Pregnancy Intentions and Teenage Pregnancy Among Latinas: A Mediation Analysis

PubMed Central

Rocca, Corinne H.; Doherty, Irene; Padian, Nancy S.; Hubbard, Alan E.; Minnis, Alexandra M.

2010-01-01

CONTEXT The extent to which pregnancy intentions mediate the relationship between individual, familial and cultural characteristics and adolescent pregnancy is not well understood. The role of intentions may be particularly important among Latina teenagers, whose attitudes toward pregnancy are more favorable than those of other groups and whose pregnancy rates are high. METHODS Prospective, time-varying data from 2001–2004 were used to investigate whether two measures of pregnancy intentions, wantedness and happiness, mediated associations between risk factors and pregnancy among 213 Latina adolescents in San Francisco. Participants were tested for pregnancy and interviewed about pregnancy intentions, partnerships, family characteristics and activities every six months for two years. Associations and mediation were examined using logistic regression. RESULTS Neither pregnancy intention variable mediated relationships between participant characteristics and pregnancy. After adjustment for other measures, wantedness was strongly associated with pregnancy (odds ratio, 2.6), while happiness was not. Having a strong family orientation was associated with happiness (3.7) but unrelated to pregnancy. Low sexual relationship power with a main partner was associated with an elevated risk of pregnancy (3.3). If the pregnancy intentions of all participants were changed to definitely not wanting pregnancy, the estimated decline in pregnancy risk would be 16%. CONCLUSIONS Pregnancy intentions were important not as mediators but rather as independent risk factors for pregnancy. Differences in pregnancy rates between groups of Latinas may be less a function of intentional choice than of situational factors. Interventions and research should focus on identifying and targeting factors that hinder effective contraceptive use among teenagers who want to avoid pregnancy. PMID:20887287

Factors Mediating the Adjustment to Involuntary Childlessness.

ERIC Educational Resources Information Center

Sabatelli, Ronald M.; And Others

1988-01-01

Explored stressors that accompany experience of involuntary childlessness and examined mediators of adjustment to infertility in married individuals. Data showed deleterious effect that coping with infertility can have on couple's sexual relationship. Findings suggest important relationship between self-esteem, marital commitment, and positive…

CAPERalpha is a novel Rel-TAD-interacting factor that inhibits lymphocyte transformation by the potent Rel/NF-kappaB oncoprotein v-Rel.

PubMed

Dutta, Jui; Fan, Gaofeng; Gélinas, Céline

2008-11-01

The Rel/NF-kappaB transcription factors are constitutively activated in many human cancers. The Rel proteins in this family are implicated in leukemia/lymphomagenesis, but the mechanism is not completely understood. Previous studies showed that the transcription activation domains (TADs) of the viral oncoprotein v-Rel and its cellular Rel/NF-kappaB homologues c-Rel and RelA are key determinants of their different transforming activities in primary lymphocytes. Substitution of a Rel TAD for that of RelA conferred a strong transforming phenotype upon RelA, which otherwise failed to transform cells. To gain insights into protein interactions that influence cell transformation by the Rel TADs, we identified factors that interact with the TAD of v-Rel, the most oncogenic member of the Rel/NF-kappaB family. We report that the coactivator for transcription factors AP-1 and estrogen receptors, CAPERalpha, interacts with the v-Rel TAD and potently synergizes v-Rel-mediated transactivation. Importantly, coexpression of CAPERalpha markedly reduced and delayed v-Rel's transforming activity in primary lymphocytes, whereas a dominant-negative mutant enhanced the kinetics of v-Rel-mediated transformation. Furthermore, small interfering RNA-mediated knockdown of CAPERalpha in v-Rel-transformed lymphocytes significantly enhanced colony formation in soft agar. Since the potency of Rel-mediated transactivation is an important determinant of lymphocyte transformation, as is Rel's ability to induce transcriptional repression, these data suggest that CAPERalpha's interaction with the Rel TAD could modulate Rel/NF-kappaB's transforming activity by facilitating expression or dampening repression of specific gene subsets important for oncogenesis. Overall, this study identifies CAPERalpha as a new transcriptional coregulator for v-Rel and reveals an important role in modulating Rel's oncogenic activity.

Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage

PubMed Central

Yang, Lu; Chen, Xufeng; Simet, Samantha M.; Hu, Guoku; Cai, Yu; Niu, Fang; Kook, Yeonhee

2016-01-01

Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell–substrate impedance sensing and FITC-dextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1α. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2–related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1α/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1α and PDGF-BB. Pharmacological blocking of HIF-1α significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension. PMID:27391108

Mediators of improved child diet quality following a health promotion intervention: the Melbourne InFANT Program.

PubMed

Spence, Alison C; Campbell, Karen J; Crawford, David A; McNaughton, Sarah A; Hesketh, Kylie D

2014-11-04

Young children's diets are currently suboptimal. Given that mothers have a critical influence on children' diets, they are typically a target of interventions to improve early childhood nutrition. Understanding the maternal factors which mediate an intervention's effect on young children's diets is important, but has not been well investigated. This research aimed to test whether maternal feeding knowledge, maternal feeding practices, maternal self-efficacy, and maternal dietary intakes acted as mediators of the effect of an intervention to improve child diet quality. The Melbourne Infant Feeding Activity and Nutrition Trial (InFANT) Program was a cluster-randomized controlled trial, conducted from 2008-2010. This novel, low-dose, health promotion intervention was delivered quarterly over 15 months and involved educational activities, promotion of peer discussion, a DVD and written materials. Post-intervention, when children were approximately 18 months of age, child diets were assessed using multiple 24-hour recalls and a purpose-developed index of diet quality, the Obesity Protective Dietary Index. Maternal mediators were assessed using a combination of previously validated and purpose-deigned tools. Mediation analysis was conducted using the test of joint significance and difference of coefficients methods. Across 62 parents' groups in Melbourne, Australia, 542 parents were recruited. Post- intervention, higher maternal feeding knowledge and lower use of foods as rewards was found to mediate the direct intervention effect on child diet quality. While other aspects of maternal feeding practices, self-efficacy and dietary intakes did not act as mediators, they were associated with child diet quality. Mediation analysis of this novel health promotion intervention showed the importance of maternal feeding knowledge and use of foods as rewards in impacting child diet quality. The other maternal factors assessed were appropriate targets but further research on how to impact these in an intervention is important. This evidence of intervention efficacy and mediation provides important insights for planning future interventions. Current Controlled Trials ISRCTN81847050, registered 23 November 2007.

Causal Mediation Analysis for the Cox Proportional Hazards Model with a Smooth Baseline Hazard Estimator.

PubMed

Wang, Wei; Albert, Jeffrey M

2017-08-01

An important problem within the social, behavioral, and health sciences is how to partition an exposure effect (e.g. treatment or risk factor) among specific pathway effects and to quantify the importance of each pathway. Mediation analysis based on the potential outcomes framework is an important tool to address this problem and we consider the estimation of mediation effects for the proportional hazards model in this paper. We give precise definitions of the total effect, natural indirect effect, and natural direct effect in terms of the survival probability, hazard function, and restricted mean survival time within the standard two-stage mediation framework. To estimate the mediation effects on different scales, we propose a mediation formula approach in which simple parametric models (fractional polynomials or restricted cubic splines) are utilized to approximate the baseline log cumulative hazard function. Simulation study results demonstrate low bias of the mediation effect estimators and close-to-nominal coverage probability of the confidence intervals for a wide range of complex hazard shapes. We apply this method to the Jackson Heart Study data and conduct sensitivity analysis to assess the impact on the mediation effects inference when the no unmeasured mediator-outcome confounding assumption is violated.

The transcriptional regulator BZR1 mediates trade-off between plant innate immunity and growth.

PubMed

Lozano-Durán, Rosa; Macho, Alberto P; Boutrot, Freddy; Segonzac, Cécile; Somssich, Imre E; Zipfel, Cyril

2013-12-31

The molecular mechanisms underlying the trade-off between plant innate immunity and steroid-mediated growth are controversial. Here, we report that activation of the transcription factor BZR1 is required and sufficient for suppression of immune signaling by brassinosteroids (BR). BZR1 induces the expression of several WRKY transcription factors that negatively control early immune responses. In addition, BZR1 associates with WRKY40 to mediate the antagonism between BR and immune signaling. We reveal that BZR1-mediated inhibition of immunity is particularly relevant when plant fast growth is required, such as during etiolation. Thus, BZR1 acts as an important regulator mediating the trade-off between growth and immunity upon integration of environmental cues. DOI: http://dx.doi.org/10.7554/eLife.00983.001.

Social capital and health in China: exploring the mediating role of lifestyle.

PubMed

Xue, Xindong; Cheng, Mingmei

2017-11-06

Although social capital as a key determinant of health has been well established in various studies, little is known about how lifestyle factors mediate this relationship. Understanding the cross-relationships between social capital, health, and lifestyle factors is important if health promotion policies are to be effective. The purpose of this study is to explore whether different dimensions of social capital and lifestyle factors are related, and whether lifestyle factors mediate the association between social capital and self-rated health (SRH) and psychological well-being (PWB) in China. This study used nationally representative data from the 2014 China Family Panel Studies (n = 28,916). The data reported on three dimensions of individual-level social capital: social trust, social relationship and Chinese Communist Party (CCP) membership. Health was assessed using SRH and PWB. Five lifestyle indicators were recorded: healthy diet, physical activity, smoking, sleeping, and non-overweight status. Logistic regression was used to examine the associations between social capital and lifestyle factors, and whether there was a mediating role of lifestyle. Odds ratios relating health status to social capital were reported before and after adjustment for lifestyle factors. Mediation analysis was then used to calculate the total, direct and indirect effects of social capital on SRH and PWB. The results show that social trust was significantly associated with all five lifestyle factors. Social relationship was significantly associated with four of the five: healthy diet, physical activity, sleeping and non-overweight. CCP membership was only significantly associated with two lifestyle factors: physical activity and non-overweight. Social trust and social relationship were significantly related to both SRH and PWB. CCP membership was only significantly related to SRH. Mediation analysis found modest evidence that lifestyle factors influenced the relationship between all three types of social capital and SRH. In contrast, only social trust and social relationship, but not CCP membership, were mediated by lifestyle factors with respect to PWB. This study is the first to explore the mediating role of lifestyle factors in the relationship between social capital and health in China. The overall findings suggest that lifestyle factors modestly mediate the association between social capital and health. The degree of mediating effect varies across different dimensions of social capital. Social capital-based health promotion policies would benefit from taking lifestyle factors into account.

Teacher’s Autonomy Support and Engagement in Math: Multiple Mediating Roles of Self-efficacy, Intrinsic Value, and Boredom

PubMed Central

Wang, Jia; Liu, Ru-De; Ding, Yi; Xu, Le; Liu, Ying; Zhen, Rui

2017-01-01

Previous studies have highlighted the impacts of environmental factors (teacher’s autonomy support) and individual factors (self-efficacy, intrinsic value, and boredom) on academic engagement. This study aimed to investigate these variables and examine the relations among them. Three structural equation models tested the multiple mediational roles of self-efficacy, intrinsic value, and boredom in the relation between teacher’s autonomy support and behavioral, emotional, and cognitive engagement, respectively, in math. A total of 637 Chinese middle school students (313 males, 324 females; mean age = 14.82) voluntarily participated in this study. Results revealed that self-efficacy, intrinsic value, and boredom played important and mediating roles between perceived teacher’s autonomy support and student engagement. Specifically, these three individual variables partly mediated the relations between perceived teacher’s autonomy support and behavioral and cognitive engagement, while fully mediating the relation between perceived teacher’s autonomy support and emotional engagement. These findings complement and extend the understanding of factors affecting students’ engagement in math. PMID:28690560

Teacher's Autonomy Support and Engagement in Math: Multiple Mediating Roles of Self-efficacy, Intrinsic Value, and Boredom.

PubMed

Wang, Jia; Liu, Ru-De; Ding, Yi; Xu, Le; Liu, Ying; Zhen, Rui

2017-01-01

Previous studies have highlighted the impacts of environmental factors (teacher's autonomy support) and individual factors (self-efficacy, intrinsic value, and boredom) on academic engagement. This study aimed to investigate these variables and examine the relations among them. Three structural equation models tested the multiple mediational roles of self-efficacy, intrinsic value, and boredom in the relation between teacher's autonomy support and behavioral, emotional, and cognitive engagement, respectively, in math. A total of 637 Chinese middle school students (313 males, 324 females; mean age = 14.82) voluntarily participated in this study. Results revealed that self-efficacy, intrinsic value, and boredom played important and mediating roles between perceived teacher's autonomy support and student engagement. Specifically, these three individual variables partly mediated the relations between perceived teacher's autonomy support and behavioral and cognitive engagement, while fully mediating the relation between perceived teacher's autonomy support and emotional engagement. These findings complement and extend the understanding of factors affecting students' engagement in math.

Virus Infection and Death Receptor-Mediated Apoptosis.

PubMed

Zhou, Xingchen; Jiang, Wenbo; Liu, Zhongshun; Liu, Shuai; Liang, Xiaozhen

2017-10-27

Virus infection can trigger extrinsic apoptosis. Cell-surface death receptors of the tumor necrosis factor family mediate this process. They either assist persistent viral infection or elicit the elimination of infected cells by the host. Death receptor-mediated apoptosis plays an important role in viral pathogenesis and the host antiviral response. Many viruses have acquired the capability to subvert death receptor-mediated apoptosis and evade the host immune response, mainly by virally encoded gene products that suppress death receptor-mediated apoptosis. In this review, we summarize the current information on virus infection and death receptor-mediated apoptosis, particularly focusing on the viral proteins that modulate death receptor-mediated apoptosis.

Virus Infection and Death Receptor-Mediated Apoptosis

PubMed Central

Zhou, Xingchen; Jiang, Wenbo; Liu, Zhongshun; Liu, Shuai; Liang, Xiaozhen

2017-01-01

Virus infection can trigger extrinsic apoptosis. Cell-surface death receptors of the tumor necrosis factor family mediate this process. They either assist persistent viral infection or elicit the elimination of infected cells by the host. Death receptor-mediated apoptosis plays an important role in viral pathogenesis and the host antiviral response. Many viruses have acquired the capability to subvert death receptor-mediated apoptosis and evade the host immune response, mainly by virally encoded gene products that suppress death receptor-mediated apoptosis. In this review, we summarize the current information on virus infection and death receptor-mediated apoptosis, particularly focusing on the viral proteins that modulate death receptor-mediated apoptosis. PMID:29077026

Mediation and moderation of the association between cynical hostility and systolic blood pressure in low-income women.

PubMed

Versey, H Shellae; Kaplan, George A

2012-04-01

Hostility may be related to risk factors for cardiovascular disease (CVD), such as blood pressure. However, the process by which hostility affects blood pressure is not fully understood. The current study sought to evaluate abdominal obesity (waist-to-hip ratio [WHR]) as a potential mediator and modifier of the relationship between cynical hostility and systolic blood pressure (SBP) in a group of disadvantaged women. Path analysis and multiple regression models were used to identify mediating and moderating pathways in the relationship between cynical hostility and SBP. Results indicate a significant interaction between WHR and cynical hostility. WHR was a partial mediator and significant moderator of the association between hostility and blood pressure. These findings highlight the potential importance of examining abdominal obesity and psychosocial factors as conjunctive determinants of CVD and risk factors for related metabolic conditions.

Stress and adult smartphone addiction: Mediation by self-control, neuroticism, and extraversion.

PubMed

Cho, Hea-Young; Kim, Dai Jin; Park, Jae Woo

2017-12-01

This study employed descriptive statistics and correlation analysis to examine the influence of stress on smartphone addiction as well as the mediating effects of self-control, neuroticism, and extraversion using 400 men and women in their 20s to 40s followed by structural equation analysis. Our findings indicate that stress had a significant influence on smartphone addiction, and self-control mediates the influence of stress on smartphone addiction. As stress increases, self-control decreases, which subsequently leads to increased smartphone addiction. Self-control was confirmed as an important factor in the prevention of smartphone addiction. Finally, among personality factors, neuroticism, and extraversion mediate the influence of stress on smartphone addiction. Copyright © 2017 John Wiley & Sons, Ltd.

Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer

PubMed Central

Damiani, Elisabetta; Ullrich, Stephen E.

2016-01-01

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome. PMID:27073146

Understanding the connection between platelet-activating factor, a UV-induced lipid mediator of inflammation, immune suppression and skin cancer.

PubMed

Damiani, Elisabetta; Ullrich, Stephen E

2016-07-01

Lipid mediators of inflammation play important roles in several diseases including skin cancer, the most prevalent type of cancer found in the industrialized world. Ultraviolet (UV) radiation is a complete carcinogen and is the primary cause of skin cancer. UV radiation is also a potent immunosuppressive agent, and UV-induced immunosuppression is a well-known risk factor for skin cancer induction. An essential mediator in this process is the glyercophosphocholine 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine commonly referred to as platelet-activating factor (PAF). PAF is produced by keratinocytes in response to diverse stimuli and exerts its biological effects by binding to a single specific G-protein-coupled receptor (PAF-R) expressed on a variety of cells. This review will attempt to describe how this lipid mediator is involved in transmitting the immunosuppressive signal from the skin to the immune system, starting from its production by keratinocytes, to its role in activating mast cell migration in vivo, and to the mechanisms involved that ultimately lead to immune suppression. Recent findings related to its role in regulating DNA repair and activating epigenetic mechanisms, further pinpoint the importance of this bioactive lipid, which may serve as a critical molecular mediator that links the environment (UVB radiation) to the immune system and the epigenome. Copyright © 2016 Elsevier B.V. All rights reserved.

Nuclear Factor-kappaB in Autoimmunity: Man and Mouse

PubMed Central

Miraghazadeh, Bahar; Cook, Matthew C.

2018-01-01

NF-κB (nuclear factor-kappa B) is a transcription complex crucial for host defense mediated by innate and adaptive immunity, where canonical NF-κB signaling, mediated by nuclear translocation of RelA, c-Rel, and p50, is important for immune cell activation, differentiation, and survival. Non-canonical signaling mediated by nuclear translocation of p52 and RelB contributes to lymphocyte maturation and survival and is also crucial for lymphoid organogenesis. We outline NF-κB signaling and regulation, then summarize important molecular contributions of NF-κB to mechanisms of self-tolerance. We relate these mechanisms to autoimmune phenotypes described in what is now a substantial catalog of immune defects conferred by mutations in NF-κB pathways in mouse models. Finally, we describe Mendelian autoimmune syndromes arising from human NF-κB mutations, and speculate on implications for understanding sporadic autoimmune disease. PMID:29686669

Direct and Indirect Effects of Five Factor Personality and Gender on Depressive Symptoms Mediated by Perceived Stress

PubMed Central

Kim, Song E.; Cho, Juhee; Kwon, Min-Jung; Chang, Yoosoo; Ryu, Seungho; Shin, Hocheol

2016-01-01

This study was designed to investigate associations among five factor personality traits, perceived stress, and depressive symptoms and to examine the roles of personality and perceived stress in the relationship between gender and depressive symptoms. The participants (N = 3,950) were part of a cohort study for health screening and examination at the Kangbuk Samsung Hospital. Personality was measured with the Revised NEO Personality Inventory (NEO-PI-R). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). Perceived stress level was evaluated with a self-reported stress questionnaire developed for the Korea National Health and Nutrition Examination Survey. A higher degree of neuroticism and lower degrees of extraversion, agreeableness, and conscientiousness were significantly associated with greater perceived stress and depressive symptoms. Neuroticism and extraversion had significant direct and indirect effects (via stress as a mediator) on depressive symptoms in both genders. Agreeableness and conscientiousness had indirect effects on depression symptoms in both genders. Multiple mediation models were used to examine the mediational roles of each personality factor and perceived stress in the link between gender and depressive symptoms. Four of the personality factors (except openness) were significant mediators, along with stress, on the relationship between gender and depressive symptoms. Our findings suggest that the links between personality factors and depressive symptoms are mediated by perceived stress. As such, personality is an important factor to consider when examining the link between gender and depression. PMID:27120051

UAP56 is an important mediator of Angiotensin II/platelet derived growth factor induced vascular smooth muscle cell DNA synthesis and proliferation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sahni, Abha; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555; Wang, Nadan

2013-02-15

Highlights: ► Knockdown of UAP56 inhibits Angiotensin II/PDGF induced vascular smooth muscle cell proliferation. ► UAP56 is a positive regulator of E2F transcriptional activation. ► UAP56 is present in the vessel wall of low flow carotid arteries. -- Abstract: Angiotensin (Ang) II and platelet-derived growth factor (PDGF) are important mediators of pathologic vascular smooth muscle cell (VSMC) proliferation. Identifying downstream mediators of Ang II and PDGF signaling may provide insights for therapies to improve vascular proliferative diseases. We have previously demonstrated that breakpoint cluster region (Bcr) is an important mediator of Ang II/PDGF signaling in VSMC. We have recently reportedmore » that the DExD/H box protein UAP56 is an interacting partner of Bcr in regulating VSMC DNA synthesis. We hypothesized that UAP56 itself is an important regulator of VSMC proliferation. In this report we demonstrate that knockdown of UAP56 inhibits Ang II/PDGF induced VSMC DNA synthesis and proliferation, and inhibits E2F transcriptional activity. In addition, we demonstrate that UAP56 is present in the vessel wall of low-flow carotid arteries. These findings suggest that UAP56 is a regulator of VSMC proliferation and identify UAP56 as a target for preventing vascular proliferative disease.« less

Nanomedicine and its application in treatment of microglia-mediated neuroinflammation.

PubMed

Baby, N; Patnala, R; Ling, Eng-Ang; Dheen, S T

2014-01-01

Nanomedicine, an emerging therapeutic tool in current medical frontiers, offers targeted drug delivery for many neurodegenerative disorders. Neuroinflammation, a hallmark of many neurodegenerative disorders, is mediated by microglia, the resident immunocompetent cells of the central nervous system (CNS). Microglial cells respond to various stimuli in the CNS resulting in their activation which may have a beneficial or a detrimental effect. In general, the activated microglia remove damaged neurons and infectious agents by phagocytosis, therefore being neuroprotective. However, their chronic activation exacerbates neuronal damage through excessive release of proinflammatory cytokines, chemokines and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. Hence, controlling microglial inflammatory response and their proliferation has been considered as an important aspect in treating neurodegenerative disorders. Regulatory factors that control microglial activation and proliferation also play an important role in microglia-mediated neuroinflammation and neurotoxicity. Various anti-inflammatory drugs and herbal compounds have been identified in treating microglia-mediated neuroinflammation in the CNS. However, hurdles in crossing blood brain barrier (BBB), expression of metabolic enzymes, presence of efflux pumps and several other factors prevent the entry of these drugs into the CNS. Use of non-degradable delivery systems and microglial activation in response to the drug delivery system further complicate drug delivery to the CNS. Nanomedicine, a nanoparticle-mediated drug delivery system, exhibits immense potential to overcome these hurdles in drug delivery to the CNS enabling new alternatives with significant promises in revolutionising the field of neurodegenerative disease therapy. This review attempts to summarise various regulatory factors in microglia, existing therapeutic strategies in controlling microglial activation, and how nanotechnology can serve to improve the delivery of therapeutic drugs across the BBB for treating microglia- mediated neuroinflammation and neurodegeneration.

Aging and social networks in Spain: the importance of pubs and churches.

PubMed

Buz, José; Sanchez, Marta; Levenson, Michael R; Aldwin, Carolyn M

2014-01-01

We examined whether the social convoy model and socioemotional selectivity theory apply in collectivistic cultures by examining the contextual factors which are hypothesized to mediate age-related differences in social support in a collectivist European country. Five hundred Spanish community-dwelling older adults (Mean age = 74.78, SD = 7.76, range = 60-93) were interviewed to examine structural aspects of their social networks. We found that age showed highly complex relationships with network size and frequency of interaction, depending on the network circle and the mediation of cultural factors. Family structure was important for social relations in the inner circle, while pubs and churches were important for peripheral relations. Surprisingly, pub attendance was the most important variable for maintenance of social support of peripheral network members. In general, the results support the applicability of the social convoy and socioemotional selectivity constructs to social support among Spanish older adults.

Motivation and Self-Management Behavior of the Individuals With Chronic Low Back Pain.

PubMed

Jung, Mi Jung; Jeong, Younhee

2016-01-01

Self-management behavior is an important component for successful pain management in individuals with chronic low back pain. Motivation has been considered as an effective way to change behavior. Because there are other physical, social, and psychological factors affecting individuals with pain, it is necessary to identify the main effect of motivation on self-management behavior without the influence of those factors. The purpose of this study was to investigate the effect of motivation on self-management in controlling pain, depression, and social support. We used a nonexperimental, cross-sectional, descriptive design with mediation analysis and included 120 participants' data in the final analysis. We also used hierarchical multiple regression to test the effect of motivation, and multiple regression analysis and Sobel test were used to examine the mediating effect. Motivation itself accounted for 23.4% of the variance in self-management, F(1, 118) = 35.003, p < .001. After controlling covariates, motivation was also a significant factor for self-management. In the mediation analysis, motivation completely mediated the relationship between education and self-management, z = 2.292, p = .021. Motivation is an important part of self-management, and self-management education is not effective without motivation. The results of our study suggest that nurses incorporate motivation in nursing intervention, rather than only giving information.

Understanding nurse anesthetists' intention to leave their job: how burnout and job satisfaction mediate the impact of personality and workplace characteristics.

PubMed

Meeusen, Vera C H; Van Dam, Karen; Brown-Mahoney, Chris; Van Zundert, Andre A J; Knape, Hans T A

2011-01-01

The retention of nurse anesthetists is of paramount importance, particularly in view of the fact that the health care workforce is shrinking. Although many health care providers find their work satisfying, they often consider leaving their jobs because of the stress. Are there ways to improve this situation? This study investigated how work environment characteristics and personality dimensions relate to burnout and job satisfaction and ultimately to turnover intention among Dutch nurse anesthetists. An online self-reporting questionnaire survey was performed among Dutch nurse anesthetists. The questionnaire included scales to assess personality dimensions, work climate, work context factors, burnout, job satisfaction, and turnover intention. The research model stated that personality dimensions, work climate, and work context factors, mediated by burnout and job satisfaction, predict turnover intention. Structural equation modeling was used to test the research model. Nine hundred twenty-three questionnaires were completed (46% response rate). Burnout mediated the relationship between personality dimensions and turnover intention; job satisfaction mediated the relationship of work climate and work context factors to turnover intention. To retain nursing staff and to maintain adequate staff strength, it is important to improve job satisfaction by creating a positive work climate and work context and to prevent burnout by selecting the most suitable employees through personality assessment.

Distress and worry as mediators in the relationship between psychosocial risks and upper body musculoskeletal complaints in highly automated manufacturing.

PubMed

Wixted, Fiona; Shevlin, Mark; O'Sullivan, Leonard W

2018-03-15

As a result of changes in manufacturing including an upward trend in automation and the advent of the fourth industrial revolution, the requirement for supervisory monitoring and consequently, cognitive demand has increased in automated manufacturing. The incidence of musculoskeletal disorders has also increased in the manufacturing sector. A model was developed based on survey data to test if distress and worry mediate the relationship between psychosocial factors (job control, cognitive demand, social isolation and skill discretion), stress states and symptoms of upper body musculoskeletal disorders in highly automated manufacturing companies (n = 235). These constructs facilitated the development of a statistically significant model (RMSEA 0.057, TLI 0.924, CFI 0.935). Cognitive demand was shown to be related to higher distress in employees, and distress to a higher incidence of self-reported shoulder and lower back symptoms. The mediation model incorporating stress states (distress, worry) as mediators is a novel approach in linking psychosocial risks to musculoskeletal disorders. Practitioners' Summary With little requirement for physical work in many modern automated manufacturing workplaces, there is often minimal management focus on Work-Related Musculoskeletal Disorders (WRMSDs) as important occupational health problems. Our model provides evidence that psychosocial factors are important risk factors in symptoms of WRMSD and should be managed.

Maternal Parenting Behaviors and Adolescent Depression: The Mediating Role of Rumination

ERIC Educational Resources Information Center

Gate, Michael A.; Watkins, Edward R.; Simmons, Julian G.; Byrne, Michelle L.; Schwartz, Orli S.; Whittle, Sarah; Sheeber, Lisa B.; Allen, Nicholas B.

2013-01-01

Substantial evidence suggests that rumination is an important vulnerability factor for adolescent depression. Despite this, few studies have examined environmental risk factors that might lead to rumination and, subsequently, depression in adolescence. This study examined the hypothesis that an adverse family environment is a risk factor for…

Factors Mediating co-occurrence of an economically valuable introduced fish and its native frog prey

Treesearch

Rosemary Hartman; Karen Pope; Sharon Lawler

2013-01-01

Habitat characteristics mediate predator-prey coexistence in many ecological systemd but are seldom considered in species introductions. When economically important introduced predators are stocked despite known impacts on native species, understanding the role of refuges, landscape configurations, and community interactions can inform habitat management plans. We...

The role of motivation in understanding social contextual influences on physical activity in underserved adolescents in the ACT Trial: a cross-sectional study.

PubMed

Lawman, Hannah G; Wilson, Dawn K; Van Horn, M Lee; Zarrett, Nicole

2012-12-01

Previous research has shown that social contextual factors are important in understanding physical activity (PA) behavior, although little is known about how these factors may relate to PA, especially in underserved adolescents (low income, minorities). This study examined how motivation may differentially mediate the relationship of two social contextual variables (i.e., peer and parent social support) and moderate-to-vigorous PA (MVPA). Baseline data (n = 1421 sixth graders, 54% female, 72% African American) from the Active by Choice Today (ACT) trial in underserved adolescents were analyzed. Motivation was examined as a mediator of the relationships between peer social support, parent social support, and MVPA (measured by 7-day accelerometer estimates). Motivation and peer but not parent support were significantly related to MVPA overall. Significant mediation effects were found indicating motivation partially mediated the relation between peer social support and MVPA and to a lesser degree parent support and MVPA. These findings provide support for the importance of social contextual influences, especially peer social support, on underserved adolescents' PA and motivation for PA.

Th17 cell-mediated immune responses promote mast cell proliferation by triggering stem cell factor in keratinocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cho, Kyung-Ah; Park, Minhwa; Kim, Yu-Hee

Although mast cells are traditionally thought to function as effector cells in allergic responses, they have increasingly been recognized as important regulators of various immune responses. Mast cells mature locally; thus, tissue-specific influences are important for promoting mast cell accumulation and survival in the skin and the gastrointestinal tract. In this study, we determined the effects of keratinocytes on mast cell accumulation during Th17-mediated skin inflammation. We observed increases in dermal mast cells in imiquimod-induced psoriatic dermatitis in mice accompanied by the expression of epidermal stem cell factor (SCF), a critical mast cell growth factor. Similar to mouse epidermal keratinocytes,more » SCF was highly expressed in the human HaCaT keratinocyte cell line following stimulation with IL−17. Further, keratinocytes promoted mast cell proliferation following stimulation with IL−17 in vitro. However, the effects of keratinocytes on mast cells were significantly diminished in the presence of anti−CD117 (stem cell factor receptor) blocking antibodies. Taken together, our results revealed that the Th17-mediated inflammatory environment promotes mast cell accumulation through keratinocyte-derived SCF. - Highlights: • Psoriasis-like skin inflammation increase dermal mast cells. • Keratinocyte produce stem cell factor in psoriasis-like skin inflammation. • Keratinocyte promote mast cell proliferation by stem cell factor dependent manner.« less

Cultural Predictors of Physical and Mental Health Status among Mexican American Women: A Mediation Model

PubMed Central

Dinh, Khanh T.; Castro, Felipe González; Tein, Jenn-Yun; Kim, Su Yeong

2016-01-01

This study, using secondary data analysis, examined a mediation model of acculturation and ethnic pride as predictors of physical and mental health outcomes in a sample of 561 Mexican American women. Factors postulated as mediators were family support and religiosity. Systematic across-group comparison analyses were conducted to examine sources of differences in the mediation model between immigrant and non-immigrant women. The results partially supported the hypothesized mediation model, indicating that family support, but not religiosity, was a significant mediator in the relationship between ethnic pride and mental health problems. In addition, as differences between immigrant and non-immigrant women were observed only in the variables means, but not in the factor loadings or regression paths, the model tested may capture a common psychosocial process that affects these women and their health outcomes. Overall, this study offers important implications for future research and the design of intervention programs for Mexican American women. PMID:19130212

The mediating role of dietary factors and leisure time physical activity on socioeconomic inequalities in body mass index among Australian adults.

PubMed

Gearon, Emma; Backholer, Kathryn; Hodge, Allison; Peeters, Anna

2013-12-21

The relationship between socioeconomic position and obesity has been clearly established, however, the extent to which specific behavioural factors mediate this relationship is less clear. This study aimed to ascertain the contribution of specific dietary elements and leisure-time physical activity (LTPA) to variations in obesity with education in the baseline (1990-1994) Melbourne Collaborative Cohort Study (MCCS). 18, 489 women and 12, 141 men were included in this cross-sectional analysis. A series of linear regression models were used in accordance with the products of coefficients method to examine the mediating role of alcohol, soft drink (regular and diet), snacks (healthy and sweet), savoury items (healthy and unhealthy), meeting fruit and vegetable guidelines and LTPA on the relationship between education and body mass index (BMI). Compared to those with lowest educational attainment, those with the highest educational attainment had a 1 kg/m2 lower BMI. Among men and women, 27% and 48%, respectively, of this disparity was attributable to differences in LTPA and diet. Unhealthy savoury item consumption and LTPA contributed most to the mediated effects for men and women. Alcohol and diet soft drink were additionally important mediators for women. Diet and LTPA are potentially modifiable behavioural risk factors for the development of obesity that contribute substantially to inequalities in BMI. Our findings highlight the importance of specific behaviours which may be useful to the implementation of effective, targeted public policy to reduce socioeconomic inequalities in obesity.

Metabolic factors and genetic risk mediate familial type 2 diabetes risk in the Framingham Heart Study

PubMed Central

Raghavan, Sridharan; Porneala, Bianca; McKeown, Nicola; Fox, Caroline S.; Dupuis, Josée; Meigs, James B.

2015-01-01

Aims/hypothesis Type 2 diabetes mellitus in parents is a strong determinant of diabetes risk in their offspring. We hypothesise that offspring diabetes risk associated with parental diabetes is mediated by metabolic risk factors. Methods We studied initially non-diabetic participants of the Framingham Offspring Study. Metabolic risk was estimated using beta cell corrected insulin response (CIR), HOMA-IR or a count of metabolic syndrome components (metabolic syndrome score [MSS]). Dietary risk and physical activity were estimated using questionnaire responses. Genetic risk score (GRS) was estimated as the count of 62 type 2 diabetes risk alleles. The outcome of incident diabetes in offspring was examined across levels of parental diabetes exposure, accounting for sibling correlation and adjusting for age, sex and putative mediators. The proportion mediated was estimated by comparing regression coefficients for parental diabetes with (βadj) and without (βunadj) adjustments for CIR, HOMA-IR, MSS and GRS (percentage mediated = 1 – βadj / βunadj). Results Metabolic factors mediated 11% of offspring diabetes risk associated with parental diabetes, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.96. GRS mediated 9% of risk, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.99. Conclusions/interpretation Metabolic risk factors partially mediated offspring type 2 diabetes risk conferred by parental diabetes to a similar magnitude as genetic risk. However, a substantial proportion of offspring diabetes risk associated with parental diabetes remains unexplained by metabolic factors, genetic risk, diet and physical activity, suggesting that important familial influences on diabetes risk remain undiscovered. PMID:25619168

Depressive mood, eating disorder symptoms, and perfectionism in female college students: a mediation analysis.

PubMed

García-Villamisar, Domingo; Dattilo, John; Del Pozo, Araceli

2012-01-01

Although perfectionism has long been established as an important risk factor for depressive mood and eating disorders, the mechanisms through which this temperamental predisposition mediates the relationship between depressive mood and eating disorder symptoms are still relatively unclear. In this study we hypothesized that both perfectionism dimensions, self-oriented perfectionism and socially prescribed perfectionism, would mediate the relationship between current symptoms of depression and eating disorders in a non-clinical sample of Spanish undergraduate females. Two hundred sixteen female undergraduate students of the University Complutense of Madrid (Spain) completed the Spanish versions of the Eating Attitudes Test (EAT-40), the Multidimensional Perfectionism Scale (MPS), OBQ-44, and BDI-II and BAI. Results demonstrated the importance of socially prescribed perfectionism in mediation of the relationship between depressive mood and symptoms of eating disorders. Socially prescribed perfectionism mediates the relationship between depressive mood and eating disorder symptoms for female college students.

The Relationship Between Challenging Behaviour, Cognitions and Stress in Mothers of Individuals with Intellectual Disabilities.

PubMed

Rose, John; Nelson, Lisa; Hardiman, Rebecca

2016-11-01

Cognitions are starting to receive more prominence as important when examining a number of factors including the topography of challenging behaviour. This study examined the relationships between maternal stress, challenging behaviour (aggressive and self-injurious behaviours) and parental cognitions and specifically whether maternal cognitions mediated the effect of challenging behaviour on parenting stress. 46 mothers of children and young adults with ID completed questionnaires regarding their child's challenging behaviour, maternal cognitions and stress. Significant correlations were found between challenging behaviour and maternal stress. The overall mediation models for aggression and self-injurious behaviour were significant. The Challenging Behaviour Perception Questionnaire: Consequences client subscale was the only independent significant mediator for both behaviours. Cognitions do play an important part in mediating the relationship between challenging behaviour and stress. Further research is needed to examine the similarities and differences between the mediation models for aggression and self-injurious behaviour.

Tuberculosis and poverty: why are the poor at greater risk in India?

PubMed

Oxlade, Olivia; Murray, Megan

2012-01-01

Although poverty is widely recognized as an important risk factor for tuberculosis (TB) disease, the specific proximal risk factors that mediate this association are less clear. The objective of our study was to investigate the mechanisms by which poverty increases the risk of TB. Using individual level data from 198,754 people from the 2006 Demographic Health Survey (DHS) for India, we assessed self-reported TB status, TB determinants and household socioeconomic status. We used these data to calculate the population attributable fractions (PAF) for each key TB risk factor based on the prevalence of determinants and estimates of the effect of these risk factors derived from published sources. We conducted a mediation analysis using principal components analysis (PCA) and regression to demonstrate how the association between poverty and TB prevalence is mediated. The prevalence of self-reported TB in the 2006 DHS for India was 545 per 100,000 and ranged from 201 in the highest quintile to 1100 in the lowest quintile. Among those in the poorest population, the PAFs for low body mass index (BMI) and indoor air pollution were 34.2% and 28.5% respectively. The PCA analysis also showed that low BMI had the strongest mediating effect on the association between poverty and prevalent TB (12%, p = 0.019). TB control strategies should be targeted to the poorest populations that are most at risk, and should address the most important determinants of disease--specifically low BMI and indoor air pollution.

Risk factors for delayed presentation and referral of symptomatic cancer: evidence for common cancers

PubMed Central

Macleod, U; Mitchell, E D; Burgess, C; Macdonald, S; Ramirez, A J

2009-01-01

Background: It has been suggested that the known poorer survival from cancer in the United Kingdom, compared with other European countries, can be attributed to more advanced cancer stage at presentation. There is, therefore, a need to understand the diagnostic process, and to ascertain the risk factors for increased time to presentation. Methods: We report the results from two worldwide systematic reviews of the literature on patient-mediated and practitioner-mediated delays, identifying the factors that may influence these. Results: Across cancer sites, non-recognition of symptom seriousness is the main patient-mediated factor resulting in increased time to presentation. There is strong evidence of an association between older age and patient delay for breast cancer, between lower socio-economic status and delay for upper gastrointestinal and urological cancers and between lower education level and delay for breast and colorectal cancers. Fear of cancer is a contributor to delayed presentation, while sanctioning of help seeking by others can be a powerful mediator of reduced time to presentation. For practitioner delay, ‘misdiagnosis' occurring either through treating patients symptomatically or relating symptoms to a health problem other than cancer, was an important theme across cancer sites. For some cancers, this could also be linked to inadequate patient examination, use of inappropriate tests or failing to follow-up negative or inconclusive test results. Conclusion: Having sought help for potential cancer symptoms, it is therefore important that practitioners recognise these symptoms, and examine, investigate and refer appropriately. PMID:19956172

Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis.

PubMed

Wang, Weiye; Xu, Suowen; Yin, Meimei; Jin, Zheng Gen

2015-02-15

Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Nrf2 Deficiency in Dendritic Cells Enhances the Adjuvant Effect of Ambient Ultrafine Particles on Allergic Sensitization

EPA Science Inventory

Airborne particulate matter (PM) is an important risk factor for asthma. Generation of oxidative stress by PM-associated chemicals is a major mechanism of its health effects. Transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) mediates antioxidant and phase II...

A mechanism regulating proteolysis of specific proteins during renal tubular cell growth.

PubMed

Franch, H A; Sooparb, S; Du, J; Brown, N S

2001-06-01

Growth factors suppress the degradation of cellular proteins in lysosomes in renal epithelial cells. Whether this process also involves specific classes of proteins that influence growth processes is unknown. We investigated chaperone-mediated autophagy, a lysosomal import pathway that depends on the 73-kDa heat shock cognate protein and allows the degradation of proteins containing a specific lysosomal import consensus sequence (KFERQ motif). Epidermal growth factor (EGF) or ammonia, but not transforming growth factor beta1, suppresses total protein breakdown in cultured NRK-52E renal epithelial cells. EGF or ammonia prolonged the half-life of glyceraldehyde-3-phosphate dehydrogenase, a classic substrate for chaperone-mediated autophagy, by more than 90%, whereas transforming growth factor beta1 did not. EGF caused a similar increase in the half-life of the KFERQ-containing paired box-related transcription factor, Pax2. The increase in half-life was accompanied by an increased accumulation of proteins with a KFERQ motif including glyceraldehyde-3-phosphate dehydrogenase and Pax2. Ammonia also increased the level of the Pax2 protein. Lysosomal import of KFERQ proteins depends on the abundance of the 96-kDa lysosomal glycoprotein protein (lgp96), and we found that EGF caused a significant decrease in lgp96 in cellular homogenates and associated with lysosomes. We conclude that EGF in cultured renal cells regulates the breakdown of proteins targeted for destruction by chaperone-mediated autophagy. Because suppression of this pathway results in an increase in Pax2, these results suggest a novel mechanism for the regulation of cell growth.

Parental Mediation of Television Viewing and Videogaming of Adolescents with Autism Spectrum Disorder and Their Siblings

ERIC Educational Resources Information Center

Kuo, Melissa H.; Magill-Evans, Joyce; Zwaigenbaum, Lonnie

2015-01-01

Adolescents with autism spectrum disorder spend considerable time in media activities. Parents play an important role in shaping adolescents' responses to media. This study explored the mediation strategies that parents of adolescents with autism spectrum disorder used to manage television and video game use, factors associated with their use of…

The Effectiveness of Computer-Mediated Communication on SLA: A Meta-Analysis and Research Synthesis

ERIC Educational Resources Information Center

Lin, Huifen

2012-01-01

Over the past two decades, a large body of research has been conducted on the effectiveness of computer-mediated communication (CMC) employed as either standalone or instructional tools in SLA classrooms. Findings from this large body of work, however, are not conclusive, making it important to identify factors that would inform its successful…

Psychosocial factors partially mediate the relationship between mechanical hyperalgesia and self-reported pain.

PubMed

Mason, Kayleigh J; O'Neill, Terence W; Lunt, Mark; Jones, Anthony K P; McBeth, John

2018-01-26

Amplification of sensory signalling within the nervous system along with psychosocial factors contributes to the variation and severity of knee pain. Quantitative sensory testing (QST) is a non-invasive test battery that assesses sensory perception of thermal, pressure, mechanical and vibration stimuli used in the assessment of pain. Psychosocial factors also have an important role in explaining the occurrence of pain. The aim was to determine whether QST measures were associated with self-reported pain, and whether those associations were mediated by psychosocial factors. Participants with knee pain identified from a population-based cohort completed a tender point count and a reduced QST battery of thermal, mechanical and pressure pain thresholds, temporal summation, mechanical pain sensitivity (MPS), dynamic mechanical allodynia (DMA) and vibration detection threshold performed following the protocol by the German Research Network on Neuropathic Pain. QST assessments were performed at the most painful knee and opposite forearm (if pain-free). Participants were asked to score for their global and knee pain intensities within the past month (range 0-10), and complete questionnaire items investigating anxiety, depression, illness perceptions, pain catastrophising, and physical functioning. QST measures (independent variable) significantly correlated (Spearman's rho) with self-reported pain intensity (dependent variable) were included in structural equation models with psychosocial factors (latent mediators). Seventy-two participants were recruited with 61 participants (36 women; median age 64 years) with complete data included in subsequent analyses. Tender point count was significantly correlated with global pain intensity. DMA at the knee and MPS at the most painful knee and opposite pain-free forearm were significantly correlated with both global pain and knee pain intensities. Psychosocial factors including pain catastrophising sub-scales (rumination and helplessness) and illness perceptions (consequences and concern) were significant partial mediators of the association with global pain intensity when loaded on to a latent mediator for: tender point count [75% total effect; 95% confidence interval (CI) 22%, 100%]; MPS at the knee (49%; 12%, 86%); and DMA at the knee (63%; 5%, 100%). Latent psychosocial factors were also significant partial mediators of the association between pain intensity at the tested knee with MPS at the knee (30%; 2%, 58%), but not for DMA at the knee. Measures of mechanical hyperalgesia at the most painful knee and pain-free opposite forearm were associated with increased knee and global pain indicative of altered central processing. Psychosocial factors were significant partial mediators, highlighting the importance of the central integration of emotional processing in pain perception. Associations between mechanical hyperalgesia at the forearm and knee, psychosocial factors and increased levels of clinical global and knee pain intensity provide evidence of altered central processing as a key mechanism in knee pain, with psychological factors playing a key role in the expression of clinical pain.

The mediating role of the home environment in relation to parental educational level and preschool children's screen time: a cross-sectional study.

PubMed

Määttä, Suvi; Kaukonen, Riikka; Vepsäläinen, Henna; Lehto, Elviira; Ylönen, Anna; Ray, Carola; Erkkola, Maijaliisa; Roos, Eva

2017-09-02

Previous studies suggest that preschoolers from low socioeconomic backgrounds engage in more screen time. Still, the factors in the social and physical home environment driving these differences in preschool children's screen time are poorly understood. This study examines potential home environment mediators in the associations between parental educational level and preschoolers' screen time. A total of 864 children aged 3-6 years and their parents participated in a cross-sectional DAGIS study in 2015-2016. Parents recorded their children's screen time in a diary (N = 823). For the analyses, the daily average screen time at home was calculated. Parental questionnaires (N = 808) assessed educational level and eight social and physical environment factors in the home (i.e., descriptive norm for children's screen time, parental screen use in front of children, parental importance for limiting children's screen time, parental attitude toward societal pressures for children's screen time, access to screens at home, parental self-efficacy for limiting children's screen time, satisfaction of children's screen time, and rules for limiting children's screen time). Parental education was grouped into low, middle, and high education. The associations were tested by conducting mediation analyses adjusted by season and children's sex and age. The significant mediators in the single-mediator models were included in the final multiple-mediator models. Of the potential eight mediators, the following four had a significant indirect association: descriptive norm for children's screen time, parental screen use in front of children, parental importance for limiting children's screen time, and parental attitude toward societal pressures for children's screen time. Parents with high education had lower descriptive norm and used fewer screens in front of children compared to parents with middle or low education, and in turn, these factors were associated with less screen time among children from parents with a higher education level. Parents with high education placed greater importance on limiting children's screen time and felt less societal pressures about children's screen time compared to parents with low education, and in turn, these factors were associated with less screen time among children from parents with a higher education level. Our study recognized multiple modifiable mediators in the associations between parental education and preschool children's screen time. When aiming to diminish socioeconomic status differences in preschool children's screen time, the focus should be on parental role models, attitudes, and norm related to children's screen time.

[Programmed necrosis mediated by receptor-interacting protein 3: a new target for liver disease research].

PubMed

Zhang, J; Jing, Y; Li, Y N; Zhou, L; Wang, B M

2016-09-20

Hepatocyte death mainly includes apoptosis and necrosis and is a critical process in the pathophysiological mechanism of liver injury caused by various reasons. Recent studies have shown that key regulatory molecules in the inhibition of apoptosis such as caspase cannot be used as targets for inhibiting disease progression in clinical practice. In recent years, programmed necrosis mediated by receptor-interacting protein 3(RIP3)becomes a new hot research topic. It not only plays an important role in inducing inflammatory response, but also is closely regulated by intracellular signal factors, and it is a type of active cell death which can be interfered with. Compared with apoptosis, programmed necrosis is accompanied by the release of various inflammatory factors, which significantly affects local immune microenvironment. RIP3-mediated programmed necrosis has been taken seriously in many diseases. Although its mechanism of action in liver disease remains unclear, the results of recent studies confirmed its important role in the development of liver disease. This article reviews the research advances in the role of RIP3-mediated programmed necrosis signaling pathway in liver disease of various causes and investigates the possibility of RIP3-mediated programmed necrosis as a new target in the treatment of liver disease.

Retinoblastoma-binding Protein 4-regulated Classical Nuclear Transport Is Involved in Cellular Senescence*

PubMed Central

Tsujii, Akira; Miyamoto, Yoichi; Moriyama, Tetsuji; Tsuchiya, Yuko; Obuse, Chikashi; Mizuguchi, Kenji; Oka, Masahiro; Yoneda, Yoshihiro

2015-01-01

Nucleocytoplasmic trafficking is a fundamental cellular process in eukaryotic cells. Here, we demonstrated that retinoblastoma-binding protein 4 (RBBP4) functions as a novel regulatory factor to increase the efficiency of importin α/β-mediated nuclear import. RBBP4 accelerates the release of importin β1 from importin α via competitive binding to the importin β-binding domain of importin α in the presence of RanGTP. Therefore, it facilitates importin α/β-mediated nuclear import. We showed that the importin α/β pathway is down-regulated in replicative senescent cells, concomitant with a decrease in RBBP4 level. Knockdown of RBBP4 caused both suppression of nuclear transport and induction of cellular senescence. This is the first report to identify a factor that competes with importin β1 to bind to importin α, and it demonstrates that the loss of this factor can trigger cellular senescence. PMID:26491019

Ethanol and corticotropin releasing factor receptor modulation of central amygdala neurocircuitry: An update and future directions.

PubMed

Silberman, Yuval; Winder, Danny G

2015-05-01

The central amygdala is a critical brain region for many aspects of alcohol dependence. Much of the work examining the mechanisms by which the central amygdala mediates the development of alcohol dependence has focused on the interaction of acute and chronic ethanol with central amygdala corticotropin releasing factor signaling. This work has led to a great deal of success in furthering the general understanding of central amygdala neurocircuitry and its role in alcohol dependence. Much of this work has primarily focused on the hypothesis that ethanol utilizes endogenous corticotropin releasing factor signaling to upregulate inhibitory GABAergic transmission in the central amygdala. Work that is more recent suggests that corticotropin releasing factor also plays an important role in mediating anxiety-like behaviors via the enhancement of central amygdala glutamatergic transmission, implying that ethanol/corticotropin releasing factor interactions may modulate excitatory neurotransmission in this brain region. In addition, a number of studies utilizing optogenetic strategies or transgenic mouse lines have begun to examine specific central amygdala neurocircuit dynamics and neuronal subpopulations to better understand overall central amygdala neurocircuitry and the role of neuronal subtypes in mediating anxiety-like behaviors. This review will provide a brief update on this literature and describe some potential future directions that may be important for the development of better treatments for alcohol addiction. Copyright © 2015 Elsevier Inc. All rights reserved.

Statistical grand rounds: understanding the mechanism: mediation analysis in randomized and nonrandomized studies.

PubMed

Mascha, Edward J; Dalton, Jarrod E; Kurz, Andrea; Saager, Leif

2013-10-01

In comparative clinical studies, a common goal is to assess whether an exposure, or intervention, affects the outcome of interest. However, just as important is to understand the mechanism(s) for how the intervention affects outcome. For example, if preoperative anemia was shown to increase the risk of postoperative complications by 15%, it would be important to quantify how much of that effect was due to patients receiving intraoperative transfusions. Mediation analysis attempts to quantify how much, if any, of the effect of an intervention on outcome goes though prespecified mediator, or "mechanism" variable(s), that is, variables sitting on the causal pathway between exposure and outcome. Effects of an exposure on outcome can thus be divided into direct and indirect, or mediated, effects. Mediation is claimed when 2 conditions are true: the exposure affects the mediator and the mediator (adjusting for the exposure) affects the outcome. Understanding how an intervention affects outcome can validate or invalidate one's original hypothesis and also facilitate further research to modify the responsible factors, and thus improve patient outcome. We discuss the proper design and analysis of studies investigating mediation, including the importance of distinguishing mediator variables from confounding variables, the challenge of identifying potential mediators when the exposure is chronic versus acute, and the requirements for claiming mediation. Simple designs are considered, as well as those containing multiple mediators, multiple outcomes, and mixed data types. Methods are illustrated with data collected by the National Surgical Quality Improvement Project (NSQIP) and utilized in a companion paper which assessed the effects of preoperative anemic status on postoperative outcomes.

Computational nanomedicine: modeling of nanoparticle-mediated hyperthermal cancer therapy

PubMed Central

Kaddi, Chanchala D; Phan, John H; Wang, May D

2016-01-01

Nanoparticle-mediated hyperthermia for cancer therapy is a growing area of cancer nanomedicine because of the potential for localized and targeted destruction of cancer cells. Localized hyperthermal effects are dependent on many factors, including nanoparticle size and shape, excitation wavelength and power, and tissue properties. Computational modeling is an important tool for investigating and optimizing these parameters. In this review, we focus on computational modeling of magnetic and gold nanoparticle-mediated hyperthermia, followed by a discussion of new opportunities and challenges. PMID:23914967

A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow.

PubMed

Wynn, Robert F; Hart, Claire A; Corradi-Perini, Carla; O'Neill, Liam; Evans, Caroline A; Wraith, J Ed; Fairbairn, Leslie J; Bellantuono, Ilaria

2004-11-01

Homing of bone marrow stromal cells (MSCs) to bone and bone marrow after transplantation, important for the correction of conditions such as metabolic storage disorders, can occur but with poor efficiency. Substantial improvements in engraftment will be required in order to derive a clinical benefit from MSC transplantation. Chemokines are the most important factors controlling cellular migration. Stromal-derived factor-1 (SDF-1) has been shown to be critical in promoting the migration of cells to the bone marrow, via its specific receptor CXCR4. The aim of our study was to investigate CXCR4 expression on MSCs and its role in mediating migration to bone marrow. We show that CXCR4, although present at the surface of a small subset of MSCs, is important for mediating specific migration of these cells to bone marrow.

Utilization of the cellular stress response to sensitize cancer cells to TRAIL-mediated apoptosis.

PubMed

Siegelin, Markus David

2012-08-01

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a promising death ligand who has received significant attention due to its specific anti-cancer activity. Recently, a number of clinical trials involving either recombinant soluble TRAIL or agonistic death receptor (DR) antibodies have even been initiated. One major caveat in TRAIL-based anti-cancer therapies is that a considerable number of cancer cells are notorious resistant to apoptosis induction by TRAIL. Overcoming this primary or secondary evolved resistance is an utmost important goal of present cancer research. The current literature suggests that TRAIL resistance is mediated by a number of endogenous factors. According to recent research, stress-related transcription factors have acquired a pivotal role in the sensitization of highly resistant cancer cells, for example, pancreatic cancer and glioblastoma cells, to TRAIL-mediated cell death. Out of this transcription factor family, C/EBP-homologous protein (CHOP) is linked to the control of DR-mediated apoptosis by modulation of several apoptotic and anti-apoptotic factors. Stress responses in certain organelles, such as endoplasmic reticulum (ER) and mitochondria, are potent inductors of CHOP expression. This report focuses on the influence of stress responses on endogenous or acquired resistance to extrinsic apoptosis in tumor cells and summarizes recent findings and results. The Medline and ClinicalTrials database with key words were used for this review. A potential novel treatment strategy for highly treatment-resistant tumors is the induction of a cellular stress response in cancer cells. The induction of an organelle-related stress response, such as nuclear, ER and mitochondrial stress, leads to a dramatic sensitization of a broad variety of cancer cells of different tumor entities to the apoptotic ligand, TRAIL. Importantly, non-neoplastic cells are not sensitized to TRAIL-mediated cell death through the unfolded protein response in most instances, suggesting that this treatment is not only of high efficacy, but even more less of unwanted toxicity in patients.

Factors mediating co-occurrence of an economically valuable introduced fish and its native frog prey.

PubMed

Hartman, Rosemary; Pope, Karen; Lawler, Sharon

2014-06-01

Habitat characteristics mediate predator-prey coexistence in many ecological systems but are seldom considered in species introductions. When economically important introduced predators are stocked despite known negative impacts on native species, understanding the role of refuges, landscape configurations, and community interactions can inform habitat management plans. We measured these factors in basins with introduced trout (Salmonidae) and the Cascades frog (Rana cascadae) to determine, which are responsible for observed patterns of co-occurrence of this economically important predator and its native prey. Large, vegetated shallows were strongly correlated to co-occurrence, and R. cascadae larvae occur in shallower water when fish are present, presumably to escape predation. The number of nearby breeding sites of R. cascadae was also correlated to co-occurrence, but only when the western toad (Anaxyrus boreas) was present. Because A. boreas larvae are unpalatable to fish and resemble R. cascadae, they may provide protection from trout via Batesian mimicry. Although rescue-effect dispersal from nearby populations may maintain co-occurrence, within-lake factors proved more important for predicting co-occurrence. Learning which factors allow co-occurrence between economically important introduced species and their native prey enables managers to make better-informed stocking decisions. © 2013 Society for Conservation Biology.

Social cognition as a mediator variable between neurocognition and functional outcome in schizophrenia: empirical review and new results by structural equation modeling.

PubMed

Schmidt, Stefanie J; Mueller, Daniel R; Roder, Volker

2011-09-01

Cognitive impairments are currently regarded as important determinants of functional domains and are promising treatment goals in schizophrenia. Nevertheless, the exact nature of the interdependent relationship between neurocognition and social cognition as well as the relative contribution of each of these factors to adequate functioning remains unclear. The purpose of this article is to systematically review the findings and methodology of studies that have investigated social cognition as a mediator variable between neurocognitive performance and functional outcome in schizophrenia. Moreover, we carried out a study to evaluate this mediation hypothesis by the means of structural equation modeling in a large sample of 148 schizophrenia patients. The review comprised 15 studies. All but one study provided evidence for the mediating role of social cognition both in cross-sectional and in longitudinal designs. Other variables like motivation and social competence additionally mediated the relationship between social cognition and functional outcome. The mean effect size of the indirect effect was 0.20. However, social cognitive domains were differentially effective mediators. On average, 25% of the variance in functional outcome could be explained in the mediation model. The results of our own statistical analysis are in line with these conclusions: Social cognition mediated a significant indirect relationship between neurocognition and functional outcome. These results suggest that research should focus on differential mediation pathways. Future studies should also consider the interaction with other prognostic factors, additional mediators, and moderators in order to increase the predictive power and to target those factors relevant for optimizing therapy effects.

Preterm Birth Affects the Risk of Developing Immune-Mediated Diseases

PubMed Central

Goedicke-Fritz, Sybelle; Härtel, Christoph; Krasteva-Christ, Gabriela; Kopp, Matthias V.; Meyer, Sascha; Zemlin, Michael

2017-01-01

Prematurity affects approximately 10% of all children, resulting in drastically altered antigen exposure due to premature confrontation with microbes, nutritional antigens, and other environmental factors. During the last trimester of pregnancy, the fetal immune system adapts to tolerate maternal and self-antigens, while also preparing for postnatal immune defense by acquiring passive immunity from the mother. Since the perinatal period is regarded as the most important “window of opportunity” for imprinting metabolism and immunity, preterm birth may have long-term consequences for the development of immune-mediated diseases. Intriguingly, preterm neonates appear to develop bronchial asthma more frequently, but atopic dermatitis less frequently in comparison to term neonates. The longitudinal study of preterm neonates could offer important insights into the process of imprinting for immune-mediated diseases. On the one hand, preterm birth may interrupt influences of the intrauterine environment on the fetus that increase or decrease the risk of later immune disease (e.g., maternal antibodies and placenta-derived factors), whereas on the other hand, it may lead to the premature exposure to protective or harmful extrauterine factors such as microbiota and nutritional antigen. Solving this puzzle may help unravel new preventive and therapeutic approaches for immune diseases. PMID:29062316

How Do Personality Traits Shape Information-Sharing Behaviour in Social Media? Exploring the Mediating Effect of Generalized Trust

ERIC Educational Resources Information Center

Deng, Shengli; Lin, Yanqing; Liu, Yong; Chen, Xiaoyu; Li, Hongxiu

2017-01-01

Introduction: Personality and trust have been found to be important precursors of information-sharing behaviour, but little is known about how these factors interact with each other in shaping information-sharing behaviour. By integrating both trust and user personality into a unified research framework, this study examines how trust mediates the…

Endocrine Disruptors: Adverse Health Effects Mediated by EGFR?

PubMed

Stolz, Ailine; Schönfelder, Gilbert; Schneider, Marlon R

2018-02-01

Although endocrine disruptors represent a serious concern to human health, the underlying molecular mechanisms leading to diseases such as cancer remain poorly understood. Recent work has uncovered the epidermal growth factor receptor (EGFR) as a possible mediator of these adverse health effects, with important implications for the role of endocrine disruptors in human diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye

PubMed Central

Edwards, Rebecca G.

2017-01-01

ABSTRACT As its name suggests, the host receptor herpesvirus entry mediator (HVEM) facilitates herpes simplex virus (HSV) entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both tumor necrosis factor (TNF) and immunoglobulin (Ig) superfamilies with diverse, and often opposing, outcomes. While HVEM was first identified as a viral entry receptor for HSV, it is only recently that HVEM has emerged as an important host factor in immunopathogenesis of ocular HSV type 1 (HSV-1) infection. Surprisingly, HVEM exacerbates disease development in the eye independently of entry. HVEM signaling has been shown to play a variety of roles in modulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated pathogenesis in the eye. Here, we review the dual branches of HVEM function during HSV infection: entry and immunomodulation. HVEM is broadly expressed; intersects two important immunologic signaling networks; and impacts autoimmunity, infection, and inflammation. We hope that by understanding the complex range of effects mediated by this receptor, we can offer insights applicable to a wide variety of disease states. PMID:28404853

The Role of Motivation in Understanding Social Contextual Influences on Physical Activity in Underserved Adolescents in the ACT Trial: A Cross-Sectional Study

PubMed Central

Wilson, Dawn K.; Van Horn, M. Lee; Zarrett, Nicole

2012-01-01

Abstract Background Previous research has shown that social contextual factors are important in understanding physical activity (PA) behavior, although little is known about how these factors may relate to PA, especially in underserved adolescents (low income, minorities). This study examined how motivation may differentially mediate the relationship of two social contextual variables (i.e., peer and parent social support) and moderate-to-vigorous PA (MVPA). Methods Baseline data (n=1421 sixth graders, 54% female, 72% African American) from the Active by Choice Today (ACT) trial in underserved adolescents were analyzed. Motivation was examined as a mediator of the relationships between peer social support, parent social support, and MVPA (measured by 7-day accelerometer estimates). Results Motivation and peer but not parent support were significantly related to MVPA overall. Significant mediation effects were found indicating motivation partially mediated the relation between peer social support and MVPA and to a lesser degree parent support and MVPA. Conclusions These findings provide support for the importance of social contextual influences, especially peer social support, on underserved adolescents' PA and motivation for PA. PMID:23181920

Trophic cascades in rocky shore tide pools: distinguishing lethal and nonlethal effects.

PubMed

Trussell, Geoffrey C; Ewanchuk, Patrick J; Bertness, Mark D; Silliman, Brian R

2004-05-01

The effects of predators on the density of their prey can have positive indirect effects on the abundance of the prey's resource via a trophic cascade. This concept has strongly influenced contemporary views of how communities are structured. However, predators also can transmit indirect effects by inducing changes in prey traits. We show that the mere presence of predator risk cues can initiate a trophic cascade in rocky shore tide pools. In large (mean surface area =9 m2), natural tide pools, we manipulated crab density and their foraging ability to examine the relative importance of lethal (density-mediated) and non-lethal (trait-mediated) predator effects to algal community development. We found that perceived predation risk reduced snail density as much as the direct predation treatment, showing that green crab predation was not an important factor regulating local snail density. Instead, snail emigration away from resident crabs appears to be the most important factor regulating local snail density. As a result, the abundance of ephemeral green algae was similar in the predation risk and direct predation treatments, suggesting that the consumption of snails by crabs plays a minimal role in mediating the trophic cascade. Increased attention to trait-mediated effects that are transmitted by predator-induced changes in prey behavior may change our view of how predators exert their strong influence on community structure.

On their best behavior: how animal behavior can help determine the combined effects of species interactions and climate change.

PubMed

Harmon, Jason P; Barton, Brandon T

2013-09-01

The increasingly appreciated link between climate change and species interactions has the potential to help us understand and predict how organisms respond to a changing environment. As this connection grows, it becomes even more important to appreciate the mechanisms that create and control the combined effect of these factors. However, we believe one such important set of mechanisms comes from species' behavior and the subsequent trait-mediated interactions, as opposed to the more often studied density-mediated effects. Behavioral mechanisms are already well appreciated for mitigating the separate effects of the environment and species interactions. Thus, they could be at the forefront for understanding the combined effects. In this review, we (1) show some of the known behaviors that influence the individual and combined effects of climate change and species interactions; (2) conceptualize general ways behavior may mediate these combined effects; and (3) illustrate the potential importance of including behavior in our current tools for predicting climate change effects. In doing so, we hope to promote more research on behavior and other mechanistic factors that may increase our ability to accurately predict climate change effects. © 2013 New York Academy of Sciences.

Exploring socio-cultural factors that mediate, facilitate, & constrain the health and empowerment of refugee youth.

PubMed

Edge, Sara; Newbold, K Bruce; McKeary, Marie

2014-09-01

Studies on youth health and well-being are predominantly quantitative and expert-driven with less attention given to how youth understand what it means to be healthy themselves and the role of socio-cultural factors in shaping this. Knowledge on the perceptions and experiences of refugee youth is particularly lacking and notable given their unique stressors related to migratory, settlement and integration experiences. We contribute a better understanding of how refugee youth themselves define and contextualize health, with particular emphasis given to socio-cultural factors that enable or constrain health promotion efforts and individual health agency. This research was undertaken at a downtown drop-in centre in Hamilton, Ontario, Canada that provided settlement and integration services to newcomer youth. We employ a grounded theory approach and draw upon participant observation, focus groups and in-depth interviews. Twenty-six youth (age 18-25 years), representing 12 different countries of origin participated. The youth defined health very broadly touching upon many typical determinants of health (e.g. education, income, etc.). Yet factors of most importance (as demonstrated by the frequency and urgency in which they were discussed by youth) included a sense of belonging, positive self-identity, emotional well-being, and sense of agency or self-determination. We conceptualize these as "mediating" factors given the youth argued they enabled or constrained their ability to cope with adversities related to other health determinant categories. The youth also discussed what we interpret as "facilitators" that encourage mediating factors to manifest positively (e.g. informal, non-biomedical settings and programs that nurture trust, break down access barriers, and promote a sense of community amongst peers, mentors, and health professionals). When creating health promotion strategies for refugee youth (and perhaps youth more generally) it is important to understand the factors that may mediate the magnitude of effects from various risks/stressors, in addition to those which facilitate health agency. Copyright © 2014 Elsevier Ltd. All rights reserved.

SOX7 Suppresses Wnt Signaling by Disrupting β-Catenin/BCL9 Interaction.

PubMed

Fan, Rong; He, HaiYan; Yao, Wang; Zhu, YanFeng; Zhou, XunJie; Gui, MingTai; Lu, Jing; Xi, Hao; Deng, ZhongLong; Fan, Min

2018-02-01

The Wnt signaling is involved in angiogenesis and tumor development. β-catenin is the core component of the Wnt pathway, which mediates oncogenic transcription and regulated by a series of proteins. Sex-determining region Y-box 7 (SOX7) is a member of high-mobility-group transcription factor family, which inhibits oncogenic Wnt signaling in lots of tumor cells with unknown mechanism. By coimmunoprecipitation (co-IP) and super Topflash reporter assay, SOX7 can bind β-catenin and inhibit β-catenin/T cell factor (TCF)-mediated transcription. Meanwhile, B cell lymphoma 9 (BCL9) drives Wnt signaling path through direct binding-mediated β-catenin. Finally, we found that SOX7 inhibits oncogenic β-catenin-mediated transcription by disrupting the β-catenin/BCL9 interaction. Mechanistically, SOX7 compete with BCL9 to bind β-catenin. Our results show SOX7 inhibited Wnt signaling as suppressor and could be an important target for anticancer therapy.

