weiying; Cheng, Michelle; Jian, Zhihong; Kovacina, Kristina; Zhao, Heng

    2014-06-01

    The proline-rich Akt substrate of 40kDa (PRAS40) protein is not only a substrate of the protein kinase Akt but also a component of the mTOR complex 1 (mTORC1), thus it links the Akt and the mTOR pathways. We investigated the potential protective role of PRAS40 in cerebral ischemia and its underlying mechanisms by using rats with lentiviral over-expression of PRAS40 and mice with PRAS40 gene knockout (PRAS40 KO). Our results show that gene transfer of PRAS40 reduced infarction size in rats by promoting phosphorylation of Akt, FKHR (FOXO1), PRAS40, and mTOR. In contrast, PRAS40 KO increased infarction size. Although the PRAS40 KO under normal condition did not alter baseline levels of phosphorylated proteins in the Akt and mTOR pathways, PRAS40 KO that underwent stroke exhibited reduced protein levels of p-S6K and p-S6 in the mTOR pathway but not p-Akt, or p-PTEN in the Akt pathway. Furthermore, co-immunoprecipitation suggests that there were less interactive effects between Akt and mTOR in the PRAS40 KO. In conclusion, PRAS40 appears to reduce brain injury by converting cell signaling from Akt to mTOR. Copyright © 2014. Published by Elsevier Inc.

  7. Metabolic analysis reveals changes in the mevalonate and juvenile hormone synthesis pathways linked to the mosquito reproductive physiology.

    PubMed

    Rivera-Perez, Crisalejandra; Nouzova, Marcela; Lamboglia, Ivanna; Noriega, Fernando G

    2014-08-01

    Juvenile hormone (JH) regulates reproductive maturation in insects; therefore interruption of JH biosynthesis has been considered as a strategy for the development of target-specific insecticides. The corpora allata (CA) from mosquitoes is highly specialized to supply variable levels of JH, which are linked to ovarian developmental stages and influenced by nutritional signals. However, very little is known about how changes in JH synthesis relate to reproductive physiology and how JH synthesis regulation is translated into changes in the CA machinery. With the advent of new methods that facilitate the analysis of transcripts, enzymes and metabolites in the minuscule CA, we were able to provide comprehensive descriptions of the mevalonic (MVA) and JH synthesis pathways by integrating information on changes in the basic components of those pathways. Our results revealed remarkable dynamic changes in JH synthesis and exposed part of a complex mechanism that regulates CA activity. Principal component (PC) analyses validated that both pathways (MVAP and JH-branch) are transcriptionally co-regulated as a single unit, and catalytic activities for the enzymes of the MVAP and JH-branch also changed in a coordinate fashion. Metabolite studies showed that global fluctuations in the intermediate pool sizes in the MVAP and JH-branch were often inversely related. PC analyses suggest that in female mosquitoes, there are at least 4 developmental switches that alter JH synthesis by modulating the flux at distinctive points in both pathways.

  8. Cellular Assays for Ferredoxins: A Strategy for Understanding Electron Flow through Protein Carriers That Link Metabolic Pathways.

    PubMed

    Atkinson, Joshua T; Campbell, Ian; Bennett, George N; Silberg, Jonathan J

    2016-12-27

    The ferredoxin (Fd) protein family is a structurally diverse group of iron-sulfur proteins that function as electron carriers, linking biochemical pathways important for energy transduction, nutrient assimilation, and primary metabolism. While considerable biochemical information about individual Fd protein electron carriers and their reactions has been acquired, we cannot yet anticipate the proportion of electrons shuttled between different Fd-partner proteins within cells using biochemical parameters that govern electron flow, such as holo-Fd concentration, midpoint potential (driving force), molecular interactions (affinity and kinetics), conformational changes (allostery), and off-pathway electron leakage (chemical oxidation). Herein, we describe functional and structural gaps in our Fd knowledge within the context of a sequence similarity network and phylogenetic tree, and we propose a strategy for improving our understanding of Fd sequence-function relationships. We suggest comparing the functions of divergent Fds within cells whose growth, or other measurable output, requires electron transfer between defined electron donor and acceptor proteins. By comparing Fd-mediated electron transfer with biochemical parameters that govern electron flow, we posit that models that anticipate energy flow across Fd interactomes can be built. This approach is expected to transform our ability to anticipate Fd control over electron flow in cellular settings, an obstacle to the construction of synthetic electron transfer pathways and rational optimization of existing energy-conserving pathways.

  9. Neurodegenerative and Inflammatory Pathway Components Linked to TNF-α/TNFR1 Signaling in the Glaucomatous Human Retina

    PubMed Central

    Yang, Xiangjun; Luo, Cheng; Cai, Jian; Powell, David W.; Yu, Dahai; Kuehn, Markus H.

    2011-01-01

    Purpose. This study aimed to determine retinal proteomic alterations in human glaucoma, with particular focus on links to TNF-α/TNFR1 signaling. Methods. Human retinal protein samples were obtained from 20 donors with (n = 10) or without (n = 10) glaucoma. Alterations in protein expression were individually analyzed by quantitative LC-MS/MS. Quantitative Western blot analysis with cleavage or phosphorylation site-specific antibodies was used for data validation, and cellular localization of selected proteins was determined by immunohistochemical analysis of the retina in an additional group of glaucomatous human donor eyes (n = 38) and nonglaucomatous controls (n = 30). Results. Upregulated retinal proteins in human glaucoma included a number of downstream adaptor/interacting proteins and protein kinases involved in TNF-α/TNFR1 signaling. Bioinformatic analysis of the high-throughput data established extended networks of diverse functional interactions with death-promoting and survival-promoting pathways and mediation of immune response. Upregulated pathways included death receptor-mediated caspase cascade, mitochondrial dysfunction, endoplasmic reticulum stress, calpains leading to apoptotic cell death, NF-κB and JAK/STAT pathways, and inflammasome-assembly mediating inflammation. Interestingly, retinal expression pattern of a regulator molecule, TNFAIP3, exhibited prominent variability between individual samples, and methylation of cytosine nucleotides in the TNFAIP3 promoter was found to be correlated with this variability among glaucomatous donors. Conclusions. Findings of this study reveal a number of proteins upregulated in the glaucomatous human retina that exhibit many links to TNF-α/TNFR1 signaling. By highlighting various signaling molecules and regulators involved in cell death and immune response pathways and by correlating proteomic findings with epigenetic alterations, these findings provide a framework motivating further research. PMID:21917936

  10. Microbial pathways in colonic sulfur metabolism and links with health and disease

    PubMed Central

    Carbonero, Franck; Benefiel, Ann C.; Alizadeh-Ghamsari, Amir H.; Gaskins, H. Rex

    2012-01-01

    Sulfur is both crucial to life and a potential threat to health. While colonic sulfur metabolism mediated by eukaryotic cells is relatively well studied, much less is known about sulfur metabolism within gastrointestinal microbes. Sulfated compounds in the colon are either of inorganic (e.g., sulfates, sulfites) or organic (e.g., dietary amino acids and host mucins) origin. The most extensively studied of the microbes involved in colonic sulfur metabolism are the sulfate-reducing bacteria (SRB), which are common colonic inhabitants. Many other microbial pathways are likely to shape colonic sulfur metabolism as well as the composition and availability of sulfated compounds, and these interactions need to be examined in more detail. Hydrogen sulfide is the sulfur derivative that has attracted the most attention in the context of colonic health, and the extent to which it is detrimental or beneficial remains in debate. Several lines of evidence point to SRB or exogenous hydrogen sulfide as potential players in the etiology of intestinal disorders, inflammatory bowel diseases (IBDs) and colorectal cancer in particular. Generation of hydrogen sulfide via pathways other than dissimilatory sulfate reduction may be as, or more, important than those involving the SRB. We suggest here that a novel axis of research is to assess the effects of hydrogen sulfide in shaping colonic microbiome structure. Clearly, in-depth characterization of the microbial pathways involved in colonic sulfur metabolism is necessary for a better understanding of its contribution to colonic disorders and development of therapeutic strategies. PMID:23226130

  11. Linking social change and developmental change: shifting pathways of human development.

    PubMed

    Greenfield, Patricia M

    2009-03-01

    P. M. Greenfield's new theory of social change and human development aims to show how changing sociodemographic ecologies alter cultural values and learning environments and thereby shift developmental pathways. Worldwide sociodemographic trends include movement from rural residence, informal education at home, subsistence economy, and low-technology environments to urban residence, formal schooling, commerce, and high-technology environments. The former ecology is summarized by the German term Gemeinschaft ("community") and the latter by the German term Gesellschaft ("society"; Tönnies, 1887/1957). A review of empirical research demonstrates that, through adaptive processes, movement of any ecological variable in a Gesellschaft direction shifts cultural values in an individualistic direction and developmental pathways toward more independent social behavior and more abstract cognition--to give a few examples of the myriad behaviors that respond to these sociodemographic changes. In contrast, the (much less frequent) movement of any ecological variable in a Gemeinschaft direction is predicted to move cultural values and developmental pathways in the opposite direction. In conclusion, sociocultural environments are not static either in the developed or the developing world and therefore must be treated dynamically in developmental research.

  12. How does communication heal? Pathways linking clinician-patient communication to health outcomes.

    PubMed

    Street, Richard L; Makoul, Gregory; Arora, Neeraj K; Epstein, Ronald M

    2009-03-01

    Although prior research indicates that features of clinician-patient communication can predict health outcomes weeks and months after the consultation, the mechanisms accounting for these findings are poorly understood. While talk itself can be therapeutic (e.g., lessening the patient's anxiety, providing comfort), more often clinician-patient communication influences health outcomes via a more indirect route. Proximal outcomes of the interaction include patient understanding, trust, and clinician-patient agreement. These affect intermediate outcomes (e.g., increased adherence, better self-care skills) which, in turn, affect health and well-being. Seven pathways through which communication can lead to better health include increased access to care, greater patient knowledge and shared understanding, higher quality medical decisions, enhanced therapeutic alliances, increased social support, patient agency and empowerment, and better management of emotions. Future research should hypothesize pathways connecting communication to health outcomes and select measures specific to that pathway. Clinicians and patients should maximize the therapeutic effects of communication by explicitly orienting communication to achieve intermediate outcomes (e.g., trust, mutual understanding, adherence, social support, self-efficacy) associated with improved health.

  13. Conceptual disorganization weakens links in cognitive pathways: Disentangling neurocognition, social cognition, and metacognition in schizophrenia.

    PubMed

    Minor, Kyle S; Marggraf, Matthew P; Davis, Beshaun J; Luther, Lauren; Vohs, Jenifer L; Buck, Kelly D; Lysaker, Paul H

    2015-12-01

    Disentangling links between neurocognition, social cognition, and metacognition offers the potential to improve interventions for these cognitive processes. Disorganized symptoms have shown promise for explaining the limiting relationship that neurocognition holds with both social cognition and metacognition. In this study, primary aims included: 1) testing whether conceptual disorganization, a specific disorganized symptom, moderated relationships between cognitive processes, and 2) examining the level of conceptual disorganization necessary for links between cognitive processes to break down. To accomplish these aims, comprehensive assessments of conceptual disorganization, neurocognition, social cognition, and metacognition were administered to 67 people with schizophrenia-spectrum disorders. We found that conceptual disorganization significantly moderated the relationship between neurocognition and metacognition, with links between cognitive processes weakening when conceptual disorganization is present even at minimal levels of severity. There was no evidence that conceptual disorganization-or any other specific disorganized symptom-drove the limiting relationship of neurocognition on social cognition. Based on our findings, conceptual disorganization appears to be a critical piece of the puzzle when disentangling the relationship between neurocognition and metacognition. Roles of specific disorganized symptoms in the neurocognition - social cognition relationship were less clear. Findings from this study suggest that disorganized symptoms are an important treatment consideration when aiming to improve cognitive impairments.

  14. Potential biological pathways linking Type-D personality and poor health: A cross-sectional investigation.

    PubMed

    Jandackova, Vera K; Koenig, Julian; Jarczok, Marc N; Fischer, Joachim E; Thayer, Julian F

    2017-01-01

    Type-D personality, defined as a combination of high negative affect and high social isolation, has been associated with poor health outcomes. However, pathways underlying this association are largely unknown. We investigated the relationship between Type-D personality and several biological and behavioral pathways including the autonomic nervous system, the immune system, glucose regulation and sleep in a large, apparently healthy sample. Data from a total of 646 respondents (age 41.6±11.5, 12,2% women) were available for analysis. Persons with Type-D (negative affect and social isolation score ≥10) were contrasted with those without Type-D. Measures of plasma fibrinogen levels, white blood cell count, high sensitivity C-reactive protein, fasting plasma glucose (FPG), cholesterol, high-density and low-density lipoprotein, glycated hemoglobin (HbA1c), creatinine, triglycerides, and albumin were derived from fasting blood samples. Urine norepinephrine and free cortisol were determined by high-performance liquid chromatography. Time-domain heart rate variability (HRV) measures were calculated for the 24hr recording period and for nighttime separately. Persons with Type-D had higher HbA1c, FPG, and fibrinogen, and lower nighttime HRV than those without Type-D, suggesting worse glycemic control, systemic inflammation and poorer autonomic nervous system modulation in Type-D persons. In addition, those with Type-D reported less social support and greater sleep difficulties while no group differences were observed for alcohol and cigarette consumption, physical activity and body mass index. Findings provide some of the first evidence for multiple possible biological and behavioral pathways between Type-D personality and increased morbidity and mortality.

  15. Saccharomyces cerevisiae KTR4, KTR5 and KTR7 encode mannosyltransferases differentially involved in the N- and O-linked glycosylation pathways.

    PubMed

    Hernández, Nahúm V; López-Ramírez, Luz A; Díaz-Jiménez, Diana F; Mellado-Mojica, Erika; Martínez-Duncker, Iván; López, Mercedes G; Mora-Montes, Héctor M

    2017-10-01

    Saccharomyces cerevisiae is a model to understand basic aspects of protein glycosylation pathways. Although these metabolic routes have been thoroughly studied, there are still knowledge gaps; among them, the role of the MNT1/KRE2 gene family. This family is composed of nine members, with only six functionally characterized. The enzymes Ktr1, Ktr3, and Mnt1/Kre2 have overlapping activities in both O-linked and N-linked glycan synthesis; while Ktr2 and Yur1 participate exclusively in the elongation of the N-linked glycan outer chain. KTR6 encodes for a phosphomannosyltransferase that synthesizes the cell wall phosphomannan. Here, we aimed to establish the functional role of KTR4, KTR5 and KTR7 in the protein glycosylation pathways, by using heterologous complementation in Candida albicans null mutants lacking members of the MNT1/KRE2 gene family. The three S. cerevisiae genes restored defects in the C. albicans N-linked glycosylation pathway. KTR5 and KTR7 partially complemented a C. albicans null mutant with defects in the synthesis of O-linked glycans, and only KTR4 fully elongated the O-linked glycans like wild-type cells. Therefore, our results suggest that the three genes have a redundant activity in the S. cerevisiae N-linked glycosylation pathway, but KTR4 plays a major role in O-linked glycan synthesis. Copyright © 2017 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  16. The aspartate-family pathway of plants: linking production of essential amino acids with energy and stress regulation.

    PubMed

    Galili, Gad

    2011-02-01

    The Asp family pathway of plants is highly important from a nutritional standpoint because it leads to the synthesis of the four essential amino acids Lys, Thr, Met and Ile. These amino acids are not synthesized by human and its monogastric livestock and should be supplemented in their diets. Among the Asp-family amino acids, Lys is considered as the nutritionally most important essential amino acid because its level is most limiting in cereal grains, representing the largest source of plant foods and feeds worldwide. Metabolic engineering approaches led to significant increase in Lys level in seeds by enhancing its synthesis and reducing its catabolism. However, results from the model plant Arabidopsis showed that this approach may retard seed germination due to a major negative effect on the levels of a number of TCA cycle metabolites that associate with cellular energy. In the present review, we discuss the regulatory metabolic link of the Asp-family pathway with the TCA cycle and its biological significance upon exposure to stress conditions that cause energy deprivation. In addition, we also discuss how deep understanding of the regulatory metabolic link of the Asp-family pathway with energy and stress regulation can be used to improve Lys level in seeds of important crop species, minimizing the interference with the cellular energy status and plant-stress interaction. This review thus provides an example showing how deep understanding the inter-regulation of metabolism with plant stress physiology can lead to successful nutritional improvements with minimal negative effect on plant growth and response to stressful environments.

  17. Insulin/glucose induces natriuretic peptide clearance receptor in human adipocytes: a metabolic link with the cardiac natriuretic pathway.

    PubMed

    Bordicchia, M; Ceresiani, M; Pavani, M; Minardi, D; Polito, M; Wabitsch, M; Cannone, V; Burnett, J C; Dessì-Fulgheri, P; Sarzani, R

    2016-07-01

    Cardiac natriuretic peptides (NP) are involved in cardiorenal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low-calorie diet. On the contrary, insulin is an antilipolytic hormone that increases sodium retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptor expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high-glucose or low-glucose media to study NP receptors and insulin/glucose-regulated pathways. Fasting blood samples and VAT samples were taken from patients on the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent upregulation of NPRC, through the phosphatidylinositol 3-kinase pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, used to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose-regulated pathways, allowing atrial natriuretic peptide to induce lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR, and atherogenic lipid levels. Insulin/glucose-dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome, and higher blood pressure by reducing NP effects on adipocytes. Copyright © 2016 the American Physiological Society.

  18. Causal pathways linking environmental change with health behaviour change: Natural experimental study of new transport infrastructure and cycling to work.

    PubMed

    Prins, R G; Panter, J; Heinen, E; Griffin, S J; Ogilvie, D B

    2016-06-01

    Mechanisms linking changes to the environment with changes in physical activity are poorly understood. Insights into mechanisms of interventions can help strengthen causal attribution and improve understanding of divergent response patterns. We examined the causal pathways linking exposure to new transport infrastructure with changes in cycling to work. We used baseline (2009) and follow-up (2012) data (N=469) from the Commuting and Health in Cambridge natural experimental study (Cambridge, UK). Exposure to new infrastructure in the form of the Cambridgeshire Guided Busway was defined using residential proximity. Mediators studied were changes in perceptions of the route to work, theory of planned behaviour constructs and self-reported use of the new infrastructure. Outcomes were modelled as an increase, decrease or no change in weekly cycle commuting time. We used regression analyses to identify combinations of mediators forming potential pathways between exposure and outcome. We then tested these pathways in a path model and stratified analyses by baseline level of active commuting. We identified changes in perceptions of the route to work, and use of the cycle path, as potential mediators. Of these potential mediators, only use of the path significantly explained (85%) the effect of the infrastructure in increasing cycling. Path use also explained a decrease in cycling among more active commuters. The findings strengthen the causal argument that changing the environment led to changes in health-related behaviour via use of the new infrastructure, but also show how some commuters may have spent less time cycling as a result. Copyright © 2016. Published by Elsevier Inc.

  19. p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation.

    PubMed

    Liu, Wei Jing; Ye, Lin; Huang, Wei Fang; Guo, Lin Jie; Xu, Zi Gan; Wu, Hong Luan; Yang, Chen; Liu, Hua Feng

    2016-01-01

    The ubiquitin-proteasome system (UPS) and autophagy are two distinct and interacting proteolytic systems. They play critical roles in cell survival under normal conditions and during stress. An increasing body of evidence indicates that ubiquitinated cargoes are important markers of degradation. p62, a classical receptor of autophagy, is a multifunctional protein located throughout the cell and involved in many signal transduction pathways, including the Keap1-Nrf2 pathway. It is involved in the proteasomal degradation of ubiquitinated proteins. When the cellular p62 level is manipulated, the quantity and location pattern of ubiquitinated proteins change with a considerable impact on cell survival. Altered p62 levels can even lead to some diseases. The proteotoxic stress imposed by proteasome inhibition can activate autophagy through p62 phosphorylation. A deficiency in autophagy may compromise the ubiquitin-proteasome system, since overabundant p62 delays delivery of the proteasomal substrate to the proteasome despite proteasomal catalytic activity being unchanged. In addition, p62 and the proteasome can modulate the activity of HDAC6 deacetylase, thus influencing the autophagic degradation.

  20. A distinct brain pathway links viral RNA exposure to sickness behavior

    PubMed Central

    Zhu, Xinxia; Levasseur, Pete R.; Michaelis, Katherine A.; Burfeind, Kevin G.; Marks, Daniel L.

    2016-01-01

    Sickness behaviors and metabolic responses to invading pathogens are common to nearly all types of infection. These responses evolved to provide short-term benefit to the host to ward off infection, but impact on quality of life, and when prolonged lead to neurodegeneration, depression, and cachexia. Among the major infectious agents, viruses most frequently enter the brain, resulting in profound neuroinflammation. We sought to define the unique features of the inflammatory response in the brain to these infections. We demonstrate that the molecular pathway defining the central response to dsRNA is distinct from that found in the periphery. The behavioral and physical response to the dsRNA mimetic poly I:C is dependent on signaling via MyD88 when it is delivered centrally, whereas this response is mediated via the TRIF pathway when delivered peripherally. We also define the likely cellular candidates for this MyD88-dependent step. These findings suggest that symptom management is possible without ameliorating protective antiviral immune responses. PMID:27435819

  1. Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

    PubMed Central

    Girgis, RR; Javitch, JA; Lieberman, JA

    2013-01-01

    The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially associated with metabolic side effects compared to first-generation antipsychotic drugs (FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the insulin signaling pathway is vital for normal brain development and function. Abnormalities of this pathway have been found in persons with schizophrenia and antipsychotic drugs may ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a common pharmacologic mechanism. This article reviews insulin metabolism in the brain and related abnormalities associated with schizophrenia with the goals of gaining insight into antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia. Finally, we speculate about one potential mechanism of action (that is, functional selectivity) that would be consistent with the data reviewed herein and make suggestions for the future investigation that is required before a therapeutic agent based on these data can be realized. PMID:18414407

  2. An essential pathway links FLT3-ITD, HCK and CDK6 in acute myeloid leukemia

    PubMed Central

    Lopez, Sophie; Voisset, Edwige; Tisserand, Julie C.; Mosca, Cyndie; Prebet, Thomas; Santamaria, David; Dubreuil, Patrice; Sepulveda, Paulo De

    2016-01-01

    CDK4/CDK6 and RB proteins drive the progression through the G1 phase of the cell cycle. In acute myeloid leukemia (AML), the activity of the CDK/Cyclin D complex is increased. The mechanism involved is unknown, as are the respective roles played by CDK4 or CDK6 in this process. Here, we report that AML cells carrying FLT3-ITD mutations are dependent on CDK6 for cell proliferation while CDK4 is not essential. We showed that FLT3-ITD signaling is responsible for CDK6 overexpression, through a pathway involving the SRC-family kinase HCK. Accordingly, FLT3-ITD failed to transform primary hematopoietic progenitor cells from Cdk6−/− mice. Our results demonstrate that CDK6 is the primary target of CDK4/CDK6 inhibitors in FLT3-ITD positive AML. Furthermore, we delineate an essential protein kinase pathway -FLT3/HCK/CDK6- in the context of AML with FLT3-ITD mutations. PMID:27323399

  3. Multiple Causal Links Between Magnocellular-Dorsal Pathway Deficit and Developmental Dyslexia.

    PubMed

    Gori, Simone; Seitz, Aaron R; Ronconi, Luca; Franceschini, Sandro; Facoetti, Andrea

    2015-09-22

    Although impaired auditory-phonological processing is the most popular explanation of developmental dyslexia (DD), the literature shows that the combination of several causes rather than a single factor contributes to DD. Functioning of the visual magnocellular-dorsal (MD) pathway, which plays a key role in motion perception, is a much debated, but heavily suspected factor contributing to DD. Here, we employ a comprehensive approach that incorporates all the accepted methods required to test the relationship between the MD pathway dysfunction and DD. The results of 4 experiments show that (1) Motion perception is impaired in children with dyslexia in comparison both with age-match and with reading-level controls; (2) pre-reading visual motion perception-independently from auditory-phonological skill-predicts future reading development, and (3) targeted MD trainings-not involving any auditory-phonological stimulation-leads to improved reading skill in children and adults with DD. Our findings demonstrate, for the first time, a causal relationship between MD deficits and DD, virtually closing a 30-year long debate. Since MD dysfunction can be diagnosed much earlier than reading and language disorders, our findings pave the way for low resource-intensive, early prevention programs that could drastically reduce the incidence of DD.

  4. Network analysis reveals cross-links of the immune pathways activated by bacteria and allergen

    NASA Astrophysics Data System (ADS)

    Campbell, Colin; Thakar, Juilee; Albert, Réka

    2011-09-01

    Many biological networks are characterized by directed edges that represent either activating (positive) or inhibiting (negative) regulation. Most graph-theoretical methods used to study biological networks either disregard this important feature, or study the role of edge sign only in the context of small subgraphs called motifs. Here, we develop path-based measures which capture, on continuous scales spanning negative and positive values, both the long- and short-range regulatory relationships among node pairs. These measures also allow the quantification of each node's overall influence on the whole network and its susceptibility to regulation by the rest of the network. We apply the measures to a network representation of the mammalian immune response to simultaneous attack by allergen and respiratory bacteria. Although allergen and bacteria elicit different immune pathways, there is significant overlap (cross-talk) and feedback between these pathways. We identify key immune components in this cross-talk; particularly revealing the importance of natural killer cells as a key regulatory target in the cross-talk.

  5. Developmental pathways linking childhood and adolescent internalizing, externalizing, academic competence, and adolescent depression.

    PubMed

    Weeks, Murray; Ploubidis, George B; Cairney, John; Wild, T Cameron; Naicker, Kiyuri; Colman, Ian

    2016-08-01

    This study examined longitudinal pathways through three domains of adaptation from ages 4-5 to 14-15 (internalizing problems, externalizing problems, and academic competence) towards depressive symptoms at age 16-17. Participants were 6425 Canadian children followed bi-annually as part of the National Longitudinal Study of Children and Youth. Within-domain (i.e., stability) effects were moderate in strength. We found longitudinal cross-domain effects across one time point (i.e., one-lag cascades) between internalizing and externalizing in early childhood (positive associations), and between academic competence and externalizing in later childhood and adolescence (negative associations). We also found cascade effects over multiple time points (i.e., multi-lag cascades); lower academic competence at age 4-5 and greater internalizing at age 6-7 predicted greater age 12-13 externalizing, and greater age 6-7 externalizing predicted greater age 16-17 depression. Important pathways towards adolescent depression include a stability path through childhood and adolescent internalizing, as well as a number of potential paths involving all domains of adaptation, highlighting the multifactorial nature of adolescent depression.

  6. Variability of Metabolite Levels Is Linked to Differential Metabolic Pathways in Arabidopsis's Responses to Abiotic Stresses

    PubMed Central

    Töpfer, Nadine; Scossa, Federico; Fernie, Alisdair; Nikoloski, Zoran

    2014-01-01

    Constraint-based approaches have been used for integrating data in large-scale metabolic networks to obtain insights into metabolism of various organisms. Due to the underlying steady-state assumption, these approaches are usually not suited for making predictions about metabolite levels. Here, we ask whether we can make inferences about the variability of metabolite levels from a constraint-based analysis based on the integration of transcriptomics data. To this end, we analyze time-resolved transcriptomics and metabolomics data from Arabidopsis thaliana under a set of eight different light and temperature conditions. In a previous study, the gene expression data have already been integrated in a genome-scale metabolic network to predict pathways, termed modulators and sustainers, which are differentially regulated with respect to a biochemically meaningful data-driven null model. Here, we present a follow-up analysis which bridges the gap between flux- and metabolite-centric methods. One of our main findings demonstrates that under certain environmental conditions, the levels of metabolites acting as substrates in modulators or sustainers show significantly lower temporal variations with respect to the remaining measured metabolites. This observation is discussed within the context of a systems-view of plasticity and robustness of metabolite contents and pathway fluxes. Our study paves the way for investigating the existence of similar principles in other species for which both genome-scale networks and high-throughput metabolomics data of high quality are becoming increasingly available. PMID:24946036

  7. Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions.

    PubMed

    Menchero, Sergio; Rayon, Teresa; Andreu, Maria Jose; Manzanares, Miguel

    2017-04-01

    The first stages of mammalian development, before implantation of the embryo in the maternal uterus, result in the establishment of three cell populations in the blastocyst: trophectoderm, epiblast, and primitive endoderm. These events involve only a small number of cells, and are initiated by morphological differences among them related to cell adhesion and polarity. Much attention has been paid to the master transcription factors that are critical for establishing and maintaining early lineage choices. Nevertheless, a large body of work also reveals that additional molecular mechanisms are involved. Here, we provide an updated view of the role of different signaling pathways in the first stages of mouse development, and how their cross-talk and interplay determine the initial lineage decisions occurring in the blastocyst. We will also discuss how these pathways are critical for translating cellular phenotypes, the product of the morphogenetic events occurring at these stages, into transcriptional responses and expression of lineage-specifying transcription factors. Developmental Dynamics 246:245-261, 2017. © 2016 Wiley Periodicals, Inc.

  8. Predicting Ethnic Minority Children's Vocabulary from Socioeconomic Status, Maternal Language and Home Reading Input: Different Pathways for Host and Ethnic Language

    ERIC Educational Resources Information Center

    Prevoo, Mariëlle J. L.; Malda, Maike; Mesman, Judi; Emmen, Rosanneke A. G.; Yeniad, Nihal; Van Ijzendoorn, Marinus; Linting, Mariëlle

    2014-01-01

    When bilingual children enter formal reading education, host language proficiency becomes increasingly important. This study investigated the relation between socioeconomic status (SES), maternal language use, reading input, and vocabulary in a sample of 111 six-year-old children of first- and second-generation Turkish immigrant parents in the…

  9. Predicting Ethnic Minority Children's Vocabulary from Socioeconomic Status, Maternal Language and Home Reading Input: Different Pathways for Host and Ethnic Language

    ERIC Educational Resources Information Center

    Prevoo, Mariëlle J. L.; Malda, Maike; Mesman, Judi; Emmen, Rosanneke A. G.; Yeniad, Nihal; Van Ijzendoorn, Marinus; Linting, Mariëlle

    2014-01-01

    When bilingual children enter formal reading education, host language proficiency becomes increasingly important. This study investigated the relation between socioeconomic status (SES), maternal language use, reading input, and vocabulary in a sample of 111 six-year-old children of first- and second-generation Turkish immigrant parents in the…

  10. Thrifty Tbc1d1 and Tbc1d4 proteins link signalling and membrane trafficking pathways

    PubMed Central

    Koumanov, Françoise; Holman, Geoffrey D.

    2007-01-01

    Establishing a complete pathway which links occupancy of the insulin receptor to GLUT4 translocation has been particularly elusive because of the complexities involved in studying both signalling and membrane trafficking processes. However, Lienhard's group has now discovered two related molecules that could function in this linking role. These proteins, Tbc1d4 (also known as AS160) and now Tbc1d1, as reported in this issue of the Biochemical Journal, have been demonstrated to be Rab GAPs (GTPase-activating proteins) that link upstream to Akt (protein kinase B) and phosphoinositide 3-kinase and downstream to Rabs involved in trafficking of GLUT4 vesicles. The data from Leinhard and colleagues suggest that high levels of Rab GAP activity lead to suppression of GLUT4 translocation and this observation has wide significance and is likely to be relevant to the recent discovery that mutations in the Tbc1d1 gene lead to some cases of severe human obesity. PMID:17376030

  11. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

    PubMed Central

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S.; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J.; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G.; Collins, Steven J.; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S. G.; Will, Robert G.; van Duijn, Cornelia M.

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  12. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

    PubMed

    Sanchez-Juan, Pascual; Bishop, Matthew T; Kovacs, Gabor G; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G; Collins, Steven J; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S G; Will, Robert G; van Duijn, Cornelia M

    2014-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.

  13. Developmental pathways linking externalizing symptoms, internalizing symptoms, and academic competence to adolescent substance use.

    PubMed

    Englund, Michelle M; Siebenbruner, Jessica

    2012-10-01

    This study extends previous research investigating the developmental pathways predicting adolescent alcohol and marijuana use by examining the cascading effects of externalizing and internalizing symptoms and academic competence in the prediction of use and level of use of these substances in adolescence. Participants (N=191) were drawn from a longitudinal study of first-born children of low-income mothers. Using data from ages 7, 9, 12, and 16 years, a series of nested two-part (semi-continuous) path models from a developmental cascade modeling framework were compared. Controlling for gender, SES, mother's age at child's birth, and minority status, we found (a) within-domain rank-order stability across time, (b) significant cross-domain effects over time, (c) higher externalizing symptoms significantly predicted use of alcohol and marijuana as well as higher levels of use in adolescence, and (d) higher levels of academic competence significantly added to the prediction of use of alcohol.

  14. A visual pathway links brain structures active during magnetic compass orientation in migratory birds.

    PubMed

    Heyers, Dominik; Manns, Martina; Luksch, Harald; Güntürkün, Onur; Mouritsen, Henrik

    2007-09-26

    The magnetic compass of migratory birds has been suggested to be light-dependent. Retinal cryptochrome-expressing neurons and a forebrain region, "Cluster N", show high neuronal activity when night-migratory songbirds perform magnetic compass orientation. By combining neuronal tracing with behavioral experiments leading to sensory-driven gene expression of the neuronal activity marker ZENK during magnetic compass orientation, we demonstrate a functional neuronal connection between the retinal neurons and Cluster N via the visual thalamus. Thus, the two areas of the central nervous system being most active during magnetic compass orientation are part of an ascending visual processing stream, the thalamofugal pathway. Furthermore, Cluster N seems to be a specialized part of the visual wulst. These findings strongly support the hypothesis that migratory birds use their visual system to perceive the reference compass direction of the geomagnetic field and that migratory birds "see" the reference compass direction provided by the geomagnetic field.

  15. A Visual Pathway Links Brain Structures Active during Magnetic Compass Orientation in Migratory Birds

    PubMed Central

    Heyers, Dominik; Manns, Martina; Luksch, Harald; Güntürkün, Onur; Mouritsen, Henrik

    2007-01-01

    The magnetic compass of migratory birds has been suggested to be light-dependent. Retinal cryptochrome-expressing neurons and a forebrain region, “Cluster N”, show high neuronal activity when night-migratory songbirds perform magnetic compass orientation. By combining neuronal tracing with behavioral experiments leading to sensory-driven gene expression of the neuronal activity marker ZENK during magnetic compass orientation, we demonstrate a functional neuronal connection between the retinal neurons and Cluster N via the visual thalamus. Thus, the two areas of the central nervous system being most active during magnetic compass orientation are part of an ascending visual processing stream, the thalamofugal pathway. Furthermore, Cluster N seems to be a specialized part of the visual wulst. These findings strongly support the hypothesis that migratory birds use their visual system to perceive the reference compass direction of the geomagnetic field and that migratory birds “see” the reference compass direction provided by the geomagnetic field. PMID:17895978

  16. The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases

    PubMed Central

    Bayat, Vafa; Jaiswal, Manish; Bellen, Hugo J.