Mediators and Treatment Factors in Intervention for Children Exposed to Interparental Violence.

PubMed

Overbeek, Mathilde M; De Schipper, J Clasien; Willemen, Agnes M; Lamers-Winkelman, Francien; Schuengel, Carlo

2017-01-01

Changes in children's emotion differentiation, coping skills, parenting stress, parental psychopathology, and parent-child interaction were explored as mediators of treatment factors in two selective preventive group interventions for children exposed to interparental violence (IPV) and their parents. One hundred thirty-four IPV-exposed children (ages 6-12 years, 52% boys) and their parents were randomized to an IPV-focused or common factors community-based group intervention and completed baseline, posttest, and follow-up assessments for posttraumatic stress (PTS). A multilevel model tested mediators that included children's ability to differentiate emotions and coping skills, parenting stress, parental psychopathology, and parent-child interactions. In both conditions, exposure to nonspecific factors, specific factors unrelated to IPV and trauma-specific intervention factors was coded from videotaped child and parent sessions. Improved parental mental health mediated the link between greater exposure to nonspecific treatment factors and decreases in PTS symptoms. In addition, an increase in emotion differentiation and a decrease in parenting stress were associated with a decrease in PTS symptoms. Greater exposure to trauma-specific factors in child sessions was associated with a small decrease in emotion differentiation, an increase in coping skills, and a decrease in PTS symptoms over time. Greater exposure to nonspecific treatment factors in child and parent sessions was associated with more positive parent-child interaction. Parental mental health appears to be an important mechanism of change that can be promoted through exposure to nonspecific factors in parent intervention. For children, the effect of greater exposure to trauma-specific factors in intervention is less clear and may not have clear benefits.

The CRF system, stress, depression and anxiety – insights from human genetic studies

PubMed Central

Binder, Elisabeth B.; Nemeroff, Charles B.

2011-01-01

A concatenation of findings from preclinical and clinical studies support a preeminent role for the corticotropin-releasing factor (CRF) system in mediating the physiological response to external stressors and in the pathophysiology of anxiety and depression. Recently, human genetic studies have provided considerable support to several long-standing hypotheses of mood and anxiety disorders, including the CRF hypothesis. These data, reviewed in this report, are congruent with the hypothesis that this system is of paramount importance in mediating stress-related psychopathology. More specifically variants in the gene encoding the CRF1 receptor interact with adverse environmental factors to predict risk for stress-related psychiatric disorders. In depth characterization of these variants will likely be important in furthering our understanding of the long term consequences of adverse experience. PMID:20010888

Subjective happiness among mothers of children with disabilities: The role of stress, attachment, guilt and social support.

PubMed

Findler, Liora; Klein Jacoby, Ayelet; Gabis, Lidia

2016-08-01

Parenting a child with disabilities might affect the happiness of the mothers. Hence we adapted Wallander, Varni, Babani, Banis, and Wilcox's (1989) disability-stress-coping model to examine the impact of risk factors (specific stressors related to the child's disability) on the mother's adaptation (happiness). Intrapersonal factors (attachment) and social-ecological factors (social support) were hypothesized to predict adaptation. Both constitute 'risk-resistant' factors, which are mediated by the mother's perceived general stress and guilt. 191 mothers of a child with a developmental disability (ages 3-7) answered questionnaires on happiness, specific and general stress, attachment, guilt and social support. Attachment avoidance was directly and negatively associated with mothers' happiness. General stress was negatively associated with happiness, and mediated the association between anxious attachment, support, and specific stress with happiness. Guilt was negatively associated with happiness, and served as a mediator between attachment anxiety and support and happiness. The findings of the current research show direct and indirect associations of risk factors with happiness and the role of general stress and feelings of guilt as mediators. This study stresses the importance of attachment and social support to happiness and sheds light on the unique role of guilt in promoting or inhibiting happiness. Copyright © 2016 Elsevier Ltd. All rights reserved.

Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong

2015-04-03

Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2more » and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells.« less

Overview of Mediated Courseware in Learning Centers.

ERIC Educational Resources Information Center

Spangenberg, Ronald W.

A limited overview of some media related factors, this document should be helpful to the learning center manager who lacks extensive experience with media. It discusses important theoretical factors associated with media selection and summarizes research concerning the use of color and of motion in learning. Descriptive information concerning…

Negative Social Relationships Predict Posttraumatic Stress Symptoms Among War-Affected Children Via Posttraumatic Cognitions.

PubMed

Palosaari, Esa; Punamäki, Raija-Leena; Peltonen, Kirsi; Diab, Marwan; Qouta, Samir R

2016-07-01

Post traumatic cognitions (PTCs) are important determinants of post traumatic stress symptoms (PTS symptoms). We tested whether risk factors of PTS symptoms (trauma, demographics, social and family-related factors) predict PTCs and whether PTCs mediate the association between risk factors and PTS symptoms among war-affected children. The participants were 240 Palestinian children 10-12 years old, half boys and half girls, and their parents. Children reported about psychological maltreatment, sibling and peer relations, war trauma, PTCs, PTS symptoms, and depression. Parents reported about their socioeconomic status and their own PTS symptoms. The associations between the variables were estimated in structural equation models. In models which included all the variables, PTCs were predicted by and mediated the effects of psychological maltreatment, war trauma, sibling conflict, and peer unpopularity on PTS symptoms. Other predictors had statistically non-significant effects. Psychological maltreatment had the largest indirect effect (b* = 0.29, p = 0.002) and the indirect effects of war trauma (b* = 0.10, p = 0.045), sibling conflict (b* = 0.10, p = 0.045), and peer unpopularity (b* = 0.10, p = 0.094) were lower and about the same size. Age-salient social relationships are potentially important in the development of both PTCs and PTS symptoms among preadolescents. Furthermore, PTCs mediate the effects of the risk factors of PTS symptoms. The causality of the associations among the variables is not established but it could be studied in the future with interventions which improve the negative aspects of traumatized children's important social relationships.

The dampening effect of employees' future orientation on cyberloafing behaviors: the mediating role of self-control.

PubMed

Zhang, Heyun; Zhao, Huanhuan; Liu, Jingxuan; Xu, Yan; Lu, Hui

2015-01-01

Previous studies on reducing employees' cyberloafing behaviors have primarily examined the external control factors but seldomly taken individual internal subjective factors into consideration. Future orientation, an important individual factor, is defined as the extent to which one plans for future time and considers future consequences of one's current behavior. To explore further whether and how employees' future orientation can dampen their cyberloafing behaviors, two studies were conducted to examine the relationship between employees' future orientation and cyberloafing behaviors. The mediation effect of employees' objective and subjective self-control between them was also examined. In Study 1, a set of questionnaires was completed, and the results revealed that the relationship between employees' future orientation and cyberloafing behaviors was negative, and objective self-control mediated the relationship. Next, we conducted a priming experiment (Study 2) to examine the causal relationship and psychological mechanism between employees' future orientation and cyberloafing behaviors. The results demonstrated that employees' future-orientation dampened their attitudes and intentions to engage in cyberloafing, and subjective self-control mediated this dampening effect. Theoretical and practical implications of these findings are also discussed.

Keep Up the Good Work! Age-Moderated Mediation Model on Intention to Retire

PubMed Central

Dordoni, Paola; Van der Heijden, Beatrice; Peters, Pascale; Kraus-Hoogeveen, Sascha; Argentero, Piergiorgio

2017-01-01

In European nations, the aging of the workforce is a major issue which is increasingly addressed both in national and organizational policies in order to sustain older workers' employability and to encourage longer working lives. Particularly older workers' employability can be viewed an important issue as this has the potential to motivate them for their work and change their intention to retire. Based on lifespan development theories and Van der Heijden's ‘employability enhancement model’, this paper develops and tests an age-moderated mediation model (which refers to the processes that we want to test in this model), linking older workers' (55 years old and over) perceptions of job support for learning (job-related factor) and perceptions of negative age stereotypes on productivity (organizational factor), on the one hand, and their intention to retire, on the other hand, via their participation in employability enhancing activities, being the mediator in our model. A total of 2,082 workers aged 55 years and above were included in the analyses. Results revealed that the two proposed relationships between the predictors and intention to retire were mediated by participation in employability enhancing activities, reflecting two mechanisms through which work context affects intention to retire (namely ‘a gain spiral and a loss spiral’). Multi-Group SEM analyses, distinguishing between two age groups (55–60 and 61–65 years old), revealed different paths for the two distinguished groups of older workers. Employability mediated the relationship between perceptions of job support for learning and intention to retire in both age groups, whereas it only mediated the relationship between perceptions of negative age stereotypes and intention to retire in the 55–60 group. From our empirical study, we may conclude that employability is an important factor in the light of older workers' intention to retire. In order to motivate this category of workers to participate in employability enhancing activities and to work longer, negative age stereotypes need to be combated. In addition, creating job support for learning over the lifespan is also an important HR practice to be implemented in nowadays' working life. PMID:29089905

Keep Up the Good Work! Age-Moderated Mediation Model on Intention to Retire.

PubMed

Dordoni, Paola; Van der Heijden, Beatrice; Peters, Pascale; Kraus-Hoogeveen, Sascha; Argentero, Piergiorgio

2017-01-01

In European nations, the aging of the workforce is a major issue which is increasingly addressed both in national and organizational policies in order to sustain older workers' employability and to encourage longer working lives. Particularly older workers' employability can be viewed an important issue as this has the potential to motivate them for their work and change their intention to retire. Based on lifespan development theories and Van der Heijden's 'employability enhancement model', this paper develops and tests an age-moderated mediation model (which refers to the processes that we want to test in this model), linking older workers' (55 years old and over) perceptions of job support for learning (job-related factor) and perceptions of negative age stereotypes on productivity (organizational factor), on the one hand, and their intention to retire, on the other hand, via their participation in employability enhancing activities, being the mediator in our model. A total of 2,082 workers aged 55 years and above were included in the analyses. Results revealed that the two proposed relationships between the predictors and intention to retire were mediated by participation in employability enhancing activities, reflecting two mechanisms through which work context affects intention to retire (namely 'a gain spiral and a loss spiral'). Multi-Group SEM analyses, distinguishing between two age groups (55-60 and 61-65 years old), revealed different paths for the two distinguished groups of older workers. Employability mediated the relationship between perceptions of job support for learning and intention to retire in both age groups, whereas it only mediated the relationship between perceptions of negative age stereotypes and intention to retire in the 55-60 group. From our empirical study, we may conclude that employability is an important factor in the light of older workers' intention to retire. In order to motivate this category of workers to participate in employability enhancing activities and to work longer, negative age stereotypes need to be combated. In addition, creating job support for learning over the lifespan is also an important HR practice to be implemented in nowadays' working life.

Mediators of the relationship between thin-ideal internalization and body dissatisfaction in the natural environment.

PubMed

Fitzsimmons-Craft, Ellen E; Bardone-Cone, Anna M; Crosby, Ross D; Engel, Scott G; Wonderlich, Stephen A; Bulik, Cynthia M

2016-09-01

Social comparisons (i.e., body, eating, exercise) and body surveillance were tested as mediators of the thin-ideal internalization-body dissatisfaction relationship using ecological momentary assessment (EMA). Participants were 232 college women who completed a 2-week EMA protocol, responding to questions three times per day. Multilevel path analysis was used to examine a 2-1-1 mediation model (thin-ideal internalization assessed as trait; between-person effects examined) and a 1-1-1 model (component of thin-ideal internalization [thin-ideal importance] assessed momentarily; within- and between-person effects examined). For the 2-1-1 model, only body comparison and body surveillance were significant specific mediators of the between-person effect. For the 1-1-1 model, all four variables were significant specific mediators of the within-person effect. Only body comparison was a significant specific mediator of the between-person effect. At the state level, many processes explain the thin-ideal internalization-body dissatisfaction relationship. However, at the trait level, body comparison and body surveillance are more important explanatory factors. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mediators of the Relationship Between Thin-Ideal Internalization and Body Dissatisfaction in the Natural Environment

PubMed Central

Fitzsimmons-Craft, Ellen E.; Bardone-Cone, Anna M.; Crosby, Ross D.; Engel, Scott G.; Wonderlich, Stephen A.; Bulik, Cynthia M.

2016-01-01

Social comparisons (i.e., body, eating, exercise) and body surveillance were tested as mediators of the thin-ideal internalization-body dissatisfaction relationship using ecological momentary assessment (EMA). Participants were 232 college women who completed a 2-week EMA protocol, responding to questions three times per day. Multilevel path analysis was used to examine a 2-1-1 mediation model (thin-ideal internalization assessed as trait; between-person effects examined) and a 1-1-1 model (component of thin-ideal internalization [thin-ideal importance] assessed momentarily; within- and between-person effects examined). For the 2-1-1 model, only body comparison and body surveillance were significant specific mediators of the between-person effect. For the 1-1-1 model, all four variables were significant specific mediators of the within-person effect. Only body comparison was a significant specific mediator of the between-person effect. At the state level, many processes explain the thin-ideal internalization-body dissatisfaction relationship. However, at the trait level, body comparison and body surveillance are more important explanatory factors. PMID:27391791

Adipose tissue NAD+ biology in obesity and insulin resistance: From mechanism to therapy.

PubMed

Yamaguchi, Shintaro; Yoshino, Jun

2017-05-01

Nicotinamide adenine dinucleotide (NAD + ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD + biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD + biosynthesis, together with its key downstream mediator, namely the NAD + -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD + biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD + biology. © 2017 WILEY Periodicals, Inc.

Applying the social cognitive perspective to volunteer intention in China: the mediating roles of self-efficacy and motivation.

PubMed

Wang, Ji-Wei; Wei, Chang-Nian; Harada, Koichi; Minamoto, Keiko; Ueda, Kimiyo; Cui, Hong-Wei; Zhang, Cheng-Gang; Cui, Zhi-Ting; Ueda, Atsushi

2011-06-01

When predicting volunteer intention, much attention is paid to the volunteer organization environment (VOE). Given that self-efficacy and motivation have emerged as important predictors of volunteer intention, we adopted a combination of ideas of Bandura's social cognitive theory and Ajzen's theory of planned behavior integrating VOE, self-efficacy and motivation to examine their effects on volunteer intention and to determine whether self-efficacy and motivation mediate the relationship between VOE and volunteer intention. The subjects of this study consisted of 198 community health volunteers in Shanghai city, China. Exploratory factor analysis was performed to identify the factor structure using standard principal component analysis. Six new factors were revealed, including two VOE factors, relation with organization and support from government; two motivation factors, personal attitude and social recognition; self-efficacy and volunteer intention. The results of a hierarchical regression analysis indicated that relation with organization accounted for 14.8% of the variance in volunteer intention, and support from government failed to add significantly to variance in volunteer intention; self-efficacy and personal attitude motivation partially mediated the effects of relation with organization on volunteer intention; social recognition motivation did not mediate the relationship between relation with organization and volunteer intention; and relation with organization, self-efficacy and personal attitude motivation accounted for 33.7% of the variance in volunteer intention. These results provide support for self-efficacy and personal attitude motivation as mediators and provide preliminary insight into the potential mechanisms for predicting volunteer intention and improving volunteering by integrating VOE, self-efficacy and motivation factors.

The social patterns of a biological risk factor for disease: race, gender, socioeconomic position, and C-reactive protein.

PubMed

Herd, Pamela; Karraker, Amelia; Friedman, Elliot

2012-07-01

Understand the links between race and C-reactive protein (CRP), with special attention to gender differences and the role of class and behavioral risk factors as mediators. This study utilizes the National Social Life, Health, and Aging Project data, a nationally representative study of older Americans aged 57-85 to explore two research questions. First, what is the relative strength of socioeconomic versus behavioral risk factors in explaining race differences in CRP levels? Second, what role does gender play in understanding race differences? Does the relative role of socioeconomic and behavioral risk factors in explaining race differences vary when examining men and women separately? When examining men and women separately, socioeconomic and behavioral risk factor mediators vary in their importance. Indeed, racial differences in CRP among men aged 57-74 are little changed after adjusting for both socioeconomic and behavioral risk factors with levels 35% higher for black men as compared to white men. For women aged 57-74, however, behavioral risk factors explain 30% of the relationship between race and CRP. The limited explanatory power of socioeconomic position and, particularly, behavioral risk factors, in elucidating the relationship between race and CRP among men, signals the need for research to examine additional mediators, including more direct measures of stress and discrimination.

Krüppel-like factor 4 is induced by rapamycin and mediates the anti-proliferative effect of rapamycin in rat carotid arteries after balloon injury.

PubMed

Wang, Ying; Zhao, Beilei; Zhang, Yi; Tang, Zhihui; Shen, Qiang; Zhang, Youyi; Zhang, Weizhen; Du, Jie; Chien, Shu; Wang, Nanping

2012-04-01

The transcription factor, Krüppel-like factor 4 (KLF4), plays an important role in regulating the proliferation of vascular smooth muscle cells. This study aimed to examine the effect of rapamycin on the expression of KLF4 and the role of KLF4 in arterial neointimal formation. Expression of KLF4 was monitored using real-time PCR and immunoblotting in cultured vascular smooth muscle cells. and in rat carotid arteries in vivo after balloon injury. Adenovirus-mediated overexpression and siRNA-mediated knockdown of KLF4 were used to examine the role of KLF4 in mediating the anti-proliferative role of rapamycin . KLF4-regulated genes were identified using cDNA microarray. Rapamycin induced the expression of KLF4 in vitro and in vivo. Overexpression of KLF4 inhibited cell proliferation and the activity of mammalian target of rapamycin (mTOR) and its downstream pathways, including 4EBP-1 and p70S6K in vascular smooth muscle cells and prevented the neointimal formation in the balloon-injured arteries. KLF4 up-regulated the expression of GADD45β, p57(kip2) and p27(kip1) . Furthermore, knockdown of KLF4 attenuated the anti-proliferative effect of rapamycin both in vitro and in vivo. KLF4 plays an important role in mediating the anti-proliferative effect of rapamycin in VSMCs and balloon-injured arteries. Thus, it is a potential target for the treatment of proliferative vascular disorders such as restenosis after angioplasty. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Pathways from parental educational attainment to adolescent blood pressure.

PubMed

Kwok, Man Ki; Schooling, Catherine Mary; Subramanian, Subu V; Leung, Gabriel M; Kawachi, Ichiro

2016-09-01

Lower parental education is associated with higher adolescent blood pressure (BP). We examined the contribution of modifiable risk factors from infancy to adolescence that could potentially explain the link between parental education and SBP and DBP in the offspring. In a prospective Chinese birth cohort, 'Children of 1997' of 5604 adolescents (68% follow-up), we analyzed the relation between parental educational attainment and sex-specific, age-specific and height-specific BP z-scores at ∼13 years. Using mediation analysis, we examined the contribution of household income at birth (both absolute income and relative income deprivation), exposures during infancy (breastfeeding and early life second-hand smoking), lifestyles during childhood (diet, physical activity and screen-time), weight or BMI status during fetal, infancy, childhood and puberty, pubertal stage as well as parental BMI. We found that adolescent BMI, but not birth weight or infant growth or childhood BMI, mediated the inverse association of parental education with adolescent SBP (proportion mediated: 24%), followed by maternal BMI (proportion mediated: 18%). Factors explaining the link between parental education and DBP were less clear. Absolute income, breastfeeding, childhood diet and physical activity, pubertal stage and paternal BMI did not mediate the association between parental education and adolescent BP. Low parental education is a risk factor for high SBP and, to a lesser extent, DBP in adolescents. Important mediators of this relation include adolescent and maternal body weight.

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

USDA-ARS?s Scientific Manuscript database

Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the '-amino group of lysi...

An Initial Evaluation of Direct Care Staff Resilience Workshops in Intellectual Disabilities Services

ERIC Educational Resources Information Center

Ingham, Barry; Riley, Jenny; Nevin, Helen; Evans, Gemma; Gair, Elodie

2013-01-01

The emotional responses to challenging behaviour of direct care staff who support people with intellectual disabilities is thought to be an important mediating factor within the stress experienced by staff and a potential maintaining factor in challenging behaviour. A brief workshop to improve direct care staff resilience was developed and…

Anti-Inflammatory Effect of Apigenin on LPS-Induced Pro-Inflammatory Mediators and AP-1 Factors in Human Lung Epithelial Cells.

PubMed

Patil, Rajeshwari H; Babu, R L; Naveen Kumar, M; Kiran Kumar, K M; Hegde, Shubha M; Nagesh, Rashmi; Ramesh, Govindarajan T; Sharma, S Chidananda

2016-02-01

Apigenin is one of the plant flavonoids present in fruits and vegetables, acting as an important nutraceutical component. It is recognized as a potential antioxidant, antimicrobial, and anti-inflammatory molecule. In the present study, the mechanism of anti-inflammatory action of apigenin on lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and activator protein-1 (AP-1) factors in human lung A549 cells was investigated. The anti-inflammatory activity of apigenin on LPS-induced inflammation was determined by analyzing the expression of pro-inflammatory cytokines, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and different AP-1 factors. Apigenin significantly inhibited the LPS-induced expression of iNOS, COX-2, expression of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, and TNF-α), and AP-1 proteins (c-Jun, c-Fos, and JunB) including nitric oxide production. Study confirms the anti-inflammatory effect of apigenin by inhibiting the expression of inflammatory mediators and AP-1 factors involved in the inflammation and its importance in the treatment of lung inflammatory diseases.

A self-determination approach to the understanding of motivation in physical education.

PubMed

Ntoumanis, N

2001-06-01

It is widely acknowledged that Physical Education (PE) can play a potentially important role in enhancing public health by creating positive attitudes toward exercise and by promoting health-related fitness programmes. However, these initiatives will have limited success if students are not motivated to participate actively in their PE lessons. A sequence of motivational processes, proposed by Vallerand (1997), was tested in this study. The sequence has the form 'social factors-->psychological mediators-->types of motivation-->consequences'. Participants were 424 British students aged 14-16 years from Northwest England. Questionnaires were used to measure cooperative learning, self-referenced improvement, and choice of tasks (social factors), perceived competence, autonomy, and relatedness (psychological mediators), intrinsic motivation, identification, introjection, external regulation, and amotivation (types of motivation), and boredom, effort, and future intention to exercise (consequences). A SEM analysis showed that perceived competence was the major psychological mediator. Intrinsic motivation was related to positive consequences, whereas external regulation and amotivation were predictors of negative consequences. A multisample analysis indicated that the model was largely invariant across gender. The findings underline the importance of perceived competence and intrinsic motivation in compulsory PE.

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans.

PubMed

Grants, Jennifer M; Ying, Lisa T L; Yoda, Akinori; You, Charlotte C; Okano, Hideyuki; Sawa, Hitoshi; Taubert, Stefan

2016-02-01

Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinase-dependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals. Copyright © 2016 by the Genetics Society of America.

Personality disorder traits, risk factors, and suicide ideation among older adults.

PubMed

Jahn, Danielle R; Poindexter, Erin K; Cukrowicz, Kelly C

2015-11-01

Personality disorder traits are relatively prevalent among older adults, and can be associated with complex and chronic difficulties, including suicide risk. However, there is a lack of research regarding personality disorders and suicide ideation in older adults. Depressive symptoms and hopelessness may be important to the relation between personality disorders and suicide risk. Additionally, variables from the interpersonal theory of suicide, perceived burdensomeness and thwarted belongingness, may be critical risk factors for suicide in this population. We hypothesized that perceived burdensomeness and thwarted belongingness, theory-based variables, would act as parallel mediators of the relation between personality disorder traits and suicide ideation, whereas depressive symptoms and hopelessness would not. The hypothesis was tested in a sample of 143 older adults recruited from a primary care setting. Participants completed self-report questionnaires of personality traits, suicide ideation, depressive symptoms, hopelessness, perceived burdensomeness, and thwarted belongingness. Findings from a non-parametric bootstrapping procedure indicated that perceived burdensomeness, thwarted belongingness, and depressive symptoms mediated the relation between total personality disorder traits and suicide ideation. Hopelessness did not act as a mediator. These findings indicate that perceived burdensomeness, thwarted belongingness, and depressive symptoms are likely important risk factors for suicide ideation among older adults. Clinicians should be aware of these issues when assessing and treating suicide risk among older adults.

Krüppel-like factor 4 regulates the expression of inducible nitric oxide synthase induced by TNF-α in human fibroblast-like synoviocyte MH7A cells.

PubMed

Mo, Xuanrong; Chen, Jie; Wang, Xinjuan; Pan, Zhenyu; Ke, Yuping; Zhou, Zhidong; Xie, Jiangwen; Lv, Guoju; Luo, Xinjing

2018-01-01

Krüppel-like factor 4 (KLF4), a zinc finger transcription factor, has been implicated in the inflammation mediated by macrophages and endothelial cells by regulating the expression of inflammatory mediators. Here, we investigated whether KLF4 affects the expression of inducible nitric oxide synthase (iNOS), an important inflammatory mediator, in the human RA fibroblast-like synovial cell line MH7A. A pcDNA3.1-KLF4 plasmid or short interfering RNA KLF4 was transfected into MH7A cells, and the iNOS expression and nitric oxide (NO) production were analyzed by quantitative PCR, immunoblotting, and nitrite measurement. The iNOS promoter activity was determined by luciferase assay. The results showed overexpression of KLF4 increased iNOS expression and NO production in the presence or absence of TNF-α. Conversely, KLF4 knockdown markedly reduced iNOS expression and NO production induced by TNF-α. KLF4 activated the transcription activity of iNOS promoter in MH7A cells stimulated by TNF-α. This study indicates that KLF4 is important for regulating the expression of iNOS by TNF-α in human synoviocytes.

A personality-based description of maturing out of alcohol problems: extension with a five-factor model and robustness to modeling challenges.

PubMed

Littlefield, Andrew K; Sher, Kenneth J; Wood, Phillip K

2010-11-01

To examine the relation of changes in Five-Factor personality traits (i.e., extraversion, agreeableness, conscientiousness, neuroticism, and openness to experience; Costa & McCrae, 1985), drinking motives, and problematic alcohol involvement in a cohort of college students (N=467) at varying risk for alcohol use disorders from ages 21 to 35. Parallel process latent growth models were estimated to determine the extent that prospective changes in personality and alcohol problems covaried as well as the extent to which drinking motives appeared to mediate these relations. Changes in neuroticism and conscientiousness covaried with changes in problematic alcohol involvement. Specifically, increases in conscientiousness and decreases in neuroticism were related to decreases in alcohol from ages 21 to 35, even after accounting for marriage and/or parenthood. Change in coping (but not enhancement) motives specifically mediated the relation between changes in conscientiousness and alcohol problems in addition to the relation between changes in neuroticism and alcohol problems. Personality changes, as assessed by a Five-Factor model of personality, are associated with "maturing out" of alcohol problems. Of equal importance, change in coping motives may be an important mediator of the relation between personality change and the "maturing out" of alcohol problems. Published by Elsevier Ltd.

Effects of antibiotic resistance (AR) and microbiota shifts on Campylobacter jejuni-mediated diseases.

PubMed

Brooks, Phillip T; Mansfield, Linda S

2017-12-01

Campylobacter jejuni is an important zoonotic pathogen recently designated a serious antimicrobial resistant (AR) threat. While most patients with C. jejuni experience hemorrhagic colitis, serious autoimmune conditions can follow including inflammatory bowel disease (IBD) and the acute neuropathy Guillain Barré Syndrome (GBS). This review examines inter-relationships among factors mediating C. jejuni diarrheal versus autoimmune disease especially AR C. jejuni and microbiome shifts. Because both susceptible and AR C. jejuni are acquired from animals or their products, we consider their role in harboring strains. Inter-relationships among factors mediating C. jejuni colonization, diarrheal and autoimmune disease include C. jejuni virulence factors and AR, the enteric microbiome, and host responses. Because AR C. jejuni have been suggested to affect the severity of disease, length of infections and propensity to develop GBS, it is important to understand how these interactions occur when strains are under selection by antimicrobials. More work is needed to elucidate host-pathogen interactions of AR C. jejuni compared with susceptible strains and how AR C. jejuni are maintained and evolve in animal reservoirs and the extent of transmission to humans. These knowledge gaps impair the development of effective strategies to prevent the emergence of AR C. jejuni in reservoir species and human populations.

Adenovirus E1a prevents the retinoblastoma gene product from repressing the activity of a cellular transcription factor.

PubMed Central

Zamanian, M; La Thangue, N B

1992-01-01

The retinoblastoma (Rb) gene product forms a complex with the cellular transcription factor DRTF1, a property assumed to be important for mediating negative growth control because certain viral oncogenes, such as adenovirus E1a, prevent this interaction and mutant Rb alleles, which have lost the capacity to regulate growth, encode proteins that fail to associate with DRTF1. In this study, we show that the wild-type Rb protein can specifically repress transcription from promoters driven by DRTF1 whereas a naturally occurring mutant Rb protein cannot. Furthermore, Rb-mediated transcriptional repression can be overridden by adenovirus E1a; this requires regions in E1a necessary for cellular transformation. The Rb protein therefore acts in trans to repress the transcriptional activity of DRTF1 whereas adenovirus E1a prevents this interaction and thus maintains DRTF1 in a constitutively active state. The Rb protein and adenovirus E1a therefore have opposite effects on the activity of a common molecular target. Transcriptional repression mediated by the Rb protein and inactivation of repression by the E1a protein are likely to play an important role in mediating their biological effects. Images PMID:1385776

Cardioprotective Role of Tumor Necrosis Factor Receptor-Associated Factor 2 by Suppressing Apoptosis and Necroptosis.

PubMed

Guo, Xiaoyun; Yin, Haifeng; Li, Lei; Chen, Yi; Li, Jing; Doan, Jessica; Steinmetz, Rachel; Liu, Qinghang

2017-08-22

Programmed cell death, including apoptosis, mitochondria-mediated necrosis, and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis and mitochondria-mediated necrosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain elusive. We examined the role of tumor necrosis factor receptor-associated factor 2 (Traf2) in regulating myocardial necroptosis and remodeling using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which Traf2 regulates necroptosis signaling. We identified a critical role for Traf2 in myocardial survival and homeostasis by suppressing necroptosis. Cardiac-specific deletion of Traf2 in mice triggered necroptotic cardiac cell death, pathological remodeling, and heart failure. Plasma tumor necrosis factor α level was significantly elevated in Traf2 -deficient mice, and genetic ablation of TNFR1 largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deletion. Mechanistically, Traf2 critically regulates receptor-interacting proteins 1 and 3 and mixed lineage kinase domain-like protein necroptotic signaling with the adaptor protein tumor necrosis factor receptor-associated protein with death domain as an upstream regulator and transforming growth factor β-activated kinase 1 as a downstream effector. It is important to note that genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity. These results identify an important Traf2-mediated, NFκB-independent, prosurvival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure. © 2017 American Heart Association, Inc.

The relationship between childhood trauma and the severity of adulthood depression and anxiety symptoms in a clinical sample: The mediating role of cognitive emotion regulation strategies.

PubMed

Huh, Hyu Jung; Kim, Kyung Hee; Lee, Hee-Kyung; Chae, Jeong-Ho

2017-04-15

Childhood trauma is an important factor in adverse mental health outcomes, including depression and anxiety. The purpose of the present study was to evaluate a hypothesized model describing a pathway of childhood trauma and its influence on psychiatric symptoms in patients with depressive disorder. In this model, childhood trauma was positively associated with current depression and anxiety symptoms, which were mediated by a cognitive emotional regulation strategy. Patients with depressive disorder (n=585, 266 men, 316 women) completed the Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Childhood Trauma Questionnaire (CTQ), and Cognitive Emotion Regulation Questionnaire (CERQ). We divided the cognitive emotion regulation strategies into adaptive and maladaptive strategies using a CERQ subscore. We employed structural equation modeling (SEM) and simple/multiple mediation analyses. The indirect effect of maladaptive strategies was significant in the relationship between overall childhood trauma and depression/anxiety severity, whereas the mediation effect of adaptive strategies was limited to depressive symptoms. With respect to specific types of trauma, maladaptive strategies mediated the association between emotional abuse and current depression/anxiety, while the mediation effect of adaptive strategies was limited to emotional neglect. This study's cross-sectional design does not allow establishment of causal relationships. Childhood trauma recall bias may be possible. These findings support the hypothesized model in which childhood trauma is associated with adulthood depression/anxiety symptoms in clinical samples, and mediated by emotion regulation strategies. These results suggest that cognitive emotion dysregulation is an important factor affecting depression/anxiety symptoms in patients with childhood trauma. Copyright © 2017 Elsevier B.V. All rights reserved.

Lipid mediators and their metabolism in the nucleous: implications for Alzheimer's disease.

PubMed

Farooqui, Akhlaq A

2012-01-01

Lipid mediators are important endogenous regulators derived from enzymatic degradation of glycerophospholipids, sphingolipids, and cholesterol by phospholipases, sphingomyelinases, and cytochrome P450 hydroxylases, respectively. In neural cells, lipid mediators are associated with proliferation, differentiation, oxidative stress, inflammation, and apoptosis. A major group of lipid mediators, which originates from the enzymatic oxidation of arachidonic acid, is called eicosanoids (i.e., prostaglandins, leukotrienes, thromboxanes, and lipoxins). The corresponding lipid mediators of docosahexaenoic acid metabolism are named as docosanoids. They include resolvins, protectins (neuroprotectins), and maresins. Docosanoids produce antioxidant, anti-inflammatory, and antiapoptotic effects in brain tissue. Other glycerophospholipid-derived lipid mediators are platelet activating factor, lysophosphatidic acid, and endocannabinoids. Degradation of sphingolipids also results in the generation of sphingolipid-derived lipid mediators, such as ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These mediators are involved in differentiation, growth, cell migration, and apoptosis. Similarly, cholesterol-derived lipid mediators, hydroxycholesterol, produce apoptosis. Abnormal metabolism of lipid mediators may be closely associated with pathogenesis of Alzheimer's disease.

Nutrients and Oxidative Stress: Friend or Foe?

PubMed Central

Tan, Bee Ling; Liew, Winnie-Pui-Pui

2018-01-01

There are different types of nutritionally mediated oxidative stress sources that trigger inflammation. Much information indicates that high intakes of macronutrients can promote oxidative stress and subsequently contribute to inflammation via nuclear factor-kappa B- (NF-κB-) mediated cell signaling pathways. Dietary carbohydrates, animal-based proteins, and fats are important to highlight here because they may contribute to the long-term consequences of nutritionally mediated inflammation. Oxidative stress is a central player of metabolic ailments associated with high-carbohydrate and animal-based protein diets and excessive fat consumption. Obesity has become an epidemic and represents the major risk factor for several chronic diseases, including diabetes, cardiovascular disease (CVD), and cancer. However, the molecular mechanisms of nutritionally mediated oxidative stress are complex and poorly understood. Therefore, this review aimed to explore how dietary choices exacerbate or dampen the oxidative stress and inflammation. We also discussed the implications of oxidative stress in the adipocyte and glucose metabolism and obesity-associated noncommunicable diseases (NCDs). Taken together, a better understanding of the role of oxidative stress in obesity and the development of obesity-related NCDs would provide a useful approach. This is because oxidative stress can be mediated by both extrinsic and intrinsic factors, hence providing a plausible means for the prevention of metabolic disorders. PMID:29643982

Nutrients and Oxidative Stress: Friend or Foe?

PubMed

Tan, Bee Ling; Norhaizan, Mohd Esa; Liew, Winnie-Pui-Pui

2018-01-01

There are different types of nutritionally mediated oxidative stress sources that trigger inflammation. Much information indicates that high intakes of macronutrients can promote oxidative stress and subsequently contribute to inflammation via nuclear factor-kappa B- (NF- κ B-) mediated cell signaling pathways. Dietary carbohydrates, animal-based proteins, and fats are important to highlight here because they may contribute to the long-term consequences of nutritionally mediated inflammation. Oxidative stress is a central player of metabolic ailments associated with high-carbohydrate and animal-based protein diets and excessive fat consumption. Obesity has become an epidemic and represents the major risk factor for several chronic diseases, including diabetes, cardiovascular disease (CVD), and cancer. However, the molecular mechanisms of nutritionally mediated oxidative stress are complex and poorly understood. Therefore, this review aimed to explore how dietary choices exacerbate or dampen the oxidative stress and inflammation. We also discussed the implications of oxidative stress in the adipocyte and glucose metabolism and obesity-associated noncommunicable diseases (NCDs). Taken together, a better understanding of the role of oxidative stress in obesity and the development of obesity-related NCDs would provide a useful approach. This is because oxidative stress can be mediated by both extrinsic and intrinsic factors, hence providing a plausible means for the prevention of metabolic disorders.

Does caregiver well-being predict stroke survivor depressive symptoms? A mediation analysis.

PubMed

Grant, Joan S; Clay, Olivio J; Keltner, Norman L; Haley, William E; Wadley, Virginia G; Perkins, Martinique M; Roth, David L

2013-01-01

Studies suggest that family caregiver well-being (ie, depressive symptoms and life satisfaction) may affect stroke survivor depressive symptoms. We used mediation analysis to assess whether caregiver well-being might be a factor explaining stroke survivor depressive symptoms, after controlling for demographic factors and stroke survivor impairments and problems. Caregiver/stroke participant dyads (N = 146) completed measures of stroke survivor impairments and problems and depressive symptoms and caregiver depressive symptoms and life satisfaction. Mediation analysis was used to examine whether caregiver well-being mediated the relationship between stroke survivor impairments and problems and stroke survivor depressive symptoms. As expected, more stroke survivor problems and impairments were associated with higher levels of stroke survivor depressive symptoms (P < .0001). After controlling for demographic factors, we found that this relationship was partially mediated by caregiver life satisfaction (29.29%) and caregiver depressive symptoms (32.95%). Although these measures combined to account for 40.50% of the relationship between survivor problems and impairments and depressive symptoms, the direct effect remained significant. Findings indicate that stroke survivor impairments and problems may affect family caregivers and stroke survivors and a high level of caregiver distress may result in poorer outcomes for stroke survivors. Results highlight the likely importance of intervening with both stroke survivors and family caregivers to optimize recovery after stroke.

Parental mediation of television viewing and videogaming of adolescents with autism spectrum disorder and their siblings.

PubMed

Kuo, Melissa H; Magill-Evans, Joyce; Zwaigenbaum, Lonnie

2015-08-01

Adolescents with autism spectrum disorder spend considerable time in media activities. Parents play an important role in shaping adolescents' responses to media. This study explored the mediation strategies that parents of adolescents with autism spectrum disorder used to manage television and video game use, factors associated with their use of different strategies, and whether mediation strategies changed over time. A secondary purpose was to examine whether parents applied different mediation strategies to adolescents with autism spectrum disorder versus siblings, and the factors that created stress related to managing media use. Parents of 29 adolescents with autism spectrum disorder and 16 siblings completed questionnaires at two time points. Parents most frequently supervised their television viewing by watching it with the adolescents, and used restrictive strategies to regulate their videogaming. Parents used similar strategies for siblings, but more frequently applied restrictive and instructive strategies for videogaming with adolescents with autism spectrum disorder than their siblings. Restrictive mediation of television viewing for the adolescents decreased significantly over the year. Adolescents' time spent in media activities, age, and behavior problems, and parents' concerns about media use were significant factors associated with the strategies that parents employed. Parents' stress related to the adolescents' behavioral and emotional responses to parental restrictions. © The Author(s) 2014.

A Successful Multifaceted Trial to Improve Hypertension Control in Primary Care: Why Did it Work?

PubMed

Margolis, Karen L; Asche, Stephen E; Bergdall, Anna R; Dehmer, Steven P; Maciosek, Michael V; Nyboer, Rachel A; O'Connor, Patrick J; Pawloski, Pamala A; Sperl-Hillen, JoAnn M; Trower, Nicole K; Tucker, Ann D; Green, Beverly B

2015-11-01

It is important to understand which components of successful multifaceted interventions are responsible for study outcomes, since some components may be more important contributors to the intervention effect than others. We conducted a mediation analysis to determine which of seven factors had the greatest effect on change in systolic blood pressure (BP) after 6 months in a trial to improve hypertension control. The study was a preplanned secondary analysis of a cluster-randomized clinical trial. Eight clinics in an integrated health system were randomized to provide usual care to their patients (n = 222), and eight were randomized to provide a telemonitoring intervention (n = 228). Four hundred three of 450 trial participants completing the 6-month follow-up visit were included. Intervention group participants received home BP telemonitors and transmitted measurements to pharmacists, who adjusted medications and provided advice to improve adherence to medications and lifestyle modification via telephone visits. Path analytic models estimated indirect effects of the seven potential mediators of intervention effect (defined as the difference between the intervention and usual care groups in change in systolic BP from baseline to 6 months). The potential mediators were change in home BP monitor use, number of BP medication classes, adherence to BP medications, physical activity, salt intake, alcohol use, and weight. The difference in change in systolic BP was 11.3 mmHg. The multivariable mediation model explained 47 % (5.3 mmHg) of the intervention effect. Nearly all of this was mediated by two factors: an increase in medication treatment intensity (24 %) and increased home BP monitor use (19 %). The other five factors were not significant mediators, although medication adherence and salt intake improved more in the intervention group than in the usual care group. Most of the explained intervention effect was attributable to the combination of self-monitoring and medication intensification. High adherence at baseline and the relatively low intensity of resources directed toward lifestyle change may explain why these factors did not contribute to the improvement in BP.

Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication.

PubMed

Ren, Xiaodi; Siegel, Rachael; Kim, Unkyu; Roeder, Robert G

2011-05-06

B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in Igh promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated Igh promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3' enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3' enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. Copyright © 2011 Elsevier Inc. All rights reserved.

Direct interactions of OCA-B and TFII-I regulate immunoglobulin heavy-chain gene transcription by facilitating enhancer-promoter communication

PubMed Central

Ren, Xiaodi; Siegel, Rachael; Kim, Unkyu; Roeder, Robert G.

2011-01-01

Summary B cell-specific coactivator OCA-B, together with Oct-1/2, binds to octamer sites in promoters and enhancers to activate transcription of immunoglobulin (Ig) genes, although the mechanisms underlying their roles in enhancer-promoter communication are unknown. Here, we demonstrate a direct interaction of OCA-B with transcription factor TFII-I, which binds to DICE elements in IgH promoters, that affects transcription at two levels. First, OCA-B relieves HDAC3-mediated IgH promoter repression by competing with HDAC3 for binding to promoter-bound TFII-I. Second, and most importantly, Igh 3′enhancer-bound OCA-B and promoter-bound TFII-I mediate promoter-enhancer interactions, in both cis and trans, that are important for Igh transcription. These and other results reveal an important function for OCA-B in Igh 3′enhancer function in vivo and strongly favor an enhancer mechanism involving looping and facilitated factor recruitment rather than a tracking mechanism. PMID:21549311

The Mediator Role of Need Satisfaction between Subjective Well-Being and Romantic Relationships Quality

ERIC Educational Resources Information Center

Eryilmaz, Ali; Dogan, Tayfun

2013-01-01

Problem Statement: The most important part of identity exploration for emerging adults is love. Establishing healthy intimate relationships support the process of identity exploration. In addition to the positive and negative factors that affect romantic relationships, the concept of quality is also very important in these romantic relationships.…

The mediating role of psychological empowerment on job satisfaction and organizational commitment for school health nurses: a cross-sectional questionnaire survey.

PubMed

Chang, Li-Chun; Shih, Chia-Hui; Lin, Shu-Man

2010-04-01

The importance of the professional role of school health nurses in promoting children's health in their school environment is widely recognized. However, studies of their working experience have revealed feelings of disempowerment that appear to be related to insufficient support from school managers. In these unsupportive working environments, it seems possible that psychological empowerment may play a mediating role to strengthen employees' satisfaction and commitment to their employing organization. The aim of this study is to test an exploratory model of empowerment in a Taiwanese sample of school health nurses by examining the mediating role of psychological empowerment in the relationship between external factors and work-related attitudes, specifically job satisfaction and organizational commitment. A cross-sectional survey with self-reported questionnaires. Probability proportional sampling was used to generate a randomly selected sample of 500 school health nurses in elementary and junior high schools in Taiwan. A total of 330 valid questionnaires were returned, yielding a response rate of 66%. The exploratory model including all hypothesized variables provided an adequate fit (chi(2)=29.24; df=17; p=.052; adjusted goodness-of-fit index [AGFI]=.96; goodness-of-fit index [GFI]=.98; root-mean-square error of approximation [RMSEA]=.05) for the data and indicated that psychological empowerment did not fully mediate the relationship between organizational empowerment and job satisfaction because of the strong direct effects of organizational empowerment on job satisfaction. The influence of empowerment on organizational commitment was mediated through job satisfaction. Psychological empowerment did not mediate the relationship between external factors and work attitudes, and job satisfaction emerged as an important factor. If school leaders can improve the job satisfaction of school health nurses, this will help them achieve greater commitment and loyalty of school health nurses to their employing schools. Copyright 2009 Elsevier Ltd. All rights reserved.

Perceived Social Ecological Factors Associated with Fruit and Vegetable Purchasing, Preparation, and Consumption among Young Adults

PubMed Central

Graham, Dan J.; Pelletier, Jennifer; Neumark-Sztainer, Dianne; Lust, Katherine; Laska, Melissa N.

2013-01-01

Most young adults do not consume recommended levels of fruits and vegetables (FV), and interventions to increase FV-related behaviors among this understudied population are needed. Therefore, it is important to identify correlates of FV intake among young adults to guide intervention development. This cross-sectional study utilized data from an online survey to identify factors related to young adults’ FV purchasing, preparation, and consumption, and to explore between-factor relationships using mediation analysis. In 2010, 1201 college students in Minnesota completed questionnaires assessing FV behaviors, as well as perceptions of FV-related individual, social, and environmental factors. Factor analysis identified questionnaire items assessing similar constructs. Seven factors were identified (personal barriers, FV knowledge, family, friends, neighborhood, access barriers, and campus) and evaluated for relationships with FV purchasing, preparation, and consumption using linear regression. Results revealed that perceived personal barriers (e.g., lacking cooking skills) were inversely related to all FV outcomes. Perception that family and friends eat healthfully and neighborhood access to FV were positively related to all outcomes. Individual-, social-, and environmental-level perceptions were related to purchasing, preparation, and consumption, and the effects of these factors were similar when accounting for mediated effects. Factors at all three levels and the ways in which these various factors operate together may be important to consider in future efforts to improve FV behaviors among young adults. PMID:23958116

ABFs, a family of ABA-responsive element binding factors.

PubMed

Choi, H; Hong, J; Ha, J; Kang, J; Kim, S Y

2000-01-21

Abscisic acid (ABA) plays an important role in environmental stress responses of higher plants during vegetative growth. One of the ABA-mediated responses is the induced expression of a large number of genes, which is mediated by cis-regulatory elements known as abscisic acid-responsive elements (ABREs). Although a number of ABRE binding transcription factors have been known, they are not specifically from vegetative tissues under induced conditions. Considering the tissue specificity of ABA signaling pathways, factors mediating ABA-dependent stress responses during vegetative growth phase may thus have been unidentified so far. Here, we report a family of ABRE binding factors isolated from young Arabidopsis plants under stress conditions. The factors, isolated by a yeast one-hybrid system using a prototypical ABRE and named as ABFs (ABRE binding factors) belong to a distinct subfamily of bZIP proteins. Binding site selection assay performed with one ABF showed that its preferred binding site is the strong ABRE, CACGTGGC. ABFs can transactivate an ABRE-containing reporter gene in yeast. Expression of ABFs is induced by ABA and various stress treatments, whereas their induction patterns are different from one another. Thus, a new family of ABRE binding factors indeed exists that have the potential to activate a large number of ABA/stress-responsive genes in Arabidopsis.

Macrophages control vascular stem/progenitor cell plasticity through tumor necrosis factor-α-mediated nuclear factor-κB activation.

PubMed

Wong, Mei Mei; Chen, Yikuan; Margariti, Andriani; Winkler, Bernhard; Campagnolo, Paola; Potter, Claire; Hu, Yanhua; Xu, Qingbo

2014-03-01

Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process. We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α-mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation. Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α-mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.

Basic Fibroblast Growth Factor Activates Serum Response Factor Gene Expression by Multiple Distinct Signaling Mechanisms

PubMed Central

Spencer, Jeffrey A.; Major, Michael L.; Misra, Ravi P.

1999-01-01

Serum response factor (SRF) plays a central role in the transcriptional response of mammalian cells to a variety of extracellular signals. It is a key regulator of many cellular early response genes which are believed to be involved in cell growth and differentiation. The mechanism by which SRF activates transcription in response to mitogenic agents has been extensively studied; however, significantly less is known about regulation of the SRF gene itself. Previously, we identified distinct regulatory elements in the SRF promoter that play a role in activation, including a consensus ETS domain binding site, a consensus overlapping Sp/Egr-1 binding site, and two SRF binding sites. We further showed that serum induces SRF by a mechanism that requires an intact SRF binding site, also termed a CArG box. In the present study we demonstrate that in response to stimulation of cells by a purified growth factor, basic fibroblast growth factor (bFGF), the SRF promoter is upregulated by a complex pathway that involves at least two independent mechanisms: a CArG box-independent mechanism that is mediated by an ETS binding site, and a novel CArG box-dependent mechanism that requires both an Sp factor binding site and the CArG motifs for maximal stimulation. Our analysis indicates that the CArG/Sp element activation mechanism is mediated by distinct signaling pathways. The CArG box-dependent component is targeted by a Rho-mediated pathway, and the Sp binding site-dependent component is targeted by a Ras-mediated pathway. Both SRF and bFGF have been implicated in playing an important role in mediating cardiogenesis during development. The implications of our findings for SRF expression during development are discussed. PMID:10330138

Loss of epigenetic Kruppel-like factor 4 histone deacetylase (KLF-4-HDAC)-mediated transcriptional suppression is crucial in increasing vascular endothelial growth factor (VEGF) expression in breast cancer.

PubMed

Ray, Alpana; Alalem, Mohamed; Ray, Bimal K

2013-09-20

Vascular endothelial growth factor (VEGF) is recognized as an important angiogenic factor that promotes angiogenesis in a series of pathological conditions, including cancer, inflammation, and ischemic disorders. We have recently shown that the inflammatory transcription factor SAF-1 is, at least in part, responsible for the marked increase of VEGF levels in breast cancer. Here, we show that SAF-1-mediated induction of VEGF is repressed by KLF-4 transcription factor. KLF-4 is abundantly present in normal breast epithelial cells, but its level is considerably reduced in breast cancer cells and clinical cancer tissues. In the human VEGF promoter, SAF-1- and KLF-4-binding elements are overlapping, whereas SAF-1 induces and KLF-4 suppresses VEGF expression. Ectopic overexpression of KLF-4 and RNAi-mediated inhibition of endogenous KLF-4 supported the role of KLF-4 as a transcriptional repressor of VEGF and an inhibitor of angiogenesis in breast cancer cells. We show that KLF-4 recruits histone deacetylases (HDACs) -2 and -3 at the VEGF promoter. Chronological ChIP assays demonstrated the occupancy of KLF-4, HDAC2, and HDAC3 in the VEGF promoter in normal MCF-10A cells but not in MDA-MB-231 cancer cells. Co-transfection of KLF-4 and HDAC expression plasmids in breast cancer cells results in synergistic repression of VEGF expression and inhibition of angiogenic potential of these carcinoma cells. Together these results identify a new mechanism of VEGF up-regulation in cancer that involves concomitant loss of KLF-4-HDAC-mediated transcriptional repression and active recruitment of SAF-1-mediated transcriptional activation.

DNA Damage Response Factors from Diverse Pathways, Including DNA Crosslink Repair, Mediate Alternative End Joining

PubMed Central

Howard, Sean M.; Yanez, Diana A.; Stark, Jeremy M.

2015-01-01

Alternative end joining (Alt-EJ) chromosomal break repair involves bypassing classical non-homologous end joining (c-NHEJ), and such repair causes mutations often with microhomology at the repair junction. Since the mediators of Alt-EJ are not well understood, we have sought to identify DNA damage response (DDR) factors important for this repair event. Using chromosomal break reporter assays, we surveyed an RNAi library targeting known DDR factors for siRNAs that cause a specific decrease in Alt-EJ, relative to an EJ event that is a composite of Alt-EJ and c-NHEJ (Distal-EJ between two tandem breaks). From this analysis, we identified several DDR factors that are specifically important for Alt-EJ relative to Distal-EJ. While these factors are from diverse pathways, we also found that most of them also promote homologous recombination (HR), including factors important for DNA crosslink repair, such as the Fanconi Anemia factor, FANCA. Since bypass of c-NHEJ is likely important for both Alt-EJ and HR, we disrupted the c-NHEJ factor Ku70 in Fanca-deficient mouse cells and found that Ku70 loss significantly diminishes the influence of Fanca on Alt-EJ. In contrast, an inhibitor of poly ADP-ribose polymerase (PARP) causes a decrease in Alt-EJ that is enhanced by Ku70 loss. Additionally, the helicase/nuclease DNA2 appears to have distinct effects from FANCA and PARP on both Alt-EJ, as well as end resection. Finally, we found that the proteasome inhibitor Bortezomib, a cancer therapeutic that has been shown to disrupt FANC signaling, causes a significant reduction in both Alt-EJ and HR, relative to Distal-EJ, as well as a substantial loss of end resection. We suggest that several distinct DDR functions are important for Alt-EJ, which include promoting bypass of c-NHEJ and end resection. PMID:25629353

Cognitive style as a factor in accounting students' perceptions of career-choice factors.

PubMed

Gul, F; Huang, A; Subramaniam, N

1992-12-01

Since prior studies of individuals' perceptions of career-choice factors have not considered the effect of cognitive styles of subjects, this study, using 68 accounting students, investigated the mediating effects of the field dependent-independent cognitive dimension on perceptions of the importance of career-choice factors. The results, in general, show that cognitive style affected individuals' perceptions of career-choice factors, suggesting that future studies of individuals' perceptions should take into account individual cognitive differences.

Gene Expression Profile of NF-κB, Nrf2, Glycolytic, and p53 Pathways During the SH-SY5Y Neuronal Differentiation Mediated by Retinoic Acid.

PubMed

de Bittencourt Pasquali, Matheus Augusto; de Ramos, Vitor Miranda; Albanus, Ricardo D Oliveira; Kunzler, Alice; de Souza, Luis Henrinque Trentin; Dalmolin, Rodrigo Juliani Siqueira; Gelain, Daniel Pens; Ribeiro, Leila; Carro, Luigi; Moreira, José Cláudio Fonseca

2016-01-01

SH-SY5Y cells, a neuroblastoma cell line that is a well-established model system to study the initial phases of neuronal differentiation, have been used in studies to elucidate the mechanisms of neuronal differentiation. In the present study, we investigated alterations of gene expression in SH-SY5Y cells during neuronal differentiation mediated by retinoic acid (RA) treatment. We evaluated important pathways involving nuclear factor kappa B (NF-κB), nuclear E2-related factor 2 (Nrf2), glycolytic, and p53 during neuronal differentiation. We also investigated the involvement of reactive oxygen species (ROS) in modulating the gene expression profile of those pathways by antioxidant co-treatment with Trolox®, a hydrophilic analogue of α-tocopherol. We found that RA treatment increases levels of gene expression of NF-κB, glycolytic, and antioxidant pathway genes during neuronal differentiation of SH-SY5Y cells. We also found that ROS production induced by RA treatment in SH-SY5Y cells is involved in gene expression profile alterations, chiefly in NF-κB, and glycolytic pathways. Antioxidant co-treatment with Trolox® reversed the effects mediated by RA NF-κB, and glycolytic pathways gene expression. Interestingly, co-treatment with Trolox® did not reverse the effects in antioxidant gene expression mediated by RA in SH-SY5Y. To confirm neuronal differentiation, we quantified endogenous levels of tyrosine hydroxylase, a recognized marker of neuronal differentiation. Our data suggest that during neuronal differentiation mediated by RA, changes in profile gene expression of important pathways occur. These alterations are in part mediated by ROS production. Therefore, our results reinforce the importance in understanding the mechanism by which RA induces neuronal differentiation in SH-SY5Y cells, principally due this model being commonly used as a neuronal cell model in studies of neuronal pathologies.

The Big Five Personality Traits and French Firefighter Burnout: The Mediating Role of Achievement Goals.

PubMed

Vaulerin, Jérôme; Colson, Serge S; Emile, Mélanie; Scoffier-Mériaux, Stéphanie; d'Arripe-Longueville, Fabienne

2016-04-01

We investigated the associations between the Big Five personality traits and occupational burnout in firefighters and the mediating role of achievement goals in this relationship. Two hundred twenty male firefighters from 20 to 62 years old participated and mediation analyses were performed. The results showed that neuroticism was positively related to the three dimensions of burnout, both directly and through mastery avoidance goals. Mastery approach goals mediated the relationships between conscientiousness and physical fatigue and between openness to experience and physical fatigue. Three of the Big Five personality traits, neuroticism, conscientiousness and openness to experience, and achievement goals, may be important factors in understanding and preventing firefighter burnout.

Mediator MED23 Links Pigmentation and DNA Repair through the Transcription Factor MITF.

PubMed

Xia, Min; Chen, Kun; Yao, Xiao; Xu, Yichi; Yao, Jiaying; Yan, Jun; Shao, Zhen; Wang, Gang

2017-08-22

DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Engagement Behaviors of Young Children with Disabilities: Relationships with Preschool Teachers' Implementation of Embedded Instruction

ERIC Educational Resources Information Center

Rakap, Salih

2013-01-01

Engagement is hypothesized to be an important mediating factor in young children's development and learning. A major purpose of early intervention for young children with disabilities is to promote child engagement. While child engagement and related factors have been descriptively investigated since the 1970s, few studies have systematically…

Suppression of nuclear factor erythroid‑2‑related factor 2‑mediated antioxidative defense in the lung injury induced by chronic exposure to methamphetamine in rats.

PubMed

Bai, Yang; Wang, Yun; Liu, Ming; Gu, Yu-Han; Jiang, Bin; Wu, Xu; Wang, Huai-Liang

2017-05-01

The imbalance between oxidative stress and antioxidant defense is important in the pathogenesis of lung diseases. Nuclear factor erythroid‑2‑related factor 2 (Nrf2) is a key transcriptional factor that regulates the antioxidant response. The purpose of the present study was to investigate whether Nrf2‑mediated antioxidative defense is involved in methamphetamine (MA)‑induced lung injury in rats. Following establishment of chronic MA toxicity in rats, Doppler ultrasonic detection was used to measure the changes of physiological indexes, followed by hematoxylin and eosin staining, ELISA and western blot analysis. MA was demonstrated to increase the heart rate and peak blood flow velocity of pulmonary arterial valves and to decrease the survival rate of rats, and resulted in lung injury characterized by perivascular exudates, airspace edema, slight hemorrhage and inflammatory cell infiltration. MA significantly inhibited the expression of nuclear Nrf2 protein and its target genes (glutamate‑cysteine ligase catalytic subunit C and heme oxygenase‑1), and dose‑dependently reduced glutathione (GSH) levels and the ratio of GSH/oxidized glutathione, accompanied by increases in reactive oxygen species (ROS) levels in rat lungs. Linear regression analysis revealed that there was a positive correlation between lung ROS level and lung injury indexes. These findings suggested that chronic exposure to MA led to lung injury by suppression of Nrf2‑mediated antioxidative defense, suggesting that Nrf2 may be an important therapeutic target for MA‑induced chronic lung toxicity.

Signal-mediated nuclear transport in the amoeba.

PubMed

Feldherr, C M; Akin, D

1999-06-01

The evolutionary changes that occur in signal-mediated nuclear transport would be expected to reflect an increasing need to regulate nucleocytoplasmic exchanges as the complexity of organisms increases. This could involve changes in both the composition and structure of the pore complex, as well as the cytosolic factors that mediate transport. In this regard, we investigated the transport process in amoebae (Amoeba proteus and Chaos carolinensis), primitive cells that would be expected to have less stringent regulatory requirements than more complex organisms. Colloidal gold particles, coated with bovine serum albumin (BSA) conjugated with simple (large T) nuclear localization signals (NLSs), bipartite (nucleoplasmin) NLSs or mutant NLSs, were used to assay nuclear import. It was found that in amoebae (1) the diameter of the particles that are able to enter the nucleoplasm is significantly less than in vertebrate cells, (2) the simple NLS is more effective in mediating nuclear import than the bipartite NLS, and (3) the nucleoporins do not appear to be glycosylated. Evidence was also obtained suggesting that, in amoebae, the simple NLS can mediate nuclear export.

The dampening effect of employees’ future orientation on cyberloafing behaviors: the mediating role of self-control

PubMed Central

Zhang, Heyun; Zhao, Huanhuan; Liu, Jingxuan; Xu, Yan; Lu, Hui

2015-01-01

Previous studies on reducing employees’ cyberloafing behaviors have primarily examined the external control factors but seldomly taken individual internal subjective factors into consideration. Future orientation, an important individual factor, is defined as the extent to which one plans for future time and considers future consequences of one’s current behavior. To explore further whether and how employees’ future orientation can dampen their cyberloafing behaviors, two studies were conducted to examine the relationship between employees’ future orientation and cyberloafing behaviors. The mediation effect of employees’ objective and subjective self-control between them was also examined. In Study 1, a set of questionnaires was completed, and the results revealed that the relationship between employees’ future orientation and cyberloafing behaviors was negative, and objective self-control mediated the relationship. Next, we conducted a priming experiment (Study 2) to examine the causal relationship and psychological mechanism between employees’ future orientation and cyberloafing behaviors. The results demonstrated that employees’ future-orientation dampened their attitudes and intentions to engage in cyberloafing, and subjective self-control mediated this dampening effect. Theoretical and practical implications of these findings are also discussed. PMID:26483735

Native low-density lipoprotein uptake by macrophage colony-stimulating factor-differentiated human macrophages is mediated by macropinocytosis and micropinocytosis.

PubMed

Anzinger, Joshua J; Chang, Janet; Xu, Qing; Buono, Chiara; Li, Yifu; Leyva, Francisco J; Park, Bum-Chan; Greene, Lois E; Kruth, Howard S

2010-10-01

To examine the pinocytotic pathways mediating native low-density lipoprotein (LDL) uptake by human macrophage colony-stimulating factor-differentiated macrophages (the predominant macrophage phenotype in human atherosclerotic plaques). We identified the kinase inhibitor SU6656 and the Rho GTPase inhibitor toxin B as inhibitors of macrophage fluid-phase pinocytosis of LDL. Assessment of macropinocytosis by time-lapse microscopy revealed that both drugs almost completely inhibited macropinocytosis, although LDL uptake and cholesterol accumulation by macrophages were only partially inhibited (approximately 40%) by these agents. Therefore, we investigated the role of micropinocytosis in mediating LDL uptake in macrophages and identified bafilomycin A1 as an additional partial inhibitor (approximately 40%) of macrophage LDL uptake that targeted micropinocytosis. When macrophages were incubated with both bafilomycin A1 and SU6656, inhibition of LDL uptake was additive (reaching 80%), showing that these inhibitors target different pathways. Microscopic analysis of fluid-phase uptake pathways in these macrophages confirmed that LDL uptake occurs through both macropinocytosis and micropinocytosis. Our findings show that human macrophage colony-stimulating factor-differentiated macrophages take up native LDL by macropinocytosis and micropinocytosis, underscoring the importance of both pathways in mediating LDL uptake by these cells.

Self-efficacy and pain acceptance as mediators of the relationship between pain and performance of valued life activities in women and men with rheumatoid arthritis.

PubMed

Ahlstrand, Inger; Vaz, Sharmila; Falkmer, Torbjörn; Thyberg, Ingrid; Björk, Mathilda

2017-06-01

To study whether personal factors (self-efficacy and pain acceptance) mediate the relationship between pain and performance of valued life activities in persons with rheumatoid arthritis. Persons with rheumatoid arthritis for at least four years ( n = 737; 73% women) answered a questionnaire measuring self-efficacy, pain acceptance, performance of valued life activities, and self-rated pain. Relationships among these constructs were explored using univariate and multivariate analyses. Structural equation modelling was then used to examine the mediational role of personal factors on the relationship between pain and performance of valued life activities. A direct negative association between pain and performance of valued life activities was identified ( Beta = .34, P < .001). This suggests that people with rheumatoid arthritis who had higher levels of pain has increased difficulties in performing valued life activities. Self-efficacy and activity engagement component of pain acceptance mediated the relationship between pain and performance of valued life activities, however the pain willingness component of pain acceptance did not influence participation in valued life activities. These findings highlight the importance of considering personal factors, such as pain acceptance and self-efficacy, in facilitating participation in valued life activities.

Depressive and anxiety disorders and short leukocyte telomere length: mediating effects of metabolic stress and lifestyle factors.

PubMed

Révész, D; Verhoeven, J E; Milaneschi, Y; Penninx, B W J H

2016-08-01

Depressive and anxiety disorders are associated with shorter leukocyte telomere length (LTL), an indicator of cellular aging. It is, however, unknown which pathways underlie this association. This study examined the extent to which lifestyle factors and physiological changes such as inflammatory or metabolic alterations mediate the relationship. We applied mediation analysis techniques to data from 2750 participants of the Netherlands Study of Depression and Anxiety. LTL was assessed using quantitative polymerase chain reaction. Independent variables were current depressive (30-item Inventory of Depressive Symptoms - Self Report) and anxiety (21-item Beck's Anxiety Inventory) symptoms and presence of a depressive or anxiety disorder diagnosis based on DSM-IV; mediator variables included physiological stress systems, metabolic syndrome components and lifestyle factors. Short LTL was associated with higher symptom severity (B = -2.4, p = 0.002) and current psychiatric diagnosis (B = -63.3, p = 0.024). C-reactive protein, interleukin-6, waist circumference, triglycerides, high-density lipoprotein cholesterol and cigarette smoking were significant mediators in the relationship between psychopathology and LTL. When all significant mediators were included in one model, the effect sizes of the relationships between LTL and symptom severity and current diagnosis were reduced by 36.7 and 32.7%, respectively, and the remaining direct effects were no longer significant. Pro-inflammatory cytokines, metabolic alterations and cigarette smoking are important mediators of the association between depressive and anxiety disorders and LTL. This calls for future research on intervention programs that take into account lifestyle changes in mental health care settings.

Childhood abuse and late-life depression: Mediating effects of psychosocial factors for early- and late-onset depression.

PubMed

Wielaard, Ilse; Hoyer, Mathijs; Rhebergen, Didi; Stek, Max L; Comijs, Hannie C

2018-03-01

Childhood abuse makes people vulnerable to developing depression, even in late life. Psychosocial factors that are common in late life, such as loneliness or lack of a partner, may explain this association. Our aim was to investigate whether the association between childhood abuse and depression in older adults can be explained by psychosocial factors. Cross-sectional data were derived from the Netherlands Study of Depression in Older Persons (aged 60-93), including 132 without lifetime depression, 242 persons with an early-onset depression (<60 years), and 125 with a late-onset (≥60 years) depression. Childhood abuse (yes/no) and a frequency-based childhood abuse index were included. Multinomial regression and multivariable mediation analyses were used to examine the association between childhood abuse and the onset of depression, and the influence of loneliness, social network, and partner status. Multinomial regression analyses showed a significant association between childhood abuse and the childhood abuse index with early- and late-onset depression. Multivariable mediation analyses showed that the association between childhood abuse and early-onset depression was partly mediated by social network size and loneliness. This was particularly present for emotional neglect and psychological abuse, but not for physical and sexual abuse. No psychosocial mediators were found for the association between childhood abuse and late-onset depression. A smaller social network and feelings of loneliness mediate the association between childhood abuse and early-onset depression in older adults. Our findings show the importance of detecting childhood abuse as well as the age at depression onset and mapping of relevant psychosocial factors in the treatment of late-life depression. Copyright © 2018 John Wiley & Sons, Ltd.

Longitudinal Evaluation of the Role of Academic and Social Impairment and Parent-Adolescent Conflict in the Development of Depression in Adolescents with ADHD.

PubMed

Eadeh, Hana-May; Bourchtein, Elizaveta; Langberg, Joshua M; Eddy, Laura D; Oddo, Lauren; Molitor, Stephen J; Evans, Steven W

2017-09-01

Older adolescents with attention-deficit/hyperactivity disorder (ADHD) have a significantly increased likelihood of developing comorbid depression. It is important to evaluate factors during the early adolescent period that may contribute to this risk. A predominant theory is that impairment and failure experiences lead to the development of low-self efficacy and depression, and that parent and family factors also play a role. In a sample of 326 young adolescents with ADHD ( Mage = 12), the present study evaluated whether parent-adolescent conflict mediated the association between social and academic impairment and the development of depression. This study builds upon prior work by evaluating these associations longitudinally and by using a multi-rater approach, including the parent, adolescent, and teacher perspectives. Social and academic impairment directly predicted depression controlling for baseline levels of depression and change in ADHD symptoms. The association between social impairment and depression was partially mediated by parent-adolescent conflict. Mediation through conflict was not found for academic impairment, and the association between academic impairment and depression was no longer significant when accounting for conflict. These findings highlight the importance of social impairment in the development of depression in adolescents with ADHD. Caregivers may play an important role in determining whether adolescents with ADHD internalize social impairment and failure experiences and develop depressive symptoms. Implications of these findings in terms of the importance of interventions focused on parent-adolescent conflict are discussed.

Importin α-importin β complex mediated nuclear translocation of insulin-like growth factor binding protein-5.

PubMed

Sun, Min; Long, Juan; Yi, Yuxin; Xia, Wei

2017-10-28

Insulin-like growth factor-binding protein (IGFBP)-5 is a secreted protein that binds to IGFs and modulates IGF actions, as well as regulates cell proliferation, migration, and apoptosis independent of IGF. Proper cellular localization is critical for the effective function of most signaling molecules. In previous studies, we have shown that the nuclear IGFBP-5 comes from ER-cytosol retro-translocation. In this study, we further investigated the pathway mediating IGFBP-5 nuclear import after it retro-translocation. Importin-α5 was identified as an IGFBP-5-interacting protein with a yeast two-hybrid system, and its interaction with IGFBP-5 was further confirmed by GST pull down and co-immunoprecipitation. Binding affinity of IGFBP-5 and importins were determined by surface plasmon resonance (IGFBP-5/importin-β: K D =2.44e-7, IGFBP-5/importin-α5: K D =3.4e-7). Blocking the importin-α5/importin-β nuclear import pathway using SiRNA or dominant negative impotin-β dramatically inhibited IGFBP-5-EGFP nuclear import, though importin-α5 overexpress does not affect IGFBP-5 nuclear import. Furthermore, nuclear IGFBP-5 was quantified using luciferase report assay. When deleted the IGFBP-5 nuclear localization sequence (NLS), IGFBP-5 ΔNLS loss the ability to translocate into the nucleus and accumulation of IGFBP-5 ΔNLS was visualized in the cytosol. Altogether, our findings provide a substantially evidence showed that the IGFBP-5 nuclear import is mediated by importin-α/importin-β complex, and NLS is critical domain in IGFBP-5 nuclear translocation.

Mediator-dependent Nuclear Receptor Functions

PubMed Central

Chen, Wei; Roeder, Robert

2011-01-01

As gene-specific transcription factors, nuclear hormone receptors are broadly involved in many important biological processes. Their function on target genes requires the stepwise assembly of different coactivator complexes that facilitate chromatin remodeling and subsequent preinitiation complex (PIC) formation and function. Mediator has proved to be a crucial, and general, nuclear receptor-interacting coactivator, with demonstrated functions in transcription steps ranging from chromatin remodeling to subsequent PIC formation and function. Here we discuss (i) our current understanding of pathways that nuclear receptors and other interacting cofactors employ to recruit Mediator to target gene enhancers and promoters, including conditional requirements for the strong NR-Mediator interactions mediated by the NR AF2 domain and the MED1 LXXLLL motifs and (ii) mechanisms by which Mediator acts to transmit signals from enhancer-bound nuclear receptors to the general transcription machinery at core promoters to effect PIC formation and function. PMID:21854863

Contributions of physical function and satisfaction with social roles to emotional distress in chronic pain: a Collaborative Health Outcomes Information Registry (CHOIR) study.

PubMed

Sturgeon, John A; Dixon, Eric A; Darnall, Beth D; Mackey, Sean C

2015-12-01

Individuals with chronic pain show greater vulnerability to depression or anger than those without chronic pain, and also show greater interpersonal difficulties and physical disability. The present study examined data from 675 individuals with chronic pain during their initial visits to a tertiary care pain clinic using assessments from Stanford University's Collaborative Health Outcomes Information Registry (CHOIR). Using a path modeling analysis, the mediating roles of Patient-Reported Outcomes Measurement Information Systems (PROMIS) Physical Function and PROMIS Satisfaction with Social Roles and Activities were tested between pain intensity and PROMIS Depression and Anger. Pain intensity significantly predicted both depression and anger, and both physical function and satisfaction with social roles mediated these relationships when modeled in separate 1-mediator models. Notably, however, when modeled together, ratings of satisfaction with social roles mediated the relationship between physical function and both anger and depression. Our results suggest that the process by which chronic pain disrupts emotional well-being involves both physical function and disrupted social functioning. However, the more salient factor in determining pain-related emotional distress seems to be disruption of social relationships, than global physical impairment. These results highlight the particular importance of social factors to pain-related distress, and highlight social functioning as an important target for clinical intervention in chronic pain.

Transcription factor ZBED6 mediates IGF2 gene expression by regulating promoter activity and DNA methylation in myoblasts

USDA-ARS?s Scientific Manuscript database

Zinc finger, BED-type containing 6 (ZBED6) is an important transcription factor in placental mammals, affecting development, cell proliferation and growth. In this study, we found that the expression of the ZBED6 and IGF2 were up regulated during C2C12 differentiation. The IGF2 expression levels wer...

Clumping factor A-mediated virulence during Staphylococcus aureus infection is retained despite fibrinogen depletion.

PubMed

Palmqvist, Niklas; Josefsson, Elisabet; Tarkowski, Andrzej

2004-02-01

Clumping factor A (ClfA), a fibrinogen-binding protein expressed on the Staphylococcus aureus cell surface, has previously been shown to act as a virulence factor in experimental septic arthritis. Although the interaction between ClfA and fibrinogen is assumed to be of importance for the virulence of S. aureus, this has not been demonstrated in any in vivo model of infection. Therefore, the objective of this study was to investigate the contribution of this interaction to ClfA-mediated virulence in murine S. aureus-induced arthritis. Ancrod, a serine protease with thrombin-like activity, was used to induce in vivo depletion of fibrinogen in mice. Ancrod treatment significantly aggravated septic arthritis following inoculation with a ClfA-expressing strain (Newman) compared to control treatment. Also, ancrod treatment tended to enhance the arthritis induced by a clfA mutant strain (DU5876), indicating that fibrinogen depletion exacerbates septic arthritis in a ClfA-independent manner. Most importantly, the ClfA-expressing strain was much more arthritogenic than the isogenic clfA mutant, following inoculation of fibrinogen-depleted mice. This finding indicates that the interaction between ClfA and free fibrinogen is not required for ClfA-mediated functions contributing to S. aureus virulence. It is conceivable that ClfA contributes to the virulence of S. aureus through interactions with other host ligands than fibrinogen.

APE/Ref-1 makes fine-tuning of CD40-induced B cell proliferation.

PubMed

Merluzzi, Sonia; Gri, Giorgia; Gattei, Valter; Pagano, Michele; Pucillo, Carlo

2008-08-01

Apurinic/apyrimidinic endonuclease-1/Redox factor-1, a multifunctional DNA base excision repair and redox regulation enzyme, plays an important role in oxidative signalling, transcription factor regulation, and cell cycle control. Recently, we have demonstrated that following the triggering of CD40 on B cells, APE/Ref-1 translocates from the cytoplasm to the nucleus and regulates the activity of B cell-specific transcription factors. In the present paper we investigate whether APE/Ref-1 plays a role in controlling CD40-mediated B cell proliferation too. We demonstrate a concurrent increase in proliferation and decrease in apoptosis of primary mouse B cells activated by CD40 cross-linking and transfected with functional APE/Ref-1 antisense oligonucleotide. Moreover, we provide evidence that a redox-mediated signalling mechanism is involved in this process and we propose that APE/Ref-1, controlling the intracellular redox state, may also affect the cell cycle by inducing nucleus-cytoplasm redistribution of p21. Together, these findings suggest that APE/Ref-1 could act as a negative regulator in an adaptive response to elevated ROS levels following CD40 cross-linking. Considering the important role of ROS and APE/Ref-1 in CD40-mediated B cell proliferation, our data will contribute to understand the mechanisms of tumor escape and suggest APE/Ref-1 as a novel target for tumor therapeutic approaches.

APE/Ref-1 makes fine-tuning of CD40-induced B cell proliferation

PubMed Central

Merluzzi, Sonia; Gri, Giorgia; Gattei, Valter; Pagano, Michele; Pucillo, Carlo

2009-01-01

Apurinic/apyrimidinic endonuclease-1/Redox factor-1, a multifunctional DNA base excision repair and redox regulation enzyme, plays an important role in oxidative signalling, transcription factor regulation, and cell cycle control. Recently, we have demonstrated that following the triggering of CD40 on B cells, APE/Ref-1 translocates from the cytoplasm to the nucleus and regulates the activity of B cell-specific transcription factors. In the present paper we investigate whether APE/Ref-1 plays a role in controlling CD40-mediated B cell proliferation too. We demonstrate a concurrent increase in proliferation and decrease in apoptosis of primary mouse B cells activated by CD40 cross-linking and transfected with functional APE/Ref-1 antisense oligonucleotide. Moreover, we provide evidence that a redox-mediated signalling mechanism is involved in this process and we propose that APE/Ref-1, controlling the intracellular redox state, may also affect the cell cycle by inducing nucleus-cytoplasm redistribution of p21. Together, these findings suggest that APE/Ref-1 could act as a negative regulator in an adaptive response to elevated ROS levels following CD40 cross-linking. Considering the important role of ROS and APE/Ref-1 in CD40-mediated B cell proliferation, our data will contribute to understand the mechanisms of tumor escape and suggest APE/Ref-1 as a novel target for tumor therapeutic approaches. PMID:18617267

[The Role of Internet Parenting for the Internet use of Children in Pre-, Primary and Secondary School].

PubMed

Festl, Ruth; Langmeyer, Alexandra N

2018-02-01

The Role of Internet Parenting for the Internet use of Children in Pre-, Primary and Secondary School The present study analyzes the relationship between mothers' and fathers' Internet parenting and children's Internet use across different age groups (1-15 years). Especially, we looked at the influencing factors of parental mediation strategies and the interplay of mothers' and fathers' Internet parenting. Based on data of the DJI-survey "Growing up in Germany" (Aufwachsen in Deutschland: Alltagswelten, AID:A II 2015, N = 1,196), dyadic structural equation models have shown that across all age groups shared parent-child online activities were important influencing factors of regulating the children's Internet use. Also, the self-perceived Internet education competence of mothers and fathers has been confirmed as a relevant factor influencing a more intense use of parental mediation strategies for school-aged children. While the amount of Internet use among young children (1-6 years) was exclusively influenced by features and strategies of mothers' Internet parenting, the transition to elementary school not only marked changes in the frequency of children's Internet use, but also in the ICT parenting of mothers and fathers. For school-aged children, we indeed found an influence of fathers as well as, in case of the oldest age group, a reduced use of parental mediation strategies. However, parents' attitudes, competences and strategies regarding Internet parenting still stayed important during adolescence.

Images of smokers and willingness to smoke among African American pre-adolescents: an application of the prototype/willingness model of adolescent health risk behavior to smoking initiation.

PubMed

Gerrard, Meg; Gibbons, Frederick X; Stock, Michelle L; Lune, Linda S Vande; Cleveland, Michael J

2005-06-01

This study used the prototype/willingness model of adolescent health risk behavior to examine factors related to onset of smoking. Two waves of data were collected from a panel of 742 African American children (mean age=10.5 at Wave 1) and their primary caregivers. Measures included cognitions outlined by the prototype model as well as self-reports of smoking by the parent and child. Structural equation modeling revealed a pattern consistent with expectations generated by the prototype model. The relation between contextual, familial, and dispositional factors-including neighborhood risk, parental smoking, and children's academic orientation-and the initiation of smoking at Wave 2, two years later, was mediated by the children's cognitions. Primary among these cognitions were the children's images of smokers and children's willingness to smoke. Smoking cognitions mediate the impact of important distal factors (such as context, family environment, and disposition) on the onset of smoking in children. Perhaps more important, it is possible to predict onset of smoking in African American children as young as age 10 by assessing the cognitive factors suggested by the prototype model.

Hardiness as a mediator between perceived stress and happiness in nurses.

PubMed

Abdollahi, A; Abu Talib, M; Yaacob, S N; Ismail, Z

2014-01-01

The relevance of the study of happiness and stress in nurses has been emphasized. In this sense, the intelligent use of hardiness is enable nurses to cope better with stress and contribute to being happier. This study aimed to examine the relationship among hardiness, perceived stress, and happiness in nurses. Moreover, we examined the mediator role of hardiness on the relationship between perceived stress and happiness in nurses. Our study revealed that hardi-attitude nurses evaluate situations as less stressful which results in a higher happiness. This study showed hardiness as being a protective factor against perceived stress and a facilitating factor for happiness in nurses. The findings could be important in training future nurses so that hardiness can be imparted, thereby giving them the ability to control their stress. Nursing is a stressful occupation with high levels of stress within the health professions. Given that hardiness is an important construct to enable nurses to cope better with stress and contribute to being happier; therefore, it is necessary we advance our knowledge about the aetiology of happiness, especially the role of hardiness in decreasing stress levels and increasing happiness. The present study sought to investigate the role of hardiness as a mediator between perceived stress and happiness. The participants, comprising 252 nurses from six private hospitals in Tehran, completed the Personal Views Survey, the Perceived Stress Scale, and the Oxford Happiness Inventory. Structural Equation Modelling (SEM) was used to analyse the data and answer the research hypotheses. As expected, hardiness partially mediated between perceived stress and happiness among nurses, and nurses with low levels of perceived stress were more likely to report greater hardiness and happiness. In addition, nurses with high levels of hardiness were more likely to report happiness. This study showed hardiness as being a protective factor against perceived stress and a facilitating factor for happiness in nurses. The findings could be important in training future nurses so that hardiness can be imparted, thereby giving them the ability to control their stress. © 2014 John Wiley & Sons Ltd.

Child Maltreatment and Risky Sexual Behavior.

PubMed

Thompson, Richard; Lewis, Terri; Neilson, Elizabeth C; English, Diana J; Litrownik, Alan J; Margolis, Benyamin; Proctor, Laura; Dubowitz, Howard

2017-02-01

Risky sexual behavior is a serious public health problem. Child sexual abuse is an established risk factor, but other forms of maltreatment appear to elevate risky behavior. The mechanisms by which child maltreatment influence risk are not well understood. This study used data from 859 high-risk youth, followed through age 18. Official reports of each form of maltreatment were coded. At age 16, potential mediators (trauma symptoms and substance use) were assessed. At age 18, risky sexual behavior (more than four partners, unprotected sex, unassertiveness in sexual refusal) was assessed. Neglect significantly predicted unprotected sex. Substance use predicted unprotected sex and four or more partners but did not mediate the effects of maltreatment. Trauma symptoms predicted unprotected sex and mediated effects of emotional maltreatment on unprotected sex and on assertiveness in sexual refusal and the effects of sexual abuse on unprotected sex. Both neglect and emotional maltreatment emerged as important factors in risky sexual behavior. Trauma symptoms appear to be an important pathway by which maltreatment confers risk for risky sexual behavior. Interventions to reduce risky sexual behavior should include assessment and treatment for trauma symptoms and for history of child maltreatment in all its forms.

The Influence of Client Risks and Treatment Engagement on Recidivism

PubMed Central

YANG, YANG; KNIGHT, KEVIN; JOE, GEORGE W.; ROWAN-SZAL, GRACE A.; LEHMAN, WAYNE E. K.; FLYNN, PATRICK M.

2018-01-01

The current study modeled 12 month post-release re-arrest (recidivism) in terms of pretreatment risk factors (i.e., criminal history, criminal thinking,) and during-treatment engagement in a sample of 653 subjects admitted to four prison-based substance treatment programs. Structural Equation Modeling was used to test during-treatment engagement as a mediator variable in explaining the relationship between the pretreatment risk factors and recidivism. Results indicated that (1) a long history of criminal conduct correlated with criminal thinking, which in turn had a significantly negative relationship with engagement in treatment; (2) the level of criminal involvement had a significant relationship with re-arrest, whereas the level of criminal thinking did not influence being re-arrested directly; (3) the relationship between criminal history and re-arrest was partially mediated by criminal thinking and treatment engagement, whereas the relationship between criminal thinking and re-arrest was fully mediated by treatment engagement. The findings suggest that it is important to design interventions targeting criminal thinking and monitor treatment engagement as an indicator of treatment performance. Clinical implications also include the importance of facilitating treatment engagement and the utility of conducting prognostic assessment to inform treatment. PMID:29353986

Factor Xa Activation of Factor V is of Paramount Importance in Initiating the Coagulation System: Lessons from a Tick Salivary Protein

PubMed Central

Schuijt, Tim J.; Bakhtiari, Kamran; Daffre, Sirlei; DePonte, Kathleen; Wielders, Simone J.H.; Marquart, J. Arnoud; Hovius, Joppe W.; van der Poll, Tom; Fikrig, Erol; Bunce, Matthew W.; Camire, Rodney M.; Nicolaes, Gerry A.F.; Meijers, Joost C.M.; van 't Veer, Cornelis

2013-01-01

Background Generation of active procoagulant cofactor FVa and its subsequent association with the enzyme FXa to form the prothrombinase complex is a pivotal initial event in blood coagulation and has been the subject of investigative effort, speculation and controversy. The current paradigm assumes that FV activation is initiated by limited proteolysis by traces of (meizo) thrombin. Methods and Results Recombinant tick salivary protein TIX-5 was produced and anticoagulant properties were studied using plasma, whole blood and purified systems. Here we report that TIX-5 specifically inhibits FXa-mediated FV activation involving the B-domain of FV and show that FXa activation of FV is pivotal for plasma and blood clotting. In line, tick feeding is impaired on TIX-5 immune rabbits displaying the in vivo importance of TIX-5. Conclusions Our data elucidate a unique molecular mechanism by which ticks inhibit the host's coagulation system. Based on our data we propose a revised blood coagulation scheme wherein direct FXa-mediated FV activation occurs in the initiation phase during which thrombin-mediated FV activation is restrained by fibrinogen and inhibitors. PMID:23817575

Causes of CNS inflammation and potential targets for anticonvulsants.

PubMed

Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

2013-08-01

Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

A longitudinal study of cannabis use initiation among high school students: Effects of social anxiety, expectancies, peers and alcohol.

PubMed

Schmits, Emilie; Mathys, Cécile; Quertemont, Etienne

2015-06-01

This study identified protective and risk factors of cannabis use initiation, including expectancies and social anxiety. A questionnaire was completed twice by 877 teenagers. Logistic regressions, mediation and moderation analyses were performed. Significant risk factors were alcohol use, peer users, perceptual enhancement, and craving expectancies. Protective factors were negative behavior expectancies and social anxiety. Social anxiety protected from initiation through the mediating role of perceptual enhancement and craving expectancies, whatever the role of peer users and alcohol use. Findings are discussed in terms of risk and protection, in an overall approach including internalizing factors. Results support the identification of an internalizing profile of adolescents for prevention or treatment and the importance of social anxiety and expectancies in intervention. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Determinants of compulsive buying behavior among young adults: The mediating role of materialism.

PubMed

Islam, Tahir; Wei, Jiuchang; Sheikh, Zaryab; Hameed, Zahid; Azam, Rauf I

2017-12-01

This research seeks to determine what makes young adults materialistic. The study examines the mediating role of materialism between the contextual factors and compulsive buying. Data was gathered from 219 Pakistani undergraduate university students. Partial Least Square (PLS) technique was used to analyze the data. The study confirms the intuition that more materialistic young adults are more likely to be involved in compulsive buying than are less materialistic young adults. The results were similar with the previous literature conducted in the western culture, indicating that also applies in a modern Islamic society. The findings of the study reveal that materialism mediated the relationship between certain sociological factors (i.e., group, media Celebrity endorsement, and TV advertisement) and compulsive buying. The study highlights the importance of understanding young adults' materialistic attitudes and consumption decisions and provides key knowledge for researchers, policymakers, and managers of leading brands. Copyright © 2017. Published by Elsevier Ltd.

Small protein-mediated quorum sensing in a gram-negative bacterium: novel targets for control of infectious disease.

PubMed

Ronald, Pamela C

2011-12-01

Control of Gram-negative bacterial infections of plants and animals remains a major challenge because conventional approaches are often not sufficient to eradicate these infections. One major reason for their persistence seems to be the capability of the bacteria to grow within biofilms that protect them from adverse environmental factors. Quorum sensing (QS) plays an important role in the formation of biofilms. In QS, small molecules serve as signals to recognize bacterial cell population size, leading to changes in expression of specific genes when a signal has accumulated to some threshold concentration. The small protein Ax21 (Activator of XA21-mediated immunity), serves as a QS factor that regulates biofilm formation and virulence in the Gram-negative bacterium, Xanthomonas oryzae pv. oryzae. Knowledge of small protein-mediated QS in Gram-negative bacteria can be used to develop new methods to control persistent Gram-negative infections. © Discovery Medicine

Does childhood misfortune raise the risk of acute myocardial infarction in adulthood?

PubMed Central

Morton, Patricia M.; Mustillo, Sarah A.; Ferraro, Kenneth F.

2014-01-01

Whereas most research on acute myocardial infarction (AMI) has focused on more proximal influences, such as adult health behaviors, the present study examines the early origins of AMI. Longitudinal data were drawn from the National Survey of Midlife Development in the United States (N=3,032), a nationally representative survey of men and women aged 25–74, which spans from 1995 to 2005. A series of event history analyses modeling age of first AMI investigated the direct effects of accumulated and separate domains of childhood misfortune as well as the mediating effects of adult health lifestyle and psychosocial factors. Findings reveal that accumulated childhood misfortune and child maltreatment increased AMI risk, net of several adult covariates, including family history of AMI. Smoking fully mediated the effects of both accumulated childhood misfortune and child maltreatment. These findings reveal the importance of the early origins of AMI and health behaviors as mediating factors. PMID:24581071

Does perceived neighborhood walkability and safety mediate the association between education and meeting physical activity guidelines?

PubMed

Pratt, Michael; Yin, Shaoman; Soler, Robin; Njai, Rashid; Siegel, Paul Z; Liao, Youlian

2015-04-09

The role of neighborhood walkability and safety in mediating the association between education and physical activity has not been quantified. We used data from the 2010 and 2012 Communities Putting Prevention to Work Behavioral Risk Factor Surveillance System and structural equation modeling to estimate how much of the effect of education level on physical activity was mediated by perceived neighborhood walkability and safety. Neighborhood walkability accounts for 11.3% and neighborhood safety accounts for 6.8% of the effect. A modest proportion of the important association between education and physical activity is mediated by perceived neighborhood walkability and safety, suggesting that interventions focused on enhancing walkability and safety could reduce the disparity in physical activity associated with education level.

Epidermal Growth Factor Enhances Cellular Uptake of Polystyrene Nanoparticles by Clathrin-Mediated Endocytosis

PubMed Central

Phuc, Le Thi Minh; Taniguchi, Akiyoshi

2017-01-01

The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF) on the uptake efficiency of polystyrene nanoparticles (PS NPs) by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs) indicated that cellular uptake of PS NPs is related to the binding of EGF–EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas, in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications. PMID:28629179

Epidermal Growth Factor Enhances Cellular Uptake of Polystyrene Nanoparticles by Clathrin-Mediated Endocytosis.

PubMed

Phuc, Le Thi Minh; Taniguchi, Akiyoshi

2017-06-19

The interaction between nanoparticles and cells has been studied extensively, but most research has focused on the effect of various nanoparticle characteristics, such as size, morphology, and surface charge, on the cellular uptake of nanoparticles. In contrast, there have been very few studies to assess the influence of cellular factors, such as growth factor responses, on the cellular uptake efficiency of nanoparticles. The aim of this study was to clarify the effects of epidermal growth factor (EGF) on the uptake efficiency of polystyrene nanoparticles (PS NPs) by A431 cells, a human carcinoma epithelial cell line. The results showed that EGF enhanced the uptake efficiency of A431 cells for PS NPs. In addition, inhibition and localization studies of PS NPs and EGF receptors (EGFRs) indicated that cellular uptake of PS NPs is related to the binding of EGF-EGFR complex and PS NPs. Different pathways are used to enter the cells depending on the presence or absence of EGF. In the presence of EGF, cellular uptake of PS NPs is via clathrin-mediated endocytosis, whereas, in the absence of EGF, uptake of PS NPs does not involve clathrin-mediated endocytosis. Our findings indicate that EGF enhances cellular uptake of PS NPs by clathrin-mediated endocytosis. This result could be important for developing safe nanoparticles and their safe use in medical applications.

The cysteine2/histidine2-type transcription factor ZINC FINGER OF ARABIDOPSIS THALIANA 6-activated C-REPEAT-BINDING FACTOR pathway is essential for melatonin-mediated freezing stress resistance in Arabidopsis.

PubMed

Shi, Haitao; Chan, Zhulong

2014-09-01

Melatonin (N-acetyl-5-methoxytryptamine) is not only a widely known animal hormone, but also an important regulator in plant development and multiple abiotic stress responses. Recently, it has been revealed that melatonin alleviated cold stress through mediating several cold-related genes, including C-REPEAT-BINDING FACTORs (CBFs)/Drought Response Element Binding factors (DREBs), COR15a, and three transcription factors (CAMTA1, ZINC FINGER OF ARABIDOPSIS THALIANA 10 (ZAT10), and ZAT12). In this study, we quantified the endogenous melatonin level in Arabidopsis plant leaves and found the endogenous melatonin levels were significantly induced by cold stress (4 °C) treatment. In addition, we found one cysteine2/histidine2-type zinc finger transcription factor, ZAT6, was involved in melatonin-mediated freezing stress response in Arabidopsis. Interestingly, exogenous melatonin enhanced freezing stress resistance was largely alleviated in AtZAT6 knockdown plants, but was enhanced in AtZAT6 overexpressing plants. Moreover, the expression levels of AtZAT6 and AtCBFs were commonly upregulated by cold stress (4 °C) and exogenous melatonin treatments, and modulation of AtZAT6 expression significantly affected the induction AtCBFs transcripts by cold stress (4 °C) and exogenous melatonin treatments. Taken together, AtZAT6-activated CBF pathway might be essential for melatonin-mediated freezing stress response in Arabidopsis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Suppressive effects of lysozyme on polyphosphate-mediated vascular inflammatory responses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Jiwoo; Ku, Sae-Kwang; Lee, Suyeon

Lysozyme, found in relatively high concentration in blood, saliva, tears, and milk, protects us from the ever-present danger of bacterial infection. Previous studies have reported proinflammatory responses of endothelial cells to the release of polyphosphate(PolyP). In this study, we examined the anti-inflammatory responses and mechanisms of lysozyme and its effects on PolyP-induced septic activities in human umbilical vein endothelial cells (HUVECs) and mice. The survival rates, septic biomarker levels, behavior of human neutrophils, and vascular permeability were determined in PolyP-activated HUVECs and mice. Lysozyme suppressed the PolyP-mediated vascular barrier permeability, upregulation of inflammatory biomarkers, adhesion/migration of leukocytes, and activation and/ormore » production of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, lysozyme demonstrated protective effects on PolyP-mediated lethal death and the levels of the related septic biomarkers. Therefore, these results indicated the therapeutic potential of lysozyme on various systemic inflammatory diseases, such as sepsis or septic shock. -- Highlights: •PolyP is shown to be an important mediator of vascular inflammation. •Lysozyme inhibited PolyP-mediated hyperpermeability. •Lysozyme inhibited PolyP-mediated septic response. •Lysozyme reduced PolyP-induced septic mortality.« less

Social Cognitive Mediators of Sociodemographic Differences in Colorectal Cancer Screening Uptake

PubMed Central

Lo, Siu Hing; Waller, Jo; Vrinten, Charlotte; Kobayashi, Lindsay; von Wagner, Christian

2015-01-01

Background. This study examined if and how sociodemographic differences in colorectal cancer (CRC) screening uptake can be explained by social cognitive factors. Methods. Face-to-face interviews were conducted with individuals aged 60–70 years (n = 1309) living in England as part of a population-based omnibus survey. Results. There were differences in screening uptake by SES, marital status, ethnicity, and age but not by gender. Perceived barriers (stand. b = −0.40, p < 0.001), social norms (stand. b = 0.33, p < 0.001), and screening knowledge (stand. b = 0.17, p < 0.001) had independent associations with uptake. SES differences in uptake were mediated through knowledge, social norms, and perceived barriers. Ethnic differences were mediated through knowledge. Differences in uptake by marital status were primarily mediated through social norms and to a lesser extent through knowledge. Age differences were largely unmediated, except for a small mediated effect via social norms. Conclusions. Sociodemographic differences in CRC screening uptake were largely mediated through social cognitive factors. Impact. Our findings suggest that multifaceted interventions might be needed to reduce socioeconomic inequalities. Ethnic differences might be reduced through improved screening knowledge. Normative interventions could emphasise screening as an activity endorsed by important others outside the immediate family to appeal to a wider audience. PMID:26504782

The BAFF receptor TACI controls IL-10 production by regulatory B cells and CLL B cells.

PubMed

Saulep-Easton, D; Vincent, F B; Quah, P S; Wei, A; Ting, S B; Croce, C M; Tam, C; Mackay, F

2016-01-01

Interleukin (IL)-10-producing B cells (B10 cells) have emerged as important regulatory elements with immunosuppressive roles. Chronic lymphocytic leukemia (CLL) B cells also secrete IL-10 and share features of B10 cells, suggesting a possible contribution of CLL B cells to immunosuppression in CLL patients. Factors controlling the emergence of B10 cells are not known. B-cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) is critical for B-cell maturation and survival, and is implicated in the development and progression of CLL. We sought to investigate the role of BAFF in the emergence of IL-10-producing regulatory B cells in healthy donors and CLL patients. Here, we report that BAFF signaling promotes IL-10 production by CLL B cells in a mouse model of CLL and in CLL patients. Moreover, BAFF-mediated IL-10 production by normal and CLL B cells is mediated via its receptor transmembrane activator and cyclophilin ligand interactor. Our work uncovered a major targetable pathway important for the generation of regulatory B cells that is detrimental to immunity in CLL.

Determining the relative importance of the mechanisms of behavior change within Alcoholics Anonymous: a multiple mediator analysis.

PubMed

Kelly, John F; Hoeppner, Bettina; Stout, Robert L; Pagano, Maria

2012-02-01

Evidence indicates that Alcoholics Anonymous (AA) participation reduces relapse risk but less is known about the mechanisms through which AA confers this benefit. Initial studies indicate self-efficacy, negative affect, adaptive social networks and spiritual practices are mediators of this effect, but because these have been tested in isolation, their relative importance remains elusive. This study tested multiple mediators simultaneously to help determine the most influential pathways. Prospective, statistically controlled, naturalistic investigation examined the extent to which these previously identified mechanisms mediated AA attendance effects on alcohol outcomes controlling for baseline outcome values, mediators, treatment, and other confounders. Nine clinical sites within the United States. Adults (n = 1726) suffering from alcohol use disorder (AUD) initially enrolled in a randomized study with two arms: aftercare (n = 774); and out-patient (n = 952) comparing three out-patient treatments (Project MATCH). AA attendance during treatment; mediators at 9 months; and outcomes [percentage of days abstinent (PDA) and drinks per drinking day (DDD)] at 15 months. Among out-patients the effect of AA attendance on alcohol outcomes was explained primarily by adaptive social network changes and increases in social abstinence self-efficacy. Among more impaired aftercare patients, in addition to mediation through adaptive network changes and increases in social self-efficacy, AA lead to better outcomes through increasing spirituality/religiosity and by reducing negative affect. The degree to which mediators explained the relationship between AA and outcomes ranged from 43% to 67%. While Alcoholics Anonymous facilitates recovery by mobilizing several processes simultaneously, it is changes in social factors which appear to be of primary importance. © 2011 The Authors, Addiction © 2011 Society for the Study of Addiction.

Fibrosis in connective tissue disease: the role of the myofibroblast and fibroblast-epithelial cell interactions

PubMed Central

Krieg, Thomas; Abraham, David; Lafyatis, Robert

2007-01-01

Fibrosis, characterized by excessive extracellular matrix accumulation, is a common feature of many connective tissue diseases, notably scleroderma (systemic sclerosis). Experimental studies suggest that a complex network of intercellular interactions involving endothelial cells, epithelial cells, fibroblasts and immune cells, using an array of molecular mediators, drives the pathogenic events that lead to fibrosis. Transforming growth factor-β and endothelin-1, which are part of a cytokine hierarchy with connective tissue growth factor, are key mediators of fibrogenesis and are primarily responsible for the differentiation of fibroblasts toward a myofibroblast phenotype. The tight skin mouse (Tsk-1) model of cutaneous fibrosis suggests that numerous other genes may also be important. PMID:17767742

Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival.

PubMed

Tiong, Kai Hung; Tan, Boon Shing; Choo, Heng Lungh; Chung, Felicia Fei-Lei; Hii, Ling-Wei; Tan, Si Hoey; Khor, Nelson Tze Woei; Wong, Shew Fung; See, Sze-Jia; Tan, Yuen-Fen; Rosli, Rozita; Cheong, Soon-Keng; Leong, Chee-Onn

2016-09-06

Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.

Plant-mediated silencing of the fatty acid- and retinoid-binding Pp-far-1 gene can reduce development of the root lesion nematode, Pratylenchus penetrans

USDA-ARS?s Scientific Manuscript database

Pratylenchus penetrans is one of the most important plant-parasitic nematodes and can act as a limiting factor of important agricultural, horticultural and industrial crops. Fatty acid- and retinoid- (FAR) binding proteins are unique to nematodes. The cDNA corresponding to a putative P. penetrans FA...

HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development

PubMed Central

Rutkowski, Timothy P.; Kohn, Anat; Sharma, Deepika; Ren, Yinshi; Mirando, Anthony J.

2016-01-01

ABSTRACT RBPjκ-dependent Notch signaling regulates multiple processes during cartilage development, including chondrogenesis, chondrocyte hypertrophy and cartilage matrix catabolism. Select members of the HES- and HEY-families of transcription factors are recognized Notch signaling targets that mediate specific aspects of Notch function during development. However, whether particular HES and HEY factors play any role(s) in the processes during cartilage development is unknown. Here, for the first time, we have developed unique in vivo genetic models and in vitro approaches demonstrating that the RBPjκ-dependent Notch targets HES1 and HES5 suppress chondrogenesis and promote the onset of chondrocyte hypertrophy. HES1 and HES5 might have some overlapping function in these processes, although only HES5 directly regulates Sox9 transcription to coordinate cartilage development. HEY1 and HEYL play no discernable role in regulating chondrogenesis or chondrocyte hypertrophy, whereas none of the HES or HEY factors appear to mediate Notch regulation of cartilage matrix catabolism. This work identifies important candidates that might function as downstream mediators of Notch signaling both during normal skeletal development and in Notch-related skeletal disorders. PMID:27160681

Evaluating the truth brand.

PubMed

Evans, W Douglas; Price, Simani; Blahut, Steven

2005-03-01

The American Legacy Foundation developed the truth campaign, an aspirational antismoking brand for adolescents. This study tested whether a multidimensional scale, brand equity in truth, mediates the relationship between campaign exposure and youth smoking. We collected brand equity responses from 2,306 youth on a nationally representative telephone survey. Factor analysis indicates that the scale has excellent psychometric properties and effectively measures brand equity. We developed a structural equation model to test the mediation hypothesis. Results show that brand equity mediates the relationship between truth and smoking. Analyses of potential cofounders show this relationship is robust. Behavioral branding (brands about a behavior or a lifestyle) is an important public health strategy.

Does empowerment mediate the effects of psychological factors on mental health, well-being, and recovery in young people?

PubMed

Grealish, Annmarie; Tai, Sara; Hunter, Andrew; Emsley, Richard; Murrells, Trevor; Morrison, Anthony P

2017-09-01

There is consensus that empowerment is key to recovery from mental health problems, enabling a person to take charge of their life and make informed choices and decisions about their life. However, little is known about the mechanisms through which empowerment affects mental health in young people. The current study involved young people aged 16-29 years and examined empowerment as a potential mediator of the relationship between psychological factors (psychosocial, cognition, coping, and control) and mental health, well-being, and recovery from personal problems. A cross-sectional, Internet-based questionnaire study recruited 423 young people aged between 16 and 29 attending universities in England (n = 336) and Ireland (n = 87). Psychological factors, mental well-being, empowerment, and recovery from personal problems were measured using self-report measures. Mediation analysis in both the single and one over-arching mediator models revealed that empowerment mediates the relationship between psychological factors (psychosocial, self-efficacy, thinking style, coping, and control) and mental health, well-being, and recovery from general life problems. This study demonstrates the importance of empowerment, showing that it mediates the relationship between psychological processes and mental health, well-being, and recovery in young people. Clinical implications for working with young people within mental health services, and facilitating their empowerment are discussed. Empowerment is currently a poorly defined concept. This study demonstrates how empowerment mediates the relationship between psychological processes and mental health, well-being, and recovery in young people. Clinicians working with young people might benefit from a structured means of understanding and assessing the different ways in which individuals manage their thinking styles. Empowerment in young people is influenced by the manner in which clinicians facilitate them in establishing social networks in support of employment, education, family/social relations and to encourage young people to take an assertive role in their own care. © 2016 The British Psychological Society.

Emerging functions of multi-protein complex Mediator with special emphasis on plants.

PubMed

Malik, Naveen; Agarwal, Pinky; Tyagi, Akhilesh

2017-10-01

Mediator is a multi-subunit protein complex which is involved in transcriptional regulation in yeast and other eukaryotes. As a co-activator, it connects information from transcriptional activators/repressors to transcriptional machinery including RNA polymerase II and general transcription factors. It is not only involved in transcription initiation but also has important roles to play in transcription elongation and termination. Functional attributes of different Mediator subunits have been largely defined in yeast and mammalian systems earlier, while such studies in plants have gained momentum recently. Mediator regulates various processes related to plant development and is also involved in biotic and abiotic stress response. Thus, plant Mediator, like yeast and mammalian Mediator complex, is indispensable for plant growth and survival. Interaction of its multiple subunits with other regulatory proteins and their ectopic expression or knockdown in model plant like Arabidopsis and certain crop plants are paving the way to biochemical analysis and unravel molecular mechanisms of action of Mediator in plants.

Targeting the Interleukin-6/Jak/Stat Pathway in Human Malignancies

PubMed Central

Sansone, Pasquale; Bromberg, Jacqueline

2012-01-01

The Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway was discovered 20 years ago as a mediator of cytokine signaling. Since this time, more than 2,500 articles have been published demonstrating the importance of this pathway in virtually all malignancies. Although there are dozens of cytokines and cytokine receptors, four Jaks, and seven Stats, it seems that interleukin-6–mediated activation of Stat3 is a principal pathway implicated in promoting tumorigenesis. This transcription factor regulates the expression of numerous critical mediators of tumor formation and metastatic progression. This review will examine the relative importance and function of this pathway in nonmalignant conditions as well as malignancies (including tumor intrinsic and extrinsic), the influence of other Stats, the development of inhibitors to this pathway, and the potential role of inhibitors in controlling or eradicating cancers. PMID:22355058

The Importance of TLR2 and Macrophages in Modulating a Humoral Response after Encountering Streptococcus pneumoniae

DTIC Science & Technology

2008-03-26

Response after Encountering Streptococcus Pneumoniae" Brian Schae:5 ,Ph.D. Department of Microbi ogy & Immunology Committee Chairperson Masters...presenting cells (APCs), such as macrophages (M ) and dendritic cells (DC) recognize microbial surface components via cell surface receptors (i.e...stimulating factor (GM-CSF). TH1 cells are able to secrete IFN- , which is important in activating M to produce mediators important for microbial

Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation

NASA Astrophysics Data System (ADS)

Tomita, Masanori; Matsumoto, Hideki; Funayama, Tomoo; Yokota, Yuichiro; Otsuka, Kensuke; Maeda, Munetoshi; Kobayashi, Yasuhiko

2015-07-01

In general, a radiation-induced bystander response is known to be a cellular response induced in non-irradiated cells after receiving bystander signaling factors released from directly irradiated cells within a cell population. Bystander responses induced by high-linear energy transfer (LET) heavy ions at low fluence are an important health problem for astronauts in space. Bystander responses are mediated via physical cell-cell contact, such as gap-junction intercellular communication (GJIC) and/or diffusive factors released into the medium in cell culture conditions. Nitric oxide (NO) is a well-known major initiator/mediator of intercellular signaling within culture medium during bystander responses. In this study, we investigated the NO-mediated bystander signal transduction induced by high-LET argon (Ar)-ion microbeam irradiation of normal human fibroblasts. Foci formation by DNA double-strand break repair proteins was induced in non-irradiated cells, which were co-cultured with those irradiated by high-LET Ar-ion microbeams in the same culture plate. Foci formation was suppressed significantly by pretreatment with an NO scavenger. Furthermore, NO-mediated reproductive cell death was also induced in bystander cells. Phosphorylation of NF-κB and Akt were induced during NO-mediated bystander signaling in the irradiated and bystander cells. However, the activation of these proteins depended on the incubation time after irradiation. The accumulation of cyclooxygenase-2 (COX-2), a downstream target of NO and NF-κB, was observed in the bystander cells 6 h after irradiation but not in the directly irradiated cells. Our findings suggest that Akt- and NF-κB-dependent signaling pathways involving COX-2 play important roles in NO-mediated high-LET heavy-ion-induced bystander responses. In addition, COX-2 may be used as a molecular marker of high-LET heavy-ion-induced bystander cells to distinguish them from directly irradiated cells, although this may depend on the time after irradiation.

Socioeconomic Associations with ADHD: Findings from a Mediation Analysis.

PubMed

Russell, Abigail Emma; Ford, Tamsin; Russell, Ginny

2015-01-01

Children from disadvantaged socioeconomic backgrounds are at greater risk of a range of negative outcomes throughout their life course than their peers; however the specific mechanisms by which socioeconomic status relates to different health outcomes in childhood are as yet unclear. The current study investigates the relationship between socioeconomic disadvantage in childhood and attention deficit/hyperactivity disorder (ADHD), and investigates putative mediators of this association in a longitudinal population-based birth cohort in the UK. Data from the Avon Longitudinal Study of Parents and Children was used (n = 8,132) to explore the relationship between different measures of socioeconomic status at birth-3 years and their association with a diagnosis of ADHD at age 7. A multiple mediation model was utilised to examine factors occurring between these ages that may mediate the association. Financial difficulties, housing tenure, maternal age at birth of child and marital status were significantly associated with an outcome of ADHD, such that families either living in financial difficulty, living in council housing, with younger or single mothers' were more likely to have a child with a research diagnosis of ADHD at age 7. Financial difficulties was the strongest predictor of ADHD (OR 2.23 95% CI 1.57-3.16). In the multiple mediation model, involvement in parenting at age 6 and presence of adversity at age 2-4 mediated 27.8% of the association. Socioeconomic disadvantage, conceptualised as reported difficulty in affording basic necessities (e.g. heating, food) has both direct and indirect impacts on a child's risk of ADHD. Lower levels of parent involvement mediates this association, as does presence of adversity; with children exposed to adversity and those with less involved parents being at an increased risk of having ADHD. This study highlights the importance of home and environmental factors as small but important contributors toward the aetiology of ADHD.

Bruton's tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-κB recruitment.

PubMed

Page, Theresa H; Urbaniak, Anna M; Espirito Santo, Ana I; Danks, Lynett; Smallie, Timothy; Williams, Lynn M; Horwood, Nicole J

2018-05-05

Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes

PubMed Central

Kim, Jung-Hyun; Baddoo, Melody C.; Park, Eun Young; Stone, Joshua K.; Park, Hyeonsoo; Butler, Thomas W.; Huang, Gang; Yan, Xiaomei; Pauli-Behn, Florencia; Myers, Richard M.; Tan, Ming; Flemington, Erik K.; Lim, Ssang-Taek; Erin Ahn, Eun-Young

2016-01-01

SUMMARY Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia. PMID:26990989

The Mediator Complex Subunit PFT1 Is a Key Regulator of Jasmonate-Dependent Defense in Arabidopsis[C][W

PubMed Central

Kidd, Brendan N.; Edgar, Cameron I.; Kumar, Krish K.; Aitken, Elizabeth A.; Schenk, Peer M.; Manners, John M.; Kazan, Kemal

2009-01-01

Jasmonate signaling plays an important role in both plant defense and development. Here, we have identified a subunit of the Mediator complex as a regulator of the jasmonate signaling pathway in Arabidopsis thaliana. The Mediator complex is a conserved multiprotein complex that acts as a universal adaptor between transcription factors and the RNA polymerase II transcriptional machinery. We report that the PHYTOCHROME AND FLOWERING TIME1 (PFT1) gene, which encodes the MEDIATOR25 subunit of Mediator, is required for jasmonate-dependent defense gene expression and resistance to leaf-infecting necrotrophic fungal pathogens. Conversely, PFT1 appears to confer susceptibility to Fusarium oxysporum, a root-infecting hemibiotrophic fungal pathogen known to hijack jasmonate responses for disease development. Consistent with this, jasmonate gene expression was suppressed in the pft1 mutant during infection with F. oxysporum. In addition, a wheat (Triticum aestivum) homolog of PFT1 complemented the defense and the developmental phenotypes of the pft1 mutant, suggesting that the jasmonate signaling functions of PFT1 may be conserved in higher plants. Overall, our results identify an important control point in the regulation of the jasmonate signaling pathway within the transcriptional machinery. PMID:19671879

Aging and low back pain among exercise participants: a follow-up study with psychological adaptation factors.

PubMed

Wilks, Scott E; Kadivar, Zahra; Guillory, Stephen A; Isaza, Jorge

2009-01-01

This study is a follow-up to a study previously published in this journal that reported the moderating function of exercise exertion amid the relationship between age and low back pain (LBP) among consistent exercise participants. The current study analyzed factors of psychological adaptation as potential mediators within the age--LBP relationship. Measures of psychological adaptation included psychological vulnerability, avoidant coping, resilient coping, and perceived resilience. The sample reported slightly moderate psychological vulnerability; a moderate extent of avoidant coping and resilient coping; and high resilience. Age inversely correlated with psychological vulnerability and avoidance coping. LBP correlated inversely with avoidant coping. Avoidant coping positively mediated (enhanced) age's effect on LBP. Results from this follow-up analysis highlight the importance of understanding and testing psychological factors in models with age and a physical health outcome.

EPAS-1 mediates SP-1-dependent FBI-1 expression and regulates tumor cell survival and proliferation.

PubMed

Wang, Xiaogang; Cao, Peng; Li, Zhiqing; Wu, Dongyang; Wang, Xi; Liang, Guobiao

2014-09-04

Factor binding IST-1 (FBI-1) plays an important role in oncogenic transformation and tumorigenesis. As FBI-1 is over-expressed in multiple human cancers, the regulation of itself would provide new effective options for cancer intervention. In this work, we aimed to study the role that EPAS-1 plays in regulating FBI-1. We use the fact that specificity protein-1 (SP-1) is one of the crucial transcription factors of FBI-1, and that SP-1 can interact with the endothelial pas domain protein-1 (EPAS-1) for the induction of hypoxia related genes. The study showed that EPAS-1 plays an indispensible role in SP-1 transcription factor-mediated FBI-1 induction, and participated in tumor cell survival and proliferation. Thus, EPAS-1 could be a novel target for cancer therapeutics.

Transcription factors as readers and effectors of DNA methylation.

PubMed

Zhu, Heng; Wang, Guohua; Qian, Jiang

2016-08-01

Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.

Transcription factors as readers and effectors of DNA methylation

PubMed Central

Zhu, Heng; Wang, Guohua; Qian, Jiang

2017-01-01

Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease. PMID:27479905

Factor H: A Complement Regulator in Health and Disease, and a Mediator of Cellular Interactions

PubMed Central

Kopp, Anne; Hebecker, Mario; Svobodová, Eliška; Józsi, Mihály

2012-01-01

Complement is an essential part of innate immunity as it participates in host defense against infections, disposal of cellular debris and apoptotic cells, inflammatory processes and modulation of adaptive immune responses. Several soluble and membrane-bound regulators protect the host from the potentially deleterious effects of uncontrolled and misdirected complement activation. Factor H is a major soluble regulator of the alternative complement pathway, but it can also bind to host cells and tissues, protecting them from complement attack. Interactions of factor H with various endogenous ligands, such as pentraxins, extracellular matrix proteins and DNA are important in limiting local complement-mediated inflammation. Impaired regulatory as well as ligand and cell recognition functions of factor H, caused by mutations or autoantibodies, are associated with the kidney diseases: atypical hemolytic uremic syndrome and dense deposit disease and the eye disorder: age-related macular degeneration. In addition, factor H binds to receptors on host cells and is involved in adhesion, phagocytosis and modulation of cell activation. In this review we discuss current concepts on the physiological and pathophysiological roles of factor H in light of new data and recent developments in our understanding of the versatile roles of factor H as an inhibitor of complement activation and inflammation, as well as a mediator of cellular interactions. A detailed knowledge of the functions of factor H in health and disease is expected to unravel novel therapeutic intervention possibilities and to facilitate the development or improvement of therapies. PMID:24970127

The association between home environmental variables and soft drink consumption among adolescents. Exploration of mediation by individual cognitions and habit strength.

PubMed

Tak, N I; Te Velde, S J; Oenema, A; Van der Horst, K; Timperio, A; Crawford, D; Brug, J

2011-04-01

Soft-drink consumption is one of the important target behaviours for the prevention of excessive weight gain among adolescents. To be able to modify these behaviours in obesity prevention interventions, further understanding of the underlying factors and mediational pathways is required. The present study aimed to explore associations between home environment variables and adolescent soft drink consumption and potential mediation of these associations by individual cognitions derived from the Theory of Planned Behaviour and habit strength. The ENDORSE study (N=1005) provided data on soft drink consumption and on home environment variables related to soft drink consumption (availability, accessibility, parental modelling, and parental rules), cognitive variables (intention, attitude, perceived behaviour control, and parental norm) and habit strength. Multiple mediation analyses were conducted using regression analyses according to the steps described by MacKinnon to assess the association between home environment variables and soft drink consumption and mediation of these associations by cognitive variables and habit strength. The bootstrapping method was used to calculate the confidence intervals. There were significant associations between the home environment variables and soft drink consumption. After inclusion of the mediators the strength of these associations was reduced. In the multiple mediator models, habit strength (39.4-62.6%) and intention (19.1-36.6%) were the strongest mediators. Intention and habit strength partly mediate the associations between home environment factors and soft drink consumption, suggesting that home environment variables influence soft drink consumption both indirectly and directly. Copyright © 2011 Elsevier Ltd. All rights reserved.

Factors limiting the spread of the protective symbiont HAMILTONELLA DEFENSA in the aphid APHIS CRACCIVORA

USDA-ARS?s Scientific Manuscript database

Many insects are associated with heritable facultative symbionts that mediate important ecological interactions, including host protection against natural enemies. Despite such benefits, facultative symbionts are commonly found at intermediate frequencies in surveyed populations. The cowpea aphid,...

Prevalence of allergic sensitization in the U.S.: Results from the National Health and Nutrition Examination Survey (NHANES) 2005–2006

PubMed Central

Salo, Päivi M.; Arbes, Samuel J.; Jaramillo, Renee; Calatroni, Agustin; Weir, Charles H.; Sever, Michelle L.; Hoppin, Jane A.; Rose, Kathryn M.; Liu, Andrew H.; Gergen, Peter J.; Mitchell, Herman E.; Zeldin, Darryl C.

2014-01-01

Background Allergic sensitization is an important risk factor for the development of atopic disease. The National Health and Nutrition Examination Survey (NHANES) 2005–2006 provides the most comprehensive information on IgE-mediated sensitization in the general US population. Objective We investigated clustering, sociodemographic and regional patterns of allergic sensitization and examined risk factors associated with IgE-mediated sensitization. Methods Data for this cross-sectional analysis were obtained from NHANES 2005–2006. Participants aged ≥1 year (N=9440) were tested for sIgEs to inhalant and food allergens; participants ≥6 years were tested for 19 sIgEs, and children aged 1–5 years for 9 sIgEs. Serum samples were analyzed using the ImmunoCAP System. Information on demographics and participant characteristics was collected by questionnaire. Results Of the study population aged 6 and older, 44.6% had detectable sIgEs, while 36.2% of children aged 1–5 years were sensitized to ≥1 allergen. Allergen-specific IgEs clustered into 7 groups that might have largely reflected biological cross-reactivity. Although sensitization to individual allergens and allergen types showed regional variation, the overall prevalence of sensitization did not differ across census regions, except in early childhood. In multivariate modeling, young age, male gender, non-Hispanic black race/ethnicity, geographic location (census region), and reported pet avoidance measures were most consistently associated with IgE-mediated sensitization. Conclusions The overall prevalence of allergic sensitization does not vary across US census regions, except in early life, although allergen-specific sensitization differs by sociodemographic and regional factors. Biological cross-reactivity may be an important, but not a sole, contributor to the clustering of allergen-specific IgEs. Clinical implications IgE-mediated sensitization shows clustering patterns and differs by sociodemographic and regional factors, but the overall prevalence of sensitization may not vary across US census regions. PMID:24522093

Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15.

PubMed

Borner, Tito; Arnold, Myrtha; Ruud, Johan; Breit, Samuel N; Langhans, Wolfgang; Lutz, Thomas A; Blomqvist, Anders; Riediger, Thomas

2017-06-01

The cancer-anorexia-cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour-derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour-derived macrophage inhibitory cytokine-1 (MIC-1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC-1 in mice. Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC-1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response. In tumour-bearing sham-operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer-induced anorexia or body weight loss. Tumour-bearing rats had substantially increased MIC-1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake. These findings demonstrate the importance of the AP in the mediation of cancer-dependent anorexia and body weight loss and support a pathological role of MIC-1 as a tumour-derived factor mediating CACS, possibly via an AP-dependent action. © 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Anorexia‐cachexia syndrome in hepatoma tumour‐bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC‐1/GDF15

PubMed Central

Borner, Tito; Arnold, Myrtha; Ruud, Johan; Breit, Samuel N.; Langhans, Wolfgang; Lutz, Thomas A.; Blomqvist, Anders

2016-01-01

Abstract Background The cancer‐anorexia‐cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour‐derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour‐derived macrophage inhibitory cytokine‐1 (MIC‐1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC‐1 in mice. Methods Using a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC‐1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response. Results In tumour‐bearing sham‐operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer‐induced anorexia or body weight loss. Tumour‐bearing rats had substantially increased MIC‐1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake. Conclusions These findings demonstrate the importance of the AP in the mediation of cancer‐dependent anorexia and body weight loss and support a pathological role of MIC‐1 as a tumour‐derived factor mediating CACS, possibly via an AP‐dependent action. PMID:28025863

Doxorubicin resistance mediated by cytoplasmic macrophage colony-stimulating factor is associated with switch from apoptosis to autophagic cell death in MCF-7 breast cancer cells

PubMed Central

Zhang, Mengxia; Zhang, Hailiang; Tang, Fan; Wang, Yuhua; Mo, Zhongcheng; Lei, Xiaoyong

2016-01-01

Macrophage colony-stimulating factor is a vital factor in maintaining the biological function of monocyte–macrophage lineage. It is expressed in many tumor tissues and cancer cells. Recent findings indicate that macrophage colony-stimulating factor might contribute to chemoresistance, but the precise mechanisms are unclear. This study was to explore the effect of macrophage colony-stimulating factor on doxorubicin resistance in MCF-7 breast cancer cells and the possible mechanism. In the study, the human breast cancer cells, MCF-7, were transfected with macrophage colony-stimulating factor. We document that cytoplasmic macrophage colony-stimulating factor induces doxorubicin resistance and inhibits apoptosis in MCF-7 cells. Further studies demonstrated that cytoplasmic macrophage colony-stimulating factor-mediated apoptosis inhibition was dependent on the activation of PI3K/Akt/Survivin pathway. More importantly, we found that macrophage colony-stimulating factor-induced autophagic cell death in doxorubicin-treated MCF-7 cells. Taken together, we show for the first time that macrophage colony-stimulating factor-induced doxorubicin resistance is associated with the changes in cell death response with defective apoptosis and promotion of autophagic cell death. PMID:27439542

Hepatitis C virus depends on E-cadherin as an entry factor and regulates its expression in epithelial-to-mesenchymal transition.

PubMed

Li, Qisheng; Sodroski, Catherine; Lowey, Brianna; Schweitzer, Cameron J; Cha, Helen; Zhang, Fang; Liang, T Jake

2016-07-05

Hepatitis C virus (HCV) enters the host cell through interactions with a cascade of cellular factors. Although significant progress has been made in understanding HCV entry, the precise mechanisms by which HCV exploits the receptor complex and host machinery to enter the cell remain unclear. This intricate process of viral entry likely depends on additional yet-to-be-defined cellular molecules. Recently, by applying integrative functional genomics approaches, we identified and interrogated distinct sets of host dependencies in the complete HCV life cycle. Viral entry assays using HCV pseudoparticles (HCVpps) of various genotypes uncovered multiple previously unappreciated host factors, including E-cadherin, that mediate HCV entry. E-cadherin silencing significantly inhibited HCV infection in Huh7.5.1 cells, HepG2/miR122/CD81 cells, and primary human hepatocytes at a postbinding entry step. Knockdown of E-cadherin, however, had no effect on HCV RNA replication or internal ribosomal entry site (IRES)-mediated translation. In addition, an E-cadherin monoclonal antibody effectively blocked HCV entry and infection in hepatocytes. Mechanistic studies demonstrated that E-cadherin is closely associated with claudin-1 (CLDN1) and occludin (OCLN) on the cell membrane. Depletion of E-cadherin drastically diminished the cell-surface distribution of these two tight junction proteins in various hepatic cell lines, indicating that E-cadherin plays an important regulatory role in CLDN1/OCLN localization on the cell surface. Furthermore, loss of E-cadherin expression in hepatocytes is associated with HCV-induced epithelial-to-mesenchymal transition (EMT), providing an important link between HCV infection and liver cancer. Our data indicate that a dynamic interplay among E-cadherin, tight junctions, and EMT exists and mediates an important function in HCV entry.

Leukemia inhibitory factor in the neuroimmune communication pathways in allergic asthma.

PubMed

Lin, Min-Juan; Lao, Xue-Jun; Liu, Sheng-Ming; Xu, Zhen-Hua; Zou, Wei-Feng

2014-03-20

In the pathogenesis of asthma, central sensitization is suggested to be an important neural mechanism, and neurotrophins and cytokines are likely to be the major mediators in the neuroimmune communication pathways of asthma. However, their impact on the central nervous system in allergic asthma remains unclear. We hypothesize that central neurogenic inflammation develops in the pathogenesis of allergic asthma, and nerve growth factor (NGF) and leukemia inhibitory factor (LIF) are important mediators in its development. An asthma model of rats was established by sensitization and challenged with ovalbumin (OVA). For further confirmation of the role of LIF in neurogenic inflammation, a subgroup was pretreated with intraperitoneally (i.p.) LIF antibody before OVA challenge. The levels of LIF and NGF were measured with reverse transcription and polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry stain in lung tissue, airway-specific dorsal root ganglia (DRG, C7-T5) and brain stem of asthmatic rats, anti-LIF pretreated rats and controls. A significantly increased number of LIF- and NGF-immunoreactive cells were detected in lung tissue, DRG and the brain stem of asthmatic rats. In the asthma group a significantly increase level of mRNA encoding LIF and NGF in lung tissue was detected, but not in DRG and the brain stem. Pretreatment with LIF antibody decreased the level of LIF and NGF in all tissues. LIF is an important mediator in the crosstalk between nerve and immune systems. Our study demonstrate that the increased level of LIF and NGF in DRG and brain stem may be not based on result from de novo synthesis, but rather on result from retrograde nerve transport or passage across the blood-brain-barrier. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Prayer and pain: the mediating role of positive re-appraisal.

PubMed

Dezutter, Jessie; Wachholtz, Amy; Corveleyn, Jozef

2011-12-01

The present study explored in a sample of Flemish pain patients the role of prayer as a possible individual factor in pain management. The focus on prayer as a personal religious factor fits with the current religious landscape in Western-Europe where personal religious factors are more important than organizational dimensions of religion. Our study is framed in the transactional theory of stress and coping by testing first, whether prayer was related with pain severity and pain tolerance and second, whether cognitive positive re-appraisal was a mediating mechanism in the association between prayer and pain. We expected that prayer would be related to pain tolerance in reducing the impact of the pain on patient's daily life, but not necessarily to pain severity. A cross-sectional questionnaire design was adopted in order to measure demographics, prayer, pain outcomes (i.e., pain severity and pain tolerance), and cognitive positive re-appraisal. Two hundred and two chronic pain (CP) patients, all members of a Flemish national patients association, completed the questionnaires. Correlational analyses showed that prayer was significantly related with pain tolerance, but not with pain severity. However, ancillary analyses revealed a moderational effect of religious affiliation in the relationship between prayer and pain severity as well as pain tolerance. Furthermore, mediation analysis revealed that cognitive positive re-appraisal was indeed an underlying mechanism in the relationship between prayer and pain tolerance. This study affirms the importance to distinguish between pain severity and pain tolerance, and indicates that prayer can play a role in pain management, especially for religious pain patients. Further, the findings can be framed within the transactional theory of stress and coping as the results indicate that positive re-appraisal might be an important underlying mechanism in the association between prayer and pain.

Does Perceived Neighborhood Walkability and Safety Mediate the Association Between Education and Meeting Physical Activity Guidelines?

PubMed Central

Yin, Shaoman; Soler, Robin; Njai, Rashid; Siegel, Paul Z.; Liao, Youlian

2015-01-01

The role of neighborhood walkability and safety in mediating the association between education and physical activity has not been quantified. We used data from the 2010 and 2012 Communities Putting Prevention to Work Behavioral Risk Factor Surveillance System and structural equation modeling to estimate how much of the effect of education level on physical activity was mediated by perceived neighborhood walkability and safety. Neighborhood walkability accounts for 11.3% and neighborhood safety accounts for 6.8% of the effect. A modest proportion of the important association between education and physical activity is mediated by perceived neighborhood walkability and safety, suggesting that interventions focused on enhancing walkability and safety could reduce the disparity in physical activity associated with education level. PMID:25855989

The Custodial Parent-Child Relationship as a Mediating Factor in the Effects of Divorce on Children.

ERIC Educational Resources Information Center

Rasmussen, Janis Carol

Hess and Camara (1979) have shown that it is post-divorce family functioning, rather than family structure, that is most important in influencing the effects of divorce on children. A child's adjustment to divorce should be viewed as a developmental process rather than as a single event. Consequently, it is important to focus on the ways in which…

The function of the Mediator complex in plant immunity.

PubMed

An, Chuanfu; Mou, Zhonglin

2013-03-01

Upon pathogen infection, plants undergo dramatic transcriptome reprogramming to shift from normal growth and development to immune response. During this rapid process, the multiprotein Mediator complex has been recognized as an important player to fine-tune gene-specific and pathway-specific transcriptional reprogramming by acting as an adaptor/coregulator between sequence-specific transcription factor and RNA polymerase II (RNAPII). Here, we review current understanding of the role of five functionally characterized Mediator subunits (MED8, MED15, MED16, MED21 and MED25) in plant immunity. All these Mediator subunits positively regulate resistance against leaf-infecting biotrophic bacteria or necrotrophic fungi. While MED21 appears to regulate defense against fungal pathogens via relaying signals from upstream regulators and chromatin modification to RNAPII, the other four Mediator subunits locate at different positions of the defense network to convey phytohormone signal(s). Fully understanding the role of Mediator in plant immunity needs to characterize more Mediator subunits in both Arabidopsis and other plant species. Identification of interacting proteins of Mediator subunits will further help to reveal their specific regulatory mechanisms in plant immunity.

Connective tissue growth factor mediates TGF-β1-induced low-grade serous ovarian tumor cell apoptosis.

PubMed

Cheng, Jung-Chien; Chang, Hsun-Ming; Leung, Peter C K

2017-10-17

Ovarian low-grade serous carcinoma (LGSC) is a rare disease and is now considered to be a distinct entity from high-grade serous carcinoma (HGSC), which is the most common and malignant form of epithelial ovarian cancer. Connective tissue growth factor (CTGF) is a secreted matricellular protein that has been shown to modulate many biological functions by interacting with multiple molecules in the microenvironment. Increasing evidence indicates that aberrant expression of CTGF is associated with cancer development and progression. Transforming growth factor-β1 (TGF-β1) is a well-known molecule that can strongly up-regulate CTGF expression in different types of normal and cancer cells. Our previous study demonstrated that TGF-β1 induces apoptosis of LGSC cells. However, the effect of TGF-β1 on CTGF expression in LGSC needs to be defined. In addition, whether CTGF mediates TGF-β1-induced LGSC cell apoptosis remains unknown. In the present study, we show that TGF-β1 treatment up-regulates CTGF expression by activating SMAD3 signaling in two human LGSC cell lines. Additionally, siRNA-mediated CTGF knockdown attenuates TGF-β1-induced cell apoptosis. Moreover, our results show that the inhibitory effect of the CTGF knockdown on TGF-β1-induced cell apoptosis is mediated by down-regulating SMAD3 expression. This study demonstrates an important role for CTGF in mediating the pro-apoptotic effects of TGF-β1 on LGCS.

p62 regulates CD40-mediated NFκB activation in macrophages through interaction with TRAF6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seibold, Kristina; Ehrenschwender, Martin, E-mail: martin.ehrenschwender@ukr.de

CD40 is a member of the tumor necrosis factor (TNF) receptor family. Activation-induced recruitment of adapter proteins, so-called TNF-receptor-associated factors (TRAFs) to the cytoplasmic tail of CD40 triggers signaling cascades important in the immune system, but has also been associated with excessive inflammation in diseases such as atherosclerosis and rheumatoid arthritis. Especially, pro-inflammatory nuclear factor κB (NFκB) signaling emanating from CD40-associated TRAF6 appears to be a key pathogenic driving force. Consequently, targeting the CD40-TRAF6 interaction is emerging as a promising therapeutic strategy, but the underlying molecular machinery of this signaling axis is to date poorly understood. Here, we identified themore » multifunctional adaptor protein p62 as a critical regulator in CD40-mediated NFκB signaling via TRAF6. CD40 activation triggered formation of a TRAF6-p62 complex. Disturbing this interaction tremendously reduced CD40-mediated NFκB signaling in macrophages, while TRAF6-independent signaling pathways remained unaffected. This highlights p62 as a potential target in hyper-inflammatory, CD40-associated pathologies. - Highlights: • CD40 activation triggers interaction of the adapter protein TRAF6 with p62. • TRAF6-p62 interaction regulates CD40-mediated NFκB signaling in macrophages. • Defective TRAF6-p62 interaction reduces CD40-mediated NFκB activation in macrophages.« less

PATHOPHYSIOLOGY AND THE CARDIORENAL CONNECTION IN HEART FAILURE. CIRCULATING HORMONES: BIOMARKERS OR MEDIATORS

PubMed Central

BUGLIONI, ALESSIA; BURNETT, JOHN C.

2014-01-01

Heart failure (HF) is a syndrome characterized by a complex pathophysiology which involves multiple organ systems, with the kidney playing a major role. HF can present with reduced ejection fraction (EF), HFrEF, or with preserved EF (HFpEF). The interplay between diverse organ systems contributing to HF is mediated by the activation of counteracting neurohormonal pathways focused to re-establishing hemodynamic homeostasis. During early stages of HF, these biochemical signals, consisting mostly of hormones and neurotransmitters secreted by a variety of cell types, are compensatory and the patient is asymptomatic. However, with disease progression, the attempt to reverse or delay cardiac dysfunction is deleterious, leading to multi-organ congestion, fibrosis and decompensation and finally symptomatic HF. In conclusion, these neurohormonal pathways mediate the evolution of HF and have become a way to monitor HF. Specifically, these mediators have become important in the diagnosis and prognosis of this highly fatal cardiovascular disease. Finally, while these multiple neurohumoral factors serve as important HF biomarkers, they can also be targeted for more effective and curative HF treatments. PMID:25445413

Interactome analysis of transcriptional coactivator multiprotein bridging factor 1 unveils a yeast AP-1-like transcription factor involved in oxidation tolerance of mycopathogen Beauveria bassiana.

PubMed

Chu, Xin-Ling; Dong, Wei-Xia; Ding, Jin-Li; Feng, Ming-Guang; Ying, Sheng-Hua

2018-02-01

Oxidation tolerance is an important determinant to predict the virulence and biocontrol potential of Beauveria bassiana, a well-known entomopathogenic fungus. As a transcriptional coactivator, multiprotein bridging factor 1 mediates the activity of transcription factor in diverse physiological processes, and its homolog in B. bassiana (BbMBF1) contributes to fungal oxidation tolerance. In this study, the BbMBF1-interactomes under oxidative stress and normal growth condition were deciphered by mass spectrometry integrated with the immunoprecipitation. BbMBF1p factor has a broad interaction with proteins that are involved in various cellular processes, and this interaction is dynamically regulated by oxidative stress. Importantly, a B. bassiana homolog of yeast AP-1-like transcription factor (BbAP-1) was specifically associated with the BbMBF1-interactome under oxidation and significantly contributed to fungal oxidation tolerance. In addition, qPCR analysis revealed that several antioxidant genes are jointly controlled by BbAP-1 and BbMBF1. Conclusively, it is proposed that BbMBF1p protein mediates BbAP-1p factor to transcribe the downstream antioxidant genes in B. bassiana under oxidative stress. This study demonstrates for the first time a proteomic view of the MBF1-interactome in fungi, and presents an initial framework to probe the transcriptional mechanism involved in fungal response to oxidation, which will provide a new strategy to improve the biocontrol efficacy of B. bassiana.