    2011-01-01

    Summary The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington’s Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF-β signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-β signaling in ALS, SMA and HD and increased signaling in HSP and MS. PMID:20832291

  17. Psychoneuroimmunology in pregnancy: immune pathways linking stress with maternal health, adverse birth outcomes, and fetal development.

    PubMed

    Christian, Lisa M

    2012-01-01

    It is well-established that psychological stress promotes immune dysregulation in nonpregnant humans and animals. Stress promotes inflammation, impairs antibody responses to vaccination, slows wound healing, and suppresses cell-mediated immune function. Importantly, the immune system changes substantially to support healthy pregnancy, with attenuation of inflammatory responses and impairment of cell-mediated immunity. This adaptation is postulated to protect the fetus from rejection by the maternal immune system. Thus, stress-induced immune dysregulation during pregnancy has unique implications for both maternal and fetal health, particularly preterm birth. However, very limited research has examined stress-immune relationships in pregnancy. The application of psychoneuroimmunology research models to the perinatal period holds great promise for elucidating biological pathways by which stress may affect adverse pregnancy outcomes, maternal health, and fetal development.

  18. Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease.

    PubMed

    Klarin, Derek; Zhu, Qiuyu Martin; Emdin, Connor A; Chaffin, Mark; Horner, Steven; McMillan, Brian J; Leed, Alison; Weale, Michael E; Spencer, Chris C A; Aguet, François; Segrè, Ayellet V; Ardlie, Kristin G; Khera, Amit V; Kaushik, Virendar K; Natarajan, Pradeep; Kathiresan, Sekar

    2017-09-01

    UK Biobank is among the world's largest repositories for phenotypic and genotypic information in individuals of European ancestry. We performed a genome-wide association study in UK Biobank testing ∼9 million DNA sequence variants for association with coronary artery disease (4,831 cases and 115,455 controls) and carried out meta-analysis with previously published results. We identified 15 new loci, bringing the total number of loci associated with coronary artery disease to 95 at the time of analysis. Phenome-wide association scanning showed that CCDC92 likely affects coronary artery disease through insulin resistance pathways, whereas experimental analysis suggests that ARHGEF26 influences the transendothelial migration of leukocytes.

  19. Emotional Awareness as a Pathway Linking Adult Attachment to Subsequent Depression

    PubMed Central

    Monti, Jennifer D.; Rudolph, Karen D.

    2014-01-01

    Although research links insecure adult attachment with depression, the emotional processes accounting for this association over time remain relatively unexplored. To address this gap, this study investigated whether deficits in emotional awareness serve as one explanatory process. Adult females caregivers (N = 417, M age = 37.83) completed questionnaires annually for three years. As anticipated, attachment avoidance exerted an indirect effect on depression via emotional awareness. Attachment anxiety directly predicted subsequent depression but the indirect effect through emotional awareness was nonsignificant. These results suggest that an avoidant attachment style interferes with the effective processing of emotions, thereby placing women at risk for depression. This research implicates emotional awareness as a potential target for interventions aimed at reducing depressive symptoms in mothers with avoidant attachment styles. PMID:25019541

  20. Emotional awareness as a pathway linking adult attachment to subsequent depression.

    PubMed

    Monti, Jennifer D; Rudolph, Karen D

    2014-07-01

    Although research links insecure adult attachment with depression, the emotional processes accounting for this association over time remain relatively unexplored. To address this gap, this study investigated whether deficits in emotional awareness serve as one explanatory process. Adult female caregivers (N = 417, Mage = 37.83) completed questionnaires annually for 3 years. As anticipated, attachment avoidance exerted an indirect effect on depression via emotional awareness. Attachment anxiety directly predicted subsequent depression, but the indirect effect through emotional awareness was nonsignificant. These results suggest that an avoidant attachment style interferes with the effective processing of emotions, thereby placing women at risk for depression. This research implicates emotional awareness as a potential target for interventions aimed at reducing depressive symptoms in mothers with avoidant attachment styles. PsycINFO Database Record (c) 2014 APA, all rights reserved.

  1. Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway

    PubMed Central

    Potu, Harish; Peterson, Luke F.; Pal, Anupama; Verhaegen, Monique; Cao, Juxiang; Talpaz, Moshe; Donato, Nicholas J.

    2014-01-01

    Usp5 is a deubiquitinase (DUB) previously shown to regulate unanchored polyubiquitin (Ub) chains, p53 transcriptional activity and double-strand DNA repair. In BRAF mutant melanoma cells, Usp5 activity was suppressed by BRAF inhibitor (vemurafenib) in sensitive but not in acquired or intrinsically resistant cells. Usp5 knockdown overcame acquired vemurafenib resistance and sensitized BRAF and NRAS mutant melanoma cells to apoptosis initiated by MEK inhibitor, cytokines or DNA-damaging agents. Knockdown and overexpression studies demonstrated that Usp5 regulates p53 (and p73) levels and alters cell growth and cell cycle distribution associated with p21 induction. Usp5 also regulates the intrinsic apoptotic pathway by modulating p53-dependent FAS expression. A small molecule DUB inhibitor (EOAI3402143) phenocopied the FAS induction and apoptotic sensitization of Usp5 knockdown and fully blocked melanoma tumor growth in mice. Overall, our results demonstrate that BRAF activates Usp5 to suppress cell cycle checkpoint control and apoptosis by blocking p53 and FAS induction; all of which can be restored by small molecule-mediated Usp5 inhibition. These results suggest that Usp5 inhibition can provide an alternate approach in recovery of diminished p53 (or p73) function in melanoma and can add to the targeted therapies already used in the treatment of melanoma. PMID:24980819

  2. Dental fluorosis linked to degassing of Ambrym volcano, Vanuatu: a novel exposure pathway.

    PubMed

    Allibone, Rachel; Cronin, Shane J; Charley, Douglas T; Neall, Vince E; Stewart, Robert B; Oppenheimer, Clive

    2012-04-01

    Ambrym in Vanuatu is a persistently degassing island volcano whose inhabitants harvest rainwater for their potable water needs. The findings from this study indicate that dental fluorosis is prevalent in the population due to fluoride contamination of rainwater by the volcanic plume. A dental survey was undertaken of 835 children aged 6-18 years using the Dean's Index of Fluorosis. Prevalence of dental fluorosis was found to be 96% in the target area of West Ambrym, 71% in North Ambrym, and 61% in Southeast Ambrym. This spatial distribution appears to reflect the prevailing winds and rainfall patterns on the island. Severe cases were predominantly in West Ambrym, the most arid part of the island, and the most commonly affected by the volcanic plume. Over 50 km downwind, on a portion of Malakula Island, the dental fluorosis prevalence was 85%, with 36% prevalence on Tongoa Island, an area rarely affected by volcanic emissions. Drinking water samples from West Ambrym contained fluoride levels from 0.7 to 9.5 ppm F (average 4.2 ppm F, n = 158) with 99% exceeding the recommended concentration of 1.0 ppm F. The pathway of fluoride-enriched rainwater impacting upon human health as identified in this study has not previously been recognised in the aetiology of fluorosis. This is an important consideration for populations in the vicinity of degassing volcanoes, particularly where rainwater comprises the primary potable water supply for humans or animals.

  3. Octopamine neuromodulation regulates Gr32a-linked aggression and courtship pathways in Drosophila males.

    PubMed

    Andrews, Jonathan C; Fernández, María Paz; Yu, Qin; Leary, Greg P; Leung, Adelaine K W; Kavanaugh, Michael P; Kravitz, Edward A; Certel, Sarah J

    2014-05-01

    Chemosensory pheromonal information regulates aggression and reproduction in many species, but how pheromonal signals are transduced to reliably produce behavior is not well understood. Here we demonstrate that the pheromonal signals detected by Gr32a-expressing chemosensory neurons to enhance male aggression are filtered through octopamine (OA, invertebrate equivalent of norepinephrine) neurons. Using behavioral assays, we find males lacking both octopamine and Gr32a gustatory receptors exhibit parallel delays in the onset of aggression and reductions in aggression. Physiological and anatomical experiments identify Gr32a to octopamine neuron synaptic and functional connections in the suboesophageal ganglion. Refining the Gr32a-expressing population indicates that mouth Gr32a neurons promote male aggression and form synaptic contacts with OA neurons. By restricting the monoamine neuron target population, we show that three previously identified OA-Fru(M) neurons involved in behavioral choice are among the Gr32a-OA connections. Our findings demonstrate that octopaminergic neuromodulatory neurons function as early as a second-order step in this chemosensory-driven male social behavior pathway.

  4. Clostridium difficile flagella predominantly activate TLR5-linked NF-κB pathway in epithelial cells.

    PubMed

    Batah, Jameel; Denève-Larrazet, Cécile; Jolivot, Pierre-Alain; Kuehne, Sarah; Collignon, Anne; Marvaud, Jean-Christophe; Kansau, Imad

    2016-04-01

    Clostridium difficile has become the most common enteropathogen responsible for intestinal nosocomial post-antibiotic infections. This has coincided with the appearance of serious cases related to the emergence of hypervirulent strains. The toxins are the main virulence factors and elicit an inflammatory response during C. difficile infection. However, other bacterial components appear to be involved in the inflammatory process. In some pathogens, flagella play a role in pathogenesis through abnormal stimulation of the TLR5-mediated host immune response. To date, few studies have addressed this role for C. difficile flagella. In the current study, we confirm in two different epithelial cell models that C. difficile thanks to its FliC flagellin interacts with TLR5. In addition, thanks to inhibition and transcriptomic studies we demonstrate that the interaction of flagellin and TLR5 predominantly activates the NF-κB and, in a lesser degree, the MAPK pathways, via TLR5, leading to up-regulation of pro-inflammatory gene expression and synthesis of pro-inflammatory mediators. These results suggest a role for C. difficile flagella in contributing to inflammatory response in host intestinal cells.

  5. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.

    PubMed

    Kumar, Raman; Corbett, Mark A; van Bon, Bregje W M; Woenig, Joshua A; Weir, Lloyd; Douglas, Evelyn; Friend, Kathryn L; Gardner, Alison; Shaw, Marie; Jolly, Lachlan A; Tan, Chuan; Hunter, Matthew F; Hackett, Anna; Field, Michael; Palmer, Elizabeth E; Leffler, Melanie; Rogers, Carolyn; Boyle, Jackie; Bienek, Melanie; Jensen, Corinna; Van Buggenhout, Griet; Van Esch, Hilde; Hoffmann, Katrin; Raynaud, Martine; Zhao, Huiying; Reed, Robin; Hu, Hao; Haas, Stefan A; Haan, Eric; Kalscheuer, Vera M; Gecz, Jozef

    2015-08-06

    Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.

  6. Developing Measures of Pathways that May Link Macro Social/Structural Changes with HIV Epidemiology.

    PubMed

    Pouget, Enrique R; Sandoval, Milagros; Nikolopoulos, Georgios K; Mateu-Gelabert, Pedro; Rossi, Diana; Smyrnov, Pavlo; Jones, Yolanda; Friedman, Samuel R

    2016-08-01

    Macro-social/structural events ("big events") such as wars, disasters, and large-scale changes in policies can affect HIV transmission by making risk behaviors more or less likely or by changing risk contexts. The purpose of this study was to develop new measures to investigate hypothesized pathways between macro-social changes and HIV transmission. We developed novel scales and indexes focused on topics including norms about sex and drug injecting under different conditions, involvement with social groups, helping others, and experiencing denial of dignity. We collected data from 300 people who inject drugs in New York City during 2012-2013. Most investigational measures showed evidence of validity (Pearson correlations with criterion variables range = 0.12-0.71) and reliability (Cronbach's alpha range = 0.62-0.91). Research is needed in different contexts to evaluate whether these measures can be used to better understand HIV outbreaks and help improve social/structural HIV prevention intervention programs.

  7. Prioritizing disease-linked variants, genes, and pathways with an interactive whole genome analysis pipeline

    PubMed Central

    Lee, In-Hee; Lee, Kyungjoon; Hsing, Michael; Choe, Yongjoon; Park, Jin-Ho; Kim, Shu Hee; Bohn, Justin M.; Neu, Matthew B.; Hwang, Kyu-Baek; Green, Robert C.; Kohane, Isaac S.; Kong, Sek Won

    2014-01-01

    Whole genome sequencing (WGS) studies are uncovering disease-associated variants in both rare and non-rare diseases. Utilizing the next-generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline –gNOME – to prioritize phenotype-associated variants while minimizing false positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype associated variants, and the result summaries are provided at variant-, gene-, and genome-levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared to population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss of function variants in known cancer pathways. gNOME web-server and source codes are freely available to the academic community. PMID:24478219

  8. Production of extrachromosomal microDNAs is linked to mismatch repair pathways and transcriptional activity

    PubMed Central

    Dillon, Laura W.; Kumar, Pankaj; Shibata, Yoshiyuki; Wang, Yuh-Hwa; Willcox, Smaranda; Griffith, Jack D.; Pommier, Yves; Takeda, Shunichi; Dutta, Anindya

    2015-01-01

    SUMMARY MicroDNAs are <400-base extrachromosomal circles found in mammalian cells. Tens of thousands of microDNAs have been found in all tissue types, including sperm. MicroDNAs arise preferentially from areas with high gene density, GC content, and exon density, from promoters with activating chromatin modifications and in sperm from the 5'-UTR of full-length LINE-1 elements, but are depleted from lamin-associated heterochromatin. Analysis of microDNAs from a set of human cancer cell lines revealed lineage-specific patterns of microDNA origins. A survey of microDNAs from chicken cells defective in various DNA repair proteins reveal that homologous recombination and nonhomologous end joining repair pathways are not required for microDNA production. Deletion of the MSH3 DNA mismatch repair protein results in a significant decrease in microDNA abundance, specifically from non-CpG genomic regions. Thus, microDNAs arise as part of normal cellular physiology; either from DNA breaks associated with RNA metabolism or from replication slippage followed by mismatch repair. PMID:26051933

  9. Inflexible ethanol intake: A putative link with the Lrrk2 pathway.

    PubMed

    da Silva E Silva, Daniel Almeida; Frozino Ribeiro, Andrea; Damasceno, Samara; Rocha, Cristiane S; Berenguer de Matos, Alexandre H; Boerngen-Lacerda, Roseli; Correia, Diego; Brunialti Godard, Ana Lúcia

    2016-10-15

    Alcoholism is a complex multifactorial disorder with a strong genetic influence. Although several studies have shown the impact of high ethanol intake on the striatal gene expression, few have addressed the relationship between the patterns of gene expression underlying the compulsive behaviour associated with the two major concerns in addiction: the excessive drug consumption and relapsing. In this study, we used a chronic three-bottle free-choice murine model to address striatal transcript regulation among animals with different ethanol intakes and preferences: Light Drinkers (preference for water throughout the experiment), Heavy Drinkers (preference for ethanol with a non-compulsive intake) and Inflexible Drinkers (preference for ethanol and simultaneous loss of control over the drug intake). Our aim was to correlate the intake patterns observed in this model with gene expression changes in the striatum, a brain region critical for the development of alcohol addiction. We found that the transcripts of the Lrrk2 gene, which encodes a multifunctional protein with kinase and GTPase activities, is upregulated only in Inflexible Drinkers suggesting, for the first time, that the Lrrk2 pathway plays a major role in the compulsive ethanol intake behaviour of addicted subjects.

  10. THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

    PubMed Central

    Kumar, Raman; Corbett, Mark A.; van Bon, Bregje W.M.; Woenig, Joshua A.; Weir, Lloyd; Douglas, Evelyn; Friend, Kathryn L.; Gardner, Alison; Shaw, Marie; Jolly, Lachlan A.; Tan, Chuan; Hunter, Matthew F.; Hackett, Anna; Field, Michael; Palmer, Elizabeth E.; Leffler, Melanie; Rogers, Carolyn; Boyle, Jackie; Bienek, Melanie; Jensen, Corinna; Van Buggenhout, Griet; Van Esch, Hilde; Hoffmann, Katrin; Raynaud, Martine; Zhao, Huiying; Reed, Robin; Hu, Hao; Haas, Stefan A.; Haan, Eric; Kalscheuer, Vera M.; Gecz, Jozef

    2015-01-01

    Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities. PMID:26166480

  11. Production of Extrachromosomal MicroDNAs Is Linked to Mismatch Repair Pathways and Transcriptional Activity.

    PubMed

    Dillon, Laura W; Kumar, Pankaj; Shibata, Yoshiyuki; Wang, Yuh-Hwa; Willcox, Smaranda; Griffith, Jack D; Pommier, Yves; Takeda, Shunichi; Dutta, Anindya

    2015-06-23

    MicroDNAs are <400-base extrachromosomal circles found in mammalian cells. Tens of thousands of microDNAs have been found in all tissue types, including sperm. MicroDNAs arise preferentially from areas with high gene density, GC content, and exon density from promoters with activating chromatin modifications and in sperm from the 5'-UTR of full-length LINE-1 elements, but are depleted from lamin-associated heterochromatin. Analysis of microDNAs from a set of human cancer cell lines revealed lineage-specific patterns of microDNA origins. A survey of microDNAs from chicken cells defective in various DNA repair proteins reveals that homologous recombination and non-homologous end joining repair pathways are not required for microDNA production. Deletion of the MSH3 DNA mismatch repair protein results in a significant decrease in microDNA abundance, specifically from non-CpG genomic regions. Thus, microDNAs arise as part of normal cellular physiology—either from DNA breaks associated with RNA metabolism or from replication slippage followed by mismatch repair.

  12. Details for Manuscript Number SSM-D-04-00268R3 “Urban-Rural Differences in the Socioeconomic Deprivation—Sexual Behavior Link in Kenya”

    PubMed Central

    Zulu, Eliya M.; Ezeh, Alex C.

    2007-01-01

    We compare the impact of socioeconomic deprivation on risky sexual outcomes in rural and urban Kenya. Quantitative data are drawn from the Demographic & Health Surveys (DHS) and qualitative data from the Sexual Networking and Associated Reproductive and Social Health Concerns study. Using two separate indicators of deprivation we show that, although poverty is significantly associated with the examined sexual outcomes in all settings, the urban poor are significantly more likely than their rural counterparts to have an early sexual debut and a greater incidence of multiple sexual partnerships. The disadvantage of the urban poor is accentuated for married women; those in Nairobi’s slums are at least three times as likely to have multiple sexual partners as their rural counterparts. The implications of these findings are discussed. PMID:17113695

  13. Projecting regional climate and cropland changes using a linked biogeophysical-socioeconomic modeling framework: 1. Model description and an equilibrium application over West Africa

    NASA Astrophysics Data System (ADS)

    Wang, Guiling; Ahmed, Kazi Farzan; You, Liangzhi; Yu, Miao; Pal, Jeremy; Ji, Zhenming

    2017-03-01

    Agricultural land use alters regional climate through modifying the surface mass, energy, and momentum fluxes; climate influences agricultural land use through their impact on crop yields. These interactions are not well understood and have not been adequately considered in climate projections. This study tackles the critical linkages within the coupled natural-human system of West Africa in a changing climate based on an equilibrium application of a modeling framework that asynchronously couples models of regional climate, crop yield, multimarket agricultural economics, and cropland expansion. Using this regional modeling framework driven with two global climate models, we assess the contributions of land use change (LUC) and greenhouse gas (GHGs) concentration changes to regional climate changes and assess the contribution of climate change and socioeconomic factors to agricultural land use changes. For future cropland expansion in West Africa, our results suggest that socioeconomic development would be the dominant driver in the east (where current cropland coverage is already high) and climate changes would be the primary driver in the west (where future yield drop is severe). For future climate, it is found that agricultural expansion would cause a dry signal in the west and a wet signal in the east downwind, with an east-west contrast similar to the GHG-induced changes. Over a substantial portion of West Africa, the strength of the LUC-induced climate signals is comparable to the GHG-induced changes. Uncertainties originating from the driving global models are small; human decision making related to land use and international trade is a major source of uncertainty.

  14. MRNA and miRNA expression patterns associated to pathways linked to metal mixture health effects.

    PubMed

    Martínez-Pacheco, M; Hidalgo-Miranda, A; Romero-Córdoba, S; Valverde, M; Rojas, E

    2014-01-10

    Metals are a threat to human health by increasing disease risk. Experimental data have linked altered miRNA expression with exposure to some metals. MiRNAs comprise a large family of non-coding single-stranded molecules that primarily function to negatively regulate gene expression post-transcriptionally. Although several human populations are exposed to low concentrations of As, Cd and Pb as a mixture, most toxicology research focuses on the individual effects that these metals exert. Thus, this study aims to evaluate global miRNA and mRNA expression changes induced by a metal mixture containing NaAsO2, CdCl2, Pb(C2H3O2)2·3H2O and to predict possible metal-associated disease development under these conditions. Our results show that this metal mixture results in a miRNA expression profile that may be responsible for the mRNA expression changes observed under experimental conditions in which coding proteins are involved in cellular processes, including cell death, growth and proliferation related to the metal-associated inflammatory response and cancer.

  15. Identification of Links Between Cellular Pathways by Genetic Interaction Mapping (GIM).

    PubMed

    Malabat, Christophe; Saveanu, Cosmin

    2016-01-01

    The yeast systematic deletion collection offered the basis for a number of different strategies that establish functional links between genes by analyzing the phenotype of cells that combine two different deletions or mutations. A distinguishing feature of the collection is the presence of molecular barcodes at each deleted locus, which can be used to quantify the presence and abundance of cells bearing a given allele in a complex mix. As a result, a large number of mutants can be tested in batch cultures, replacing tedious manipulation of thousands of individual strains with a barcode microarray readout. Barcode-based genetic screens like Genetic Interaction Mapping (GIM) thus require little investment in terms of specific equipment, are fast to perform, and allow precise measurements of double mutant growth rates for both aggravating (synthetic sick) and alleviating (epistatic) effects. We describe here protocols for preparing the pools of haploid double mutant S. cerevisiae cells, testing their composition with barcode microarrays, and analyzing the results to extract useful functional information.

  16. Linking prenatal maternal adversity to developmental outcomes in infants: the role of epigenetic pathways.

    PubMed

    Monk, Catherine; Spicer, Julie; Champagne, Frances A

    2012-11-01

    Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with risk of psychopathology. Although the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this article, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and we review findings illustrating prenatal-postnatal interplay and the developmental and epigenetic consequences of postnatal mother-infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress.

  17. Linking Prenatal Maternal Adversity to Developmental Outcomes in Infants: The Role of Epigenetic Pathways

    PubMed Central

    Monk, Catherine; Spicer, Julie; Champagne, Frances A.

    2013-01-01

    Prenatal exposure to maternal stress, anxiety, and depression can have lasting effects on infant development with consequences for risk of psychopathology. Though the impact of prenatal maternal distress has been well documented, the potential mechanisms through which maternal psychosocial variables shape development have yet to be fully elucidated. Advances in molecular biology have highlighted the role of epigenetic mechanisms in regulating gene activity, neurobiology, and behavior and the potential role of environmentally-induced epigenetic variation in linking early life exposures to long-term biobehavioral outcomes. In this review, we discuss evidence illustrating the association between maternal prenatal distress and both fetal and infant developmental trajectories and the potential role of epigenetic mechanisms in mediating these effects. Postnatal experiences may have a critical moderating influence on prenatal effects, and here we review findings illustrating prenatal-postnatal interplay and the developmental and epigenetic consequences of postnatal mother-infant interactions. The in utero environment is regulated by placental function and there is emerging evidence that the placenta is highly susceptible to maternal distress and a target of epigenetic dysregulation. Integrating studies of prenatal exposures, placental function, and postnatal maternal care with the exploration of epigenetic mechanisms may provide novel insights into the pathophysiology induced by maternal distress. PMID:23062303

  18. Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia.

    PubMed

    Minutoli, Letteria; Rinaldi, Mariagrazia; Marini, Herbert; Irrera, Natasha; Crea, Giovanni; Lorenzini, Cesare; Puzzolo, Domenico; Valenti, Andrea; Pisani, Antonina; Adamo, Elena B; Altavilla, Domenica; Squadrito, Francesco; Micali, Antonio

    2016-08-11

    Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targets either the static component of BPH, including finasteride and dutasteride, or the dynamic component of BPH, including α-adrenoceptor antagonists such as tamsulosin and alfuzosin. Both these classes of drugs significantly interfere with the apoptosis machinery. Furthermore, phytotherapic supplements and new drugs may also modulate several molecular steps of apoptosis.

  19. Apoptotic Pathways Linked to Endocrine System as Potential Therapeutic Targets for Benign Prostatic Hyperplasia

    PubMed Central

    Minutoli, Letteria; Rinaldi, Mariagrazia; Marini, Herbert; Irrera, Natasha; Crea, Giovanni; Lorenzini, Cesare; Puzzolo, Domenico; Valenti, Andrea; Pisani, Antonina; Adamo, Elena B.; Altavilla, Domenica; Squadrito, Francesco; Micali, Antonio

    2016-01-01

    Benign prostatic hyperplasia (BPH) is a chronic condition common in older men that can result in bothersome lower urinary tract symptoms. The molecular mechanisms and networks underlying the development and the progression of the disease are still far from being fully understood. BPH results from smooth muscle cell and epithelial cell proliferation, primarily within the transition zone of the prostate. Apoptosis and inflammation play important roles in the control of cell growth and in the maintenance of tissue homeostasis. Disturbances in molecular mechanisms of apoptosis machinery have been linked to BPH. Increased levels of the glycoprotein Dickkopf-related protein 3 in BPH cause an inhibition of the apoptosis machinery through a reduction in B cell lymphoma (Bcl)-2 associated X protein (Bax) expression. Inhibitors of apoptosis proteins influence cell death by direct inhibition of caspases and modulation of the transcription factor nuclear factor-κB. Current pharmacotherapy targets either the static component of BPH, including finasteride and dutasteride, or the dynamic component of BPH, including α-adrenoceptor antagonists such as tamsulosin and alfuzosin. Both these classes of drugs significantly interfere with the apoptosis machinery. Furthermore, phytotherapic supplements and new drugs may also modulate several molecular steps of apoptosis. PMID:27529214

  20. Emotion regulation strategies in trauma-related disorders: pathways linking neurobiology and clinical manifestations.

    PubMed

    Del Río-Casanova, Lucía; González, Anabel; Páramo, Mario; Van Dijke, Annemiek; Brenlla, Julio

    2016-06-01

    Emotion regulation impairments with traumatic origins have mainly been studied from posttraumatic stress disorder (PTSD) models by studying cases of adult onset and single-incident trauma exposure. The effects of adverse traumatic experiences, however, go beyond the PTSD. Different authors have proposed that PTSD, borderline personality, dissociative, conversive and somatoform disorders constitute a full spectrum of trauma-related conditions. Therefore, a comprehensive review of the neurobiological findings covering this posttraumatic spectrum is needed in order to develop an all-encompassing model for trauma-related disorders with emotion regulation at its center. The present review has sought to link neurobiology findings concerning cortico-limbic function to the field of emotion regulation. In so doing, trauma-related disorders have been placed in a continuum between under- and over-regulation of affect strategies. Under-regulation of affect was predominant in borderline personality disorder, PTSD with re-experiencing symptoms and positive psychoform and somatoform dissociative symptoms. Over-regulation of affect was more prevalent in somatoform disorders and pathologies characterized by negative psychoform and somatoform symptoms. Throughout this continuum, different combinations between under- and over-regulation of affect strategies were also found.

  1. Developing food allergy: a potential immunologic pathway linking skin barrier to gut

    PubMed Central

    Wang, Yui-Hsi

    2016-01-01

    Immunoglobulin E (IgE)-mediated food allergy is an adverse reaction to foods and is driven by uncontrolled type-2 immune responses. Current knowledge cannot explain why only some individuals among those with food allergy are prone to develop life-threatening anaphylaxis. It is increasingly evident that the immunologic mechanisms involved in developing IgE-mediated food allergy are far more complex than allergic sensitization. Clinical observations suggest that patients who develop severe allergic reactions to food are often sensitized through the skin in early infancy. Environmental insults trigger epidermal thymic stromal lymphopoietin and interleukin-33 (IL-33) production, which endows dendritic cells with the ability to induce CD4 +TH2 cell-mediated allergic inflammation. Intestinal IL-25 propagates the allergic immune response by enhancing collaborative interactions between resident type-2 innate lymphoid cells and CD4 +TH2 cells expanded by ingested antigens in the gastrointestinal tract. IL-4 signaling provided by CD4 +TH2 cells induces emigrated mast cell progenitors to become multi-functional IL-9-producing mucosal mast cells, which then expand greatly after repeated food ingestions. Inflammatory cytokine IL-33 promotes the function and maturation of IL-9-producing mucosal mast cells, which amplify intestinal mastocytosis, resulting in increased clinical reactivity to ingested food allergens. These findings provide the plausible view that the combinatorial signals from atopic status, dietary allergen ingestions, and inflammatory cues may govern the perpetuation of allergic reactions from the skin to the gut and promote susceptibility to life-threatening anaphylaxis. Future in-depth studies of the molecular and cellular factors composing these stepwise pathways may facilitate the discovery of biomarkers and therapeutic targets for diagnosing, preventing, and treating food allergy. PMID:27853507

  2. Carboxypeptidase Z (CPZ) links thyroid hormone and Wnt signaling pathways in growth plate chondrocytes.

    PubMed

    Wang, Lai; Shao, Yvonne Y; Ballock, R Tracy

    2009-02-01

    Carboxypeptidase Z (CPZ) removes carboxyl-terminal basic amino acid residues, particularly arginine residues, from proteins. CPZ contains a cysteine-rich domain (CRD) similar to the CRD found in the frizzled family of Wnt receptors. We have previously shown that thyroid hormone regulates terminal differentiation of growth plate chondrocytes through activation of Wnt-4 expression and Wnt/beta-catenin signaling. The Wnt-4 protein contains a C-terminal arginine residue and binds to CPZ through the CRD. The objective of this study was to determine whether CPZ modulates Wnt/beta-catenin signaling and terminal differentiation of growth plate chondrocytes. Our results show that CPZ and Wnt-4 mRNA are co-expressed throughout growth plate cartilage. In primary pellet cultures of rat growth plate chondrocytes, thyroid hormone increases both Wnt-4 and CPZ expression, as well as CPZ enzymatic activity. Knockdown of either Wnt-4 or CPZ mRNA levels using an RNA interference technique or blocking CPZ enzymatic activity with the carboxypeptidase inhibitor GEMSA reduces the thyroid hormone effect on both alkaline phosphatase activity and Col10a1 mRNA expression. Adenoviral overexpression of CPZ activates Wnt/beta-catenin signaling and promotes the terminal differentiation of growth plate cells. Overexpression of CPZ in growth plate chondrocytes also removes the C-terminal arginine residue from a synthetic peptide consisting of the carboxyl-terminal 16 amino acids of the Wnt-4 protein. Removal of the C-terminal arginine residue of Wnt-4 by site-directed mutagenesis enhances the positive effect of Wnt-4 on terminal differentiation. These data indicate that thyroid hormone may regulate terminal differentiation of growth plate chondrocytes in part by modulating Wnt signaling pathways through the induction of CPZ and subsequent CPZ-enhanced activation of Wnt-4.

  3. Streptococcus pyogenes Malate Degradation Pathway Links pH Regulation and Virulence

    PubMed Central

    Paluscio, Elyse

    2015-01-01

    The ability of Streptococcus pyogenes to infect different niches within its human host most likely relies on its ability to utilize alternative carbon sources. In examining this question, we discovered that all sequenced S. pyogenes strains possess the genes for the malic enzyme (ME) pathway, which allows malate to be used as a supplemental carbon source for growth. ME is comprised of four genes in two adjacent operons, with the regulatory two-component MaeKR required for expression of genes encoding a malate permease (maeP) and malic enzyme (maeE). Analysis of transcription indicated that expression of maeP and maeE is induced by both malate and low pH, and induction in response to both cues is dependent on the MaeK sensor kinase. Furthermore, both maePE and maeKR are repressed by glucose, which occurs via a CcpA-independent mechanism. Additionally, malate utilization requires the PTS transporter EI enzyme (PtsI), as a PtsI– mutant fails to express the ME genes and is unable to utilize malate. Virulence of selected ME mutants was assessed in a murine model of soft tissue infection. MaeP–, MaeK–, and MaeR– mutants were attenuated for virulence, whereas a MaeE– mutant showed enhanced virulence compared to that of the wild type. Taken together, these data show that ME contributes to S. pyogenes' carbon source repertory, that malate utilization is a highly regulated process, and that a single regulator controls ME expression in response to diverse signals. Furthermore, malate uptake and utilization contribute to the adaptive pH response, and ME can influence the outcome of infection. PMID:25583521

  4. Polo kinase links the stress pathway to cell cycle control and tip growth in fission yeast.

    PubMed

    Petersen, Janni; Hagan, Iain M

    2005-05-26

    Stress-activated mitogen-activated protein kinase cascades instigate a range of changes to enable eukaryotic cells to cope with particular insults. In Schizosaccharomyces pombe these responses include the transcription of specific gene sets and inhibition of entry into mitosis. The S. pombe stress response pathway (SRP) also promotes commitment to mitosis in unperturbed cell cycles to allow cells to match their rate of division with nutrient availability. The nature of this SRP function in cell cycle control is unknown. Entry into mitosis is controlled by mitosis-promoting factor (MPF; Cdc2/cyclin B) activity. Inhibitory phosphorylation of Cdc2 by Wee1 kinase inactivates MPF until Cdc25 removes this phosphate to promote mitosis. The balance between Wee1 and Cdc25 activities is influenced by the recruitment of polo kinase (Plo1) to the spindle pole body (SPB). The SPB component Cut12 mediates this recruitment. Hyper-activating mutations in either cut12 or plo1 enable Cdc25-defective cells to enter mitosis. The hyperactive cut12.s11 mutation suppresses cdc25.22, as it promotes recruitment of active Plo1 to interphase SPBs. Here we show that the SRP promotes phosphorylation of Plo1 on Ser 402. In unperturbed cell cycles, SRP-mediated phosphorylation of Ser 402 promotes Plo1 recruitment to SPBs and thus commitment to mitosis. Ser 402 phosphorylation also ensures efficient reinitiation of cell tip growth and cell division during recovery from particular stresses. Thus, phosphorylation of Plo1 Ser 402 not only enables SRP signalling to modulate the timing of mitotic commitment in response to nutrient status in unperturbed cycles, but also promotes the return to normal cell cycle control after stress.