Genetics or environment in drug transport: the case of organic anion transporting polypeptides and adverse drug reactions.

PubMed

Clarke, John D; Cherrington, Nathan J

2012-03-01

Organic anion transporting polypeptide (OATP) uptake transporters are important for the disposition of many drugs and perturbed OATP activity can contribute to adverse drug reactions (ADRs). It is well documented that both genetic and environmental factors can alter OATP expression and activity. Genetic factors include single nucleotide polymorphisms (SNPs) that change OATP activity and epigenetic regulation that modify OATP expression levels. SNPs in OATPs contribute to ADRs. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver diseases such as non-alcoholic fatty liver disease, cholestasis and hepatocellular carcinoma change the expression of multiple OATP isoforms. The role of liver diseases in the occurrence of ADRs is unknown. This article covers the roles OATPs play in ADRs when considered in the context of genetic or environmental factors. The reader will gain a greater appreciation for the current evidence regarding the salience and importance of each factor in OATP-mediated ADRs. A SNP in a single OATP transporter can cause changes in drug pharmacokinetics and contribute to ADRs but, because of overlap in substrate specificities, there is potential for compensatory transport by other OATP isoforms. By contrast, the expression of multiple OATP isoforms is decreased in liver diseases, reducing compensatory transport and thereby increasing the probability of ADRs. To date, most research has focused on the genetic factors in OATP-mediated ADRs while the impact of environmental factors has largely been ignored.

SRC-mediated EGF Receptor Activation Regulates Ozone-induced Interleukin 8 Expression in Human Bronchial Epithelial Cells

EPA Science Inventory

BACKGROUND: Human exposure to ozone (03) results in pulmonary function decrements and airway inflammation. The mechanisms underlying these adverse effects remain unclear. Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of lung inflammation. ...

Nutritionally mediated programming of the developing immune system.

PubMed

Palmer, Amanda C

2011-09-01

A growing body of evidence highlights the importance of a mother's nutrition from preconception through lactation in programming the emerging organ systems and homeostatic pathways of her offspring. The developing immune system may be particularly vulnerable. Indeed, examples of nutrition-mediated immune programming can be found in the literature on intra-uterine growth retardation, maternal micronutrient deficiencies, and infant feeding. Current models of immune ontogeny depict a "layered" expansion of increasingly complex defenses, which may be permanently altered by maternal malnutrition. One programming mechanism involves activation of the maternal hypothalamic-pituitary-adrenal axis in response to nutritional stress. Fetal or neonatal exposure to elevated stress hormones is linked in animal studies to permanent changes in neuroendocrine-immune interactions, with diverse manifestations such as an attenuated inflammatory response or reduced resistance to tumor colonization. Maternal malnutrition may also have a direct influence, as evidenced by nutrient-driven epigenetic changes to developing T regulatory cells and subsequent risk of allergy or asthma. A 3rd programming pathway involves placental or breast milk transfer of maternal immune factors with immunomodulatory functions (e.g. cytokines). Maternal malnutrition can directly affect transfer mechanisms or influence the quality or quantity of transferred factors. The public health implications of nutrition-mediated immune programming are of particular importance in the developing world, where prevalent maternal undernutrition is coupled with persistent infectious challenges. However, early alterations to the immune system, resulting from either nutritional deficiencies or excesses, have broad relevance for immune-mediated diseases, such as asthma, and chronic inflammatory conditions like cardiovascular disease.

Activating RNAs associate with Mediator to enhance chromatin architecture and transcription.

PubMed

Lai, Fan; Orom, Ulf A; Cesaroni, Matteo; Beringer, Malte; Taatjes, Dylan J; Blobel, Gerd A; Shiekhattar, Ramin

2013-02-28

Recent advances in genomic research have revealed the existence of a large number of transcripts devoid of protein-coding potential in multiple organisms. Although the functional role for long non-coding RNAs (lncRNAs) has been best defined in epigenetic phenomena such as X-chromosome inactivation and imprinting, different classes of lncRNAs may have varied biological functions. We and others have identified a class of lncRNAs, termed ncRNA-activating (ncRNA-a), that function to activate their neighbouring genes using a cis-mediated mechanism. To define the precise mode by which such enhancer-like RNAs function, we depleted factors with known roles in transcriptional activation and assessed their role in RNA-dependent activation. Here we report that depletion of the components of the co-activator complex, Mediator, specifically and potently diminished the ncRNA-induced activation of transcription in a heterologous reporter assay using human HEK293 cells. In vivo, Mediator is recruited to ncRNA-a target genes and regulates their expression. We show that ncRNA-a interact with Mediator to regulate its chromatin localization and kinase activity towards histone H3 serine 10. The Mediator complex harbouring disease- displays diminished ability to associate with activating ncRNAs. Chromosome conformation capture confirmed the presence of DNA looping between the ncRNA-a loci and its targets. Importantly, depletion of Mediator subunits or ncRNA-a reduced the chromatin looping between the two loci. Our results identify the human Mediator complex as the transducer of activating ncRNAs and highlight the importance of Mediator and activating ncRNA association in human disease.

Perceived social-ecological factors associated with fruit and vegetable purchasing, preparation, and consumption among young adults.

PubMed

Graham, Dan J; Pelletier, Jennifer E; Neumark-Sztainer, Dianne; Lust, Katherine; Laska, Melissa N

2013-10-01

Most young adults do not consume recommended levels of fruits and vegetables (F/V), and interventions to increase F/V-related behaviors among this understudied population are needed. Therefore, it is important to identify correlates of F/V intake among young adults to guide intervention development. This cross-sectional study used data from an online survey to identify factors related to young adults' F/V purchasing, preparation, and consumption, and to explore between-factor relationships using mediation analysis. In 2010, 1,201 college students in Minnesota completed questionnaires assessing F/V behaviors as well as perceptions of F/V-related individual, social, and environmental factors. Factor analysis identified questionnaire items assessing similar constructs. Seven factors were identified (personal barriers, F/V knowledge, family, friends, neighborhood, access barriers, and campus) and evaluated for relationships with F/V purchasing, preparation, and consumption using linear regression. Results revealed that perceived personal barriers (eg, lacking cooking skills) were inversely related to all F/V outcomes. Perception that family and friends eat healthfully and neighborhood access to F/V were positively related to all outcomes. Individual-, social-, and environment-level perceptions were related to purchasing, preparation, and consumption, and the effects of these factors were similar when accounting for mediated effects. Factors at all three levels and the ways in which these various factors operate together may be important to consider in future efforts to improve F/V behaviors among young adults. Copyright © 2013 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

Plant hormone jasmonate prioritizes defense over growth by interfering with gibberellin signaling cascade.

PubMed

Yang, Dong-Lei; Yao, Jian; Mei, Chuan-Sheng; Tong, Xiao-Hong; Zeng, Long-Jun; Li, Qun; Xiao, Lang-Tao; Sun, Tai-ping; Li, Jigang; Deng, Xing-Wang; Lee, Chin Mei; Thomashow, Michael F; Yang, Yinong; He, Zuhua; He, Sheng Yang

2012-05-08

Plants must effectively defend against biotic and abiotic stresses to survive in nature. However, this defense is costly and is often accompanied by significant growth inhibition. How plants coordinate the fluctuating growth-defense dynamics is not well understood and remains a fundamental question. Jasmonate (JA) and gibberellic acid (GA) are important plant hormones that mediate defense and growth, respectively. Binding of bioactive JA or GA ligands to cognate receptors leads to proteasome-dependent degradation of specific transcriptional repressors (the JAZ or DELLA family of proteins), which, at the resting state, represses cognate transcription factors involved in defense (e.g., MYCs) or growth [e.g. phytochrome interacting factors (PIFs)]. In this study, we found that the coi1 JA receptor mutants of rice (a domesticated monocot crop) and Arabidopsis (a model dicot plant) both exhibit hallmark phenotypes of GA-hypersensitive mutants. JA delays GA-mediated DELLA protein degradation, and the della mutant is less sensitive to JA for growth inhibition. Overexpression of a selected group of JAZ repressors in Arabidopsis plants partially phenocopies GA-associated phenotypes of the coi1 mutant, and JAZ9 inhibits RGA (a DELLA protein) interaction with transcription factor PIF3. Importantly, the pif quadruple (pifq) mutant no longer responds to JA-induced growth inhibition, and overexpression of PIF3 could partially overcome JA-induced growth inhibition. Thus, a molecular cascade involving the COI1-JAZ-DELLA-PIF signaling module, by which angiosperm plants prioritize JA-mediated defense over growth, has been elucidated.

The TAM-family receptor Mer mediates production of HGF through the RhoA-dependent pathway in response to apoptotic cells.

PubMed

Park, Hyun-Jung; Baen, Ji-Yeon; Lee, Ye-Ji; Choi, Youn-Hee; Kang, Jihee Lee

2012-08-01

The TAM receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. We investigated the roles of the TAM receptors in mediating the induction of hepatocyte growth factor (HGF) during the interaction of macrophages with apoptotic cells. Mer-specific neutralizing antibody, small interfering RNA (siRNA), and a recombinant Mer protein (Mer/Fc) inhibited HGF mRNA and protein expression, as well as activation of RhoA, Akt, and specific mitogen-activated protein (MAP) kinases in response to apoptotic cells. Inhibition of Axl or Tyro3 with specific antibodies, siRNA, or Fc-fusion proteins did not prevent apoptotic cell-induced HGF mRNA and protein expression and did not inhibit activation of the postreceptor signaling molecules RhoA and certain MAP kinases, including extracellular signal-regulated protein kinase and c-Jun NH(2)-terminal kinase. However, Axl- and Tyro3-specific blockers did inhibit the activation of Akt and p38 MAP kinase in response to apoptotic cells. In addition, none of the TAM receptors mediated the effects of apoptotic cells on transforming growth factor-β or epidermal growth factor mRNA expression. However, they were involved in the induction of vascular endothelial growth factor mRNA expression. Our data provide evidence that when macrophages interact with apoptotic cells, only Mer of the TAM-family receptors is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway.

Childhood temperament: passive gene-environment correlation, gene-environment interaction, and the hidden importance of the family environment.

PubMed

Lemery-Chalfant, Kathryn; Kao, Karen; Swann, Gregory; Goldsmith, H Hill

2013-02-01

Biological parents pass on genotypes to their children, as well as provide home environments that correlate with their genotypes; thus, the association between the home environment and children's temperament can be genetically (i.e., passive gene-environment correlation) or environmentally mediated. Furthermore, family environments may suppress or facilitate the heritability of children's temperament (i.e., gene-environment interaction). The sample comprised 807 twin pairs (mean age = 7.93 years) from the longitudinal Wisconsin Twin Project. Important passive gene-environment correlations emerged, such that home environments were less chaotic for children with high effortful control, and this association was genetically mediated. Children with high extraversion/surgency experienced more chaotic home environments, and this correlation was also genetically mediated. In addition, heritability of children's temperament was moderated by home environments, such that effortful control and extraversion/surgency were more heritable in chaotic homes, and negative affectivity was more heritable under crowded or unsafe home conditions. Modeling multiple types of gene-environment interplay uncovered the complex role of genetic factors and the hidden importance of the family environment for children's temperament and development more generally.

Do Sleep and Psychological Distress Mediate the Association Between Neighborhood Factors and Pain?

PubMed

Brooks Holliday, Stephanie; Dubowitz, Tamara; Ghosh-Dastidar, Bonnie; Beckman, Robin; Buysse, Daniel; Hale, Lauren; Buman, Matthew; Troxel, Wendy

2018-05-14

Pain affects millions of American adults. However, individuals from socioeconomically disadvantaged groups experience higher rates of pain, and individuals from racial/ethnic minorities report greater pain severity and pain-related disability. Some studies find an association between neighborhood socioeconomic status and pain. The present study aimed to further understand the association between neighborhood disadvantage and pain, including the role of objective (e.g., crime rates) and subjective neighborhood characteristics (e.g., perceived safety, neighborhood satisfaction), and to examine sleep and psychological distress as potential mediators of these associations. The sample included 820 participants from two predominantly African American socioeconomically disadvantaged neighborhoods. Trained data collectors interviewed participants on a number of self-report measures, and objective neighborhood characteristics were obtained from city crime data and street segment audits. Subjective characteristics, specifically perceived infrastructure and perceived safety, were associated with pain. Based on bootstrapped regression models, sleep efficiency and psychological distress were tested as mediators of the association between these neighborhood factors and pain. Results of mediation testing indicated that psychological distress served as a significant mediator. Though sleep efficiency was not a mediator, it had a significant independent association with pain. Understanding the contribution of sleep problems and psychological distress to pain among at-risk individuals living in disadvantaged neighborhoods is important to identifying ways that individual- and neighborhood-level interventions may be leveraged to reduce pain-related disparities.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Jeong Su; Yonsei Biomedical Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752; Kang, Dong Hoon

p70 ribosomal S6 kinase 1 (S6K1) is an important serine/threonine kinase and downstream target of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. PF-4708671 is a specific inhibitor of S6K1, and prevents S6K1-mediated phosphorylation of the S6 protein. PF-4708671 treatment often leads to apoptotic cell death. However, the protective mechanism against PF-4708671-induced cell death has not been elucidated. The nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) pathway is essential for protecting cells against oxidative stress. p62, an adaptor protein in the autophagic process, enhances Nrf2 activation through the impairment of Keap1 activity. In thismore » study, we showed that PF-4708671 induces autophagic Keap1 degradation-mediated Nrf2 activation in p62-dependent manner. Furthermore, p62-dependent Nrf2 activation plays a crucial role in protecting cells from PF-4708671-mediated apoptosis. - Highlights: • PF-4708671, a S6K1-specific inhibitor, prevents S6K1-mediated S6 phosphorylation. • However, PF-4708671 treatment often leads to apoptotic cell death. • Protective mechanism against PF-4708671-induced cell death remains to be elucidated. • PF-4708671 induced p62-dependent, autophagic Keap1 degradation-mediated Nrf2 activation. • p62-dependent Nrf2 activation protects cells from PF-4708671-mediated apoptosis.« less

Coping as a mechanism linking stressful life events and mental health problems in adolescents.

PubMed

Meng, Xiu Hong; Tao, Fang Biao; Wan, Yu Hui; Hu, Yan; Wang, Ren Xi

2011-12-01

Although stressful life events represent an etiologic factor of mental health problems in adolescents, few studies have been conducted to address mechanisms linking the stress-psychopathology relation. The present study was designed to examine coping as a mediate factor on the relationship between stressful life events and symptoms of anxiety and depression. The participants were 13 512 students from eight cities of China, who participated in a school-based survey. Data were collected by a questionnaire comprising coping, stressful life events, anxiety, and depressive symptoms. As a model, a series of regression equations were used to examine whether coping mediated the association between stressful life events and symptoms of anxiety and depression. Each dimension of stressful life events showed significant correlation with anxiety, depression and coping (all P<0.001). In the model to analyze mediate effects, all standardized coefficients (β) were significant (all P<0.01), indicating marked mediator effects. Furthermore, negative coping might account for more mediate effects than positive coping on this relationship. Coping partially mediated the relationship between stressful life events and mental health during adolescence. This study highlighted an important public health priority for preventive interventions targeting stress-related psychopathology, and for further promoting adolescents' mental health. Copyright © 2011 The Editorial Board of Biomedical and Environmental Sciences. Published by Elsevier B.V. All rights reserved.

Soluble Mediators and Clinical Features Discern Risk of Transitioning to Classified Disease in Relatives of Systemic Lupus Erythematosus Patients

PubMed Central

Munroe, Melissa E.; Young, Kendra A.; Kamen, Diane L.; Guthridge, Joel M.; Niewold, Timothy B.; Costenbader, Karen H.; Weisman, Michael H.; Ishimori, Mariko L.; Wallace, Daniel J.; Gilkeson, Gary S.; Karp, David R.; Harley, John B.; Norris, Jill M.; James, Judith A.

2016-01-01

Objective Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential to curtail irreversible inflammatory damage. The objective of this study was to identify factors associated with transition to classified disease that inform SLE risk. Methods Previously identified lupus patient blood relatives with < 4 American College of Rheumatology SLE classification criteria at baseline (n=409) were enrolled in this follow-up study. Participants provided detailed family, demographic, and clinical information, including the SLE-specific portion of the Connective Tissue Disease Screening Questionnaire (SLE-CSQ). Plasma samples were tested for the presence of lupus-associated autoantibodies and 52 soluble mediators. Generalized estimating equations (GEE) were applied to identify factors anticipating disease transition. Results Forty-five relatives (11%) transitioned to classified SLE during follow-up (mean time=6.4 years). Relatives who transitioned displayed more lupus-associated autoantibody specificities and higher SLE-CSQ scores (p<0.0001) at baseline than non-transitioned relatives. Importantly, they also had elevated baseline plasma levels of inflammatory mediators, including B-lymphocyte stimulator (BLyS), stem cell factor (SCF), and interferon-associated chemokines (p≤0.02), with concurrent decreases in levels of regulatory mediators, tumor growth factor (TGF)-β and interleukin (IL)-10 (p≤0.03). GEE revealed that baseline SLE-CSQ or ACR scores and plasma levels of SCF and TGF-β (p≤0.03), but not autoantibodies, were significant and independent predictors of SLE transition. Conclusions Altered levels of soluble mediators anticipate transition to classified disease in lupus relatives. Thus, immune perturbations precede SLE classification and can help identify high-risk relatives for rheumatology referral and potential enrollment in prevention trials. PMID:27863174

Food insecurity, diet quality and body mass index of women participating in the Supplemental Nutrition Assistance Program: The role of intrapersonal, home environment, community and social factors.

PubMed

Sanjeevi, Namrata; Freeland-Graves, Jeanne; Hersh, Matthew

2018-06-01

Obesity is a public health problem that disproportionately affects low-income populations. Moreover, participation in Supplemental Nutrition Assistance Program (SNAP) has been associated with obesity among low-income women. The goal of this study was to determine the impact of intrapersonal, home environment, community and social factors on diet quality and body mass index (BMI) of low-income women participating in SNAP. This study also aimed to examine the role of these factors in mediating the relationship between food insecurity and diet quality, and BMI. A total of 152 women receiving SNAP benefits were recruited from low-income neighborhood centers and housing communities, and administered a demographics questionnaire, the United States adult food security scale, food frequency questionnaire, and multi-dimensional home environment scale (MHES). They also were measured for height and weight to calculate BMI. The Dietary Guidelines Adherence Index 2015 was used to measure diet quality. Regression analyses were conducted to determine the MHES subscales that were significant predictors of diet quality and BMI. The Preacher and Hayes mediation model was used to evaluate the mediation of the relationship between food insecurity and diet quality, and BMI by the MHES. Emotional eating resistance and favorable social eating behaviors were positively associated with diet quality; whereas emotional eating resistance, lower availability of unhealthy food at home, neighborhood safety and favorable social eating behaviors were inversely associated with BMI in women participating in SNAP. The MHES significantly mediated the relationship between food insecurity and BMI. These results emphasize the importance of intrapersonal, home environment, community and social factors in mediating the relationship between food insecurity and BMI in low-income women. Copyright © 2018 Elsevier Ltd. All rights reserved.

Temporary reversal by topotecan of marked insulin resistance in a patient with myelodysplastic syndrome: case report and possible mechanism for tumor necrosis factor alpha (TNF-alpha)-induced insulin resistance.

PubMed

Huntington, M O; Krell, K E; Armour , W E; Liljenquist, J E

2001-06-01

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor. We report here a remarkable degree of insulin resistance in a patient with adult respiratory distress syndrome and myelodysplasia.

Future time orientation predicts academic engagement among first-year university students.

PubMed

Horstmanshof, Louise; Zimitat, Craig

2007-09-01

Enhancing student engagement is considered an important strategy for improving retention. Students' Time Perspective is an under-researched factor that may significantly influence student engagement. This study examines interrelationships between elements of student engagement and relationship with Time Perspective. We propose that there are significant relationships between psychological and behavioural elements of student engagement. We also posit that time orientation is an important factor in facilitating psychological and behavioural elements of student engagement. Participants (N=347) were first-year undergraduate students who had completed one semester of study and re-enrolled for a further semester of study at an Australian university. Participants were surveyed using instruments designed to measure Academic Application, Academic Orientation (McInnis, James, & Hartley, 2000), Time Perspective (Zimbardo & Boyd, 1999), the shortened version of the Study Process Questionnaire (Fox, McManus, & Winder, 2001) and hours spent preparing for class. There were interrelationships between the elements of student engagement (e.g. Academic Application) with productive educational behaviours (e.g. deep approach to learning). Students' perceptions of time appeared as a key factor mediating levels of Academic Application and Academic Orientation. Orientation to the Future emerged as a significant predictor of these elements of engagement. Future orientation emerged as an important factor mediating students' academic engagement in these students who completed one semester of study. Interventions focusing on the development of time perspective may be helpful in encouraging and supporting academic engagement and, ultimately, persistence in higher education.

Attachment to parents and peers as a risk factor for adolescent depressive disorders: the mediating role of emotion regulation.

PubMed

Kullik, Angelika; Petermann, Franz

2013-08-01

This study examined emotion regulation as a mediator in the relationship of attachment and depression in adolescents. Participants (N girls = 127; M age = 14.50; N boys = 121; M age = 14.31) completed self-report questionnaires of attachment to parents and peers, emotion regulation and depression. Models with dysfunctional emotion regulation as a mediation variable were tested via hierarchical multiple regression analyses and bootstrapping procedure. Results revealed significant relations between attachment to parents and peers, dysfunctional emotion regulation and depression. For girls, internal-dysfunctional emotion regulation was a mediator in the relation of attachment to parents and depression and partly mediated the association of attachment to peers. For boys, internal- and external-dysfunctional emotion regulation acted as partly mediators in association of attachment to parents and depression. Results indicate important mechanisms that contribute to the refinement of conceptual models and provide indications for gender specific prevention and intervention for depressive disorders.

Does positivity mediate the relation of extraversion and neuroticism with subjective happiness?

PubMed

Lauriola, Marco; Iani, Luca

2015-01-01

Recent theories suggest an important role of neuroticism, extraversion, attitudes, and global positive orientations as predictors of subjective happiness. We examined whether positivity mediates the hypothesized relations in a community sample of 504 adults between the ages of 20 and 60 years old (females = 50%). A model with significant paths from neuroticism to subjective happiness, from extraversion and neuroticism to positivity, and from positivity to subjective happiness fitted the data (Satorra-Bentler scaled chi-square (38) = 105.91; Comparative Fit Index = .96; Non-Normed Fit Index = .95; Root Mean Square Error of Approximation = .060; 90% confidence interval = .046, .073). The percentage of subjective happiness variance accounted for by personality traits was only about 48%, whereas adding positivity as a mediating factor increased the explained amount of subjective happiness to 78%. The mediation model was invariant by age and gender. The results show that the effect of extraversion on happiness was fully mediated by positivity, whereas the effect of neuroticism was only partially mediated. Implications for happiness studies are also discussed.

BET Bromodomain Inhibition Releases the Mediator Complex from Select cis-Regulatory Elements.

PubMed

Bhagwat, Anand S; Roe, Jae-Seok; Mok, Beverly Y L; Hohmann, Anja F; Shi, Junwei; Vakoc, Christopher R

2016-04-19

The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. A shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Pathways to delinquency and substance use among African American youth: Does future orientation mediate the effects of peer norms and parental monitoring?

PubMed

Marotta, Phillip L; Voisin, Dexter R

2017-10-01

The following study assessed whether future orientation mediated the effects of peer norms and parental monitoring on delinquency and substance use among 549 African American adolescents. Structural equation modeling computed direct and indirect (meditational) relationships between parental monitoring and peer norms through future orientation. Parental monitoring significantly correlated with lower delinquency through future orientation ( B = -.05, standard deviation = .01, p < .01). Future orientation mediated more than quarter (27.70%) of the total effect of parental monitoring on delinquency. Overall findings underscore the importance of strengthening resilience factors for African American youth, especially those who live in low-income communities.

Sleep and organizational citizenship behavior: the mediating role of job satisfaction.

PubMed

Barnes, Christopher M; Ghumman, Sonia; Scott, Brent A

2013-01-01

We examine sleep as an important factor beyond the work domain that is relevant to organizational citizenship behavior. In a field study of 87 employees from a variety of organizations, an objective measure of sleep quantity predicted organizational citizenship behavior directed toward organizations but not organizational citizenship behavior directed toward individuals. Additionally, job satisfaction mediated this relationship. In a second field study of 85 working college students, we found that natural variation in daily sleep over the course of a work week predicted daily variance in organizational citizenship behavior directed toward both individuals and organizations, and that job satisfaction mediated these relationships. Based on these findings, we discuss theoretical and practical implications of sleep-deprived employees.

Role of thrombospondin-1 and nuclear factor-kappa B signaling pathways in anti-angiogenesis of infantile hemangioma.

PubMed

Xu, Weili; Li, Suolin; Yu, Fengxue; Zhang, Yongting; Yang, Xiaofeng; An, Wenting; Wang, Wenbo; Sun, Chi

2018-06-12

Propranolol (PRO) is the first-line drug for infantile hemangioma treatment. However, its mechanism of action remains unclear. Nuclear factor-kappa B (NF-κB) is highly expressed in tumors, directly or indirectly promoting angiogenesis. Thrombospondin-1 (TSP-1) is the most important anti-angiogenesis protein in vivo. These proteins mediate signaling pathways, probably playing an important role in hemangioma treatment. This study explored the synergistic regulation of TSP-1 and NF-κB signaling pathways in the treatment of hemangioma with PRO. The hemangioma-derived endothelial cells (HemECs) were sorted out from the specimens of proliferative hemangioma by flow cytometry. Furthermore, a BALB/c nude mice hemangioma model was established. Viability and proliferation of HemECs, and the role of TSP-1 and NF-κB signaling pathways were observed after PRO administration in vitro and in vivo. The expressions of TSP-1 and its receptor cluster of differentiation 36 (CD36) in HemECs gradually increased with the increase in PRO concentration, while the expressions of NF-κBp65, phosphorylated inhibitor of kappa B alpha (p-IκBα), and phosphorylated inhibitor of NF-κB kinase beta (p-IκKβ) weakened gradually (p < 0.05). In vivo, the tumors shrank gradually after PRO treatment, with increase in TSP-1 and CD36, and decrease in NF-κBp65, p-IκBα, and p-IκKβ (p < 0.05). Glucocorticoid improved the anti-angiogenesis mediated by TSP-1/CD36 and inhibited the angiogenesis mediated by NF-κB/IκB (p < 0.05). Negative regulation occurred between the two signaling pathways. The treatment of infantile hemangioma with PRO is promising to promote TSP-1-mediated anti-angiogenesis and block NF-κB-mediated angiogenesis.

Cytoskeleton in Mast Cell Signaling

PubMed Central

Dráber, Pavel; Sulimenko, Vadym; Dráberová, Eduarda

2012-01-01

Mast cell activation mediated by the high affinity receptor for IgE (FcεRI) is a key event in allergic response and inflammation. Other receptors on mast cells, as c-Kit for stem cell factor and G protein-coupled receptors (GPCRs) synergistically enhance the FcεRI-mediated release of inflammatory mediators. Activation of various signaling pathways in mast cells results in changes in cell morphology, adhesion to substrate, exocytosis, and migration. Reorganization of cytoskeleton is pivotal in all these processes. Cytoskeletal proteins also play an important role in initial stages of FcεRI and other surface receptors induced triggering. Highly dynamic microtubules formed by αβ-tubulin dimers as well as microfilaments build up from polymerized actin are affected in activated cells by kinases/phosphatases, Rho GTPases and changes in concentration of cytosolic Ca2+. Also important are nucleation proteins; the γ-tubulin complexes in case of microtubules or Arp 2/3 complex with its nucleation promoting factors and formins in case of microfilaments. The dynamic nature of microtubules and microfilaments in activated cells depends on many associated/regulatory proteins. Changes in rigidity of activated mast cells reflect changes in intermediate filaments build up from vimentin. This review offers a critical appraisal of current knowledge on the role of cytoskeleton in mast cells signaling. PMID:22654883

Role of Modulator of Inflammation Cyclooxygenase-2 in Gammaherpesvirus Mediated Tumorigenesis

PubMed Central

Gandhi, Jaya; Khera, Lohit; Gaur, Nivedita; Paul, Catherine; Kaul, Rajeev

2017-01-01

Chronic inflammation is recognized as a threat factor for cancer progression. Release of inflammatory molecules generates microenvironment which is highly favorable for development of tumor, cancer progression and metastasis. In cases of latent viral infections, generation of such a microenvironment is one of the major predisposing factors related to virus mediated tumorigenesis. Among various inflammatory mediators implicated in pathological process associated with cancer, the cyclooxygenase (COX) and its downstream effector molecules are of greater significance. Though the role of infectious agents in causing inflammation leading to transformation of cells has been more or less well established, however, the mechanism by which inflammation in itself modulates the events in life cycle of infectious agent is not very much clear. This is specifically important for gammaherpesviruses infections where viral life cycle is characterized by prolonged periods of latency when the virus remains hidden, immunologically undetectable and expresses only a very limited set of genes. Therefore, it is important to understand the mechanisms for role of inflammation in virus life cycle and tumorigenesis. This review is an attempt to summarize the latest findings highlighting the significance of COX-2 and its downstream signaling effectors role in life cycle events of gammaherpesviruses leading to progression of cancer. PMID:28400769

Suppressive Effects of Pelargonidin on Endothelial Protein C Receptor Shedding via the Inhibition of TACE Activity and MAP Kinases.

PubMed

Kang, Hyejin; Lee, Taeho; Bae, Jong-Sup

2016-01-01

Beyond its role in the activation of protein C, the endothelial cell protein C receptor (EPCR) plays an important role in the cytoprotective pathway. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-[Formula: see text] converting enzyme (TACE). Pelargonidin is a well-known red pigment found in plants, and has been reported to have important biological activities that are potentially beneficial to human health. However, little is known about the effects of pelargonidin on EPCR shedding. We investigated this issue by monitoring the effects of pelargonidin on phorbol-12-myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-[Formula: see text]-, interleukin (IL)-1β-, and cecal ligation and puncture (CLP)-mediated EPCR shedding and by investigating the underlying mechanism of pelargonidin action. Data demonstrate that pelargonidin induced potent inhibition of PMA-, TNF-[Formula: see text]-, IL-1β-, and CLP-induced EPCR shedding by inhibiting the phosphorylation of mitogen-activated protein kinases (MAPKs) such as p38, janus kinase (JNK), and extracellular signal-regulated kinase (ERK) 1/2. Pelargonidin also inhibited the expression and activity of PMA-induced TACE in endothelial cells. These results demonstrate the potential of pelargonidin as an anti-EPCR shedding reagent against PMA- and CLP-mediated EPCR shedding.

Dual personality of Mad1: regulation of nuclear import by a spindle assembly checkpoint protein.

PubMed

Cairo, Lucas V; Ptak, Christopher; Wozniak, Richard W

2013-01-01

Nuclear transport is a dynamic process that can be modulated in response to changes in cellular physiology. We recently reported that the transport activity of yeast nuclear pore complexes (NPCs) is altered in response to kinetochore-microtubule (KT-MT) interaction defects. Specifically, KT detachment from MTs activates a signaling pathway that prevents the nuclear import of cargos by the nuclear transport factor Kap121p. This loss of Kap121p-mediated import is thought to influence the nuclear environment, including the phosphorylation state of nuclear proteins. A key regulator of this process is the spindle assembly checkpoint protein Mad1p. In response to unattached KTs, Mad1p dynamically cycles between NPCs and KTs. This cycling appears to induce NPC molecular rearrangements that prevent the nuclear import of Kap121p-cargo complexes. Here, we discuss the underlying mechanisms and the physiological relevance of Mad1p cycling and the inhibition of Kap121p-mediated nuclear import, focusing on outstanding questions within the pathway.

EPAS-1 Mediates SP-1-Dependent FBI-1 Expression and Regulates Tumor Cell Survival and Proliferation

PubMed Central

Wang, Xiaogang; Cao, Peng; Li, Zhiqing; Wu, Dongyang; Wang, Xi; Liang, Guobiao

2014-01-01

Factor binding IST-1 (FBI-1) plays an important role in oncogenic transformation and tumorigenesis. As FBI-1 is over-expressed in multiple human cancers, the regulation of itself would provide new effective options for cancer intervention. In this work, we aimed to study the role that EPAS-1 plays in regulating FBI-1. We use the fact that specificity protein-1 (SP-1) is one of the crucial transcription factors of FBI-1, and that SP-1 can interact with the endothelial pas domain protein-1 (EPAS-1) for the induction of hypoxia related genes. The study showed that EPAS-1 plays an indispensible role in SP-1 transcription factor-mediated FBI-1 induction, and participated in tumor cell survival and proliferation. Thus, EPAS-1 could be a novel target for cancer therapeutics. PMID:25192290

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1)

PubMed Central

Wolfe, Andrew; Divall, Sara; Wu, Sheng

2014-01-01

The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. PMID:24929098

Maternal obesity and childhood wheezing and asthma.

PubMed

Rusconi, Franca; Popovic, Maja

2017-03-01

Obesity represents one of the major public health problems worldwide, with an increased prevalence also among women of reproductive age. Maternal pre-pregnancy overweight and obesity are important risk factors for a number of maternal and foetal/neonatal complications. The objective of this review is to provide an overview of the most recent evidence regarding the associations between pre-pregnancy overweight/obesity and wheezing and asthma in childhood. Potential mechanisms, mediators and confounding factors involved in these associations are also discussed. Despite the relatively large body of studies examining these associations and taking into account main confounders and potential mediators, the causal relationship between maternal obesity and wheezing and asthma in childhood is still uncertain. This uncertainty is not trivial, as any prevention strategy aimed at reducing the burden of these conditions would necessarily imply better understanding of the factors that are in the causal chain. Copyright © 2016. Published by Elsevier Ltd.

NFIB-mediated repression of the epigenetic factor Ezh2 regulates cortical development.

PubMed

Piper, Michael; Barry, Guy; Harvey, Tracey J; McLeay, Robert; Smith, Aaron G; Harris, Lachlan; Mason, Sharon; Stringer, Brett W; Day, Bryan W; Wray, Naomi R; Gronostajski, Richard M; Bailey, Timothy L; Boyd, Andrew W; Richards, Linda J

2014-02-19

Epigenetic mechanisms are essential in regulating neural progenitor cell self-renewal, with the chromatin-modifying protein Enhancer of zeste homolog 2 (EZH2) emerging as a central player in promoting progenitor cell self-renewal during cortical development. Despite this, how Ezh2 is itself regulated remains unclear. Here, we demonstrate that the transcription factor nuclear factor IB (NFIB) plays a key role in this process. Nfib(-/-) mice exhibit an increased number of proliferative ventricular zone cells that express progenitor cell markers and upregulation of EZH2 expression within the neocortex and hippocampus. NFIB binds to the Ezh2 promoter and overexpression of NFIB represses Ezh2 transcription. Finally, key downstream targets of EZH2-mediated epigenetic repression are misregulated in Nfib(-/-) mice. Collectively, these results suggest that the downregulation of Ezh2 transcription by NFIB is an important component of the process of neural progenitor cell differentiation during cortical development.

Local Control of Blood Flow

ERIC Educational Resources Information Center

Clifford, Philip S.

2011-01-01

Organ blood flow is determined by perfusion pressure and vasomotor tone in the resistance vessels of the organ. Local factors that regulate vasomotor tone include myogenic and metabolic autoregulation, flow-mediated and conducted responses, and vasoactive substances released from red blood cells. The relative importance of each of these factors…

A mediator effect size in randomized clinical trials.

PubMed

Kraemer, Helena Chmura

2014-12-01

To understand the process by which a treatment (T) achieves an effect on outcome (O) and thus to improve the effect of T on O, it is vital to detect mediators, to compare the impact of different mediators, and to develop hypotheses about the causal factors (all mediators) linking T and O. An index is needed to facilitate interpretation of the potential clinical importance of a mediator (M) of choice of T on treatment O in randomized clinical trials (RCTs). Ideally such a mediator effect size should (1) be invariant under any rescaling of M and O consistent with the model used, and (2) reflect the difference between the overall observed effect of T on O and what the maximal effect of T on O could be were the association between T and M broken. A mediator effect size is derived first for the traditional linear model, and then more generally for any categorical (ordered or non-ordered) potential mediator. Issues such as the problem of multiple treatments, outcomes and mediators, and of causal inferences, and the correspondence between this approach and earlier ones, are discussed. Illustrations are given of the application of the approach. Copyright © 2014 John Wiley & Sons, Ltd.

Cellular and molecular mechanisms in the hypoxic tissue: role of HIF-1 and ROS.

PubMed

Zepeda, Andrea B; Pessoa, Adalberto; Castillo, Rodrigo L; Figueroa, Carolina A; Pulgar, Victor M; Farías, Jorge G

2013-08-01

Reactive oxygen species such as superoxide anion radicals (O2 (-) ) and hydrogen peroxide (H2 O2 ) have for long time been recognized as undesirable by-products of the oxidative mitochondrial generation of adenosine triphosphate (ATP). Recently, these highly reactive species have been associated to important signaling pathways in diverse physiological conditions such as those activated in hypoxic microenvironments. The molecular response to hypoxia requires fast-acting mechanisms acting within a wide range of partial pressures of oxygen (O2 ). Intracellular O2 sensing is an evolutionary preserved feature, and the best characterized molecular responses to hypoxia are mediated through transcriptional activation. The transcription factor, hypoxia-inducible factor 1 (HIF-1), is a critical mediator of these adaptive responses, and its activation by hypoxia involves O2 -dependent posttranslational modifications and nuclear translocation. Through the induction of the expression of its target genes, HIF-1 coordinately regulates tissue O2 supply and energetic metabolism. Other transcription factors such as nuclear factor κB are also redox sensitive and are activated in pro-oxidant and hypoxic conditions. The purpose of this review is to summarize new developments in HIF-mediated O2 sensing mechanisms and their interactions with reactive oxygen species-generating pathways in normal and abnormal physiology. Copyright © 2013 John Wiley & Sons, Ltd.

Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD).

PubMed

Hemmings, Sîan M J; Kinnear, Craig J; Van der Merwe, Lize; Lochner, Christine; Corfield, Valerie A; Moolman-Smook, Johanna C; Stein, Dan J

2008-01-01

Although evidence from family studies suggest that genetic factors play an important role in mediating obsessive-compulsive disorder (OCD), results from genetic case-control association analyses have been inconsistent. Discrepant findings may be attributed to the lack of phenotypic resolution, and population stratification. The aim of the present study was to investigate the role that the val66met variant within the gene encoding brain-derived neurotrophic factor (BDNF) may play in mediating the development of selected OCD subtypes accounting for the aforementioned confounding factors. One hundred and twelve OCD subjects and 140 controls were selected from the South African Afrikaner population. A significant association was observed in the male subgroup, with the met66 allele implicated as the risk allele in the development of OCD. This allele was also found to be associated with an earlier age at onset of OCD in males. On the other hand, the val66val genotype was associated with more severe OCD in the female population. No evidence of population stratification was observed in Afrikaner control subjects. These preliminary results point towards genetically distinct characteristics of OCD mediated by dysfunctions in BDNF. The present investigation forms part of ongoing research to elucidate the genetic components involved in the aetiology of OCD and OCD-related characteristics.

Revisiting Traditional Risk Factors for Rejection and Graft Loss after Kidney Transplantation

PubMed Central

Dunn, TB; Noreen, H; Gillingham, K; Maurer, D; Ozturk, O. Goruroglu; Pruett, TL; Bray, RA; Gebel, HM; Matas, AJ

2011-01-01

Single antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor-specific antibody (DSA). We grouped 587 kidney transplants using clinical history and SAB testing of day of transplant serum as 1) unsensitized; PRA=0 (n= 178), 2) 3rd party sensitized; no DSA (n=363), or 3) donor sensitized; with DSA (n=46), and studied rejection rates, death censored graft survival (DCGS), and risk factors for rejection. Antibody-mediated rejection (AMR) rates were increased with DSA (p<0.0001), but not with PRA in the absence of DSA. Cell-mediated rejection (CMR) rates were increased with DSA (p<0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p=0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization. PMID:21812918

3,4,5-Tricaffeoylquinic acid inhibits tumor necrosis factor-α-stimulated production of inflammatory mediators in keratinocytes via suppression of Akt- and NF-κB-pathways.

PubMed

Lee, Chung Soo; Lee, Seon Ae; Kim, Yun Jeong; Seo, Seong Jun; Lee, Min Won

2011-11-01

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Caffeoyl derivatives are demonstrated to have anti-inflammatory and anti-oxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid prepared from Aconium koreanum on the pro-inflammatory cytokine-stimulated keratinocyte responses remains uncertain. In human keratinocytes, we investigated the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB and cell signaling Akt, which regulates the transcription genes involved in immune and inflammatory responses. 3,4,5-Tricaffeoylquinic acid inhibited the TNF-α-stimulated production of cytokines (IL-1β and IL-8) and chemokine (CCL17 and CCL27) in keratinocytes. Bay 11-7085 (an inhibitor of NF-κB activation) and Akt inhibitor attenuated the TNF-α-induced formation of inflammatory mediators. 3,4,5-Tricaffeoylquinic acid, Bay 11-7085, Akt inhibitor and N-acetylcysteine inhibited the TNF-α-induced activation of NF-κB, activation of Akt, and formation of reactive oxygen and nitrogen species. The results show that 3,4,5-tricaffeoylquinic acid seems to attenuate the TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of Akt and NF-κB pathways which may be mediated by reactive oxygen species. The findings suggest that 3,4,5-tricaffeoylquinic acid may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease. Copyright © 2011 Elsevier B.V. All rights reserved.

Investigating the role of appearance-based factors in predicting sunbathing and tanning salon use.

PubMed

Joel Hillhouse, Guy Cafri; Thompson, J Kevin; Jacobsen, Paul B; Hillhouse, Joel

2009-12-01

UV exposure via sunbathing and utilization of sun lamps and tanning beds are considered important risk factors for the development of skin cancer. Psychosocial models of UV exposure are often based on theories of health behavior, but theory from the body image field can be useful as well. The current study examines models that prospectively predict sunbathing and indoor tanning behaviors using constructs and interrelationships derived from the tripartite theory of body image, theory of reasoned action, health belief model, revised protection motivation theory, and a proposed integration of several health behavior models. The results generally support a model in which intentions mediate the relationship between appearance attitudes and tanning behaviors, appearance reasons to tan and intentions mediate the relationship between sociocultural influences and tanning behaviors, and appearance reasons not to tan and intentions mediate the role of perceived threat on behaviors. The implications of these findings are considered. © Springer Science+Business Media, LLC 2009

Mast Cells Condition Dendritic Cells to Mediate Allograft Tolerance

PubMed Central

de Vries, Victor C.; Pino-Lagos, Karina; Nowak, Elizabeth C.; Bennett, Kathy A.; Oliva, Carla; Noelle, Randolph J.

2013-01-01

SUMMARY Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior (“conditioning”) to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNFα)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNFα and GM-CSF on the migration and function of tolerogenic DCs. PMID:22035846

Predicting cancer risk knowledge and information seeking: the role of social and cognitive factors.

PubMed

Hovick, Shelly R; Liang, Ming-Ching; Kahlor, Leeann

2014-01-01

This study tests an expanded Structural Influence Model (SIM) to gain a greater understanding of the social and cognitive factors that contribute to disparities in cancer risk knowledge and information seeking. At the core of this expansion is the planned risk information seeking model (PRISM). This study employed an online sample (N = 1,007) of African American, Hispanic, and non-Hispanic White adults. The addition of four cognitive predictors to the SIM substantially increased variance explained in cancer risk knowledge (R(2) = .29) and information seeking (R(2) = .56). Health literacy mediated the effects of social determinants (socioeconomic status [SES] and race/ethnicity) on cancer risk knowledge, while subjective norms mediated their effects on cancer risk information seeking. Social capital and perceived seeking control were also shown to be important mediators of the relationships between SES and cancer communication outcomes. Our results illustrate the social and cognitive mechanisms by which social determinants impact cancer communication outcomes, as well as several points of intervention to reduce communication disparities.

Ectopically tethered CP190 induces large-scale chromatin decondensation

NASA Astrophysics Data System (ADS)

Ahanger, Sajad H.; Günther, Katharina; Weth, Oliver; Bartkuhn, Marek; Bhonde, Ramesh R.; Shouche, Yogesh S.; Renkawitz, Rainer

2014-01-01

Insulator mediated alteration in higher-order chromatin and/or nucleosome organization is an important aspect of epigenetic gene regulation. Recent studies have suggested a key role for CP190 in such processes. In this study, we analysed the effects of ectopically tethered insulator factors on chromatin structure and found that CP190 induces large-scale decondensation when targeted to a condensed lacO array in mammalian and Drosophila cells. In contrast, dCTCF alone, is unable to cause such a decondensation, however, when CP190 is present, dCTCF recruits it to the lacO array and mediates chromatin unfolding. The CP190 induced opening of chromatin may not be correlated with transcriptional activation, as binding of CP190 does not enhance luciferase activity in reporter assays. We propose that CP190 may mediate histone modification and chromatin remodelling activity to induce an open chromatin state by its direct recruitment or targeting by a DNA binding factor such as dCTCF.

Bromodomain and Extraterminal (BET) Protein Inhibition Suppresses Human T Cell Leukemia Virus 1 (HTLV-1) Tax Protein-mediated Tumorigenesis by Inhibiting Nuclear Factor κB (NF-κB) Signaling*

PubMed Central

Wu, Xuewei; Qi, Jun; Bradner, James E.; Xiao, Gutian; Chen, Lin-Feng

2013-01-01

The etiology of human T cell leukemia virus 1 (HTLV-1)-mediated adult T cell leukemia is associated with the ability of viral oncoprotein Tax to induce sustained NF-κB activation and the expression of many NF-κB target genes. Acetylation of the RelA subunit of NF-κB and the subsequent recruitment of bromodomain-containing factor Brd4 are important for the expression of NF-κB target genes in response to various stimuli. However, their contributions to Tax-mediated NF-κB target gene expression and tumorigenesis remain unclear. Here we report that Tax induced the acetylation of lysine 310 of RelA and the binding of Brd4 to acetylated RelA to facilitate Tax-mediated transcriptional activation of NF-κB. Depletion of Brd4 down-regulated Tax-mediated NF-κB target gene expression and cell proliferation. Inhibiting the interaction of Brd4 and acetylated RelA with the bromodomain extraterminal protein inhibitor JQ1 suppressed the proliferation of Tax-expressing rat fibroblasts and Tax-positive HTLV-1-infected cells and Tax-mediated cell transformation and tumorigenesis. Moreover, JQ1 attenuated the Tax-mediated transcriptional activation of NF-κB, triggering the polyubiquitination and proteasome-mediated degradation of constitutively active nuclear RelA. Our results identify Brd4 as a key regulator for Tax-mediated NF-κB gene expression and suggest that targeting epigenetic regulators such as Brd4 with the bromodomain extraterminal protein inhibitor might be a potential therapeutic strategy for cancers and other diseases associated with HTLV-1 infection. PMID:24189064

Attachment, dysfunctional attitudes, self-esteem, and association to depressive symptoms in patients with mood disorders.

PubMed

Fuhr, Kristina; Reitenbach, Ivanina; Kraemer, Jan; Hautzinger, Martin; Meyer, Thomas D

2017-04-01

Cognitive factors might be the link between early attachment experiences and later depression. Similar cognitive vulnerability factors are discussed as relevant for both unipolar and bipolar disorders. The goals of the study were to test if there are any differences concerning attachment style and cognitive factors between remitted unipolar and bipolar patients compared to controls, and to test if the association between attachment style and depressive symptoms is mediated by cognitive factors. A path model was tested in 182 participants (61 with remitted unipolar and 61 with remitted bipolar disorder, and 60 healthy subjects) in which adult attachment insecurity was hypothesized to affect subsyndromal depressive symptoms through the partial mediation of dysfunctional attitudes and self-esteem. No differences between patients with remitted unipolar and bipolar disorders concerning attachment style, dysfunctional attitudes, self-esteem, and subsyndromal depressive symptoms were found, but both groups reported a more dysfunctional pattern than healthy controls. The path models confirmed that the relationship between attachment style and depressive symptoms was mediated by the cognitive variables 'dysfunctional attitudes' and 'self-esteem'. With the cross-sectional nature of the study, results cannot explain causal development over time. The results emphasize the relevance of a more elaborate understanding of cognitive and interpersonal factors in mood disorders. It is important to address cognitive biases and interpersonal experiences in treatment of mood disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

From action planning and plan enactment to fruit consumption: moderated mediation effects.

PubMed

Kasten, Stefanie; van Osch, Liesbeth; Eggers, Sander Matthijs; de Vries, Hein

2017-10-23

Sufficient fruit consumption is beneficial for a healthy live. While many Dutch adults intent to eat the recommended amount of fruit, only 5-10% of the population actually adheres to the recommendation. One mechanism that can help to narrow this gap between intention and actual fruit consumption is action planning. However, action planning is only assumed to be effective if plans are enacted. This study assessed which action plans are made and enacted, and further aimed to investigate two main hypotheses: 1. the effect of action planning (at T1) on fruit consumption (at T2) is mediated by plan enactment (at T3); 2. positive intentions (2a), high self-efficacy (2b) and a strong habit to eat fruit (2c) enhance the mediation of plan enactment, whereas a strong habit to eat snacks (2d) hinders the mediation of plan enactment. This study was a self-reported longitudinal online survey study. A total of 428 participants filled in a survey, measuring demographic factors (e.g. gender, age, education level), several socio-cognitive constructs (i.e. attitudes, self-efficacy, habit, action planning, plan enactment), and fruit consumption, at three points in time (baseline, after 1 month, and after 3 months). Mediation and moderated mediation analyses were used to investigate the planning-plan enactment- fruit consumption relationship. Up to 70% of the participants reported to have enacted their T1 action plans at T2. Action planning on fruit consumption was fully mediated by plan enactment (Hypothesis 1). All four proposed moderators (i.e. intention, self-efficacy, habit to consume fruit, and habit to consume snacks) significantly influenced the mediation (Hypotheses 2a-2d). Mediation of plan enactment was only present with high levels of intention, high levels of self-efficacy, strong habits to eat fruit, and weak habits to eat snacks. The study suggests the importance of plan enactment for fruit consumption. Furthermore, it emphasizes the necessity of facilitating factors. High levels of intention, self-efficacy and a strong habit to consume fruit clearly aid the enactment of action plans. This suggests that when these factors are moderately low, plan enactment may fail and thus an intervention may require first steps to foster these moderating factors.

Predicting homophobic behavior among heterosexual youth: domain general and sexual orientation-specific factors at the individual and contextual level.

PubMed

Poteat, V Paul; DiGiovanni, Craig D; Scheer, Jillian R

2013-03-01

As a form of bias-based harassment, homophobic behavior remains prominent in schools. Yet, little attention has been given to factors that underlie it, aside from bullying and sexual prejudice. Thus, we examined multiple domain general (empathy, perspective-taking, classroom respect norms) and sexual orientation-specific factors (sexual orientation identity importance, number of sexual minority friends, parents' sexual minority attitudes, media messages). We documented support for a model in which these sets of factors converged to predict homophobic behavior, mediated through bullying and prejudice, among 581 students in grades 9-12 (55 % female). The structural equation model indicated that, with the exception of media messages, these additional factors predicted levels of prejudice and bullying, which in turn predicted the likelihood of students to engage in homophobic behavior. These findings highlight the importance of addressing multiple interrelated factors in efforts to reduce bullying, prejudice, and discrimination among youth.

Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells

PubMed Central

MacVicar, Thomas D. B.; Mannack, Lilith V. J. C.; Lees, Robert M.; Lane, Jon D.

2015-01-01

Autophagy is an important stress response pathway responsible for the removal and recycling of damaged or redundant cytosolic constituents. Mitochondrial damage triggers selective mitochondrial autophagy (mitophagy), mediated by a variety of response factors including the Pink1/Parkin system. Using human retinal pigment epithelial cells stably expressing autophagy and mitophagy reporters, we have conducted parallel screens of regulators of endoplasmic reticulum (ER) and mitochondrial morphology and function contributing to starvation-induced autophagy and damage-induced mitophagy. These screens identified the ER chaperone and Ca2+ flux modulator, sigma non-opioid intracellular receptor 1 (SIGMAR1), as a regulator of autophagosome expansion during starvation. Screens also identified phosphatidyl ethanolamine methyl transferase (PEMT) and the IP3-receptors (IP3Rs) as mediators of Parkin-induced mitophagy. Further experiments suggested that IP3R-mediated transfer of Ca2+ from the ER lumen to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MCU) primes mitochondria for mitophagy. Importantly, recruitment of Parkin to damaged mitochondria did not require IP3R-mediated ER-to-mitochondrial Ca2+ transfer, but mitochondrial clustering downstream of Parkin recruitment was impaired, suggesting involvement of regulators of mitochondrial dynamics and/or transport. Our data suggest that Ca2+ flux between ER and mitochondria at presumed ER/mitochondrial contact sites is needed both for starvation-induced autophagy and for Parkin-mediated mitophagy, further highlighting the importance of inter-organellar communication for effective cellular homeostasis. PMID:26110381

Current understanding of egg allergy

PubMed Central

Caubet, Jean-Christoph; Wang, Julie

2011-01-01

SYNOPSIS Egg is one of the most important allergens in childhood feeding, and egg allergy can pose quality of life concerns. A clear clinical history and the detection of egg white specific IgE will confirm the diagnosis of IgE-mediated reactions. Non-IgE-mediated symptoms such as in eosinophilic diseases of the gut might also be observed. Egg avoidance and education regarding the treatment of allergic reactions are the cornerstones of management of egg allergy. In this review, we discuss epidemiology, risk factors, diagnosis, treatment and natural history of egg allergy. PMID:21453811

Impact of socio-demographic factors on the mitigating actions for climate change: a path analysis with mediating effects of attitudinal variables.

PubMed

Masud, Muhammad Mehedi; Akhatr, Rulia; Nasrin, Shamima; Adamu, Ibrahim Mohammed

2017-12-01

Socio-demographic factors play a significant role in increasing the individual's climate change awareness and in setting a favorable individual attitude towards its mitigation. To better understand how the adversative effects of climate change can be mitigated, this study attempts to investigate the impact of socio-demographic factors on the mitigating actions of the individuals (MAOI) on climate change. Qualitative data were collected from a face-to-face survey of 360 respondents in the Kuala Lumpur region of Malaysia through a close-ended questionnaire. Analysis was conducted on the mediating effects of attitudinal variables through the path model by using the SEM. Findings indicate that the socio-demographic factors such as gender, age, education, income, and ethnicity can greatly influence the individual's awareness, attitude, risk perception, and knowledge of climate change issues. The results drawn from this study also revealed that the attitudinal factors act as a mediating effect between the socio-demographic factors and the MAOI, thereby, indicating that both the socio-demographic factors and the attitudinal factors have significant effects on the MAOI towards climate change. The outcome of this study can help policy makers and other private organizations to decide on the appropriate actions to take in managing climate change effects. These actions which encompass improving basic climate change education and making the public more aware of the local dimensions of climate change are important for harnessing public engagement and support that can also stimulate climate change awareness and promote mitigating actions to n protect the environment from the impact of climate change.

Moderated mediation analysis: An illustration using the association of gender with delinquency and mental health.

PubMed

Miles, Jeremy N V; Kulesza, Magdalena; Ewing, Brett; Shih, Regina A; Tucker, Joan S; D'Amico, Elizabeth J

When researchers find an association between two variables, it is useful to evaluate the role of other constructs in this association. While assessing these mediation effects, it is important to determine if results are equal for different groups. It is possible that the strength of a mediation effect may differ for males and females, for example - such an effect is known as moderated mediation. Participants were 2532 adolescents from diverse ethnic/racial backgrounds and equally distributed across gender. The goal of this study was to investigate parental respect as a potential mediator of the relationship between gender and delinquency and mental health, and to determine whether observed mediation is moderated by gender. Parental respect mediated the association between gender and both delinquency and mental health. Specifically, parental respect was a protective factor against delinquency and mental health problems for both females and males. Demonstrated the process of estimating models in Lavaan, using two approaches (i.e. single group regression and multiple group regression model), and including covariates in both models.

Moderated mediation analysis: An illustration using the association of gender with delinquency and mental health

PubMed Central

Miles, Jeremy N.V.; Kulesza, Magdalena; Ewing, Brett; Shih, Regina A.; Tucker, Joan S.; D’Amico, Elizabeth J.

2015-01-01

Purpose When researchers find an association between two variables, it is useful to evaluate the role of other constructs in this association. While assessing these mediation effects, it is important to determine if results are equal for different groups. It is possible that the strength of a mediation effect may differ for males and females, for example – such an effect is known as moderated mediation. Design Participants were 2532 adolescents from diverse ethnic/racial backgrounds and equally distributed across gender. The goal of this study was to investigate parental respect as a potential mediator of the relationship between gender and delinquency and mental health, and to determine whether observed mediation is moderated by gender. Findings Parental respect mediated the association between gender and both delinquency and mental health. Specifically, parental respect was a protective factor against delinquency and mental health problems for both females and males. Practical implications Demonstrated the process of estimating models in Lavaan, using two approaches (i.e. single group regression and multiple group regression model), and including covariates in both models. PMID:26500722

Mediators of sexual functioning and marital quality in chronically depressed adults with and without a history of childhood sexual abuse.

PubMed

Dunlop, Boadie W; Hill, Eric; Johnson, Benjamin N; Klein, Daniel N; Gelenberg, Alan J; Rothbaum, Barbara O; Thase, Michael E; Kocsis, James H

2015-03-01

Sexual dysfunction is common among depressed adults. Childhood sexual abuse (CSA) and depressive symptomology are among the risk factors for sexual dysfunction, and these factors may interact to predict adult relationship functioning. Several models have been developed postulating interactions between these variables. We tested models of the effects of CSA and elucidate the associations between CSA, sexual dysfunction, depression severity, anxiety, and relationship quality in chronically depressed adults. Baseline data from 808 chronically depressed outpatients enrolled in the Research Evaluating the Value of Augmenting Medication with Psychotherapy study were evaluated using structural equation modeling. The Inventory of Depressive Symptomology, self-report version (IDS-SR) assessed depression severity, and the Mood and Anxiety Symptom Questionnaire Anxious Arousal subscale assessed anxiety. Sexual function was assessed with the Arizona Sexual Experiences Scale (ASEX), and the Quality of Marriage Index (QMI) assessed relationship quality for patients in stable relationships. CSA scores predicted depression severity on the IDS-SR, as well as lower relationship quality and sexual satisfaction. ASEX scores were significantly associated with depression severity but were not correlated with the QMI. Two models were evaluated to elucidate these associations, revealing that (i) depression severity and anxious arousal mediated the relationship between CSA and adult sexual function, (ii) anxious arousal and sexual functioning mediated the association between CSA and depression symptoms, and (iii) when these models were combined, anxious arousal emerged as the most important mediator of CSA on depression which, in turn, mediated associations with adult sexual satisfaction and relationship quality. Although CSA predicts lower relationship and sexual satisfaction among depressed adults, the long-term effects of CSA appear to be mediated by depressive and anxious symptoms. It is important to address depression and anxiety symptoms when treating patients with CSA who present with sexual dysfunction or marital concerns. © 2014 International Society for Sexual Medicine.

Characterization of the Phospholipid Platelet-Activating Factor As a Mediator of Inflammation in Chickens

PubMed Central

Garrido, Damien; Chanteloup, Nathalie K.; Trotereau, Angélina; Lion, Adrien; Bailleul, Geoffrey; Esnault, Evelyne; Trapp, Sascha; Quéré, Pascale; Schouler, Catherine; Guabiraba, Rodrigo

2017-01-01

Lipid mediators are known to play important roles in the onset and resolution phases of the inflammatory response in mammals. The phospholipid platelet-activating factor (PAF) is a pro-inflammatory lipid mediator which participates in vascular- and innate immunity-associated processes by increasing vascular permeability, by facilitating leukocyte adhesion to the endothelium, and by contributing to phagocyte activation. PAF exerts its function upon binding to its specific receptor, PAF receptor (PAFR), which is abundantly expressed in leukocytes and endothelial cells (ECs). In chickens, lipid mediators and their functions are still poorly characterized, and the role of PAF as an inflammatory mediator has not yet been investigated. In the present study we demonstrate that primary chicken macrophages express PAFR and lysophosphatidylcholine acyltransferase 2 (LPCAT2), the latter being essential to PAF biosynthesis during inflammation. Also, exogenous PAF treatment induces intracellular calcium increase, reactive oxygen species release, and increased phagocytosis by primary chicken macrophages in a PAFR-dependent manner. We also show that PAF contributes to the Escherichia coli lipopolysaccharide (LPS)-induced pro-inflammatory response and boosts the macrophage response to E. coli LPS via phosphatidylinositol 3-kinase/Akt- and calmodulin kinase II-mediated intracellular signaling pathways. Exogenous PAF treatment also increases avian pathogenic E. coli intracellular killing by chicken macrophages, and PAFR and LPCAT2 are upregulated in chicken lungs and liver during experimental pulmonary colibacillosis. Finally, exogenous PAF treatment increases cell permeability and upregulates the expression of genes coding for proteins involved in leukocyte adhesion to the endothelium in primary chicken endothelial cells (chAEC). In addition to these vascular phenomena, PAF boosts the chAEC inflammatory response to bacteria-associated molecular patterns in a PAFR-dependent manner. In conclusion, we identified PAF as an inflammation amplifier in chicken macrophages and ECs, which suggests that PAF could play important roles in the endothelium-innate immunity interface in birds during major bacterial infectious diseases such as colibacillosis. PMID:29326957

Condom negotiation strategies as a mediator of the relationship between self-efficacy and condom use.

PubMed

French, Sabine Elizabeth; Holland, Kathryn J

2013-01-01

College students are a group at high risk of sexually transmitted infections due to inconsistent condom use and engaging in other risky sexual behaviors. This study examined whether condom use self-efficacy predicted the use of condom negotiation strategies (i.e., condom influence strategies) and whether condom influence strategies mediated the relationship between condom use self-efficacy and condom use within this population, as well as whether gender moderated the mediation model. Results showed a strong relationship between condom use self-efficacy and condom influence strategies. Additionally, condom influence strategies completely mediated the relationship between condom use self-efficacy and condom use. Although condom use self-efficacy was related to condom use, the ability to use condom negotiation strategies was the most important factor predicting condom use. The mediation model held across genders, except for the condom influence strategy withholding sex, where it was not significant for men. For women, condom use self-efficacy promoted the use of a very assertive negotiation strategy, withholding sex, and was consequently related to increased condom use. Overall, using assertive condom negotiation strategies (e.g., withholding sex and direct request) were found to be the most important aspects of increasing condom use for both women and men. Implications and suggestions for prevention programming are discussed.

The Role of Career Adaptabilities for Mid-Career Changers

ERIC Educational Resources Information Center

Brown, Alan; Bimrose, Jenny; Barnes, Sally-Anne; Hughes, Deirdre

2012-01-01

Career adaptability is mediated by personality factors and socio-psychological processes, with learning playing an important role. Using a five-fold career adapt-abilities competency framework (defined here as control, curiosity, commitment, confidence and concern), which was developed from the international quantitative study that is the focus of…

Flow and Reading Comprehension: Testing the Mediating Role of Emotioncy

ERIC Educational Resources Information Center

Shahian, Leila; Pishghadam, Reza; Khajavy, Gholam Hassan

2017-01-01

Considering the importance of psychological factors in learners' reading abilities, this study examines the relationship between flow, emotioncy, and reading comprehension. To this end, 238 upper-intermediate and advanced English as a Foreign Language (EFL) learners were asked to take four tests of reading comprehension along with flow and…

Quantitative High-Throughput Screening and Confirmation Studies for Identification of Compounds that Activate the Aryl Hydrocarbon Receptor Pathway (SETAC)

EPA Science Inventory

The aryl hydrocarbon receptor (AhR) is a transcription factor that mediates adaptive responses to known environmental pollutants, such as aromatic hydrocarbons, through regulation of Phase I and II xenobiotic metabolizing enzymes as well as important growth and differentiation pa...

College Students' Social Goals and Psychological Adjustment: Mediation via Emotion Regulation

ERIC Educational Resources Information Center

Shim, Sungok Serena; Wang, Cen; Makara, Kara A.; Xu, Xiao-Guang; Xie, Li-Na; Zhong, Ming

2017-01-01

University life can be stressful and students may struggle to adjust socially. We examined students' social achievement goals--their orientations towards their relationships with their peers--as one important factor underlying students' social and psychological adjustment in college. When investigating the direct and indirect effects of social…

Role of APOE Isforms in the Pathogenesis of TBI Induced Alzheimer’s Disease

DTIC Science & Technology

2014-10-01

the inheritance of APOe4 is the only proven genetic risk factor for sporadic Alzheimer disease (AD). Importantly, TBI is a risk factor for the...mice on human APOE genetic background were exceptionally difficult to generate. We are considering changes in the genotype of those particular groups...mediated through ABCA1. 2 Keywords Traumatic brain injury, APOE isoforms, ABCA1, Alzheimer disease, APPmice, amyloid beta, axonal injury, inflamma

CRH Affects the Phenotypic Expression of Sepsis-Associated Virulence Factors by Streptococcus pneumoniae Serotype 1 In vitro

PubMed Central

Ngo Ndjom, Colette G.; Kantor, Lindsay V.; Jones, Harlan P.

2017-01-01

Sepsis is a life-threatening health condition caused by infectious pathogens of the respiratory tract, and accounts for 28–50% of annual deaths in the US alone. Current treatment regimen advocates the use of corticosteroids as adjunct treatment with antibiotics, for their broad inhibitory effect on the activity and production of pro-inflammatory mediators. However, despite their use, corticosteroids have not proven to be able to reverse the death incidence among septic patients. We have previously demonstrated the potential for neuroendocrine factors to directly influence Streptococcus pneumoniae virulence, which may in turn mediate disease outcome leading to sepsis and septic shock. The current study investigated the role of Corticotropin-releasing hormone (CRH) in mediating key markers of pneumococcal virulence as important phenotypic determinants of sepsis and septic shock risks. In vitro cultures of serotype 1 pneumococcal strain with CRH promoted growth rate, increased capsule thickness and penicillin resistance, as well as induced pneumolysin gene expression. These results thus provide significant insights of CRH–pathogen interactions useful in understanding the underlying mechanisms of neuroendocrine factor's role in the onset of community acquired pneumonias (CAP), sepsis and septic shock. PMID:28690980

Stress and multiple sclerosis: A systematic review considering potential moderating and mediating factors and methods of assessing stress.

PubMed

Briones-Buixassa, Laia; Milà, Raimon; Mª Aragonès, Josep; Bufill, Enric; Olaya, Beatriz; Arrufat, Francesc Xavier

2015-07-01

Research about the effects of stress on multiple sclerosis has yielded contradictory results. This study aims to systematically review the evidence focusing on two possible causes: the role of stress assessment and potential moderating and mediating factors. The Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases were searched for relevant articles published from 1900 through December 2014 using the terms "stress*" AND "multiple sclerosis." Twenty-three articles were included. Studies focused on the effect of stress on multiple sclerosis onset ( n  = 9) were mostly retrospective, and semi-structured interviews and scales yielded the most consistent associations. Studies focused on multiple sclerosis progression ( n  = 14) were mostly prospective, and self-reported diaries yielded the most consistent results. The most important modifying factors were stressor duration, severity, and frequency; cardiovascular reactivity and heart rate; and social support and escitalopram intake. Future studies should consider the use of prospective design with self-reported evaluations and the study of moderators and mediators related to amount of stress and autonomic nervous system reactivity to determine the effects of stress on multiple sclerosis.

Stress and multiple sclerosis: A systematic review considering potential moderating and mediating factors and methods of assessing stress

PubMed Central

Briones-Buixassa, Laia; Milà, Raimon; Mª Aragonès, Josep; Bufill, Enric; Olaya, Beatriz; Arrufat, Francesc Xavier

2015-01-01

Research about the effects of stress on multiple sclerosis has yielded contradictory results. This study aims to systematically review the evidence focusing on two possible causes: the role of stress assessment and potential moderating and mediating factors. The Web of Knowledge (MEDLINE and Web of Science), Scopus, and PsycINFO databases were searched for relevant articles published from 1900 through December 2014 using the terms “stress*” AND “multiple sclerosis.” Twenty-three articles were included. Studies focused on the effect of stress on multiple sclerosis onset (n = 9) were mostly retrospective, and semi-structured interviews and scales yielded the most consistent associations. Studies focused on multiple sclerosis progression (n = 14) were mostly prospective, and self-reported diaries yielded the most consistent results. The most important modifying factors were stressor duration, severity, and frequency; cardiovascular reactivity and heart rate; and social support and escitalopram intake. Future studies should consider the use of prospective design with self-reported evaluations and the study of moderators and mediators related to amount of stress and autonomic nervous system reactivity to determine the effects of stress on multiple sclerosis. PMID:28070374

Alcohol Expectancies Mediate and Moderate the Associations between Big Five Personality Traits and Adolescent Alcohol Consumption and Alcohol-Related Problems.

PubMed

Ibáñez, Manuel I; Camacho, Laura; Mezquita, Laura; Villa, Helena; Moya-Higueras, Jorge; Ortet, Generós

2015-01-01

Personality and expectancies are relevant psychological factors for the development of adolescent alcohol use and misuse. The present study examined their direct, mediated and moderated effects on different drinking behaviors in adolescence. Personality domains of the five-factor model, positive and negative alcohol expectancies (AEs), alcohol use during the week and the weekend, and alcohol-related problems were assessed in a sample of 361 adolescents. Different personality dimensions were directly associated with specific alcohol outcomes: Extraversion, low Conscientiousness and low Openness were associated with weekend alcohol use; low Agreeableness was related to weekday use; whereas low Agreeableness, low Conscientiousness and Extraversion were associated with alcohol-related problems. In addition, positive AEs mediated the relationship between Extraversion and alcohol use, whereas both positive and negative expectancies mediated the association between Neuroticism and alcohol consumption and alcohol-related problems. Finally, both types of expectancies interacted with Extraversion to predict alcohol problems. Our results highlight the importance of examining the complex interplay of comprehensive personality models and AEs to gain a better understanding of the development of different alcohol use and misuse patterns in adolescence.

Adversity and persecutory ideation: A moderated mediational model.

PubMed

Valiente, Carmen; Espinosa, Regina; Villavicencio, Patricia; Cantero, Dolores; Fuentenebro, Filiberto

2017-12-01

Adversity has been identified as an important factor in models of psychopathology and can help in understanding persecutory ideation, although potential moderators and mediators for adult psychopathology have not been sufficiently examined. Experiential avoidance (EA) and Self-esteem (SE) are relevant factors to understand how adversity leads to persecutory ideation. This study hypothesized that adversity would be associated with persecutory ideation through heightened EA, and that this association would be strengthened in individuals with a discrepant high SE. Participants with persecutory ideation (n = 52), with depression (n = 35) and healthy controls (n = 51) were assessed with the Trauma History Screen, the Paranoia and Deservedness Scale, and the Beck Depression Inventory. A SE discrepancy index was calculated subtracting the normalized explicit SE score from the normalized implicit SE score (measured by a version of a Go/No-go association task). Our analysis revealed that adversity was associated with higher levels of paranoia and was mediated by EA. In addition, we found that the relationship between adversity and EA was moderated by SE discrepancy. Identification of moderating and mediating variables allows for increased understanding of persecutory ideation and the processes that should be targeted in the course of recovery. Copyright © 2017 Elsevier B.V. All rights reserved.

Tumor Necrosis Factor-α, a Regulator and Therapeutic Agent on Breast Cancer.

PubMed

Liu, Dongwu; Wang, Xiaoqian; Chen, Zhiwei

2016-01-01

The cell-mediated immunity and cytotoxic agents play a significant role on tumor cell apoptosis. Tumor necrosis factor-α (TNF-α) is an intricate linker between inflammation and cancer through mediating the process of apoptosis and cell-mediated immunity. A variety of evidences have confirmed the critical role of TNF-α on tumor migration, proliferation, matrix degradation, tumor metastasis, invasion, and angiogenesis. Through binding to receptors, TNF-α participates in activating multiple cell signaling cascades that link inflammation, survival and evolution towards breast cancer. TNF-α is an important agent for tumor biotherapy, but its clinical application is limited for its severe fatal systemic toxicity. The poly-lactic acid microspheres (PLAM) with intratumoral cytokine release hold tremendous potential for the immunotherapy of breast cancer, and TNF-α antagonists may offer therapeutic potential in solid tumors. In addition, TNF-α is related with the blockage of estrogen and progesterone receptors. For breast cancer treatment, it is necessary to understand the molecular signaling pathways that mediate TNF-α and the aggressive behavior of negative breast cancer. The aim of present review is to summarize the effect of TNF-α on breast cancer cells.

Negative emotions and emotional eating: the mediating role of experiential avoidance.

PubMed

Litwin, Rachel; Goldbacher, Edie M; Cardaciotto, LeeAnn; Gambrel, Laura Eubanks

2017-03-01

Emotional eating is a risk factor for eating pathology across the life- and weight-span. Research demonstrates that negative emotions are a precipitant of emotional eating, particularly among female college students. However, the underlying factors that explain this relationship are unclear. Experiential avoidance, a propensity toward being unwilling to remain in contact with aversive private experiences, may explain the association between negative emotions and emotional eating. The purpose of this study was to examine whether experiential avoidance would mediate the association between negative emotions and emotional eating. A sample of 132 women (17.4 % African American, 59.8 % White) completed measures of mood, experiential avoidance and emotional eating. Bias-corrected bootstrapping mediational analyses were conducted. Experiential avoidance mediated the relationship between negative emotions and emotional eating b = -0.21, 95 % BC CI [-0.43, -0.07]. The indirect effect through experiential avoidance accounted for 9 % of the variance, which represents a medium effect (k 2  = 0.09, 95 % BC CI [0.03, 0.18]). Results suggest that experiential avoidance is important for understanding the relationship between negative emotions and emotional eating and may inform potential strategies for prevention and treatment.

Advanced glycation end-products: modifiable environmental factors profoundly mediate insulin resistance

PubMed Central

Ottum, Mona S.; Mistry, Anahita M.

2015-01-01

Advanced glycation end-products are toxic by-products of metabolism and are also acquired from high-temperature processed foods. They promote oxidative damage to proteins, lipids and nucleotides. Aging and chronic diseases are strongly associated with markers for oxidative stress, especially advanced glycation end-products, and resistance to peripheral insulin-mediated glucose uptake. Modifiable environmental factors including high levels of refined and simple carbohydrate diets, hypercaloric diets and sedentary lifestyles drive endogenous formation of advanced glycation end-products via accumulation of highly reactive glycolysis intermediates and activation of the polyol/aldose reductase pathway producing high intracellular fructose. High advanced glycation end-products overwhelm innate defenses of enzymes and receptor-mediated endocytosis and promote cell damage via the pro-inflammatory and pro-oxidant receptor for advanced glycation end-products. Oxidative stress disturbs cell signal transduction, especially insulin-mediated metabolic responses. Here we review emerging evidence that restriction of dietary advanced glycation end-products significantly reduces total systemic load and insulin resistance in animals and humans in diabetes, polycystic ovary syndrome, healthy populations and dementia. Of clinical importance, this insulin sensitizing effect is independent of physical activity, caloric intake and adiposity level. PMID:26236094

Cross-talk between GPER and growth factor signaling.

PubMed

Lappano, Rosamaria; De Marco, Paola; De Francesco, Ernestina Marianna; Chimento, Adele; Pezzi, Vincenzo; Maggiolini, Marcello

2013-09-01

G protein-coupled receptors (GPCRs) and growth factor receptors mediate multiple physio-pathological responses to a diverse array of extracellular stimuli. In this regard, it has been largely demonstrated that GPCRs and growth factor receptors generate a multifaceted signaling network, which triggers relevant biological effects in normal and cancer cells. For instance, some GPCRs transactivate the epidermal growth factor receptor (EGFR), which stimulates diverse transduction pathways leading to gene expression changes, cell migration, survival and proliferation. Moreover, it has been reported that a functional interaction between growth factor receptors and steroid hormones like estrogens is involved in the growth of many types of tumors as well as in the resistance to endocrine therapy. This review highlights recent findings on the cross-talk between a member of the GPCR family, the G protein-coupled estrogen receptor 1 (GPER, formerly known as GPR30) and two main growth factor receptors like EGFR and insulin-like growth factor-I receptor (IGF-IR). The biological implications of the functional interaction between these important mediators of cell responses particularly in cancer are discussed. This article is part of a Special Issue entitled 'CSR 2013'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Regulation of cell growth by redox-mediated extracellular proteolysis of platelet-derived growth factor receptor beta.

PubMed

Okuyama, H; Shimahara, Y; Kawada, N; Seki, S; Kristensen, D B; Yoshizato, K; Uyama, N; Yamaoka, Y

2001-07-27

Redox-regulated processes are important elements in various cellular functions. Reducing agents, such as N-acetyl-l-cysteine (NAC), are known to regulate signal transduction and cell growth through their radical scavenging action. However, recent studies have shown that reactive oxygen species are not always involved in ligand-stimulated intracellular signaling. Here, we report a novel mechanism by which NAC blocks platelet-derived growth factor (PDGF)-induced signaling pathways in hepatic stellate cells, a fibrogenic player in the liver. Unlike in vascular smooth muscle cells, we found that reducing agents, including NAC, triggered extracellular proteolysis of PDGF receptor-beta, leading to desensitization of hepatic stellate cells toward PDGF-BB. This effect was mediated by secreted mature cathepsin B. In addition, type II transforming growth factor-beta receptor was also down-regulated. Furthermore, these events seemed to cause a dramatic improvement of rat liver fibrosis. These results indicated that redox processes impact the cell's response to growth factors by regulating the turnover of growth factor receptors and that "redox therapy" is promising for fibrosis-related disease.

Suicidality in male prisoners: influence of childhood adversity mediated by dimensions of personality.

PubMed

Godet-Mardirossian, Hélène; Jehel, Louis; Falissard, Bruno

2011-07-01

This study aims to study the influence of childhood adversity on suicidal behavior in male prisoners. Including a random sample of 899 male prisoners (French National Mental Health Prison Survey, 2003), this paper studied suicidal ideations and suicide attempts using MINI criteria, and personality using Temperament and Character Inventory. Risk factors of suicidality were examined, and structural equations studied the influence of childhood trauma on suicidality, mediated by personality dimensions. The prisoners reported high levels of childhood adversity. More than a third reported recent suicidal ideations. Childhood adversity and dimensions of personality were associated with suicidality. Structural equations showed that childhood adversity was positively associated with suicidality, mediated by poor dimensions of character (affective stability, self-cooperativeness, and self-transcendence). In conclusion, these results confirm the importance of screening and treatment of childhood trauma among male prisoners. They suggest the importance to study dimensions of personality and tailor treatment to specific needs. © 2011 American Academy of Forensic Sciences.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moon, Yuseok; Yang, Hyun; Kim, Yung Bu

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to relieve pain and inflammation and have also received considerable attention because of their preventive effects against human cancer. However, the drug application is sometimes limited by the severe gastrointestinal ulcers and mucosal complications. In the present study, NSAID sulindac sulfide was investigated for the cytotoxic injury in the intestinal epithelial cells in association with an immediate inducible factor, early growth response gene 1 (EGR-1). Previously we reported that sulindac sulfide can suppress tumor cell invasion by inducing EGR-1. Extending the previous study, EGR-1 induction by sulindac sulfide was observed both in the non-transformedmore » and transformed human intestinal epithelial cell lines. In terms of signaling pathway, ERK1/2 MAP kinases and its substrate Elk-1 transcription factor were involved in the sulindac sulfide-induced EGR-1 gene expression. Moreover, sulindac sulfide stimulated the nuclear translocation of the transcription factor EGR-1, which was also mediated by ERK1/2 signaling pathway. The roles of EGR-1 signals in the apoptotic cell death were assessed in the intestinal epithelial cells. Suppression of EGR-1 expression retarded cellular growth and colony forming activity in the intestinal epithelial cells. Moreover, induced EGR-1 ameliorated sulindac sulfide-mediated apoptotic cell death and enhanced the cellular survival. Taken all together, sulindac sulfide activated ERK1/2 MAP kinases which then mediated EGR-1 induction and nuclear translocation, all of which played important roles in the cellular survival from NSAID-mediated cytotoxicity in the human intestinal epithelial cells, implicating the protective roles of EGR-1 in the NSAID-mediated mucosal injuries.« less

The DRUID study: racism and self-assessed health status in an indigenous population

PubMed Central

2012-01-01

Background There is now considerable evidence from around the world that racism is associated with both mental and physical ill-health. However, little is known about the mediating factors between racism and ill-health. This paper investigates relationships between racism and self-assessed mental and physical health among Indigenous Australians as well as potential mediators of these relationships. Methods A total of 164 adults in the Darwin Region Urban Indigenous Diabetes (DRUID) study completed a validated instrument assessing interpersonal racism and a separate item on discrimination-related stress. Self-assessed health status was measured using the SF-12. Stress, optimism, lack of control, social connections, cultural identity and reactions/responses to interpersonal racism were considered as mediators and moderators of the relationship between racism/discrimination and self-assessed health status. Results After adjusting for socio-demographic factors, interpersonal racism was significantly associated with the SF-12 mental (but not the physical) health component. Stress, lack of control and feeling powerless as a reaction to racism emerged as significant mediators of the relationship between racism and general mental health. Similar findings emerged for discrimination-related stress. Conclusions Racism/discrimination is significantly associated with poor general mental health among this indigenous population. The mediating factors between racism and mental health identified in this study suggest new approaches to ameliorating the detrimental effects of racism on health. In particular, the importance of reducing racism-related stress, enhancing general levels of mastery, and minimising negative social connections in order to ameliorate the negative consequences of racism. PMID:22333047

The Pseudomonas aeruginosa AmrZ C-terminal domain mediates tetramerization and is required for its activator and repressor functions

PubMed Central

Xu, Binjie; Ju, Yue; Soukup, Randal J.; Ramsey, Deborah M.; Fishel, Richard; Wysocki, Vicki H.; Wozniak, Daniel J.

2015-01-01

Summary Pseudomonas aeruginosa is an important bacterial opportunistic pathogen, presenting a significant threat towards individuals with underlying diseases such as cystic fibrosis. The transcription factor AmrZ regulates expression of multiple P. aeruginosa virulence factors. AmrZ belongs to the ribbon-helix-helix protein superfamily, in which many members function as dimers, yet others form higher-order oligomers. In this study, four independent approaches were undertaken and demonstrated that the primary AmrZ form in solution is tetrameric. Deletion of the AmrZ C-terminal domain leads to loss of tetramerization and reduced DNA binding to both activated and repressed target promoters. Additionally, the C-terminal domain is essential for efficient AmrZ-mediated activation and repression of its targets. PMID:26549743

Progesterone-Mediated Non-Classical Signaling.

PubMed

Garg, Deepika; Ng, Sinnie Sin Man; Baig, K Maravet; Driggers, Paul; Segars, James

2017-09-01

Progesterone is essential for pregnancy maintenance and menstrual cycle regulation. Hormone action has been primarily ascribed to the well-characterized classical signaling pathway involving ligand binding, activation of nuclear progesterone receptors (PRs), and subsequent activation of genes containing progesterone response elements (PREs). Recent studies have revealed progesterone actions via non-classical signaling pathways, often mediated by non-genomic signaling. Progesterone signaling, in conjunction with growth factor signaling, impacts on the function of growth factors and regulates important physiological actions such as cell growth and remodeling, as well as apoptosis. This review focuses on non-classical progesterone signaling pathways, both including and excluding PR, and highlights how research in this area will provide a better understanding of progesterone actions and may inform novel therapeutic strategies. Copyright © 2017. Published by Elsevier Ltd.

Depression in small-vessel disease relates to white matter ultrastructural damage, not disability.

PubMed

Brookes, Rebecca L; Herbert, Vanessa; Lawrence, Andrew J; Morris, Robin G; Markus, Hugh S

2014-10-14

To determine whether cerebral small-vessel disease (SVD) is a specific risk factor for depression, whether any association is mediated via white matter damage, and to study the role of depressive symptoms and disability on quality of life (QoL) in this patient group. Using path analyses in cross-sectional data, we modeled the relationships among depression, disability, and QoL in patients with SVD presenting with radiologically confirmed lacunar stroke (n = 100), and replicated results in a second SVD cohort (n = 100). We then compared the same model in a non-SVD stroke cohort (n = 50) and healthy older adults (n = 203). In a further study, to determine the role of white matter damage in mediating the association with depression, a subgroup of patients with SVD (n = 101) underwent diffusion tensor imaging (DTI). Reduced QoL was associated with depression in patients with SVD, but this association was not mediated by disability or cognition; very similar results were found in the replication SVD cohort. In contrast, the non-SVD stroke group and the healthy older adult group showed a direct relationship between disability and depression. The DTI study showed that fractional anisotropy, a marker of white matter damage, was related to depressive symptoms in patients with SVD. These results suggest that in stroke patients without SVD, disability is an important causal factor for depression, whereas in SVD stroke, other factors specific to this stroke subtype have a causal role. White matter damage detected on DTI is one factor that mediates the association between SVD and depression. © 2014 American Academy of Neurology.

Mediation of glucolipotoxicity in INS-1 rat insulinoma cells by small heterodimer partner interacting leucine zipper protein (SMILE).

PubMed

Lee, Kyeong-Min; Seo, Ye Jin; Kim, Mi-Kyung; Seo, Hyun-Ae; Jeong, Ji-Yun; Choi, Hueng-Sik; Lee, In-Kyu; Park, Keun-Gyu

2012-03-23

Sustained elevations of glucose and free fatty acid concentration have deleterious effects on pancreatic beta cell function. One of the hallmarks of such glucolipotoxicity is a reduction in insulin gene expression, resulting from decreased insulin promoter activity. Sterol regulatory element binding protein-1c (SREBP-1c), a lipogenic transcription factor, is related to the development of beta cell dysfunction caused by elevated concentrations of glucose and free fatty acid. Small heterodimer partner (SHP) interacting leucine zipper protein (SMILE), also known as Zhangfei, is a novel protein which interacts with SHP that mediates glucotoxicity in INS-1 rat insulinoma cells. Treatment of INS-1 cells with high concentrations of glucose and palmitate increased SREBP-1c and SMILE expression, and decreased insulin gene expression. Adenovirus-mediated overexpression of SREBP-1c in INS-1 cells induced SMILE expression. Moreover, adenovirus-mediated overexpression of SMILE (Ad-SMILE) in INS-1 cells impaired glucose-stimulated insulin secretion as well as insulin gene expression. Ad-SMILE overexpression also inhibited the expression of beta-cell enriched transcription factors including pancreatic duodenal homeobox factor-1, beta cell E box transactivator 2 and RIPE3b1/MafA, in INS-1 cells. Finally, in COS-1 cells, expression of SMILE inhibited the insulin promoter activity induced by these same beta-cell enriched transcription factors. These results collectively suggest that SMILE plays an important role in the development of beta cell dysfunction induced by glucolipotoxicity. Copyright © 2012 Elsevier Inc. All rights reserved.

Do individual cognitions mediate the association of socio-cultural and physical environmental factors with adolescent sports participation?

PubMed

van der Horst, Klazine; Oenema, Anke; te Velde, Saskia J; Brug, Johannes

2010-10-01

To examine the associations of perceived physical environmental factors (availability of physical activity (PA) attributes at home, PA facilities in the neighbourhood, neighbourhood pleasantness and safety) and social environmental factors (parental sports behaviour and parental rule regarding sports participation) with adolescent leisure-time sports participation, and to explore whether the associations found were mediated by individual cognitions as derived from the theory of planned behaviour (TPB). Cross-sectional study. In school-year 2005/2006 adolescents from seventeen schools in Rotterdam, the Netherlands, completed a questionnaire during school hours that included self-reported measures of leisure-time sports participation, perceived physical environmental factors and TPB variables. Information about parental sports behaviour and parental rule was obtained from a questionnaire that was completed by one parent of the adolescents. Data were collected from 584 adolescent-parent combinations. Data were analysed with multi-level logistic regression analyses. Availability of PA attributes at home (OR = 1·26), parents' sports behaviour (OR = 2·03) and parental rule (OR = 1·64) were associated with a higher likelihood of adolescents' leisure-time sports participation. These associations were partly mediated by attitude and intention. Adolescents were more likely to engage in leisure-time sports when PA attributes were available at home, when parents participated in sports activities and had a rule about their offspring participation in sports activities. These associations were partly mediated by attitude and intention. These results suggest that parents can importantly promote sports participation among their offspring by making sports activities accessible and a family routine.

Blueberry (Vaccinium corymbosum L.).

PubMed

Song, Guo-Qing; Sink, Kenneth C

2006-01-01

Recent advances in plant biotechnology have led to a reliable and reproductive method for genetic transformation of blueberry. These efforts built on previous attempts at transient and stable transformation of blueberry that demonstrated the potential of Agrobacterium tumefaciens-mediated transformation, and as well, the difficulties of selecting and regenerating transgenic plants. As a prerequisite for successful stable transformation, efficient regeneration systems were required despite many reports on factors controlling shoot regeneration from leaf explants. The A. tumefaciens-mediated transformation protocol described in this chapter is based on combining efficient regeneration methods and the results of A. tumefaciens-mediated transient transformation studies to optimize selected parameters for gene transfer. The protocol has led to successful regeneration of transgenic plants of four commercially important highbush blueberry cultivars.

Intracellular mediators of transforming growth factor beta superfamily signaling localize to endosomes in chicken embryo and mouse lenses in vivo.

PubMed

Rajagopal, Ramya; Ishii, Shunsuke; Beebe, David C

2007-06-25

Endocytosis is a key regulator of growth factor signaling pathways. Recent studies showed that the localization to endosomes of intracellular mediators of growth factor signaling may be required for their function. Although there is substantial evidence linking endocytosis and growth factor signaling in cultured cells, there has been little study of the endosomal localization of signaling components in intact tissues or organs. Proteins that are downstream of the transforming growth factor-beta superfamily signaling pathway were found on endosomes in chicken embryo and postnatal mouse lenses, which depend on signaling by members of the TGFbeta superfamily for their normal development. Phosphorylated Smad1 (pSmad1), pSmad2, Smad4, Smad7, the transcriptional repressors c-Ski and TGIF and the adapter molecules Smad anchor for receptor activation (SARA) and C184M, localized to EEA-1- and Rab5-positive vesicles in chicken embryo and/or postnatal mouse lenses. pSmad1 and pSmad2 also localized to Rab7-positive late endosomes. Smad7 was found associated with endosomes, but not caveolae. Bmpr1a conditional knock-out lenses showed decreased nuclear and endosomal localization of pSmad1. Many of the effectors in this pathway were distributed differently in vivo from their reported distribution in cultured cells. Based on the findings reported here and data from other signaling systems, we suggest that the localization of activated intracellular mediators of the transforming growth factor-beta superfamily to endosomes is important for the regulation of growth factor signaling.

Nutritionally Mediated Programming of the Developing Immune System12

PubMed Central

Palmer, Amanda C.

2011-01-01

A growing body of evidence highlights the importance of a mother’s nutrition from preconception through lactation in programming the emerging organ systems and homeostatic pathways of her offspring. The developing immune system may be particularly vulnerable. Indeed, examples of nutrition-mediated immune programming can be found in the literature on intra-uterine growth retardation, maternal micronutrient deficiencies, and infant feeding. Current models of immune ontogeny depict a “layered” expansion of increasingly complex defenses, which may be permanently altered by maternal malnutrition. One programming mechanism involves activation of the maternal hypothalamic-pituitary-adrenal axis in response to nutritional stress. Fetal or neonatal exposure to elevated stress hormones is linked in animal studies to permanent changes in neuroendocrine-immune interactions, with diverse manifestations such as an attenuated inflammatory response or reduced resistance to tumor colonization. Maternal malnutrition may also have a direct influence, as evidenced by nutrient-driven epigenetic changes to developing T regulatory cells and subsequent risk of allergy or asthma. A 3rd programming pathway involves placental or breast milk transfer of maternal immune factors with immunomodulatory functions (e.g. cytokines). Maternal malnutrition can directly affect transfer mechanisms or influence the quality or quantity of transferred factors. The public health implications of nutrition-mediated immune programming are of particular importance in the developing world, where prevalent maternal undernutrition is coupled with persistent infectious challenges. However, early alterations to the immune system, resulting from either nutritional deficiencies or excesses, have broad relevance for immune-mediated diseases, such as asthma, and chronic inflammatory conditions like cardiovascular disease. PMID:22332080

TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17

PubMed Central

Cook, Andrew D.; Khiew, Hsu-Wei; Christensen, Anne D.; Fleetwood, Andrew J.; Lacey, Derek C.; Smith, Julia E.; Förster, Irmgard

2018-01-01

TNF and granulocyte macrophage-colony stimulating factor (GM-CSF) have proinflammatory activity and both contribute, for example, to rheumatoid arthritis pathogenesis. We previously identified a new GM-CSF→JMJD3 demethylase→interferon regulatory factor 4 (IRF4)→CCL17 pathway that is active in monocytes/macrophages in vitro and important for inflammatory pain, as well as for arthritic pain and disease. Here we provide evidence for a nexus between TNF and this pathway, and for TNF and GM-CSF interdependency. We report that the initiation of zymosan-induced inflammatory pain and zymosan-induced arthritic pain and disease are TNF dependent. Once arthritic pain and disease are established, blockade of GM-CSF or CCL17, but not of TNF, is still able to ameliorate them. TNF is required for GM-CSF–driven inflammatory pain and for initiation of GM-CSF–driven arthritic pain and disease, but not once they are established. TNF-driven inflammatory pain and TNF-driven arthritic pain and disease are dependent on GM-CSF and mechanistically require the same downstream pathway involving GM-CSF→CCL17 formation via JMJD3-regulated IRF4 production, indicating that GM-CSF and CCL17 can mediate some of the proinflammatory and algesic actions of TNF. Given we found that TNF appears important only early in arthritic pain and disease progression, targeting a downstream mediator, such as CCL17, which appears to act throughout the course of disease, could be effective at ameliorating chronic inflammatory conditions where TNF is implicated. PMID:29563337

Self-Stigma and Its Relationship with Victimization, Psychotic Symptoms and Self-Esteem among People with Schizophrenia Spectrum Disorders

PubMed Central

Horsselenberg, Ellen M. A.; van Busschbach, Jooske T.; Aleman, Andre; Pijnenborg, Gerdine H. M.

2016-01-01

Objective Self-stigma is highly prevalent in schizophrenia and can be seen as an important factor leading to low self-esteem. It is however unclear how psychological factors and actual adverse events contribute to self-stigma. This study empirically examines how symptom severity and the experience of being victimized affect both self-stigma and self-esteem. Methods Persons with a schizophrenia spectrum disorder (N = 102) were assessed with a battery of self-rating questionnaires and interviews. Structural equation modelling (SEM) was subsequently applied to test the fit of three models: a model with symptoms and victimization as direct predictors of self-stigma and negative self-esteem, a model with an indirect effect for symptoms mediated by victimization and a third model with a direct effect for negative symptoms and an indirect effect for positive symptoms mediated by victimization. Results Results showed good model fit for the direct effects of both symptoms and victimization: both lead to an increase of self-stigma and subsequent negative self-esteem. Negative symptoms had a direct association with self-stigma, while the relationship between positive symptoms and self-stigma was mediated by victimization. Conclusions Our findings suggest that symptoms and victimization may contribute to self-stigma, leading to negative self-esteem in individuals with a schizophrenia spectrum disorder. Especially for patients with positive symptoms victimization seems to be an important factor in developing self-stigma. Given the burden of self-stigma on patients and the constraining effects on societal participation and service use, interventions targeting victimization as well as self-stigma are needed. PMID:27783677

Intelligence is negatively associated with the number of functional somatic symptoms.

PubMed

Kingma, E M; Tak, L M; Huisman, M; Rosmalen, J G M

2009-11-01

Functional somatic symptoms (FSS), that is, symptoms that cannot be conclusively explained by organic pathology, have a poorly understood aetiology. Intelligence was studied as a risk factor for FSS. It was hypothesised that intelligence is negatively associated with the number of FSS. To investigate the specific role of intelligence in FSS as opposed to medically explained symptoms (MES), the association of intelligence with FSS was compared with that of intelligence with MES. It was also hypothesised that lifestyle factors and socioeconomic factors mediate the relationship between intelligence and both FSS and MES, whereas psychological distress is especially important for FSS. All analyses were performed in a longitudinal study with two measurement waves in a general population cohort of 947 participants (age 33-79 years, 47.9% male). The Generalized Aptitude-Test Battery was used to derive an index for general intelligence, and the somatisation section of the Composite International Diagnostic Interview was used to measure the number of FSS and MES. General intelligence was significantly associated with the number of FSS. The association of intelligence and FSS but not MES was mediated by work situation: participants of lower intelligence who reported more FSS were more often (unwanted) economically inactive. No evidence was found for a mediating role of psychological distress in the association of intelligence with FSS, even though distress was an important predictor of FSS. Intelligence is negatively associated with the number of FSS in the general population. Part of the association of intelligence with FSS is explained by a more unfavourable work situation for adults of lower intelligence.

Self-Stigma and Its Relationship with Victimization, Psychotic Symptoms and Self-Esteem among People with Schizophrenia Spectrum Disorders.

PubMed

Horsselenberg, Ellen M A; van Busschbach, Jooske T; Aleman, Andre; Pijnenborg, Gerdine H M

2016-01-01

Self-stigma is highly prevalent in schizophrenia and can be seen as an important factor leading to low self-esteem. It is however unclear how psychological factors and actual adverse events contribute to self-stigma. This study empirically examines how symptom severity and the experience of being victimized affect both self-stigma and self-esteem. Persons with a schizophrenia spectrum disorder (N = 102) were assessed with a battery of self-rating questionnaires and interviews. Structural equation modelling (SEM) was subsequently applied to test the fit of three models: a model with symptoms and victimization as direct predictors of self-stigma and negative self-esteem, a model with an indirect effect for symptoms mediated by victimization and a third model with a direct effect for negative symptoms and an indirect effect for positive symptoms mediated by victimization. Results showed good model fit for the direct effects of both symptoms and victimization: both lead to an increase of self-stigma and subsequent negative self-esteem. Negative symptoms had a direct association with self-stigma, while the relationship between positive symptoms and self-stigma was mediated by victimization. Our findings suggest that symptoms and victimization may contribute to self-stigma, leading to negative self-esteem in individuals with a schizophrenia spectrum disorder. Especially for patients with positive symptoms victimization seems to be an important factor in developing self-stigma. Given the burden of self-stigma on patients and the constraining effects on societal participation and service use, interventions targeting victimization as well as self-stigma are needed.

Regulation of Na(+)/K(+)-ATPase by nuclear respiratory factor 1: implication in the tight coupling of neuronal activity, energy generation, and energy consumption.

PubMed

Johar, Kaid; Priya, Anusha; Wong-Riley, Margaret T T

2012-11-23

NRF-1 regulates mediators of neuronal activity and energy generation. NRF-1 transcriptionally regulates Na(+)/K(+)-ATPase subunits α1 and β1. NRF-1 functionally regulates mediators of energy consumption in neurons. NRF-1 mediates the tight coupling of neuronal activity, energy generation, and energy consumption at the molecular level. Energy generation and energy consumption are tightly coupled to neuronal activity at the cellular level. Na(+)/K(+)-ATPase, a major energy-consuming enzyme, is well expressed in neurons rich in cytochrome c oxidase, an important enzyme of the energy-generating machinery, and glutamatergic receptors that are mediators of neuronal activity. The present study sought to test our hypothesis that the coupling extends to the molecular level, whereby Na(+)/K(+)-ATPase subunits are regulated by the same transcription factor, nuclear respiratory factor 1 (NRF-1), found recently by our laboratory to regulate all cytochrome c oxidase subunit genes and some NMDA and AMPA receptor subunit genes. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation, promoter mutational analysis, and real-time quantitative PCR, NRF-1 was found to functionally bind to the promoters of Atp1a1 and Atp1b1 genes but not of the Atp1a3 gene in neurons. The transcripts of Atp1a1 and Atp1b1 subunit genes were up-regulated by KCl and down-regulated by tetrodotoxin. Atp1b1 is positively regulated by NRF-1, and silencing of NRF-1 with small interference RNA blocked the up-regulation of Atp1b1 induced by KCl, whereas overexpression of NRF-1 rescued these transcripts from being suppressed by tetrodotoxin. On the other hand, Atp1a1 is negatively regulated by NRF-1. The binding sites of NRF-1 on Atp1a1 and Atp1b1 are conserved among mice, rats, and humans. Thus, NRF-1 regulates key Na(+)/K(+)-ATPase subunits and plays an important role in mediating the tight coupling between energy consumption, energy generation, and neuronal activity at the molecular level.

B16-BL6 melanoma cells release inhibitory factor(s) of active pump activity in isolated lymph vessels.

PubMed

Nakaya, K; Mizuno, R; Ohhashi, T

2001-12-01

We investigated whether supernatant cultured with melanoma cell lines B16-BL6 and K1735 or the Lewis lung carcinoma cell line (LLC) can regulate lymphatic pump activity with bioassay preparations isolated from murine iliac lymph vessels. B16-BL6 and LLC supernatants caused significant dilation of lymph microvessels with cessation of pump activity. B16-BL6 supernatant produced dose-related cessation of lymphatic pump activity. There was no significant tachyphylaxis in the supernatant-mediated inhibitory response of lymphatic pump activity. Pretreatment with 3 x 10(-5) M N(omega)-nitro-L-arginine methyl ester (L-NAME) or 10(-7) M or 10(-6) M glibenclamide and 5 x 10(-4) M 5-hydroxydecanoic acid caused significant reduction of supernatant-mediated inhibitory responses. Simultaneous treatment with 10(-3) M L-arginine and 3 x 10(-5) M L-NAME significantly lessened L-NAME-induced inhibition of the supernatant-mediated response, suggesting that endogenous nitric oxide (NO) plays important roles in supernatant-mediated inhibitory responses. Chemical treatment dialyzed substances of <1,000 molecular weight (MW), producing complete reduction of the supernatant-mediated response. In contrast, pretreatment with heating or digestion with protease had no significant effect on supernatant-mediated response. These findings suggest that B16-BL6 cells may release nonpeptide substance(s) of <1,000 MW, resulting in significant cessation of lymphatic pump activity via production and release of endogenous NO and activation of mitochondrial ATP-sensitive K(+) channels.

Work-family conflict and burnout among Chinese female nurses: the mediating effect of psychological capital.

PubMed

Wang, Yang; Chang, Ying; Fu, Jialiang; Wang, Lie

2012-10-29

Burnout among nurses not only threatens their own health, but also that of their patients. Exploring risk factors of nurse' burnout is important to improve nurses' health and to increase the quality of health care services. This study aims to explore the relationship between work-family conflict and burnout among Chinese female nurses and the mediating role of psychological capital in this relationship. This cross-sectional study was performed during the period of September and October 2010. A questionnaire that consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the work-family conflict scale and the psychological capital questionnaire (PCQ-24) scale, as well as demographic and working factors, was distributed to nurses in Liaoning province, China. A total of 1,332 individuals (effective response rate: 78.35%) became our subjects. Hierarchical linear regression analyses were performed to explore the mediating role of psychological capital. Both work interfering family conflict and family interfering work conflict were positively related with emotional exhaustion and cynicism. However, work interfering family conflict was positively related with professional efficacy whereas family interfering work conflict was negatively related with it. Psychological capital partially mediated the relationship of work interfering family conflict with emotional exhaustion and cynicism; and partially mediated the relationship of family interfering work conflict with emotional exhaustion, cynicism and professional efficacy. Work-family conflict had effects on burnout and psychological capital was a mediator in this relationship among Chinese nurses. Psychological capital was a positive resource for fighting against nurses' burnout.

Effort-reward imbalance at work and 5-year changes in blood pressure: the mediating effect of changes in body mass index among 1400 white-collar workers.

PubMed

Trudel, Xavier; Brisson, Chantal; Milot, Alain; Masse, Benoit; Vézina, Michel

2016-11-01

A number of prospective studies have documented the effect of adverse psychosocial work factors (work stress) on high blood pressure (BP). Weight gain could be an important pathway by which work stress exerts its effect on BP. No previous prospective study has examined this mediating effect. The aim of the present study was to examine the mediating effect of body mass index (BMI) in the association between psychosocial work factors from Siegrist's effort-reward imbalance model (ERI) and ambulatory BP (ABP). A prospective study was conducted among 1436 white-collar workers. Data were collected three times during a 5-year period. ERI was measured using validated scales, at each time. BMI was measured by a trained assistant. ABP was measured every 15 min during a working day. ERI exposure onset over 3 years was indirectly associated with ABP changes (0.49 mmHg; 95 % CI 0.05, 1.22), through BMI changes, in women with baseline BMI ≥25 kg/m 2 . An effect of similar magnitude and of borderline significance was observed for ERI chronic exposure. No mediating effect was observed among men, and using ERI exposure over 5 years. The mediating effect of BMI was of small magnitude and observed in certain subgroups and time frame only. Subgroup-specific mediating pathways might be involved to explain the effect of work stress on cardiovascular diseases risk.

Neighborhood, Family, and Peer Factors Associated with Early Adolescent Smoking and Alcohol Use.

PubMed

Cambron, Christopher; Kosterman, Rick; Catalano, Richard F; Guttmannova, Katarina; Hawkins, J David

2018-02-01

There is broad agreement that neighborhood contexts are important for adolescent development, but there is less consensus about their association with adolescent smoking and alcohol use. Few studies have examined associations between neighborhood socioeconomic contexts and smoking and alcohol use while also accounting for differences in family and peer risk factors for substance use. Data drawn from the Seattle Social Development Project (N = 808), a gender-balanced (female = 49%), multiethnic, theory-driven longitudinal study originating in Seattle, WA, were used to estimate trajectories of smoking and alcohol use from 5th to 9th grade. Time-varying measures of neighborhood socioeconomic, family, and peer factors were associated with smoking and alcohol use at each wave after accounting for average growth in smoking and alcohol use over time and demographic differences. Results indicated that living in more socioeconomically disadvantaged neighborhoods, lower family income, lower family general functioning, more permissive family smoking environments, and affiliation with deviant peers were independently associated with increased smoking. Lower family functioning, more permissive family alcohol use environments, and deviant peers were independently associated with increased alcohol use. The effect of neighborhood disadvantage on smoking was mediated by family income and deviant peers while the effect of neighborhood disadvantage on alcohol use was mediated by deviant peers alone. Family functioning and family substance use did not mediate associations between neighborhood disadvantage and smoking or alcohol use. The results highlight the importance of neighborhood, family, and peer factors in early adolescent smoking and alcohol use. Future studies should examine the unique association of neighborhood disadvantage with adolescent smoking net of family socioeconomics, functioning, and substance use, as well as peer affiliations. Better understanding of the role of contextual factors in early adolescent smoking and alcohol use can help bolster efforts to prevent both short and long harms from substance use.

Cyber Victimization and Internalizing Difficulties: The Mediating Roles of Coping Self-Efficacy and Emotion Dysregulation.

PubMed

Trompeter, Nora; Bussey, Kay; Fitzpatrick, Sally

2018-07-01

Cyber victimization has consistently been associated with internalizing difficulties in adolescents. However, the underlying psychological mechanisms linking this relationship have not been adequately examined. The present study aimed to investigate the mediational roles of coping self-efficacy and emotion dysregulation in the relationships between cyber victimization with depression and social anxiety. Participants were 459 students (199 girls) from independent middle-class schools in grades 8 (M age  = 13 years 9 months) and 10 (M age  = 15 years 7 months). They completed a self-report questionnaire about cyberbullying participation, internalizing symptoms, coping self-efficacy, and emotion dysregulation. Structural equation modeling revealed that most domains of coping self-efficacy and emotion dysregulation partially mediated the relationship between cyber victimization and depression, and fully mediated the relationship between cyber victimization and social anxiety. The results highlight the importance of targeting these mediating factors in intervention programs to reduce the negative impact of cyber victimization on adolescents.

Factors shaping bacterial phylogenetic and functional diversity in coastal waters of the NW Mediterranean Sea

NASA Astrophysics Data System (ADS)

Boras, Julia A.; Vaqué, Dolors; Maynou, Francesc; Sà, Elisabet L.; Weinbauer, Markus G.; Sala, Maria Montserrat

2015-03-01

To evaluate the main factors shaping bacterioplankton phylogenetic and functional diversity in marine coastal waters, we carried out a two-year study based on a monthly sampling in Blanes Bay (NW Mediterranean). We expected the key factors driving bacterial diversity to be (1) temperature and nutrient concentration, together with chlorophyll a concentration as an indicator of phytoplankton biomass and, hence, a carbon source for bacteria (here called bottom-up factors), and (2) top-down pressure (virus- and protist-mediated mortality of bacteria). Phylogenetic diversity was analyzed by denaturing gradient gel electrophoresis (DGGE) of 16S rRNA. Functional diversity was assessed by using monomeric carbon sources in Biolog EcoPlates and by determining the activity of six extracellular enzymes. Our results indicate that the bacterial phylogenetic and functional diversity in this coastal system is shaped mainly by bottom-up factors. A dendrogram analysis of the DGGE banding patterns revealed three main sample clusters. Two clusters differed significantly in temperature, nitrate and chlorophyll a concentration, and the third was characterized by the highest losses of bacterial production due to viral lysis detected over the whole study period. Protistan grazing had no effect on bacterial functional diversity, since there were no correlations between protist-mediated mortality (PMM) and extracellular enzyme activities, and utilization of only two out of the 31 carbon sources (N-acetyl-D-glucosamine and α-cyclodextrin) was correlated with PMM. In contrast, virus-mediated mortality correlated with changes in the percentage of use of four carbon sources, and also with specific leu-aminopeptidase and β-glucosidase activity. This suggests that viral lysate provides a pool of labile carbon sources, presumably including amino acids and glucose, which may inhibit proteolytic and glucosidic activity. Our results indicate that bottom-up factors play a more important role than top-down factors (i.e. viral lysis and protistan grazing) in shaping bacterial community structure and activity. Furthermore, they suggest that viruses play a more important role than protists in modifying community structure and functional diversity of bacteria in oligotrophic marine coastal waters.

A Distinct and Parallel Pathway for the Nuclear Import of an mRNA-binding Protein

PubMed Central

Pemberton, Lucy F.; Rosenblum, Jonathan S.; Blobel, Günter

1997-01-01

Three independent pathways of nuclear import have so far been identified in yeast, each mediated by cognate nuclear transport factors, or karyopherins. Here we have characterized a new pathway to the nucleus, mediated by Mtr10p, a protein first identified in a screen for strains defective in polyadenylated RNA export. Mtr10p is shown to be responsible for the nuclear import of the shuttling mRNA-binding protein Npl3p. A complex of Mtr10p and Npl3p was detected in cytosol, and deletion of Mtr10p was shown to lead to the mislocalization of nuclear Npl3p to the cytoplasm, correlating with a block in import. Mtr10p bound peptide repeat-containing nucleoporins and Ran, suggesting that this import pathway involves a docking step at the nuclear pore complex and is Ran dependent. This pathway of Npl3p import is distinct and does not appear to overlap with another known import pathway for an mRNA-binding protein. Thus, at least two parallel pathways function in the import of mRNA-binding proteins, suggesting the need for the coordination of these pathways. PMID:9412460

Child Negative Emotionality and Parental Harsh Discipline in Chinese Preschoolers: The Different Mediating Roles of Maternal and Paternal Anxiety

PubMed Central

Xing, Xiaopei; Zhang, Hongli; Shao, Shuhui; Wang, Meifang

2017-01-01

Previous research has suggested that harsh discipline is still prevalent in modern Chinese families and it is necessary to explore the cause and the potential mechanisms of Chinese parental use of harsh discipline. This study examined the mediating effects of parental anxiety in the relations between child negative emotionality and parental harsh discipline in China. Using a sample of 328 Chinese father-mother dyads with their young children, findings revealed that maternal anxiety mediated the relations between child negative emotionality and maternal psychological aggression and corporal punishment, but the mediating effects of paternal anxiety on the relations between child negative emotionality and paternal harsh discipline was not significant. The findings provide an important supplement and extension to previous examinations of the factors associated with Chinese parental use of harsh discipline and its mechanisms. PMID:28326056

Prediction and optimization of the laccase-mediated synthesis of the antimicrobial compound iodine (I2).

PubMed

Schubert, M; Fey, A; Ihssen, J; Civardi, C; Schwarze, F W M R; Mourad, S

2015-01-10

An artificial neural network (ANN) and genetic algorithm (GA) were applied to improve the laccase-mediated oxidation of iodide (I(-)) to elemental iodine (I2). Biosynthesis of iodine (I2) was studied with a 5-level-4-factor central composite design (CCD). The generated ANN network was mathematically evaluated by several statistical indices and revealed better results than a classical quadratic response surface (RS) model. Determination of the relative significance of model input parameters, ranking the process parameters in order of importance (pH>laccase>mediator>iodide), was performed by sensitivity analysis. ANN-GA methodology was used to optimize the input space of the neural network model to find optimal settings for the laccase-mediated synthesis of iodine. ANN-GA optimized parameters resulted in a 9.9% increase in the conversion rate. Copyright © 2014 Elsevier B.V. All rights reserved.

Child Negative Emotionality and Parental Harsh Discipline in Chinese Preschoolers: The Different Mediating Roles of Maternal and Paternal Anxiety.

PubMed

Xing, Xiaopei; Zhang, Hongli; Shao, Shuhui; Wang, Meifang

2017-01-01

Previous research has suggested that harsh discipline is still prevalent in modern Chinese families and it is necessary to explore the cause and the potential mechanisms of Chinese parental use of harsh discipline. This study examined the mediating effects of parental anxiety in the relations between child negative emotionality and parental harsh discipline in China. Using a sample of 328 Chinese father-mother dyads with their young children, findings revealed that maternal anxiety mediated the relations between child negative emotionality and maternal psychological aggression and corporal punishment, but the mediating effects of paternal anxiety on the relations between child negative emotionality and paternal harsh discipline was not significant. The findings provide an important supplement and extension to previous examinations of the factors associated with Chinese parental use of harsh discipline and its mechanisms.

Characterization of karyopherins in androgen receptor intracellular trafficking in the yeast model

PubMed Central

Nguyen, Minh M; Harmon, Robert M; Wang, Zhou

2014-01-01

Background: Mechanisms regulating androgen receptor (AR) subcellular localization represent an essential component of AR signaling. Karyopherins are a family of nucleocytoplasmic trafficking factors. In this paper, we used the yeast model to study the effects of karyopherins on the subcellular localization of the AR. Methods: Yeast mutants deficient in different nuclear transport factors were transformed with various AR based, GFP tagged constructs and their localization was monitored using microscopy. Results: We showed that yeast can mediate androgen-induced AR nuclear localization and that in addition to the import factor, Importinα/β, this process required the import karyopherin Sxm1. We also showed that a previously identified nuclear export sequence (NESAR) in the ligand binding domain of AR does not appear to rely on karyopherins for cytoplasmic localization. Conclusions: These results suggest that while AR nuclear import relies on karyopherin activity, AR nuclear export and/or cytoplasmic localization may require other undefined mechanisms. PMID:25031696

Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification

PubMed Central

Liu, Ling; Liu, Xu; Ren, Xudong; Tian, Yue; Chen, Zhenyu; Xu, Xiangjie; Du, Yanhua; Jiang, Cizhong; Fang, Yujiang; Liu, Zhongliang; Fan, Beibei; Zhang, Quanbin; Jin, Guohua; Yang, Xiao; Zhang, Xiaoqing

2016-01-01

The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events. PMID:26905010

Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification.

PubMed

Liu, Ling; Liu, Xu; Ren, Xudong; Tian, Yue; Chen, Zhenyu; Xu, Xiangjie; Du, Yanhua; Jiang, Cizhong; Fang, Yujiang; Liu, Zhongliang; Fan, Beibei; Zhang, Quanbin; Jin, Guohua; Yang, Xiao; Zhang, Xiaoqing

2016-02-24

The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events.

Childhood Temperament: Passive Gene-Environment Correlation, Gene-Environment Interaction, and the Hidden Importance of the Family Environment

PubMed Central

Lemery-Chalfant, Kathryn; Kao, Karen; Swann, Gregory; Goldsmith, H. Hill

2013-01-01

Biological parents pass on genotypes to their children, as well as provide home environments that correlate with their genotypes; thus, the association between the home environment and children's temperament can be genetically (i.e. passive gene-environment correlation) or environmentally mediated. Furthermore, family environments may suppress or facilitate the heritability of children's temperament (i.e. gene-environment interaction). The sample comprised 807 twin pairs (M age = 7.93 years) from the longitudinal Wisconsin Twin Project. Important passive gene-environment correlations emerged, such that home environments were less chaotic for children with high Effortful Control, and this association was genetically mediated. Children with high Extraversion/Surgency experienced more chaotic home environments, and this correlation was also genetically mediated. In addition, heritability of children's temperament was moderated by home environments, such that Effortful Control and Extraversion/Surgency were more heritable in chaotic homes, and Negative Affectivity was more heritable under crowded or unsafe home conditions. Modeling multiple types of gene-environment interplay uncovered the complex role of genetic factors and the hidden importance of the family environment for children's temperament and development more generally. PMID:23398752

Role of Transcription Factors in Pulmonary Artery Smooth Muscle Cells: An Important Link to Hypoxic Pulmonary Hypertension.

PubMed

Di Mise, Annarita; Wang, Yong-Xiao; Zheng, Yun-Min

2017-01-01

Hypoxia, namely a lack of oxygen in the blood, induces pulmonary vasoconstriction and vasoremodeling, which serve as essential pathologic factors leading to pulmonary hypertension (PH). The underlying molecular mechanisms are uncertain; however, pulmonary artery smooth muscle cells (PASMCs) play an essential role in hypoxia-induced pulmonary vasoconstriction, vasoremodeling, and PH. Hypoxia causes oxidative damage to DNAs, proteins, and lipids. This damage (oxidative stress) modulates the activity of ion channels and elevates the intracellular calcium concentration ([Ca 2+ ] i , Ca 2+ signaling) of PASMCs. The oxidative stress and increased Ca 2+ signaling mutually interact with each other, and synergistically results in a variety of cellular responses. These responses include functional and structural abnormalities of mitochondria, sarcoplasmic reticulum, and nucleus; cell contraction, proliferation, migration, and apoptosis, as well as generation of vasoactive substances, inflammatory molecules, and growth factors that mediate the development of PH. A number of studies reveal that various transcription factors (TFs) play important roles in hypoxia-induced oxidative stress, disrupted PAMSC Ca 2+ signaling and the development and progress of PH. It is believed that in the pathogenesis of PH, hypoxia facilitates these roles by mediating the expression of multiple genes. Therefore, the identification of specific genes and their transcription factors implicated in PH is necessary for the complete understanding of the underlying molecular mechanisms. Moreover, this identification may aid in the development of novel and effective therapeutic strategies for PH.

Glia Maturation Factor-γ Regulates Monocyte Migration through Modulation of β1-Integrin*

PubMed Central

Aerbajinai, Wulin; Liu, Lunhua; Zhu, Jianqiong; Kumkhaek, Chutima; Chin, Kyung; Rodgers, Griffin P.

2016-01-01

Monocyte migration requires the dynamic redistribution of integrins through a regulated endo-exocytosis cycle, but the complex molecular mechanisms underlying this process have not been fully elucidated. Glia maturation factor-γ (GMFG), a novel regulator of the Arp2/3 complex, has been shown to regulate directional migration of neutrophils and T-lymphocytes. In this study, we explored the important role of GMFG in monocyte chemotaxis, adhesion, and β1-integrin turnover. We found that knockdown of GMFG in monocytes resulted in impaired chemotactic migration toward formyl-Met-Leu-Phe (fMLP) and stromal cell-derived factor 1α (SDF-1α) as well as decreased α5β1-integrin-mediated chemoattractant-stimulated adhesion. These GMFG knockdown impaired effects could be reversed by cotransfection of GFP-tagged full-length GMFG. GMFG knockdown cells reduced the cell surface and total protein levels of α5β1-integrin and increased its degradation. Importantly, we demonstrate that GMFG mediates the ubiquitination of β1-integrin through knockdown or overexpression of GMFG. Moreover, GMFG knockdown retarded the efficient recycling of β1-integrin back to the plasma membrane following normal endocytosis of α5β1-integrin, suggesting that the involvement of GMFG in maintaining α5β1-integrin stability may occur in part by preventing ubiquitin-mediated degradation and promoting β1-integrin recycling. Furthermore, we observed that GMFG interacted with syntaxin 4 (STX4) and syntaxin-binding protein 4 (STXBP4); however, only knockdown of STXBP4, but not STX4, reduced monocyte migration and decreased β1-integrin cell surface expression. Knockdown of STXBP4 also substantially inhibited β1-integrin recycling in human monocytes. These results indicate that the effects of GMFG on monocyte migration and adhesion probably occur through preventing ubiquitin-mediated proteasome degradation of α5β1-integrin and facilitating effective β1-integrin recycling back to the plasma membrane. PMID:26895964

Multiple mediators of the relationships among maternal childhood abuse, intimate partner violence, and offspring psychopathology.

PubMed

Miranda, Jenniffer K; de la Osa, Nuria; Granero, Roser; Ezpeleta, Lourdes

2013-09-01

The aim of the study was to examine whether maternal depression, mothers' and fathers' parenting, child physical punishment and negative life events (NLE) mediate the effect of maternal childhood abuse (CA), intimate partner violence (IPV) and cumulative violence (both CA and IPV) on Spanish children's and adolescents' psychopathology. Furthermore, multiple mediator models examine whether IPV mediates the effect of CA on the contextual and family factors mentioned above. Three hundred and eighteen Spanish outpatients aged 7 to 18 and their parents were assessed using a structured interview and other instruments for measuring the study variables. Structural equation models (SEMs) showed multiple pathways explaining psychopathological problems among offspring of mothers who suffered CA, IPV and both of these violent experiences. In particular, mothers' depression mediated the link between maternal CA, IPV, cumulative violence and children's externalizing, and total behavior problems. Child NLE was an important pathway between maternal CA and total behavior problems, as well as between cumulative violence and both externalizing and total problems. IPV contributed to explaining the link between maternal CA and contextual and family factors, such as child physical punishment and NLE, which were in turn, associated with children's behavior problems. Findings show the complex interconnections between different types of violence and their harmful effects on the mental health of women and their offspring, as well as the need to extend our knowledge on this subject.

Molecular characterization of EG-VEGF-mediated angiogenesis: differential effects on microvascular and macrovascular endothelial cells.

PubMed

Brouillet, Sophie; Hoffmann, Pascale; Benharouga, Mohamed; Salomon, Aude; Schaal, Jean-Patrick; Feige, Jean-Jacques; Alfaidy, Nadia

2010-08-15

Endocrine gland derived vascular endothelial growth factor (EG-VEGF) also called prokineticin (PK1), has been identified and linked to several biological processes including angiogenesis. EG-VEGF is abundantly expressed in the highest vascularized organ, the human placenta. Here we characterized its angiogenic effect using different experimental procedures. Immunohistochemistry was used to localize EG-VEGF receptors (PROKR1 and PROKR2) in placental and umbilical cord tissue. Primary microvascular placental endothelial cell (HPEC) and umbilical vein-derived macrovascular EC (HUVEC) were used to assess its effects on proliferation, migration, cell survival, pseudovascular organization, spheroid sprouting, permeability and paracellular transport. siRNA and neutralizing antibody strategies were used to differentiate PROKR1- from PROKR2-mediated effects. Our results show that 1) HPEC and HUVEC express both types of receptors 2) EG-VEGF stimulates HPEC's proliferation, migration and survival, but increases only survival in HUVECs. and 3) EG-VEGF was more potent than VEGF in stimulating HPEC sprout formation, pseudovascular organization, and it significantly increases HPEC permeability and paracellular transport. More importantly, we demonstrated that PROKR1 mediates EG-VEGF angiogenic effects, whereas PROKR2 mediates cellular permeability. Altogether, these data characterized angiogenic processes mediated by EG-VEGF, depicted a new angiogenic factor in the placenta, and suggest a novel view of the regulation of angiogenesis in placental pathologies.

Biochemical and redox characterization of the mediator complex and its associated transcription factor GeBPL, a GLABROUS1 enhancer binding protein.

PubMed

Shaikhali, Jehad; Davoine, Céline; Brännström, Kristoffer; Rouhier, Nicolas; Bygdell, Joakim; Björklund, Stefan; Wingsle, Gunnar

2015-06-15

The eukaryotic mediator integrates regulatory signals from promoter-bound transcription factors (TFs) and transmits them to RNA polymerase II (Pol II) machinery. Although redox signalling is important in adjusting plant metabolism and development, nothing is known about a possible redox regulation of mediator. In the present study, using pull-down and yeast two-hybrid assays, we demonstrate the association of mediator (MED) subunits MED10a, MED28 and MED32 with the GLABROUS1 (GL1) enhancer-binding protein-like (GeBPL), a plant-specific TF that binds a promoter containing cryptochrome 1 response element 2 (CryR2) element. All the corresponding recombinant proteins form various types of covalent oligomers linked by intermolecular disulfide bonds that are reduced in vitro by the thioredoxin (TRX) and/or glutathione/glutaredoxin (GRX) systems. The presence of recombinant MED10a, MED28 and MED32 subunits or changes of its redox state affect the DNA-binding capacity of GeBPL suggesting that redox-driven conformational changes might modulate its activity. Overall, these results advance our understanding of how redox signalling affects transcription and identify mediator as a novel actor in redox signalling pathways, relaying or integrating redox changes in combination with specific TFs as GeBPL. © The Authors Journal compilation © 2015 Biochemical Society.

BDNF mediates improvements in executive function following a 1-year exercise intervention

PubMed Central

Leckie, Regina L.; Oberlin, Lauren E.; Voss, Michelle W.; Prakash, Ruchika S.; Szabo-Reed, Amanda; Chaddock-Heyman, Laura; Phillips, Siobhan M.; Gothe, Neha P.; Mailey, Emily; Vieira-Potter, Victoria J.; Martin, Stephen A.; Pence, Brandt D.; Lin, Mingkuan; Parasuraman, Raja; Greenwood, Pamela M.; Fryxell, Karl J.; Woods, Jeffrey A.; McAuley, Edward; Kramer, Arthur F.; Erickson, Kirk I.

2014-01-01

Executive function declines with age, but engaging in aerobic exercise may attenuate decline. One mechanism by which aerobic exercise may preserve executive function is through the up-regulation of brain-derived neurotropic factor (BDNF), which also declines with age. The present study examined BDNF as a mediator of the effects of a 1-year walking intervention on executive function in 90 older adults (mean age = 66.82). Participants were randomized to a stretching and toning control group or a moderate intensity walking intervention group. BDNF serum levels and performance on a task-switching paradigm were collected at baseline and follow-up. We found that age moderated the effect of intervention group on changes in BDNF levels, with those in the highest age quartile showing the greatest increase in BDNF after 1-year of moderate intensity walking exercise (p = 0.036). The mediation analyses revealed that BDNF mediated the effect of the intervention on task-switch accuracy, but did so as a function of age, such that exercise-induced changes in BDNF mediated the effect of exercise on task-switch performance only for individuals over the age of 71. These results demonstrate that both age and BDNF serum levels are important factors to consider when investigating the mechanisms by which exercise interventions influence cognitive outcomes, particularly in elderly populations. PMID:25566019

Mothers' Personal and Interpersonal Function as Potential Mediators Between Maternal Maltreatment History and Child Behavior Problems.

PubMed

Pereira, Jessica; Ludmer, Jaclyn A; Gonzalez, Andrea; Atkinson, Leslie

2018-05-01

This study examined maternal depressive symptoms, social support, parenting, and adult attachment as mediators explaining the relation between maternal childhood maltreatment and child behavior in offspring. We assessed a community sample of 96 mother-child dyads. At child age 16 months, mothers self-reported maltreatment history, adult attachment, depressive symptoms, and social support, and maternal sensitivity was assessed via 2 hr of direct behavioral observation. Maternal reports of child behavior were collected at 5 years. Single and parallel mediation models were constructed. Only maternal depressive symptoms mediated the relation between maternal maltreatment history and children's internalizing problems. Maternal sensitivity emerged as a suppressor variable. With respect to the relation between maternal maltreatment history and children's externalizing problems, when entered singly, maternal depressive symptoms, social support, and avoidant attachment emerged as mediators. When examined in parallel, only maternal depressive symptoms and avoidant attachment accounted for unique mediating variance. Findings have implications with respect to important maternal factors that might be targeted to reduce the probability of maladaptive child behavior.

Does Positivity Mediate the Relation of Extraversion and Neuroticism with Subjective Happiness?

PubMed Central

Lauriola, Marco; Iani, Luca

2015-01-01

Recent theories suggest an important role of neuroticism, extraversion, attitudes, and global positive orientations as predictors of subjective happiness. We examined whether positivity mediates the hypothesized relations in a community sample of 504 adults between the ages of 20 and 60 years old (females = 50%). A model with significant paths from neuroticism to subjective happiness, from extraversion and neuroticism to positivity, and from positivity to subjective happiness fitted the data (Satorra–Bentler scaled chi-square (38) = 105.91; Comparative Fit Index = .96; Non-Normed Fit Index = .95; Root Mean Square Error of Approximation = .060; 90% confidence interval = .046, .073). The percentage of subjective happiness variance accounted for by personality traits was only about 48%, whereas adding positivity as a mediating factor increased the explained amount of subjective happiness to 78%. The mediation model was invariant by age and gender. The results show that the effect of extraversion on happiness was fully mediated by positivity, whereas the effect of neuroticism was only partially mediated. Implications for happiness studies are also discussed. PMID:25781887

Testing a mediation framework for the link between perceived discrimination and psychological distress among sexual minority individuals.

PubMed

Liao, Kelly Yu-Hsin; Kashubeck-West, Susan; Weng, Chih-Yuan; Deitz, Cori

2015-04-01

Perceived discrimination is a risk factor for mental health problems among sexual minority individuals. An increasing number of research studies have investigated the mechanisms through which stigma-related stressors such as perceived discrimination are linked with adverse mental health outcomes for sexual minority populations. The integrative mediation framework proposed by Hatzenbuehler (2009) underscores the importance of identifying mediators in the association between stigma-related stressors and mental health outcomes. This study tested 3 mediators--expectations of rejection, anger rumination, and self-compassion--in the perceived discrimination-distress link. Moreover, it examined associations among these mediators. A nationwide sample of 265 sexual minorities responded to an online survey. Structural equation modeling results supported the mediator roles of expectations of rejection, anger rumination, and self-compassion. More specifically, perceived discrimination was associated with expectations of rejection, which, in turn, was associated with increased anger rumination and less self-compassion, resulting in greater psychological distress. The findings suggest several avenues for prevention and intervention with sexual minority individuals. (c) 2015 APA, all rights reserved).

The Role of Social-Emotional and Social Network Factors in the Relationship Between Academic Achievement and Risky Behaviors.

PubMed

Wong, Mitchell D; Strom, Danielle; Guerrero, Lourdes R; Chung, Paul J; Lopez, Desiree; Arellano, Katherine; Dudovitz, Rebecca N

2017-08-01

We examined whether standardized test scores and grades are related to risky behaviors among low-income minority adolescents and whether social networks and social-emotional factors explained those relationships. We analyzed data from 929 high school students exposed by natural experiment to high- or low-performing academic environments in Los Angeles. We collected information on grade point average (GPA), substance use, sexual behaviors, participation in fights, and carrying a weapon from face-to-face interviews and obtained California math and English standardized test results. Logistic regression and mediation analyses were used to examine the relationship between achievement and risky behaviors. Better GPA and California standardized test scores were strongly associated with lower rates of substance use, high-risk sexual behaviors, and fighting. The unadjusted relative odds of monthly binge drinking was 0.72 (95% confidence interval, 0.56-0.93) for 1 SD increase in standardized test scores and 0.46 (95% confidence interval, 0.29-0.74) for GPA of B- or higher compared with C+ or lower. Most associations disappeared after controlling for social-emotional and social network factors. Averaged across the risky behaviors, mediation analysis revealed social-emotional factors accounted for 33% of the relationship between test scores and risky behaviors and 43% of the relationship between GPA with risky behaviors. Social network characteristics accounted for 31% and 38% of the relationship between behaviors with test scores and GPA, respectively. Demographic factors, parenting, and school characteristics were less important explanatory factors. Social-emotional factors and social network characteristics were the strongest explanatory factors of the achievement-risky behavior relationship and might be important to understanding the relationship between academic achievement and risky behaviors. Published by Elsevier Inc.

Family Health Climate and Adolescents' Physical Activity and Healthy Eating: A Cross-Sectional Study with Mother-Father-Adolescent Triads.

PubMed

Niermann, Christina Y N; Kremers, Stef P J; Renner, Britta; Woll, Alexander

2015-01-01

The importance of the family environment for children's and adolescents' health behavior has been demonstrated, the underlying mechanisms of this influence remain unclear. Therefore, the aim of the study was to investigate the relationship between family environmental and individual determinants. It was hypothesized that the Family Health Climate (FHC) is associated with adolescents' physical activity and dietary behavior and that intrinsic motivation mediates this association. Cross-sectional data were collected from 198 families (mother, father, and child) using questionnaires. Perceptions of FHC of mothers, fathers, and their children were assessed using the FHC-scales for physical activity (FHC-PA) and nutrition (FHC-NU). The adolescents also rated their intrinsic motivation for exercise and healthy eating, their physical activity and consumption of healthful food. A structural equation model was analyzed and a bootstrapping procedure was used to test direct and indirect effects. The FHC-PA was related to the amount of weekly physical activity and the FHC-NU to the consumption of fruit, vegetables and salad. These effects were mediated by adolescents' intrinsic motivation; the indirect effects were significant for both behaviors. These results emphasize the importance of the FHC in shaping adolescents' physical activity and dietary behavior. Individual motivational factors are potential mediators of family and parental influences. Considering family-level variables and their interaction with individual factors contributes to the understanding of adolescents' health behavior.

Social inequality in chronic disease outcomes.

PubMed

Nordahl, Helene

2014-11-01

Socioeconomic differences in morbidity and mortality, particularly across educational groups, are widening. Differential exposures to behavioural risk factors have been shown to play an important mediating role on the social inequality in chronic diseases such as heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, and lung cancer. However, much less attention has been given to the potential role of interaction, where the same level of exposure to a behavioural risk factor has different effect across socioeconomic groups, creating subgroups that are more vulnerable than others. In this thesis, Paper 1 describes the unique cohort consortium which was established by pooling and harmonising prospective data from existing cohort studies in Denmark. This consortium generated a large study population with long follow-up sufficient to study power demanding questions of mechanisms underlying social inequalities in chronic disease outcomes. In Paper 2 on incidence of coronary heart disease, smoking and body mass index partially mediated the observed educational differences. This result suggested that some of the social inequality in coronary heart disease may be enhanced by differential exposure to behavioural risk factors (i.e. smoking and obesity). In Paper 3 on incidence of stroke, an observed interaction between education and smoking indicated that participants, particularly men, with low level of education may be more vulnerable to the effect of smoking than those with high level of education in terms of ischemic stroke. Finally, Paper 4 revealed that behavioural risk factors, primarily smoking, explained a considerable part of the educational differences in cause-specific mortality. Further, this paper added important knowledge about the considerable part of the mediated effect, which could be due to interaction between education and smoking. In conclusion, the research in this thesis is a practical implementation of contemporary statistical methodology, the additive hazards models, in which the potential role of behavioural risk factors can be regarded not only as mediation but also as interaction with the effect of socioeconomic position on chronic disease outcomes. The results support that two central mechanisms, differential exposure and differential vulnerability to behavioural risk factors, particularly smoking; have contributed substantially to the social inequality in chronic disease outcomes in Denmark. These mechanism are not mutually exclusive and should be regarded simultaneously. However, the findings could be non-causal associations due to, for instance, psychosocial or environmental factors. Nevertheless, research on social inequality in chronic disease outcomes should regard not only that the smoking prevalence is higher in lower socioeconomic groups (differential exposure), but also that health consequences of being a smoker seem to be worse in these subgroups (differential vulnerability).

School Dissatisfaction in a Post-Disaster Environment: The Mediating Role of Posttraumatic Stress Symptoms

ERIC Educational Resources Information Center

Sims, Alexandra J.; Boasso, Alyssa M.; Burch, Berre; Naser, Shereen; Overstreet, Stacy

2015-01-01

Background: School satisfaction is linked to a number of important school outcomes like academic performance and school engagement. Following exposure to disasters, adolescents may undergo mental health challenges that threaten factors critical to school satisfaction, such as positive school climate and supportive school relationships. Objective:…

Numerical Ordering Ability Mediates the Relation between Number-Sense and Arithmetic Competence

ERIC Educational Resources Information Center

Lyons, Ian M.; Beilock, Sian L.

2011-01-01

What predicts human mathematical competence? While detailed models of number representation in the brain have been developed, it remains to be seen exactly how basic number representations link to higher math abilities. We propose that representation of ordinal associations between numerical symbols is one important factor that underpins this…

Queer Decisions? Gay Male Students' University Choices

ERIC Educational Resources Information Center

Taulke-Johnson, Richard

2010-01-01

This article examines the reported influences on the university choices of 17 gay male undergraduate students attending a UK institution. It is argued that this process is strongly mediated by, and, therefore, has to be considered in relation to, class. Data analysis provides insight into the factors gay students say are important in selecting…

Signalling properties and pharmacological analysis of two sulfakinin receptors from the red flour beetle, Tribolium castaneum

USDA-ARS?s Scientific Manuscript database

Sulfakinin is an insect neuropeptide that constitutes an important component of the complex network of hormonal and neural factors that regulate feeding and digestion. The key modulating functions of sulfakinin are mediated by binding and signaling via G-protein coupled receptors. Although a subst...