  5. The Global Food System as a Transport Pathway for Hazardous Chemicals: The Missing Link between Emissions and Exposure

    PubMed Central

    Ng, Carla A.; von Goetz, Natalie

    2016-01-01

    Background: Food is a major pathway for human exposure to hazardous chemicals. The modern food system is becoming increasingly complex and globalized, but models for food-borne exposure typically assume locally derived diets or use concentrations directly measured in foods without accounting for food origin. Such approaches may not reflect actual chemical intakes because concentrations depend on food origin, and representative analysis is seldom available. Processing, packaging, storage, and transportation also impart different chemicals to food and are not yet adequately addressed. Thus, the link between environmental emissions and realistic human exposure is effectively broken. Objectives: We discuss the need for a fully integrated treatment of the modern industrialized food system, and we propose strategies for using existing models and relevant supporting data sources to track chemicals during production, processing, packaging, storage, and transport. Discussion: Fate and bioaccumulation models describe how chemicals distribute in the environment and accumulate through local food webs. Human exposure models can use concentrations in food to determine body burdens based on individual or population characteristics. New models now include the impacts of processing and packaging but are far from comprehensive. We propose to close the gap between emissions and exposure by utilizing a wider variety of models and data sources, including global food trade data, processing, and packaging models. Conclusions: A comprehensive approach that takes into account the complexity of the modern global food system is essential to enable better prediction of human exposure to chemicals in food, sound risk assessments, and more focused risk abatement strategies. Citation: Ng CA, von Goetz N. 2017. The global food system as a transport pathway for hazardous chemicals: the missing link between emissions and exposure. Environ Health Perspect 125:1–7; http://dx.doi.org/10.1289/EHP

  6. G protein-linked signaling pathways in bipolar and major depressive disorders

    PubMed Central

    Tomita, Hiroaki; Ziegler, Mary E.; Kim, Helen B.; Evans, Simon J.; Choudary, Prabhakara V.; Li, Jun Z.; Meng, Fan; Dai, Manhong; Myers, Richard M.; Neal, Charles R.; Speed, Terry P.; Barchas, Jack D.; Schatzberg, Alan F.; Watson, Stanley J.; Akil, Huda; Jones, Edward G.; Bunney, William E.; Vawter, Marquis P.

    2013-01-01

    The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, “activated” cAMP signaling activity in BPD and “blunted” cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects. PMID:24391664

  7. STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation

    PubMed Central

    Liu, Jing; Wu, Kuangpei; Yao, Shan; Sun, Yang; Zhou, Lei; Deng, Tanggang; Chen, Ying; Huang, Chenghan; Tan, Weihong

    2015-01-01

    The ubiquitin-specific protease USP7 stabilizes both Mdm2 and p53 by removing ubiquitins, hence playing an important enzymatic role in the p53-Mdm2 pathway. However, it is poorly understood how USP7 executes its dual-stabilization effect on Mdm2 and p53 in cellular context. Here, we report that STIP is a novel macromolecular scaffold that links USP7 to the p53-Mdm2 pathway. STIP and a fraction of USP7 interact and constitutively colocalize in nucleoplasma. Overexpression of STIP stabilizes Mdm2 and p53, whereas downregulation of STIP decreases Mdm2 and p53 levels. The effect of STIP on Mdm2 and p53 depends on USP7 function as a deubiquitinating enzyme. Furthermore, we demonstrate that STIP mediates the assembly of two separate ternary protein complexes in vivo as STIP-USP7-Mdm2 and STIP-USP7-p53, which facilitates USP7-mediated stabilization of Mdm2 and p53. Collectively, these results pinpoint a new molecular function of STIP and reveal a novel mechanism whereby USP7 executes its dual-stabilization effect on Mdm2 and p53 via STIP scaffolding. PMID:26460617

  8. STIP is a critical nuclear scaffolding protein linking USP7 to p53-Mdm2 pathway regulation.

    PubMed

    Ye, Mao; Tang, Yani; Tang, Shijun; Liu, Jing; Wu, Kuangpei; Yao, Shan; Sun, Yang; Zhou, Lei; Deng, Tanggang; Chen, Ying; Huang, Chenghan; Tan, Weihong

    2015-10-27

    The ubiquitin-specific protease USP7 stabilizes both Mdm2 and p53 by removing ubiquitins, hence playing an important enzymatic role in the p53-Mdm2 pathway. However, it is poorly understood how USP7 executes its dual-stabilization effect on Mdm2 and p53 in cellular context. Here, we report that STIP is a novel macromolecular scaffold that links USP7 to the p53-Mdm2 pathway. STIP and a fraction of USP7 interact and constitutively colocalize in nucleoplasma. Overexpression of STIP stabilizes Mdm2 and p53, whereas downregulation of STIP decreases Mdm2 and p53 levels. The effect of STIP on Mdm2 and p53 depends on USP7 function as a deubiquitinating enzyme. Furthermore, we demonstrate that STIP mediates the assembly of two separate ternary protein complexes in vivo as STIP-USP7-Mdm2 and STIP-USP7-p53, which facilitates USP7-mediated stabilization of Mdm2 and p53. Collectively, these results pinpoint a new molecular function of STIP and reveal a novel mechanism whereby USP7 executes its dual-stabilization effect on Mdm2 and p53 via STIP scaffolding.

  9. Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo

    PubMed Central

    Bapiro, T E; Frese, K K; Courtin, A; Bramhall, J L; Madhu, B; Cook, N; Neesse, A; Griffiths, J R; Tuveson, D A; Jodrell, D I; Richards, F M

    2014-01-01

    Background: The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRASG12D; p53R172H; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism. Methods: LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay. Results: In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates in vitro, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells in vitro, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition. Conclusions: GdPC is an important element of the intra-tumoural dFdC metabolic pathway in vivo. PMID:24874484

  10. Adolescent smoking and tertiary education: opposing pathways linking socio‐economic background to alcohol consumption

    PubMed Central

    Leyland, Alastair H.; Sweeting, Helen; Benzeval, Michaela

    2016-01-01

    Abstract Background and Aims If socio‐economic disadvantage is associated with more adolescent smoking, but less participation in tertiary education, and smoking and tertiary education are both associated with heavier drinking, these may represent opposing pathways to heavy drinking. This paper examines contextual variation in the magnitude and direction of these associations. Design Comparing cohort studies. Setting United Kingdom. Participants Participants were from the 1958 National Child Development Study (NCDS58; n = 15 672), the British birth cohort study (BCS70; n = 12 735) and the West of Scotland Twenty‐07 1970s cohort (T07; n = 1515). Measurements Participants self‐reported daily smoking and weekly drinking in adolescence (age 16 years) and heavy drinking (> 14/21 units in past week) in early adulthood (ages 22–26 years). Parental occupational class (manual versus non‐manual) indicated socio‐economic background. Education beyond age 18 was coded as tertiary. Models were adjusted for parental smoking and drinking, family structure and adolescent psychiatric distress. Findings Respondents from a manual class were more likely to smoke and less likely to enter tertiary education (e.g. in NCDS58, probit coefficients were 0.201 and –0.765, respectively; P < 0.001 for both) than respondents from a non‐manual class. Adolescent smokers were more likely to drink weekly in adolescence (0.346; P < 0.001) and more likely to drink heavily in early adulthood (0.178; P < 0.001) than adolescent non‐smokers. Respondents who participated in tertiary education were more likely to drink heavily in early adulthood (0.110 for males, 0.182 for females; P < 0.001 for both) than respondents with no tertiary education. With some variation in magnitude, these associations were consistent across all three cohorts. Conclusions In Britain, young adults are more likely to drink heavily both if they smoke and participate in tertiary education (college

  11. Linking γ-aminobutyric acid A receptor to epidermal growth factor receptor pathways activation in human prostate cancer.

    PubMed

    Wu, Weijuan; Yang, Qing; Fung, Kar-Ming; Humphreys, Mitchell R; Brame, Lacy S; Cao, Amy; Fang, Yu-Ting; Shih, Pin-Tsen; Kropp, Bradley P; Lin, Hsueh-Kung

    2014-03-05

    Neuroendocrine (NE) differentiation has been attributed to the progression of castration-resistant prostate cancer (CRPC). Growth factor pathways including the epidermal growth factor receptor (EGFR) signaling have been implicated in the development of NE features and progression to a castration-resistant phenotype. However, upstream molecules that regulate the growth factor pathway remain largely unknown. Using androgen-insensitive bone metastasis PC-3 cells and androgen-sensitive lymph node metastasis LNCaP cells derived from human prostate cancer (PCa) patients, we demonstrated that γ-aminobutyric acid A receptor (GABA(A)R) ligand (GABA) and agonist (isoguvacine) stimulate cell proliferation, enhance EGF family members expression, and activate EGFR and a downstream signaling molecule, Src, in both PC-3 and LNCaP cells. Inclusion of a GABA(A)R antagonist, picrotoxin, or an EGFR tyrosine kinase inhibitor, Gefitinib (ZD1839 or Iressa), blocked isoguvacine and GABA-stimulated cell growth, trans-phospohorylation of EGFR, and tyrosyl phosphorylation of Src in both PCa cell lines. Spatial distributions of GABAAR α₁ and phosphorylated Src (Tyr416) were studied in human prostate tissues by immunohistochemistry. In contrast to extremely low or absence of GABA(A)R α₁-positive immunoreactivity in normal prostate epithelium, elevated GABA(A)R α₁ immunoreactivity was detected in prostate carcinomatous glands. Similarly, immunoreactivity of phospho-Src (Tyr416) was specifically localized and limited to the nucleoli of all invasive prostate carcinoma cells, but negative in normal tissues. Strong GABAAR α₁ immunoreactivity was spatially adjacent to the neoplastic glands where strong phospho-Src (Tyr416)-positive immunoreactivity was demonstrated, but not in adjacent to normal glands. These results suggest that the GABA signaling is linked to the EGFR pathway and may work through autocrine or paracine mechanism to promote CRPC progression. Copyright © 2013 Elsevier

  12. Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation.

    PubMed

    De Preter, Géraldine; Neveu, Marie-Aline; Danhier, Pierre; Brisson, Lucie; Payen, Valéry L; Porporato, Paolo E; Jordan, Bénédicte F; Sonveaux, Pierre; Gallez, Bernard

    2016-01-19

    Glucose fermentation through glycolysis even in the presence of oxygen (Warburg effect) is a common feature of cancer cells increasingly considered as an enticing target in clinical development. This study aimed to analyze the link between metabolism, energy stores and proliferation rates in cancer cells. We found that cell proliferation, evaluated by DNA synthesis quantification, is correlated to glycolytic efficiency in six cancer cell lines as well as in isogenic cancer cell lines. To further investigate the link between glycolysis and proliferation, a pharmacological inhibitor of the pentose phosphate pathway (PPP) was used. We demonstrated that reduction of PPP activity decreases cancer cells proliferation, with a profound effect in Warburg-phenotype cancer cells. The crucial role of the PPP in sustaining cancer cells proliferation was confirmed using siRNAs against glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the PPP. In addition, we found that dichloroacetate (DCA), a new clinically tested compound, induced a switch of glycolytic cancer cells to a more oxidative phenotype and decreased proliferation. By demonstrating that DCA decreased the activity of the PPP, we provide a new mechanism by which DCA controls cancer cells proliferation.

  13. A new concept linking observable stable isotope fractionation to transformation pathways of organic pollutants.

    PubMed

    Elsner, Martin; Zwank, Luc; Hunkeler, Daniel; Schwarzenbach, Rene P

    2005-09-15

    ): AKIEc = 1.01-1.03 and AKIEH = 2-23 for oxidation of C-H bonds; AKIEc = 1.03-1.07 for SN2-reactions; AKIEc = 1.02-1.03 for reductive cleavage of C-Cl bonds; AKIEc = 1.00-1.01 for C=C bond epoxidation; AKIEc = 1.02-1.03 for C=C bond oxidation by permanganate. Hence, the evaluation scheme presented bridges a gap between basic and environmental (bio)chemistry and provides insight into factors that control the magnitude of bulk isotope fractionation factors. It also serves as a basis to identify degradation pathways using isotope data. It is shown how such an analysis may be even possible in complex field situations and/or in cases where AKIE values are smaller than intrinsic KIE values, provided that isotope fractionation is measured for two elements simultaneously ("two-dimensional isotope analysis"). Finally, the procedure is used (1) to point outthe possibility of estimating approximate epsilonbulk values for new compounds and (2) to discuss the moderate, but non-negligible variability that may quite generally be associated with epsilonbulk values. Future research is suggested to better understand and take into account the various factors that may cause such variability.

  14. Exploring links to unorganized and organized physical activity during adolescence: the role of gender, socioeconomic status, weight status, and enjoyment of physical education.

    PubMed

    García Bengoechea, Enrique; Sabiston, Catherine M; Ahmed, Rashid; Farnoush, Michelle

    2010-03-01

    There is limited research on participation context in studies of physical activity correlates during adolescence. Using an ecological approach, this study explored the association of gender; socioeconomic status (SES), weight status, and physical education enjoyment with participation in organized and unorganized physical activity contexts in a representative sample of Canadian adolescents. Drawing on data from the National Longitudinal Survey of Children and Youth (Cycle 3), we conducted multiple logistic regression analyses to model the associations among the variables of interest. Girls participated less frequently in unorganized physical activities than boys (adjusted odds ratios [AORs] ranging from 0.57 to 0.65, 95% confidence intervals [CIs] range: 0. 46-0.72 to 0.52-0.81). Adolescents in the middle and high SES categories participated more in organized physical activity than their peers in the low SES category (AOR = 1.40-1.87, CI = 1.06-1.84 to 1.41-2.47). Obese adolescents were generally less active than their overweight and normal weight counterparts, particularly in unorganized physical activity contexts (AOR = 0.63-0.66, CI = 0.43-0.92 to 0.44-0.99). Physical education enjoyment was consistently correlated with participation in organized and unorganized physical activity when all variables were considered (AOR = 1.58-3.98, CI = 1.22-2.05 to 3.14-5.03).

  15. Socioeconomic Adversity, Negativity in the Parent Child-Relationship, and Physiological Reactivity: An Examination of Pathways and Interactive Processes Affecting Young Children's Physical Health.

    PubMed

    Hagan, Melissa J; Roubinov, Danielle S; Adler, Nancy E; Boyce, William Thomas; Bush, Nicole R

    We tested the hypothesis that socioeconomic status (SES) would predict children's physical health problems at the end of kindergarten among children whose parent reported greater parent-child relationship (PCR) negativity and/or who exhibited greater parasympathetic (RSA) reactivity. We also tested whether RSA and PCR negativity mediated the SES-health association. Data were collected from 338 children (mean [SD] age, 5.32 [.32] years) and their primary caregivers (87% biological mothers) during the fall and subsequent spring of kindergarten. In the fall, parents reported income and education level (SES) and PCR negativity, and RSA reactivity was assessed via a standardized challenge protocol for young children. In the fall and then spring, parents reported children's chronic medical conditions and physical health impairments. Multivariate regression was conducted within a structural equation-modeling framework to test hypotheses. Significant interactions were found between SES and PCR negativity (b = -0.074, p = .035) and between SES and RSA reactivity (b = 0.169, p = .019) as predicts children's spring health impairment, adjusting for health in the preceding fall. Lower SES was associated with greater health impairment among children whose parents reported more PCR negativity (b = -0.110, p = .024) and children who showed greater RSA reactivity (b = -0.106, p = .011). Socioeconomic status was unrelated to physical health at low PCR negativity or RSA reactivity. Mediation models were not supported. Parent-child relationship quality and individual differences in stress reactivity may modulate the influence of SES on physical health in childhood.

  16. Favorable Socioeconomic Status and Recreational Polydrug Use Are Linked With Sexual Hepatitis C Virus Transmission Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men

    PubMed Central

    Chen, Yun-Chi; Wiberg, Kjell J.; Hsieh, Yu-Hsiang; Bansal, Arun; Bolzan, Philipe; Guy, Janelle A.; Maina, Erastus N.; Cox, Andrea L.; Thio, Chloe L.

    2016-01-01

    Background. Sexual transmission of hepatitis C virus (HCV) among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) is an emerging issue. Studies addressing the temporal trends and risk factors associated with incident HCV in HIV-infected MSM in the community-based primary care settings in the United States are scarce. Methods. Using a retrospective cohort study design, HCV incidence, defined as HCV antibody seroconversion, was determined in 1147 HIV-infected men receiving care at Chase Brexton Health Care clinics in Baltimore, Maryland between 2004 and 2014. Multivariate regression analyses were used to identify factors associated with incident HCV. Results. There were 42 incident HCV infections during 5242 person-years (PY) of follow up (incidence rate [IR], 8.01/1000 PY). Thirty-seven (88%) of the incident infections were in MSM, of whom 31 (84%) reported no injection-drug use (IDU). The annual IRs for MSM were 13.1–15.8/1000 PY between 2004 and 2007, decreased to 2.7–6.2/1000 PY between 2008 and 2011, and increased to 10.4/1000 PY and 13.3/1000 PY in 2013 and 2014, respectively. Injection-drug use was strongly associated with incident HCV among all MSM (IR ratio [IRR], 14.15; P = .003); however, among MSM without IDU, entering care between 2010 and 2013 (IRR, 3.32; P = .01), being employed (IRR, 3.14; P = .03), and having a history of ulcerative sexually transmitted infections (IRR, 3.70; P = .009) or of polydrug use (IRR, 5.54; P = .01) independently predicted incident HCV. Conclusions. In this cohort of HIV-infected men, a re-emerging HCV epidemic was observed from 2011 to 2014 among MSM. In addition to IDU, high-risk sexual behaviors, favorable socioeconomic status, and polydrug use fueled this increase in HCV infections. PMID:27703998

  17. Maternal education and child nutritional status in Bolivia: finding the links.

    PubMed

    Frost, Michelle Bellessa; Forste, Renata; Haas, David W

    2005-01-01

    This study models various pathways linking maternal education and child nutritional status in Bolivia, using a national sample of children. Pathways examined include socioeconomic status, health knowledge, modern attitudes towards health care, female autonomy, and reproductive behavior. The data come from the 1998 Bolivia Demographic and Health Survey. Logistic regression results suggest that socioeconomic factors are the most important pathways linking maternal education and child nutritional status, and that modern attitudes about health care also explain the impact of education. Health care knowledge accounts for less of the effect of maternal education on child nutritional status, with autonomy being the weakest pathway. Other pathways, such as reproductive behaviors, appear to influence nutritional status independent of maternal education. Overall, the pathways examined accounted for 60 percent of the effect of maternal education on child nutritional status.

  18. Linking of primary care records to census data to study the association between socioeconomic status and cancer incidence in Southern Europe: a nation-wide ecological study.

    PubMed

    Garcia-Gil, Maria; Elorza, Josep-Maria; Banque, Marta; Comas-Cufí, Marc; Blanch, Jordi; Ramos, Rafel; Méndez-Boo, Leonardo; Hermosilla, Eduardo; Bolibar, Bonaventura; Prieto-Alhambra, Daniel

    2014-01-01

    Area-based measures of economic deprivation are seldom applied to large medical records databases to establish population-scale associations between deprivation and disease. To study the association between deprivation and incidence of common cancer types in a Southern European region. Retrospective ecological study using the SIDIAP (Information System for the Development of Research in Primary Care) database of longitudinal electronic medical records for a representative population of Catalonia (Spain) and the MEDEA index based on urban socioeconomic indicators in the Spanish census. Study outcomes were incident cervical, breast, colorectal, prostate, and lung cancer in 2009-2012. The completeness of SIDIAP cancer recording was evaluated through linkage of a geographic data subset to a hospital cancer registry. Associations between MEDEA quintiles and cancer incidence was evaluated using zero-inflated Poisson regression adjusted for sex, age, smoking, alcoholism, obesity, hypertension, and diabetes. SIDIAP sensitivity was 63% to 92% for the five cancers studied. There was direct association between deprivation and lung, colorectal, and cervical cancer: incidence rate ratios (IRR) 1.82 [1.64-2.01], IRR 1.60 [1.34-1.90], IRR 1.22 [1.07-1.38], respectively, comparing the most deprived to most affluent areas. In wealthy areas, prostate and breast cancers were more common: IRR 0.92 [0.80-1.00], IRR 0.91 [0.78-1.06]. Adjustment for confounders attenuated the association with lung cancer risk (fully adjusted IRR 1.16 [1.08-1.25]), reversed the direction of the association with colorectal cancer (IRR 0.90 [0.84-0.95]), and did not modify the associations with cervical (IRR 1.27 [1.11-1.45]), prostate (0.74 [0.69-0.80]), and breast (0.76 [0.71-0.81]) cancer. Deprivation is associated differently with the occurrence of various cancer types. These results provide evidence that MEDEA is a useful, area-based deprivation index for analyses of the SIDIAP database. This

  19. Linking of Primary Care Records to Census Data to Study the Association between Socioeconomic Status and Cancer Incidence in Southern Europe: A Nation-Wide Ecological Study

    PubMed Central

    Garcia-Gil, Maria; Elorza, Josep-Maria; Banque, Marta; Comas-Cufí, Marc; Blanch, Jordi; Ramos, Rafel; Méndez-Boo, Leonardo; Hermosilla, Eduardo; Bolibar, Bonaventura; Prieto-Alhambra, Daniel

    2014-01-01

    Background Area-based measures of economic deprivation are seldom applied to large medical records databases to establish population-scale associations between deprivation and disease. Objective To study the association between deprivation and incidence of common cancer types in a Southern European region. Methods Retrospective ecological study using the SIDIAP (Information System for the Development of Research in Primary Care) database of longitudinal electronic medical records for a representative population of Catalonia (Spain) and the MEDEA index based on urban socioeconomic indicators in the Spanish census. Study outcomes were incident cervical, breast, colorectal, prostate, and lung cancer in 2009–2012. The completeness of SIDIAP cancer recording was evaluated through linkage of a geographic data subset to a hospital cancer registry. Associations between MEDEA quintiles and cancer incidence was evaluated using zero-inflated Poisson regression adjusted for sex, age, smoking, alcoholism, obesity, hypertension, and diabetes. Results SIDIAP sensitivity was 63% to 92% for the five cancers studied. There was direct association between deprivation and lung, colorectal, and cervical cancer: incidence rate ratios (IRR) 1.82 [1.64–2.01], IRR 1.60 [1.34–1.90], IRR 1.22 [1.07–1.38], respectively, comparing the most deprived to most affluent areas. In wealthy areas, prostate and breast cancers were more common: IRR 0.92 [0.80–1.00], IRR 0.91 [0.78–1.06]. Adjustment for confounders attenuated the association with lung cancer risk (fully adjusted IRR 1.16 [1.08–1.25]), reversed the direction of the association with colorectal cancer (IRR 0.90 [0.84–0.95]), and did not modify the associations with cervical (IRR 1.27 [1.11–1.45]), prostate (0.74 [0.69–0.80]), and breast (0.76 [0.71–0.81]) cancer. Conclusions Deprivation is associated differently with the occurrence of various cancer types. These results provide evidence that MEDEA is a useful, area

  20. Predicting ethnic minority children's vocabulary from socioeconomic status, maternal language and home reading input: different pathways for host and ethnic language.

    PubMed

    Prevoo, Mariëlle J L; Malda, Maike; Mesman, Judi; Emmen, Rosanneke A G; Yeniad, Nihal; Van Ijzendoorn, Marinus H; Linting, Mariëlle

    2014-09-01

    When bilingual children enter formal reading education, host language proficiency becomes increasingly important. This study investigated the relation between socioeconomic status (SES), maternal language use, reading input, and vocabulary in a sample of 111 six-year-old children of first- and second-generation Turkish immigrant parents in the Netherlands. Mothers reported on their language use with the child, frequency of reading by both parents, and availability of children's books in the ethnic and the host language. Children's Dutch and Turkish vocabulary were tested during a home visit. SES was related to maternal language use and to host language reading input. Reading input mediated the relation between SES and host language vocabulary and between maternal language use and host language vocabulary, whereas only maternal language use was related to ethnic language vocabulary. During transition to formal reading education, one should be aware that children from low-SES families receive less host language reading input.

  1. Childhood socioeconomic status and adult health.

    PubMed

    Cohen, Sheldon; Janicki-Deverts, Denise; Chen, Edith; Matthews, Karen A

    2010-02-01

    Socioeconomic status (SES) exposures during childhood are powerful predictors of adult cardiovascular morbidity, cardiovascular mortality, all-cause mortality, and mortality due to a range of specific causes. However, we still know little about when childhood SES exposures matter most, how long they need to last, what behavioral, psychological, or physiological pathways link the childhood SES experience to adult health, and which specific adult health outcomes are vulnerable to childhood SES exposures. Here, we discuss the evidence supporting the link between childhood and adolescent SES and adult health, and explore different environmental, behavioral, and physiological pathways that might explain how early SES would influence adult health. We also address the ages when SES exposures matter most for setting adult health trajectories as well as the role of exposure duration in SES influences on later health. While early childhood exposures seem to be potent predictors of a range of health outcomes, we emphasize that later childhood and adolescent exposures are risks for other health outcomes.

  2. Different neural pathways linking personality traits and eudaimonic well-being: a resting-state functional magnetic resonance imaging study.

    PubMed

    Kong, Feng; Liu, Ling; Wang, Xu; Hu, Siyuan; Song, Yiying; Liu, Jia

    2015-06-01

    Eudaimonic well-being (EWB) is the fulfillment of human potential and a meaningful life. Previous studies have shown that personality traits, especially extraversion, neuroticism, and conscientiousness, significantly contribute to EWB. However, the neurobiological pathways linking personality and EWB are not understood. Here, we used resting-state functional magnetic resonance imaging (rs-fMRI) to investigate this issue. Specifically, we correlated individuals' EWB scores with the regional fractional amplitude of low-frequency fluctuations (fALFF) of the brain, and then examined how personality traits predicted EWB-related spontaneous brain activity. We found that EWB was positively correlated with the fALFF in the right posterior superior temporal gyrus (pSTG) and thalamus, and negatively correlated with the strength of the thalamic-insular connectivity. More importantly, we found that personality traits influenced EWB in different ways. At the regional level, the fALFF in the pSTG and thalamus mediated the effects of neuroticism and extraversion on EWB, whereas the thalamus mediated the effect of conscientiousness on EWB. At the functional connectivity level, the thalamic-insular connectivity only mediated the effect of neuroticism on EWB. Taken together, our study provides the first evidence that EWB is associated with personality traits through different neural substrates.

  3. Endocrine and Metabolic Pathways Linked to Keratoconus: Implications for the Role of Hormones in the Stromal Microenvironment

    PubMed Central

    McKay, Tina B; Hjortdal, Jesper; Sejersen, Henrik; Asara, John M; Wu, Jennifer; Karamichos, Dimitrios

    2016-01-01

    Hormones play a critical role in regulating tissue function by promoting cell survival, proliferation, and differentiation. Our study explores the influence of endocrine function in regulating metabolism and inflammatory pathways in Keratoconus (KC), which is a corneal thinning disease associated with reduced stromal deposition. KC is known to be a multifactorial disease with an elusive pathogenesis. We utilized a cross-sectional study analyzing clinical features and saliva samples from sixty-four KC patients and fourteen healthy controls. In order to determine if endocrine function varied between healthy controls and KC, we measured hormone levels in saliva and found significantly increased dehydroepiandrosterone sulfate (DHEA-S) and reduced estrone levels in KC patients compared to healthy controls. We measured significant variations in metabolites associated with pro-inflammatory processes, including myoinositol and 1-methyl-histidine, by targeted mass spectrometry. We also measured significantly increased IL-16 and stem cell factor in KC saliva samples compared to healthy controls, with higher expression of these pro-inflammatory proteins correlating with increased KC clinical grade, corneal curvature, and stromal thinning. Our results identify a novel mechanism linking KC and pro-inflammatory markers and suggest that altered hormone levels modulate metabolism, cytokine, and growth factor expression leading to increased severity of the KC condition. PMID:27157003

  4. A diet-sensitive BAF60a-mediated pathway links hepatic bile acid metabolism to cholesterol absorption and atherosclerosis

    PubMed Central

    Meng, Zhuo-Xian; Wang, Lin; Chang, Lin; Sun, Jingxia; Bao, Jiangyin; Li, Yaqiang; Chen, Y. Eugene; Lin, Jiandie D.

    2015-01-01

    Summary Dietary nutrients interact with gene networks to orchestrate adaptive responses during metabolic stress. Here we identify Baf60a as a diet-sensitive subunit of the SWI/SNF chromatin-remodeling complexes in the mouse liver that links the consumption of fat- and cholesterol-rich diet to elevated plasma cholesterol levels. Baf60a expression was elevated in the liver following feeding with a western diet. Hepatocyte-specific inactivation of Baf60a reduced bile acid production and cholesterol absorption, and attenuated diet-induced hypercholesterolemia and atherosclerosis in mice. Baf60a stimulates expression of genes involved in bile acid synthesis, modification, and transport through a CAR/Baf60a feedforward regulatory loop. Baf60a is required for the recruitment of the SWI/SNF chromatin-remodeling complexes to facilitate an activating epigenetic switch on target genes. These studies elucidate a regulatory pathway that mediates the hyperlipidemic and atherogenic effects of western diet consumption. PMID:26586440

  5. A common pathway for O-linked protein-glycosylation and synthesis of capsule in Acinetobacter baumannii.

    PubMed

    Lees-Miller, Robert G; Iwashkiw, Jeremy A; Scott, Nichollas E; Seper, Andrea; Vinogradov, Evgeny; Schild, Stefan; Feldman, Mario F

    2013-09-01

    Multi-drug resistant strains of Acinetobacter baumannii are increasingly being isolated in hospitals worldwide. Among the virulence factors identified in this bacterium there is a general O-glycosylation system that appears to be important for biofilm formation and virulence, and the capsular polysaccharide, which is essential for resistance to complement killing. In this work, we identified a locus that is responsible for the synthesis of the O-pentasaccharide found on the glycoproteins. Besides the enzymes required for the assembly of the glycan, additional proteins typically involved in polymerization and transport of capsule were identified within or adjacently to the locus. Mutagenesis of PglC, the initiating glycosyltransferase prevented the synthesis of both glycoproteins and capsule, resulting in abnormal biofilm structures and attenuated virulence in mice. These results, together with the structural analysis of A. baumannii 17978 capsular polysaccharide via NMR, demonstrated that the pentasaccharides that decorate the glycoproteins are also the building blocks for capsule biosynthesis. Two linked subunits, but not longer glycan chains, were detected on proteins via MS. The discovery of a bifurcated pathway for O-glycosylation and capsule synthesis not only provides insight into the biology of A. baumannii but also identifies potential novel candidates for intervention against this emerging pathogen.

  6. Involvement of Net and Hif1α in Distinct yet Intricately Linked Hypoxia-induced Signaling Pathways*

    PubMed Central

    Serchov, Tsvetan; Dubois-Pot-Schneider, Helene; Charlot, Celine; Rösl, Frank; Wasylyk, Bohdan

    2010-01-01

    The present study compares negative Ets transcription factor (Net) and hypoxia-inducible factor 1α (HIF1α) regulation by hypoxia. Their protein stabilities are differently regulated by hypoxia, defining three periods in the kinetics: normoxia (high Net levels and low HIF1α levels), early hypoxia (high levels of Net and HIF1α), and late hypoxia (degradation of Net and HIF1α). Modulators of prolyl hydroxylase domain protein (PHD) activity induce a mobility shift of Net, similar to HIF1α, suggesting that post-translational modifications of both factors depend on PHD activity. The three PHDs have different roles in the regulation of Net protein levels; PHD1 and PHD3 are involved in the stabilization of Net, whereas PHD2 controls its degradation in late hypoxia. Net physically interacts with PHD2 in hypoxia, whereas PHD1 and PHD3 bind to Net in normoxia and hypoxia. Under the same conditions, PHD2 and PHD3 regulate both HIF1α stabilization in early hypoxia and its degradation at late hypoxia, whereas PHD1 is involved in HIF1α degradation in late hypoxia. We describe interconnections between the regulation of both Net and HIF1α at the protein level. Evidence is provided for a direct physical interaction between Net and HIF1α and indirect transcriptional regulation loops that involve the PHDs. Taken together our results indicate that Net and HIF1α are components of distinct signaling pathways that are intricately linked. PMID:20427288

  7. A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity.

    PubMed

    El-Ami, Tayir; Moll, Lorna; Carvalhal Marques, Filipa; Volovik, Yuli; Reuveni, Hadas; Cohen, Ehud

    2014-02-01

    Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging-regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD-associated peptide, Aβ- and the HD-linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD-like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long-lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD- and HD-associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging.

  8. A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways.

    PubMed Central

    Horii, Y; Beeler, J F; Sakaguchi, K; Tachibana, M; Miki, T

    1994-01-01

    Transfection of NIH3T3 cells with an osteosarcoma expression cDNA library led to the appearance of foci of morphologically transformed cells which were found to harbor a novel oncogene, ost. The ost product was activated by truncation of the N-terminal domain of the ost proto-oncogene and was highly tumorigenic in nude mouse assays. The proto-ost cDNA, isolated subsequently, encodes a predicted protein of 100 kDa containing DH (Db1 homology) and PH (pleckstrin homology) domains. Ost is mainly phosphorylated on serine and localized in the cytoplasm. Purified Ost protein catalyzed guanine nucleotide exchange on RhoA and Cdc42 among the Rho and Ras family members tested, indicating that Ost can activate these small GTP-binding proteins. Ost did not detectably associate with RhoA or Cdc42, but interacted specifically with the GTP-bound form of Rac1, suggesting that Ost can function as an effector of Rac1. These results suggest that Ost is a critical regulatory component which links pathways that signal through Rac1, RhoA and Cdc42. Of the tissues examined, expression of ost was the highest in brain and could be localized to neurons and alpha-tanycytes, suggesting that Ost may participate in axonal transport in these specialized cells. Images PMID:7957046

  9. The methyltransferase Suv39h1 links the SUMO pathway to HP1α marking at pericentric heterochromatin

    PubMed Central

    Maison, Christèle; Bailly, Delphine; Quivy, Jean-Pierre; Almouzni, Geneviève

    2016-01-01

    The trimethylation of histone H3 on lysine 9 (H3K9me3) – a mark recognized by HP1 that depends on the Suv39h lysine methyltransferases (KMTs) – has provided a basis for the reader/writer model to explain HP1 accumulation at pericentric heterochromatin in mammals. Here, we identify the Suv39h1 paralog, as a unique enhancer of HP1α sumoylation both in vitro and in vivo. The region responsible for promoting HP1α sumoylation (aa1–167) is distinct from the KMT catalytic domain and mediates binding to Ubc9. Tethering the 1–167 domain of Suv39h1 to pericentric heterochromatin, but not mutants unable to bind Ubc9, accelerates the de novo targeting of HP1α to these domains. Our results establish an unexpected feature of Suv39h1, distinct from the KMT activity, with a major role for heterochromatin formation. We discuss how linking Suv39h1 to the SUMO pathway provides conceptual implications for our general view on nuclear domain organization and physiological functions. PMID:27426629

  10. Pharmacological inhibition of nicotinamide phosphoribosyltransferase/visfatin enzymatic activity identifies a new inflammatory pathway linked to NAD.