Cyberbullying: Predictors and Prevalence in American and German Middle School Students

ERIC Educational Resources Information Center

Gaio, Vanesa

2017-01-01

The purpose of this study was to investigate several factors associated with cyberbullying and its victims; gender, age, and the time spent using various forms of computer-mediated communication (CMC). Because cross-national studies are so important to understanding the similarities and differences found in this global problem, the current study…

A Culture Model as Mediator and Repository Source for Innovation

ERIC Educational Resources Information Center

Mohammadisadr, Mohammad; Siadat, Seyed Ali; Azizollah, Arbabisarjou; Ebrahim, Ebrahimitabas

2012-01-01

As innovation has become one of the most important competitive advantages, academic practitioner's interest in the matter has increased. But, still the question "why lots of organizations fail in their path of article to be innovative" is remained unanswered. In this, among many factors influencing innovation capacity of an organization;…

Personality, Aging Self-Perceptions, and Subjective Health: A Mediation Model

ERIC Educational Resources Information Center

Moor, Caroline; Zimprich, Daniel; Schmitt, Marina; Kliegel, Matthias

2006-01-01

Since the global item of subjective health has emerged as a strong predictor of important health outcomes such as mortality, there have been many attempts to uncover its correlates. In this study, we tested whether personality as assessed via the five-factor model of personality predicted subjective health when physician-rated health and…

Dieting, Dating and Denial: Whose Body Is It?

ERIC Educational Resources Information Center

Brand, Lori; Hong, Luoluo

Until recently, understanding about women's health has been traditionally mediated by the medical model, which tends to regard each health problem in a vacuum. Such an approach ignored important considerations, such as body image. In an effort to explore this health factor, a review of the literature regarding women's health and its relation to…

Strategies for Success in Education: Time Management Is More Important for Part-Time than Full-Time Community College Students

ERIC Educational Resources Information Center

MacCann, Carolyn; Fogarty, Gerard J.; Roberts, Richard D.

2012-01-01

This paper examines relationships between the Big Five personality factors, time management, and grade-point-average in 556 community colleges students. A path model controlling for vocabulary, gender, and demographic covariates demonstrated that time management mediates the relationship between conscientiousness and students' academic achievement…

Community size and composition of ammonia oxidizers and denitrifiers in an alluvial intertidal wetland ecosystem

PubMed Central

Hu, Ziye; Meng, Han; Shi, Jin-Huan; Bu, Nai-Shun; Fang, Chang-Ming; Quan, Zhe-Xue

2014-01-01

Global nitrogen cycling is mainly mediated by the activity of microorganisms. Nitrogen cycle processes are mediated by functional groups of microorganisms that are affected by constantly changing environmental conditions and substrate availability. In this study, we investigated the temporal and spatial patterns of nitrifier and denitrifier communities in an intertidal wetland. Soil samples were collected over four distinct seasons from three locations with different vegetative cover. Multiple environmental factors and process rates were measured and analyzed together with the community size and composition profiles. We observed that the community size and composition of the nitrifiers and denitrifiers are affected significantly by seasonal factors, while vegetative cover affected the community composition. The seasonal impacts on the community size of ammonia oxidizing archaea (AOA) are much higher than that of ammonia oxidizing bacteria (AOB). The seasonal change was a more important indicator for AOA community composition patterns, while vegetation was more important for the AOB community patterns. The microbial process rates were correlated with both the community size and composition. PMID:25101072

A rhamnose-rich O-antigen mediates adhesion, virulence, and host colonization for the xylem-limited phytopathogen Xylella fastidiosa.

PubMed

Clifford, Jennifer C; Rapicavoli, Jeannette N; Roper, M Caroline

2013-06-01

Xylella fastidiosa is a gram-negative, xylem-limited bacterium that causes a lethal disease of grapevine called Pierce's disease. Lipopolysaccharide (LPS) composes approximately 75% of the outer membrane of gram-negative bacteria and, because it is largely displayed on the cell surface, it mediates interactions between the bacterial cell and its surrounding environment. LPS is composed of a conserved lipid A-core oligosaccharide component and a variable O-antigen portion. By targeting a key O-antigen biosynthetic gene, we demonstrate the contribution of the rhamnose-rich O-antigen to surface attachment, cell-cell aggregation, and biofilm maturation: critical steps for successful infection of the host xylem tissue. Moreover, we have demonstrated that a fully formed O-antigen moiety is an important virulence factor for Pierce's disease development in grape and that depletion of the O-antigen compromises its ability to colonize the host. It has long been speculated that cell-surface polysaccharides play a role in X. fastidiosa virulence and this study confirms that LPS is a major virulence factor for this important agricultural pathogen.

Members of the Dof transcription factor family in Triticum aestivum are associated with light-mediated gene regulation.

PubMed

Shaw, Lindsay M; McIntyre, C Lynne; Gresshoff, Peter M; Xue, Gang-Ping

2009-11-01

DNA binding with One Finger (Dof) protein is a plant-specific transcription factor implicated in the regulation of many important plant-specific processes, including photosynthesis and carbohydrate metabolism. This study has identified 31 Dof genes (TaDof) in bread wheat through extensive analysis of current nucleotide databases. Phylogenetic analysis suggests that the TaDof family can be divided into four clades. Expression analysis of the TaDof family across all major organs using quantitative RT-PCR and searches of the wheat genome array database revealed that the majority of TaDof members were predominately expressed in vegetative organs. A large number of TaDof members were down-regulated by drought and/or were responsive to the light and dark cycle. Further expression analysis revealed that light up-regulated TaDof members were highly correlated in expression with a number of genes that are involved in photosynthesis or sucrose transport. These data suggest that the TaDof family may have an important role in light-mediated gene regulation, including involvement in the photosynthetic process.

Perceived Age Discrimination as a Mediator of the Association Between Income Inequality and Older People's Self-Rated Health in the European Region.

PubMed

Vauclair, Christin-Melanie; Marques, Sibila; Lima, Maria L; Abrams, Dominic; Swift, Hannah; Bratt, Christopher

2015-11-01

The relative income hypothesis predicts poorer health in societies with greater income inequality. This article examines whether the psychosocial factors of perceived age discrimination and (lack of) social capital may help explain the adverse effect of inequality on older people's health. Self-rated health, perceived age discrimination, and social capital were assessed in the 2008/9 European Social Survey (European Social Survey Round 4 Data, 2008). The Gini coefficient was used to represent national inequalities in income in each of the 28 European Social Survey countries. Mediation analyses (within a multilevel structural equation modeling paradigm) on a subsample of respondents over 70 years of age (N = 7,819) were used to examine whether perceived age discrimination mediates the negative effect of income inequality on older people's self-rated health. Perceived age discrimination fully mediated the associations between income inequality and self-rated health. When social capital was included into the model, only age discrimination remained a significant mediator and predictor of self-rated health. Concrete instances of age discrimination in unequal societies are an important psychosocial stressor for older people. Awareness that the perception of ageism can be an important stressor and affect older patient's self-reported health has important implications for the way health practitioners understand and treat the sources of patient's health problems in later life. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways

PubMed Central

Singh, Bhupendra; Shoulson, Rivka; Chatterjee, Anwesha; Ronghe, Amruta; Bhat, Nimee K.; Dim, Daniel C.; Bhat, Hari K.

2014-01-01

The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective pathways. PMID:24894866

Relationship between body dissatisfaction and disordered eating: mediating role of self-esteem and depression.

PubMed

Brechan, Inge; Kvalem, Ingela Lundin

2015-04-01

The purpose of this study was to investigate the hypothesis that the effect of body dissatisfaction on disordered eating behavior is mediated through self-esteem and depression. If the effect of body dissatisfaction on disordered eating can be explained by self-esteem and depression, treatment may benefit from focusing more on self-esteem and depression than body dissatisfaction. We also hypothesized body image importance to be associated with lower self-esteem, stronger symptoms of depression, and more disordered eating. The results showed that the effect of body dissatisfaction on disorder eating was completely mediated, whereas the effect of body image importance was partly mediated. Both self-esteem and depression were significant mediators. Body image importance and self-esteem had a direct effect on restrained eating and compensatory behavior. Depression had a direct effect on binge eating. This effect was significantly stronger among women. Depression also had a direct effect on restrained eating. This effect was positive among women, but negative among men. The results support emotion regulation and cognitive behavioral theories of eating disorders, indicating that self-esteem and depression are the most proximal factors, whereas the effect of body dissatisfaction is indirect. The results point out the importance of distinguishing between different symptoms of bulimia. Depression may cause binge eating, but compensatory behavior depends on self-esteem and body image importance. The results suggest that women may turn to both binge eating and restrained eating to escape awareness of negative emotions, whereas men focus on eating to a lesser extent than women. Existing treatment focuses on eating behavior first and mechanisms such as self-esteem and depression second. The results from this study suggest that an earlier focus on self-esteem and depression may be warranted in the treatment of disordered eating. Copyright © 2015 Elsevier Ltd. All rights reserved.

DIRECT MODULATION OF THE PROTEIN KINASE A CATALYTIC SUBUNIT α BY GROWTH FACTOR RECEPTOR TYROSINE KINASES

PubMed Central

Caldwell, George B.; Howe, Alan K.; Nickl, Christian K.; Dostmann, Wolfgang R.; Ballif, Bryan A.; Deming, Paula B.

2011-01-01

The cyclic-AMP-dependent protein kinase A (PKA) regulates processes such as cell proliferation and migration following activation of growth factor receptor tyrosine kinases (RTKs), yet the signaling mechanisms that link PKA with growth factor receptors remain largely undefined. Here we report that RTKs can directly modulate the function of the catalytic subunit of PKA (PKA-C) through post-translational modification. In vitro kinase assays revealed that both the epidermal growth factor and platelet derived growth factor receptors (EGFR and PDGFR, respectively) tyrosine phosphorylate PKA-C. Mass spectrometry identified tyrosine 330 (Y330) as a receptor-mediated phosphorylation site and mutation of Y330 to phenylalanine (Y330F) all but abolished the RTK-mediated phosphorylation of PKA-C in vitro. Y330 resides within a conserved region at the C-terminal tail of PKA-C that allosterically regulates enzymatic activity. Therefore, the effect of phosphorylation at Y330 on the activity of PKA-C was investigated. The Km for a peptide substrate was markedly decreased when PKA-C subunits were tyrosine phosphorylated by the receptors as compared to un-phosphorylated controls. Importantly, tyrosine-phosphorylated PKA-C subunits were detected in cells stimulated with EGF, PDGF and FGF2 and in fibroblasts undergoing PDGF-mediated chemotaxis. These results demonstrate a direct, functional interaction between RTKs and PKA-C and identify tyrosine phosphorylation as a novel mechansim for regulating PKA activity. PMID:21866565

The interplay between risk and preventive factors explains why some children develop allergies to certain foods and others show tolerance.

PubMed

Remes, Sami; Kulmala, Petri

2018-05-11

A number of studies have clarified the tolerance mechanisms and risk factors for food allergies. Our aim was to explore food allergy symptoms by target organs, together with the risk factors and how to prevent food allergies and induce tolerance. We carried out a thorough review of studies on paediatric food allergies published in the last decade. Food allergy symptoms may affect the skin, nasal and oral mucosa, conjunctivae, gastrointestinal tract, or, in severe cases, the respiratory tract and cardiovascular organs. Immunoglobulin E (IgE) mediated symptoms appear rapidly after exposure to the offending allergen, whereas non-IgE mediated symptoms are typically delayed. The immunological processes involved in non-IgE mediated allergic reactions are poorly understood, but T cell activation is probably involved. There are several factors that influence the food sensitisation process: genetic predisposition, disruption of oral tolerance development, impaired skin barriers in atopic eczema and the influence of microbiomes. The symptoms and intensity of reactions vary considerably with regard to food allergies and these depend on the individual's concomitant immunological and regulatory mechanisms. There is strong evidence that dietary diversity is important for children, even when they come from families with high allergy risks. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The Effects of Constraints and Mastery on Mental and Physical Health: Conceptual and Methodological Considerations

PubMed Central

Infurna, Frank J.; Mayer, Axel

2015-01-01

Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of two facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the two-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). In order to demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using two models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not) pathways in developmental processes. Our discussion focuses on the conceptual and methodological implications of a two facet model of perceived control and the strengths of longitudinal mediation designs for testing conceptual models of human development. PMID:25938243

The effects of constraints and mastery on mental and physical health: Conceptual and methodological considerations.

PubMed

Infurna, Frank J; Mayer, Axel

2015-06-01

Perceived control and health are closely interrelated in adulthood and old age. However, less is known regarding the differential implications of 2 facets of perceived control, constraints and mastery, for mental and physical health. Furthermore, a limitation of previous research testing the pathways linking perceived control to mental and physical health is that mediation was tested with cross-sectional designs and not in a longitudinal mediation design that accounts for temporal ordering and prior confounds. Using data from the Health and Retirement Study (HRS; n = 7,612, M age = 68, SD = 10.66; 59% women) we examined the effect of constraints and mastery on 4-year changes in mental and physical health and whether physical activity mediated such effects in a longitudinal mediation design. Using confirmatory factor analysis, we modeled the 2-factor structure of perceived control that consisted of constraints and mastery. In our longitudinal mediation model, where we accounted for possible confounders (e.g., age, gender, education, neuroticism, conscientiousness, memory, and health conditions), constraints showed a stronger total effect on mental and physical health, than mastery, such that more constraints were associated with 4-year declines in mental and physical health. Physical activity did not mediate the effect of constraints and mastery on mental and physical health (indirect effect). To demonstrate the importance of a longitudinal mediation model that accounts for confounders, we also estimated the mediated effect using 2 models commonly used in the literature: cross-sectional mediation model and longitudinal mediation model without accounting for confounders. These mediation models indicated a spurious indirect effect that cannot be causally interpreted. Our results showcase that constraints and mastery have differential implications for mental and physical health, as well as how a longitudinal mediation design can illustrate (or not) pathways in developmental processes. Our discussion focuses on the conceptual and methodological implications of a 2 facet model of perceived control and the strengths of longitudinal mediation designs for testing conceptual models of human development. (c) 2015 APA, all rights reserved.

Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly.

PubMed

Wang, Hong; Guo, Haoran; Su, Jiaming; Rui, Yajuan; Zheng, Wenwen; Gao, Wenying; Zhang, Wenyan; Li, Zhaolong; Liu, Guanchen; Markham, Richard B; Wei, Wei; Yu, Xiao-Fang

2017-05-01

The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or host helicase transcription factor (HLTF), respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that posttranslational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood. Here, we report that zinc coordination is an important regulator of Vpx-CRL4 E3 ligase assembly. Residues in a conserved zinc-binding motif of Vpx were essential for the recruitment of the CRL4 (DCAF1) E3 complex and Vpx-induced SAMHD1 degradation. Importantly, altering the intracellular zinc concentration by treatment with the zinc chelator N , N , N '-tetrakis-(2'-pyridylmethyl)ethylenediamine (TPEN) potently blocked Vpx-mediated SAMHD1 degradation and inhibited wild-type SIVmac (simian immunodeficiency virus of macaques) infection of myeloid cells, even in the presence of Vpx. TPEN selectively inhibited Vpx and DCAF1 binding but not the Vpx-SAMHD1 interaction or Vpx virion packaging. Moreover, we have shown that zinc coordination is also important for the assembly of the HIV-1 Vpr-CRL4 E3 ligase. In particular, Vpr zinc-binding motif mutation or TPEN treatment efficiently inhibited Vpr-CRL4 (DCAF1) E3 ligase assembly and Vpr-mediated HLTF degradation or Vpr-induced G 2 cell cycle arrest. Collectively, our study sheds light on a conserved strategy by the viral proteins Vpx and Vpr to recruit host CRL4 (DCAF1) E3 ligase, which represents a target for novel anti-human immunodeficiency virus (HIV) drug development. IMPORTANCE The Vpr and its paralog Vpx are accessory proteins encoded by different human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) lentiviruses. To facilitate viral replication, Vpx has evolved to induce SAMHD1 degradation and Vpr to mediate HLTF degradation. Both Vpx and Vpr perform their functions by recruiting CRL4 (DCAF1) E3 ligase. In this study, we demonstrate that the assembly of the Vpx- or Vpr-CRL4 E3 ligase requires a highly conserved zinc-binding motif. This motif is specifically required for the DCAF1 interaction but not for the interaction of Vpx or Vpr with its substrate. Selective disruption of Vpx- or Vpr-CRL4 E3 ligase function was achieved by zinc sequestration using N , N , N '-tetrakis-(2'-pyridylmethyl)ethylenediamine (TPEN). At the same time, zinc sequestration had no effect on zinc-dependent cellular protein functions. Therefore, information obtained from this study may be important for novel anti-HIV drug development. Copyright © 2017 American Society for Microbiology.

Nuclear import of transcription factor BR-C is mediated by its interaction with RACK1.

PubMed

Cheng, Daojun; Qian, Wenliang; Wang, Yonghu; Meng, Meng; Wei, Ling; Li, Zhiqing; Kang, Lixia; Peng, Jian; Xia, Qingyou

2014-01-01

The transcription factor Broad Complex (BR-C) is an early ecdysone response gene in insects and contains two types of domains: two zinc finger domains for the activation of gene transcription and a Bric-a-brac/Tramtrack/Broad complex (BTB) domain for protein-protein interaction. Although the mechanism of zinc finger-mediated gene transcription is well studied, the partners interacting with the BTB domain of BR-C has not been elucidated until now. Here, we performed a yeast two-hybrid screen using the BTB domain of silkworm BR-C as bait and identified the receptor for activated C-kinase 1 (RACK1), a scaffolding/anchoring protein, as the novel partner capable of interacting with BR-C. The interaction between BR-C and RACK1 was further confirmed by far-western blotting and pull-down assays. Importantly, the disruption of this interaction, via RNAi against the endogenous RACK1 gene or deletion of the BTB domain, abolished the nuclear import of BR-C in BmN4 cells. In addition, RNAi against the endogenous PKC gene as well as phosphorylation-deficient mutation of the predicted PKC phosphorylation sites at either Ser373 or Thr406 in BR-C phenocopied RACK1 RNAi and altered the nuclear localization of BR-C. However, when BTB domain was deleted, phosphorylation mimics of either Ser373 or Thr406 had no effect on the nuclear import of BR-C. Moreover, mutating the PKC phosphorylation sites at Ser373 and Thr406 or deleting the BTB domain significantly decreased the transcriptional activation of a BR-C target gene. Given that RACK1 is necessary for recruiting PKC to close and phosphorylate target proteins, we suggest that the PKC-mediated phosphorylation and nuclear import of BR-C is determined by its interaction with RACK1. This novel finding will be helpful for further deciphering the mechanism underlying the role of BR-C proteins during insect development.

Nuclear Import of Transcription Factor BR-C Is Mediated by Its Interaction with RACK1

PubMed Central

Wang, Yonghu; Meng, Meng; Wei, Ling; Li, Zhiqing; Kang, Lixia; Peng, Jian; Xia, Qingyou

2014-01-01

The transcription factor Broad Complex (BR-C) is an early ecdysone response gene in insects and contains two types of domains: two zinc finger domains for the activation of gene transcription and a Bric-a-brac/Tramtrack/Broad complex (BTB) domain for protein-protein interaction. Although the mechanism of zinc finger-mediated gene transcription is well studied, the partners interacting with the BTB domain of BR-C has not been elucidated until now. Here, we performed a yeast two-hybrid screen using the BTB domain of silkworm BR-C as bait and identified the receptor for activated C-kinase 1 (RACK1), a scaffolding/anchoring protein, as the novel partner capable of interacting with BR-C. The interaction between BR-C and RACK1 was further confirmed by far-western blotting and pull-down assays. Importantly, the disruption of this interaction, via RNAi against the endogenous RACK1 gene or deletion of the BTB domain, abolished the nuclear import of BR-C in BmN4 cells. In addition, RNAi against the endogenous PKC gene as well as phosphorylation-deficient mutation of the predicted PKC phosphorylation sites at either Ser373 or Thr406 in BR-C phenocopied RACK1 RNAi and altered the nuclear localization of BR-C. However, when BTB domain was deleted, phosphorylation mimics of either Ser373 or Thr406 had no effect on the nuclear import of BR-C. Moreover, mutating the PKC phosphorylation sites at Ser373 and Thr406 or deleting the BTB domain significantly decreased the transcriptional activation of a BR-C target gene. Given that RACK1 is necessary for recruiting PKC to close and phosphorylate target proteins, we suggest that the PKC-mediated phosphorylation and nuclear import of BR-C is determined by its interaction with RACK1. This novel finding will be helpful for further deciphering the mechanism underlying the role of BR-C proteins during insect development. PMID:25280016

Pathways to functional outcomes following a first episode of psychosis: The roles of premorbid adjustment, verbal memory and symptom remission.

PubMed

Jordan, Gerald; Veru, Franz; Lepage, Martin; Joober, Ridha; Malla, Ashok; Iyer, Srividya N

2017-12-01

Most studies have investigated either the singular or relative contributions of premorbid adjustment, verbal memory and symptom remission to functional outcomes in first-episode psychosis. Fewer studies have examined the pathways of these factors in impacting functioning. Our study addresses this gap. The objective was to determine whether the relationship between premorbid adjustment and functional outcomes was mediated by verbal memory and symptom remission. A total of 334 first-episode psychosis participants (aged 14-35 years) were assessed on premorbid adjustment, verbal memory upon entry, and positive and negative symptom remission and functioning at multiple time points over a 2-year follow-up. Mediation analyses showed that over the first year, the relationship between premorbid adjustment and functioning was mediated by verbal memory and positive symptom remission (β = -0.18; 95% confidence interval = [-0.51, -0.04]), as well as by verbal memory and negative symptom remission (β = -0.41; 95% confidence interval = [-1.11, -1.03]). Over 2 years, the relationship between premorbid adjustment and functioning was mediated by verbal memory and only negative symptom remission (β = -0.38; 95% confidence interval = [-1.46, -0.02]). Comparatively less malleable factors (premorbid adjustment and verbal memory) may contribute to functional outcomes through more malleable factors (symptoms). Promoting remission may be an important parsimonious means to achieving better functional outcomes.

Mediators of weight loss in a family-based intervention presented over the internet.

PubMed

White, Marney A; Martin, Pamela D; Newton, Robert L; Walden, Heather M; York-Crowe, Emily E; Gordon, Stewart T; Ryan, Donna H; Williamson, Donald A

2004-07-01

To assess the process variables involved in a weight loss program for African-American adolescent girls. Several process variables have been identified as affecting success in in vivo weight loss programs for adults and children, including program adherence, self-efficacy, and social support. The current study sought to broaden the understanding of these process variables as they pertain to an intervention program that is presented using the Internet. It was hypothesized that variables such as program adherence, dietary self-efficacy, psychological factors, and family environment factors would mediate the effect of the experimental condition on weight loss. Participants were 57 adolescent African-American girls who joined the program with one obese parent; family pairs were randomized to either a behavioral or control condition in an Internet-based weight loss program. Outcome data (weight loss) are reported for the first 6 months of the intervention. Results partially supported the hypotheses. For weight loss among adolescents, parent variables pertaining to life and family satisfaction were the strongest mediating variables. For parental weight loss, changes in dietary practices over the course of 6 months were the strongest mediators. The identification of factors that enhance or impede weight loss for adolescents is an important step in improving weight loss programs for this group. The current findings suggest that family/parental variables exert a strong influence on weight loss efforts for adolescents and should be considered in developing future programs. Copyright 2004 NAASO

Gender Nonconformity, Homophobic Peer Victimization, and Mental Health: How Same-Sex Attraction and Biological Sex Matter.

PubMed

van Beusekom, Gabriël; Baams, Laura; Bos, Henny M W; Overbeek, Geertjan; Sandfort, Theo G M

2016-01-01

We assessed whether homophobic name-calling accounts for the relationship between gender nonconformity and mental health (social anxiety and psychological distress) in a sample of 1,026 Dutch adolescents (boys: n = 517) ages 11 to 16 (Mage = 13.4). We also explored whether this hypothesized mediation differs by sexual attraction and biological sex. Data were collected by means of paper-and-pencil questionnaires at five secondary schools located in urban areas in the Netherlands. Mediation analysis indicated that gender nonconformity was related to both social anxiety and psychological distress partially via homophobic name-calling. Moderated mediation analysis further showed that the mediating role of homophobic name-calling varied according to levels of same-sex attraction (SSA) and biological sex. The mediation effects increased in magnitude when levels of SSA increased and were significant only for adolescents with mean and high levels of SSA. The mediation effects were significant for boys and girls in general, although the mediation effects were stronger for boys than for girls. Our findings emphasize the importance of research and school-level interventions to focus on factors that promote acceptance of cross-gender behavior among adolescents.

Gender Nonconformity, Homophobic Peer Victimization and Mental Health: How Same-Sex Attraction and Biological Sex Matter

PubMed Central

van Beusekom, Gabriël; Baams, Laura; Bos, Henny M.W.; Overbeek, Geert J.; Sandfort, Theo G.M.

2018-01-01

We assessed whether homophobic name-calling accounts for the relationship between gender nonconformity and mental health (social anxiety and psychological distress) in a sample of 1,026 Dutch adolescents (boys: n = 517) aged 11–16 years (Mage = 13.4). We also explored whether this hypothesized mediation differs by sexual attraction and biological sex. Data were collected by means of paper–pencil questionnaires at five secondary schools located in urban areas in the Netherlands. Mediation analysis indicated that gender nonconformity was related with both social anxiety and psychological distress partially via homophobic name-calling. Moderated mediation analysis further showed that the mediating role of homophobic name-calling varied according to levels of same-sex attraction (SSA) and biological sex. The mediation effects increased in magnitude when levels of SSA increased and were significant only for adolescents with mean and high levels of SSA. The mediation effects were significant for boys and girls in general, although the mediation effects were stronger for boys than for girls. Our findings emphasize the importance of research and school-level interventions to focus on factors that promote acceptance of cross-gender behaviour among adolescents. PMID:26099017

A Nasal Epithelial Receptor for Staphylococcus aureus WTA Governs Adhesion to Epithelial Cells and Modulates Nasal Colonization

PubMed Central

Faulstich, Manuela; Grau, Timo; Severin, Yannik; Unger, Clemens; Hoffmann, Wolfgang H.; Rudel, Thomas; Autenrieth, Ingo B.; Weidenmaier, Christopher

2014-01-01

Nasal colonization is a major risk factor for S. aureus infections. The mechanisms responsible for colonization are still not well understood and involve several factors on the host and the bacterial side. One key factor is the cell wall teichoic acid (WTA) of S. aureus, which governs direct interactions with nasal epithelial surfaces. We report here the first receptor for the cell wall glycopolymer WTA on nasal epithelial cells. In several assay systems this type F-scavenger receptor, termed SREC-I, bound WTA in a charge dependent manner and mediated adhesion to nasal epithelial cells in vitro. The impact of WTA and SREC-I interaction on epithelial adhesion was especially pronounced under shear stress, which resembles the conditions found in the nasal cavity. Most importantly, we demonstrate here a key role of the WTA-receptor interaction in a cotton rat model of nasal colonization. When we inhibited WTA mediated adhesion with a SREC-I antibody, nasal colonization in the animal model was strongly reduced at the early onset of colonization. More importantly, colonization stayed low over an extended period of 6 days. Therefore we propose targeting of this glycopolymer-receptor interaction as a novel strategy to prevent or control S. aureus nasal colonization. PMID:24788600

Longitudinal analysis of adolescent NSSI: the role of intrapersonal and interpersonal factors.

PubMed

Tatnell, Ruth; Kelada, Lauren; Hasking, Penelope; Martin, Graham

2014-08-01

Non-suicidal self-injury (NSSI) occurs in approximately 10 % of adolescents. To establish effective prevention and intervention initiatives, it is important to understand onset, maintenance and cessation of NSSI. We explored whether the relationships between interpersonal factors (i.e. attachment, social support) and NSSI were mediated by intrapersonal factors (i.e. emotion regulation, self-esteem, self-efficacy). Participants were 1973 students (1414 female and 559 male) aged between 12 and 18 years (M = 13.89, SD = 0.97) recruited from 40 Australian high schools. Participants completed a questionnaire at two time-points with a 12-month interval. At baseline, 8.3 % of adolescents engaged in NSSI, increasing to 11.9 % at follow-up. Family support was most salient in onset, maintenance and cessation of NSSI. Attachment anxiety was related to NSSI onset. Of the intrapersonal variables, self-esteem and self-efficacy were significant in predicting onset of NSSI. Self-esteem, self-efficacy and cognitive reappraisal mediated the relationship between attachment anxiety and NSSI onset. A combination of interpersonal and intrapersonal variables contributes to the onset, maintenance and cessation of NSSI in adolescence. Perceived family support appears to be an important safeguard against NSSI. Strategies targeting family functioning and teaching cognitive reappraisal techniques to adolescents may reduce the number engaging in NSSI.

The importance of context in early autism intervention: A qualitative South African study.

PubMed

Guler, Jessy; de Vries, Petrus J; Seris, Noleen; Shabalala, Nokuthula; Franz, Lauren

2017-09-01

The majority of individuals with autism spectrum disorder live in low- and middle-income countries and receive little or no services from health or social care systems. The development and validation of autism spectrum disorder interventions has almost exclusively occurred in high-income countries, leaving many unanswered questions regarding what contextual factors would need to be considered to ensure the effectiveness of interventions in low- and middle-income countries. This study qualitatively explored contextual factors relevant to the adaptation of a caregiver-mediated early autism spectrum disorder intervention in a low-resource South African setting. We conducted four focus groups and four in-depth interviews with 28 caregivers of young children with autism spectrum disorder and used thematic analysis to identify key themes. Eight contextual factors including culture, language, location of treatment, cost of treatment, type of service provider, support, parenting practices, and stigma emerged as important. Caregivers reported a preference for an affordable, in-home, individualized early autism spectrum disorder intervention, where they have an active voice in shaping treatment goals. Distrust of community-based health workers and challenges associated with autism spectrum disorder-related stigma were identified. Recommendations that integrate caregiver preferences with the development of a low-cost and scalable caregiver-mediated early autism spectrum disorder intervention are included.

Consequences of prenatal toxin exposure for mental health in children and adolescents: a systematic review.

PubMed

Williams, Justin H G; Ross, Louise

2007-06-01

Drug use during pregnancy is common and the developing foetus may be exposed to a range of environmental toxins that have long-term consequences for neurodevelopment. We conducted a systematic review of the literature to explore the results of longitudinal cohort studies that have examined this question. Out of 2,977 abstracts identified, 7 previous systematic reviews and 95 original articles met further selection criteria. These mostly addressed the neurodevelopmental effects of exposure to lead, polychlorinated biphenyls, mercury, cocaine, alcohol, marijuana, cigarettes and antidepressants. Radiation, opiates, steroids, amphetamines and caffeine have received much less attention. Findings are difficult to interpret because risk factors tend to cluster together and interact. However, some findings are consistent. Lead and PCB's have a general effect on brain development, whilst marijuana and alcohol appear to have long-term effects specifically on attentional skills. The effects of alcohol increase with maternal age and binge drinking is more important than average intake. The effects of cocaine diminish with age and are largely mediated through psychosocial factors, whilst the relation between smoking and later delinquency is largely mediated by genetically inherited factors. Exposure to toxins during pregnancy may constitute an important but relatively unacknowledged cause of child psychiatric morbidity.

Development of Neuroendocrine Prostate Cancers by the Ser/Arg Repetitive Matrix 4-Mediated RNA Splicing Network.

PubMed

Lee, Ahn R; Che, Nicole; Lovnicki, Jessica M; Dong, Xuesen

2018-01-01

While the use of next-generation androgen receptor pathway inhibition (ARPI) therapy has significantly increased the survival of patients with metastatic prostate adenocarcinoma (AdPC), several groups have reported a treatment-resistant mechanism, whereby cancer cells can become androgen receptor (AR) indifferent and gain a neuroendocrine (NE)-like phenotype. This subtype of castration-resistant prostate cancer has been termed "treatment-induced castration-resistant neuroendocrine prostate cancer" (CRPC-NE). Recent reports indicate that the overall genomic landscapes of castration-resistant tumors with AdPC phenotypes and CRPC-NE are not significantly altered. However, CRPC-NE tumors have been found to contain a NE-specific pattern throughout their epigenome and splicing transcriptome, which are significantly modified. The molecular mechanisms by which CRPC-NE develops remain unclear, but several factors have been implicated in the progression of the disease. Recently, Ser/Arg repetitive matrix 4 (SRRM4), a neuronal-specific RNA splicing factor that is upregulated in CRPC-NE tumors, has been shown to establish a CRPC-NE-unique splicing transcriptome, to induce a NE-like morphology in AdPC cells, and, most importantly, to transform AdPC cells into CRPC-NE xenografts under ARPI. Moreover, the SRRM4-targeted splicing genes are highly enriched in various neuronal processes, suggesting their roles in facilitating a CRPC-NE program. This article will address the importance of SRRM4-mediated alternative RNA splicing in reprogramming translated proteins to facilitate NE differentiation, survival, and proliferation of cells to establish CRPC-NE tumors. In addition, we will discuss the potential roles of SRRM4 in conjunction with other known pathways and factors important for CRPC-NE development, such as the AR pathway, TP53 and RB1 genes, the FOXA family of proteins, and environmental factors. This study aims to explore the multifaceted functions of SRRM4 and SRRM4-mediated splicing in driving a CRPC-NE program as a coping mechanism for therapy resistance, as well as define future SRRM4-targeted therapeutic approaches for treating CRPC-NE or mitigating its development.

Development of Neuroendocrine Prostate Cancers by the Ser/Arg Repetitive Matrix 4-Mediated RNA Splicing Network

PubMed Central

Lee, Ahn R.; Che, Nicole; Lovnicki, Jessica M.; Dong, Xuesen

2018-01-01

While the use of next-generation androgen receptor pathway inhibition (ARPI) therapy has significantly increased the survival of patients with metastatic prostate adenocarcinoma (AdPC), several groups have reported a treatment-resistant mechanism, whereby cancer cells can become androgen receptor (AR) indifferent and gain a neuroendocrine (NE)-like phenotype. This subtype of castration-resistant prostate cancer has been termed “treatment-induced castration-resistant neuroendocrine prostate cancer” (CRPC-NE). Recent reports indicate that the overall genomic landscapes of castration-resistant tumors with AdPC phenotypes and CRPC-NE are not significantly altered. However, CRPC-NE tumors have been found to contain a NE-specific pattern throughout their epigenome and splicing transcriptome, which are significantly modified. The molecular mechanisms by which CRPC-NE develops remain unclear, but several factors have been implicated in the progression of the disease. Recently, Ser/Arg repetitive matrix 4 (SRRM4), a neuronal-specific RNA splicing factor that is upregulated in CRPC-NE tumors, has been shown to establish a CRPC-NE-unique splicing transcriptome, to induce a NE-like morphology in AdPC cells, and, most importantly, to transform AdPC cells into CRPC-NE xenografts under ARPI. Moreover, the SRRM4-targeted splicing genes are highly enriched in various neuronal processes, suggesting their roles in facilitating a CRPC-NE program. This article will address the importance of SRRM4-mediated alternative RNA splicing in reprogramming translated proteins to facilitate NE differentiation, survival, and proliferation of cells to establish CRPC-NE tumors. In addition, we will discuss the potential roles of SRRM4 in conjunction with other known pathways and factors important for CRPC-NE development, such as the AR pathway, TP53 and RB1 genes, the FOXA family of proteins, and environmental factors. This study aims to explore the multifaceted functions of SRRM4 and SRRM4-mediated splicing in driving a CRPC-NE program as a coping mechanism for therapy resistance, as well as define future SRRM4-targeted therapeutic approaches for treating CRPC-NE or mitigating its development. PMID:29666783

Investigating the Mechanical Properties of Plasma von Willebrand Factor Using Atomic Force Microscopy

NASA Astrophysics Data System (ADS)

Wijeratne, Sitara; Botello, Eric; Yeh, Hui-Chun; Zhou, Zhou; Bergeron, Angela; Frey, Eric; Moake, Joel; Dong, Jing-Fei; Kiang, Ching-Hwa

2011-10-01

Single-molecule manipulation allows us to study the real-time kinetics of complex cellular processes. The mechanochemistry of different forms of von Willebrand factor (VWF) and their receptor-ligand binding kinetics can be probed by atomic force microscopy (AFM). Since plasma VWF can be activated upon shear, the structural and functional properties of VWF that are critical in mediating thrombus formation become important. Here we characterized the mechanical resistance to domain unfolding of VWF to determine its conformational states. We found the shear-induced conformational changes, hence the mechanical property, can be detected by the change in unfolding forces. The relaxation rate of such effect is much longer than expected. Our results offer an insight in establishing strategies for regulating VWF adhesion activity, increasing our understanding of surface-induced thrombosis as mediated by VWF.

MEDIATOR25 Acts as an Integrative Hub for the Regulation of Jasmonate-Responsive Gene Expression in Arabidopsis1[C][W

PubMed Central

Çevik, Volkan; Kidd, Brendan N.; Zhang, Peijun; Hill, Claire; Kiddle, Steve; Denby, Katherine J.; Holub, Eric B.; Cahill, David M.; Manners, John M.; Schenk, Peer M.; Beynon, Jim; Kazan, Kemal

2012-01-01

The PHYTOCHROME AND FLOWERING TIME1 gene encoding the MEDIATOR25 (MED25) subunit of the eukaryotic Mediator complex is a positive regulator of jasmonate (JA)-responsive gene expression in Arabidopsis (Arabidopsis thaliana). Based on the function of the Mediator complex as a bridge between DNA-bound transcriptional activators and the RNA polymerase II complex, MED25 has been hypothesized to function in association with transcriptional regulators of the JA pathway. However, it is currently not known mechanistically how MED25 functions to regulate JA-responsive gene expression. In this study, we show that MED25 physically interacts with several key transcriptional regulators of the JA signaling pathway, including the APETALA2 (AP2)/ETHYLENE RESPONSE FACTOR (ERF) transcription factors OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59 and ERF1 as well as the master regulator MYC2. Physical interaction detected between MED25 and four group IX AP2/ERF transcription factors was shown to require the activator interaction domain of MED25 as well as the recently discovered Conserved Motif IX-1/EDLL transcription activation motif of MED25-interacting AP2/ERFs. Using transcriptional activation experiments, we also show that OCTADECANOID-RESPONSIVE ARABIDOPSIS AP2/ERF59- and ERF1-dependent activation of PLANT DEFENSIN1.2 as well as MYC2-dependent activation of VEGETATIVE STORAGE PROTEIN1 requires a functional MED25. In addition, MED25 is required for MYC2-dependent repression of pathogen defense genes. These results suggest an important role for MED25 as an integrative hub within the Mediator complex during the regulation of JA-associated gene expression. PMID:22822211

Macrophage migration inhibitory factor deficiency is associated with impaired killing of gram-negative bacteria by macrophages and increased susceptibility to Klebsiella pneumoniae sepsis.

PubMed

Roger, Thierry; Delaloye, Julie; Chanson, Anne-Laure; Giddey, Marlyse; Le Roy, Didier; Calandra, Thierry

2013-01-15

The cytokine macrophage migration inhibitory factor (MIF) is an important component of the early proinflammatory response of the innate immune system. However, the antimicrobial defense mechanisms mediated by MIF remain fairly mysterious. In the present study, we examined whether MIF controls bacterial uptake and clearance by professional phagocytes, using wild-type and MIF-deficient macrophages. MIF deficiency did not affect bacterial phagocytosis, but it strongly impaired the killing of gram-negative bacteria by macrophages and host defenses against gram-negative bacterial infection, as shown by increased mortality in a Klebsiella pneumonia model. Consistent with MIF's regulatory role of Toll-like 4 expression in macrophages, MIF-deficient cells stimulated with lipopolysaccharide or Escherichia coli exhibited reduced nuclear factor κB activity and tumor necrosis factor (TNF) production. Addition of recombinant MIF or TNF corrected the killing defect of MIF-deficient macrophages. Together, these data show that MIF is a key mediator of host responses against gram-negative bacteria, acting in part via a modulation of bacterial killing by macrophages.

Bioactive Food Components, Inflammatory Targets, and Cancer Prevention

PubMed Central

Kim, Young S.; Young, Matthew R.; Bobe, Gerd; Colburn, Nancy H.; Milner, John A.

2012-01-01

Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-κB–mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-β. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor β. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous. PMID:19258539

Psychosocial mediators of the impact of acculturation on adolescent substance abuse.

PubMed

Saint-Jean, Gilbert; Martinez, Carlos A; Crandall, Lee A

2008-04-01

To identify and evaluate socio-psychological factors that are associated with differences in substance abuse prevalence between non-acculturated and acculturated Florida youth, we employed t-test and logistic regression to analyze self-reported data from 63,000 middle and high school student participants in the 2004 Florida Youth Substance Abuse Survey. Questionnaire items covered socio-demographics, tobacco, alcohol, and illicit substance use; and perceptions and attitudes toward drug use. The outcome variables were past 30 day use of "any illicit drug." The key independent variable was language used at home (English/Another language). The covariates were 32 socio-psychological factors that are considered risk and protective factors for adolescent drug abuse. Findings support the growing body of evidence suggesting that acculturation status is a strong predictor of substance use among adolescents. This effect may be mediated principally through the family and peer/individual psychosocial domains. The findings may have important implications for the design and implementation of drug prevention programs targeting teenagers.

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).

PubMed

Wolfe, Andrew; Divall, Sara; Wu, Sheng

2014-10-01

The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction. Copyright © 2014 Elsevier Inc. All rights reserved.

Innovation implementation in the public sector: an integration of institutional and collective dynamics.

PubMed

Choi, Jin Nam; Chang, Jae Yoon

2009-01-01

The present study integrates institutional factors and employee-based collective processes as predictors of 2 key implementation outcomes: implementation effectiveness and innovation effectiveness (Klein, Conn, & Sorra, 2001). Specifically, the authors proposed that institutional factors shape employees' collective implementation efficacy and innovation acceptance. The authors further hypothesized that these employee-based collective processes mediate the effects of institutional factors on implementation outcomes. This integrative framework was examined in the context of 47 agencies and ministries of the Korean Government that were implementing a process innovation called E-Government. Three-wave longitudinal data were collected from 60 external experts and 1,732 government employees. The results reveal the importance of management support for collective implementation efficacy, which affected employees' collective acceptance of the innovation. As hypothesized, these collective employee dynamics mediated the effects of institutional enablers on successful implementation as well as the amount of long-term benefit that accrued to the agencies and ministries. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

Amygdala volume mediates the relationship between externalizing symptoms and daily smoking in adolescence: A prospective study.

PubMed

Cheetham, Ali; Allen, Nicholas B; Whittle, Sarah; Simmons, Julian; Yücel, Murat; Lubman, Dan I

2018-06-30

The current study examined amygdala and orbitofrontal cortex (OFC) volumes as mediators of the relationship between externalizing symptoms and daily smoking in adolescence. Externalizing behaviors are among the most robust predictors of adolescent smoking, and there is emerging evidence that volume reductions in the amygdala and OFC are associated with risk for substance misuse as well as aggressive, impulsive, and disinhibited tendencies. Using a prospective longitudinal design, we recruited 109 adolescents who provided data on brain volume and externalizing behaviors at age 12, and on smoking at age 18. Daily smoking at age 18 (n = 27) was predicted by externalizing behaviors (measured by the self-report Child Behavior Checklist, CBCL) as well as smaller right amygdala volumes. Right amygdala volumes mediated the relationship between externalizing symptoms and later smoking. These findings provide important insight into the neurobiological risk factors associated with adolescent smoking, and, more generally, into factors that may be associated with vulnerability to substance use disorders and related psychopathology. Copyright © 2018 Elsevier B.V. All rights reserved.

Endoplasmic reticulum stress preconditioning attenuates methylmercury-induced cellular damage by inducing favorable stress responses

PubMed Central

Usuki, Fusako; Fujimura, Masatake; Yamashita, Akio

2013-01-01

We demonstrate that methylmercury (MeHg)-susceptible cells preconditioned with an inhibitor of endoplasmic reticulum (ER) Ca2+-ATPase, thapsigargin, showed resistance to MeHg cytotoxicity through favorable stress responses, which included phosphorylation of eukaryotic initiation factor 2 alpha (Eif2α), accumulation of activating transcription factor 4 (Atf4), upregulation of stress-related proteins, and activation of extracellular signal regulated kinase pathway. In addition, ER stress preconditioning induced suppression of nonsense-mediated mRNA decay (NMD) mainly through the phospho-Eif2α-mediated general suppression of translation initiation and possible combined effects of decreased several NMD components expression. Atf4 accumulation was not mediated by NMD inhibition but translation inhibition of its upstream open reading frame (uORF) and translation facilitation of its protein-coding ORF by the phospho-Eif2α. These results suggested that ER stress plays an important role in MeHg cytotoxicity and that the modulation of ER stress has therapeutic potential to attenuate MeHg cytotoxicity, the underlying mechanism being the induction of integrated stress responses. PMID:23907635

A path model investigation of neurocognition, theory of mind, social competence, negative symptoms and real-world functioning in schizophrenia.

PubMed

Couture, Shannon M; Granholm, Eric L; Fish, Scott C

2011-02-01

Problems in real-world functioning are pervasive in schizophrenia and much recent effort has been devoted to uncovering factors which contribute to poor functioning. The goal of this study was to examine the role of four such factors: social cognition (theory of mind), neurocognition, negative symptoms, and functional capacity (social competence). 178 individuals with schizophrenia or schizoaffective disorder completed measures of theory of mind, neurocognition, negative symptoms, social competence, and self-reported functioning. Path models sought to determine the relationships among these variables. Theory of mind as indexed by the Hinting Task partially mediated the relationship between neurocognition and social competence, and negative symptoms and social competence demonstrated significant direct paths with self-reported functioning. Study results suggest theory of mind serves as an important mediator in addition to previously investigated social cognitive domains of emotional and social perception. The current study also highlights the need to determine variables which mediate the relationship between functional capacity and real-world functioning. Copyright © 2010 Elsevier B.V. All rights reserved.

Thioredoxin-mediated denitrosylation regulates cytokine-induced nuclear factor κB (NF-κB) activation.

PubMed

Kelleher, Zachary T; Sha, Yonggang; Foster, Matthew W; Foster, W Michael; Forrester, Michael T; Marshall, Harvey E

2014-01-31

S-nitrosylation of nuclear factor κB (NF-κB) on the p65 subunit of the p50/p65 heterodimer inhibits NF-κB DNA binding activity. We have recently shown that p65 is constitutively S-nitrosylated in the lung and that LPS-induced injury elicits a decrease in SNO-p65 levels concomitant with NF-κB activation in the respiratory epithelium and initiation of the inflammatory response. Here, we demonstrate that TNFα-mediated activation of NF-κB in the respiratory epithelium similarly induces p65 denitrosylation. This process is mediated by the denitrosylase thioredoxin (Trx), which becomes activated upon cytokine-induced degradation of thioredoxin-interacting protein (Txnip). Similarly, inhibition of Trx activity in the lung attenuates LPS-induced SNO-p65 denitrosylation, NF-κB activation, and airway inflammation, supporting a pathophysiological role for this mechanism in lung injury. These data thus link stimulus-coupled activation of NF-κB to a specific, protein-targeted denitrosylation mechanism and further highlight the importance of S-nitrosylation in the regulation of the immune response.

Identification of a Novel Pathway That Selectively Modulates Apoptosis of Breast Cancer Cells

PubMed Central

Tinnikov, Alexander A.; Yeung, Kay T.; Das, Sharmistha; Samuels, Herbert H.

2014-01-01

Expression of the nuclear receptor interacting factor 3 (NRIF3) coregulator in a wide variety of breast cancer cells selectively leads to rapid caspase-2–dependent apoptotic cell death. A novel death domain (DD1) was mapped to a 30– amino acid region of NRIF3. Because the cytotoxicity of NRIF3 and DD1 seems to be cell type–specific, these studies suggest that breast cancer cells contain a novel “death switch” that can be specifically modulated by NRIF3 or DD1. Using an MCF-7 cell cDNA library in a yeast two-hybrid screen, we cloned a factor that mediates apoptosis by DD1 and refer to this factor as DD1-interacting factor-1 (DIF-1). DIF-1 is a transcriptional repressor that mediates its effect through SirT1, and this repression is attenuated by the binding of NRIF3/DD1. DIF-1 expression rescues breast cancer cells from NRIF3/DD1-induced apoptosis. Small interfering RNA (siRNA) knockdown of DIF-1 selectively leads to apoptosis of breast cancer cells, further suggesting that DIF-1 plays a key role in NRIF3/DD1-mediated apoptosis. A protein kinase A inhibitor (H89) also elicits apoptosis of breast cancer cells but not of the other cell types examined, and DIF-1 also protects these cells from H89-mediated apoptosis. In addition, H89 incubation results in a rapid increase in NRIF3 levels and siRNA knockdown of NRIF3 protects breast cancer cells from H89-mediated apoptosis. Our results indicate that DIF-1 plays a key role in breast cancer cell survival and further characterizing this pathway may provide important insights into developing novel therapies to selec tively target breast cancer cells for apoptosis. PMID:19190336

Do material, psychosocial and behavioural factors mediate the relationship between disability acquisition and mental health? A sequential causal mediation analysis.

PubMed

Aitken, Zoe; Simpson, Julie Anne; Gurrin, Lyle; Bentley, Rebecca; Kavanagh, Anne Marie

2018-01-29

There is evidence of a causal relationship between disability acquisition and poor mental health; however, the mechanism by which disability affects mental health is poorly understood. This gap in understanding limits the development of effective interventions to improve the mental health of people with disabilities. We used four waves of data from the Household, Income and Labour Dynamics in Australia Survey (2011-14) to compare self-reported mental health between individuals who acquired any disability (n=387) and those who remained disability-free (n=7936). We tested three possible pathways from disability acquisition to mental health, examining the effect of material, psychosocial and behavioural mediators. The effect was partitioned into natural direct and indirect effects through the mediators using a sequential causal mediation analysis approach. Multiple imputation using chained equations was used to assess the impact of missing data. Disability acquisition was estimated to cause a five-point decline in mental health [estimated mean difference: -5.3, 95% confidence interval (CI) -6.8, -3.7]. The indirect effect through material factors was estimated to be a 1.7-point difference (-1.7, 95% CI -2.8, -0.6), explaining 32% of the total effect, with a negligible proportion of the effect explained by the addition of psychosocial characteristics (material and psychosocial: -1.7, 95% CI -3.0, -0.5) and a further 5% by behavioural factors (material-psychosocial-behavioural: -2.0, 95% CI -3.4, -0.6). The finding that the effect of disability acquisition on mental health operates predominantly through material rather than psychosocial and behavioural factors has important implications. The results highlight the need for better social protection, including income support, employment and education opportunities, and affordable housing for people who acquire a disability. © The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Parent Expectations Mediate Outcomes for Young Adults with Autism Spectrum Disorder.

PubMed

Kirby, Anne V

2016-05-01

Understanding the complex relationships among factors that may predict the outcomes of young adults with autism spectrum disorder (ASD) is of utmost importance given the increasing population undergoing and anticipating the transition to adulthood. With a sample of youth with ASD (n = 1170) from the National Longitudinal Transition Study-2, structural equation modeling techniques were used to test parent expectations as a mediator of young adult outcomes (i.e., employment, residential independence, social participation) in a longitudinal analysis. The mediation hypothesis was confirmed; family background and functional performance variables significantly predicted parent expectations which significantly predicted outcomes. These findings add context to previous studies examining the role of parent expectations on young adult outcomes and inform directions for family-centered interventions and future research.

'Post-deployment appraisal' and the relationship with stress and psychological health in Australian veterans.

PubMed

Wright, Breanna; Forbes, Andrew; Kelsall, Helen; Clarke, David; Ikin, Jill; Sim, Malcolm

2015-12-01

Understanding how veterans appraise their post-deployment experiences could provide insight into better assisting their deployment transitions. We aimed to assess the factor structure of positive and negative post-deployment appraisals in Australian veterans and to examine the resultant factors in their relationship with military stress and psychological health. Questions capturing post-deployment attitudes were developed by the researchers in collaboration with veterans. The questions were administered to 1938 veterans and the results factor analysed. The relationships between post-deployment appraisal, military stress and psychological health were examined using Structural Equation Modelling. A three-factor solution was found for the post-deployment appraisal questions; representing personal development, lack of recognition, and appreciation of life and country. Military stress was associated with the three factors and psychological health. The three factors were weakly to moderately associated with psychological health. Mediation between military stress and psychological health by any post-deployment appraisal factor was minimal. Post-deployment appraisal measures three important attitudes and concerns of veterans after deployment. Military stress is associated with the post-deployment appraisal factors. However, the factors did not mediate the relationship between military stress and psychological health. These factors provide insight into how veterans appraise their complex array of post-deployment experiences, and may provide useful in regard to transitions and integration into civilian life.

Explaining the effects of a 1-year intervention promoting a low fat diet in adolescent girls: a mediation analysis.

PubMed

Haerens, Leen; Cerin, Ester; Deforche, Benedicte; Maes, Lea; De Bourdeaudhuij, Ilse

2007-11-09

Although it is important to investigate how interventions work, no formal mediation analyses have been conducted to explain behavioral outcomes in school-based fat intake interventions in adolescents. The aim of the present study was to examine mediation effects of changes in psychosocial determinants of dietary fat intake (attitude, social support, self-efficacy, perceived benefits and barriers) on changes in fat intake in adolescent girls. Data from a 1-year prospective intervention study were used. A random sample of 804 adolescent girls was included in the study. Girls in the intervention group (n = 415) were exposed to a multi-component school-based intervention program, combining environmental changes with a computer tailored fat intake intervention and parental support. Fat intake and psychosocial determinants of fat intake were measured with validated self-administered questionnaires. To assess mediating effects, a product-of-coefficient test, appropriate for cluster randomized controlled trials, was used. None of the examined psychosocial factors showed a reliable mediating effect on changes in fat intake. The single-mediator model revealed a statistically significant suppression effect of perceived barriers on changes in fat intake (p = 0.011). In the multiple-mediator model, this effect was no longer significant, which was most likely due to changes in perceived barriers being moderately related to changes in self-efficacy (-0.30) and attitude (-0.25). The overall mediated-suppressed effect of the examined psychosocial factors was virtually zero (total mediated effect = 0.001; SE = 7.22; p = 0.992). Given the lack of intervention effects on attitudes, social support, self-efficacy and perceived benefits and barriers, it is suggested that future interventions should focus on the identification of effective strategies for changing these theoretical mediators in the desired direction. Alternatively, it could be argued that these constructs need not be targeted in interventions aimed at adolescents, as they may not be responsible for the intervention effects on fat intake. To draw any conclusions regarding mediators of fat-intake change in adolescent' girls and regarding optimal future intervention strategies, more systematic research on the mediating properties of psychosocial variables is needed.

Parental bonding and depression: personality as a mediating factor.

PubMed

Avagianou, Penelope-Alexia; Zafiropoulou, Maria

2008-01-01

According to Bowlby's theory of attachment, the role of early experience and parenting is of crucial importance to child development and mental health. In addition, several research findings suggest that parental bonding and different types of attachment play a crucial role in personality development. The present study examines the association between parental bonding experiences (lack of parental care, overprotection or both) and depression during adulthood. The objective of the present study was to evaluate different personality dimensions as possible mediators of the relation between perceptions of parental bonding and depressive symptoms in adult life. 181 participants (15- 49-years-old) completed the Parental Bonding Instrument (PBI), the Beck Depression Inventory (BDI) and the 16 Personality Factor Questionnaire (16PF). The results show that lack of parental care and overprotection is linked with depressive symptoms and a number of personality characteristics, such as low self-esteem, introversion, distress and emotional instability. In contrast, high care and low protection (optimal bonding) is linked with increased self-confidence, less distress and less depressive symptoms. The results presented here are in line with Bowlby's theory of attachment and show that parental bonding is linked with problematic personality development and psychopathology. The present study provided evidence that personality factors may mediate the observed relationship between parental rearing style and depression. The potential causal mechanisms warrant longitudinal evaluation.

Transcription factor CREB is involved in CaSR-mediated cytoskeleton gene expression.

PubMed

Huang, Shuaishuai; Ren, Yu; Wang, Ping; Li, Yanyuan; Wang, Xue; Zhuang, Haihui; Fang, Rong; Wang, Yuduo; Liu, Ningsheng; Hehir, Michael; Zhou, Jeff X

2015-03-01

Our previous studies illustrated that a steady increase of intracellular calcium concentration ([Ca2+]i) was important for maintaining microtubules (MTs) rearrangement in apoptotic cells. However, little is known about the effect of calcium sensing receptor (CaSR)-mediated increase in [Ca2+]i on cytoskeleton gene expression. We examined the impact of taxol or CaSR agonist/antagonist on the regulation of [Ca2+]i concentration, cytoskeleton arrangement, phosphorylated CREB and cytoskeleton gene expressions in HeLa cells with dominant negative plasmid of CREB (PM). This study demonstrated that Gdcl3 (a specific CaSR agonist) evoked a rapid increase of [Ca2+]i, formed a rigid bundle of MTs which surrounded the nucleus and decreased the cytoskeleton gene expressions in HeLa cells. These effects were rescued by addition of NPS2390 (a specific CaSR antagonist). Moreover, CaSR activity affected cytoskeleton gene expression through transcription factor CREB. Histoscores of pCREB immunoreactivity in tissues of cervical adenocarcinoma, renal clear cell carcinoma, and diffuse large B-cell lymphoma were markedly increased compared with non malignant tissue. These data demonstrate, for the first time, that CaSR-mediated increase in [Ca2+]i probably modulate cytoskeleton organization and gene expression via transcription factor. © 2014 Wiley Periodicals, Inc.

Local adaptation in migrated interior Douglas-fir seedlings is mediated by ectomycorrhizas and other soil factors.

PubMed

Pickles, Brian J; Twieg, Brendan D; O'Neill, Gregory A; Mohn, William W; Simard, Suzanne W

2015-08-01

Separating edaphic impacts on tree distributions from those of climate and geography is notoriously difficult. Aboveground and belowground factors play important roles, and determining their relative contribution to tree success will greatly assist in refining predictive models and forestry strategies in a changing climate. In a common glasshouse, seedlings of interior Douglas-fir (Pseudotsuga menziesii var. glauca) from multiple populations were grown in multiple forest soils. Fungicide was applied to half of the seedlings to separate soil fungal and nonfungal impacts on seedling performance. Soils of varying geographic and climatic distance from seed origin were compared, using a transfer function approach. Seedling height and biomass were optimized following seed transfer into drier soils, whereas survival was optimized when elevation transfer was minimised. Fungicide application reduced ectomycorrhizal root colonization by c. 50%, with treated seedlings exhibiting greater survival but reduced biomass. Local adaptation of Douglas-fir populations to soils was mediated by soil fungi to some extent in 56% of soil origin by response variable combinations. Mediation by edaphic factors in general occurred in 81% of combinations. Soil biota, hitherto unaccounted for in climate models, interacts with biogeography to influence plant ranges in a changing climate. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

The Influence of Cognitive Load on Empathy and Intention in Response to Infant Crying.

PubMed

Hiraoka, Daiki; Nomura, Michio

2016-06-16

Many studies have explored risk factors for child maltreatment, but little research has focused on situational risk factors such as cognitive load, which involves within-individual fluctuation. The current study sought to determine whether cognitive load led to within-individual changes in intention in response to infant crying. The study also sought to ascertain whether state empathy, empathic concern (EC), and personal distress mediated or moderated this relationship. Sixty-six participants completed a memory task (remembering meaningless, two- or eight-letter, English alphabet string), during which they were required to keep these letters in mind while hearing infant crying (or a tone). Subsequently, participants rated questions concerning state empathy and intention in response to the crying (i.e., intentions involving caregiving, neglect, or physical abuse). Results showed that cognitive load reduced caregiving intention and increased intention to perpetrate neglect. In addition, EC mediated the relationship between cognitive load and intention to provide care or perpetrate neglect. Moreover, cognitive load interacted with state empathy to predict intention to provide care or perpetrate neglect. These findings highlighted the importance of focusing on situational cognitive risk factors for child maltreatment and elucidated the role of state empathy as a mediator or moderator in child maltreatment research.

The Influence of Cognitive Load on Empathy and Intention in Response to Infant Crying

PubMed Central

Hiraoka, Daiki; Nomura, Michio

2016-01-01

Many studies have explored risk factors for child maltreatment, but little research has focused on situational risk factors such as cognitive load, which involves within-individual fluctuation. The current study sought to determine whether cognitive load led to within-individual changes in intention in response to infant crying. The study also sought to ascertain whether state empathy, empathic concern (EC), and personal distress mediated or moderated this relationship. Sixty-six participants completed a memory task (remembering meaningless, two- or eight-letter, English alphabet string), during which they were required to keep these letters in mind while hearing infant crying (or a tone). Subsequently, participants rated questions concerning state empathy and intention in response to the crying (i.e., intentions involving caregiving, neglect, or physical abuse). Results showed that cognitive load reduced caregiving intention and increased intention to perpetrate neglect. In addition, EC mediated the relationship between cognitive load and intention to provide care or perpetrate neglect. Moreover, cognitive load interacted with state empathy to predict intention to provide care or perpetrate neglect. These findings highlighted the importance of focusing on situational cognitive risk factors for child maltreatment and elucidated the role of state empathy as a mediator or moderator in child maltreatment research. PMID:27305959

Protein Kinase D-dependent Phosphorylation and Nuclear Export of Histone Deacetylase 5 Mediates Vascular Endothelial Growth Factor-induced Gene Expression and Angiogenesis*S⃞

PubMed Central

Ha, Chang Hoon; Wang, Weiye; Jhun, Bong Sook; Wong, Chelsea; Hausser, Angelika; Pfizenmaier, Klaus; McKinsey, Timothy A.; Olson, Eric N.; Jin, Zheng-Gen

2008-01-01

Vascular endothelial growth factor (VEGF) is essential for normal and pathological angiogenesis. However, the signaling pathways linked to gene regulation in VEGF-induced angiogenesis are not fully understood. Here we demonstrate a critical role of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) in VEGF-induced gene expression and angiogenesis. We found that VEGF stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a VEGF receptor 2-phospholipase Cγ-protein kinase C-PKD-dependent pathway. We further showed that the PKD-HDAC5 pathway mediated myocyte enhancer factor-2 transcriptional activation and a specific subset of gene expression in response to VEGF, including NR4A1, an orphan nuclear receptor involved in angiogenesis. Specifically, inhibition of PKD by overexpression of the PKD kinase-negative mutant prevents VEGF-induced HDAC5 phosphorylation and nuclear export as well as NR4A1 induction. Moreover, a mutant of HDAC5 specifically deficient in PKD-dependent phosphorylation inhibited VEGF-mediated NR4A1 expression, endothelial cell migration, and in vitro angiogenesis. These findings suggest that the PKD-HDAC5 pathway plays an important role in VEGF regulation of gene transcription and angiogenesis. PMID:18332134

Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo

NASA Astrophysics Data System (ADS)

Kim, K. Jin; Li, Bing; Winer, Jane; Armanini, Mark; Gillett, Nancy; Phillips, Heidi S.; Ferrara, Napoleone

1993-04-01

THE development of new blood vessels (angiogenesis) is required for many physiological processes including embryogenesis, wound healing and corpus luteum formation1,2. Blood vessel neoformation is also important in the pathogenesis of many disorders1-5, particularly rapid growth and metastasis of solid tumours3-5. There are several potential mediators of tumour angiogenesis, including basic and acidic fibroblast growth factors, tumour necrosis factor-α and transforming factors-α and -β 1,2. But it is unclear whether any of these agents actually mediates angiogenesis and tumour growth in vivo. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen and an angiogenesis inducer released by a variety of tumour cells and expressed in human tumours in situ. To test whether VEGF may be a tumour angiogenesis factor in vivo, we injected human rhabdomyosar-coma, glioblastoma multiforme or leiomyosarcoma cell lines into nude mice. We report here that treatment with a monoclonal antibody specific for VEGF inhibited the growth of the tumours, but had no effect on the growth rate of the tumour cells In vitro. The density of vessels was decreased in the antibody-treated tumours. These findings demonstrate that inhibition of the action of an angiogenic factor spontaneously produced by tumour cells may suppress tumour growth in vivo.

The Relationship between Impulsivity and Internet Gaming Disorder in Young Adults: Mediating Effects of Interpersonal Relationships and Depression.

PubMed

Ryu, Hyera; Lee, Ji-Yoon; Choi, Aruem; Park, Sunyoung; Kim, Dai-Jin; Choi, Jung-Seok

2018-03-06

Background: This study aimed to explore relationships between impulsivity, interpersonal relationships, depression, and Internet Gaming Disorder (IGD) symptoms. Methods: A total of 118 young adults participated in this study: 67 IGD patients who met five or more of the DSM-5 diagnostic criteria for IGD and 56 healthy controls. We administered questionnaires to assess IGD symptoms (Young's Internet Addiction Test; Y-IAT), impulsivity (Barratt Impulsiveness Scale; BIS-11), interpersonal relationship (Relationship Change Scale; RCS), and depression (Beck Depression Inventory; BDI). We used PROCESS macro in SPSS to perform mediation analysis. Results: IGD symptom was positively related to depression and impulsivity, and negatively related to the quality of interpersonal relationships. Mediation analysis revealed full mediation effects of interpersonal relationships and depression on the association between impulsivity and IGD symptoms in the IGD group. Specifically, even after adjusting for gender as a covariate, high impulsivity was associated with greater difficulty with interpersonal relationships; which further affected depression and increased the risk of IGD. Conclusions: These results demonstrate the importance of early intervention in IGD patients, particularly in young adults with high impulsivity. When intervening in adults' IGD, we should consider not only individual factors (e.g., depression) but also socioenvironmental factors (e.g., interpersonal relationships).

The Relationship between Impulsivity and Internet Gaming Disorder in Young Adults: Mediating Effects of Interpersonal Relationships and Depression

PubMed Central

Ryu, Hyera; Lee, Ji-Yoon; Choi, Aruem; Park, Sunyoung; Kim, Dai-Jin

2018-01-01

Background: This study aimed to explore relationships between impulsivity, interpersonal relationships, depression, and Internet Gaming Disorder (IGD) symptoms. Methods: A total of 118 young adults participated in this study: 67 IGD patients who met five or more of the DSM-5 diagnostic criteria for IGD and 56 healthy controls. We administered questionnaires to assess IGD symptoms (Young’s Internet Addiction Test; Y-IAT), impulsivity (Barratt Impulsiveness Scale; BIS-11), interpersonal relationship (Relationship Change Scale; RCS), and depression (Beck Depression Inventory; BDI). We used PROCESS macro in SPSS to perform mediation analysis. Results: IGD symptom was positively related to depression and impulsivity, and negatively related to the quality of interpersonal relationships. Mediation analysis revealed full mediation effects of interpersonal relationships and depression on the association between impulsivity and IGD symptoms in the IGD group. Specifically, even after adjusting for gender as a covariate, high impulsivity was associated with greater difficulty with interpersonal relationships; which further affected depression and increased the risk of IGD. Conclusions: These results demonstrate the importance of early intervention in IGD patients, particularly in young adults with high impulsivity. When intervening in adults’ IGD, we should consider not only individual factors (e.g., depression) but also socioenvironmental factors (e.g., interpersonal relationships). PMID:29509708

Hypoxia induces cancer-associated cAMP/PKA signalling through HIF-mediated transcriptional control of adenylyl cyclases VI and VII.

PubMed

Simko, Veronika; Iuliano, Filippo; Sevcikova, Andrea; Labudova, Martina; Barathova, Monika; Radvak, Peter; Pastorekova, Silvia; Pastorek, Jaromir; Csaderova, Lucia

2017-08-31

Hypoxia is a phenomenon often arising in solid tumours, linked to aggressive malignancy, bad prognosis and resistance to therapy. Hypoxia-inducible factor-1 has been identified as a key mediator of cell and tissue adaptation to hypoxic conditions through transcriptional activation of many genes involved in glucose metabolism and other cancer-related processes, such as angiogenesis, cell survival and cell invasion. Cyclic adenosine 3'5'-monophosphate is one of the most ancient and evolutionarily conserved signalling molecules and the cAMP/PKA signalling pathway plays an important role in cellular adaptation to hypoxia. We have investigated possible new mechanisms behind hypoxic activation of the cAMP/PKA pathway. For the first time, we have shown that hypoxia induces transcriptional up-regulation of the system of adenylyl cyclases, enzymes responsible for cAMP production, in a panel of carcinoma cell lines of various origin. Our data prove functional relevance of the hypoxic increase of adenylyl cyclases VI and VII at least partially mediated by HIF-1 transcription factor. We have identified adenylyl cyclase VI and VII isoforms as mediators of cellular response to hypoxia, which led to the elevation of cAMP levels and enhanced PKA activity, with an impact on cell migration and pH regulation.