    PubMed

    Busso, Nathalie; Karababa, Mahir; Nobile, Massimo; Rolaz, Aline; Van Gool, Frédéric; Galli, Mara; Leo, Oberdan; So, Alexander; De Smedt, Thibaut

    2008-05-21

    Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNFalpha levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders.

  11. Identification of Components of the Murine Histone Deacetylase 6 Complex: Link between Acetylation and Ubiquitination Signaling Pathways

    PubMed Central

    Seigneurin-Berny, Daphné; Verdel, André; Curtet, Sandrine; Lemercier, Claudie; Garin, Jérôme; Rousseaux, Sophie; Khochbin, Saadi

    2001-01-01

    The immunopurification of the endogenous cytoplasmic murine histone deacetylase 6 (mHDAC6), a member of the class II HDACs, from mouse testis cytosolic extracts allowed the identification of two associated proteins. Both were mammalian homologues of yeast proteins known to interact with each other and involved in the ubiquitin signaling pathway: p97/VCP/Cdc48p, a homologue of yeast Cdc48p, and phospholipase A2-activating protein, a homologue of yeast UFD3 (ubiquitin fusion degradation protein 3). Moreover, in the C-terminal region of mHDAC6, a conserved zinc finger-containing domain named ZnF-UBP, also present in several ubiquitin-specific proteases, was discovered and was shown to mediate the specific binding of ubiquitin by mHDAC6. By using a ubiquitin pull-down approach, nine major ubiquitin-binding proteins were identified in mouse testis cytosolic extracts, and mHDAC6 was found to be one of them. All of these findings strongly suggest that mHDAC6 could be involved in the control of protein ubiquitination. The investigation of biochemical properties of the mHDAC6 complex in vitro further supported this hypothesis and clearly established a link between protein acetylation and protein ubiquitination. PMID:11689694

  12. The "LEARn" (latent early-life associated regulation) model: an epigenetic pathway linking metabolic and cognitive disorders.

    PubMed

    Lahiri, Debomoy K; Maloney, Bryan

    2012-01-01

    Diabetes, cardiovascular disease, hypertension, and other disorders have been unified within the metabolic syndrome. Recently, it has been proposed that Alzheimer's disease (AD) and other degenerative, age-related neurological disorders may also be etiologically linked to the metabolic syndrome in a metabolic-cognitive syndrome. We review current evidence in the field for this unification. In addition, we describe how the latent early-life associated regulation (LEARn) model provides specific mechanisms to predict genetic targets for both metabolic disorders, e.g., diabetes, and neurodegenerative disorders, e.g., AD. The LEARn model is based on environmental induction of latent epigenetic misregulation, which develops into disease upon suffering additional environmental insults. We review structural differences between gene sequences that are and are not susceptible to LEARn misregulation. In addition to suggesting research targets such as the IDE and SORCS1 genes, which are implicated in both AD and diabetes, LEARn suggests specific mechanisms for pre-disease remediation, based on nutritional adjustment of aberrant DNA methylation and oxidation. The possibility of a single metabolic-cognitive disorder opens up the possibility of unified preventative treatments that reduce monetary and social costs of disease. LEARn suggests specific, testable pathways within the large theory.

  13. The Fanconi anemia/BRCA pathway is involved in DNA interstrand cross-link repair of adriamycin-resistant leukemia cells.

    PubMed

    Yao, Chenjiao; Du, Wei; Chen, Haibing; Xiao, Sheng; Huang, Lihua; Chen, Fangping

    2015-03-01

    The Fanconi anemia/BRCA (FA/BRCA) pathway plays a vital role in DNA damage repair induced by DNA cross-linking agents and is closely related to drug response in cancer treatment. Here we demonstrate that the FA/BRCA pathway contributes to acquired drug resistance in adriamycin (ADR)-resistant leukemia cell lines, and disruption of this pathway partially reverses the drug resistance. We observed that ADR-resistant cells have reduced DNA interstrand cross-links (ICL) compared with ADR-sensitive cells. Western blot studies demonstrated enhanced FA protein expression in ADR-resistant cells. Using siRNA to knock down FANCF in K562/R drug-resistant cells showed increases in sensitivity to ADR and ADR-induced DNA damage, and demonstrated a direct relationship between the FA/BRCA pathway and drug sensitivity. Overexpression of FANCF in K562 drug-sensitive cells partially reproduced the drug-resistant phenotype. These results show that the FA/BRCA pathway is involved in acquired ADR resistance of leukemia cells. The FA/BRCA pathway may be a new target to reverse ADR resistance in leukemia treatment.

  14. Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human.

    PubMed

    Shepelin, Denis; Korzinkin, Mikhail; Vanyushina, Anna; Aliper, Alexander; Borisov, Nicolas; Vasilov, Raif; Zhukov, Nikolay; Sokov, Dmitry; Prassolov, Vladimir; Gaifullin, Nurshat; Zhavoronkov, Alex; Bhullar, Bhupinder; Buzdin, Anton

    2016-01-05

    Melanoma is the most aggressive and dangerous type of skin cancer, but its molecular mechanisms remain largely unclear. For transcriptomic data of 478 primary and metastatic melanoma, nevi and normal skin samples, we performed high-throughput analysis of intracellular molecular networks including 592 signaling and metabolic pathways. We showed that at the molecular pathway level, the formation of nevi largely resembles transition from normal skin to primary melanoma. Using a combination of bioinformatic machine learning algorithms, we identified 44 characteristic signaling and metabolic pathways connected with the formation of nevi, development of primary melanoma, and its metastases. We created a model describing formation and progression of melanoma at the level of molecular pathway activation. We discovered six novel associations between activation of metabolic molecular pathways and progression of melanoma: for allopregnanolone biosynthesis, L-carnitine biosynthesis, zymosterol biosynthesis (inhibited in melanoma), fructose 2, 6-bisphosphate synthesis and dephosphorylation, resolvin D biosynthesis (activated in melanoma), D-myo-inositol hexakisphosphate biosynthesis (activated in primary, inhibited in metastatic melanoma). Finally, we discovered fourteen tightly coordinated functional clusters of molecular pathways. This study helps to decode molecular mechanisms underlying the development of melanoma.

  15. Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human

    PubMed Central

    Shepelin, Denis; Korzinkin, Mikhail; Vanyushina, Anna; Aliper, Alexander; Borisov, Nicolas; Vasilov, Raif; Zhukov, Nikolay; Sokov, Dmitry; Prassolov, Vladimir; Gaifullin, Nurshat; Zhavoronkov, Alex; Bhullar, Bhupinder; Buzdin, Anton

    2016-01-01

    Melanoma is the most aggressive and dangerous type of skin cancer, but its molecular mechanisms remain largely unclear. For transcriptomic data of 478 primary and metastatic melanoma, nevi and normal skin samples, we performed high-throughput analysis of intracellular molecular networks including 592 signaling and metabolic pathways. We showed that at the molecular pathway level, the formation of nevi largely resembles transition from normal skin to primary melanoma. Using a combination of bioinformatic machine learning algorithms, we identified 44 characteristic signaling and metabolic pathways connected with the formation of nevi, development of primary melanoma, and its metastases. We created a model describing formation and progression of melanoma at the level of molecular pathway activation. We discovered six novel associations between activation of metabolic molecular pathways and progression of melanoma: for allopregnanolone biosynthesis, L-carnitine biosynthesis, zymosterol biosynthesis (inhibited in melanoma), fructose 2, 6-bisphosphate synthesis and dephosphorylation, resolvin D biosynthesis (activated in melanoma), D-myo-inositol hexakisphosphate biosynthesis (activated in primary, inhibited in metastatic melanoma). Finally, we discovered fourteen tightly coordinated functional clusters of molecular pathways. This study helps to decode molecular mechanisms underlying the development of melanoma. PMID:26624979

  16. Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework

    PubMed Central

    Teeguarden, Justin. G.; Tan, Yu-Mei; Edwards, Stephen W.; Leonard, Jeremy A.; Anderson, Kim A.; Corley, Richard A.; Harding, Anna K; Kile, Molly L.; Simonich, Staci M; Stone, David; Tanguay, Robert L.; Waters, Katrina M.; Harper, Stacey L.; Williams, David E.

    2016-01-01

    Synopsis Driven by major scientific advances in analytical methods, biomonitoring, computational tools, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the Aggregate Exposure Pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the Adverse Outcome Pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more efficient integration of exposure assessment and hazard identification. Together, the two pathways form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making. PMID:26759916

  17. The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis.

    PubMed

    Fu, Jing; Qu, Zhaoxia; Yan, Pengrong; Ishikawa, Chie; Aqeilan, Rami I; Rabson, Arnold B; Xiao, Gutian

    2011-02-03

    Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.

  18. The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis

    PubMed Central

    Fu, Jing; Qu, Zhaoxia; Yan, Pengrong; Ishikawa, Chie; Aqeilan, Rami I.; Rabson, Arnold B.

    2011-01-01

    Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis. PMID:21115974

  19. The Fat/Hippo signaling pathway links within-disc morphogen patterning to whole-animal signals during phenotypically plastic growth in insects.

    PubMed

    Gotoh, Hiroki; Hust, James A; Miura, Toru; Niimi, Teruyuki; Emlen, Douglas J; Lavine, Laura C

    2015-05-22

    Insects exhibit a diversity of environmentally sensitive phenotypes that allow them to be an extraordinarily successful group. For example, mandible size in male stag beetles is exquisitely sensitive to the larval nutritional environment and is a reliable signal of male condition. To date, studies of how such phenotypically plastic traits develop have focused on two types of mechanistic processes. Local, tissue-specific genetic mechanisms specify the shape and approximate final size of structures, whereas whole-animal hormonal signaling mechanisms modulate trait growth in response to environmental circumstance, including the body size and nutritional state of each individual. Hormones such as juvenile hormone, ecdysteroids, and/or ligands of the insulin-signaling pathway specify whether traits grow and regulate how much growth occurs across a diversity of insect groups. What remains to be shown is how the local, tissue-specific developmental genetic pathways interact with these whole animal hormonal signaling pathways during development to yield phenotypically plastic patterns of trait growth. Because the Fat/Hippo signaling pathway coordinates trait growth and development through its interactions with morphogens and hormonal pathways, we propose that Fat/Hippo signaling is a missing mechanistic link coordinating environmentally sensitive trait development in insects. Developmental Dynamics, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  20. l-xylo-3-Hexulose Reductase Is the Missing Link in the Oxidoreductive Pathway for d-Galactose Catabolism in Filamentous Fungi*

    PubMed Central

    Mojzita, Dominik; Herold, Silvia; Metz, Benjamin; Seiboth, Bernhard; Richard, Peter

    2012-01-01

    In addition to the well established Leloir pathway for the catabolism of d-galactose in fungi, the oxidoreductive pathway has been recently identified. In this oxidoreductive pathway, d-galactose is converted via a series of NADPH-dependent reductions and NAD+-dependent oxidations into d-fructose. The pathway intermediates include galactitol, l-xylo-3-hexulose, and d-sorbitol. This study identified the missing link in the pathway, the l-xylo-3-hexulose reductase that catalyzes the conversion of l-xylo-3-hexulose to d-sorbitol. In Trichoderma reesei (Hypocrea jecorina) and Aspergillus niger, we identified the genes lxr4 and xhrA, respectively, that encode the l-xylo-3-hexulose reductases. The deletion of these genes resulted in no growth on galactitol and in reduced growth on d-galactose. The LXR4 was heterologously expressed, and the purified protein showed high specificity for l-xylo-3-hexulose with a Km = 2.0 ± 0.5 mm and a Vmax = 5.5 ± 1.0 units/mg. We also confirmed that the product of the LXR4 reaction is d-sorbitol. PMID:22654107

  1. Psychological pathways linking social support to health outcomes: a visit with the "ghosts" of research past, present, and future.

    PubMed

    Uchino, Bert N; Bowen, Kimberly; Carlisle, McKenzie; Birmingham, Wendy

    2012-04-01

    Contemporary models postulate the importance of psychological mechanisms linking perceived and received social support to physical health outcomes. In this review, we examine studies that directly tested the potential psychological mechanisms responsible for links between social support and health-relevant physiological processes (1980s-2010). Inconsistent with existing theoretical models, no evidence was found that psychological mechanisms such as depression, perceived stress, and other affective processes are directly responsible for links between support and health. We discuss the importance of considering statistical/design issues, emerging conceptual perspectives, and limitations of our existing models for future research aimed at elucidating the psychological mechanisms responsible for links between social support and physical health outcomes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Completing the link between exposure science and toxicology for improved environmental health decision making: The aggregate exposure pathway framework

    SciTech Connect

    Teeguarden, Justin G.; Tan, Yu -Mei; Edwards, Stephen W.; Leonard, Jeremy A.; Anderson, Kim A.; Corley, Richard A.; Kile, Molly L.; Simonich, Staci M.; Stone, David; Tanguay, Robert L.; Waters, Katrina M.; Harper, Stacey L.; Williams, David E.; Harding, Anna K.

    2016-01-13

    Here, driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.

  3. Completing the link between exposure science and toxicology for improved environmental health decision making: The aggregate exposure pathway framework

    DOE PAGES

    Teeguarden, Justin G.; Tan, Yu -Mei; Edwards, Stephen W.; ...

    2016-01-13

    Here, driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences.more » Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.« less

  4. Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework.

    PubMed

    Teeguarden, Justin G; Tan, Yu-Mei; Edwards, Stephen W; Leonard, Jeremy A; Anderson, Kim A; Corley, Richard A; Kile, Molly L; Simonich, Staci M; Stone, David; Tanguay, Robert L; Waters, Katrina M; Harper, Stacey L; Williams, David E

    2016-05-03

    Driven by major scientific advances in analytical methods, biomonitoring, computation, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the "systems approaches" used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. Aggregate exposure pathways offer an intuitive framework to organize exposure data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathways and adverse outcome pathways, completing the source to outcome continuum for more meaningful integration of exposure assessment and hazard identification. Together, the two frameworks form and inform a decision-making framework with the flexibility for risk-based, hazard-based, or exposure-based decision making.

  5. The noa gene is functionally linked to the activation of the Toll/Imd signaling pathways in Bactrocera dorsalis (Hendel).

    PubMed

    Dong, Xiaolong; Li, Qiujia; Zhang, Hongyu

    2016-02-01

    The noa gene is an essential gene encoding a very long chain fatty acid elongase. In this study, we cloned the noa gene of Bactrocera dorsalis, which encodes a protein sharing 84.50% identity to the NOA in Drosophila melanogaster. The expression profiles indicated that the transcriptional level of noa was high at the egg stage and in the testis tissue. The results showed that noa expression was up-regulated after Listeria monocytogenes, Staphylococcus aureus and Escherichia coli infection. Silencing of noa would influence the expression of immune related genes, including MyD88 and defensin in the Toll pathway and relish and diptericin in the Imd pathway. Moreover, infection with L. monocytogenes and S. aureus after feeding ds-noa, the expression of MyD88 and defensin down-regulated significantly in ds-noa group compared with in ds-egfp group, indicating that noa interference influenced the activation of the Toll pathway. Meanwhile, infection with L. monocytogenes and E. coli, which activated the Imd pathway, do not cause increase of the mRNA levels of relish and diptericin in ds-noa group as severely as in ds-egfp treatment, indicating that the Imd pathway was also repressed after silences of noa.

  6. Genome-wide genetic screen identified the link between dG9a and epidermal growth factor receptor signaling pathway in vivo.

    PubMed

    Shimaji, Kouhei; Konishi, Takahiro; Yoshida, Hideki; Kimura, Hiroshi; Yamaguchi, Masamitsu

    2016-08-01

    G9a is one of the histone H3 Lys 9 (H3K9) specific methyltransferases first identified in mammals. Drosophila G9a (dG9a) has been reported to induce H3K9 dimethylation in vivo, and the target genes of dG9a were identified during embryonic and larval stages. Although dG9a is important for a variety of developmental processes, the link between dG9a and signaling pathways are not addressed yet. Here, by genome-wide genetic screen, taking advantage of the rough eye phenotype of flies that over-express dG9a in eye discs, we identified 16 genes that enhanced the rough eye phenotype induced by dG9a over-expression. These 16 genes included Star, anterior open, bereft and F-box and leucine-rich repeat protein 6 which are components of epidermal growth factor receptor (EGFR) signaling pathway. When dG9a over-expression was combined with mutation of Star, differentiation of R7 photoreceptors in eye imaginal discs as well as cone cells and pigment cells in pupal retinae was severely inhibited. Furthermore, the dG9a over-expression reduced the activated ERK signals in eye discs. These data demonstrate a strong genetic link between dG9a and the EGFR signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells

    PubMed Central

    Chen, Qing; Van der Sluis, Pieter C.; Boulware, David; Hazlehurst, Lori A.; Dalton, William S.

    2005-01-01

    Melphalan, a DNA cross-linker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). In this report, we demonstrate that enhanced interstrand cross-link (ICL) repair via the Fanconi anemia (FA)/BRCA pathway contributes to acquired drug resistance in melphalan-resistant myeloma cell lines, and disruption of this pathway reverses drug resistance. Using the alkaline comet assay (single-cell gel electrophoresis), we observed that melphalan-resistant cells have reduced ICL formation and enhanced ICL repair compared with melphalan-sensitive cells. Cell-cycle studies demonstrated that enhanced ICL repair released cells from melphalan-induced cell-cycle delay. Using siRNA to knock down FANCF in 8226/LR5 and U266/LR6 drug-resistant cells demonstrated a direct relationship between ICL repair capacity and drug sensitivity. Overexpression of FANCF in 8226/S and U266/S drug-sensitive cells partially reproduced the drug-resistant phenotype. These data show that enhanced DNA repair via the Fanconi anemia/BRCA pathway is involved in acquired melphalan resistance. Our findings provide for a new target to enhance response to DNA cross-linking agents in cancer treatment. (Blood. 2005;106:698-705) PMID:15802532

  8. Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke

    PubMed Central

    Ishida, Akimasa; Isa, Kaoru; Umeda, Tatsuya; Kobayashi, Kazuto; Kobayashi, Kenta; Hida, Hideki

    2016-01-01

    Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH. SIGNIFICANCE STATEMENT The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the

  9. The association of attention deficit hyperactivity disorder with socioeconomic disadvantage: alternative explanations and evidence.

    PubMed

    Russell, Ginny; Ford, Tamsin; Rosenberg, Rachel; Kelly, Susan

    2014-05-01

    Studies throughout Northern Europe, the United States and Australia have found an association between childhood attention deficit hyperactivity disorder (ADHD) and family socioeconomic disadvantage. We report further evidence for the association and review potential causal pathways that might explain the link. Secondary analysis of a UK birth cohort (the Millennium Cohort Study, N = 19,519) was used to model the association of ADHD with socioeconomic disadvantage and assess evidence for several potential explanatory pathways. The case definition of ADHD was a parent-report of whether ADHD had been identified by a medical doctor or health professional when children were 7 years old. ADHD was associated with a range of indicators of social and economic disadvantage including poverty, housing tenure, maternal education, income, lone parenthood and younger motherhood. There was no evidence to suggest childhood ADHD was a causal factor of socioeconomic disadvantage: income did not decrease for parents of children with ADHD compared to controls over the 7-year study period. No clinical bias towards labelling ADHD in low SES groups was detected. There was evidence to suggest that parent attachment/family conflict mediated the relationship between ADHD and SES. Although genetic and neurological determinants may be the primary predictors of difficulties with activity level and attention, aetiology appears to be influenced by socioeconomic situation. © 2013 The Authors Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.

  10. [Role of integrin-linked kinase signaling pathway in skin lesions and wound healing in diabetic rats].

    PubMed

    Zhou, Rixing; Li, Yeyang; Li, Gang; Lin, Weihua; Sun, Jing' en; Zhou, Wangbiao

    2016-04-01

    To investigate the role of integrin-linked kinase (ILK) signaling pathway in the skin lesions and wound healing in diabetic rats. Thirty-six SD rats were divided into diabetic wound group (D) and non-diabetic wound group (N) according to the random number table, with 18 rats in each group. 10 g/L streptozocin (60 mg/kg) was intraperitoneally injected in rats in group D, while the rats in group N were given same quantity of sodium citrate buffer. Two weeks after successful reproduction of diabetic model of rats in group D, two full-thickness skin of an area of 2 cm × 2 cm was resected on both sides of back of rats in the two groups. Wounds of three rats of each group were photographed and examined on post injury day (PID) 1, 3, 7, 10, 14, and 21, and the wound healing rates were calculated. The non-injured skin and wound tissue (central part) on back of three rats of the rest 15 rats in the two groups were harvested on PID 3, 7, 10, 14, and 21, respectively. Morphology of the non-injured skin tissue was observed with HE staining, and the thickness of full-thickness skin and epidermis were measured. The mRNA expression levels of ILK, protein kinase B (Akt), and glycogen synthase kinase-3β (GSK-3β) in non-injured skin tissue were determined with real-time fluorescent quantitative RT-PCR. The protein expression levels of ILK, Akt, phosphorylated Akt, GSK-3β, and phosphorylated GSK-3β in non-injured skin tissue, and ILK, phosphorylated Akt in wound tissue were assessed with Western blotting. Data were processed with two independent-sample t test, one-way analysis of variance, SNK test and analysis of variance of factorial design. (1) After injury, the wound scabs of rats in group N were dry, and red granulation tissue with no excretion were seen when the scabs fell off, and the wound healed fast. After injury, excretion under the wound scabs of rats in group D was seen, and the scabs easily fell off with exposure of pink granulation tissue with much excretion, and

  11. Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework

    SciTech Connect

    Teeguarden, Justin G.; Tan, Yu-Mei; Edwards, Stephen W.; Leonard, Jeremy A.; Anderson, Kim A.; Corley, Richard A.; Kile, Molly L.; Simonich, Staci M.; Stone, David; Tanguay, Robert L.; Waters, Katrina M.; Harper, Stacey L.; Williams, David E.

    2016-05-03

    Driven by major scientific advances in analytical methods, biomonitoring, and computational exposure assessment, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the computationally enabled “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. The AEP framework offers an intuitive approach to successful organization of exposure science data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathway and adverse outcome pathways, completing the source to outcome continuum and setting the stage for more efficient integration of exposure science and toxicity testing information. Together these frameworks form and inform a decision making framework with the flexibility for risk-based, hazard-based or exposure-based decisions.

  12. Psychosis, Socioeconomic Disadvantage, and Health Service Use in South Australia: Findings from the Second Australian National Survey of Psychosis

    PubMed Central

    Sweeney, Shaun; Air, Tracy; Zannettino, Lana; Galletly, Cherrie

    2015-01-01

    an important focus for mental health services. Such health policy would provide accessible treatment programs and linked pathways to illness recovery and diminish the pressure on the delivery of health services. Consequently, the development of policy and practice that seeks to redress the socioeconomic and health inequalities created by disadvantage should be an important focus for the improvement of mental health services. PMID:26636059

  13. Bullying perpetration and victimization as externalizing and internalizing pathways: A retrospective study linking parenting styles and self-esteem to depression, alcohol use, and alcohol-related problems

    PubMed Central

    Patock-Peckham, Julie A; Medina, Mia; Terrell, Nathan; Belton, Daniel; King, Kevin M

    2016-01-01

    Emerging research suggests significant positive associations between bullying and substance use behaviors. However, these studies typically focused either on the link between substance use and bullying perpetration or victimization, and few have conceptualized bullying perpetration and/or victimization as mediators. In this study, we simultaneously tested past bullying perpetration and victimization as mediational pathways from retrospective report of parenting styles and global self-esteem to current depressive symptoms, alcohol use and alcohol-related problems. Data were collected from a college sample of 419 drinkers. Mediation effects were conducted using a bias-corrected bootstrap technique in structural equation modeling. Two-path mediation analyses indicated that mother and father authoritativeness were protective against bully victimization and depression through higher self-esteem. Conversely, having a permissive or authoritarian mother was positively linked to bullying perpetration, which in turn was associated with increased alcohol use, and to a lesser degree, more alcohol-related problems. Mother authoritarianism was associated with alcohol-related problems through depressive symptoms. Three-path mediation analyses suggested a trend in which individuals with higher self-esteem were less likely to report alcohol-related problems through lower levels of bullying victimization and depression. Results suggested that bullying perpetration and victimization may respectively serve as externalizing and internalizing pathways through which parenting styles and self-esteem are linked to depression and alcohol-related outcomes. The present study identified multiple modifiable precursors of, and mediational pathways to, alcohol-related problems which could guide the development and implementation of prevention programs targeting problematic alcohol use. PMID:26757486

  14. Bullying Perpetration and Victimization as Externalizing and Internalizing Pathways: A Retrospective Study Linking Parenting Styles and Self-Esteem to Depression, Alcohol Use, and Alcohol-Related Problems.

    PubMed

    Luk, Jeremy W; Patock-Peckham, Julie A; Medina, Mia; Terrell, Nathan; Belton, Daniel; King, Kevin M

    2016-01-02

    Emerging research suggests significant positive associations between bullying and substance use behaviors. However, these studies typically focused either on the link between substance use and bullying perpetration or victimization, and few have conceptualized bullying perpetration and/or victimization as mediators. In this study, we simultaneously tested past bullying perpetration and victimization as mediational pathways from retrospective report of parenting styles and global self-esteem to current depressive symptoms, alcohol use, and alcohol-related problems. Data were collected from a college sample of 419 drinkers. Mediation effects were conducted using a bias-corrected bootstrap technique within a structural equation modeling framework. Two-path mediation analyses indicated that mother and father authoritativeness were protective against bully victimization and depression through higher self-esteem. Conversely, having a permissive or authoritarian mother was positively linked to bullying perpetration, which in turn, was associated with increased alcohol use, and to a lesser degree, more alcohol-related problems. Mother authoritarianism was associated with alcohol-related problems through depressive symptoms. Three-path mediation analyses suggested a trend in which individuals with higher self-esteem were less likely to report alcohol-related problems through lower levels of bullying victimization and depression. Results suggested that bullying perpetration and victimization may, respectively, serve as externalizing and internalizing pathways through which parenting styles and self-esteem are linked to depression and alcohol-related outcomes. The present study identified multiple modifiable precursors of, and mediational pathways to, alcohol-related problems which could guide the development and implementation of prevention programs targeting problematic alcohol use.

  15. Substrate recognition and catalysis by GH47 α-mannosidases involved in Asn-linked glycan maturation in the mammalian secretory pathway

    SciTech Connect

    Xiang, Yong; Karaveg, Khanita; Moremen, Kelley W.

    2016-11-17

    Asn-linked glycosylation of newly synthesized polypeptides occurs in the endoplasmic reticulum of eukaryotic cells. Glycan structures are trimmed and remodeled as they transit the secretory pathway, and processing intermediates play various roles as ligands for folding chaperones and signals for quality control and intracellular transport. Key steps for the generation of these trimmed intermediates are catalyzed by glycoside hydrolase family 47 (GH47) α-mannosidases that selectively cleave α1,2-linked mannose residues. Despite the sequence and structural similarities among the GH47 enzymes, the molecular basis for residue-specific cleavage remains obscure. The present studies reveal enzyme–substrate complex structures for two related GH47 α-mannosidases and provide insights into how these enzymes recognize the same substrates differently and catalyze the complementary glycan trimming reactions necessary for glycan maturation.

  16. Biochemical characterization of the O-linked glycosylation pathway in Neisseria gonorrhoeae responsible for biosynthesis of protein glycans containing N,N'-diacetylbacillosamine.

    PubMed

    Hartley, Meredith D; Morrison, Michael J; Aas, Finn Erik; Børud, Bente; Koomey, Michael; Imperiali, Barbara

    2011-06-07

    The O-linked protein glycosylation pathway in Neisseria gonorrhoeae is responsible for the synthesis of a complex oligosaccharide on undecaprenyl diphosphate and subsequent en bloc transfer of the glycan to serine residues of select periplasmic proteins. Protein glycosylation (pgl) genes have been annotated on the basis of bioinformatics and top-down mass spectrometry analysis of protein modifications in pgl-null strains [Aas, F. E., et al. (2007) Mol. Microbiol. 65, 607-624; Vik, A., et al. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 4447-4452], but relatively little biochemical analysis has been performed to date. In this report, we present the expression, purification, and functional characterization of seven Pgl enzymes. Specifically, the enzymes studied are responsible for synthesis of an uncommon uridine diphosphate (UDP)-sugar (PglD, PglC, and PglB-acetyltransferase domain), glycan assembly (PglB-phospho-glycosyltransferase domain, PglA, PglE, and PglH), and final oligosaccharide transfer (PglO). UDP-2,4-diacetamido-2,4,6-trideoxy-α-d-hexose (DATDH), which is the first sugar in glycan biosynthesis, was produced enzymatically, and the stereochemistry was assigned as uridine diphosphate N'-diacetylbacillosamine (UDP-diNAcBac) by nuclear magnetic resonance characterization. In addition, the substrate specificities of the phospho-glycosyltransferase, glycosyltransferases, and oligosaccharyltransferase (OTase) were analyzed in vitro, and in most cases, these enzymes exhibited strong preferences for the native substrates relative to closely related glycans. In particular, PglO, the O-linked OTase, and PglB(Cj), the N-linked OTase from Campylobacter jejuni, preferred the native N. gonorrhoeae and C. jejuni substrates, respectively. This study represents the first comprehensive biochemical characterization of this important O-linked glycosylation pathway and provides the basis for further investigations of these enzymes as antibacterial targets.

  17. Malic Enzyme and Malolactic Enzyme Pathways Are Functionally Linked but Independently Regulated in Lactobacillus casei BL23

    PubMed Central

    Landete, José María; Ferrer, Sergi; Monedero, Vicente

    2013-01-01

    Lactobacillus casei is the only lactic acid bacterium in which two pathways for l-malate degradation have been described: the malolactic enzyme (MLE) and the malic enzyme (ME) pathways. Whereas the ME pathway enables L. casei to grow on l-malate, MLE does not support growth. The mle gene cluster consists of three genes encoding MLE (mleS), the putative l-malate transporter MleT, and the putative regulator MleR. The mae gene cluster consists of four genes encoding ME (maeE), the putative transporter MaeP, and the two-component system MaeKR. Since both pathways compete for the same substrate, we sought to determine whether they are coordinately regulated and their role in l-malate utilization as a carbon source. Transcriptional analyses revealed that the mle and mae genes are independently regulated and showed that MleR acts as an activator and requires internalization of l-malate to induce the expression of mle genes. Notwithstanding, both l-malate transporters were required for maximal l-malate uptake, although only an mleT mutation caused a growth defect on l-malate, indicating its crucial role in l-malate metabolism. However, inactivation of MLE resulted in higher growth rates and higher final optical densities on l-malate. The limited growth on l-malate of the wild-type strain was correlated to a rapid degradation of the available l-malate to l-lactate, which cannot be further metabolized. Taken together, our results indicate that L. casei l-malate metabolism is not optimized for utilization of l-malate as a carbon source but for deacidification of the medium by conversion of l-malate into l-lactate via MLE. PMID:23835171

  18. Genetic link between Cabeza, a Drosophila homologue of Fused in Sarcoma (FUS), and the EGFR signaling pathway

    SciTech Connect

    Shimamura, Mai; Kyotani, Akane; Azuma, Yumiko; Yoshida, Hideki; Binh Nguyen, Thanh; Mizuta, Ikuko; Yoshida, Tomokatsu; Mizuno, Toshiki; Nakagawa, Masanori; Tokuda, Takahiko; Yamaguchi, Masamitsu

    2014-08-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular weakness. Fused in Sarcoma (FUS) that has been identified in familial ALS is an RNA binding protein that is normally localized in the nucleus. However, its function in vivo is not fully understood. Drosophila has Cabeza (Caz) as a FUS homologue and specific knockdown of Caz in the eye imaginal disc and pupal retina using a GMR-GAL4 driver was here found to induce an abnormal morphology of the adult compound eyes, a rough eye phenotype. This was partially suppressed by expression of the apoptosis inhibitor P35. Knockdown of Caz exerted no apparent effect on differentiation of photoreceptor cells. However, immunostaining with an antibody to Cut that marks cone cells revealed fusion of these and ommatidia of pupal retinae. These results indicate that Caz knockdown induces apoptosis and also inhibits differentiation of cone cells, resulting in abnormal eye morphology in adults. Mutation in EGFR pathway-related genes, such as rhomboid-1, rhomboid-3 and mirror suppressed the rough eye phenotype induced by Caz knockdown. Moreover, the rhomboid-1 mutation rescued the fusion of cone cells and ommatidia observed in Caz knockdown flies. The results suggest that Caz negatively regulates the EGFR signaling pathway required for determination of cone cell fate in Drosophila. - Highlights: • Knockdown of Cabeza induced rough eye phenotype. • Knockdown of Cabeza induced fusion of cone cells in pupal retinae. • Knockdown of Cabeza induced apoptosis in pupal retinae. • Mutation in EGFR pathway-related genes suppressed the rough eye phenotype. • Cabeza may negatively regulate the EGFR pathway.

  19. Corona cell RNA sequencing from individual oocytes revealed transcripts and pathways linked to euploid oocyte competence and live birth.

    PubMed

    Parks, Jason C; Patton, Alyssa L; McCallie, Blair R; Griffin, Darren K; Schoolcraft, William B; Katz-Jaffe, Mandy G

    2016-05-01

    Corona cells surround the oocyte and maintain a close relationship through transzonal processes and gap junctions, and may be used to assess oocyte competence. In this study, the corona cell transcriptome of individual cumulus oocyte complexes (COCs) was investigated. Isolated corona cells were collected from COCs that developed into euploid blastocysts and were transferred in a subsequent frozen embryo transfer. Ten corona cell samples underwent RNA-sequencing to generate unique gene expression profiles. Live birth was compared with negative implantation after the transfer of a euploid blastocyst using bioinformatics and statistical analysis. Individual corona cell samples produced a mean of 21.2 million sequence reads, and 307 differentially expressed transcrpits (P < 0.05; fold change ≥ 2). Enriched pathway analysis showed Wnt signalling, mitogen-activated protein kinases signalling, focal adhesion and tricarboxylic acid cycle to be affected by implantation outcome. The Wnt/beta-catenin signalling pathway, including genes APC, AXIN and GSK3B, were independently validated by real-time quantitative reverse transcription. Individual, corona cell transcriptome was successfully generated using RNA-sequencing. Key genes and signalling pathways were identified in association with implantation outcome after the transfer of a euploid blastocyst in a frozen embryo transfer. These data could provide novel biomarkers for the non-invasive assessment of embryo viability.