Spatio-temporal trends in crop damage inform recent climate-mediated expansion of a large boreal herbivore into an agro-ecosystem.

PubMed

Laforge, Michel P; Michel, Nicole L; Brook, Ryan K

2017-11-09

Large-scale climatic fluctuations have caused species range shifts. Moose (Alces alces) have expanded their range southward into agricultural areas previously not considered moose habitat. We found that moose expansion into agro-ecosystems is mediated by broad-scale climatic factors and access to high-quality forage (i.e., crops). We used crop damage records to quantify moose presence across the Canadian Prairies. We regressed latitude of crop damage against North Atlantic Oscillation (NAO) and crop area to test the hypotheses that NAO-mediated wetland recharge and occurrence of more nutritious crop types would result in more frequent occurrences of crop damage by moose at southerly latitudes. We examined local-scale land use by generating a habitat selection model to test our hypothesis that moose selected for areas of high crop cover in agro-ecosystems. We found that crop damage by moose occurred farther south during dry winters and in years with greater coverage of oilseeds. The results of our analyses support our hypothesis that moose movement into cropland is mediated by high-protein crops, but not by thermoregulatory habitat at the scale examined. We conclude that broad-scale climate combined with changing land-use regimes are causal factors in species' range shifts and are important considerations when studying changing animal distributions.

The role of anger and ongoing stressors in mental health following a natural disaster.

PubMed

Forbes, David; Alkemade, Nathan; Waters, Elizabeth; Gibbs, Lisa; Gallagher, Colin; Pattison, Phillipa; Lusher, Dean; MacDougall, Colin; Harms, Louise; Block, Karen; Snowdon, Elyse; Kellet, Connie; Sinnott, Vikki; Ireton, Greg; Richardson, John; Bryant, Richard A

2015-08-01

Research has established the mental health sequelae following disaster, with studies now focused on understanding factors that mediate these outcomes. This study focused on anger, alcohol, subsequent life stressors and traumatic events as mediators in the development of mental health disorders following the 2009 Black Saturday Bushfires, Australia's worst natural disaster in over 100 years. This study examined data from 1017 (M = 404, F = 613) adult residents across 25 communities differentially affected by the fires and participating in the Beyond Bushfires research study. Data included measures of fire exposure, posttraumatic stress disorder, depression, alcohol abuse, anger and subsequent major life stressors and traumatic events. Structural equation modeling assessed the influence of factors mediating the effects of fire exposure on mental health outcomes. Three mediation models were tested. The final model recorded excellent fit and observed a direct relationship between disaster exposure and mental health outcomes (b = .192, p < .001) and mediating relationships via Anger (b = .102, p < .001) and Major Life Stressors (b = .128, p < .001). Each gender was compared with multiple group analyses and while the mediation relationships were still significant for both genders, the direct relationship between exposure and outcome was no longer significant for men (p = .069), but remained significant (b = .234, p < .001) for women. Importantly, anger and major life stressors mediate the relationship between disaster exposure and development of mental health problems. The findings have significant implications for the assessment of anger post disaster, the provision of targeted anger-focused interventions and delivery of government and community assistance and support in addressing ongoing stressors in the post-disaster context to minimize subsequent mental health consequences. © The Royal Australian and New Zealand College of Psychiatrists 2015.

PRRX2 as a novel TGF-β-induced factor enhances invasion and migration in mammary epithelial cell and correlates with poor prognosis in breast cancer.

PubMed

Juang, Yu-Lin; Jeng, Yung-Ming; Chen, Chi-Long; Lien, Huang-Chun

2016-12-01

TGF-β and cancer progression share a multifaceted relationship. Despite the knowledge of TGF-β biology in the development of cancer, several factors that mediate the cancer-promoting role of TGF-β continue to be identified. This study aimed to identify and characterise novel factors potentially related to TGF-β-mediated tumour aggression in breast cells. We treated the human mammary epithelial cell line MCF10A with TGF-β and identified TGF-β-dependent upregulation of PRRX2, the gene encoding paired-related homeobox 2 transcription factor. Overexpression of PRRX2 enhanced migration, invasion and anchorage-independent growth of MCF10A cells and induced partial epithelial mesenchymal transition (EMT), as determined by partial fibroblastoid morphology of cells, upregulation of EMT markers and partially disrupted acinar structure in a three-dimensional culture. We further identified PLAT, the gene encoding tissue-type plasminogen activator (tPA), as the highest differentially expressed gene in PRRX2-overexpressing MCF10A cells, and demonstrated direct binding and transactivation of the PLAT promoter by PRRX2. Furthermore, PLAT knockdown inhibited PRRX2-mediated enhanced migration and invasion, suggesting that tPA may mediate PRRX2-induced migration and invasion. Finally, the significant correlation of PRRX2 expression with poor survival in 118 primary breast tumour samples (P = 0.027) and the increased PRRX2 expression in metaplastic breast carcinoma samples, which is pathogenetically related to EMT, validated the biological importance of PRRX2-enhanced migration and invasion and PRRX2-induced EMT. Thus, our data suggest that upregulation of PRRX2 may be a mechanism contributing to TGF-β-induced invasion and EMT in breast cancer. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A predictive model of Health Related Quality of life of parents of chronically ill children: the importance of care-dependency of their child and their support system.

PubMed

Hatzmann, Janneke; Maurice-Stam, Heleen; Heymans, Hugo S A; Grootenhuis, Martha A

2009-07-28

Parents of chronically ill children are at risk for a lower Health Related Quality of Life (HRQoL). Insight in the dynamics of factors influencing parental HRQoL is necessary for development of interventions. Aim of the present study was to explore the influence of demographic and disease related factors on parental HRQoL, mediated by employment, income, leisure time, holiday and emotional support in a comprehensive model. In a cross-sectional design, 543 parents of chronically ill children completed questionnaires. A conceptual model of parental HRQoL was developed. Structural equation modeling was performed to explore the relations in the conceptual model, and to test if the model fitted the data. The model fitted the data closely (CHISQ(14) = 11.37, p = 0.66; RMSEA = 0.0, 90%CI [0.00;0.034]. The effect of socio-demographic and medical data on HRQoL was mediated by days on holiday (MCS: beta = .21) and emotional support (PCS: beta = .14; MCS: beta = .28). Also, female gender (beta = -.10), age (beta = .10), being chronically ill as a parent (beta = -.34), and care dependency of the child (beta = -.14; beta = -.15) were directly related to parental HRQoL. The final model was slightly different from the conceptual model. Main factors explaining parental HRQoL seemed to be emotional support, care dependency, days on holiday and being chronically ill as a parent. Holiday and emotional support mediated the effect of demographic and disease-related factors on HRQoL. Hours of employment, leisure time and household income did not mediate between background characteristics and HRQoL, contrasting the hypotheses.

Fungal mediator tail subunits contain classical transcriptional activation domains.

PubMed

Liu, Zhongle; Myers, Lawrence C

2015-04-01

Classical activation domains within DNA-bound eukaryotic transcription factors make weak interactions with coactivator complexes, such as Mediator, to stimulate transcription. How these interactions stimulate transcription, however, is unknown. The activation of reporter genes by artificial fusion of Mediator subunits to DNA binding domains that bind to their promoters has been cited as evidence that the primary role of activators is simply to recruit Mediator. We have identified potent classical transcriptional activation domains in the C termini of several tail module subunits of Saccharomyces cerevisiae, Candida albicans, and Candida dubliniensis Mediator, while their N-terminal domains are necessary and sufficient for their incorporation into Mediator but do not possess the ability to activate transcription when fused to a DNA binding domain. This suggests that Mediator fusion proteins actually are functioning in a manner similar to that of a classical DNA-bound activator rather than just recruiting Mediator. Our finding that deletion of the activation domains of S. cerevisiae Med2 and Med3, as well as C. dubliniensis Tlo1 (a Med2 ortholog), impairs the induction of certain genes shows these domains function at native promoters. Activation domains within coactivators are likely an important feature of these complexes and one that may have been uniquely leveraged by a common fungal pathogen. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Visibility from roads predict the distribution of invasive fishes in agricultural ponds.

PubMed

Kizuka, Toshikazu; Akasaka, Munemitsu; Kadoya, Taku; Takamura, Noriko

2014-01-01

Propagule pressure and habitat characteristics are important factors used to predict the distribution of invasive alien species. For species exhibiting strong propagule pressure because of human-mediated introduction of species, indicators of introduction potential must represent the behavioral characteristics of humans. This study examined 64 agricultural ponds to assess the visibility of ponds from surrounding roads and its value as a surrogate of propagule pressure to explain the presence and absence of two invasive fish species. A three-dimensional viewshed analysis using a geographic information system quantified the visual exposure of respective ponds to humans. Binary classification trees were developed as a function of their visibility from roads, as well as five environmental factors: river density, connectivity with upstream dam reservoirs, pond area, chlorophyll a concentration, and pond drainage. Traditional indicators of human-mediated introduction (road density and proportion of urban land-use area) were alternatively included for comparison instead of visual exposure. The presence of Bluegill (Lepomis macrochirus) was predicted by the ponds' higher visibility from roads and pond connection with upstream dam reservoirs. Results suggest that fish stocking into ponds and their dispersal from upstream sources facilitated species establishment. Largemouth bass (Micropterus salmoides) distribution was constrained by chlorophyll a concentration, suggesting their lower adaptability to various environments than that of Bluegill. Based on misclassifications from classification trees for Bluegill, pond visual exposure to roads showed greater predictive capability than traditional indicators of human-mediated introduction. Pond visibility is an effective predictor of invasive species distribution. Its wider use might improve management and mitigate further invasion. The visual exposure of recipient ecosystems to humans is important for many invasive species that spread with frequent instances of human-mediated introduction.

CRM1 protein-mediated regulation of nuclear clusterin (nCLU), an ionizing radiation-stimulated, Bax-dependent pro-death factor.

PubMed

Leskov, Konstantin S; Araki, Shinako; Lavik, John-Paul; Gomez, Jose A; Gama, Vivian; Gonos, Efstathios S; Trougakos, Ioannis P; Matsuyama, Shigemi; Boothman, David A

2011-11-18

Expression of the clusterin (CLU) gene results in the synthesis of a conventional secretory isoform set (pre- and mature secretory clusterin proteins, psCLU/sCLU), as well as another set of intracellular isoforms, appearing in the cytoplasm (pre-nuclear CLU, pnCLU) and in the nucleus as an ∼55-kDa mature nuclear clusterin (nCLU) form. These two isoform sets have opposing cell functions: pro-survival and pro-death, respectively. Although much is known about the regulation and function of sCLU as a pro-survival factor, the regulation and function of endogenous nCLU in cell death are relatively unexplored. Here, we show that depletion of endogenous nCLU protein using siRNA specific to its truncated mRNA increased clonogenic survival of ionizing radiation (IR)-exposed cells. nCLU-mediated apoptosis was Bax-dependent, and lethality correlated with accumulation of mature nCLU protein. nCLU accumulation was regulated by CRM1 because binding between CRM1 and nCLU proteins was significantly diminished by leptomycin B (LMB), and nuclear levels of nCLU protein were significantly enhanced by LMB and IR co-treatment. Moreover, LMB treatment significantly enhanced IR-induced nCLU-mediated cell death responses. Importantly, bax(-/-) and bax(-/-)/bak(-/-) double knock-out cells were resistant to nCLU-mediated cell death, whereas bak(-/-) or wild-type bax(+/+)/bak(+/+) cells were hypersensitive. The regulation of nCLU by CRM1 nuclear export/import may explain recent clinical results showing that highly malignant tumors have lost the ability to accumulate nCLU levels, thereby avoiding growth inhibition and cell death.

High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity.

PubMed

Schulz, Manon D; Atay, Ciğdem; Heringer, Jessica; Romrig, Franziska K; Schwitalla, Sarah; Aydin, Begüm; Ziegler, Paul K; Varga, Julia; Reindl, Wolfgang; Pommerenke, Claudia; Salinas-Riester, Gabriela; Böck, Andreas; Alpert, Carl; Blaut, Michael; Polson, Sara C; Brandl, Lydia; Kirchner, Thomas; Greten, Florian R; Polson, Shawn W; Arkan, Melek C

2014-10-23

Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.

Loop III region of platelet-derived growth factor (PDGF) B-chain mediates binding to PDGF receptors and heparin.

PubMed Central

Schilling, D; Reid IV, J D; Hujer, A; Morgan, D; Demoll, E; Bummer, P; Fenstermaker, R A; Kaetzel, D M

1998-01-01

Site-directed mutagenesis of the platelet-derived growth factor (PDGF) B-chain was conducted to determine the importance of cationic amino acid residues (Arg160-Lys161-Lys162; RKK) located within the loop III region in mediating the biological and cell-association properties of the molecule. Binding to both PDGF alpha-and beta-receptors was inhibited by the conversion of all three cationic residues into anionic glutamates (RKK-->EEE), whereas an RKK-->SSS mutant also exhibited a modest loss in affinity for beta-receptors. Replacements with serine at either Arg160 (RKK-->SKK) or at all three positions (RKK-->SSS) had little effect on binding to alpha-receptors. Replacements with either glutamic or serine residues at any of the three positions also resulted in significant inhibition of heparin-binding activity. Furthermore, the RKK-->EEE mutant exhibited decreased association with the cell surface and accumulated in the culture medium as 29-32 kDa forms. Stable transfection of U87 astrocytoma cells with RKK-->EEE mutants of either the A-chain or the B-chain inhibited malignant growth in athymic nude mice. Despite altered receptor-binding activities, each of the loop III mutants retained full mitogenic activity when applied to cultured Swiss 3T3 cells. CD spectrophotometric analysis of the RKK-->EEE mutant revealed a secondary structure indistinguishable from the wild type, with a high degree of beta-sheet structure and random coil content (50% and 43% respectively). These findings indicate an important role of the Arg160-Lys161-Lys162 sequence in mediating the biological and cell-associative activities of the PDGF-BB homodimer, and reveal that the mitogenic activity of PDGF-BB is insufficient to mediate its full oncogenic properties. PMID:9677323

Role of protein and amino acids in promoting lean mass accretion with resistance exercise and attenuating lean mass loss during energy deficit in humans.

PubMed

Churchward-Venne, Tyler A; Murphy, Caoileann H; Longland, Thomas M; Phillips, Stuart M

2013-08-01

Amino acids are major nutrient regulators of muscle protein turnover. After protein ingestion, hyperaminoacidemia stimulates increased rates of skeletal muscle protein synthesis, suppresses muscle protein breakdown, and promotes net muscle protein accretion for several hours. These acute observations form the basis for strategized protein intake to promote lean mass accretion, or prevent lean mass loss over the long term. However, factors such as protein dose, protein source, and timing of intake are important in mediating the anabolic effects of amino acids on skeletal muscle and must be considered within the context of evaluating the reported efficacy of long-term studies investigating protein supplementation as part of a dietary strategy to promote lean mass accretion and/or prevent lean mass loss. Current research suggests that dietary protein supplementation can augment resistance exercise-mediated gains in skeletal muscle mass and strength and can preserve skeletal muscle mass during periods of diet-induced energy restriction. Perhaps less appreciated, protein supplementation can augment resistance training-mediated gains in skeletal muscle mass even in individuals habitually consuming 'adequate' (i.e., >0.8 g kg⁻¹ day⁻¹) protein. Additionally, overfeeding energy with moderate to high-protein intake (15-25 % protein or 1.8-3.0 g kg⁻¹ day⁻¹) is associated with lean, but not fat mass accretion, when compared to overfeeding energy with low protein intake (5 % protein or ~0.68 g kg⁻¹ day⁻¹). Amino acids represent primary nutrient regulators of skeletal muscle anabolism, capable of enhancing lean mass accretion with resistance exercise and attenuating the loss of lean mass during periods of energy deficit, although factors such as protein dose, protein source, and timing of intake are likely important in mediating these effects.

The transcription factor MEF2C mediates cardiomyocyte hypertrophy induced by IGF-1 signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munoz, Juan Pablo; Collao, Andres; Chiong, Mario

2009-10-09

Myocyte enhancer factor 2C (MEF2C) plays an important role in cardiovascular development and is a key transcription factor for cardiac hypertrophy. Here, we describe MEF2C regulation by insulin-like growth factor-1 (IGF-1) and its role in IGF-1-induced cardiac hypertrophy. We found that IGF-1 addition to cultured rat cardiomyocytes activated MEF2C, as evidenced by its increased nuclear localization and DNA binding activity. IGF-1 stimulated MEF2 dependent-gene transcription in a time-dependent manner, as indicated by increased MEF2 promoter-driven reporter gene activity; IGF-1 also induced p38-MAPK phosphorylation, while an inhibitor of p38-MAPK decreased both effects. Additionally, inhibitors of phosphatidylinositol 3-kinase and calcineurin prevented IGF-1-inducedmore » MEF2 transcriptional activity. Via MEF2C-dependent signaling, IGF-1 also stimulated transcription of atrial natriuretic factor and skeletal {alpha}-actin but not of fos-lux reporter genes. These novel data suggest that MEF2C activation by IGF-1 mediates the pro-hypertrophic effects of IGF-1 on cardiac gene expression.« less

Work-family conflict and burnout among Chinese female nurses: the mediating effect of psychological capital

PubMed Central

2012-01-01

Background Burnout among nurses not only threatens their own health, but also that of their patients. Exploring risk factors of nurse’ burnout is important to improve nurses’ health and to increase the quality of health care services. This study aims to explore the relationship between work-family conflict and burnout among Chinese female nurses and the mediating role of psychological capital in this relationship. Methods This cross-sectional study was performed during the period of September and October 2010. A questionnaire that consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the work-family conflict scale and the psychological capital questionnaire (PCQ-24) scale, as well as demographic and working factors, was distributed to nurses in Liaoning province, China. A total of 1,332 individuals (effective response rate: 78.35%) became our subjects. Hierarchical linear regression analyses were performed to explore the mediating role of psychological capital. Results Both work interfering family conflict and family interfering work conflict were positively related with emotional exhaustion and cynicism. However, work interfering family conflict was positively related with professional efficacy whereas family interfering work conflict was negatively related with it. Psychological capital partially mediated the relationship of work interfering family conflict with emotional exhaustion and cynicism; and partially mediated the relationship of family interfering work conflict with emotional exhaustion, cynicism and professional efficacy. Conclusion Work-family conflict had effects on burnout and psychological capital was a mediator in this relationship among Chinese nurses. Psychological capital was a positive resource for fighting against nurses’ burnout. PMID:23107113

Adenoviral mediated interferon-alpha 2b gene therapy suppresses the pro-angiogenic effect of vascular endothelial growth factor in superficial bladder cancer.

PubMed

Adam, Liana; Black, Peter C; Kassouf, Wassim; Eve, Beryl; McConkey, David; Munsell, Mark F; Benedict, William F; Dinney, Colin P N

2007-05-01

Intravesical adenovirus mediated interferon-alpha gene transfer has a potent therapeutic effect against superficial human bladder carcinoma xenografts growing in the bladder of athymic nude mice. We determined whether the inhibition of angiogenesis might contribute to the antitumor effect. We treated several human urothelial carcinoma cells with adenovirus mediated interferon-alpha 2b and monitored its effects on the production of angiogenic factors using real-time reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemical analysis and a gel shift based transcription factor array. To assess the role of adenovirus mediated interferon 2b in angiogenic activity we used in vitro invasion assays and evaluated the anti-angiogenic effects of adenovirus mediated interferon gene therapy in an orthotopic murine model of human superficial bladder cancer. In adenovirus mediated interferon-alpha infected 253J B-V cells vascular endothelial growth factor was decreased and anti-angiogenic interferon-gamma inducible protein 10 was up-regulated. In contrast, the addition of as much as 100,000 IU recombinant interferon had no apparent effect on vascular endothelial growth factor production. Conditioned medium derived from adenovirus mediated interferon 2b infected 253J B-V cells greatly decreased the invasive potential of human endothelial cells and down-regulated their matrix metalloproteinase 2 expression compared to controls. Furthermore, adenovirus mediated interferon 2b blocked pro-angiogenic nuclear signals, such as the transcription factors activating protein-1 and 2, stimulating protein-1, nuclear factor kappaB and c-myb. In vivo experiments revealed significant vascular endothelial growth factor down-regulation and decreased tumor vessel density in the adenovirus mediated interferon 2b treated group compared to controls. Treatment with adenovirus mediated interferon 2b increases the angiostatic activity of the bladder cancer microenvironment. This inhibition may prove beneficial for treating superficial bladder cancer with adenovirus mediated interferon-alpha and hopefully contribute to a decreased recurrence rate of this neoplasm.

Borderline Personality Features, Anger, and Intimate Partner Violence: An Experimental Manipulation of Rejection.

PubMed

Armenti, Nicholas A; Babcock, Julia C

2018-04-01

Individuals with borderline personality features may be susceptible to react to situational stressors with negative and interpersonally maladaptive emotionality (e.g., anger) and aggression. The current study attempted to test two moderated mediation models to investigate dispositional risk factors associated with borderline personality features and intimate partner violence (IPV). Results from an experimental rejection induction paradigm were examined using moderated regression to observe contextual reactions to imagined romantic rejection from a current romantic partner among individuals with borderline personality features. An ethnically diverse sample of 218 undergraduates at a large public university in the southwestern United States was recruited. Participants responded to demographic questions and self-report measures, and engaged in an experimental rejection induction paradigm. Borderline personality features was positively associated with rejection sensitivity, physical assault, and psychological aggression. Contrary to initial hypotheses, rejection sensitivity did not serve as a mediator of the relations between borderline personality features and physical assault and psychological aggression. However, trait anger mediated the relation between borderline personality features and psychological aggression. As such, trait anger may be an important explanatory variable in the relation between borderline personality features and psychological aggression specifically. Results of the rejection induction paradigm indicated that, for individuals who were asked to imagine an ambiguous rejection, the relation between borderline personality features and state anger post-rejection was strengthened. For individuals who imagined a critical rejection, there was no significant relation between borderline personality features and state anger post-rejection. Findings suggest that trait anger may be an important dispositional factor in the link between borderline personality features and IPV. In addition, contextual factors, such as ambiguous rejection by an intimate partner, may be especially relevant in activating anger or aggression in individuals with borderline personality features.

Opposite Effects of Dihydrosphingosine 1-Phosphate and Sphingosine 1-Phosphate on Transforming Growth Factor-β/Smad Signaling Are Mediated through the PTEN/PPM1A-dependent Pathway*S⃞

PubMed Central

Bu, Shizhong; Kapanadze, Bagrat; Hsu, Tien; Trojanowska, Maria

2008-01-01

Transforming growth factor-β (TGF-β) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-β through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-β signaling. In contrast to S1P, dhS1P inhibits TGF-β-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-β signaling. Consequently, overexpression of PTEN abrogates TGF-β-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-β signaling pathways may play an important role in physiological and pathological TGF-β signaling. PMID:18482992

Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on transforming growth factor-beta/Smad signaling are mediated through the PTEN/PPM1A-dependent pathway.

PubMed

Bu, Shizhong; Kapanadze, Bagrat; Hsu, Tien; Trojanowska, Maria

2008-07-11

Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-beta through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-beta signaling. In contrast to S1P, dhS1P inhibits TGF-beta-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-beta signaling. Consequently, overexpression of PTEN abrogates TGF-beta-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-beta signaling pathways may play an important role in physiological and pathological TGF-beta signaling.

Perceived School Climate and Chinese Adolescents' Suicidal Ideation and Suicide Attempts: The Mediating Role of Sleep Quality

ERIC Educational Resources Information Center

Li, Dongping; Bao, Zhenzhou; Li, Xian; Wang, Yanhui

2016-01-01

Background: School factors play important roles in adolescent suicide. However, little is known about how school climate is associated with adolescent suicide. This study examined the relationship between perceived school climate and adolescent suicidal ideation and suicide attempts, and whether these relations were explained by adolescent sleep…

Adolescents' School-Related Self-Concept Mediates Motor Skills and Psychosocial Well-Being

ERIC Educational Resources Information Center

Viholainen, Helena; Aro, Tuija; Purtsi, Jarno; Tolvanen, Asko; Cantell, Marja

2014-01-01

Background: The health benefits of exercise participation and physical activity for mental health and psychosocial well-being (PSWB) have been shown in several studies. However, one important background factor, that is, motor skills (MSs), has largely been ignored. In addition, most of the existing research focuses on poor MSs, that is, poor MSs…

Parent Expectations Mediate Outcomes for Young Adults with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Kirby, Anne V.

2016-01-01

Understanding the complex relationships among factors that may predict the outcomes of young adults with autism spectrum disorder (ASD) is of utmost importance given the increasing population undergoing and anticipating the transition to adulthood. With a sample of youth with ASD (n = 1170) from the National Longitudinal Transition Study-2,…

Uncovering the Links between Prospective Teachers' Personal Responsibility, Academic Optimism, Hope, and Emotions about Teaching: A Mediation Analysis

ERIC Educational Resources Information Center

Eren, Altay

2014-01-01

Prospective teachers' sense of personal responsibility has not been examined together with their academic optimism, hope, and emotions about teaching in a single study to date. However, to consider hope, academic optimism, and emotions about teaching together with personal responsibility is important to uncover the factors affecting…

Clarifying Associations between Childhood Adversity, Social Support, Behavioral Factors, and Mental Health, Health, and Well-Being in Adulthood: A Population-Based Study

PubMed Central

Sheikh, Mashhood A.; Abelsen, Birgit; Olsen, Jan A.

2016-01-01

Previous studies have shown that socio-demographic factors, childhood socioeconomic status (CSES), childhood traumatic experiences (CTEs), social support and behavioral factors are associated with health and well-being in adulthood. However, the relative importance of these factors for mental health, health, and well-being has not been studied. Moreover, the mechanisms by which CTEs affect mental health, health, and well-being in adulthood are not clear. Using data from a representative sample (n = 12,981) of the adult population in Tromsø, Norway, this study examines (i) the relative contribution of structural conditions (gender, age, CSES, psychological abuse, physical abuse, and substance abuse distress) to social support and behavioral factors in adulthood; (ii) the relative contribution of socio-demographic factors, CSES, CTEs, social support, and behavioral factors to three multi-item instruments of mental health (SCL-10), health (EQ-5D), and subjective well-being (SWLS) in adulthood; (iii) the impact of CTEs on mental health, health, and well-being in adulthood, and; (iv) the mediating role of adult social support and behavioral factors in these associations. Instrumental support (24.16%, p < 0.001) explained most of the variation in mental health, while gender (21.32%, p < 0.001) explained most of the variation in health, and emotional support (23.34%, p < 0.001) explained most of the variation in well-being. Psychological abuse was relatively more important for mental health (12.13%), health (7.01%), and well-being (9.09%), as compared to physical abuse, and substance abuse distress. The subjective assessment of childhood financial conditions was relatively more important for mental health (6.02%), health (10.60%), and well-being (20.60%), as compared to mother's and father's education. CTEs were relatively more important for mental health, while, CSES was relatively more important for health and well-being. Respondents exposed to all three types of CTEs had a more than two-fold increased risk of being mentally unhealthy (RRTotal Effect = 2.75, 95% CI: 2.19–3.10), an 89% increased risk of being unhealthy (RRTotal Effect = 1.89, 95% CI: 1.47–1.99), and a 42% increased risk of having a low level of well-being in adulthood (RRTotal Effect = 1.42, 95% CI: 1.29–1.52). Social support and behavioral factors mediate 11–18% (p < 0.01) of these effects. The study advances the theoretical understanding of how CTEs influence adult mental health, health, and well-being. PMID:27252668

The Enduring Significance of Racism: Discrimination and Delinquency Among Black American Youth

PubMed Central

Martin, Monica J.; McCarthy, Bill; Conger, Rand D.; Gibbons, Frederick X.; Simons, Ronald L.; Cutrona, Carolyn E.; Brody, Gene H.

2011-01-01

Prominent explanations of the overrepresentation of Black Americans in criminal justice statistics focus on the effects of neighborhood concentrated disadvantage, racial isolation, and social disorganization. We suggest that perceived personal discrimination is an important but frequently neglected complement to these factors. We test this hypothesis with longitudinal data on involvement in general and violent juvenile delinquency in a sample of Black youth from a variety of communities in 2 states. We examine the direct effects of concentrated disadvantage and racial isolation and the direct and mediating effects of social organization, support for violence, and personal discrimination. Consistent with our hypothesis, perceived personal discrimination has notable direct effects on both general and violent delinquency and is an important mediator between neighborhood structural conditions and offending; moreover, its effects exceed those associated with neighborhood conditions. PMID:21941426

Racial and Ethnic Differences in Breast Cancer Survival: Mediating Effect of Tumor Characteristics and Sociodemographic and Treatment Factors

PubMed Central

Warner, Erica T.; Tamimi, Rulla M.; Hughes, Melissa E.; Ottesen, Rebecca A.; Wong, Yu-Ning; Edge, Stephen B.; Theriault, Richard L.; Blayney, Douglas W.; Niland, Joyce C.; Winer, Eric P.; Weeks, Jane C.; Partridge, Ann H.

2015-01-01

Purpose To evaluate the relationship between race/ethnicity and breast cancer–specific survival according to subtype and explore mediating factors. Patients and Methods Participants were women presenting with stage I to III breast cancer between January 2000 and December 2007 at National Comprehensive Cancer Network centers with survival follow-up through December 2009. Cox proportional hazards regression was used to compare breast cancer–specific survival among Asians (n = 533), Hispanics (n = 1,122), and blacks (n = 1,345) with that among whites (n = 14,268), overall and stratified by subtype (luminal A like, luminal B like, human epidermal growth factor receptor 2 type, and triple negative). Model estimates were used to derive mediation proportion and 95% CI for selected risk factors. Results In multivariable adjusted models, overall, blacks had 21% higher risk of breast cancer–specific death (hazard ratio [HR], 1.21; 95% CI, 1.00 to 1.45). For estrogen receptor–positive tumors, black and white survival differences were greatest within 2 years of diagnosis (years 0 to 2: HR, 2.65; 95% CI, 1.34 to 5.24; year 2 to end of follow-up: HR, 1.50; 95% CI, 1.12 to 2.00). Blacks were 76% and 56% more likely to die as a result of luminal A–like and luminal B–like tumors, respectively. No disparities were observed for triple-negative or human epidermal growth factor receptor 2–type tumors. Asians and Hispanics were less likely to die as a result of breast cancer compared with whites (Asians: HR, 0.56; 95% CI, 0.37 to 0.85; Hispanics: HR, 0.74; 95% CI, 0.58 to 0.95). For blacks, tumor characteristics and stage at diagnosis were significant disparity mediators. Body mass index was an important mediator for blacks and Asians. Conclusion Racial disparities in breast cancer survival vary by tumor subtype. Interventions are needed to reduce disparities, particularly in the first 2 years after diagnosis among black women with estrogen receptor–positive tumors. PMID:25964252

Emotion dysregulation as a mediator between childhood emotional abuse and current depression in a low-income African-American sample.

PubMed

Crow, Thomas; Cross, Dorthie; Powers, Abigail; Bradley, Bekh

2014-10-01

Abuse and neglect in childhood are well-established risk factors for later psychopathology. Past research has suggested that childhood emotional abuse may be particularly harmful to psychological development. The current cross-sectional study employed multiple regression techniques to assess the effects of childhood trauma on adulthood depression and emotion dysregulation in a large sample of mostly low-income African Americans recruited in an urban hospital. Bootstrap analyses were used to test emotion dysregulation as a potential mediator between emotional abuse in childhood and current depression. Childhood emotional abuse significantly predicted depressive symptoms even when accounting for all other childhood trauma types, and we found support for a complementary mediation of this relationship by emotion dysregulation. Our findings highlight the importance of emotion dysregulation and childhood emotional abuse in relation to adult depression. Moving forward, clinicians should consider the particular importance of emotional abuse in the development of depression, and future research should seek to identify mechanisms through which emotional abuse increases risk for depression and emotion dysregulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Emotion dysregulation as a mediator between childhood emotional abuse and current depression in a low-income African-American sample☆

PubMed Central

Crow, Thomas; Cross, Dorthie; Powers, Abigail; Bradley, Bekh

2014-01-01

Abuse and neglect in childhood are well-established risk factors for later psychopathology. Past research has suggested that childhood emotional abuse may be particularly harmful to psychological development. The current cross-sectional study employed multiple regression techniques to assess the effects of childhood trauma on adulthood depression and emotion dysregulation in a large sample of mostly low-income African Americans recruited in an urban hospital. Bootstrap analyses were used to test emotion dysregulation as a potential mediator between emotional abuse in childhood and current depression. Childhood emotional abuse significantly predicted depressive symptoms even when accounting for all other childhood trauma types, and we found support for a complementary mediation of this relationship by emotion dysregulation. Our findings highlight the importance of emotion dysregulation and childhood emotional abuse in relation to adult depression. Moving forward, clinicians should consider the particular importance of emotional abuse in the development of depression, and future research should seek to identify mechanisms through which emotional abuse increases risk for depression and emotion dysregulation. PMID:25035171

Social-cognitive antecedents of hand washing: Action control bridges the planning-behaviour gap.

PubMed

Reyes Fernández, Benjamín; Knoll, Nina; Hamilton, Kyra; Schwarzer, Ralf

2016-08-01

To examine motivational and volitional factors for hand washing in young adults, using the Health Action Process Approach (HAPA) as a theoretical framework. In a longitudinal design with two measurement points, six weeks apart, university students (N = 440) completed paper-based questionnaires. Prior hand washing frequency, self-efficacy, outcome expectancies, intention and action planning were measured at baseline, and coping planning, action control and hand washing frequency were measured at follow-up. A theory-based structural equation model was specified. In line with the HAPA, the motivational factors of self-efficacy and outcome expectancies predicted intention, whereas the volitional factors of planning and action control mediated between intention and changes in hand washing frequency. Action control was confirmed as the most proximal factor on hand washing behaviour, thus representing a bridge of the planning-behaviour gap. Both motivational and volitional processes are important to consider in the improvement of hand hygiene practices. Moreover, the statistically significant effects for planning and action control illustrate the importance of these key self-regulatory factors in the prediction of hand hygiene. The current study highlights the importance of adopting models that account for motivational and volitional factors to better understand hand washing behaviour.

A Genetic Screen Identifies a Requirement for Cysteine-Rich-Receptor-Like Kinases in Rice NH1 (OsNPR1)-Mediated Immunity.

PubMed

Chern, Mawsheng; Xu, Qiufang; Bart, Rebecca S; Bai, Wei; Ruan, Deling; Sze-To, Wing Hoi; Canlas, Patrick E; Jain, Rashmi; Chen, Xuewei; Ronald, Pamela C

2016-05-01

Systemic acquired resistance, mediated by the Arabidopsis NPR1 gene and the rice NH1 gene, confers broad-spectrum immunity to diverse pathogens. NPR1 and NH1 interact with TGA transcription factors to activate downstream defense genes. Despite the importance of this defense response, the signaling components downstream of NPR1/NH1 and TGA proteins are poorly defined. Here we report the identification of a rice mutant, snim1, which suppresses NH1-mediated immunity and demonstrate that two genes encoding previously uncharacterized cysteine-rich-receptor-like kinases (CRK6 and CRK10), complement the snim1 mutant phenotype. Silencing of CRK6 and CRK10 genes individually in the parental genetic background recreates the snim1 phenotype. We identified a rice mutant in the Kitaake genetic background with a frameshift mutation in crk10; this mutant also displays a compromised immune response highlighting the important role of crk10. We also show that elevated levels of NH1 expression lead to enhanced CRK10 expression and that the rice TGA2.1 protein binds to the CRK10 promoter. These experiments demonstrate a requirement for CRKs in NH1-mediated immunity and establish a molecular link between NH1 and induction of CRK10 expression.

Abnormal Neurocirculatory Control During Exercise in Humans with Chronic Renal Failure

PubMed Central

Park, Jeanie; Middlekauff, Holly R.

2014-01-01

Abnormal neurocirculatory control during exercise is one important mechanism leading to exercise intolerance in patients with both end-stage renal disease (ESRD) and earlier stages of chronic kidney disease (CKD). This review will provide an overview of mechanisms underlying abnormal neurocirculatory and hemodynamic responses to exercise in patients with kidney disease. Recent studies have shown that ESRD and CKD patients have an exaggerated increase in blood pressure (BP) during both isometric and rhythmic exercise. Subsequent studies examining the role of the exercise pressor reflex in the augmented pressor response revealed that muscle sympathetic nerve activity (MSNA) was not augmented during exercise in these patients, and metaboreflex-mediated increases in MSNA were blunted, while mechanoreflex-mediated increases were preserved under basal conditions. However, normalizing the augmented BP response during exercise via infusion of nitroprusside (NTP), and thereby equalizing baroreflex-mediated suppression of MSNA, an important modulator of the final hemodynamic response to exercise, revealed that CKD patients had an exaggerated increase in MSNA during isometric and rhythmic exercise. In addition, mechanoreflex-mediated control was augmented, and metaboreceptor blunting was no longer apparent in CKD patients with baroreflex normalization. Factors leading to mechanoreceptor sensitization, and other mechanisms underlying the exaggerated exercise pressor response, such as impaired functional sympatholysis, should be investigated in future studies. PMID:25458430

Cannabidiol-2',6'-dimethyl ether as an effective protector of 15-lipoxygenase-mediated low-density lipoprotein oxidation in vitro.

PubMed

Takeda, Shuso; Hirayama, Akari; Urata, Shino; Mano, Nobutaka; Fukagawa, Keiko; Imamura, Midori; Irii, Ayumi; Kitajima, Satomi; Masuyama, Tomoko; Nomiyama, Mai; Tatei, Sachiko; Tomita, Saari; Kudo, Taichi; Noguchi, Momoko; Yamaguchi, Yasuhiro; Okamoto, Yoshiko; Amamoto, Toshiaki; Fukunishi, Yoshifumi; Watanabe, Kazuhito; Omiecinski, Curtis John; Aramaki, Hironori

2011-01-01

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis. Both enzymatic (15-LOX) and non-enzymatic (Cu(2+)) mechanisms have been proposed for the production of ox-LDL. We have recently reported that cannabidiol-2',6'-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation (Takeda et al., Drug Metab. Dispos., 37, 1733-1737 (2009)). In the LDL, linoleic acid is present as cholesteryl linoleate, the major fatty acid esterified to cholesterol, and is susceptible to oxidative modification by 15-LOX or Cu(2+). In this investigation, we examined the efficacy of CBDD on i) 15-LOX-catalyzed oxygenation of cholesteryl linoleate, and ii) ox-LDL formation catalyzed by 15-LOX versus Cu(2+)-mediated non-enzymatic generation of this important mediator. The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway. These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.

Cannabidiol-2′,6′-dimethyl Ether as an Effective Protector of 15-Lipoxygenase-Mediated Low-Density Lipoprotein Oxidation in Vitro

PubMed Central

Takeda, Shuso; Hirayama, Akari; Urata, Shino; Mano, Nobutaka; Fukagawa, Keiko; Imamura, Midori; Irii, Ayumi; Kitajima, Satomi; Masuyama, Tomoko; Nomiyama, Mai; Tatei, Sachiko; Tomita, Saari; Kudo, Taichi; Noguchi, Momoko; Yamaguchi, Yasuhiro; Okamoto, Yoshiko; Amamoto, Toshiaki; Fukunishi, Yoshifumi; Watanabe, Kazuhito; Omiecinski, Curtis John; Aramaki, Hironori

2014-01-01

15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis. Both enzymatic (15-LOX) and non-enzymatic (Cu2+) mechanisms have been proposed for the production of ox-LDL. We have recently reported that cannabidiol-2′,6′-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation (Takeda et al., Drug Metab. Dispos., 37, 1733–1737 (2009)). In the LDL, linoleic acid is present as cholesteryl linoleate, the major fatty acid esterified to cholesterol, and is susceptible to oxidative modification by 15-LOX or Cu2+. In this investigation, we examined the efficacy of CBDD on i) 15-LOX-catalyzed oxygenation of cholesteryl linoleate, and ii) ox-LDL formation catalyzed by 15-LOX versus Cu2+-mediated non-enzymatic generation of this important mediator. The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway. These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis. PMID:21804214

Complement-mediated bactericidal activity of anti-factor H binding protein monoclonal antibodies against the meningococcus relies upon blocking factor H binding.

PubMed

Giuntini, Serena; Reason, Donald C; Granoff, Dan M

2011-09-01

Binding of the complement-downregulating protein factor H (fH) to the surface of the meningococcus is important for survival of the organism in human serum. The meningococcal vaccine candidate factor H binding protein (fHbp) is an important ligand for human fH. While some fHbp-specific monoclonal antibodies (MAbs) block binding of fH to fHbp, the stoichiometry of blocking in the presence of high serum concentrations of fH and its effect on complement-mediated bactericidal activity are unknown. To investigate this question, we constructed chimeric antibodies in which the human IgG1 constant region was paired with three murine fHbp-specific binding domains designated JAR 3, JAR 5, and MAb502. By surface plasmon resonance, the association rates for binding of all three MAbs to immobilized fHbp were >50-fold higher than that for binding of fH to fHbp, and the MAb dissociation rates were >500-fold lower than that for fH. While all three MAbs elicited similar C1q-dependent C4b deposition on live bacteria (classical complement pathway), only those antibodies that inhibited binding of fH to fHbp (JAR 3 and JAR 5) had bactericidal activity with human complement. MAb502, which did not inhibit fH binding, had complement-mediated bactericidal activity only when tested with fH-depleted human complement. When an IgG1 anti-fHbp MAb binds to sparsely exposed fHbp on the bacterial surface, there appears to be insufficient complement activation for bacteriolysis unless fH binding also is inhibited. The ability of fHbp vaccines to elicit protective antibodies, therefore, is likely to be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rahman, Shaikh M., E-mail: rmizanoor@hotmail.com; Choudhury, Mahua; Janssen, Rachel C.

Highlights: Black-Right-Pointing-Pointer LXR agonist activation increases liver TG accumulation by increasing lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta}{sup -/-} mouse prevents LXR activation-mediated induction of hepatic lipogenesis. Black-Right-Pointing-Pointer C/EBP{beta} deletion increases mitochondrial transport chain function. Black-Right-Pointing-Pointer Beneficial effects of LXR activation on liver cholesterol metabolism did not change. Black-Right-Pointing-Pointer C/EBP{beta} inhibition might have important therapeutic potential. -- Abstract: Drugs designed specifically to activate liver X receptors (LXRs) have beneficial effects on lowering cholesterol metabolism and inflammation but unfortunately lead to severe hepatic steatosis. The transcription factor CCAAT/enhancer binding protein beta (C/EBP{beta}) is an important regulator of liver gene expression but little is known aboutmore » its involvement in LXR-based steatosis and cholesterol metabolism. The present study investigated the role of C/EBP{beta} expression in LXR agonist (T0901317)-mediated alteration of hepatic triglyceride (TG) and lipogenesis in mice. C/EBP{beta} deletion in mice prevented LXR agonist-mediated induction of lipogenic gene expression in liver in conjunction with significant reduction of liver TG accumulation. Surprisingly, C/EBP{beta}{sup -/-} mice showed a major increase in liver mitochondrial electron chain function compared to WT mice. Furthermore, LXR activation in C/EBP{beta}{sup -/-} mice increased the expression of liver ATP-binding cassette transporter ABCG1, a gene implicated in cholesterol efflux and reducing blood levels of total and LDL-cholesterol. Together, these findings establish a central role for C/EBP{beta} in the LXR-mediated steatosis and mitochondrial function, without impairing the influence of LXR activation on lowering LDL and increasing HDL-cholesterol. Inactivation of C/EBP{beta} might therefore be an important therapeutic strategy to prevent LXR activation-mediated adverse effects on liver TG metabolism without disrupting its beneficial effects on cholesterol metabolism.« less

Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue

PubMed Central

Kopp, Hans-Georg; Ramos, Carlos A.; Rafii, Shahin

2010-01-01

Purpose of review During the last several years, a substantial amount of evidence from animal as well as human studies has advanced our knowledge of how bone marrow derived cells contribute to neoangiogenesis. In the light of recent findings, we may have to redefine our thinking of endothelial cells as well as of perivascular mural cells. Recent findings Inflammatory hematopoietic cells, such as macrophages, have been shown to promote neoangiogenesis during tumor growth and wound healing. Dendritic cells, B lymphocytes, monocytes, and other immune cells have also been found to be recruited to neoangiogenic niches and to support neovessel formation. These findings have led to the concept that subsets of hematopoietic cells comprise proangiogenic cells that drive adult revascularization processes. While evidence of the importance of endothelial progenitor cells in adult vasculogenesis increased further, the role of these comobilized hematopoietic cells has been intensely studied in the last few years. Summary Angiogenic factors promote mobilization of vascular endothelial growth factor receptor 1-positive hematopoietic cells through matrix metalloproteinase-9 mediated release of soluble kit-ligand and recruit these proangiogenic cells to areas of hypoxia, where perivascular mural cells present stromal-derived factor 1 (CXCL-12) as an important retention signal. The same factors are possibly involved in mobilization of vascular endothelial growth factor receptor 2-positive endothelial precursors that may participate in neovessel formation. The complete characterization of mechanisms, mediators and signaling pathways involved in these processes will provide novel targets for both anti and proangiogenic therapeutic strategies. PMID:16567962

Proteomic analysis reveals novel extracellular virulence-associated proteins and functions regulated by the diffusible signal factor (DSF) in Xanthomonas oryzae pv. oryzicola.

PubMed

Qian, Guoliang; Zhou, Yijing; Zhao, Yancun; Song, Zhiwei; Wang, Suyan; Fan, Jiaqin; Hu, Baishi; Venturi, Vittorio; Liu, Fengquan

2013-07-05

Quorum sensing (QS) in Xanthomonas oryzae pv. oryzicola (Xoc), the causal agent of bacterial leaf streak, is mediated by the diffusible signal factor (DSF). DSF-mediating QS has been shown to control virulence and a set of virulence-related functions; however, the expression profiles and functions of extracellular proteins controlled by DSF signal remain largely unclear. In the present study, 33 DSF-regulated extracellular proteins, whose functions include small-protein mediating QS, oxidative adaptation, macromolecule metabolism, cell structure, biosynthesis of small molecules, intermediary metabolism, cellular process, protein catabolism, and hypothetical function, were identified by proteomics in Xoc. Of these, 15 protein encoding genes were in-frame deleted, and 4 of them, including three genes encoding type II secretion system (T2SS)-dependent proteins and one gene encoding an Ax21 (activator of XA21-mediated immunity)-like protein (a novel small-protein type QS signal) were determined to be required for full virulence in Xoc. The contributions of these four genes to important virulence-associated functions, including bacterial colonization, extracellular polysaccharide, cell motility, biofilm formation, and antioxidative ability, are presented. To our knowledge, our analysis is the first complete list of DSF-regulated extracellular proteins and functions in a Xanthomonas species. Our results show that DSF-type QS played critical roles in regulation of T2SS and Ax21-mediating QS, which sheds light on the role of DSF signaling in Xanthomonas.

Fumaric acid attenuates the eotaxin-1 expression in TNF-α-stimulated fibroblasts by suppressing p38 MAPK-dependent NF-κB signaling.

PubMed

Roh, Kyung-Baeg; Jung, Eunsun; Park, Deokhoon; Lee, Jongsung

2013-08-01

Eotaxin-1 is a potent chemoattractant for eosinophils and a critical mediator during the development of eosinophilic inflammation. Fumaric acid is an intermediate product of the citric acid cycle, which is source of intracellular energy. Although fumaric acid ameliorates psoriasis and multiple sclerosis, its involvement in eotaxin-1-mediated effects has not been assessed. In this study, we investigated the effects of fumaric acid on eotaxin-1 expression in a mouse fibroblast cell line. We found that fumaric acid significantly inhibited tumor necrosis factor-α (TNF-α-induced eotaxin-1 expression. This fumaric acid effect was mediated through the inhibition of p38 mitogen-activated protein kinase (MAPK)-dependent nuclear factor (NF)-κB signaling. We also found that fumaric acid operates downstream of MEKK3 during TNF-α-induced NF-κB signaling, which upregulated eotaxin-1 expression. In addition, fumaric acid attenuated expression of CC-chemokine receptor 3 (CCR3), an eotaxin-1 receptor, and adhesion molecules that play important roles in eosinophil binding to induce allergic inflammation. Taken together, these findings indicate that inhibiting TNF-α-induced eotaxin-1 expression by fumaric acid occurs primarily through suppression of NF-κB signaling, which is mediated by inhibiting p38 MAPK and suggest that fumaric acid may be used as a complementary treatment option for eotaxin-1-mediated diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

Molecular imaging of drug-modulated protein-protein interactions in living subjects.

PubMed

Paulmurugan, Ramasamy; Massoud, Tarik F; Huang, Jing; Gambhir, Sanjiv S

2004-03-15

Networks of protein interactions mediate cellular responses to environmental stimuli and direct the execution of many different cellular functional pathways. Small molecules synthesized within cells or recruited from the external environment mediate many protein interactions. The study of small molecule-mediated interactions of proteins is important to understand abnormal signal transduction pathways in cancer and in drug development and validation. In this study, we used split synthetic renilla luciferase (hRLUC) protein fragment-assisted complementation to evaluate heterodimerization of the human proteins FRB and FKBP12 mediated by the small molecule rapamycin. The concentration of rapamycin required for efficient dimerization and that of its competitive binder ascomycin required for dimerization inhibition were studied in cell lines. The system was dually modulated in cell culture at the transcription level, by controlling nuclear factor kappaB promoter/enhancer elements using tumor necrosis factor alpha, and at the interaction level, by controlling the concentration of the dimerizer rapamycin. The rapamycin-mediated dimerization of FRB and FKBP12 also was studied in living mice by locating, quantifying, and timing the hRLUC complementation-based bioluminescence imaging signal using a cooled charged coupled device camera. This split reporter system can be used to efficiently screen small molecule drugs that modulate protein-protein interactions and also to assess drugs in living animals. Both are essential steps in the preclinical evaluation of candidate pharmaceutical agents targeting protein-protein interactions, including signaling pathways in cancer cells.

Central mediators involved in the febrile response: effects of antipyretic drugs

PubMed Central

Zampronio, Aleksander R; Soares, Denis M; Souza, Glória E P

2015-01-01

Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1β, tumor necrosis factor-α, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions. PMID:27227071

Deciphering the combinatorial architecture of a Drosophila homeotic gene enhancer

PubMed Central

Drewell, Robert A.; Nevarez, Michael J.; Kurata, Jessica S.; Winkler, Lauren N.; Li, Lily; Dresch, Jacqueline M.

2013-01-01

Summary In Drosophila, the 330 kb bithorax complex regulates cellular differentiation along the anterio-posterior axis during development in the thorax and abdomen and is comprised of three homeotic genes: Ultrabithorax, abdominal-A, and Abdominal-B. The expression of each of these genes is in turn controlled through interactions between transcription factors and a number of cis-regulatory modules in the neighboring intergenic regions. In this study, we examine how the sequence architecture of transcription factor binding sites mediates the functional activity of one of these cis-regulatory modules. Using computational, mathematical modeling and experimental molecular genetic approaches we investigate the IAB7b enhancer, which regulates Abdominal-B expression specifically in the presumptive seventh and ninth abdominal segments of the early embryo. A cross-species comparison of the IAB7b enhancer reveals an evolutionarily conserved signature motif containing two FUSHI-TARAZU activator transcription factor binding sites. We find that the transcriptional repressors KNIRPS, KRUPPEL and GIANT are able to restrict reporter gene expression to the posterior abdominal segments, using different molecular mechanisms including short-range repression and competitive binding. Additionally, we show the functional importance of the spacing between the two FUSHI-TARAZU binding sites and discuss the potential importance of cooperativity for transcriptional activation. Our results demonstrate that the transcriptional output of the IAB7b cis-regulatory module relies on a complex set of combinatorial inputs mediated by specific transcription factor binding and that the sequence architecture at this enhancer is critical to maintain robust regulatory function. PMID:24514265

Release of Severe Acute Respiratory Syndrome Coronavirus Nuclear Import Block Enhances Host Transcription in Human Lung Cells

PubMed Central

Tilton, Susan C.; Menachery, Vineet D.; Gralinski, Lisa E.; Schäfer, Alexandra; Matzke, Melissa M.; Webb-Robertson, Bobbie-Jo M.; Chang, Jean; Luna, Maria L.; Long, Casey E.; Shukla, Anil K.; Bankhead, Armand R.; Burkett, Susan E.; Zornetzer, Gregory; Tseng, Chien-Te Kent; Metz, Thomas O.; Pickles, Raymond; McWeeney, Shannon; Smith, Richard D.; Katze, Michael G.; Waters, Katrina M.; Baric, Ralph S.

2013-01-01

The severe acute respiratory syndrome coronavirus accessory protein ORF6 antagonizes interferon signaling by blocking karyopherin-mediated nuclear import processes. Viral nuclear import antagonists, expressed by several highly pathogenic RNA viruses, likely mediate pleiotropic effects on host gene expression, presumably interfering with transcription factors, cytokines, hormones, and/or signaling cascades that occur in response to infection. By bioinformatic and systems biology approaches, we evaluated the impact of nuclear import antagonism on host expression networks by using human lung epithelial cells infected with either wild-type virus or a mutant that does not express ORF6 protein. Microarray analysis revealed significant changes in differential gene expression, with approximately twice as many upregulated genes in the mutant virus samples by 48 h postinfection, despite identical viral titers. Our data demonstrated that ORF6 protein expression attenuates the activity of numerous karyopherin-dependent host transcription factors (VDR, CREB1, SMAD4, p53, EpasI, and Oct3/4) that are critical for establishing antiviral responses and regulating key host responses during virus infection. Results were confirmed by proteomic and chromatin immunoprecipitation assay analyses and in parallel microarray studies using infected primary human airway epithelial cell cultures. The data strongly support the hypothesis that viral antagonists of nuclear import actively manipulate host responses in specific hierarchical patterns, contributing to the viral pathogenic potential in vivo. Importantly, these studies and modeling approaches not only provide templates for evaluating virus antagonism of nuclear import processes but also can reveal candidate cellular genes and pathways that may significantly influence disease outcomes following severe acute respiratory syndrome coronavirus infection in vivo. PMID:23365422

Sumoylation of Smad3 stimulates its nuclear export during PIASy-mediated suppression of TGF-{beta} signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imoto, Seiyu; Ohbayashi, Norihiko; Ikeda, Osamu

2008-05-30

Sma- and MAD-related protein 3 (Smad3) plays crucial roles in the transforming growth factor-{beta} (TGF-{beta})-mediated signaling pathway, which produce a variety of cellular responses, including cell proliferation and differentiation. In our previous study, we demonstrated that protein inhibitor of activated STATy (PIASy) suppresses TGF-{beta} signaling by interacting with and sumoylating Smad3. In the present study, we examined the molecular mechanisms of Smad3 sumoylation during PIASy-mediated suppression of TGF-{beta} signaling. We found that small-interfering RNA-mediated reduction of endogenous PIASy expression enhanced TGF-{beta}-induced gene expression. Importantly, coexpression of Smad3 with PIASy and SUMO1 affected the DNA-binding activity of Smad3. Furthermore, coexpression ofmore » Smad3 with PIASy and SUMO1 stimulated the nuclear export of Smad3. Finally, fluorescence resonance energy transfer analyses revealed that Smad3 interacted with SUMO1 in the cytoplasm. These results suggest that PIASy regulates TGF-{beta}/Smad3-mediated signaling by stimulating sumoylation and nuclear export of Smad3.« less

The mediating role of emotional symptomatology between anticipatory fatigue and the perception of fatigue.

PubMed

Rodríguez Testal, Juan F; Fuentes Márquez, Sandra; Senín Calderón, Cristina; Carrasco, Miguel A

2016-05-01

Clinical research stresses the importance of cognitive variables for predisposition, onset, and especially, perpetuation of perceived fatigue. The aim was to analyze the mediating effects of emotional symptomatology (somatic, depressive and anxiety) between anticipatory fatigue and perception of physical and cognitive fatigue. The sample was composed of 317 participants (29% from a clinical population) aged 18 to 76. Anticipatory fatigue and perception of fatigue were measured by fatigue scales. Emotional symptoms were assessed by the General Health Questionnaire, GHQ-28.  Results : Depressive symptomatology mediated the relationship between anticipatory fatigue and cognitive fatigue in both groups, and also somatic symptoms/somatization in patients. The indirect effect of physical fatigue was observed only in the clinical group, with depressive symptoms partially mediating the anticipatory fatigue and cognitive fatigue relationship. Anticipatory fatigue has a partial indirect effect on total physical fatigue, and full indirect effect on cognitive fatigue, mediated by depressive and somatic symptoms. Anticipatory fatigue is a relevant cognitive factor in the design of psychological intervention for improvement of cognitive and physical fatigue.

Staufen-mediated mRNA decay

PubMed Central

Park, Eonyoung; Maquat, Lynne E.

2013-01-01

Staufen1 (STAU1)-mediated mRNA decay (SMD) is an mRNA degradation process in mammalian cells that is mediated by the binding of STAU1 to a STAU1-binding site (SBS) within the 3'-untranslated region (3'UTR) of target mRNAs. During SMD, STAU1, a double-stranded (ds) RNA-binding protein, recognizes dsRNA structures formed either by intramolecular base-pairing of 3'UTR sequences or by intermolecular base-pairing of 3'UTR sequences with a long noncoding RNA (lncRNA) via partially complementary Alu elements. Recently, STAU2, a paralog of STAU1, has also been reported to mediate SMD. Both STAU1 and STAU2 interact directly with the ATP-dependent RNA helicase UPF1, a key SMD factor, enhancing its helicase activity to promote effective SMD. Moreover, STAU1 and STAU2 form homodimeric and heterodimeric interactions via domain-swapping. Since both SMD and the mechanistically related nonsense-mediated mRNA decay (NMD) employ UPF1, SMD and NMD are competitive pathways. Competition contributes to cellular differentiation processes, such as myogenesis and adipogenesis, placing SMD at the heart of various physiologically important mechanisms. PMID:23681777

Dimensions of Emotional Intelligence and Online Gaming Addiction in Adolescence: The Indirect Effects of Two Facets of Perceived Stress.

PubMed

Che, Dexin; Hu, Jianping; Zhen, Shuangju; Yu, Chengfu; Li, Bin; Chang, Xi; Zhang, Wei

2017-01-01

This study tested a parallel two-mediator model in which the relationship between dimensions of emotional intelligence and online gaming addiction are mediated by perceived helplessness and perceived self-efficacy, respectively. The sample included 931 male adolescents (mean age = 16.18 years, SD = 0.95) from southern China. Data on emotional intelligence (four dimensions, including self-management of emotion, social skills, empathy and utilization of emotions), perceived stress (two facets, including perceived self-efficacy and perceived helplessness) and online gaming addiction were collected, and bootstrap methods were used to test this parallel two-mediator model. Our findings revealed that perceived self-efficacy mediated the relationship between three dimensions of emotional intelligence (i.e., self-management, social skills, and empathy) and online gaming addiction, and perceived helplessness mediated the relationship between two dimensions of emotional intelligence (i.e., self-management and emotion utilization) and online gaming addiction. These findings underscore the importance of separating the four dimensions of emotional intelligence and two facets of perceived stress to understand the complex relationship between these factors and online gaming addiction.

Dimensions of Emotional Intelligence and Online Gaming Addiction in Adolescence: The Indirect Effects of Two Facets of Perceived Stress

PubMed Central

Che, Dexin; Hu, Jianping; Zhen, Shuangju; Yu, Chengfu; Li, Bin; Chang, Xi; Zhang, Wei

2017-01-01

This study tested a parallel two-mediator model in which the relationship between dimensions of emotional intelligence and online gaming addiction are mediated by perceived helplessness and perceived self-efficacy, respectively. The sample included 931 male adolescents (mean age = 16.18 years, SD = 0.95) from southern China. Data on emotional intelligence (four dimensions, including self-management of emotion, social skills, empathy and utilization of emotions), perceived stress (two facets, including perceived self-efficacy and perceived helplessness) and online gaming addiction were collected, and bootstrap methods were used to test this parallel two-mediator model. Our findings revealed that perceived self-efficacy mediated the relationship between three dimensions of emotional intelligence (i.e., self-management, social skills, and empathy) and online gaming addiction, and perceived helplessness mediated the relationship between two dimensions of emotional intelligence (i.e., self-management and emotion utilization) and online gaming addiction. These findings underscore the importance of separating the four dimensions of emotional intelligence and two facets of perceived stress to understand the complex relationship between these factors and online gaming addiction. PMID:28751876

Social Cognitive Antecedents of Fruit and Vegetable Consumption in Truck Drivers: A Sequential Mediation Analysis.

PubMed

Hamilton, Kyra; Vayro, Caitlin; Schwarzer, Ralf

2015-01-01

To examine a mechanism by which social cognitive factors may predict fruit and vegetable consumption in long-haul truck drivers. Dietary self-efficacy, positive outcome expectancies, and intentions were assessed in 148 Australian truck drivers, and 1 week later they reported their fruit and vegetable consumption. A theory-guided sequential mediation model was specified that postulated self-efficacy and intention as mediators between outcome expectancies and behavior. The hypothesized model was confirmed. A direct effect of outcome expectancies was no longer present when mediators were included, and all indirect effects were significant, including the 2-mediator chain (β = .15; P < .05; 95% confidence interval, 0.05-0.32). Truck drivers who expected benefits from dietary change, felt confident about being capable to do so, and formed an intention were likely to report larger amounts of fruit and vegetable intake. The results suggest that the role of outcome expectancies and self-efficacy are important to consider for understanding and predicting healthy eating intentions in truck drivers. Copyright © 2015 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.

Mediation of wound-related Rous sarcoma virus tumorigenesis by TFG (transforming growth factor)-. beta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sieweke, M.H.; Bissell, M.J.; Thompson, N.L.

1990-06-29

In Rous sarcoma virus (RSV)-infected chickens, wounding leads to tumor formation with nearly 100% frequency in tissues that would otherwise remain tumor-free. Identifying molecular mediators of this phenomenon should yield important clues to the mechanisms involved in RSV tumorigenesis. Immunohistochemical staining showed that TGF-{beta} is present locally shortly after wounding, but not in unwounded controls. In addition, subcutaneous administration of recombinant transforming growth factor {beta}1 (TGF-{beta}1) could substitute completely for wounding in tumor induction. A treatment protocol of four doses of 800 nanograms of TGF-{beta} resulted in v-src-expressing tumors with 100% frequency; four doses of only 10 nanograms still ledmore » to tumor formation in 80% of the animals. This effect was specific, as other growth factors with suggested roles in would healing did not elicit the same response. Epidermal growth factor (EGF) or TGF-{alpha} had no effect, and platelet-derived growth factor (PDGF) or insulin-like growth factor-1 (IGF-1) yielded only occasional tumors after longer latency. TGF-{beta} release during the would-healing response may thus be a critical event that creates a conducive environment for RSV tumorigenesis and may act as a cofactor for transformation in this system. 31 refs., 3 figs., 2 tabs.« less

Inflammatory Bowel Disease: Pathophysiology and Current Therapeutic Approaches.

PubMed

Abraham, Bincy P; Ahmed, Tasneem; Ali, Tauseef

2017-01-01

Inflammatory bowel diseases, most commonly categorized as Crohn's disease and ulcerative colitis, are immune mediated chronic inflammatory disorders of the gastrointestinal tract. The etiopathogenesis is multifactorial with different environmental, genetic, immune mediated, and gut microbial factors playing important role. The current goals of therapy are to improve clinical symptoms, control inflammation, prevent complications, and improve quality of life. Different therapeutic agents, with their indications, mechanisms of action, and side effects are discussed in this chapter. Anti-integrin therapy, a newer therapeutic class, with its potential beneficial role in both Crohn's disease and ulcerative colitis is also mentioned. In the end, therapeutic algorithms for both diseases are reviewed.

Searching for Components of Conceptual Ecology That Mediate Development of Epistemological Beliefs in Science

NASA Astrophysics Data System (ADS)

Deniz, Hasan

2011-12-01

This paper articulates the importance of epistemological beliefs (EBs) and draws a parallel between EBs literature in educational psychology and nature of science (NOS) literature in science education. The paper stresses that EBs in science and NOS ideas have common ground and they can be best improved through explicit-reflective instruction informed by conceptual change theory. The paper concludes that future studies should explore the factors that mediate the development of EBs in science and NOS ideas rather than documenting the changes in students' and teachers' EBs in science and NOS ideas after explicit-reflective instruction through pre- and post assessments.

Epigenetics and Therapeutic Targets Mediating Neuroprotection

PubMed Central

Qureshi, Irfan A.; Mehler, Mark F.

2015-01-01

The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. PMID:26236020

Parental influences on adolescent fruit consumption: the role of adolescent self-efficacy.

PubMed

Pearson, Natalie; Ball, Kylie; Crawford, David

2012-02-01

The aims of this study were to examine whether adolescent self-efficacy mediates the associations between parental control, perceptions of the importance of healthy nutrition for child health and barriers to buying fruits and vegetables and adolescent fruit consumption using a theoretically derived explanatory model. Data were drawn from a community-based sample of 1606 adolescents in Years 7 and 9 of secondary school and their parents, from Victoria, Australia. Adolescents completed a web-based survey assessing their fruit consumption and self-efficacy for increasing fruit consumption. Parents completed a survey delivered via mail assessing parental control, perceptions and barriers to buying fruit and vegetables. Adolescent self-efficacy for increasing fruit consumption mediated the positive associations between parental control and perceptions of the importance of healthy nutrition for child health and adolescent fruit consumption. Furthermore, adolescent self-efficacy mediated the negative association between parental barriers to buying fruits and vegetables and adolescent fruit consumption. The importance of explicating the mechanisms through which parental factors influence adolescent fruit consumption not only relates to the advancement of scientific knowledge but also offers potential avenues for intervention. Future research should assess the effectiveness of methods to increase adolescent fruit consumption by focussing on both improving adolescents' dietary self-efficacy and on targeting parental control, perceptions and barriers.

Perceived Interpersonal Burdensomeness as a Mediator between Nightmare Distress and Suicidal Ideation in Nightmare Sufferers

PubMed Central

Suh, Sooyeon; Schneider, Matthew; Lee, Ruda; Joiner, Thomas

2016-01-01

Previous studies have supported the significant association between nightmares and suicidal ideation, but the underlying mechanisms are largely unknown. The purpose of the present study was to investigate perceived burdensomeness and thwarted belongingness as mediators in the relationship between nightmare distress and suicidal ideation. This sample consisted of 301 undergraduate students who endorsed experiencing nightmares (mean age 21.87 ± 2.17, 78.1% female). All participants completed questionnaires on nightmare distress (Nightmare Distress Questionnaire), unmet interpersonal needs (Interpersonal Needs Questionnaire), and suicidal ideation (Depressive Symptom Inventory – Suicidality Subscale). Analyses were performed using multiple mediation regression. Results indicated that nightmare distress was associated with perceived burdensomeness (r = 0.17, p < 0.001) and suicidal ideation (r = 0.24, p < 0.001), but was not related to thwarted belongingness (r = 0.10, p = 0.06). Multiple mediation analyses revealed that perceived burdensomeness partially mediated the relationship between nightmares and suicidal ideation, but thwarted belongingness did not. Additionally, this mediating relationship for perceived burdensomeness was moderated by gender, being significant only for females. These findings highlight the important role of interpersonal factors in the relationship between nightmares and suicidal ideation. PMID:27917142

A KRAS GTPase K104Q Mutant Retains Downstream Signaling by Offsetting Defects in Regulation*

PubMed Central

Kistler, Samantha; George, Samuel D.; Kuhlmann, Nora; Garvey, Leslie; Huynh, Minh; Bagni, Rachel K.; Lammers, Michael; Der, Channing J.; Campbell, Sharon L.

2017-01-01

The KRAS GTPase plays a critical role in the control of cellular growth. The activity of KRAS is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and also post-translational modification. Lysine 104 in KRAS can be modified by ubiquitylation and acetylation, but the role of this residue in intrinsic KRAS function has not been well characterized. We find that lysine 104 is important for GEF recognition, because mutations at this position impaired GEF-mediated nucleotide exchange. Because the KRAS K104Q mutant has recently been employed as an acetylation mimetic, we conducted a series of studies to evaluate its in vitro and cell-based properties. Herein, we found that KRAS K104Q exhibited defects in both GEF-mediated exchange and GAP-mediated GTP hydrolysis, consistent with NMR-detected structural perturbations in localized regions of KRAS important for recognition of these regulatory proteins. Despite the partial defect in both GEF and GAP regulation, KRAS K104Q did not alter steady-state GTP-bound levels or the ability of the oncogenic KRAS G12V mutant to cause morphologic transformation of NIH 3T3 mouse fibroblasts and of WT KRAS to rescue the growth defect of mouse embryonic fibroblasts deficient in all Ras genes. We conclude that the KRAS K104Q mutant retains both WT and mutant KRAS function, probably due to offsetting defects in recognition of factors that up-regulate (GEF) and down-regulate (GAP) RAS activity. PMID:28154176

Examining the Relationship Between Pain Catastrophizing and Suicide Risk in Patients with Rheumatic Disease: the Mediating Role of Depression, Perceived Social Support, and Perceived Burdensomeness.