  20. An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes

    PubMed Central

    Huard, Jérémy; Mueller, Stephanie; Gilles, Ernst D; Klingmüller, Ursula; Klamt, Steffen

    2012-01-01

    During liver regeneration, quiescent hepatocytes re-enter the cell cycle to proliferate and compensate for lost tissue. Multiple signals including hepatocyte growth factor, epidermal growth factor, tumor necrosis factor α, interleukin-6, insulin and transforming growth factor β orchestrate these responses and are integrated during the G1 phase of the cell cycle. To investigate how these inputs influence DNA synthesis as a measure for proliferation, we established a large-scale integrated logical model connecting multiple signaling pathways and the cell cycle. We constructed our model based upon established literature knowledge, and successively improved and validated its structure using hepatocyte-specific literature as well as experimental DNA synthesis data. Model analyses showed that activation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways was sufficient and necessary for triggering DNA synthesis. In addition, we identified key species in these pathways that mediate DNA replication. Our model predicted oncogenic mutations that were compared with the COSMIC database, and proposed intervention targets to block hepatocyte growth factor-induced DNA synthesis, which we validated experimentally. Our integrative approach demonstrates that, despite the complexity and size of the underlying interlaced network, logical modeling enables an integrative understanding of signaling-controlled proliferation at the cellular level, and thus can provide intervention strategies for distinct perturbation scenarios at various regulatory levels. PMID:22443451

  1. An atypical orthologue of 6-pyruvoyltetrahydropterin synthase can provide the missing link in the folate biosynthesis pathway of malaria parasites

    PubMed Central

    Dittrich, Sabine; Mitchell, Sarah L; Blagborough, Andrew M; Wang, Qi; Wang, Ping; Sims, Paul F G; Hyde, John E

    2008-01-01

    Folate metabolism in malaria parasites is a long-standing, clinical target for chemotherapy and prophylaxis. However, despite determination of the complete genome sequence of the lethal species Plasmodium falciparum, the pathway of de novo folate biosynthesis remains incomplete, as no candidate gene for dihydroneopterin aldolase (DHNA) could be identified. This enzyme catalyses the third step in the well-characterized pathway of plants, bacteria, and those eukaryotic microorganisms capable of synthesizing their own folate. Utilizing bioinformatics searches based on both primary and higher protein structures, together with biochemical assays, we demonstrate that P. falciparum cell extracts lack detectable DHNA activity, but that the parasite possesses an unusual orthologue of 6-pyruvoyltetrahydropterin synthase (PTPS), which simultaneously gives rise to two products in comparable amounts, the predominant of which is 6-hydroxymethyl-7,8-dihydropterin, the substrate for the fourth step in folate biosynthesis (catalysed by 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase; PPPK). This can provide a bypass for the missing DHNA activity and thus a means of completing the biosynthetic pathway from GTP to dihydrofolate. Supported by site-directed mutagenesis experiments, we ascribe the novel catalytic activity of the malarial PTPS to a Cys to Glu change at its active site relative to all previously characterized PTPS molecules, including that of the human host. PMID:18093090

  2. A Direct Link between Abscisic Acid Sensing and the Chromatin-Remodeling ATPase BRAHMA via Core ABA Signaling Pathway Components.

    PubMed

    Peirats-Llobet, Marta; Han, Soon-Ki; Gonzalez-Guzman, Miguel; Jeong, Cheol Woong; Rodriguez, Lesia; Belda-Palazon, Borja; Wagner, Doris; Rodriguez, Pedro L

    2016-01-04

    Optimal response to drought is critical for plant survival and will affect biodiversity and crop performance during climate change. Mitotically heritable epigenetic or dynamic chromatin state changes have been implicated in the plant response to the drought stress hormone abscisic acid (ABA). The Arabidopsis SWI/SNF chromatin-remodeling ATPase BRAHMA (BRM) modulates response to ABA by preventing premature activation of stress response pathways during germination. We show that core ABA signaling pathway components physically interact with BRM and post-translationally modify BRM by phosphorylation/dephosphorylation. Genetic evidence suggests that BRM acts downstream of SnRK2.2/2.3 kinases, and biochemical studies identified phosphorylation sites in the C-terminal region of BRM at SnRK2 target sites that are evolutionarily conserved. Finally, the phosphomimetic BRM(S1760D S1762D) mutant displays ABA hypersensitivity. Prior studies showed that BRM resides at target loci in the ABA pathway in the presence and absence of the stimulus, but is only active in the absence of ABA. Our data suggest that SnRK2-dependent phosphorylation of BRM leads to its inhibition, and PP2CA-mediated dephosphorylation of BRM restores the ability of BRM to repress ABA response. These findings point to the presence of a rapid phosphorylation-based switch to control BRM activity; this property could be potentially harnessed to improve drought tolerance in plants. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

  3. Synthetic promoters consisting of defined cis-acting elements link multiple signaling pathways to probenazole-inducible system.

    PubMed

    Zhu, Zheng; Gao, Jiong; Yang, Jin-xiao; Wang, Xiao-yan; Ren, Guo-dong; Ding, Yu-long; Kuai, Ben-ke

    2015-04-01

    Probenazole (3-allyloxy-1,2-benzisothiazole-1,1-dioxide, PBZ), the active component of Oryzemate, could induce systemic acquired resistance (SAR) in plants through the induction of salicylic acid (SA) biosynthesis. As a widely used chemical inducer, PBZ is a good prospect for establishing a new chemical-inducible system. We first designed artificially synthetic promoters with tandem copies of a single type of cis-element (SARE, JERE, GCC, GST1, HSRE, and W-box) that could mediate the expression of the β-glucuronidase (GUS) reporter gene in plants upon PBZ treatment. Then we combined different types of elements in order to improve inducibility in the PBZ-inducible system. On the other hand, we were surprised to find that the cis-elements, which are responsive to jasmonic acid (JA) and ethylene, also responded to PBZ, implying that SA, JA, and ethylene pathways also would play important roles in PBZ's action. Further analysis demonstrated that PBZ also induced early events of innate immunity via a signaling pathway in which Ca(2+) influx and mitogen-activated protein kinase (MAPK) activity were involved. We constructed synthesized artificial promoters to establish a PBZ chemical-inducible system, and preliminarily explored SA, JA, ethylene, calcium, and MAPK signaling pathways via PBZ-inducible system, which could provide an insight for in-depth study.

  4. Synthetic promoters consisting of defined cis-acting elements link multiple signaling pathways to probenazole-inducible system * #

    PubMed Central

    Zhu, Zheng; Gao, Jiong; Yang, Jin-xiao; Wang, Xiao-yan; Ren, Guo-dong; Ding, Yu-long; Kuai, Ben-ke

    2015-01-01

    Probenazole (3-allyloxy-1,2-benzisothiazole-1,1-dioxide, PBZ), the active component of Oryzemate, could induce systemic acquired resistance (SAR) in plants through the induction of salicylic acid (SA) biosynthesis. As a widely used chemical inducer, PBZ is a good prospect for establishing a new chemical-inducible system. We first designed artificially synthetic promoters with tandem copies of a single type of cis-element (SARE, JERE, GCC, GST1, HSRE, and W-box) that could mediate the expression of the β-glucuronidase (GUS) reporter gene in plants upon PBZ treatment. Then we combined different types of elements in order to improve inducibility in the PBZ-inducible system. On the other hand, we were surprised to find that the cis-elements, which are responsive to jasmonic acid (JA) and ethylene, also responded to PBZ, implying that SA, JA, and ethylene pathways also would play important roles in PBZ’s action. Further analysis demonstrated that PBZ also induced early events of innate immunity via a signaling pathway in which Ca2+ influx and mitogen-activated protein kinase (MAPK) activity were involved. We constructed synthesized artificial promoters to establish a PBZ chemical-inducible system, and preliminarily explored SA, JA, ethylene, calcium, and MAPK signaling pathways via PBZ-inducible system, which could provide an insight for in-depth study. PMID:25845359

  5. Linking the physical and the socio-economic compartments of an integrated water and land use management model on a river basin scale using an object-oriented water supply model

    NASA Astrophysics Data System (ADS)

    Barthel, Roland; Nickel, Darla; Meleg, Alejandro; Trifkovic, Aleksandar; Braun, Juergen

    Within the framework of the research project ‘GLOWA-Danube’, a model of the water supply sector has been developed. GLOWA-Danube investigates long-term changes in the water cycle of the Upper Danube river basin in light of global change. For this purpose, the decision support system DANUBIA, comprising 15 fully coupled models, has been developed. Within DANUBIA the water supply model (‘WaterSupply’) forms the link between various physical models determining water quality and availability and several socio-economic models determining water consumption and demand. Having a central focus on public drinking water supply, its purpose is to correctly simulate the present day system of water extraction and distribution and the related costs, but also to allow meaningful response to possible future changes of boundary conditions, first and foremost changes in water demand or water availability and quality. Response mechanisms are also envisioned for changes in political and economic boundary conditions, and advances in technology. The model will be used locate critical regions which could experience water stress in the future, but does not aim to find the appropriate solutions or to predict the optimal organisation of water supply in the Danube Basin under such changing conditions. In the object-oriented model structure, both water supply companies (WSC) and communities are represented by main classes. Both classes have a limited view and knowledge of their environment. A community knows where and how much water is consumed and from which WSC it is served. A WSC possesses information regarding extraction sites and water rights, raw water quality and potential collaborating WSC. The WSC can perform actions that are different from ‘business as usual’. These deviations from their usual behaviour can be interpreted by decision makers but should not be regarded as a replacement for the decision-making process itself. The model is conceptualised using object

  6. Depression and the Link with Cardiovascular Disease

    PubMed Central

    Dhar, Arup K.; Barton, David A.

    2016-01-01

    This review provides an outline of the association between major depressive disorder (MDD) and coronary heart disease (CHD). Much is known about the two individual clinical conditions; however, it is not until recently, biological mechanisms have been uncovered that link both MDD and CHD. The activation of stress pathways have been implicated as a neurochemical mechanism that links MDD and CHD. Depression is known to be associated with poorer outcomes of CHD. Psychological factors, such as major depression and stress, are now known as risk factors for developing CHD, which is as important and is independent of classic risk factors, such as hypertension, diabetes mellitus, and cigarette smoking. Both conditions have great socioeconomic importance given that depression and CHD are likely to be two of the three leading causes of global burden of disease. Better understanding of the common causal pathways will help us delineate more appropriate treatments. PMID:27047396

  7. Socioeconomic Disparities and Influenza Hospitalizations, Tennessee, USA

    PubMed Central

    Sloan, Chantel; Chandrasekhar, Rameela; Mitchel, Edward; Schaffner, William

    2015-01-01

    We examined population-based surveillance data from the Tennessee Emerging Infections Program to determine whether neighborhood socioeconomic status was associated with influenza hospitalization rates. Hospitalization data collected during October 2007–April 2014 were geocoded (N = 1,743) and linked to neighborhood socioeconomic data. We calculated age-standardized annual incidence rates, relative index of inequality, and concentration curves for socioeconomic variables. Influenza hospitalizations increased with increased percentages of persons who lived in poverty, had female-headed households, lived in crowded households, and lived in population-dense areas. Influenza hospitalizations decreased with increased percentages of persons who were college educated, were employed, and had health insurance. Higher incidence of influenza hospitalization was also associated with lower neighborhood socioeconomic status when data were stratified by race. PMID:26292106

  8. Socioeconomic Disparities and Influenza Hospitalizations, Tennessee, USA.

    PubMed

    Sloan, Chantel; Chandrasekhar, Rameela; Mitchel, Edward; Schaffner, William; Lindegren, Mary Lou

    2015-09-01

    We examined population-based surveillance data from the Tennessee Emerging Infections Program to determine whether neighborhood socioeconomic status was associated with influenza hospitalization rates. Hospitalization data collected during October 2007-April 2014 were geocoded (N = 1,743) and linked to neighborhood socioeconomic data. We calculated age-standardized annual incidence rates, relative index of inequality, and concentration curves for socioeconomic variables. Influenza hospitalizations increased with increased percentages of persons who lived in poverty, had female-headed households, lived in crowded households, and lived in population-dense areas. Influenza hospitalizations decreased with increased percentages of persons who were college educated, were employed, and had health insurance. Higher incidence of influenza hospitalization was also associated with lower neighborhood socioeconomic status when data were stratified by race.

  9. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    PubMed Central

    Figueiredo-Pereira, Maria E.; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2015-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  10. Nicotinic Acetylcholine Receptors Sensitize a MAPK-linked Toxicity Pathway on Prolonged Exposure to β-Amyloid*

    PubMed Central

    Arora, Komal; Cheng, Justin; Nichols, Robert A.

    2015-01-01

    Among putative downstream synaptic targets of β-amyloid (Aβ) are signaling molecules involved in synaptic function, memory formation and cognition, such as the MAP kinases, MKPs, CaMKII, CREB, Fyn, and Tau. Here, we assessed the activation and interaction of signaling pathways upon prolonged exposure to Aβ in model nerve cells expressing nicotinic acetylcholine receptors (nAChRs). Our goal was to characterize the steps underlying sensitization of the nerve cells to neurotoxicity when Aβ-target receptors are present. Of particular focus was the connection of the activated signaling molecules to oxidative stress. Differentiated neuroblastoma cells expressing mouse α4β2-nAChRs were exposed to Aβ1–42 for intervals from 30 min to 3 days. The cells and cell-derived protein extracts were then probed for activation of signaling pathway molecules (ERK, JNK, CaMKII, CREB, MARCKS, Fyn, tau). Our results show substantial, progressive activation of ERK in response to nanomolar Aβ exposure, starting at the earliest time point. Increased ERK activation was followed by JNK activation as well as an increased expression of PHF-tau, paralleled by increased levels of reactive oxygen species (ROS). The impact of prolonged Aβ on the levels of pERK, pJNK, and ROS was attenuated by MEK-selective and JNK-selective inhibitors. In addition, the MEK inhibitor as well as a JNK inhibitor attenuated Aβ-induced nuclear fragmentation, which followed the changes in ROS levels. These results demonstrate that the presence of nAChRs sensitizes neurons to the neurotoxic action of Aβ through the timed activation of discrete intracellular signaling molecules, suggesting pathways involved in the early stages of Alzheimer disease. PMID:26139609

  11. Modeling Socioeconomic Status Effects on Language Development

    ERIC Educational Resources Information Center

    Thomas, Michael S. C.; Forrester, Neil A.; Ronald, Angelica

    2013-01-01

    Socioeconomic status (SES) is an important environmental predictor of language and cognitive development, but the causal pathways by which it operates are unclear. We used a computational model of development to explore the adequacy of manipulations of environmental information to simulate SES effects in English past-tense acquisition, in a data…

  12. Modeling Socioeconomic Status Effects on Language Development

    ERIC Educational Resources Information Center

    Thomas, Michael S. C.; Forrester, Neil A.; Ronald, Angelica

    2013-01-01

    Socioeconomic status (SES) is an important environmental predictor of language and cognitive development, but the causal pathways by which it operates are unclear. We used a computational model of development to explore the adequacy of manipulations of environmental information to simulate SES effects in English past-tense acquisition, in a data…

  13. D₂-dopaminergic receptor-linked pathways: critical regulators of CYP3A, CYP2C, and CYP2D.

    PubMed

    Daskalopoulos, Evangelos P; Lang, Matti A; Marselos, Marios; Malliou, Foteini; Konstandi, Maria

    2012-10-01

    Various hormonal and monoaminergic systems play determinant roles in the regulation of several cytochromes P450 (P450s) in the liver. Growth hormone (GH), prolactin, and insulin are involved in P450 regulation, and their release is under dopaminergic control. This study focused on the role of D₂-dopaminergic systems in the regulation of the major drug-metabolizing P450s, i.e., CYP3A, CYP2C, and CYP2D. Blockade of D₂-dopaminergic receptors with either sulpiride (SULP) or 4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol (L-741,626) markedly down-regulated CYP3A1/2, CYP2C11, and CYP2D1 expression in rat liver. This suppressive effect appeared to be mediated by the insulin/phosphatidylinositol 3-kinase/Akt/FOXO1 signaling pathway. Furthermore, inactivation of the GH/STAT5b signaling pathway appeared to play a role in D₂-dopaminergic receptor-mediated down-regulating effects on these P450s. SULP suppressed plasma GH levels, with subsequently reduced activation of STAT5b, which is the major GH pulse-activated transcription factor and has up-regulating effects on various P450s in hepatic tissue. Levels of prolactin, which exerts down-regulating control on P450s, were increased by SULP, which may contribute to SULP-mediated effects. Finally, it appears that SULP-induced inactivation of the cAMP/protein kinase A/cAMP-response element-binding protein signaling pathway, which is a critical regulator of pregnane X receptor and hepatocyte nuclear factor 1α, and inactivation of the c-Jun N-terminal kinase contribute to SULP-induced down-regulation of the aforementioned P450s. Taken together, the present data provide evidence that drugs acting as D₂-dopaminergic receptor antagonists might interfere with several major signaling pathways involved in the regulation of CYP3A, CYP2C, and CYP2D, which are critical enzymes in drug metabolism, thus affecting the effectiveness of the majority of prescribed drugs and the toxicity and carcinogenic potency of a plethora of

  14. Neural Correlates of Socioeconomic Status in the Developing Human Brain

    ERIC Educational Resources Information Center

    Noble, Kimberly G.; Houston, Suzanne M.; Kan, Eric; Sowell, Elizabeth R.

    2012-01-01

    Socioeconomic disparities in childhood are associated with remarkable differences in cognitive and socio-emotional development during a time when dramatic changes are occurring in the brain. Yet, the neurobiological pathways through which socioeconomic status (SES) shapes development remain poorly understood. Behavioral evidence suggests that…

  15. Neural Correlates of Socioeconomic Status in the Developing Human Brain

    ERIC Educational Resources Information Center

    Noble, Kimberly G.; Houston, Suzanne M.; Kan, Eric; Sowell, Elizabeth R.

    2012-01-01

    Socioeconomic disparities in childhood are associated with remarkable differences in cognitive and socio-emotional development during a time when dramatic changes are occurring in the brain. Yet, the neurobiological pathways through which socioeconomic status (SES) shapes development remain poorly understood. Behavioral evidence suggests that…

  16. Linking genome content to biofuel production yields: a meta-analysis of major catabolic pathways among select H2 and ethanol-producing bacteria

    PubMed Central

    2012-01-01

    to have little impact on H2 production in organisms that do not encode ethanol producing pathways, they do influence reduced end-product yields in those that do. Conclusions Here we show that composition of genes encoding pathways involved in pyruvate catabolism and end-product synthesis pathways can be used to approximate potential end-product distribution patterns. We have identified a number of genetic biomarkers for streamlining ethanol and H2 producing capabilities. By linking genome content, reaction thermodynamics, and end-product yields, we offer potential targets for optimization of either ethanol or H2 yields through metabolic engineering. PMID:23249097

  17. Investigation of the Staphylococcus aureus GraSR regulon reveals novel links to virulence, stress response and cell wall signal transduction pathways.

    PubMed

    Falord, Mélanie; Mäder, Ulrike; Hiron, Aurélia; Débarbouillé, Michel; Msadek, Tarek

    2011-01-01

    The GraS/GraR two-component system has been shown to control cationic antimicrobial peptide (CAMP) resistance in the major human pathogen Staphylococcus aureus. We demonstrated that graX, also involved in CAMP resistance and cotranscribed with graRS, encodes a regulatory cofactor of the GraSR signaling pathway, effectively constituting a three-component system. We identified a highly conserved ten base pair palindromic sequence (5' ACAAA TTTGT 3') located upstream from GraR-regulated genes (mprF and the dlt and vraFG operons), which we show to be essential for transcriptional regulation by GraR and induction in response to CAMPs, suggesting it is the likely GraR binding site. Genome-based predictions and transcriptome analysis revealed several novel GraR target genes. We also found that the GraSR TCS is required for growth of S. aureus at high temperatures and resistance to oxidative stress. The GraSR system has previously been shown to play a role in S. aureus pathogenesis and we have uncovered previously unsuspected links with the AgrCA peptide quorum-sensing system controlling virulence gene expression. We also show that the GraSR TCS controls stress reponse and cell wall metabolism signal transduction pathways, sharing an extensive overlap with the WalKR regulon. This is the first report showing a role for the GraSR TCS in high temperature and oxidative stress survival and linking this system to stress response, cell wall and pathogenesis control pathways.

  18. Identification of a gene involved in the biosynthesis pathway of the terminal sugar of the archaellin N-linked tetrasaccharide in Methanococcus maripaludis.

    PubMed

    Ding, Yan; Jones, Gareth M; Brimacombe, Cedric; Uchida, Kaoru; Aizawa, Shin-Ichi; Logan, Susan M; Kelly, John F; Jarrell, Ken F

    2016-01-01

    In Methanococcus maripaludis, the three archaellins which comprise the archaellum are modified at multiple sites with an N-linked tetrasaccharide with the structure of Sug-4-β-ManNAc3NAmA6Thr-4-β-GlcNAc3NAcA-3-β-GalNAc, where Sug is a unique sugar (5S)-2-acetamido-2,4-dideoxy-5-O-methyl-L-erythro-hexos-5-ulo-1,5-pyranose, so far found exclusively in this species. In this study, a six-gene cluster mmp1089-1094, neighboring one of the genomic regions already known to contain genes involved with the archaellin N-glycosylation pathway, was examined for its potential involvement in the archaellin N-glycosylation or sugar biosynthesis pathway. The co-transcription of these six genes was demonstrated by RT-PCR. Mutants carrying an in-frame deletion in mmp1090, mmp1091 or mmp1092 were successfully generated. The Δmmp1090 deletion mutant was archaellated when examined by electron microscopy and mass spectrometry analysis of purified archaella showed that the archaellins were modified with a truncated N-glycan in which the terminal sugar residue and the threonine linked to the third sugar residue were missing. Both gene annotation and bioinformatic analyses indicate that MMP1090 is a UDP-glucose 4-epimerase, suggesting that the unique terminal sugar of the archaellin N-glycan might be synthesised from UDP-glucose or UDP-N-acetylglucosamine with an essential early step in synthesis catalysed by MMP1090. In contrast, no detectable phenotype related to archaellin glycosylation was observed in mutants deleted for either mmp1091 or mmp1092 while attempts to delete mmp1089, mmp1093 and mmp1094 were unsuccessful. Based on its demonstrated involvement in the archaellin N-glycosylation pathway, we designated mmp1090 as aglW.

  19. The Nuclear Factor κB pathway: A link to the immune system in the radiation response.

    PubMed

    Hellweg, Christine E

    2015-11-28

    Exposure to ionizing radiation modulates immune responses in a complex dose-dependent pattern, with possible anti-inflammatory effects in the low dose range, expression of pro-inflammatory cytokines at moderate doses and immunosuppression after exposure to higher doses due to precursor cell death together with concomitant exacerbated innate immune responses. A central regulator in the immune system is the transcription factor Nuclear Factor κB (NF-κB). NF-κB is involved in the regulation of cellular survival, immune responses and inflammation, resulting in eminent importance in cancerogenesis. After exposure to ionizing radiation, NF-κB activation is initially triggered by ATM which is activated by DNA double strand breaks. Together with the NF-κB essential modulator (NEMO), it serves as a nucleoplasmic shuttle. The pathway converges with the classical NF-κB pathway at IκB kinase (IKK) complex activation. Resulting cytokine expression can activate NF-κB in a positive feed forward loop. Danger signals released from dying cells can activate NF-κB via Toll-like receptors (TLRs). The resulting immune activation can be beneficial or detrimental. In the low dose range, pro- and anticancerogenic effects are possible. In the radiotherapy-relevant dose range, tolerogenic immune responses should be avoided, and an anti-tumor immune response might be supported by TLR agonists activating NF-κB. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Genetic link between Cabeza, a Drosophila homologue of Fused in Sarcoma (FUS), and the EGFR signaling pathway.

    PubMed

    Shimamura, Mai; Kyotani, Akane; Azuma, Yumiko; Yoshida, Hideki; Binh Nguyen, Thanh; Mizuta, Ikuko; Yoshida, Tomokatsu; Mizuno, Toshiki; Nakagawa, Masanori; Tokuda, Takahiko; Yamaguchi, Masamitsu

    2014-08-01

    Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive muscular weakness. Fused in Sarcoma (FUS) that has been identified in familial ALS is an RNA binding protein that is normally localized in the nucleus. However, its function in vivo is not fully understood. Drosophila has Cabeza (Caz) as a FUS homologue and specific knockdown of Caz in the eye imaginal disc and pupal retina using a GMR-GAL4 driver was here found to induce an abnormal morphology of the adult compound eyes, a rough eye phenotype. This was partially suppressed by expression of the apoptosis inhibitor P35. Knockdown of Caz exerted no apparent effect on differentiation of photoreceptor cells. However, immunostaining with an antibody to Cut that marks cone cells revealed fusion of these and ommatidia of pupal retinae. These results indicate that Caz knockdown induces apoptosis and also inhibits differentiation of cone cells, resulting in abnormal eye morphology in adults. Mutation in EGFR pathway-related genes, such as rhomboid-1, rhomboid-3 and mirror suppressed the rough eye phenotype induced by Caz knockdown. Moreover, the rhomboid-1 mutation rescued the fusion of cone cells and ommatidia observed in Caz knockdown flies. The results suggest that Caz negatively regulates the EGFR signaling pathway required for determination of cone cell fate in Drosophila.

  1. Non-targeted metabolomic approach reveals urinary metabolites linked to steroid biosynthesis pathway after ingestion of citrus juice.

    PubMed

    Medina, S; Ferreres, F; García-Viguera, C; Horcajada, M N; Orduna, J; Savirón, M; Zurek, G; Martínez-Sanz, J M; Gil, J I; Gil-Izquierdo, A

    2013-01-15

    Citrus juice intake has been highlighted because of its health-promoting effects. LC-MS based metabolomics approaches are applied to obtain a better knowledge on changes in the concentration of metabolites due to its dietary intake and allow a better understanding of involved metabolic pathways. Eight volunteers daily consumed 400 mL of juice for four consecutive days and urine samples were collected before intake and 24h after each citrus juice intake. Urine samples were analysed by nanoHPLC-q-TOF, followed by principal component analysis (PCA) and Student's t-test (p<0.05). PCA showed a separation between two groups (before and after citrus juice consumption). This approach allowed the identification of four endocrine compounds (tetrahydroaldosterone-3-glucuronide, cortolone-3-glucuronide, testosterone-glucuronide and 17-hydroxyprogesterone), which belonged to the steroid biosynthesis pathway as significant metabolites upregulated by citrus juice intake. Additionally, these results confirmed the importance of using the non-targeted metabolomics technique to identify new endogenous metabolites, up- or down-regulated as a consequence of food intake. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Towards a pathway definition of Parkinson's disease: a complex disorder with links to cancer, diabetes and inflammation.

    PubMed

    Moran, Linda B; Graeber, Manuel B

    2008-02-01

    We have previously established a first whole genome transcriptomic profile of sporadic Parkinson's disease (PD). After extensive brain tissue-based validation combined with cycles of iterative data analysis and by focusing on the most comparable cases of the cohort, we have refined our analysis and established a list of 892 highly dysregulated priority genes that are considered to form the core of the diseased Parkinsonian metabolic network. The substantia nigra pathways, now under scrutiny, contain more than 100 genes whose association with PD is known from the literature. Of those, more than 40 genes belong to the highly significantly dysregulated group identified in our dataset. Apart from the complete list of 892 priority genes, we present pathways revealing PD 'hub' as well as 'peripheral' network genes. The latter include Lewy body components or interact with known PD genes. Biological associations of PD with cancer, diabetes and inflammation are discussed and interactions of the priority genes with several drugs are provided. Our study illustrates the value of rigorous clinico-pathological correlation when analysing high-throughput data to make optimal use of the histopathological phenome, or morphonome which currently serves as the key diagnostic reference for most human diseases. The need for systematic human tissue banking, following the highest possible professional and ethical standard to enable sustainability, becomes evident.

  3. Starvation-Dependent Regulation of Golgi Quality Control Links the TOR Signaling and Vacuolar Protein Sorting Pathways.

    PubMed

    Dobzinski, Niv; Chuartzman, Silvia G; Kama, Rachel; Schuldiner, Maya; Gerst, Jeffrey E

    2015-09-22

    Upon amino acid (AA) starvation and TOR inactivation, plasma-membrane-localized permeases rapidly undergo ubiquitination and internalization via the vacuolar protein sorting/multivesicular body (VPS-MVB) pathway and are degraded in the yeast vacuole. We now show that specific Golgi proteins are also directed to the vacuole under these conditions as part of a Golgi quality-control (GQC) process. The degradation of GQC substrates is dependent upon ubiquitination by the defective-for-SREBP-cleavage (DSC) complex, which was identified via genetic screening and includes the Tul1 E3 ligase. Using a model GQC substrate, GFP-tagged Yif1, we show that vacuolar targeting necessitates upregulation of the VPS pathway via proteasome-mediated degradation of the initial endosomal sorting complex required for transport, ESCRT-0, but not downstream ESCRT components. Thus, early cellular responses to starvation include the targeting of specific Golgi proteins for degradation, a phenomenon reminiscent of the inactivation of BTN1, the yeast Batten disease gene ortholog.

  4. MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked

    PubMed Central

    Dobó, József; Szakács, Dávid; Oroszlán, Gábor; Kortvely, Elod; Kiss, Bence; Boros, Eszter; Szász, Róbert; Závodszky, Péter; Gál, Péter; Pál, Gábor

    2016-01-01

    MASP-3 was discovered 15 years ago as the third mannan-binding lectin (MBL)-associated serine protease of the complement lectin pathway. Lacking any verified substrate its role remained ambiguous. MASP-3 was shown to compete with a key lectin pathway enzyme MASP-2 for MBL binding, and was therefore considered to be a negative complement regulator. Later, knock-out mice experiments suggested that MASP-1 and/or MASP-3 play important roles in complement pro-factor D (pro-FD) maturation. However, studies on a MASP-1/MASP-3-deficient human patient produced contradicting results. In normal resting blood unperturbed by ongoing coagulation or complement activation, factor D is present predominantly in its active form, suggesting that resting blood contains at least one pro-FD activating proteinase that is not a direct initiator of coagulation or complement activation. We have recently showed that all three MASPs can activate pro-FD in vitro. In resting blood, however, using our previously evolved MASP-1 and MASP-2 inhibitors we proved that neither MASP-1 nor MASP-2 activates pro-FD. Other plasma proteinases, particularly MASP-3, remained candidates for that function. For this study we evolved a specific MASP-3 inhibitor and unambiguously proved that activated MASP-3 is the exclusive pro-FD activator in resting blood, which demonstrates a fundamental link between the lectin and alternative pathways. PMID:27535802

  5. Evidence that the Entamoeba histolytica Mitochondrial Carrier Family Links Mitosomal and Cytosolic Pathways through Exchange of 3'-Phosphoadenosine 5'-Phosphosulfate and ATP.

    PubMed

    Mi-ichi, Fumika; Nozawa, Akira; Yoshida, Hiroki; Tozawa, Yuzuru; Nozaki, Tomoyoshi

    2015-11-01

    Entamoeba histolytica, a microaerophilic protozoan parasite, possesses mitosomes. Mitosomes are mitochondrion-related organelles that have largely lost typical mitochondrial functions, such as those involved in the tricarboxylic acid cycle and oxidative phosphorylation. The biological roles of Entamoeba mitosomes have been a long-standing enigma. We previously demonstrated that sulfate activation, which is not generally compartmentalized to mitochondria, is a major function of E. histolytica mitosomes. Sulfate activation cooperates with cytosolic enzymes, i.e., sulfotransferases (SULTs), for the synthesis of sulfolipids, one of which is cholesteryl sulfate. Notably, cholesteryl sulfate plays an important role in encystation, an essential process in the Entamoeba life cycle. These findings identified a biological role for Entamoeba mitosomes; however, they simultaneously raised a new issue concerning how the reactions of the pathway, separated by the mitosomal membranes, cooperate. Here, we demonstrated that the E. histolytica mitochondrial carrier family (EhMCF) has the capacity to exchange 3'-phosphoadenosine 5'-phosphosulfate (PAPS) with ATP. We also confirmed the cytosolic localization of all the E. histolytica SULTs, suggesting that in Entamoeba, PAPS, which is produced through mitosomal sulfate activation, is translocated to the cytosol and becomes a substrate for SULTs. In contrast, ATP, which is produced through cytosolic pathways, is translocated into the mitosomes and is a necessary substrate for sulfate activation. Taking our findings collectively, we suggest that EhMCF functions as a PAPS/ATP antiporter and plays a crucial role in linking the mitosomal sulfate activation pathway to cytosolic SULTs for the production of sulfolipids.

  6. Linking family economic pressure and supportive parenting to adolescent health behaviors: two developmental pathways leading to health promoting and health risk behaviors.

    PubMed

    Kwon, Josephine A; Wickrama, K A S

    2014-07-01

    Adolescent health behaviors, especially health risk behaviors, have previously been linked to distal (i.e., family economic pressure) and proximal (i.e., parental support) contributors. However, few studies have examined both types of contributors along with considering health promoting and health risk behaviors separately. The present study investigated the influences of family economic hardship, supportive parenting as conceptualized by self-determination theory, and individual psychosocial and behavioral characteristics (i.e., mastery and delinquency, respectively) on adolescents' health promoting and health risk behaviors. We used structural equation modeling to analyze longitudinal data from a sample of Caucasian adolescent children and their mothers and fathers (N = 407, 54 % female) to examine direct and indirect effects, as well as gender symmetry and asymmetry. Findings suggest that family economic pressure contributed to adolescent mastery and delinquency through supportive parenting. Further, supportive parenting indirectly affected adolescent health risk behaviors only through delinquency, whereas supportive parenting indirectly influenced health promoting behaviors only through mastery, suggesting different developmental pathways for adolescent health risk and health promoting behaviors. Testing for gender symmetry of the full model showed that maternal and paternal parenting contributed to females' health risk behaviors directly, while maternal and paternal parenting contributed to males' health risk behaviors through delinquency. Gender symmetry was largely unsupported. The study highlights key direct and indirect pathways to adolescent health risk and health promoting behaviors within a family stress model and self-determination theory framework, and also highlights important gender differences in these developmental pathways.

  7. Modeling the air-soil transport pathway of perfluorooctanoic acid in the mid-Ohio Valley using linked air dispersion and vadose zone models

    NASA Astrophysics Data System (ADS)

    Shin, Hyeong-Moo; Ryan, P. Barry; Vieira, Verónica M.; Bartell, Scott M.

    2012-05-01

    As part of an extensive modeling effort on the air-soil-groundwater transport pathway of perfluorooctanoic acid (PFOA), this study was designed to compare the performance of different air dispersion modeling systems (AERMOD vs. ISCST3), and different approaches to handling incomplete meteorological data using a data set with substantial soil measurements and a well characterized point source for air emissions. Two of the most commonly used EPA air dispersion models, AERMOD and ISCST3, were linked with the EPA vadose zone model PRZM-3. Predicted deposition rates from the air dispersion model were used as input values for the vadose zone model to estimate soil concentrations of PFOA at different depths. We applied 34 years of meteorological data including hourly surface measurements from Parkersburg Airport and 5 years of onsite wind direction and speed to the air dispersion models. We compared offsite measured soil concentrations to predictions made for the corresponding sampling depths, focusing on soil rather than air measurements because the offsite soil samples were less likely to be influenced by short-term variability in emission rates and meteorological conditions. PFOA concentrations in surface soil (0-30 cm depth) were under-predicted and those in subsurface soil (>30 cm depth) were over-predicted compared to observed concentrations by both linked air and vadose zone model. Overall, the simulated values from the linked modeling system were positively correlated with those observed in surface soil (Spearman's rho, Rsp = 0.59-0.70) and subsurface soil (Rsp = 0.46-0.48). This approach provides a useful modeling scheme for similar exposure and risk analyses where the air-soil-groundwater transport is a primary contamination pathway.

  8. Lung Cancer Cell Line Screen Links Fanconi Anemia/BRCA Pathway Defects to Increased Relative Biological Effectiveness of Proton Radiation

    SciTech Connect

    Liu, Qi; Ghosh, Priyanjali; Magpayo, Nicole; Testa, Mauro; Tang, Shikui; Gheorghiu, Liliana; Biggs, Peter; Paganetti, Harald; Efstathiou, Jason A.; Lu, Hsiao-Ming; Held, Kathryn D.; Willers, Henning

    2015-04-01

    Purpose: Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials: For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and {sup 137}Cs γ-rays were used. To estimate the RBE of protons relative to {sup 60}Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results: Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions: Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.

  9. Housing and health inequalities: A synthesis of systematic reviews of interventions aimed at different pathways linking housing and health

    PubMed Central

    Gibson, Marcia; Petticrew, Mark; Bambra, Clare; Sowden, Amanda J.; Wright, Kath E.; Whitehead, Margaret

    2011-01-01

    Housing and neighbourhood conditions are widely acknowledged to be important social determinants of health, through three main pathways: (1) internal housing conditions, (2) area characteristics and (3) housing tenure. We conducted a systematic overview of systematic reviews of intervention studies to provide an overview of the evidence on the impact of housing and neighbourhood interventions on health and health inequalities. There is relatively strong evidence for interventions aimed at improving area characteristics and compelling evidence for warmth and energy efficiency interventions targeted at vulnerable individuals. However, the health impacts of area-level internal housing improvement interventions are as yet unclear. We found no reviews of interventions aimed at altering housing tenure. This remains an important area for further research and potentially new evidence syntheses. PMID:21159542

  10. Transposable Element Misregulation Is Linked to the Divergence between Parental piRNA Pathways in Drosophila Hybrids

    PubMed Central

    Romero-Soriano, Valèria; Modolo, Laurent; Lopez-Maestre, Hélène; Mugat, Bruno; Pessia, Eugénie; Chambeyron, Séverine; Vieira, Cristina

    2017-01-01

    Abstract Interspecific hybridization is a genomic stress condition that leads to the activation of transposable elements (TEs) in both animals and plants. In hybrids between Drosophila buzzatii and Drosophila koepferae, mobilization of at least 28 TEs has been described. However, the molecular mechanisms underlying this TE release remain poorly understood. To give insight on the causes of this TE activation, we performed a TE transcriptomic analysis in ovaries (notorious for playing a major role in TE silencing) of parental species and their F1 and backcrossed (BC) hybrids. We find that 15.2% and 10.6% of the expressed TEs are deregulated in F1 and BC1 ovaries, respectively, with a bias toward overexpression in both cases. Although differences between parental piRNA (Piwi-interacting RNA) populations explain only partially these results, we demonstrate that piRNA pathway proteins have divergent sequences and are differentially expressed between parental species. Thus, a functional divergence of the piRNA pathway between parental species, together with some differences between their piRNA pools, might be at the origin of hybrid instabilities and ultimately cause TE misregulation in ovaries. These analyses were complemented with the study of F1 testes, where TEs tend to be less expressed than in D. buzzatii. This can be explained by an increase in piRNA production, which probably acts as a defence mechanism against TE instability in the male germline. Hence, we describe a differential impact of interspecific hybridization in testes and ovaries, which reveals that TE expression and regulation are sex-biased. PMID:28854624

  11. Two Independent Pathways for Self-Recognition in Proteus mirabilis Are Linked by Type VI-Dependent Export

    PubMed Central

    Wenren, Larissa M.; Sullivan, Nora L.; Cardarelli, Lia; Septer, Alecia N.; Gibbs, Karine A.

    2013-01-01

    ABSTRACT Swarming colonies of the bacterium Proteus mirabilis are capable of self-recognition and territorial behavior. Swarms of independent P. mirabilis isolates can recognize each other as foreign and establish a visible boundary where they meet; in contrast, genetically identical swarms merge. The ids genes, which encode self-identity proteins, are necessary but not sufficient for this territorial behavior. Here we have identified two new gene clusters: one (idr) encodes rhs-related products, and another (tss) encodes a putative type VI secretion (T6S) apparatus. The Ids and Idr proteins function independently of each other in extracellular transport and in territorial behaviors; however, these self-recognition systems are linked via this type VI secretion system. The T6S system is required for export of select Ids and Idr proteins. Our results provide a mechanistic and physiological basis for the fundamental behaviors of self-recognition and territoriality in a bacterial model system. PMID:23882014

  12. Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway

    PubMed Central

    2011-01-01

    Background The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression. Results We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation. Conclusions Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein β (C/EBPβ). PMID:22087873

  13. Socioeconomic background and high school completion: Mediation by health and moderation by national context.

    PubMed

    Sznitman, Sharon R; Reisel, Liza; Khurana, Atika

    2017-04-01

    This study uses longitudinal data from the Norwegian Health Study linked with registry data (n = 13262) and the U.S. National Longitudinal Survey of Youth 1997 (n = 3604) to examine (1) whether adolescent health mediates the well-established relationship between socioeconomic background and successful high school completion, and (2) whether this mediated pathway of influence varies by national context. Adolescents from lower educated and lower income families reported poorer health, which negatively impacted their likelihood of graduating from high school. The partial mediational effect of adolescent health was stronger in the U.S. than in Norway. These results suggest that policies aimed at preventing high school dropout need to address adolescent health, in addition to the unequal opportunities derived from socioeconomic disadvantage. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. Integrated analysis of oral tongue squamous cell carcinoma identifies key variants and pathways linked to risk habits, HPV, clinical parameters and tumor recurrence

    PubMed Central

    Krishnan, Neeraja; Gupta, Saurabh; Palve, Vinayak; Varghese, Linu; Pattnaik, Swetansu; Jain, Prach; Khyriem, Costerwell; Hariharan, Arun; Dhas, Kunal; Nair, Jayalakshmi; Pareek, Manisha; Prasad, Venkatesh; Siddappa, Gangotri; Suresh, Amritha; Kekatpure, Vikram; Kuriakose, Moni; Panda, Binay

    2015-01-01

    Oral tongue squamous cell carcinomas (OTSCC) are a homogeneous group of tumors characterized by aggressive behavior, early spread to lymph nodes and a higher rate of regional failure. Additionally, the incidence of OTSCC among younger population (<50yrs) is on the rise; many of whom lack the typical associated risk factors of alcohol and/or tobacco exposure. We present data on single nucleotide variations (SNVs), indels, regions with loss of heterozygosity (LOH), and copy number variations (CNVs) from fifty-paired oral tongue primary tumors and link the significant somatic variants with clinical parameters, epidemiological factors including human papilloma virus (HPV) infection and tumor recurrence. Apart from the frequent somatic variants harbored in TP53, CASP8, RASA1, NOTCH and CDKN2A genes, significant amplifications and/or deletions were detected in chromosomes 6-9, and 11 in the tumors. Variants in CASP8 and CDKN2A were mutually exclusive. CDKN2A, PIK3CA, RASA1 and DMD variants were exclusively linked to smoking, chewing, HPV infection and tumor stage. We also performed a whole-genome gene expression study that identified matrix metalloproteases to be highly expressed in tumors and linked pathways involving arachidonic acid and NF-k-B to habits and distant metastasis, respectively. Functional knockdown studies in cell lines demonstrated the role of CASP8 in a HPV-negative OTSCC cell line. Finally, we identified a 38-gene minimal signature that predicts tumor recurrence using an ensemble machine-learning method. Taken together, this study links molecular signatures to various clinical and epidemiological factors in a homogeneous tumor population with a relatively high HPV prevalence. PMID:26834999

  15. Quantitative proteomics links metabolic pathways to specific developmental stages of the plant-pathogenic oomycete Phytophthora capsici.

    PubMed

    Pang, Zhili; Srivastava, Vaibhav; Liu, Xili; Bulone, Vincent

    2017-04-01

    The oomycete Phytophthora capsici is a plant pathogen responsible for important losses to vegetable production worldwide. Its asexual reproduction plays an important role in the rapid propagation and spread of the disease in the field. A global proteomics study was conducted to compare two key asexual life stages of P. capsici, i.e. the mycelium and cysts, to identify stage-specific biochemical processes. A total of 1200 proteins was identified using qualitative and quantitative proteomics. The transcript abundance of some of the enriched proteins was also analysed by quantitative real-time polymerase chain reaction. Seventy-three proteins exhibited different levels of abundance between the mycelium and cysts. The proteins enriched in the mycelium are mainly associated with glycolysis, the tricarboxylic acid (or citric acid) cycle and the pentose phosphate pathway, providing the energy required for the biosynthesis of cellular building blocks and hyphal growth. In contrast, the proteins that are predominant in cysts are essentially involved in fatty acid degradation, suggesting that the early infection stage of the pathogen relies primarily on fatty acid degradation for energy production. The data provide a better understanding of P. capsici biology and suggest potential metabolic targets at the two different developmental stages for disease control. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  16. TRYCAT pathways link peripheral inflammation, nicotine, somatization and depression in the etiology and course of Parkinson's disease.

    PubMed

    Anderson, George; Maes, Michael

    2014-02-01

    Increased depression, somatization, gut inflammation and wider peripheral inflammation are all associated with the early stages of Parkinson's disease (PD). Classically such concurrent conditions have been viewed as "comorbidities", driven by high levels of stress in a still poorly understood and treated disorder. Here we review the data on how oxidative and nitrosative stress in association with immuno-inflammatory responses, drives alteration in tryptophan catabolites, including kynurenine, kynurenic acid and quinolinic acid that drive not only the 'comorbidities" of PD but also important processes in the etiology and course of PD per se. The induction of indoleamine 2,3-dioxygenase, leading to the driving of tryptophan into neuroregulatory tryptophan catabolite products and away from serotonin and melatonin production, has significant implications for understanding the role of nicotine, melatonin, and caffeine in regulating PD susceptibility. Tryptophan catabolite pathway activation will also regulate blood-brain barrier permeability, glia and mast cell reactivity as well as wider innate and adaptive immune cell responses, all relevant to the course of PD. As such, the "comorbidities" of PD such as depression, somatization and peripheral inflammatory disorders can all be conceptualized as being an intricate part of the biological underpinnings of both the etiology and course of PD. As a consequence, the data reviewed here has treatment implications; relevant to both the course of PD and in the management of L-DOPA induced dyskinesias.

  17. Identification of Norway Spruce MYB-bHLH-WDR Transcription Factor Complex Members Linked to Regulation of the Flavonoid Pathway

    PubMed Central

    Nemesio-Gorriz, Miguel; Blair, Peter B.; Dalman, Kerstin; Hammerbacher, Almuth; Arnerup, Jenny; Stenlid, Jan; Mukhtar, Shahid M.; Elfstrand, Malin

    2017-01-01

    Transcription factors (TFs) forming MYB-bHLH-WDR complexes are known to regulate the biosynthesis of specialized metabolites in angiosperms through an intricate network. These specialized metabolites participate in a wide range of biological processes including plant growth, development, reproduction as well as in plant immunity. Studying the regulation of their biosynthesis is thus essential. While MYB (TFs) have been previously shown to control specialized metabolism (SM) in gymnosperms, the identity of their partners, in particular bHLH or WDR members, has not yet been revealed. To gain knowledge about MYB-bHLH-WDR transcription factor complexes in gymnosperms and their regulation of SW, we identified two bHLH homologs of AtTT8, six homologs of the MYB transcription factor AtTT2 and one WDR ortholog of AtTTG1 in Norway spruce. We investigated the expression levels of these genes in diverse tissues and upon treatments with various stimuli including methyl-salicylate, methyl-jasmonate, wounding or fungal inoculation. In addition, we also identified protein-protein interactions among different homologs of MYB, bHLH and WDR. Finally, we generated transgenic spruce cell lines overexpressing four of the Norway spruce AtTT2 homologs and observed differential regulation of genes in the flavonoid pathway and flavonoid contents. PMID:28337212

  18. Discovering causal pathways linking genomic events to transcriptional states using Tied Diffusion Through Interacting Events (TieDIE).

    PubMed

    Paull, Evan O; Carlin, Daniel E; Niepel, Mario; Sorger, Peter K; Haussler, David; Stuart, Joshua M

    2013-11-01

    Identifying the cellular wiring that connects genomic perturbations to transcriptional changes in cancer is essential to gain a mechanistic understanding of disease initiation, progression and ultimately to predict drug response. We have developed a method called Tied Diffusion Through Interacting Events (TieDIE) that uses a network diffusion approach to connect genomic perturbations to gene expression changes characteristic of cancer subtypes. The method computes a subnetwork of protein-protein interactions, predicted transcription factor-to-target connections and curated interactions from literature that connects genomic and transcriptomic perturbations. Application of TieDIE to The Cancer Genome Atlas and a breast cancer cell line dataset identified key signaling pathways, with examples impinging on MYC activity. Interlinking genes are predicted to correspond to essential components of cancer signaling and may provide a mechanistic explanation of tumor character and suggest subtype-specific drug targets. Software is available from the Stuart lab's wiki: https://sysbiowiki.soe.ucsc.edu/tiedie. jstuart@ucsc.edu. Supplementary data are available at Bioinformatics online.

  19. Indirect CO2 Emission Implications of Energy System Pathways: Linking IO and TIMES Models for the UK.

    PubMed

    Daly, Hannah E; Scott, Kate; Strachan, Neil; Barrett, John

    2015-09-01

    Radical changes to current national energy systems-including energy efficiency and the decarbonization of electricity-will be required in order to meet challenging carbon emission reduction commitments. Technology explicit energy system optimization models (ESOMs) are widely used to define and assess such low-carbon pathways, but these models only account for the emissions associated with energy combustion and either do not account for or do not correctly allocate emissions arising from infrastructure, manufacturing, construction and transport associated with energy technologies and fuels. This paper addresses this shortcoming, through a hybrid approach that estimates the upstream CO2 emissions across current and future energy technologies for the UK using a multiregional environmentally extended input-output model, and explicitly models the direct and indirect CO2 emissions of energy supply and infrastructure technologies within a national ESOM (the UK TIMES model). Results indicate the large significance of nondomestic indirect emissions, particularly coming from fossil fuel imports, and finds that the marginal abatement cost of mitigating all emissions associated with UK energy supply is roughly double that of mitigating only direct emissions in 2050.

  20. RpiR Homologues May Link Staphylococcus aureus RNAIII Synthesis and Pentose Phosphate Pathway Regulation ▿ †

    PubMed Central

    Zhu, Yefei; Nandakumar, Renu; Sadykov, Marat R.; Madayiputhiya, Nandakumar; Luong, Thanh T.; Gaupp, Rosmarie; Lee, Chia Y.; Somerville, Greg A.

    2011-01-01

    Staphylococcus aureus is a medically important pathogen that synthesizes a wide range of virulence determinants. The synthesis of many staphylococcal virulence determinants is regulated in part by stress-induced changes in the activity of the tricarboxylic acid (TCA) cycle. One metabolic change associated with TCA cycle stress is an increased concentration of ribose, leading us to hypothesize that a pentose phosphate pathway (PPP)-responsive regulator mediates some of the TCA cycle-dependent regulatory effects. Using bioinformatics, we identified three potential ribose-responsive regulators that belong to the RpiR family of transcriptional regulators. To determine whether these RpiR homologues affect PPP activity and virulence determinant synthesis, the rpiR homologues were inactivated, and the effects on PPP activity and virulence factor synthesis were assessed. Two of the three homologues (RpiRB and RpiRC) positively influence the transcription of the PPP genes rpiA and zwf, while the third homologue (RpiRA) is slightly antagonistic to the other homologues. In addition, inactivation of RpiRC altered the temporal transcription of RNAIII, the effector molecule of the agr quorum-sensing system. These data confirm the close linkage of central metabolism and virulence determinant synthesis, and they establish a metabolic override for quorum-sensing-dependent regulation of RNAIII transcription. PMID:21926234

  1. Identification of Norway Spruce MYB-bHLH-WDR Transcription Factor Complex Members Linked to Regulation of the Flavonoid Pathway.

    PubMed

    Nemesio-Gorriz, Miguel; Blair, Peter B; Dalman, Kerstin; Hammerbacher, Almuth; Arnerup, Jenny; Stenlid, Jan; Mukhtar, Shahid M; Elfstrand, Malin

    2017-01-01

    Transcription factors (TFs) forming MYB-bHLH-WDR complexes are known to regulate the biosynthesis of specialized metabolites in angiosperms through an intricate network. These specialized metabolites participate in a wide range of biological processes including plant growth, development, reproduction as well as in plant immunity. Studying the regulation of their biosynthesis is thus essential. While MYB (TFs) have been previously shown to control specialized metabolism (SM) in gymnosperms, the identity of their partners, in particular bHLH or WDR members, has not yet been revealed. To gain knowledge about MYB-bHLH-WDR transcription factor complexes in gymnosperms and their regulation of SW, we identified two bHLH homologs of AtTT8, six homologs of the MYB transcription factor AtTT2 and one WDR ortholog of AtTTG1 in Norway spruce. We investigated the expression levels of these genes in diverse tissues and upon treatments with various stimuli including methyl-salicylate, methyl-jasmonate, wounding or fungal inoculation. In addition, we also identified protein-protein interactions among different homologs of MYB, bHLH and WDR. Finally, we generated transgenic spruce cell lines overexpressing four of the Norway spruce AtTT2 homologs and observed differential regulation of genes in the flavonoid pathway and flavonoid contents.

  2. Biological marks of early-life socioeconomic experience is detected in the adult inflammatory transcriptome

    PubMed Central

    Castagné, Raphaële; Kelly-Irving, Michelle; Campanella, Gianluca; Guida, Florence; Krogh, Vittorio; Palli, Domenico; Panico, Salvatore; Sacerdote, Carlotta; Tumino, Rosario; Kleinjans, Jos; de Kok, Theo; Kyrtopoulos, Soterios A.; Lang, Thierry; Stringhini, Silvia; Vermeulen, Roel; Vineis, Paolo; Delpierre, Cyrille; Chadeau-Hyam, Marc

    2016-01-01

    Consistent evidence is accumulating to link lower socioeconomic position (SEP) and poorer health, and the inflammatory system stands out as a potential pathway through which socioeconomic environment is biologically embedded. Using bloodderived genome-wide transcriptional profiles from 268 Italian participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we evaluated the association between early life, young and later adulthood SEP and the expression of 845 genes involved in human inflammatory responses. These were examined individually and jointly using several inflammatory scores. Our results consistently show that participants whose father had a manual (as compared to nonmanual) occupation exhibit, later in life, a higher inflammatory score, hence indicating an overall increased level of expression for the selected inflammatory-related genes. Adopting a life course approach, these associations remained statistically significant upon adjustment for later-in-life socioeconomic experiences. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated, and were replicated in an independent study. Our study provides additional evidence that childhood SEP is associated with a sustainable upregulation of the inflammatory transcriptome, independently of subsequent socioeconomic experiences. Our results support the hypothesis that early social inequalities impacts adult physiology. PMID:27934951

  3. Learning Motivation Mediates Gene-by-Socioeconomic Status Interaction on Mathematics Achievement in Early Childhood.

    PubMed

    Tucker-Drob, Elliot M; Harden, K Paige

    2012-02-01

    There is accumulating evidence that genetic influences on achievement are more pronounced among children living in higher socioeconomic status homes, and that these gene-by-environment interactions occur prior to children's entry into formal schooling. We hypothesized that one pathway through which socioeconomic status promotes genetic influences on early achievement is by facilitating the processes by which children select, evoke, and attend to learning experiences that are consistent with genetically influenced individual differences in their motivation to learn. We examined this hypothesis in a nationally representative sample of approximately 650 pairs of four-year old identical and fraternal twins who were administered a measure of math achievement, and rated by their parents on a broad set of items assessing learning motivation. Results indicated a genetic link between learning motivation and math achievement that varied positively with family socioeconomic status: Genetic differences in learning motivation contributed to math achievement more strongly in more advantaged homes. Once this effect of learning motivation was controlled for, gene-by-socioeconomic status interaction on math achievement was reduced from previously significant levels, to nonsignificant levels.

  4. Signal transduction pathway of interleukin-4 and interleukin-13 in human B cells derived from X-linked severe combined immunodeficiency patients.

    PubMed

    Izuhara, K; Heike, T; Otsuka, T; Yamaoka, K; Mayumi, M; Imamura, T; Niho, Y; Harada, N

    1996-01-12

    Interleukin-4 (IL-4) and IL-13 are functionally similar cytokines. The functional IL-4 receptor (IL-4R) consists of the IL-4R alpha chain (IL-4R alpha) and the IL-2R gamma chain (gamma c), which is shared by the IL-2, IL-7, IL-9, and IL-15 receptors. The functional IL-13R is thought to involve the IL-4R alpha but not gamma c. In this study, we have analyzed activation of members of the Janus tyrosine kinase (Jak) family and signal transducers and activators of transcription (STAT) 6 induced by IL-4 and IL-13 in Epstein-Barr virus-transformed B cells derived from two patients of X-linked severe combined immunodeficiency, who have mutations of the gamma c gene in the extracellular and intracellular domains. In these B cells, IL-4 failed to induce tyrosine phosphorylation of Jak3 and activation of STAT6, or activation of these molecules was significantly decreased compared with Epstein-Barr virus-transformed normal B cells. In contrast, IL-13 activated STAT6 in these cells as well as normal B cells. However, Jak3 was not activated by IL-13, even in normal B cells. These results clearly indicated that gamma c is essential for activation of Jak3 and STAT6 in the signal transduction pathway of IL-4 in human B cells and that IL-13 does not utilize gamma c but activates STAT6 through an alternative pathway, which is not impaired in B cells of X-linked severe combined immunodeficiency patients.

  5. Serine/threonine protein phosphatase-mediated control of the peptidoglycan cross-linking L,D-transpeptidase pathway in Enterococcus faecium.

    PubMed

    Sacco, Emmanuelle; Cortes, Mélanie; Josseaume, Nathalie; Rice, Louis B; Mainardi, Jean-Luc; Arthur, Michel

    2014-07-08

    The last step of peptidoglycan polymerization involves two families of unrelated transpeptidases that are the essential targets of β-lactam antibiotics. D,D-transpeptidases of the penicillin-binding protein (PBP) family are active-site serine enzymes that use pentapeptide precursors and are the main or exclusive cross-linking enzymes in nearly all bacteria. However, peptidoglycan cross-linking is performed mainly by active-site cysteine L,D-transpeptidases that use tetrapeptides in Mycobacterium tuberculosis, Clostridium difficile, and β-lactam-resistant mutants of Enterococcus faecium. We have investigated reprogramming of the E. faecium peptidoglycan assembly pathway by a switch from pentapeptide to tetrapeptide precursors and bypass of PBPs by L,D-transpeptidase Ldtfm. Mutational alterations of two signal transduction systems were necessary and sufficient for activation of the L,D-transpeptidation pathway, which is essentially cryptic in wild-type strains. The first one is a classical two-component regulatory system, DdcRS, that controls the activity of Ldtfm at the substrate level. As previously described, loss of DdcS phosphatase activity leads to production of the D,D-carboxypeptidase DdcY and conversion of the pentapeptide into the tetrapeptide substrate of Ldtfm. Here we show that full bypass of PBPs by Ldtfm also requires increased Ser/Thr protein phosphorylation resulting from impaired activity of phosphoprotein phosphatase StpA. This enzyme negatively controlled the level of protein phosphorylation both by direct dephosphorylation of target proteins and by dephosphorylation of its cognate kinase Stk. In combination with production of DdcY, increased protein phosphorylation by this eukaryotic-enzyme-like Ser/Thr protein kinase was sufficient for activation of the L,D-transpeptidation pathway in the absence of mutational alteration of peptidoglycan synthesis enzymes. Importance: The mechanism of acquisition of high-level ampicillin resistance involving

  6. Cocktail of Four Active Components Derived from Sheng Mai San Inhibits Hydrogen Peroxide-Induced PC12 Cell Apoptosis Linked with the Caspase-3/ROCK1/MLC Pathway.

    PubMed

    Shen, Kai; Wang, Yan; Zhang, Yuanyuan; Zhou, Huana; Song, Yunfei; Cao, Zhengyu; Kou, Junping; Yu, Boyang

    2015-12-01

    SMXZF, a combination of four active components including ginsenoside Rb1, ginsenoside Rg1, schizandrin, and DT-13 (6:9:5:4) that is derived from Sheng Mai San, has previously been shown to exhibit a neuroprotective effect against focal ischemia/reperfusion injury. Due to the key role of oxidative stress-induced neuronal apoptosis in the pathogenesis of stroke, we examined the effect of SMXZF in oxidative stress responses and related signaling pathways in differentiated pheochromocytoma (PC12) cells. Our results showed that incubation with 100 μM hydrogen peroxide (H2O2) for 12 hr could reduce cell viability and superoxide dismutase (SOD) activity with an increase of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA). In contrast, SMXZF alleviated oxidative stress by reducing the over-production of ROS and MDA in parallel to concentration dependently increasing SOD activity. In addition, SMXZF significantly attenuated H2O2-induced caspase-3 cleavage, Rho-associated coiled-coil-containing protein kinase-1 (ROCK1) activation, and myosin light-chain (MLC) phosphorylation. Inhibiting either caspase-3 or ROCK1 mimicked the effect. Consequently, our results suggest that SMXZF inhibits H2O2-induced neuronal apoptosis linked with the caspase-3/ROCK1/MLC pathway, which has also been confirmed to be a positive feedback loop in oxidative stress-injured PC12 cells. These findings support the pharmacological potential of SMXZF for neurodegenerative diseases and stroke.

  7. Interaction between small GTPase Rab7 and PI3KC3 links autophagy and endocytosis: A new Rab7 effector protein sheds light on membrane trafficking pathways.

    PubMed

    Lin, Mary Grace; Zhong, Qing

    2011-03-01

    Endocytosis and autophagy are both membrane trafficking pathways vital for cell survival. Endocytosis, the primary means by which cells internalize material such as cell-surface receptors and their protein ligands, is essential for proper cell growth and communication. Autophagy is a catabolic process that degrades cargo ranging from organelles to protein aggregates to bacteria, and it is important for maintaining cellular homeostasis. Defects in both endosome and autophagosome maturation lead to an array of human diseases, including cancer; however, the molecular mechanisms underlying endosome and autophagosome maturation are not well characterized. In the case of endocytosis, small GTPases, key players in membrane organization, are required for endosome maturation. Specifically, activation of the small GTPase Rab7 is required for the initiation of the early-to-late endosome transition, although how this is regulated is largely unknown. Now recent findings from our laboratory show that Rubicon, a component of the PI3KC3 complex, inhibits endosome maturation by preventing activation of Rab7. Not only do our results clarify the molecular link between PI3KC3 and Rab7 function in endosome maturation, they lead us to propose new models for PI3KC3 involvement in membrane trafficking, particularly at the convergence between the endosome and autophagosome pathways.

  8. Pathways to policy: Lessons learned in multisectoral collaboration for physical activity and built environment policy development from the Coalitions Linking Action and Science for Prevention (CLASP) initiative.

    PubMed

    Politis, Christopher E; Mowat, David L; Keen, Deb

    2017-06-16

    The Canadian Partnership Against Cancer funded 12 large-scale knowledge to action cancer and chronic disease prevention projects between 2009 and 2016 through the Coalitions Linking Action and Science for Prevention (CLASP) initiative. Two projects, Healthy Canada by Design (HCBD) and Children's Mobility, Health and Happiness (CMHH), developed policies to address physical activity and the built environment through a multisectoral approach. A qualitative analysis involving a review of 183 knowledge products and 8 key informant interviews was conducted to understand what policy changes occurred, and the underlying critical success factors, through these projects. Both projects worked at the local level to change physical activity and built environment policy in 203 sites, including municipalities and schools. Both projects brought multisectoral expertise (e.g., public health, land use planning, transportation engineering, education, etc.) together to inform the development of local healthy public policy in the areas of land use, transportation and school travel planning. Through the qualitative analysis of the knowledge products and key informant interviews, 163 policies were attributed to HCBD and CMHH work. Fourteen "pathways to policy" were identified as critical success factors facilitating and accelerating the development and implementation of physical activity and built environment policy. Of the 14 pathways to policy, 8 had a focus on multisectoral collaboration. The lessons learned from the CLASP experience could support enhanced multisectoral collaborations to accelerate the development and implementation of physical activity and built environment policy in new jurisdictions across Canada and internationally.

  9. PolymiRTS Database 3.0: linking polymorphisms in microRNAs and their target sites with human diseases and biological pathways.

    PubMed

    Bhattacharya, Anindya; Ziebarth, Jesse D; Cui, Yan

    2014-01-01

    Polymorphisms in microRNAs (miRNAs) and their target sites (PolymiRTS) are known to disrupt miRNA function, leading to the development of disease and variation in physiological and behavioral phenotypes. Here, we describe recent updates to the PolymiRTS database (http://compbio.uthsc.edu/miRSNP), an integrated platform for analyzing the functional impact of genetic polymorphisms in miRNA seed regions and miRNA target sites. Recent advances in genomic technologies have made it possible to identify miRNA-mRNA binding sites from direct mapping experiments such as CLASH (cross linking, ligation and sequencing of hybrids). We have integrated data from CLASH experiments in the PolymiRTS database to provide more complete and accurate miRNA-mRNA interactions. Other significant new features include (i) small insertions and deletions in miRNA seed regions and miRNA target sites, (ii) TargetScan context + score differences for assessing the impact of polymorphic miRNA-mRNA interactions and (iii) biological pathways. The browse and search pages of PolymiRTS allow users to explore the relations between the PolymiRTSs and gene expression traits, physiological and behavioral phenotypes, human diseases and biological pathways.

  10. A plastid envelope location of Arabidopsis ent-kaurene oxidase links the plastid and endoplasmic reticulum steps of the gibberellin biosynthesis pathway.

    PubMed

    Helliwell, C A; Sullivan, J A; Mould, R M; Gray, J C; Peacock, W J; Dennis, E S

    2001-10-01

    We have used fusions of gibberellin biosynthesis enzymes to green fluorescent protein (GFP) to determine the subcellular localization of the early steps of the pathway. Gibberellin biosynthesis from geranylgeranyl diphosphate is catalysed by enzymes of the terpene cyclase, cytochrome P450 mono-oxygenase and 2-oxoglutarate-dependent dioxygenase classes. We show that the N-terminal pre-sequences of the Arabidopsis thaliana terpene cyclases copalyl diphosphate synthase (AtCPS1) and ent-kaurene synthase (AtKS1) direct GFP to chloroplasts in transient assays following microprojectile bombardment of tobacco leaves. The AtKS1-GFP fusion is also imported by isolated pea chloroplasts. The N-terminal portion of the cytochrome P450 protein ent-kaurene oxidase (AtKO1) directs GFP to chloroplasts in tobacco leaf transient assays. Chloroplast import assays with 35S-labelled AtKO1 protein show that it is targeted to the outer face of the chloroplast envelope. The leader sequences of the two ent-kaurenoic acid oxidases (AtKAO1 and AtKAO2) from Arabidopsis direct GFP to the endoplasmic reticulum. These data suggest that the AtKO1 protein links the plastid- and endoplasmic reticulum-located steps of the gibberellin biosynthesis pathway by association with the outer envelope of the plastid.

  11. Signaling Pathways Linked to Serotonin-Induced Superoxide Anion Production: A Physiological Role for Mitochondria in Pulmonary Arteries

    PubMed Central

    Genet, Nafiisha; Billaud, Marie; Rossignol, Rodrigue; Dubois, Mathilde; Gillibert-Duplantier, Jennifer; Isakson, Brant E.; Marthan, Roger; Savineau, Jean-Pierre; Guibert, Christelle

    2017-01-01

    Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion (O2•_) is commonly associated to cellular damages due to O2•_ overproduction, we previously demonstrated that, in physiological conditions, O2•_ also participates to the 5-HT contraction in intrapulmonary arteries (IPA). Here, we focused on the signaling pathways leading to O2•_ production in response to 5-HT in rat IPA. Using electron paramagnetic resonance on rat IPA, we showed that 5-HT (100 μM)-induced O2•_ production was inhibited by ketanserin (1 μM—an inhibitor of the 5-HT2 receptor), absence of extracellular calcium, two blockers of voltage-independent calcium permeable channels (RHC80267 50 μM and LOE-908 10 μM) and a blocker of the mitochondrial complex I (rotenone—100 nM). Depletion of calcium from the sarcoplasmic reticulum or nicardipine (1 μM—an inhibitor of the L-type voltage-dependent calcium channel) had no effect on the 5-HT-induced O2•_ production. O2•_ levels were also increased by α-methyl-5-HT (10 μM—a 5-HT2 receptors agonist) whereas GR127935 (1 μM—an antagonist of the 5-HT1B/D receptor) and citalopram (1 μM—a 5-HT transporter inhibitor) had no effect on the 5-HT-induced O2•_ production. Peroxynitrites were increased in response to 5-HT (100 μM). In isolated pulmonary arterial smooth muscle cells loaded with rhod-2 or mitosox probes, we respectively showed that 5-HT increased both mitochondrial calcium and O2•_ levels, which were both abrogated in absence of extracellular calcium. Mitochondrial O2•_ levels were also abolished in the presence of rotenone (100 nM). In pulmonary arterial smooth muscle cells loaded with TMRM, we showed that 5-HT transiently depolarized the mitochondrial membrane whereas in the absence of extracellular calcium the mitochondrial membrane depolarisation was delayed and sustained in

  12. Signaling Pathways Linked to Serotonin-Induced Superoxide Anion Production: A Physiological Role for Mitochondria in Pulmonary Arteries.

    PubMed

    Genet, Nafiisha; Billaud, Marie; Rossignol, Rodrigue; Dubois, Mathilde; Gillibert-Duplantier, Jennifer; Isakson, Brant E; Marthan, Roger; Savineau, Jean-Pierre; Guibert, Christelle

    2017-01-01

    Serotonin (5-HT) is a potent vasoconstrictor agonist and contributes to several vascular diseases including systemic or pulmonary hypertension and atherosclerosis. Although superoxide anion ([Formula: see text]) is commonly associated to cellular damages due to [Formula: see text] overproduction, we previously demonstrated that, in physiological conditions, [Formula: see text] also participates to the 5-HT contraction in intrapulmonary arteries (IPA). Here, we focused on the signaling pathways leading to [Formula: see text] production in response to 5-HT in rat IPA. Using electron paramagnetic resonance on rat IPA, we showed that 5-HT (100 μM)-induced [Formula: see text] production was inhibited by ketanserin (1 μM-an inhibitor of the 5-HT2 receptor), absence of extracellular calcium, two blockers of voltage-independent calcium permeable channels (RHC80267 50 μM and LOE-908 10 μM) and a blocker of the mitochondrial complex I (rotenone-100 nM). Depletion of calcium from the sarcoplasmic reticulum or nicardipine (1 μM-an inhibitor of the L-type voltage-dependent calcium channel) had no effect on the 5-HT-induced [Formula: see text] production. [Formula: see text] levels were also increased by α-methyl-5-HT (10 μM-a 5-HT2 receptors agonist) whereas GR127935 (1 μM-an antagonist of the 5-HT1B/D receptor) and citalopram (1 μM-a 5-HT transporter inhibitor) had no effect on the 5-HT-induced [Formula: see text] production. Peroxynitrites were increased in response to 5-HT (100 μM). In isolated pulmonary arterial smooth muscle cells loaded with rhod-2 or mitosox probes, we respectively showed that 5-HT increased both mitochondrial calcium and [Formula: see text] levels, which were both abrogated in absence of extracellular calcium. Mitochondrial [Formula: see text] levels were also abolished in the presence of rotenone (100 nM). In pulmonary arterial smooth muscle cells loaded with TMRM, we showed that 5-HT transiently depolarized the mitochondrial membrane whereas

  13. The Nuclear Factor kappaB Pathway: A Link to the Immune System in the Radiation Response

    NASA Astrophysics Data System (ADS)

    Hellweg, Christine; Baumstark-Khan, Christa; Reitz, Guenther; Chishti, Arif Ali; Koch, Kristina; Manchanda, Kashish

    Understanding the cellular radiation response is an essential prerequisite for the risk assessment of astronauts’ space radiation exposure during long-term space missions and for effective countermeasure development. In addition to the space radiation effects, other environmental factors during space missions such as microgravity have profound effects on the body, e.g. suppression of the innate and acquired immune response. Exposure to ionizing radiation modulates immune responses in a complex dose-dependent pattern, with possible anti-inflammatory effects in the low dose range, expression of pro-inflammatory cytokines at moderate doses and immunosuppression after exposure to higher doses due to precursor cell death together with concomitant exacerbated innate immune responses. A central regulator in the immune system is the transcription factor Nuclear Factor kB (NF-kappaB). In this work, the role of NF-kappaB in the cellular response to space relevant radiation qualities was analyzed. It was shown with a recombinant human NF-kappaB reporter cell line that heavy ions with a linear energy transfer (LET) of 100-300 keV/µm have a nine times higher potential to activate the NF-kappaB pathway compared to X-rays (150 kV). ATM was essential for NF-kappaB activation in response to X-rays and heavy ions. Knockdown of the NF-kappaB subunit RelA (p65) resulted in higher sensitivity towards X-rays. Reverse Transcriptase real-time quantitative PCR (RT-qPCR) experiments showed that after exposure to radiation, NF-kappaB predominantly upregulates genes involved in intercellular communication processes, especially genes coding for chemokines, suggesting an important contribution of NF-kappaB in the molecular profile of the reaction to radiation, which can comprise features of inflammation and wound healing processes. This is process is strictly NF-kappaB dependent as this response is completely absent in RelA knockdown cells. These results show that the role of NF-kappaB in

  14. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death.

    PubMed

    LaLone, Carlie A; Villeneuve, Daniel L; Wu-Smart, Judy; Milsk, Rebecca Y; Sappington, Keith; Garber, Kristina V; Housenger, Justin; Ankley, Gerald T

    2017-04-15

    Ongoing honey bee (Apis mellifera) colony losses are of significant international concern because of the essential role these insects play in pollinating crops. Both chemical and non-chemical stressors have been implicated as possible contributors to colony failure; however, the potential role(s) of commonly-used neonicotinoid insecticides has emerged as particularly concerning. Neonicotinoids act on the nicotinic acetylcholine receptors (nAChRs) in the central nervous system to eliminate pest insects. However, mounting evidence indicates that neonicotinoids also may adversely affect beneficial pollinators, such as the honey bee, via impairments on learning and memory, and ultimately foraging success. The specific mechanisms linking activation of the nAChR to adverse effects on learning and memory are uncertain. Additionally, clear connections between observed impacts on individual bees and colony level effects are lacking. The objective of this review was to develop adverse outcome pathways (AOPs) as a means to evaluate the biological plausibility and empirical evidence supporting (or refuting) the linkage between activation of the physiological target site, the nAChR, and colony level consequences. Potential for exposure was not a consideration in AOP development and therefore this effort should not be considered a risk assessment. Nonetheless, development of the AOPs described herein has led to the identification of research gaps which, for example, may be of high priority in understanding how perturbation of pathways involved in neurotransmission can adversely affect normal colony functions, causing colony instability and subsequent bee population failure. A putative AOP network was developed, laying the foundation for further insights as to the role of combined chemical and non-chemical stressors in impacting bee populations. Insights gained from the AOP network assembly, which more realistically represents multi-stressor impacts on honey bee colonies, are

  15. Evidence that the Entamoeba histolytica Mitochondrial Carrier Family Links Mitosomal and Cytosolic Pathways through Exchange of 3′-Phosphoadenosine 5′-Phosphosulfate and ATP

    PubMed Central

    Mi-ichi, Fumika; Nozawa, Akira; Yoshida, Hiroki

    2015-01-01

    Entamoeba histolytica, a microaerophilic protozoan parasite, possesses mitosomes. Mitosomes are mitochondrion-related organelles that have largely lost typical mitochondrial functions, such as those involved in the tricarboxylic acid cycle and oxidative phosphorylation. The biological roles of Entamoeba mitosomes have been a long-standing enigma. We previously demonstrated that sulfate activation, which is not generally compartmentalized to mitochondria, is a major function of E. histolytica mitosomes. Sulfate activation cooperates with cytosolic enzymes, i.e., sulfotransferases (SULTs), for the synthesis of sulfolipids, one of which is cholesteryl sulfate. Notably, cholesteryl sulfate plays an important role in encystation, an essential process in the Entamoeba life cycle. These findings identified a biological role for Entamoeba mitosomes; however, they simultaneously raised a new issue concerning how the reactions of the pathway, separated by the mitosomal membranes, cooperate. Here, we demonstrated that the E. histolytica mitochondrial carrier family (EhMCF) has the capacity to exchange 3′-phosphoadenosine 5′-phosphosulfate (PAPS) with ATP. We also confirmed the cytosolic localization of all the E. histolytica SULTs, suggesting that in Entamoeba, PAPS, which is produced through mitosomal sulfate activation, is translocated to the cytosol and becomes a substrate for SULTs. In contrast, ATP, which is produced through cytosolic pathways, is translocated into the mitosomes and is a necessary substrate for sulfate activation. Taking our findings collectively, we suggest that EhMCF functions as a PAPS/ATP antiporter and plays a crucial role in linking the mitosomal sulfate activation pathway to cytosolic SULTs for the production of sulfolipids. PMID:26385892

  16. SARS Coronavirus Papain-Like Protease Inhibits the TLR7 Signaling Pathway through Removing Lys63-Linked Polyubiquitination of TRAF3 and TRAF6.

    PubMed

    Li, Shih-Wen; Wang, Ching-Ying; Jou, Yu-Jen; Huang, Su-Hua; Hsiao, Li-Hsin; Wan, Lei; Lin, Ying-Ju; Kung, Szu-Hao; Lin, Cheng-Wen

    2016-05-05

    Severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLPro) reportedly inhibits the production of type I interferons (IFNs) and pro-inflammatory cytokines in Toll-like receptor 3 (TLR3) and retinoic acid-inducible gene 1 (RIG-I) pathways. The study investigated the inhibitory effect and its antagonistic mechanism of SARS-CoV PLPro on TLR7-mediated cytokine production. TLR7 agonist (imiquimod (IMQ)) concentration-dependently induced activation of ISRE-, NF-κB- and AP-1-luciferase reporters, as well as the production of IFN-α, IFN-β, TNF-α, IL-6 and IL-8 in human promonocyte cells. However, SARS-CoV PLPro significantly inhibited IMQ-induced cytokine production through suppressing the activation of transcription factors IRF-3, NF-κB and AP-1. Western blot analysis with anti-Lys48 and anti-Lys63 ubiquitin antibodies indicated the SARS-CoV PLPro removed Lys63-linked ubiquitin chains of TRAF3 and TRAF6, but not Lys48-linked ubiquitin chains in un-treated and treated cells. The decrease in the activated state of TRAF3 and TRAF6 correlated with the inactivation of TBK1 in response to IMQ by PLPro. The results revealed that the antagonism of SARS-CoV PLPro on TLR7-mediated innate immunity was associated with the negative regulation of TRAF3/6-TBK1-IRF3/NF-κB/AP1 signals.

  17. Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats.

    PubMed

    Wu, Jiang; Zhang, Yang; Yang, Peng; Enkhjargal, Budbazar; Manaenko, Anatol; Tang, Jiping; Pearce, William J; Hartman, Richard; Obenaus, Andre; Chen, Gang; Zhang, John H

    2016-05-01

    receptor/integrin-linked kinase/Rac-1 pathway. © 2016 American Heart Association, Inc.

  18. Mortality by indicators of socioeconomic status among the Finnish elderly.

    PubMed

    Martelin, T

    1994-05-01

    Socioeconomic mortality differentials among the entire Finnish elderly population (those aged 60 years and over) during 1981-85 are examined on the basis of linked data, compiled by means of linking death records of 1981-85 to the 1980 census. Several indicators of socioeconomic position are used: own educational level and occupational class, spouse's education and class, household disposable income, and housing conditions. Marked differences are found according to each of the indicators. Mortality differentials tend to decrease with age and be more pronounced among men as compared to women. In most cases differences persist even when the other socioeconomic indicators are taken into account although they diminish. The interpretation of socioeconomic mortality differentials and the problems of measuring the socioeconomic status of the elderly are discussed.

  19. TGFβ2 Induces the Formation of Cross-Linked Actin Networks (CLANs) in Human Trabecular Meshwork Cells Through the Smad and Non-Smad Dependent Pathways

    PubMed Central

    Montecchi-Palmer, Michela; Bermudez, Jaclyn Y.; Webber, Hannah C.; Patel, Gaurang C.; Clark, Abbot F.; Mao, Weiming

    2017-01-01

    Purpose Increased intraocular pressure results from increased aqueous humor (AH) outflow resistance at the trabecular meshwork (TM) due to pathologic changes including the formation of cross-linked actin networks (CLANs). Transforming growth factor β2 (TGFβ2) is elevated in the AH and TM of primary open angle glaucoma (POAG) patients and induces POAG-associated TM changes, including CLANs. We determined the role of individual TGFβ2 signaling pathways in CLAN formation. Methods Cultured nonglaucomatous human TM (NTM) cells were treated with control or TGFβ2, with or without the inhibitors of TGFβ receptor, Smad3, c-Jun N-terminal kinases (JNK), extracellular signal regulated kinase (ERK), P38, or Rho-associated protein kinase (ROCK). NTM cells were cotreated with TGFβ2 plus inhibitors for 10 days or pretreated with TGFβ2 for 10 days followed by 1-hour inhibitor treatment. NTM cells were immunostained with phalloidin-Alexa-488 and 4′,6-diamidino-2-phenylindole (DAPI). Data were analyzed using 1-way ANOVA and Dunnett's post hoc test. Results TGFβ2 significantly induced CLAN formation (n = 6 to 12, P < 0.05), which was completely inhibited by TGFβ receptor, Smad3, and ERK inhibitors, as well as completely or partially inhibited by JNK, P38, and ROCK inhibitors, depending on cell strains. One-hour exposure to ROCK inhibitor completely resolved formed CLANs (P < 0.05), whereas TGFβ receptor, Smad3 inhibitor, and ERK inhibitors resulted in partial or complete resolution. The JNK and P38 inhibitors showed partial or no resolution. Among these inhibitors, the ROCK inhibitor was the most disruptive to the actin stress fibers, whereas ERK inhibition showed the least disruption. Conclusions TGFβ2-induced CLANs in NTM cells were prevented and resolved using various pathway inhibitors. Apart from CLAN inhibition, some of these inhibitors also had different effects on actin stress fibers. PMID:28241317

  20. An essential role for the integrin-linked kinase-glycogen synthase kinase-3 beta pathway during dendrite initiation and growth.

    PubMed

    Naska, Sibel; Park, Katya J; Hannigan, Gregory E; Dedhar, Shoukat; Miller, Freda D; Kaplan, David R

    2006-12-20

    Multiple cues, including growth factors and circuit activity, signal to regulate the initiation and growth of mammalian dendrites. In this study, we have asked how these environmental cues regulate dendrite formation, and in particular, whether dendrite initiation and growth requires integrin-linked kinase (ILK) or its downstream effector, glycogen synthase kinase-3beta (GSK-3beta). In cultured sympathetic neurons, NGF and neuronal depolarization activated ILK and promoted dendrite initiation and growth, and inhibition of ILK (either pharmacologically, with a dominant-negative form of ILK, or by genetic knockdown) reduced depolarization-induced dendrite formation. In sympathetic neurons, ILK phosphorylated and inhibited GSK-3beta, and inhibition of GSK-3beta (either pharmacologically, with dominant-negative GSK-3beta, or by genetic knockdown) caused robust dendrite initiation. GSK-3beta inhibition also caused dendrite initiation in cultured cortical neurons and growth of hippocampal neurons in slice cultures. GSK-3beta functioned downstream of ILK to regulate dendrite formation, because inhibition of GSK-3beta promoted dendrite initiation even when ILK was simultaneously inhibited. Moreover, GSK-3beta promoted dendrite formation in sympathetic neurons by regulating the activity of a key dendrite formation effector, the MAP (microtubule-associated protein) kinase kinase (MEK)-extracellular signal-regulated protein kinase (ERK) pathway. Specifically, inhibition of GSK-3beta led to increased ERK phosphorylation, and inhibition of MEK completely blocked the effects of GSK-3beta inhibition on dendrite initiation and growth. Thus, the ILK-GSK-3beta pathway plays a key role in regulating dendrite formation in developing mammalian neurons.

  1. Apoptosis-linked gene-2 (ALG-2)/Sec31 interactions regulate endoplasmic reticulum (ER)-to-Golgi transport: a potential effector pathway for luminal calcium.

    PubMed

    Helm, Jared R; Bentley, Marvin; Thorsen, Kevin D; Wang, Ting; Foltz, Lauren; Oorschot, Viola; Klumperman, Judith; Hay, Jesse C

    2014-08-22

    Luminal calcium released from secretory organelles has been suggested to play a regulatory role in vesicle transport at several steps in the secretory pathway; however, its functional roles and effector pathways have not been elucidated. Here we demonstrate for the first time that specific luminal calcium depletion leads to a significant decrease in endoplasmic reticulum (ER)-to-Golgi transport rates in intact cells. Ultrastructural analysis revealed that luminal calcium depletion is accompanied by increased accumulation of intermediate compartment proteins in COPII buds and clusters of unfused COPII vesicles at ER exit sites. Furthermore, we present several lines of evidence suggesting that luminal calcium affected transport at least in part through calcium-dependent interactions between apoptosis-linked gene-2 (ALG-2) and the Sec31A proline-rich region: 1) targeted disruption of ALG-2/Sec31A interactions caused severe defects in ER-to-Golgi transport in intact cells; 2) effects of luminal calcium and ALG-2/Sec31A interactions on transport mutually required each other; and 3) Sec31A function in transport required luminal calcium. Morphological phenotypes of disrupted ALG-2/Sec31A interactions were characterized. We found that ALG-2/Sec31A interactions were not required for the localization of Sec31A to ER exit sites per se but appeared to acutely regulate the stability and trafficking of the cargo receptor p24 and the distribution of the vesicle tether protein p115. These results represent the first outline of a mechanism that connects luminal calcium to specific protein interactions regulating vesicle trafficking machinery. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells.

    PubMed

    de Queiroz, Rafaela Muniz; Madan, Rashna; Chien, Jeremy; Dias, Wagner Barbosa; Slawson, Chad

    2016-09-02

    O-GlcNAcylation is a dynamic post-translational modification consisting of the addition of a single N-acetylglucosamine sugar to serine and threonine residues in proteins by the enzyme O-linked β-N-acetylglucosamine transferase (OGT), whereas the enzyme O-GlcNAcase (OGA) removes the modification. In cancer, tumor samples present with altered O-GlcNAcylation; however, changes in O-GlcNAcylation are not consistent between tumor types. Interestingly, the tumor suppressor p53 is modified by O-GlcNAc, and most solid tumors contain mutations in p53 leading to the loss of p53 function. Because ovarian cancer has a high frequency of p53 mutation rates, we decided to investigate the relationship between O-GlcNAcylation and p53 function in ovarian cancer. We measured a significant decrease in O-GlcNAcylation of tumor tissue in an ovarian tumor microarray. Furthermore, O-GlcNAcylation was increased, and OGA protein and mRNA levels were decreased in ovarian tumor cell lines not expressing the protein p53. Treatment with the OGA inhibitor Thiamet-G (TMG), silencing of OGA, or overexpression of OGA and OGT led to p53 stabilization, increased nuclear localization, and increased protein and mRNA levels of p53 target genes. These data suggest that changes in O-GlcNAc homeostasis activate the p53 pathway. Combination treatment of the chemotherapeutic cisplatin with TMG decreased tumor cell growth and enhanced cell cycle arrest without impairing cytotoxicity. The effects of TMG on tumor cell growth were partially dependent on wild type p53 activation. In conclusion, changes in O-GlcNAc homeostasis activate the wild type p53 pathway in ovarian cancer cells, and OGA inhibition has the potential as an adjuvant treatment for ovarian carcinoma.

  3. optix functions as a link between the retinal determination network and the dpp pathway to control morphogenetic furrow progression in Drosophila

    PubMed Central

    Li, Yumei; Jiang, Yuwei; Chen, Yiyun; Karandikar, Umesh; Hoffman, Kristi; Chattopadhyay, Abanti; Mardon, Graeme; Chen, Rui

    2013-01-01

    optix, the Drosophila ortholog of the SIX3/6 gene family in vertebrate, encodes a homeodomain protein with a SIX protein-protein interaction domain. In vertebrates, Six3/6 genes are required for normal eye as well as brain development. However, the normal function of optix in Drosophila remains unknown due to lack of loss-of-function mutation. Previous studies suggest that optix is likely to play important role as part of the retinal determination (RD) network. To elucidate normal optix function during retinal development, multiple null alleles for optix have been generated. Loss-of-function mutations in optix result in lethality at the pupae stage. Surprisingly, close examination of its function during eye development reveals that, unlike other members of the RD network, optix is required only for morphogenetic furrow (MF) progression, but not initiation. The mechanisms by which optix regulates MF progression is likely through regulation of signaling molecules in the furrow. Specifically, although unaffected during MF initiation, expression of dpp in the MF is dramatically reduced in optix mutant clones. In parallel, we find that optix is regulated by sine oculis and eyes absent, key members of the RD network. Furthermore, positive feedback between optix and sine oculis and eyes absent is observed, which is likely mediated through dpp signaling pathway. Together with the observation that optix expression does not depend on hh or dpp, we propose that optix functions together with hh to regulate dpp in the MF, serving as a link between the RD network and the patterning pathways controlling normal retinal development. PMID:23792115

  4. Socioeconomic Status, Schooling, and the Developmental Trajectories of Adolescents

    ERIC Educational Resources Information Center

    Crosnoe, Robert; Huston, Aletha C.

    2007-01-01

    The socioeconomic stratification of American society profoundly influences how the life course unfolds by shaping various developmental pathways as well as the connections among these pathways. Drawing on a nationally representative sample of American adolescents, this study charted trajectories of personal control and parental consultation from…

  5. Uranium contaminated drinking water linked to leukaemia-Revisiting a case study from South Africa taking alternative exposure pathways into account.

    PubMed

    Winde, Frank; Erasmus, Ewald; Geipel, Gerhard

    2017-01-01

    The paper presents results of a follow-up to an earlier study which established a geospatial link between naturally elevated uranium (U) levels in borehole water and haematological abnormalities in local residents serving as a proxy for leukaemia prevalent in the area. While the original study focussed on drinking water only, this paper also explores alternative exposure pathways including the inhalation of dust and the food chain. U-levels in grass and tissue of sheep generally reflect U-levels in nearby borehole water and exceed background concentrations by 20 to nearly 500 times. U-levels in sheep tissue increase with age of the animal. Wool showed the highest U-concentration followed by other non-consumable tissue such as hooves, teeth and bones. Lower levels occur in edible parts such as meat and inner organs. The U-deposition rate in wool is several orders of magnitudes higher than in bone as a known target organ. Wool is an easy-to-sample non-invasive bioindicator for U-levels in meat. Depending on the original water content, dried samples show up to 5 times higher U-levels than identical fresh material. Contaminated drinking water is the main exposure pathway for farm residents resulting in U-uptake rates exceeding the WHO's tolerable daily intake (TDI) limit by up to 900%. This is somewhat mitigated by the fact that U-speciation is dominated by a neutral calcium-uranyl-carbonate complex of relatively low toxicity. Commercially available household filters are able to significantly reduce U-levels in well water and are thus recommended as a short-term intervention. Based on average consumption rates sheep meat, as local staple food, accounts for 34% of the TDI for U. Indoor levels of radon should be monitored, too, since it is linked to both, U and leukaemia. With elevated U-levels being present in other geological formations across South Africa boreholes in these areas should be surveyed. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. USP8 links the PTEN-Akt-AIP4 pathway to the control of FLIPS stability and TRAIL sensitivity in glioblastoma multiforme

    PubMed Central

    Panner, Amith; Crane, Courtney A.; Weng, Changjiang; Feletti, Alberto; Fang, Shanna; Parsa, Andrew T.; Pieper, Russell O.

    2010-01-01

    The anti-apoptotic protein FLIPS is a key suppressor of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis in human glioblastoma multiforme (GBM) cells. We previously reported that a novel phosphatase and tensin homolog (PTEN)-Akt-atrophin interacting protein 4 (AIP4) pathway regulates FLIPS ubiquitination and stability, although the means by which PTEN and Akt were linked to AIP4 activity were unclear. We here report that a second regulator of ubiquitin metabolism, the ubiquitin-specific protease (USP) 8, is a downstream target of Akt, and that USP8 links Akt to AIP4 and the regulation of FLIPS stability and TRAIL resistance. In human GBM xenografts, levels of USP8 correlated inversely with pAkt levels, and genetic or pharmacologic manipulation of Akt regulated USP8 levels in an inverse manner. Over-expression of WT USP8, but not catalytically inactive USP8, increased FLIPS ubiquitination, decreased FLIPS half-life, decreased FLIPS steady-state levels, and decreased TRAIL resistance, while siRNA-mediated suppression of USP8 levels had the opposite effects. Because high levels of the USP8 deubiquitinase correlated with high levels of FLIPS ubiquitination, USP8 appeared to control FLIPS ubiquitination through an intermediate target. Consistent with this idea, over-expression of WT USP8 decreased ubiquitination of the FLIPS E3 ubiquitin ligase AIP4, an event previously shown to increase AIP4-FLIPS interaction, while siRNA-mediated suppression of USP8 increased AIP4 ubiquitination. Furthermore, the suppression of FLIPS levels by USP8 over-expression was reversed by introduction of siRNA targeting AIP4. These results show that USP8, a downstream target of Akt, regulates the ability of AIP4 to control FLIPS stability and TRAIL sensitivity. PMID:20484045

  7. The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway.

    PubMed

    Pucilowska, Joanna; Vithayathil, Joseph; Tavares, Emmanuel J; Kelly, Caitlin; Karlo, J Colleen; Landreth, Gary E

    2015-02-18

    Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting ∼1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27(Kip1) during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion.

  8. Genetic ablation of N-linked glycosylation reveals two key folding pathways for R345W fibulin-3, a secreted protein associated with retinal degeneration

    PubMed Central

    Hulleman, John D.; Kelly, Jeffery W.

    2015-01-01

    An R345W mutation in the N-glycoprotein, fibulin-3 (F3), results in inefficient F3 folding/secretion and higher intracellular F3 levels. Inheritance of this mutation causes the retinal dystrophy malattia leventinese. N-Linked glycosylation is a common cotranslational protein modification that can regulate protein folding efficiency and energetics. Therefore, we explored how N-glycosylation alters the protein homeostasis or proteostasis of wild-type (WT) and R345W F3 in ARPE-19 cells. Enzymatic and lectin binding assays confirmed that WT and R345W F3 are both primarily N-glycosylated at Asn249. Tunicamycin treatment selectively reduced R345W F3 secretion by 87% (vs. WT F3). Genetic elimination of F3 N-glycosylation (via an N249Q mutation) caused R345W F3 to aggregate intracellularly and adopt an altered secreted conformation. The endoplasmic reticulum (ER) chaperones GRP78 (glucose-regulated protein 78) and GRP94 (glucose-regulated protein 94), and the ER lectins calnexin and calreticulin were identified as F3 binding partners by immunoprecipitation. Significantly more N249Q and N249Q/R345W F3 interacted with GRP94, while substantially less N249Q and N249Q/R345W interacted with the ER lectins than their N-glycosylated counterparts. Inhibition of GRP94 ATPase activity reduced only N249Q/R345W F3 secretion (by 62%), demonstrating this variant’s unique reliance on GRP94 for secretion. These observations suggest that R345W F3, but not WT F3, requires N-glycosylation to acquire a stable, native-like structure.—Hulleman, J. D., Kelly, J. W. Genetic ablation of N-linked glycosylation reveals two key folding pathways for R345W fibulin-3, a secreted protein associated with retinal degeneration. PMID:25389134

  9. Mac-1 directly binds to the endothelial protein C-receptor: a link between the protein C anticoagulant pathway and inflammation?

    PubMed

    Fink, Katrin; Busch, Hans-Jörg; Bourgeois, Natascha; Schwarz, Meike; Wolf, Dennis; Zirlik, Andreas; Peter, Karlheinz; Bode, Christoph; von Zur Muhlen, Constantin

    2013-01-01

    The endothelial protein C-receptor (EPCR) is an endothelial transmembrane protein that binds protein C and activated protein C (APC) with equal affinity, thereby facilitating APC formation. APC has anticoagulant, antiapoptotic and antiinflammatory properties. Soluble EPCR, released by the endothelium, may bind activated neutrophils, thereby modulating cell adhesion. EPCR is therefore considered as a possible link between the anticoagulant properties of protein C and the inflammatory response of neutrophils. In the present study, we aimed to provide proof of concept for a direct binding of EPCR to the β2-integrin Mac-1 on monocytic cells under static and physiological flow conditions. Under static conditions, human monocytes bind soluble EPCR in a concentration dependent manner, as demonstrated by flow cytometry. Binding can be inhibited by specific antibodies (anti-EPCR and anti-Mac-1). Specific binding was confirmed by a static adhesion assay, where a transfected Mac-1 expressing CHO cell line (Mac-1+ cells) bound significantly more recombinant EPCR compared to Mac-1+ cells blocked by anti-Mac-1-antibody and native CHO cells. Under physiological flow conditions, monocyte binding to the endothelium could be significantly blocked by both, anti-EPCR and anti-Mac-1 antibodies in a dynamic adhesion assay at physiological flow conditions. Pre-treatment of endothelial cells with APC (drotrecogin alfa) diminished monocyte adhesion significantly in a comparable extent to anti-EPCR. In the present study, we demonstrate a direct binding of Mac-1 on monocytes to the endothelial protein C receptor under static and flow conditions. This binding suggests a link between the protein C anticoagulant pathway and inflammation at the endothelium side, such as in acute vascular inflammation or septicaemia.

  10. Cross-linking of dicyclotyrosine by the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis proceeds through a catalytic shunt pathway.

    PubMed

    Dornevil, Kednerlin; Davis, Ian; Fielding, Andrew J; Terrell, James R; Ma, Li; Liu, Aimin

    2017-08-18

    CYP121, the cytochrome P450 enzyme in Mycobacterium tuberculosis that catalyzes a single intramolecular C-C cross-linking reaction in the biosynthesis of mycocyclosin, is crucial for the viability of this pathogen. This C-C coupling reaction represents an expansion of the activities carried out by P450 enzymes distinct from oxygen insertion. Although the traditional mechanism for P450 enzymes has been well studied, it is unclear whether CYP121 follows the general P450 mechanism or uses a different catalytic strategy for generating an iron-bound oxidant. To gain mechanistic insight into the CYP121-catalyzed reaction, we tested the peroxide shunt pathway by using rapid kinetic techniques to monitor the enzyme activity with its substrate dicyclotyrosine (cYY) and observed the formation of the cross-linked product mycocyclosin by LC-MS. In stopped-flow experiments, we observed that cYY binding to CYP121 proceeds in a two-step process, and EPR spectroscopy indicates that the binding induces active site reorganization and uniformity. Using rapid freeze-quenching EPR, we observed the formation of a high-spin intermediate upon the addition of peracetic acid to the enzyme-substrate complex. This intermediate exhibits a high-spin (S = 5/2) signal with g values of 2.00, 5.77, and 6.87. Likewise, iodosylbenzene could also produce mycocyclosin, implicating compound I as the initial oxidizing species. Moreover, we also demonstrated that CYP121 performs a standard peroxidase type of reaction by observing substrate-based radicals. On the basis of these results, we propose plausible free radical-based mechanisms for the C-C bond coupling reaction. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Substrate recognition and catalysis by GH47 α-mannosidases involved in Asn-linked glycan maturation in the mammalian secretory pathway

    PubMed Central

    Xiang, Yong; Karaveg, Khanita; Moremen, Kelley W.

    2016-01-01

    Maturation of Asn-linked oligosaccharides in the eukaryotic secretory pathway requires the trimming of nascent glycan chains to remove all glucose and several mannose residues before extension into complex-type structures on the cell surface and secreted glycoproteins. Multiple glycoside hydrolase family 47 (GH47) α-mannosidases, including endoplasmic reticulum (ER) α-mannosidase I (ERManI) and Golgi α-mannosidase IA (GMIA), are responsible for cleavage of terminal α1,2-linked mannose residues to produce uniquely trimmed oligomannose isomers that are necessary for ER glycoprotein quality control and glycan maturation. ERManI and GMIA have similar catalytic domain structures, but each enzyme cleaves distinct residues from tribranched oligomannose glycan substrates. The structural basis for branch-specific cleavage by ERManI and GMIA was explored by replacing an essential enzyme-bound Ca2+ ion with a lanthanum (La3+) ion. This ion swap led to enzyme inactivation while retaining high-affinity substrate interactions. Cocrystallization of La3+-bound enzymes with Man9GlcNAc2 substrate analogs revealed enzyme–substrate complexes with distinct modes of glycan branch insertion into the respective enzyme active-site clefts. Both enzymes had glycan interactions that extended across the entire glycan structure, but each enzyme engaged a different glycan branch and used different sets of glycan interactions. Additional mutagenesis and time-course studies of glycan cleavage probed the structural basis of enzyme specificity. The results provide insights into the enzyme catalytic mechanisms and reveal structural snapshots of the sequential glycan cleavage events. The data also indicate that full steric access to glycan substrates determines the efficiency of mannose-trimming reactions that control the conversion to complex-type structures in mammalian cells. PMID:27856750

  12. Pathways of Intergenerational Transmission of Advantages during Adolescence: Social Background, Cognitive Ability, and Educational Attainment.

    PubMed

    Schulz, Wiebke; Schunck, Reinhard; Diewald, Martin; Johnson, Wendy

    2017-07-25

    Educational attainment in adolescence is of paramount importance for attaining higher education and for shaping subsequent life chances. Sociological accounts focus on the role of differences in socioeconomic resources in intergenerational reproduction of educational inequalities. These often disregard the intergenerational transmission of cognitive ability and the importance of children's cognitive ability to educational attainment. Psychological perspectives stress the importance of cognitive ability for educational attainment but underemphasize potentially different roles of specific socioeconomic resources in shaping educational outcomes, as well as individual differences in cognitive ability. By integrating two strands of research, a clearer picture of the pathways linking the family of origin, cognitive ability, and early educational outcomes can be reached. Using the population-based TwinLife study in Germany, we investigated multidimensional pathways linking parental socioeconomic position to their children's cognitive ability and academic track attendance in the secondary school. The sample included twins (N = 4008), respectively ages 11 and 17, and siblings (N = 801). We observed strong genetic influences on cognitive ability, whereas shared environmental influences were much more important for academic tracking. In multilevel analyses, separate dimensions of socioeconomic resources influenced child cognitive ability, controlling parental cognitive ability. Controlling adolescent cognitive ability and parental cognitive ability, parental socioeconomic resources also directly affected track attendance. This indicated that it is crucial to investigate the intertwined influences on educational outcomes in adolescence of both cognitive ability and the characteristics of the family of origin.

  13. Investigation of the mechanism and apoptotic pathway induced by 4β cinnamido linked podophyllotoxins against human lung cancer cells A549.

    PubMed

    Kamal, Ahmed; Nayak, V Lakshma; Bagul, Chandrakant; Vishnuvardhan, M V P S; Mallareddy, Adla

    2015-11-01

    Apoptosis is essential for normal development and the maintenance of homeostasis. It plays a necessary role to protect against carcinogenesis by eliminating damaged cells. Many studies have demonstrated that the dysregulation of apoptosis results in cancer and this provides an approach to develop therapeutic agents via inducing apoptosis. In our previous studies 4β-cinnamido linked podophyllotoxin conjugates were synthesized and evaluated for their cytotoxic activity in a panel of five human cancer cell lines and the new molecules like 17a and 17f were considered as potential leads. The cytotoxic activity was comparable to etoposide. These observations prompted us to investigate the mechanism underplaying the cytotoxic activity and apoptotic pathway induced by these compounds in human lung cancer cells A459. The results of the present study revealed that these compounds exhibited DNA topoisomerase IIα inhibition and induced mitochondrial mediated apoptosis. It was further confirmed by Mitochondrial membrane potential, Cytochrome c release, cleavage of poly (ADP-ribose) polymerase (PARP), Reactive oxygen species (ROS) generation, regulation of antiapoptotic protein Bcl-2 and pro apoptotic protein Bax studied by Western blot analysis. Annexin V-FITC assay also suggested that these compounds induced cell death by apoptosis. Pretreatment with N-acetyl-L-cysteine (NAC) prevented the generation of ROS. Further, pretreatment with NAC significantly inhibited 17a and 17f induced apoptosis, suggesting that ROS are the key mediators for 17a and 17f induced apoptosis. These data indicate that these compounds might induce apoptosis in A549 cells through a ROS mediated mitochondrial dysfunction pathway. Moreover, these compounds did not significantly inhibit the noncancerous human embryonic kidney cells, HEK-293. Docking studies also elucidate the potential of these molecules to bind to the DNA topoisomerase II. Podophyllotoxin analogs were investigated for their mechanism and

  14. A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: In vitro and in vivo efficacy and molecular mechanisms

    SciTech Connect

    Derrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo; Oh, Shin Bi; Lee, Hyuck Jin; Earnest, Kaylin G.; Suh, Nayoung; Peck, Kristy L.; Ozbil, Mehmet; Korshavn, Kyle J.; Ramamoorthy, Ayyalusamy; Prabhakar, Rajeev; Merino, Edward J.; Shearer, Jason; Lee, Joo -Yong; Ruotolo, Brandon T.; Lim, Mi Hee

    2015-11-17

    Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. In this paper, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand–peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Altogether our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

  15. Cross-linking of CD32 induces maturation of human monocyte-derived dendritic cells via NF-kappa B signaling pathway.

    PubMed

    Bánki, Zoltán; Kacani, Laco; Müllauer, Brigitte; Wilflingseder, Doris; Obermoser, Gerlinde; Niederegger, Harald; Schennach, Harald; Sprinzl, Georg M; Sepp, Norbert; Erdei, Anna; Dierich, Manfred P; Stoiber, Heribert

    2003-04-15

    Dendritic cells (DC) represent a unique set of APCs that initiate immune responses through priming of naive T cells. Maturation of DC is a crucial step during Ag presentation and can be induced by triggering a broad spectrum of DC surface receptors. Although human DC express several receptors for the Fc portion of IgG which were described to play an important role in Ag internalization, little is known about the effects of IgG or immune complexes on DC maturation. In this study, we show that cross-linking of FcgammaR-type II (CD32) with immobilized IgG (imIgG) can induce maturation of human monocyte-derived DC via the NF-kappaB signaling pathway. IgG-mediated maturation was accompanied by a moderate increase of IL-10 secretion, whereas no IL-12 production was observed. Involvement of CD32 was further supported by experiments with the anti-CD32 mAb, which blocked IgG-triggered DC maturation and cytokine secretion significantly. Furthermore, DC cultivated in the presence of imIgG induced allogeneic T cell proliferation. Because this imIgG-induced maturation was considerably impaired in monocyte-derived DC from systemic lupus erythematosus patients, we suggest that DC, which matured in the presence of immune complexes, may contribute to prevention of pathological immune responses.

  16. The c-Myc Target Glycoprotein1bα Links Cytokinesis Failure to Oncogenic Signal Transduction Pathways in Cultured Human Cells

    PubMed Central

    Li, Youjun; Prochownik, Edward V.; Saunders, William S.

    2010-01-01

    An increase in chromosome number, or polyploidization, is associated with a variety of biological changes including breeding of cereal crops and flowers, terminal differentiation of specialized cells such as megakaryocytes, cellular stress and oncogenic transformation. Yet it remains unclear how cells tolerate the major changes in gene expression, chromatin organization and chromosome segregation that invariably accompany polyploidization. We show here that cancer cells can initiate increases in chromosome number by inhibiting cell division through activation of glycoprotein1b alpha (GpIbα), a component of the c-Myc signaling pathway. We are able to recapitulate cytokinesis failure in primary cells by overexpression of GpIbα in a p53-deficient background. GpIbα was found to localize to the cleavage furrow by microscopy analysis and, when overexpressed, to interfere with assembly of the cellular cortical contraction apparatus and normal division. These results indicate that cytokinesis failure and tetraploidy in cancer cells are directly linked to cellular hyperproliferation via c-Myc induced overexpression of GpIbα. PMID:20520840

  17. A Redox-Active, Compact Molecule for Cross-Linking Amyloidogenic Peptides into Nontoxic, Off-Pathway Aggregates: In Vitro and In Vivo Efficacy and Molecular Mechanisms

    SciTech Connect

    Derrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo; Oh, Shin Bi; Lee, Hyuck Jin; Earnest, Kaylin G.; Suh, Nayoung; Peck, Kristy L.; Ozbil, Mehmet; Korshavn, Kyle J.; Ramamoorthy, Ayyalusamy; Prabhakar, Rajeev; Merino, Edward J.; Shearer, Jason; Lee, Joo-Yong; Ruotolo, Brandon T.; Lim, Mi Hee

    2015-11-25

    Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. Herein, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand–peptide adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Overall, our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.

  18. A redox-active, compact molecule for cross-linking amyloidogenic peptides into nontoxic, off-pathway aggregates: In vitro and in vivo efficacy and molecular mechanisms

    DOE PAGES

    Derrick, Jeffrey S.; Kerr, Richard A.; Nam, Younwoo; ...

    2015-11-17

    Chemical reagents targeting and controlling amyloidogenic peptides have received much attention for helping identify their roles in the pathogenesis of protein-misfolding disorders. In this paper, we report a novel strategy for redirecting amyloidogenic peptides into nontoxic, off-pathway aggregates, which utilizes redox properties of a small molecule (DMPD, N,N-dimethyl-p-phenylenediamine) to trigger covalent adduct formation with the peptide. In addition, for the first time, biochemical, biophysical, and molecular dynamics simulation studies have been performed to demonstrate a mechanistic understanding for such an interaction between a small molecule (DMPD) and amyloid-β (Aβ) and its subsequent anti-amyloidogenic activity, which, upon its transformation, generates ligand–peptidemore » adducts via primary amine-dependent intramolecular cross-linking correlated with structural compaction. Furthermore, in vivo efficacy of DMPD toward amyloid pathology and cognitive impairment was evaluated employing 5xFAD mice of Alzheimer’s disease (AD). Such a small molecule (DMPD) is indicated to noticeably reduce the overall cerebral amyloid load of soluble Aβ forms and amyloid deposits as well as significantly improve cognitive defects in the AD mouse model. Altogether our in vitro and in vivo studies of DMPD toward Aβ with the first molecular-level mechanistic investigations present the feasibility of developing new, innovative approaches that employ redox-active compounds without the structural complexity as next-generation chemical tools for amyloid management.« less

  19. Evidence of molecular links between PKR and mTOR signalling pathways in Abeta neurotoxicity: role of p53, Redd1 and TSC2.

    PubMed

    Morel, Milena; Couturier, Julien; Pontcharraud, Raymond; Gil, Roger; Fauconneau, Bernard; Paccalin, Marc; Page, Guylène

    2009-10-01

    The control of translation is disturbed in Alzheimer's disease (AD). This study analysed the crosslink between the up regulation of double-stranded RNA-dependent-protein kinase (PKR) and the down regulation of mammalian target of rapamycin (mTOR) signalling pathways via p53, the protein Regulated in the Development and DNA damage response 1 (Redd1) and the tuberous sclerosis complex (TSC2) factors in two beta-amyloid peptide (Abeta) neurotoxicity models. In SH-SY5Y cells, Abeta42 induced an increase of P(T451)-PKR and of the ratio p66/(p66+p53) in nuclei and a physical interaction between these proteins. Redd1 gene levels increased and P(T1462)-TSC2 decreased. These disturbances were earlier in rat primary neurons with nuclear co-localization of Redd1 and PKR. The PKR gene silencing in SH-SY5Y cells prevented these alterations. p53, Redd1 and TSC2 could represent the molecular links between PKR and mTOR in Abeta neurotoxicity. PKR could be a critical target in a therapeutic program of AD.

  20. Different exercise modalities have distinct effects on the integrin-linked kinase (ILK) and Ca2+ signaling pathways in the male rat bone

    PubMed Central

    Sontam, Dharani M; Firth, Elwyn C; Tsai, Peter; Vickers, Mark H; O’Sullivan, Justin M

    2015-01-01

    Mechanical loading is essential to maintain optimal skeletal health. Despite the fact that early-life exercise has positive, long-lasting effects on the musculo-skeletal system, the response of the musculo-skeletal system to spontaneous low-impact exercise has been poorly studied. Previously, we identified subtle morphological changes in the femoral diaphysis of exercised animals compared to nonexercised controls. We hypothesized that significant changes in gene expression of cells should precede significant measurable phenotypic changes in the tissues of which they are part. Here, we employed RNA-Seq to analyse the transcriptome of the cortical bone from the femoral mid-diaphysis of prepubertal male Sprague-Dawley rats that were assigned to control (CON); bipedal stance (BPS); or wheel exercise (WEX) groups for 15 days. We identified 808 and 324 differentially expressed transcripts in the BPS and WEX animals respectively. While a number of transcripts change their levels in an exercise-specific manner, we identified 191 transcripts that were differentially expressed in both BPS and WEX. Importantly, we observed that the exercise mode had diametrically opposite effects on transcripts for multiple genes within the integrin-linked kinase (ILK) and Ca2+ signaling pathways such that they were up-regulated in BPS and down-regulated in WEX. The findings are important for our understanding of possible ways in which different exercise regimens might affect bone when normal activities apply mechanical stimuli during postnatal growth and development. PMID:26471755

  1. C. elegans SIR-2.1 translocation is linked to a proapoptotic pathway parallel to cep-1/p53 during DNA damage-induced apoptosis

    PubMed Central

    Greiss, Sebastian; Hall, Julie; Ahmed, Shawn; Gartner, Anton

    2008-01-01

    Caenorhabditis elegans SIR-2.1, a member of the sirtuin family related to Saccharomyces cerevisiae Sir2p, has previously been implicated in aging. The mammalian homolog SIRT1 plays important roles in multiple cellular processes including transcriptional repression and stress response. We show that sir-2.1 is essential for the execution of apoptosis in response to DNA damage, and that sir-2.1 genetically acts in parallel to the worm p53-like gene cep-1. This novel cep-1-independent proapoptotic pathway does not require the daf-16 FOXO transcription factor. Cytological analysis of SIR-2.1 suggests a novel mechanism of apoptosis induction. During apoptosis SIR-2.1 changes its subcellular localization from the nucleus to the cytoplasm and transiently colocalizes with the C. elegans Apaf-1 homolog CED-4 at the nuclear periphery. SIR-2.1 translocation is an early event in germ cell apoptosis and is independent of apoptosis execution and cep-1, raising the possibility that SIR-2.1 translocation is linked to the induction of DNA damage-induced apoptosis. PMID:18923081

  2. Is the link between movement and mental health a two-way street? Prospective associations between physical activity, sedentary behaviour and depressive symptoms among women living in socioeconomically disadvantaged neighbourhoods.

    PubMed

    Teychenne, Megan; Abbott, Gavin; Lamb, Karen E; Rosenbaum, Simon; Ball, Kylie

    2017-09-01

    This study aimed to investigate the bi-directional relationship between different domains of physical activity (PA), sedentary behaviour (SB) and depressive symptoms among women living in socioeconomically disadvantaged neighbourhoods in Victoria, Australia. Women (n=1033), aged 18-46years at Wave 1 (2007/08), completed self-report measures of PA (leisure-time, transport, occupational, domestic), SB (TV viewing, computer use, overall sitting time) and depressive symptoms (CES-D 10) at each study time-point (Wave 2: 2010/11, Wave 3: 2012/13). Separate linear mixed models were fitted to examine if change in depressive symptoms differed dependent on each of the baseline PA or SB measures. Similarly, baseline depressive symptoms were used as a predictor of change in PA and SB. In secondary analyses, associations between baseline PA or SB and odds of becoming 'at risk' of depression among those not 'at risk' at baseline were examined using logistic regression. There was no evidence that change in depressive symptoms differed depending on PA or SB at baseline. In general, there was also no evidence that change in PA or SB differed depending on baseline depressive symptoms. One exception was change in leisure-time PA, which declined more among those with heightened depressive symptoms at baseline (Interaction: β=-0.003, 95% CI=-0.007, -0.0003). Transport-related PA (adjusted OR=1.06, 95% CI=1.013, 1.101) and domestic PA (adjusted OR=1.02, 95% CI=1.003, 1.040) were associated with greater odds of becoming at risk of depression at wave 3. There was limited evidence of a bi-directional relationship between PA, SB and depressive symptoms in women living in socioeconomically disadvantaged neighbourhoods. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Rethinking the relationship between socio-economic status and health: Making the case for sociological theory in health inequality research.

    PubMed

    Øversveen, Emil; Rydland, Håvard T; Bambra, Clare; Eikemo, Terje A

    2017-03-01

    The aim of this study is to analyse previous explanations of social inequality in health and argue for a closer integration of sociological theory into future empirical research. We examine cultural-behavioural, materialist, psychosocial and life-course approaches, in addition to fundamental cause theory. Giddens' structuration theory and a neo-materialist approach, inspired by Bruno Latour, Gilles Deleuze and Felix Guattari, are proposed as ways of rethinking the causal relationship between socio-economic status and health. Much of the empirical research on health inequalities has tended to rely on explanations with a static and unidirectional view of the association between socio-economic status and health, assuming a unidirectional causal relationship between largely static categories. We argue for the use of sociological theory to develop more dynamic models that enhance the understanding of the complex pathways and mechanisms linking social structures to health.

  4. Evolution of MIR159/319 microRNA genes and their post-transcriptional regulatory link to siRNA pathways

    PubMed Central

    2011-01-01

    -transcriptional level to express multiple mature products with variable proportions under different circumstances. Moreover, our analyses reveal conserved regulatory link of MIR159/319 genes to siRNA pathway through post-transcriptional regulation. PMID:21569383

  5. Evolution of MIR159/319 microRNA genes and their post-transcriptional regulatory link to siRNA pathways.

    PubMed

    Li, Yang; Li, Chaoqun; Ding, Guohui; Jin, Youxin

    2011-05-12

    multiple mature products with variable proportions under different circumstances. Moreover, our analyses reveal conserved regulatory link of MIR159/319 genes to siRNA pathway through post-transcriptional regulation.

  6. Amyotrophic lateral sclerosis-linked mutant VAPB inclusions do not interfere with protein degradation pathways or intracellular transport in a cultured cell model.

    PubMed

    Genevini, Paola; Papiani, Giulia; Ruggiano, Annamaria; Cantoni, Lavinia; Navone, Francesca; Borgese, Nica

    2014-01-01

    VAPB is a ubiquitously expressed, ER-resident adaptor protein involved in interorganellar lipid exchange, membrane contact site formation, and membrane trafficking. Its mutant form, P56S-VAPB, which has been linked to a dominantly inherited form of Amyotrophic Lateral Sclerosis (ALS8), generates intracellular inclusions consisting in restructured ER domains whose role in ALS pathogenesis has not been elucidated. P56S-VAPB is less stable than the wild-type protein and, at variance with most pathological aggregates, its inclusions are cleared by the proteasome. Based on studies with cultured cells overexpressing the mutant protein, it has been suggested that VAPB inclusions may exert a pathogenic effect either by sequestering the wild-type protein and other interactors (loss-of-function by a dominant negative effect) or by a more general proteotoxic action (gain-of-function). To investigate P56S-VAPB degradation and the effect of the inclusions on proteostasis and on ER-to-plasma membrane protein transport in a more physiological setting, we used stable HeLa and NSC34 Tet-Off cell lines inducibly expressing moderate levels of P56S-VAPB. Under basal conditions, P56S-VAPB degradation was mediated exclusively by the proteasome in both cell lines, however, it could be targeted also by starvation-stimulated autophagy. To assess possible proteasome impairment, the HeLa cell line was transiently transfected with the ERAD (ER Associated Degradation) substrate CD3δ, while autophagic flow was investigated in cells either starved or treated with an autophagy-stimulating drug. Secretory pathway functionality was evaluated by analyzing the transport of transfected Vesicular Stomatitis Virus Glycoprotein (VSVG). P56S-VAPB expression had no effect either on the degradation of CD3δ or on the levels of autophagic markers, or on the rate of transport of VSVG to the cell surface. We conclude that P56S-VAPB inclusions expressed at moderate levels do not interfere with protein

  7. Caffeine, cognition, and socioeconomic status.

    PubMed

    Kyle, Janet; Fox, Helen C; Whalley, Lawrence J

    2010-01-01

    There is interest in age-related cognitive decline and environmental risk factors for Alzheimer's disease (AD). This interest is focused on individual differences in exposure to agents that may harm or protect cognitive function. Caffeine is used as a short acting mental stimulant and may possess longer-term properties that protect against age-related decline and, possibly, AD. The current study aimed to: 1) examine current cognitive function in a narrow age range sample (n=351) without dementia (MMSE>25) who are, by reason of age, entering the period of increased risk of AD; and 2) link cognitive function to self-reported intake of caffeine and socioeconomic status (SES). Possible confounding by gender, childhood intelligence, education, and symptoms of anxiety and depression was introduced into the statistical model. There were significant differences between SES groups in caffeine intake (p< 0.05) and cognitive performance (p< 0.001). Higher quartiles of caffeine intake were associated with slower digit symbol speed (F =3.38, p< 0.02) but this finding was removed after allowing for SES. The results are discussed in terms of the withdrawal effects of caffeine during cognitive testing and strong links between SES and cognitive performance. No evidence in support of cognitive enhancing effects of caffeine was found.

  8. GIPC and GAIP form a complex with TrkA: a putative link between G protein and receptor tyrosine kinase pathways.

    PubMed

    Lou, X; Yano, H; Lee, F; Chao, M V; Farquhar, M G

    2001-03-01

    NGF initiates the majority of its neurotrophic effects by promoting the activation of the tyrosine kinase receptor TrkA. Here we describe a novel interaction between TrkA and GIPC, a PDZ domain protein. GIPC binds to the juxtamembrane region of TrkA through its PDZ domain. The PDZ domain of GIPC also interacts with GAIP, an RGS (regulators of G protein signaling) protein. GIPC and GAIP are components of a G protein-coupled signaling complex thought to be involved in vesicular trafficking. In transfected HEK 293T cells GIPC, GAIP, and TrkA form a coprecipitable protein complex. Both TrkA and GAIP bind to the PDZ domain of GIPC, but their binding sites within the PDZ domain are different. The association of endogenous GIPC with the TrkA receptor was confirmed by coimmunoprecipitation in PC12 (615) cells stably expressing TrkA. By immunofluorescence GIPC colocalizes with phosphorylated TrkA receptors in retrograde transport vesicles located in the neurites and cell bodies of differentiated PC12 (615) cells. These results suggest that GIPC, like other PDZ domain proteins, serves to cluster transmembrane receptors with signaling molecules. When GIPC is overexpressed in PC12 (615) cells, NGF-induced phosphorylation of mitogen-activated protein (MAP) kinase (Erk1/2) decreases; however, there is no effect on phosphorylation of Akt, phospholipase C-gamma1, or Shc. The association of TrkA receptors with GIPC and GAIP plus the inhibition of MAP kinase by GIPC suggests that GIPC may provide a link between TrkA and G protein signaling pathways.

  9. GIPC and GAIP Form a Complex with TrkA: A Putative Link between G Protein and Receptor Tyrosine Kinase Pathways

    PubMed Central

    Lou, Xiaojing; Yano, Hiroko; Lee, Francis; Chao, Moses V.; Farquhar, Marilyn Gist

    2001-01-01

    NGF initiates the majority of its neurotrophic effects by promoting the activation of the tyrosine kinase receptor TrkA. Here we describe a novel interaction between TrkA and GIPC, a PDZ domain protein. GIPC binds to the juxtamembrane region of TrkA through its PDZ domain. The PDZ domain of GIPC also interacts with GAIP, an RGS (regulators of G protein signaling) protein. GIPC and GAIP are components of a G protein-coupled signaling complex thought to be involved in vesicular trafficking. In transfected HEK 293T cells GIPC, GAIP, and TrkA form a coprecipitable protein complex. Both TrkA and GAIP bind to the PDZ domain of GIPC, but their binding sites within the PDZ domain are different. The association of endogenous GIPC with the TrkA receptor was confirmed by coimmunoprecipitation in PC12 (615) cells stably expressing TrkA. By immunofluorescence GIPC colocalizes with phosphorylated TrkA receptors in retrograde transport vesicles located in the neurites and cell bodies of differentiated PC12 (615) cells. These results suggest that GIPC, like other PDZ domain proteins, serves to cluster transmembrane receptors with signaling molecules. When GIPC is overexpressed in PC12 (615) cells, NGF-induced phosphorylation of mitogen-activated protein (MAP) kinase (Erk1/2) decreases; however, there is no effect on phosphorylation of Akt, phospholipase C-γ1, or Shc. The association of TrkA receptors with GIPC and GAIP plus the inhibition of MAP kinase by GIPC suggests that GIPC may provide a link between TrkA and G protein signaling pathways. PMID:11251075

  10. Thiocolchicoside Exhibits Anticancer Effects through Downregulation of NF-κB Pathway and Its Regulated Gene Products Linked to Inflammation and Cancer

    PubMed Central

    Reuter, Simone; Prasad, Sahdeo; Phromnoi, Kanokkarn; Ravindran, Jayaraj; Sung, Bokyung; Yadav, Vivek R.; Kannappan, Ramaswamy; Chaturvedi, Madan M.; Aggarwal, Bharat B.

    2011-01-01

    The discovery of new uses for older, clinically approved drugs is one way to expedite drug development for cancer. Thiocolchicoside, a semisynthetic colchicoside from the plant Gloriosa superba, is a muscle relaxant and used to treat rheumatologic and orthopedic disorders because of its analgesic and anti-inflammatory mechanisms. Given that activation of the transcription factor NF-κB plays a major role in inflammation and tumorigenesis, we postulated that thiocolchicoside would inhibit NF-κB and exhibit anticancer effects through the modulation of NF-κB–regulated proteins. We show that thiocolchicoside inhibited proliferation of leukemia, myeloma, squamous cell carcinoma, breast, colon, and kidney cancer cells. Formation of tumor colonies was also suppressed by thiocolchicoside. The colchicoside induced apoptosis, as indicated by caspase-3 and poly(ADP-ribose) polymerase cleavage, and suppressed the expression of cell survival [e.g., Bcl-2, X-linked inhibitor of apoptosis (XIAP), MCL-1, bcl-xL, cIAP-1, cIAP-2, and cFLIP] proteins. Cell proliferation biomarkers such as c-MYC and phosphorylation of phosphoinositide 3-kinase and glycogen synthase kinase 3β were also blocked by thiocolchicoside. Because most cell survival and proliferation gene products are regulated by NF-κB, we studied the effect of thiocolchicoside on this transcription factor and found that thiocolchicoside inhibited NF-κB activation, degradation of inhibitory κBα (IκBα), IκBα ubiquitination, and phosphorylation, abolished the activation of IκBα kinase, and suppressed p65 nuclear translocation. This effect of thiocolchicoside on the NF-κB pathway led to inhibition of NF-κB reporter activity and cyclooxygenase-2 promoter activity. Our results indicate that thiocolchicoside exhibits anticancer activity through inhibition of NF-κB and NF-κB–regulated gene products, which provides novel insight into a half-century old drug. PMID:20978115

  11. Thiocolchicoside exhibits anticancer effects through downregulation of NF-κB pathway and its regulated gene products linked to inflammation and cancer.

    PubMed

    Reuter, Simone; Prasad, Sahdeo; Phromnoi, Kanokkarn; Ravindran, Jayaraj; Sung, Bokyung; Yadav, Vivek R; Kannappan, Ramaswamy; Chaturvedi, Madan M; Aggarwal, Bharat B

    2010-11-01

    The discovery of new uses for older, clinically approved drugs is one way to expedite drug development for cancer. Thiocolchicoside, a semisynthetic colchicoside from the plant Gloriosa superba, is a muscle relaxant and used to treat rheumatologic and orthopedic disorders because of its analgesic and anti-inflammatory mechanisms. Given that activation of the transcription factor NF-κB plays a major role in inflammation and tumorigenesis, we postulated that thiocolchicoside would inhibit NF-κB and exhibit anticancer effects through the modulation of NF-κB-regulated proteins. We show that thiocolchicoside inhibited proliferation of leukemia, myeloma, squamous cell carcinoma, breast, colon, and kidney cancer cells. Formation of tumor colonies was also suppressed by thiocolchicoside. The colchicoside induced apoptosis, as indicated by caspase-3 and poly(ADP-ribose) polymerase cleavage, and suppressed the expression of cell survival [e.g., Bcl-2, X-linked inhibitor of apoptosis (XIAP), MCL-1, bcl-xL, cIAP-1, cIAP-2, and cFLIP] proteins. Cell proliferation biomarkers such as c-MYC and phosphorylation of phosphoinositide 3-kinase and glycogen synthase kinase 3β were also blocked by thiocolchicoside. Because most cell survival and proliferation gene products are regulated by NF-κB, we studied the effect of thiocolchicoside on this transcription factor and found that thiocolchicoside inhibited NF-κB activation, degradation of inhibitory κBα (IκBα), IκBα ubiquitination, and phosphorylation, abolished the activation of IκBα kinase, and suppressed p65 nuclear translocation. This effect of thiocolchicoside on the NF-κB pathway led to inhibition of NF-κB reporter activity and cyclooxygenase-2 promoter activity. Our results indicate that thiocolchicoside exhibits anticancer activity through inhibition of NF-κB and NF-κB-regulated gene products, which provides novel insight into a half-century old drug.

  12. Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression.

    PubMed

    Saeed, Muhammad Tariq; Ahmad, Jamil; Kanwal, Shahzina; Holowatyj, Andreana N; Sheikh, Iftikhar A; Zafar Paracha, Rehan; Shafi, Aamir; Siddiqa, Amnah; Bibi, Zurah; Khan, Mukaram; Ali, Amjad

    2016-01-01

    The alteration of glucose metabolism, through increased uptake of glucose and glutamine addiction, is essential to cancer cell growth and invasion. Increased flux of glucose through the Hexosamine Biosynthetic Pathway (HBP) drives increased cellular O-GlcNAcylation (hyper-O-GlcNAcylation) and contributes to cancer progression by regulating key oncogenes. However, the association between hyper-O-GlcNAcylation and activation of these oncogenes remains poorly characterized. Here, we implement a qualitative modeling framework to analyze the role of the Biological Regulatory Network in HBP activation and its potential effects on key oncogenes. Experimental observations are encoded in a temporal language format and model checking is applied to infer the model parameters and qualitative model construction. Using this model, we discover step-wise genetic alterations that promote cancer development and invasion due to an increase in glycolytic flux, and reveal critical trajectories involved in cancer progression. We compute delay constraints to reveal important associations between the production and degradation rates of proteins. O-linked N-acetylglucosamine transferase (OGT), an enzyme used for addition of O-GlcNAc during O-GlcNAcylation, is identified as a key regulator to promote oncogenesis in a feedback mechanism through the stabilization of c-Myc. Silencing of the OGT and c-Myc loop decreases glycolytic flux and leads to programmed cell death. Results of network analyses also identify a significant cycle that highlights the role of p53-Mdm2 circuit oscillations in cancer recovery and homeostasis. Together, our findings suggest that the OGT and c-Myc feedback loop is critical in tumor progression, and targeting these mediators may provide a mechanism-based therapeutic approach to regulate hyper-O-GlcNAcylation in human cancer.

  13. Formal modeling and analysis of the hexosamine biosynthetic pathway: role of O-linked N-acetylglucosamine transferase in oncogenesis and cancer progression

    PubMed Central

    Saeed, Muhammad Tariq; Holowatyj, Andreana N.; Sheikh, Iftikhar A.; Zafar Paracha, Rehan; Shafi, Aamir; Siddiqa, Amnah; Bibi, Zurah; Khan, Mukaram

    2016-01-01

    The alteration of glucose metabolism, through increased uptake of glucose and glutamine addiction, is essential to cancer cell growth and invasion. Increased flux of glucose through the Hexosamine Biosynthetic Pathway (HBP) drives increased cellular O-GlcNAcylation (hyper-O-GlcNAcylation) and contributes to cancer progression by regulating key oncogenes. However, the association between hyper-O-GlcNAcylation and activation of these oncogenes remains poorly characterized. Here, we implement a qualitative modeling framework to analyze the role of the Biological Regulatory Network in HBP activation and its potential effects on key oncogenes. Experimental observations are encoded in a temporal language format and model checking is applied to infer the model parameters and qualitative model construction. Using this model, we discover step-wise genetic alterations that promote cancer development and invasion due to an increase in glycolytic flux, and reveal critical trajectories involved in cancer progression. We compute delay constraints to reveal important associations between the production and degradation rates of proteins. O-linked N-acetylglucosamine transferase (OGT), an enzyme used for addition of O-GlcNAc during O-GlcNAcylation, is identified as a key regulator to promote oncogenesis in a feedback mechanism through the stabilization of c-Myc. Silencing of the OGT and c-Myc loop decreases glycolytic flux and leads to programmed cell death. Results of network analyses also identify a significant cycle that highlights the role of p53-Mdm2 circuit oscillations in cancer recovery and homeostasis. Together, our findings suggest that the OGT and c-Myc feedback loop is critical in tumor progression, and targeting these mediators may provide a mechanism-based therapeutic approach to regulate hyper-O-GlcNAcylation in human cancer. PMID:27703839

  14. Fiber tractography of the axonal pathways linking the basal ganglia and cerebellum in Parkinson disease: implications for targeting in deep brain stimulation

    PubMed Central

    Sweet, Jennifer A.; Walter, Benjamin L.; Gunalan, Kabilar; Chaturvedi, Ashutosh; Mcintyre, Cameron C.; Miller, Jonathan P.

    2015-01-01

    Object Stimulation of white matter pathways near targeted structures may contribute to therapeutic effects of deep brain stimulation (DBS) for patients with Parkinson disease (PD). Two tracts linking the basal ganglia and cerebellum have been described in primates: the subthalamopontocerebellar tract (SPCT) and the dentatothalamic tract (DTT). The authors used fiber tractography to evaluate white matter tracts that connect the cerebellum to the region of the basal ganglia in patients with PD who were candidates for DBS. Methods Fourteen patients with advanced PD underwent 3-T MRI, including 30-directional diffusion-weighted imaging sequences. Diffusion tensor tractography was performed using 2 regions of interest: ipsilateral subthalamic and red nuclei, and contralateral cerebellar hemisphere. Nine patients underwent subthalamic DBS, and the course of each tract was observed relative to the location of the most effective stimulation contact and the volume of tissue activated. Results In all patients 2 distinct tracts were identified that corresponded closely to the described anatomical features of the SPCT and DTT, respectively. The mean overall distance from the active contact to the DTT was 2.18 ± 0.35 mm, and the mean proportional distance relative to the volume of tissue activated was 1.35 ± 0.48. There was a nonsignificant trend toward better postoperative tremor control in patients with electrodes closer to the DTT. Conclusions The SPCT and the DTT may be related to the expression of symptoms in PD, and this may have implications for DBS targeting. The use of tractography to identify the DTT might assist with DBS targeting in the future. PMID:24484226

  15. Vulnerability to depression: a moderated mediation model of the roles of child maltreatment, peer victimization, and serotonin transporter linked polymorphic region genetic variation among children from low socioeconomic status backgrounds.

    PubMed

    Banny, Adrienne M; Cicchetti, Dante; Rogosch, Fred A; Oshri, Assaf; Crick, Nicki R

    2013-08-01

    Child maltreatment, peer victimization, and a polymorphism of the serotonin transporter gene (5-HTTLPR) were examined as predictors of depressive symptomatology. Children (M age = 11.26, SD = 1.65), including 156 maltreated and 145 nonmaltreated children from comparable low socioeconomic backgrounds, provided DNA samples and self-reports of relational peer victimization, overt peer victimization, and depressive symptoms. Path analysis showed that relational and overt victimization mediated the association between child maltreatment and depressive symptoms. Bootstrapping procedures were used to test moderated mediation and demonstrated that genotype moderated the indirect effects of relational and overt victimization on child depressive symptoms, such that victimized children with the long/long variation were at an increased risk for depressive symptoms compared to victimized children carrying a short allele. Results highlight the utility of examining process models that incorporate biological and psychological factors contributing to the development of depressive symptomatology and provide direction toward understanding and promoting resilience among high-risk youth from a multiple levels of analysis approach.

  16. Ether Link Cleavage Is the Major Pathway of Iodothyronine Metabolism in the Phagocytosing Human Leukocyte and also Occurs In Vivo in the Rat

    PubMed Central

    Burger, Albert G.; Engler, Dennis; Buergi, Ulrich; Weissel, Michael; Steiger, Gertraud; Ingbar, Sidney H.; Rosin, Richard E.; Babior, Bernard M.

    1983-01-01

    These studies were performed to test the hypothesis that ether link cleavage (ELC) is an important pathway for the metabolism of thyroxine (T4) in the phagocytosing human leukocyte. When tyrosyl ring-labeled [125I]T4([Tyr125I]T4) was incubated with phagocytosing leukocytes, 50% of the degraded label was converted into [125I]3,5-diiodotyrosine ([125I]DIT). Of the remaining [Tyr125I]T4 that was degraded, two-thirds was recovered as [125I]-nonextractable iodine ([125I]NEI), and one-third as [125I]iodide. The production of [125I]DIT was not observed when phenolic ring-labeled [125I]T4 ([Phen125I]T4) was used, although [125I]NEI and [125I]iodide were produced. None of these iodinated compounds were formed in leukocytes that were not carrying out phagocytosis. The fraction of T4 degraded by ELC was decreased by the addition of unlabeled T4 and by preheating the leukocytes, findings which suggested that the process was enzymic in nature. ELC was enhanced by the catalase inhibitor aminotriazole, and was inhibited by the peroxidase inhibitor propylthiouracil, suggesting that the enzyme is a peroxidase and that hydrogen peroxide (H2O2) is a necessary cofactor in the reaction. To test this hypothesis, studies were performed in several inherited leukocytic disorders. ELC was not observed in the leukocytes of patients with chronic granulomatous disease, in which the respiratory burst that accompanies phagocytosis is absent. ELC was normal in the leukocytes of two subjects homozygous for Swiss-type acatalasemia, and aminotriazole enhanced ELC in these cells to an extent not significantly different from that observed in normal cells. ELC was normal in the leukocytes of a patient with myeloperoxidase deficiency, but could be induced by the incubation of [Tyr125I]T4 with H2O2 and horseradish peroxidase in the absence of leukocytes. The in vivo occurrence of ELC in the rat was confirmed by demonstrating the appearance of [125I]DIT in serum from parenterally injected [125I]3

  17. A three-tiered approach for linking pharmacokinetic considerations to the adverse outcome pathway framework for chemical-specific risk assessment

    EPA Science Inventory

    The power of the adverse outcome pathway (AOP) framework arises from its utilization of pathway-based data to describe the initial interaction of a chemical with a molecular target (molecular initiating event; (MIE), followed by a progression through a series of key events that l...

  18. A three-tiered approach for linking pharmacokinetic considerations to the adverse outcome pathway framework for chemical-specific risk assessment

    EPA Science Inventory

    The po