PubMed

Shim, Eun -Jung; Song, Yeong Wook; Park, Seung-Hee; Lee, Kwang-Min; Go, Dong Jin; Hahm, Bong-Jin

2017-08-01

Little research has examined the role of pain catastrophizing (PC) in predicting suicide among patients with rheumatic disease or the mechanisms through which it works. This study examines whether depression, perceived social support (PSS), and perceived burdensomeness (PB) mediate the relationship between PC and suicide risk. It also examines the relative importance of sociodemographic, clinical, and psychological factors in predicting suicide risk. Three hundred sixty patients from a rheumatology clinic in Korea completed measures of pain catastrophizing, social support, depression, and perceived burdensomeness. In hierarchical multiple regression analysis, the PC magnification, PB, physical disability, and PSS were significantly related to suicide risk. Results of the serial multiple mediation analysis indicated that the total indirect effect of PC magnification on suicide risk was significant while the direct effect was not. Four specific indirect effects of PC magnification were found to be statistically significant. First of all, PC magnification was associated with suicide risk through PB and through depression and PB. PC magnification was also associated with suicide risk through depression and PSS. Lastly, PC magnification was associated with suicide risk through depression, PSS, and PB. The identified pathways through which PC affects suicide risk suggest the importance of depression, PSS, and PB. Evaluation and intervention targeted at physical disability and the psychological factors of PC magnification, depression, PSS, and PB may be integrated into the management of suicide risk in patients with rheumatic disease.

Family Health Climate and Adolescents’ Physical Activity and Healthy Eating: A Cross-Sectional Study with Mother-Father-Adolescent Triads

PubMed Central

Niermann, Christina Y. N.; Kremers, Stef P. J.; Renner, Britta; Woll, Alexander

2015-01-01

Introduction The importance of the family environment for children’s and adolescents’ health behavior has been demonstrated, the underlying mechanisms of this influence remain unclear. Therefore, the aim of the study was to investigate the relationship between family environmental and individual determinants. It was hypothesized that the Family Health Climate (FHC) is associated with adolescents’ physical activity and dietary behavior and that intrinsic motivation mediates this association. Methods Cross-sectional data were collected from 198 families (mother, father, and child) using questionnaires. Perceptions of FHC of mothers, fathers, and their children were assessed using the FHC-scales for physical activity (FHC-PA) and nutrition (FHC-NU). The adolescents also rated their intrinsic motivation for exercise and healthy eating, their physical activity and consumption of healthful food. A structural equation model was analyzed and a bootstrapping procedure was used to test direct and indirect effects. Results The FHC-PA was related to the amount of weekly physical activity and the FHC-NU to the consumption of fruit, vegetables and salad. These effects were mediated by adolescents’ intrinsic motivation; the indirect effects were significant for both behaviors. Discussion These results emphasize the importance of the FHC in shaping adolescents’ physical activity and dietary behavior. Individual motivational factors are potential mediators of family and parental influences. Considering family-level variables and their interaction with individual factors contributes to the understanding of adolescents’ health behavior. PMID:26606157

Nuclear alternate estrogen receptor GPR30 mediates 17beta-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts.

PubMed

Madeo, Antonio; Maggiolini, Marcello

2010-07-15

Fibroblasts are the principal cellular component of connective tissue and are associated with cancer cells at all stages of tumor progression. Structural and functional contributions of fibroblasts to the growth, survival, and invasive capacity of cancer cells are beginning to emerge. In breast carcinoma, approximately 80% of stromal fibroblasts termed cancer-associated fibroblasts (CAF) are thought to manifest an activated phenotype that promotes cancer cell proliferation tumor growth at metastatic sites similar to the primary tumor. In this report, we show that CAFs respond to physiologic concentrations of 17beta-estradiol (E2) by rapidly inducing extracellular signal-regulated kinase phosphorylation and immediate early gene expression, including c-fos and connective tissue growth factor, and cyclin D1. Notably, the E2 response is mediated by the alternate estrogen receptor GPR30, which interfaces with the epidermal growth factor receptor (EGFR) signaling pathway. In particular, E2 stimulates a physical interaction between GPR30 and phosphorylated EGFR, recruiting them to the cyclin D1 gene promoter. Nuclear localization induced by E2 was confirmed by cellular immunofluorescence methods. GPR30 was required for CAF proliferation and migration induced by E2. Our results provide important new mechanistic insights into how CAFs are stimulated by estrogen through a GPR30-mediated nuclear signaling pathway. More generally, they define estrogenic GPR30 signaling as a functionally important component of the tumor microenvironment. (c)2010 AACR.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehmood, Rashid; Yasuhara, Noriko; Oe, Souichi

The transition from undifferentiated pluripotent cells to terminally differentiated neurons is coordinated by a repertoire of transcription factors. NeuroD1 is a type II basic helix loop helix (bHLH) transcription factor that plays critical roles in neuronal differentiation and maintenance in the central nervous system. Its dimerization with E47, a type I bHLH transcription factor, leads to the transcriptional regulation of target genes. Mounting evidence suggests that regulating the localization of transcription factors contributes to the regulation of their activity during development as defects in their localization underlie a variety of developmental disorders. In this study, we attempted to understand themore » nuclear import mannerisms of NeuroD1 and E47. We found that the nuclear import of NeuroD1 and E47 is energy-dependent and involves the Ran-mediated pathway. Herein, we demonstrate that NeuroD1 and E47 can dimerize inside the cytoplasm before their nuclear import. Moreover, this dimerization promotes nuclear import as the nuclear accumulation of NeuroD1 was enhanced in the presence of E47 in an in vitro nuclear import assay, and NLS-deficient NeuroD1 was successfully imported into the nucleus upon E47 overexpression. NeuroD1 also had a similar effect on the nuclear accumulation of NLS-deficient E47. These findings suggest a novel role for dimerization that may promote, at least partially, the nuclear import of transcription factors allowing them to function efficiently in the nucleus.« less

Potentially modifiable lifestyle factors, cognitive reserve, and cognitive function in later life: A cross-sectional study

PubMed Central

Wu, Yu-Tzu

2017-01-01

Background Potentially modifiable lifestyle factors may influence cognitive health in later life and offer potential to reduce the risk of cognitive decline and dementia. The concept of cognitive reserve has been proposed as a mechanism to explain individual differences in rates of cognitive decline, but its potential role as a mediating pathway has seldom been explored using data from large epidemiological studies. We explored the mediating effect of cognitive reserve on the cross-sectional association between lifestyle factors and cognitive function in later life using data from a population-based cohort of healthy older people. Methods and findings We analysed data from 2,315 cognitively healthy participants aged 65 y and over in the Cognitive Function and Ageing Study Wales (CFAS-Wales) cohort collected in 2011–2013. Linear regression modelling was used to investigate the overall associations between five lifestyle factors—cognitive and social activity, physical activity, diet, alcohol consumption, and smoking—and cognition, adjusting for demographic factors and chronic conditions. Mediation analysis tested for indirect effects of the lifestyle factors on cognition via cognitive reserve. After controlling for age, gender, and the presence of chronic conditions, cognitive and social activity, physical activity, healthy diet, and light-to-moderate alcohol consumption were positively associated with cognitive function, together accounting for 20% (95% CI 17%–23%) of variance in cognitive test scores. Cognitive reserve was an important mediator of this association, with indirect effects via cognitive reserve contributing 21% (95% CI 15%–27%) of the overall effect on cognition. The main limitations of the study derive from the cross-sectional nature of the data and the challenges of accurately measuring the latent construct of cognitive reserve. Conclusions Cross-sectional associations support the view that enhancing cognitive reserve may benefit cognition, and maintenance of cognitive health may be supported by a healthy and active lifestyle, in later life. PMID:28323829

An Analysis of Pathological Activities of CCN Proteins in Joint Disorders: Mechanical Stretch-Mediated CCN2 Expression in Cultured Meniscus Cells.

PubMed

Furumatsu, Takayuki; Ozaki, Toshifumi

2017-01-01

The multifunctional growth factor CYR61/CTGF/NOV (CCN) 2, also known as connective tissue growth factor, regulates cellular proliferation, differentiation, and tissue regeneration. Recent literatures have described important roles of CCN2 in the meniscus metabolism. However, the mechanical stress-mediated transcriptional regulation of CCN2 in the meniscus remains unclear. The meniscus is a fibrocartilaginous tissue that controls complex biomechanics of the knee joint. Therefore, the injured unstable meniscus has a poor healing potential especially in the avascular inner region. In addition, dysfunction of the meniscus correlates with the progression of degenerative knee joint disorders and joint space narrowing. Here, we describe an experimental approach that investigates the distinct cellular behavior of inner and outer meniscus cells in response to mechanical stretch. Our experimental model can analyze the relationships between stretch-induced CCN2 expression and its functional role in the meniscus homeostasis.

SOCIOECONOMIC DISPARITIES IN MORTALITY AMONG CHINESE ELDERLY*

PubMed Central

Luo, Weixiang; Xie, Yu

2014-01-01

This study examines the association of three different SES indicators (education, economic independence, and household per-capita income) with mortality, using a large, nationally representative longitudinal sample of 12,437 Chinese ages 65 and older. While the results vary by measures used, we find overall strong evidence for a negative association between SES and all-cause mortality. Exploring the association between SES and cause-specific mortality, we find that SES is more strongly related to a reduction of mortality from more preventable causes (i.e., circulatory disease and respiratory disease) than from less preventable causes (i.e., cancer). Moreover, we consider mediating causal factors such as support networks, health-related risk behaviors, and access to health care in contributing to the observed association between SES and mortality. Among these mediating factors, medical care is of greatest importance. This pattern holds true for both all-cause and cause-specific mortality. PMID:25098961

Probing the Mechanical Properties of Plasma von Willebrand Factor Using Atomic Force Microscopy

NASA Astrophysics Data System (ADS)

Wijeratne, Sitara; Botello, Eric; Frey, Eric; Kiang, Ching-Hwa; Dong, Jing-Fei; Yeh, Hui-Chun

2010-03-01

Single-molecule manipulation allows us to study the real time kinetics of many complex cellular processes. The mechanochemistry of different forms of von Willebrand factor (VWF) and their receptor-ligand binding kinetics can be unraveled by atomic force microscopy (AFM). Since plasma VWF can be activated upon shear, the structural and functional properties of VWF are critical in mediating thrombus formation become important. Here we characterized the mechanical resistance to domain unfolding of VWF to determine the conformational states of VWF. We found the shear induced conformational, hence mechanical property changes can be detected by the change in unfolding forces. The relaxation rate of such effect is much longed than expected. This supports the model of lateral association VWF under shear stress. Our results offer an insight in establishing strategies for regulating VWF adhesion activity, increasing our understanding of surface-induced thrombosis as mediated by VWF.

HTLV-1 Tax plugs and freezes UPF1 helicase leading to nonsense-mediated mRNA decay inhibition.

PubMed

Fiorini, Francesca; Robin, Jean-Philippe; Kanaan, Joanne; Borowiak, Malgorzata; Croquette, Vincent; Le Hir, Hervé; Jalinot, Pierre; Mocquet, Vincent

2018-01-30

Up-Frameshift Suppressor 1 Homolog (UPF1) is a key factor for nonsense-mediated mRNA decay (NMD), a cellular process that can actively degrade mRNAs. Here, we study NMD inhibition during infection by human T-cell lymphotropic virus type I (HTLV-1) and characterise the influence of the retroviral Tax factor on UPF1 activity. Tax interacts with the central helicase core domain of UPF1 and might plug the RNA channel of UPF1, reducing its affinity for nucleic acids. Furthermore, using a single-molecule approach, we show that the sequential interaction of Tax with a RNA-bound UPF1 freezes UPF1: this latter is less sensitive to the presence of ATP and shows translocation defects, highlighting the importance of this feature for NMD. These mechanistic insights reveal how HTLV-1 hijacks the central component of NMD to ensure expression of its own genome.

Structural Basis for the Interaction of Mutasome Assembly Factor REV1 with Ubiquitin.

PubMed

Cui, Gaofeng; Botuyan, Maria Victoria; Mer, Georges

2018-05-18

REV1 is an evolutionarily conserved translesion synthesis (TLS) DNA polymerase and an assembly factor key for the recruitment of other TLS polymerases to DNA damage sites. REV1-mediated recognition of ubiquitin in the proliferative cell nuclear antigen is thought to be the trigger for TLS activation. Here we report the solution NMR structure of a 108-residue fragment of human REV1 encompassing the two putative ubiquitin-binding motifs UBM1 and UBM2 in complex with ubiquitin. While in mammals UBM1 and UBM2 are both required for optimal association of REV1 with replication factories after DNA damage, we show that only REV1 UBM2 binds ubiquitin. Structure-guided mutagenesis in Saccharomyces cerevisiae further highlights the importance of UBM2 for REV1-mediated mutagenesis and DNA damage tolerance. Copyright © 2018 Elsevier Ltd. All rights reserved.

NF-kappaB activation in cancer: a challenge for ubiquitination- and proteasome-based therapeutic approach.

PubMed

Amit, Sharon; Ben-Neriah, Yinon

2003-02-01

Nuclear factor-kappa B (NF-kappaB) activation relies primarily on ubiquitin-mediated degradation of its inhibitor IkappaB. NF-kappaB plays an important role in many aspects of tumor development, progression, and therapy. Some types of cancer are characterized by constitutive NF-kappaB activity, whereas in others such activity is induced following chemotherapy. NF-kappaB-harboring tumors are generally resistant to chemotherapy and their eradication requires NF-kappaB inhibition. Here we describe the mechanisms of NF-kappaB activation in normal and tumor cells, review prevalent notions regarding the factor's contribution to tumorigenicity and discuss present and future options for NF-kappaB inhibition in cancer. The ubiquitination-mediated activation of NF-kappaB is intersected by another cancer-associated protein, beta-catenin. We, therefore, compare the related activation pathways and discuss the possibility of differential targeting of the involved ubiquitination machinery. Copyright 2002 Elsevier Science Ltd.

Age differences in conservatism: evidence on the mediating effects of personality and cognitive style.

PubMed

Cornelis, Ilse; Van Hiel, Alain; Roets, Arne; Kossowska, Malgorzata

2009-02-01

The present study investigates the commonly found age-conservatism relationship by combining insights from studies on the development of personality and motivated social cognition with findings on the relationships between these factors and conservative beliefs. Based on data collected in Belgium (N=2,373) and Poland (N=939), we found the expected linear effect of age on indicators of social-cultural conservatism in Belgium and Poland and the absence of such effects for indicators of economic-hierarchical conservatism. We further demonstrated that these effects of age on indicators of cultural conservatism in both countries were (in part) mediated through the personality factor Openness to Experience and the motivated cognition variable Need for Closure. The consistency of these findings in two countries with a very dissimilar sociopolitical history attests to the importance of the developmental perspective for the study of the relationship between age and conservatism.

Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy

PubMed Central

Kendziorra, Emil; Ahlborn, Kerstin; Spitzner, Melanie; Rave-Fränk, Margret; Emons, Georg; Gaedcke, Jochen; Kramer, Frank; Wolff, Hendrik A.; Becker, Heinz; Beissbarth, Tim; Ebner, Reinhard; Ghadimi, B.Michael; Pukrop, Tobias; Ried, Thomas; Grade, Marian

2011-01-01

A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a β-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G2/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy. PMID:21983179

Forsythia suspensa extract attenuates lipopolysaccharide-induced inflammatory liver injury in rats via promoting antioxidant defense mechanisms.

PubMed

Zhao, Panfeng; Piao, Xiangshu; Pan, Long; Zeng, Zhikai; Li, Qingyun; Xu, Xiao; Wang, Hongliang

2017-06-01

Reactive oxygen species (ROS) have been shown to have a role in inflammation. We investigated whether Forsythia suspensa extract (FSE) could exert its antioxidant potential against lipopolysaccharide (LPS)-induced inflammatory liver injury in rats. Rats were orally fed FSE once daily for 7 consecutive days prior to LPS (Escherichia coli, serotype O55:B5) injection. LPS treatment caused liver dysfunction as evidenced by massive histopathological changes and increased serum alanine aminotransferase and aspartate aminotransferase activities which were ameliorated by FSE pretreatment. FSE attenuated LPS-induced depletion of cytosolic nuclear factor-erythroid 2-related factor 2 (Nrf2) and suppression of Nrf2 nuclear translocation in liver, and the generation of ROS and malondialdehyde in serum and liver. FSE increased the Nrf2-mediated induction of heme oxygenase-1 in liver, as well as superoxide dismutase and glutathione peroxidase activities in serum and liver. Importantly, FSE attenuated LPS-induced nuclear factor-кB (NF-кB) nuclear translocation in liver, and subsequently decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels in serum and liver, which were associated with FSE-induced activation of Nrf2 in liver. These results indicate that the protective mechanisms of FSE may be involved in the attenuation of oxidative stress and the inhibition of the NF-кB-mediated inflammatory response by modulating the Nrf2-mediated antioxidant response against LPS-induced inflammatory liver injury. © 2016 Japanese Society of Animal Science.

Nature and Nurture: the complex genetics of myopia and refractive error

PubMed Central

Wojciechowski, Robert

2010-01-01

The refractive errors, myopia and hyperopia, are optical defects of the visual system that can cause blurred vision. Uncorrected refractive errors are the most common causes of visual impairment worldwide. It is estimated that 2.5 billion people will be affected by myopia alone with in the next decade. Experimental, epidemiological and clinical research has shown that refractive development is influenced by both environmental and genetic factors. Animal models have demonstrated that eye growth and refractive maturation during infancy are tightly regulated by visually-guided mechanisms. Observational data in human populations provide compelling evidence that environmental influences and individual behavioral factors play crucial roles in myopia susceptibility. Nevertheless, the majority of the variance of refractive error within populations is thought to be due to hereditary factors. Genetic linkage studies have mapped two dozen loci, while association studies have implicated more than 25 different genes in refractive variation. Many of these genes are involved in common biological pathways known to mediate extracellular matrix composition and regulate connective tissue remodeling. Other associated genomic regions suggest novel mechanisms in the etiology of human myopia, such as mitochondrial-mediated cell death or photoreceptor-mediated visual signal transmission. Taken together, observational and experimental studies have revealed the complex nature of human refractive variation, which likely involves variants in several genes and functional pathways. Multiway interactions between genes and/or environmental factors may also be important in determining individual risks of myopia, and may help explain the complex pattern of refractive error in human populations. PMID:21155761

Revisiting traditional risk factors for rejection and graft loss after kidney transplantation.

PubMed

Dunn, T B; Noreen, H; Gillingham, K; Maurer, D; Ozturk, O G; Pruett, T L; Bray, R A; Gebel, H M; Matas, A J

2011-10-01

Single-antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor-specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single-antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third-party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death-censored graft survival (DCGS) and risk factors for rejection. Antibody-mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell-mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Hypoxia-inducible factor 1α is a critical downstream mediator for hypoxia-induced mitogenic factor (FIZZ1/RELMα)-induced pulmonary hypertension

PubMed Central

Johns, Roger A.; Takimoto, Eiki; Meuchel, Lucas W.; Elsaigh, Esra; Zhang, Ailan; Heller, Nicola M.; Semenza, Gregg L.; Yamaji-Kegan, Kazuyo

2017-01-01

Objective Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or RELMα) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/−) mice. HIMF-induced PH was significantly diminished in HIF-1α+/− mice and was accompanied by a dysregulated VEGF-A–VEGF receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β (RELMβ), significantly increased IL-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human RELMβ significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6–expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, VEGF-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology. PMID:26586659

Socioeconomic inequalities in adolescent smoking across 35 countries: a multilevel analysis of the role of family, school and peers.

PubMed

Moor, Irene; Rathmann, Katharina; Lenzi, Michela; Pförtner, Timo-Kolja; Nagelhout, Gera E; de Looze, Margreet; Bendtsen, Pernille; Willemsen, Marc; Kannas, Lasse; Kunst, Anton E; Richter, Matthias

2015-06-01

Tobacco-related heath inequalities are a major public health concern, with smoking being more prevalent among lower socioeconomic groups. The aim of this study is to investigate the mechanisms leading to socioeconomic inequalities in smoking among 15-year-old adolescents by examining the mediating role of psychosocial factors in the peer group, family and school environment. Data were derived from the international WHO-collaborative 'Health Behaviour in School-aged Children (HBSC)' study 2005/2006, including 52 907 15-year-old students from 35 European and North American countries. Socioeconomic position was measured by the Family Affluence Scale. Multilevel logistic regression models were conducted to examine the contribution of family, school and peer factors in explaining the association between family affluence and weekly smoking. Across countries, adolescents from low affluent families had an increased risk of weekly smoking (OR(boys) 1.14, confidence interval (CI) 1.05-1.23; OR(girls) 1.36, CI 1.26-1.46) compared with adolescents from high affluent families. Family and school factors mediated the association between family affluence and smoking to a high extent up to 100% (boys) and 81% (girls) in joint analyses. The most important single factors were family structure, relationships with parents, academic achievement and school satisfaction. Peer factors did not mediate the association between family affluence and adolescent smoking. The association between socioeconomic status and adolescent weekly smoking can largely be explained by an unequal distribution of family- and school-related factors. Focusing on the parent-adolescent relationship and adolescent school achievement can help to better understand inequalities in adolescent smoking behaviour. © The Author 2015. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

Maternal educational level and children's healthy eating behaviour: role of the home food environment (cross-sectional results from the INPACT study).

PubMed

van Ansem, Wilke Jc; Schrijvers, Carola Tm; Rodenburg, Gerda; van de Mheen, Dike

2014-09-12

The aims of this study are 1) to investigate the association between maternal educational level and healthy eating behaviour of 11-year-old children (fruit, vegetables and breakfast consumption), and 2) to examine whether factors in the home food environment (parental intake of fruit, vegetables and breakfast; rules about fruit and vegetables and home availability of fruit and vegetables) mediate these associations. Data were obtained from the Dutch INPACT study. In total, 1318 parent-child dyads were included in this study. Multilevel regression models were used to investigate whether factors of the home food environment mediated the association between maternal educational level and children's healthy eating behaviour. Children of mothers with a high educational level consumed more pieces of fruit per day (B = 0.13, 95% CI: 0.04-0.22), more grams of vegetables per day (B = 23.81, 95% CI = 14.93-32.69) and were more likely to have breakfast on a daily basis (OR = 2.97, 95% CI: 1.38-6.39) than children of mothers with a low educational level. Home availability, food consumption rules and parental consumption mediated the association between maternal education level and children's fruit and vegetable consumption. Parental breakfast consumption mediated the association between maternal education level and children's breakfast consumption. Factors in the home food environment play an important role in the explanation of socio-economic disparities in children's healthy eating behaviour and may be promising targets for interventions.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arpiainen, Satu; Jaervenpaeae, Sanna-Mari; Manninen, Aki

The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor {gamma} coactivator (PGC)-1{alpha} triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1{alpha} and CYP2A5 mRNAsmore » in murine primary hepatocytes. Furthermore, the elevation of the PGC-1{alpha} expression level by adenovirus mediated gene transfer increased CYP2A5 transcription. Co-transfection of Cyp2a5 5' promoter constructs with the PGC-1{alpha} expression vector demonstrated that PGC-1{alpha} is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4{alpha} response element in the proximal promoter of the Cyp2a5 gene. Chromatin immunoprecipitation assays showed that PGC-1{alpha} binds, together with HNF-4{alpha}, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1{alpha} mediates the expression of CYP2A5 induced by cAMP in mouse hepatocytes through coactivation of transcription factor HNF-4{alpha}. This strongly suggests that PGC-1{alpha} is the major factor mediating the fasting response of CYP2A5.« less

Psychosocial mediation of religious coping styles: a study of short-term psychological distress following cardiac surgery.

PubMed

Ai, Amy L; Park, Crystal L; Huang, Bu; Rodgers, Willard; Tice, Terrence N

2007-06-01

Although religiousness and religious coping styles are well-documented predictors of well-being, research on the mechanisms through which religious coping styles operate is sparse. This prospective study examined religious coping styles, hope, and social support as pathways of the influence of general religiousness (religious importance and involvement) on the reduced postoperative psychological distress of 309 cardiac patients. Results of structural equation modeling indicated that controlling for preoperative distress, gender, and education, religiousness contributed to positive religious coping, which in turn was associated with less distress via a path fully mediated by the secular factors of social support and hope. Furthermore, negative religious coping styles, although correlated at the bivariate level with preoperative distress but not with religiousness, were associated both directly and indirectly with greater post-operative distress via the same mediators.

EWS/FLI1 regulates EYA3 in Ewing's sarcoma via modulation of microRNA-708, resulting in increased cell survival and chemoresistance

PubMed Central

Robin, Tyler P; Smith, Anna; McKinsey, Erin; Reaves, Lisa; Jedlicka, Paul; Ford, Heide L.

2012-01-01

Ewing's sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histological response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we demonstrate that the DNA-repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing's sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell of origin of Ewing's sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further demonstrate that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a microRNA that targets the EYA3 3′UTR, rather than by binding the EYA3 promoter directly. Importantly, we demonstrate that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing's sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and demonstrate, that loss of EYA3 decreases survival of Ewing's sarcoma cells. Most importantly, knockdown of EYA3 in Ewing's sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing's sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing's sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance. PMID:22723308

Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.

PubMed

Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer Mi; Doh, Kyung-Oh; Hui, Chi-Chung; Sung, Hoon-Ki

2017-11-01

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage

PubMed Central

Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer MI; Doh, Kyung-Oh; Hui, Chi-chung; Sung, Hoon-Ki

2017-01-01

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders. PMID:29039412

Maternal Depressive Symptoms, Maternal Behavior, and Toddler Internalizing Outcomes: A Moderated Mediation Model

PubMed Central

Hummel, Alexandra C.; Kiel, Elizabeth J.

2014-01-01

Maternal depression relates to child internalizing outcomes, but one missing aspect of this association is how variation in depressive symptoms, including mild and moderate symptoms, relates to young children’s outcomes. The current study examined a moderated mediation model to investigate how maternal behaviors may mediate this association in the context of child temperament and gender. Mothers and toddlers completed a free-play/clean-up task in the laboratory. Mothers rated their depressive symptoms and their toddlers’ temperament and internalizing behaviors. Results indicated a significant indirect of maternal warmth on the relation between maternal depressive symptoms and toddler internalizing outcomes for boys with low negative emotionality. Toddler gender and temperament moderated the relation between maternal intrusiveness and toddler internalizing outcomes, but mediation was not supported. Results highlight the important interaction between child and maternal variables in predicting child outcomes, and suggest mechanisms by and conditions under which mild maternal depressive symptomatology can be a risk factor for toddler internalizing outcomes. PMID:24553739

Acid-Base and the Skeleton

NASA Astrophysics Data System (ADS)

Bushinsky, David A.

2008-09-01

Chronic metabolic acidosis increases urine calcium (Ca) excretion in the absence of a concomitant increase in intestinal Ca absorption resulting in a net loss of total body. The source of this additional urine Ca is almost certainly the skeleton, the primary reservoir of body Ca. In vitro metabolic acidosis, modeled as a primary reduction in medium bicarbonate concentration, acutely (<24 h) stimulates Ca efflux primarily through physicochemical mineral dissolution while at later time periods (>24 h) cell-mediated mechanisms predominate. In cultured neonatal mouse calvariae, acidosis-induced, cell-mediated Ca efflux is mediated by effects on both osteoblasts and osteoclasts. Metabolic acidosis inhibits extracellular matrix production by osteoblasts, as determined by measurement of collagen levels and levels for the non-collagenous matrix proteins osteopontin and matrix gla protein. Metabolic acidosis upregulates osteoblastic expression of RANKL (Receptor Activator of NFκB Ligand), an important osteoclastogenic and osteoclast-activating factor. Acidosis also increases osteoclastic activity as measured by release of β-glucuronidase, an enzyme whose secretion correlates with osteoclast-mediated bone resorption.

Do Social Connections and Hope Matter in Predicting Early Adolescent Violence?

PubMed Central

Stoddard, Sarah A.; McMorris, Barbara J.; Sieving, Renee E.

2011-01-01

We tested relationships between social connections, hope, and violence among young adolescents from socially distressed urban neighborhoods, and examined whether relationships between adolescents’ family and school connectedness and violence involvement were mediated by hopefulness. Data were from middle school students involved in the Lead Peace demonstration study. The sample (N = 164) was 51.8% female; 42% African American, 28% Asian, 13% Hispanic, and 17% mixed race or other race; average age was 12.1 years; 46% reported physical fighting in the past year. In multivariate models, parent-family connectedness was protective against violence; school connectedness was marginally protective. Hopefulness was related to lower levels of violence. The relationship between school connectedness and violence was mediated by hopefulness; some evidence for mediation also existed in the family-parent connectedness and violence relationship. Findings warrant continued exploration of hopefulness as an important protective factor against violence involvement, and as a mediator in relationships between social connections and violence involvement. PMID:21181556

Adolescents' Communication with Parents, Other Adult Family Members and Teachers on Sexuality: Effects of School-Based Interventions in South Africa and Tanzania.

PubMed

Namisi, Francis; Aarø, Leif Edvard; Kaaya, Sylvia; Kajula, Lusajo J; Kilonzo, Gad P; Onya, Hans; Wubs, Annegreet; Mathews, Catherine

2015-12-01

Cluster-randomized controlled trials were carried out to examine effects on sexual practices of school-based interventions among adolescents in three sites in sub-Saharan Africa. In this publication, effects on communication about sexuality with significant adults (including parents) and such communication as a mediator of other outcomes were examined. Belonging to the intervention group was significantly associated with fewer reported sexual debuts in Dar es Salaam only (OR 0.648). Effects on communication with adults about sexuality issues were stronger for Dar es Salaam than for the other sites. In Dar, increase in communication with adults proved to partially mediate associations between intervention and a number of social cognition outcomes. The hypothesized mediational effect of communication on sexual debut was not confirmed. Promoting intergenerational communication on sexuality issues is associated with several positive outcomes and therefore important. Future research should search for mediating factors influencing behavior beyond those examined in the present study.

[Relationship Between General Cognitive Abilities and School Achievement: The Mediation Role of Learning Behavior].

PubMed

Weber, H M; Rücker, S; Büttner, P; Petermann, F; Daseking, M

2015-10-01

General cognitive abilities are still considered as the most important predictor of school achievement and success. Whether the high correlation (r=0.50) can be explained by other variables has not yet been studied. Learning behavior can be discussed as one factor that influences the relationship between general cognitive abilities and school achievement. This study examined the relationship between intelligence, school achievement and learning behavior. Mediator analyses were conducted to check whether learning behavior would mediate the relationship between general cognitive abilities and school grades in mathematics and German. Statistical analyses confirmed that the relationship between general cognitive abilities and school achievement was fully mediated by learning behavior for German, whereas intelligence seemed to be the only predictor for achievement in mathematics. These results could be confirmed by non-parametric bootstrapping procedures. RESULTS indicate that special training of learning behavior may have a positive impact on school success, even for children and adolescents with low IQ. © Georg Thieme Verlag KG Stuttgart · New York.

Family Environments and Children's Executive Function: The Mediating Role of Children's Affective State and Stress.

PubMed

He, Zhong-Hua; Yin, Wen-Gang

2016-09-01

There is increasing evidence that inadequate family environments (family material environment and family psychosocial environment) are not only social problems but also factors contributing to adverse neurocognitive outcomes. In the present study, the authors investigated the relationship among family environments, children's naturalistic affective state, self-reported stress, and executive functions in a sample of 157 Chinese families. These findings revealed that in inadequate family material environments, reduced children's cognitive flexibility is associated with increased naturalistic negative affectivity and self-reported stress. In addition, naturalistic negative affectivity mediated the association between family expressiveness and children's cognitive flexibility. The authors used a structural equation model to examine the mediation model hypothesis, and the results confirmed the mediating roles of naturalistic negative affectivity and self-reported stress between family environments and the cognitive flexibility of Chinese children. These findings indicate the importance of reducing stress and negative emotional state for improving cognitive functions in children of low socioeconomic status.

How do stressors lead to burnout? The mediating role of motivation.

PubMed

Rubino, Cristina; Luksyte, Aleksandra; Perry, Sara Jansen; Volpone, Sabrina D

2009-07-01

We extend existing stressor-strain theoretical models by including intrinsic motivation as a mediator between well-established job stressors and burnout. Though the link between situational stressors and burnout is well established, little is known about mechanisms behind this relationship. With a sample of 284 self-employed individuals, we examined motivation as a mediator to explain why situational factors impact 3 dimensions of burnout: emotional exhaustion, cynicism, and inefficacy. Motivation is an explanatory mechanism that drives human behavior and thought, and thus may have an impact on important well-being outcomes. As expected, intrinsic motivation was a full mediator for the effect of perceived fit on the inefficacy dimension of burnout. Unexpectedly, neither perceived fit nor motivation was related to the other 2 dimensions of burnout, and role ambiguity had only a direct effect on the inefficacy dimension; it was also unrelated to exhaustion and cynicism. We discuss implications of these findings for researchers as well as for practitioners. (c) 2009 APA, all rights reserved.

You can hide but you have to run: direct detection with vector mediators

NASA Astrophysics Data System (ADS)

D'Eramo, Francesco; Kavanagh, Bradley J.; Panci, Paolo

2016-08-01

We study direct detection in simplified models of Dark Matter (DM) in which interactions with Standard Model (SM) fermions are mediated by a heavy vector boson. We consider fully general, gauge-invariant couplings between the SM, the mediator and both scalar and fermion DM. We account for the evolution of the couplings between the energy scale of the mediator mass and the nuclear energy scale. This running arises from virtual effects of SM particles and its inclusion is not optional. We compare bounds on the mediator mass from direct detection experiments with and without accounting for the running. In some cases the inclusion of these effects changes the bounds by several orders of magnitude, as a consequence of operator mixing which generates new interactions at low energy. We also highlight the importance of these effects when translating LHC limits on the mediator mass into bounds on the direct detection cross section. For an axial-vector mediator, the running can alter the derived bounds on the spin-dependent DM-nucleon cross section by a factor of two or more. Finally, we provide tools to facilitate the inclusion of these effects in future studies: general approximate expressions for the low energy couplings and a public code runDM to evolve the couplings between arbitrary energy scales.

Listeria monocytogenes Alters Mast Cell Phenotype, Mediator and Osteopontin Secretion in a Listeriolysin-Dependent Manner

PubMed Central

Jobbings, Catherine E.; Sandig, Hilary; Whittingham-Dowd, Jayde K.; Roberts, Ian S.; Bulfone-Paus, Silvia

2013-01-01

Whilst mast cells participate in the immune defence against the intracellular bacterium Listeria monocytogenes, there is conflicting evidence regarding the ability of L. monocytogenes to infect mast cells. It is known that the pore-forming toxin listeriolysin (LLO) is important for mast cell activation, degranulation and the release of pro-inflammatory cytokines. Mast cells, however, are a potential source of a wide range of cytokines, chemokines and other mediators including osteopontin, which contributes to the clearing of L. monocytogenes infections in vivo, although its source is unknown. We therefore aimed to resolve the controversy of mast cell infection by L. monocytogenes and investigated the extent of mediator release in response to the bacterium. In this paper we show that the infection of bone marrow-derived mast cells by L. monocytogenes is inefficient and LLO-independent. LLO, however, is required for calcium-independent mast cell degranulation as well as for the transient and selective downregulation of cell surface CD117 (c-kit) on mast cells. We demonstrate that in addition to the key pro-inflammatory cytokines TNF-α and IL-6, mast cells release a wide range of other mediators in response to L. monocytogenes. Osteopontin, IL-2, IL-4, IL-13 and granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokines including CCL2, CCL3, CCL4 and CCL5 are released in a MyD88-dependent manner. The wide range of mediators released by mast cells in response to L. monocytogenes may play an important role in the recruitment and activation of a variety of immune cells in vivo. The cocktail of mediators, however, is unlikely to skew the immune response to a particular effector response. We propose that mast cells provide a hitherto unreported source of osteopontin, and may provide an important role in co-ordinating the immune response during Listeria infection. PMID:23460827

Anti-inflammatory effects of Chinese medicinal herbs on cerebral ischemia.

PubMed

Su, Shan-Yu; Hsieh, Ching-Liang

2011-07-09

Recent studies have demonstrated the importance of anti-inflammation, including cellular immunity, inflammatory mediators, reactive oxygen species, nitric oxide and several transcriptional factors, in the treatment of cerebral ischemia. This article reviews the roles of Chinese medicinal herbs as well as their ingredients in the inflammatory cascade induced by cerebral ischemia. Chinese medicinal herbs exert neuroprotective effects on cerebral ischemia. The effects include inhibiting the activation of microglia, decreasing levels of adhesion molecules such as intracellular adhesion molecule-1, attenuating expression of pro-inflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, reducing inducible nitric oxide synthase and reactive oxygen species, and regulating transcription factors such as nuclear factor-κB.

Mood instability as a precursor to depressive illness: A prospective and mediational analysis.

PubMed

Marwaha, Steven; Balbuena, Lloyd; Winsper, Catherine; Bowen, Rudy

2015-06-01

Mood instability levels are high in depression, but temporal precedence and potential mechanisms are unknown. Hypotheses tested were as follows: (1) mood instability is associated with depression cross-sectionally, (2) mood instability predicts new onset and maintenance of depression prospectively and (3) the mood instability and depression link are mediated by sleep problems, alcohol abuse and life events. Data from the National Psychiatric Morbidity Survey 2000 at baseline (N = 8580) and 18-month follow-up (N = 2413) were used. Regression modeling controlling for socio-demographic factors, anxiety and hypomanic mood was conducted. Multiple mediational analyses were used to test our conceptual path model. Mood instability was associated with depression cross-sectionally (odds ratio: 5.28; 95% confidence interval: [3.67, 7.59]; p < 0.001) and predicted depression inception (odds ratio: 2.43; 95% confidence interval: [1.03-5.76]; p = 0.042) after controlling for important confounders. Mood instability did not predict maintenance of depression. Sleep difficulties and severe problems with close friends and family significantly mediated the link between mood instability and new onset depression (23.05% and 6.19% of the link, respectively). Alcohol abuse and divorce were not important mediators in the model. Mood instability is a precursor of a depressive episode, predicting its onset. Difficulties in sleep are a significant part of the pathway. Interventions targeting mood instability and sleep problems have the potential to reduce the risk of depression. © The Royal Australian and New Zealand College of Psychiatrists 2015.

A national cohort study of parental socioeconomic status and non-fatal suicidal behaviour-the mediating role of school performance

PubMed Central

2012-01-01

Background A link between low parental socioeconomic status and mental health problems in offspring is well established in previous research. The mechanisms that explain this link are largely unknown. The present study investigated whether school performance was a mediating and/or moderating factor in the path between parental socioeconomic status and the risk of hospital admission for non-fatal suicidal behaviour. Methods A national cohort of 447 929 children born during 1973-1977 was followed prospectively in the National Patient Discharge Register from the end of their ninth and final year of compulsory school until 2001. Multivariate Cox proportional hazards and linear regression analyses were performed to test whether the association between parental socioeconomic status and non-fatal suicidal behaviour was mediated or moderated by school performance. Results The results of a series of multiple regression analyses, adjusted for demographic variables, revealed that school performance was as an important mediator in the relationship between parental socioeconomic status and risk of non-fatal suicidal behaviour, accounting for 60% of the variance. The hypothesized moderation of parental socioeconomic status-non-fatal suicidal behaviour relationship by school performance was not supported. Conclusions School performance is an important mediator through which parental socioeconomic status translates into a risk for non-fatal suicidal behaviour. Prevention efforts aimed to reduce socioeconomic inequalities in non-fatal suicidal behaviour among young people will need to consider socioeconomic inequalities in school performance. PMID:22230577

Career Identity and Life Satisfaction: The Mediating Role of Tolerance for Uncertainty and Positive/Negative Affect

ERIC Educational Resources Information Center

Garrison, Yunkyoung Loh; Lee, Ki-Hak; Ali, Saba Rasheed

2017-01-01

Identity formation is considered as a key factor in the conceptualization of life satisfaction (LS). Recent volatility in labor markets has negatively influenced college students' LS and attending to the relationship between their career identity (CI) and LS has become important for career researchers and counselors. The purpose of this study is…

The Importance of Context and Social Support in Moderating Depression in Mothers of Young Infants. Michigan Family Study.

ERIC Educational Resources Information Center

Follett, Chantal; Dayton, Carolyn; Simonds, Julia; Rosenblum, Katherine

Researchers have hypothesized that the impact of environmental risk on infants and young children may be mediated by the impact of environmental risk on mothers. Epidemiological surveys have found high-risk environments to be associated with depression in adults. Further clarification about the factors which may exacerbate or alleviate the impact…

Processing Speed, Inhibitory Control, and Working Memory: Three Important Factors to Account for Age-Related Cognitive Decline

ERIC Educational Resources Information Center

Pereiro Rozas, Arturo X.; Juncos-Rabadan, Onesimo; Gonzalez, Maria Soledad Rodriguez

2008-01-01

Processing speed, inhibitory control and working memory have been identified as the main possible culprits of age-related cognitive decline. This article describes a study of their interrelationships and dependence on age, including exploration of whether any of them mediates between age and the others. We carried out a LISREL analysis of the…

Educational Leadership in Hong Kong Schools, 1950-2000: Critical Reflections on Changing Themes

ERIC Educational Resources Information Center

Evers, Colin W.; Katyal, Kokila

2008-01-01

As a former colony, Hong Kong's education system has been powerfully influenced by ideas from the West. However, these influences have been mediated by a number of factors of contingency--the most important of which is culture--which shapes implementation, particularly of what counts as successful practice. The aim of this paper is to trace the…

The Direct Effects of Principal-Student Discussions upon Eighth Grade Students' Gains in Reading Achievement: An Experimental Study

ERIC Educational Resources Information Center

Silva, Jack P.

2010-01-01

School effectiveness and instructional leadership research over the past thirty years have largely concluded that principal effects on student achievement are small and indirect; it has been assumed that principal effect is important, but mediated through other school factors. To the contrary, this experimental study found that one-on-one…

The Direct Effects of Principal-Student Discussions on Eighth Grade Students' Gains in Reading Achievement: An Experimental Study

ERIC Educational Resources Information Center

Silva, Jack P.; White, George P.; Yoshida, Roland K.

2011-01-01

Purpose: School effectiveness and instructional leadership research over the past 30 years has largely concluded that principal effects on student achievement are small and indirect. It has been assumed that the principal effect is important but mediated through other school factors. Findings: This experimental study found that one-on-one…

The importance and conservation of ectomycorrizal fungal diversity in forest ecosystems: lessons from Europe and the Pacific Northwest.

Treesearch

Michael P. Amaranthus

1998-01-01

Ectomycorrhizal fungi (EMF) consist of about 5,000 species and profoundly affect forest ecosystems by mediating nutrient and water uptake, protecting roots from pathogens and environmental extremes, and maintaining soil structure and forest food webs. Diversity of EMF likely aids forest ecosystem resilience in the face of changing environmental factors such as...

Hypothesis: Leukocyte Endogenous Mediator/Endogenous Pyrogen/Lymphocyte-Activating Factor Modulates the Development of Nonspecific and Specific Immunity and Affects Nutritional Status

DTIC Science & Technology

1982-04-01

Hypothesis: leukocyte endogenous mediator/ endogenous pyrogen /lymphocyte-activating factor modulates the development of nonspecific and specific... endogenous pyrogen /lympho- NI cyte-activating factor (LEM/EP/LAF) integrates the host’s nonspecific and specific immune responses to infection by...mediator/ endogenous pyrogen /lymphocyte-activating factor, nonspecific and specific immunity, infection, metabolism, nutrition. Introduction LAF which lead

Early trauma, negative affect, and anxious attachment: the role of metacognition.

PubMed

Myers, Samuel G; Wells, Adrian

2015-01-01

Metacognition is linked to the etiology and maintenance of negative emotions and psychological disorder in the Self-Regulatory Executive Function Model. Although there is significant evidence supporting the model, little is currently known about the situational factors for developing dysfunctional metacognitions. The current study explored the hypothesis that early aversive experiences might be important and also tested if metacognitions could mediate the relationship between such experiences and psychological symptoms. Three hundred and fifty non-clinical adults completed a retrospective early trauma measure, as well as measures of current metacognitive beliefs, negative affect, and anxious attachment. Early emotional abuse positively and significantly correlated with several metacognitive belief dimensions but other forms of early trauma did not. Metacognition fully mediated the relationship between emotional abuse and negative affect. Anxious attachment was also positively and significantly associated with metacognitive beliefs and specific relationships remained after controlling for early emotional abuse and current negative affect. Findings are consistent with the ideas that: (i) early negative experiences, and emotional abuse in particular, could be a factor in the formation of problematic metacognitions and (ii) these metacognitions may be important in determining the effects of abuse on subsequent psychological symptoms.

Safety climate and safety behaviors in the construction industry: The importance of co-workers commitment to safety.

PubMed

Schwatka, Natalie V; Rosecrance, John C

2016-06-16

There is growing empirical evidence that as safety climate improves work site safety practice improve. Safety climate is often measured by asking workers about their perceptions of management commitment to safety. However, it is less common to include perceptions of their co-workers commitment to safety. While the involvement of management in safety is essential, working with co-workers who value and prioritize safety may be just as important. To evaluate a concept of safety climate that focuses on top management, supervisors and co-workers commitment to safety, which is relatively new and untested in the United States construction industry. Survey data was collected from a cohort of 300 unionized construction workers in the United States. The significance of direct and indirect (mediation) effects among safety climate and safety behavior factors were evaluated via structural equation modeling. Results indicated that safety climate was associated with safety behaviors on the job. More specifically, perceptions of co-workers commitment to safety was a mediator between both management commitment to safety climate factors and safety behaviors. These results support workplace health and safety interventions that build and sustain safety climate and a commitment to safety amongst work teams.

Krüppel-like factor 4, a novel transcription factor regulates microglial activation and subsequent neuroinflammation.

PubMed

Kaushik, Deepak K; Gupta, Malvika; Das, Sulagna; Basu, Anirban

2010-10-15

Activation of microglia, the resident macrophages of the central nervous system (CNS), is the hallmark of neuroinflammation in neurodegenerative diseases and other pathological conditions associated with CNS infection. The activation of microglia is often associated with bystander neuronal death. Nuclear factor-κB (NF-κB) is one of the important transcription factors known to be associated with microglial activation which upregulates the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (Cox-2) and other pro-inflammatory cytokines. Recent studies have focused on the role of Krüppel-like factor 4 (Klf4), one of the zinc-finger transcription factors, in mediating inflammation. However, these studies were limited to peripheral system and its role in CNS is not understood. Our studies focused on the possible role of Klf4 in mediating CNS inflammation. For in vitro studies, mouse microglial BV-2 cell lines were treated with 500 ng/ml Salmonella enterica lipopolysacchride (LPS). Brain tissues were isolated from BALB/c mice administered with 5 mg/kg body weight of LPS. Expressions of Klf4, Cox-2, iNOS and pNF-κB were evaluated using western blotting, quantitative real time PCR, and reverse transcriptase polymerase chain reactions (RT-PCRs). Klf4 knockdown was carried out using SiRNA specific for Klf4 mRNA and luciferase assays and electromobility shift assay (EMSA) were performed to study the interaction of Klf4 to iNOS promoter elements in vitro. Co-immunoprecipitation of Klf4 and pNF-κB was done in order to study a possible interaction between the two transcription factors. LPS stimulation increased Klf4 expression in microglial cells in a time- and dose-dependent manner. Knockdown of Klf4 resulted in decreased levels of the pro-inflammatory cytokines TNF-α, MCP-1 and IL-6, along with a significant decrease in iNOS and Cox-2 expression. NO production also decreased as a result of Klf4 knockdown. We found that Klf4 can potentially interact with pNF-κB and is important for iNOS and Cox-2 promoter activity in vitro. These studies demonstrate the role of Klf4 in microglia in mediating neuroinflammation in response to the bacterial endotoxin LPS.

Exploring the relationships among food insecurity, alcohol use, and sexual risk taking among men and women living in South African townships

PubMed Central

Eaton, Lisa A.; Cain, Demetria N.; Pitpitan, Eileen V.; Carey, Kate B.; Carey, Michael P.; Mehlomakulu, Vuyelwa; Simbayi, Leickness C.; Mwaba, Kelvin; Kalichman, Seth C.

2014-01-01

South African townships have among the highest rates of HIV infection in the world. Considerable research on understanding the high rates of HIV transmission in this country has identified alcohol use as a critical factor in driving the HIV epidemic. Although the relationship between alcohol use and sexual risk-taking is well documented, less is known about how other factors, such as food insecurity, might be important in understanding alcohol’s role in sexual risk-taking. Furthermore, prior research has highlighted how patterns of alcohol use and sexual risk-taking tend to vary by gender. We examined how food insecurity is related to both alcohol use and sexual risk-taking. We administered anonymous community surveys to men (n=1137) and women (n=458) residing within four contiguous Black African townships outside of Cape Town, South Africa. In multivariate linear regression, we found that food insecurity was related to having higher numbers of male sex partners and condom-protected sex acts among women only. These relationships, however, were fully mediated by women’s alcohol use. Among men, we found that food insecurity was negatively related to unprotected sex; that is, men with greater food security reported more unprotected sex acts. Unlike the results found among women, this relationship was not mediated by alcohol use. Food insecurity appears to be an important factor in understanding patterns of sexual risk-taking in regards to gender and alcohol use, and may serve as an important point of intervention for reducing HIV transmission rates. PMID:24806889

Exploring the relationships among food insecurity, alcohol use, and sexual risk taking among men and women living in South African townships.

PubMed

Eaton, Lisa A; Cain, Demetria N; Pitpitan, Eileen V; Carey, Kate B; Carey, Michael P; Mehlomakulu, Vuyelwa; Simbayi, Leickness C; Mwaba, Kelvin; Kalichman, Seth C

2014-08-01

South African townships have among the highest rates of HIV infection in the world. Considerable research on understanding the high rates of HIV transmission in this country has identified alcohol use as a critical factor in driving the HIV epidemic. Although the relationship between alcohol use and sexual risk-taking is well documented, less is known about how other factors, such as food insecurity, might be important in understanding alcohol's role in sexual risk-taking. Furthermore, prior research has highlighted how patterns of alcohol use and sexual risk-taking tend to vary by gender. We examined how food insecurity is related to both alcohol use and sexual risk-taking. We administered anonymous community surveys to men (n = 1,137) and women (n = 458) residing within four contiguous Black African townships outside of Cape Town, South Africa. In multivariate linear regression, we found that food insecurity was related to having higher numbers of male sex partners and condom-protected sex acts among women only. These relationships, however, were fully mediated by women's alcohol use. Among men, we found that food insecurity was negatively related to unprotected sex; that is, men with greater food security reported more unprotected sex acts. Unlike the results found among women, this relationship was not mediated by alcohol use. Food insecurity appears to be an important factor in understanding patterns of sexual risk-taking in regards to gender and alcohol use, and may serve as an important point of intervention for reducing HIV transmission rates.

Crosstalk between ERK2 and RXR regulates nuclear import of transcription factor NGFI-B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jacobs, Chris M.; Paulsen, Ragnhild E.

2005-10-21

Transcription factor NGFI-B initiates apoptosis when allowed to translocate to mitochondria. Retinoid-X receptor (RXR), another member of the nuclear receptor family, regulates NGFI-B signaling through heterodimerization and nuclear export. Growth factor EGF activates ERK2, which phosphorylates NGFI-B and determines if NGFI-B is allowed to translocate to mitochondria. In the present study, EGF treatment resulted in an increased nuclear import of NGFI-B. Likewise, active ERK2 resulted in a preferential nuclear localization of NGFI-B. When coexpressed with RXR the nuclear import and nuclear localization induced by active ERK2 were strongly reduced. In the presence of its ligand 9-cis-retinoic acid, RXR no longermore » inhibited ERK2-induced nuclear import. Thus, RXR serves a permissive role for ERK2-mediated nuclear accumulation of NGFI-B. This finding represents a novel crosstalk between ERK2 and RXR signaling pathways, and explains how two independent inhibitors of apoptosis (EGF and 9-cis-retinoic acid) may cooperate to regulate nuclear targeting of apoptosis inducer NGFI-B.« less

Characterization of Transcription Factor Gene OsDRAP1 Conferring Drought Tolerance in Rice

PubMed Central

Huang, Liyu; Wang, Yinxiao; Wang, Wensheng; Zhao, Xiuqin; Qin, Qiao; Sun, Fan; Hu, Fengyi; Zhao, Yan; Li, Zichao; Fu, Binying; Li, Zhikang

2018-01-01

HIGHLIGHTS Overexpressing and RNA interfering OsDRAP1 transgenic rice plants exhibited significantly improved and reduced drought tolerance, but accompanied with negative effects on development and yield. The dehydration responsive element binding (DREBs) genes are important transcription factors which play a crucial role in plant abiotic stress tolerances. In this study, we functionally characterized a DREB2-like gene, OsDRAP1 conferring drought tolerance (DT) in rice. OsDRAP1, containing many cis-elements in its promoter region, was expressed in all organs (mainly expressed in vascular tissues) of rice, and induced by a variety of environmental stresses and plant hormones. Overexpressing OsDRAP1 transgenic plants exhibited significantly improved DT; while OsDRAP1 RNA interfering plants exhibited significantly reduced DT which also accompanied with significant negative effects on development and yield. Overexpression of OsDRAP1 has a positive impact on maintaining water balance, redox homeostasis and vascular development in transgenic rice plants under drought stress. OsDRAP1 interacted with many genes/proteins and could activate many downstream DT related genes, including important transcription factors such as OsCBSX3 to response drought stress, indicating the OsDRAP1-mediated pathways for DT involve complex genes networks. All these results provide a basis for further complete understanding of the OsDRAP1 mediated gene networks and their related phenotypic effects. PMID:29449862

Social phobia: etiology, neurobiology, and treatment.

PubMed

Coupland, N J

2001-01-01

Social phobia is a common and often disabling condition, with an etiology that is not established. There is evidence at several levels for an interplay of biological and psychological processes in social phobia. Genetic studies show that both genetic and environmental factors are important, with evidence pointing to associations with 2 genetic conditions, autism and fragile X syndrome. Behavioral inhibition has emerged as an important precursor to social phobia and possibly to other anxiety disorders. Epidemiologic and clinical studies have suggested that factors within the family environment, such as overprotection, overcontrol, modeling of anxiety, criticism, and in some cases abuse, can play a role in the development of social phobia. During childhood, complex interactions between brain system disturbances that mediate responses to negative social cues and factors in the social setting may lead to the development of a distorted set of internal "blueprints" for social behavior. The impact of severe social anxiety on brain systems that mediate behavioral change may prevent patients from learning better "blueprints." These can be taught through cognitive-behavioral therapies. The effective control of social anxiety with medications enables patients to recover; whether recovery can last after discontinuation of medications may depend on whether a new "blueprint" has been developed and whether stable changes in affected brain systems have occurred. Neuroimaging techniques are at the early stage of identifying abnormalities at the neurotransmitter and systems levels.

The mediating effect of psychosocial factors on suicidal probability among adolescents.

PubMed

Hur, Ji-Won; Kim, Won-Joong; Kim, Yong-Ku

2011-01-01

Suicidal probability is an actual tendency including negative self-evaluation, hopelessness, suicidal ideation, and hostility. The purpose of this study was to examine the role of psychosocial variances in the suicidal probability of adolescents, especially the role of mediating variance. This study investigated the mediating effects of psychosocial factors such as depression, anxiety, self-esteem, stress, and social support on the suicidal probability among 1,586 adolescents attending middle and high schools in the Kyunggi Province area of South Korea. The relationship between depression and anxiety/suicidal probability was mediated by both social resources and self-esteem. Furthermore, the influence of social resources was mediated by interpersonal and achievement stress as well as self-esteem. This study suggests that suicidal probability in adolescents has various relationships, including mediating relations, with several psychosocial factors. The interventions on suicidal probability in adolescents should focus on social factors as well as clinical symptoms.

The relationship between ADHD symptoms, mood instability, and self-reported offending.

PubMed

Gudjonsson, Gisli H; Sigurdsson, Jon Fridrik; Adalsteinsson, Tomas F; Young, Susan

2013-05-01

To investigate the relative importance of ADHD symptoms, mood instability, and antisocial personality disorder traits in predicting self-reported offending. A total of 295 Icelandic students completed two scales of offending behavior and measures of ADHD symptoms, mood instability, and antisocial personality traits. Self-reported offending from the two independent scales correlated significantly with ADHD symptoms, mood instability, and antisocial personality traits with medium to large effect size. Multiple regressions showed that ADHD symptoms contributed to the two outcome measures beyond that of age and gender with a medium effect size. The ADHD effects were only partly mediated by mood instability and antisocial personality traits for general offending but were almost completely mediated by the more reactive measure of antisocial behavior. ADHD appears to be a potential risk factor for general offending in its own right irrespective of the presence of comorbidity, whereas mood instability is more important with regard to reactive behavior.

Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation.

PubMed

Su, Grace L

2002-08-01

Endogenous gut-derived bacterial lipopolysaccharides have been implicated as important cofactors in the pathogenesis of liver injury. However, the molecular mechanisms by which lipopolysaccharides exert their effect are not entirely clear. Recent studies have pointed to proinflammatory cytokines such as tumor necrosis factor-alpha as mediators of hepatocyte injury. Within the liver, Kupffer cells are major sources of proinflammatory cytokines that are produced in response to lipopolysaccharides. This review will focus on three important molecular components of the pathway by which lipopolysaccharides activate Kupffer cells: CD14, Toll-like receptor 4, and lipopolysaccharide binding protein. Within the liver, lipopolysaccharides bind to lipopolysaccharide binding protein, which then facilitates its transfer to membrane CD14 on the surface of Kupffer cells. Signaling of lipopolysaccharide through CD14 is mediated by the downstream receptor Toll-like receptor 4 and results in activation of Kupffer cells. The role played by these molecules in liver injury will be examined.

Emotion regulation and childhood aggression: longitudinal associations.

PubMed

Röll, Judith; Koglin, Ute; Petermann, Franz

2012-12-01

Accumulating evidence suggests that emotion dysregulation is associated with psychopathology. This paper provides a review of recent longitudinal studies that investigate the relationship between emotion regulation and aggressive behavior in childhood age. While there is substantial evidence for assuming a close relation of emotion regulation and aggressive behavior, moderating and mediating factors like gender and peer rejection have been established. Furthermore, results suggest emotion dysregulation as an important risk factor of aggressive behavior. Several directions for future research are pointed out to further validate and refine the reviewed relationships.

The Influence of Neurocognitive Impairment, Depression, and Alcohol Use Disorders on Health-Related Quality of Life among Incarcerated, HIV-Infected, Opioid Dependent Malaysian Men: A Moderated Mediation Analysis.

PubMed

Shrestha, Roman; Weikum, Damian; Copenhaver, Michael; Altice, Frederick L

2017-04-01

Prior research has widely recognized neurocognitive impairment (NCI), depression, and alcohol use disorders (AUDs) as important negative predictors of health-related quality of life (HRQoL) among people living with HIV (PLWH). No studies to date, however, have explored how these neuropsychological factors operate together and affect HRQoL. Incarcerated male PLWH (N = 301) meeting criteria for opioid dependence were recruited from Malaysia's largest prison. Standardized scales for NCI, depression, alcohol use disorders (AUDs) and HRQoL were used to conduct a moderated mediation model to explore the extent to which depression mediated the relationship between NCI, HRQoL, and AUDs using an ordinary least squares regression-based path analytic framework. Results showed that increasing levels of NCI (B = -0.1773, p < 0.001) and depression (B = -0.6147, p < 0.001) were negatively associated with HRQoL. The effect of NCI on HRQoL was significantly (Sobel z = -3.5600, p < 0.001) mediated via depression (B = -0.1230, p < 0.001). Furthermore, the conditional indirect effect of NCI on HRQoL via depression for individuals with AUDs was significant (B = -0.9099, p = 0.0087), suggesting a moderated mediation effect. The findings disentangle the complex relationship using a moderated mediation model, demonstrating that increasing levels of NCI, which can be reduced with HIV treatment, negatively influenced HRQoL via depression for individuals with AUDs. This highlights the need for future interventions to target these complex interplay between neuropsychological factors in order to improve HRQoL among PLWH, particularly incarcerated PLWH with AUDs.

The Influence of Neurocognitive Impairment, Depression, and Alcohol Use Disorders on Health-Related Quality of Life among Incarcerated, HIV-Infected, Opioid Dependent Malaysian Men: A Moderated Mediation Analysis

PubMed Central

Shrestha, Roman; Weikum, Damian; Copenhaver, Michael; Altice, Frederick L.

2017-01-01

Prior research has widely recognized neurocognitive impairment (NCI), depression, and alcohol use disorders (AUDs) as important negative predictors of health-related quality of life (HRQoL) among people living with HIV (PLWH). No studies to date, however, have explored how these neuropsychological factors operate together and affect HRQoL. Incarcerated male PLWH (N=301) meeting criteria for opioid dependence were recruited from Malaysia’s largest prison. Standardized scales for NCI, depression, alcohol use disorders (AUDs) and HRQoL were used to conduct a moderated mediation model to explore the extent to which depression mediated the relationship between NCI, HRQoL, and AUDs using an ordinary least squares regression-based path analytic framework. Results showed that increasing levels of NCI (B = −.1773, p<0.001) and depression (B = −.6147, p<0.001) were negatively associated with HRQoL. The effect of NCI on HRQoL was significantly (Sobel z = −3.5600, p < 0.001) mediated via depression (B = −.1230, p < 0.001). Furthermore, the conditional indirect effect of NCI on HRQoL via depression for individuals with AUDs was significant (B = −.9099, p = .0087), suggesting a moderated mediation effect. The findings disentangle the complex relationship using a moderated mediation model, demonstrating that increasing levels of NCI, which can be reduced with HIV treatment, negatively influenced HRQoL via depression for individuals with AUDs. This highlights the need for future interventions to target these complex interplay between neuropsychological factors in order to improve HRQoL among PLWH, particularly incarcerated PLWH with AUDs. PMID:27544515

Trait anxiety mediates the effect of stress exposure on post-traumatic stress disorder and depression risk in cardiac surgery patients.

PubMed

Kok, Lotte; Sep, Milou S; Veldhuijzen, Dieuwke S; Cornelisse, Sandra; Nierich, Arno P; van der Maaten, Joost; Rosseel, Peter M; Hofland, Jan; Dieleman, Jan M; Vinkers, Christiaan H; Joëls, Marian; van Dijk, Diederik; Hillegers, Manon H

2016-12-01

Post-traumatic stress disorder (PTSD) and depression are common after cardiac surgery. Lifetime stress exposure and personality traits may influence the development of these psychiatric conditions. Self-reported rates of PTSD and depression and potential determinants (i.e., trait anxiety and stress exposure) were established 1.5 to 4 years after cardiac surgery. Data was available for 1125 out of 1244 (90.4%) participants. Multivariable linear regressions were conducted to investigate mediating and/or moderating effects of trait anxiety on the relationship between stress exposure, and PTSD and depression. Pre-planned subgroup analyses were performed for both sexes. PTSD and depression symptoms were present in 10.2% and 13.1% of the participants, respectively. Trait anxiety was a full mediator of the association between stress exposure and depression in both the total cohort and female and male subgroups. Moreover, trait anxiety partially mediated the relationship between stress exposure and PTSD in the full cohort and the male subgroup, whereas trait anxiety fully mediated this relationship in female patients. Trait anxiety did not play a moderating role in the total patient sample, nor after stratification on gender. The unequal distribution of male (78%) and female patients (22%) might limit the generalizability of our findings. Furthermore, risk factors were investigated retrospectively and with variable follow-up time. In cardiac surgery patients, trait anxiety was found to be an important mediator of postoperative PTSD and depression. Prospective research is necessary to verify whether these factors are reliable screening measures of individuals' vulnerability for psychopathology development after cardiac surgery. Copyright © 2016 Elsevier B.V. All rights reserved.

FHF2 isoforms differentially regulate Nav1.6 mediated resurgent sodium currents in dorsal root ganglion neurons

PubMed Central

Barbosa, Cindy; Xiao, Yucheng; Johnson, Andrew J.; Xie, Wenrui; Strong, Judith A.; Zhang, Jun-Ming; Cummins, Theodore R.

2017-01-01

Nav1.6 and Nav1.6 mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6 mediated resurgent currents by isoforms of Fibroblast growth Factor Homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas, FHF2B enhances resurgent currents. Overall our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies. PMID:27999940

Altered plasma levels of cytokines, soluble adhesion molecules and matrix metalloproteases in venous thrombosis.

PubMed

Mosevoll, Knut Anders; Lindås, Roald; Tvedt, Tor Henrik Anderson; Bruserud, Øystein; Reikvam, Håkon

2015-07-01

Recent studies have emphasized the importance of the inflammatory response mediated by monocyte and neutrophil activation in deep venous thrombosis (DVT); we therefore investigated whether this response was reflected in the plasma profile of inflammatory mediators in patients with suspected DVT. We included a group of 169 consecutive patients admitted to hospital from the primary health care service with suspected lower limb DVT. Plasma levels of 43 mediators were examined for a cohort of 89 consecutive patients and 20 healthy controls by Luminex multiplex analyses, i.e. 13 interleukins, 3 immunomodulatory cytokines, 8 chemokines, 8 growth factors, 3 adhesion molecules and 8 matrix metalloproteases. Selected mediators were analyzed for a second cohort of 80 consecutive patients. Thirty-five of 169 (21%) of referred patients were diagnosed with DVT. Only P-selectin (p<0.0001), vascular cell adhesion protein 1 (VCAM-1, p=0.0009), matrix metalloprotease 8 (MMP-8, p=0.0151) and hepatocyte growth factor (HGF, p=0.0415) differed significantly when comparing patients with and without DVT. When comparing DVT patients with healthy controls we observed significant differences for several mediators, where P-selectin (p=0.0009), VCAM-1 (p<0.0001), all the MMPs (all p<0.0014) and HGF (p<0.0001) showed the strongest significant differences. Unsupervised hierarchical clustering analyses based on biomarkers showing differences between patients with and without DVT could be used to identify patient subsets that differed significantly in DVT frequency. Plasma biomarker profiling of selected soluble mediators can be used to identify subsets among patients with suspected lower limb thrombosis that differ significantly in their frequencies of DVT. Copyright © 2015 Elsevier Ltd. All rights reserved.

Transcriptome-Wide Analysis of Hepatitis B Virus-Mediated Changes to Normal Hepatocyte Gene Expression.

PubMed

Lamontagne, Jason; Mell, Joshua C; Bouchard, Michael J

2016-02-01

Globally, a chronic hepatitis B virus (HBV) infection remains the leading cause of primary liver cancer. The mechanisms leading to the development of HBV-associated liver cancer remain incompletely understood. In part, this is because studies have been limited by the lack of effective model systems that are both readily available and mimic the cellular environment of a normal hepatocyte. Additionally, many studies have focused on single, specific factors or pathways that may be affected by HBV, without addressing cell physiology as a whole. Here, we apply RNA-seq technology to investigate transcriptome-wide, HBV-mediated changes in gene expression to identify single factors and pathways as well as networks of genes and pathways that are affected in the context of HBV replication. Importantly, these studies were conducted in an ex vivo model of cultured primary hepatocytes, allowing for the transcriptomic characterization of this model system and an investigation of early HBV-mediated effects in a biologically relevant context. We analyzed differential gene expression within the context of time-mediated gene-expression changes and show that in the context of HBV replication a number of genes and cellular pathways are altered, including those associated with metabolism, cell cycle regulation, and lipid biosynthesis. Multiple analysis pipelines, as well as qRT-PCR and an independent, replicate RNA-seq analysis, were used to identify and confirm differentially expressed genes. HBV-mediated alterations to the transcriptome that we identified likely represent early changes to hepatocytes following an HBV infection, suggesting potential targets for early therapeutic intervention. Overall, these studies have produced a valuable resource that can be used to expand our understanding of the complex network of host-virus interactions and the impact of HBV-mediated changes to normal hepatocyte physiology on viral replication.

Crisis of Meaning Predicts Suicidality in Youth Independently of Depression.

PubMed

Schnell, Tatjana; Gerstner, Rebekka; Krampe, Henning

2018-02-23

At times, the question for meaning comes to nothing and a crisis of meaning ensues. This state is very painful, but difficult to account. Both those who suffer from it and care professionals find themselves at a loss for words. This study introduces an operationalization of a crisis of meaning. It aims to distinguish the concept from depression, and to investigate whether a crisis of meaning can explain suicidality beyond the known protective and risk factors self-esteem, family functioning, life-event load, and depression. Final-year school pupils in Ecuador (N = 300) completed questionnaires assessing the above variables. Data were analyzed using chi-square, hierarchic multiple regression, serial mediation, and moderator analyses. Crisis of meaning was distinguished from depression. It explained a significant amount of variance in suicidality beyond the mentioned protective and risk factors. For males, crisis of meaning was the only significant risk factor, and the strongest predictor overall. The acute risk factors depression and crisis of meaning mediated the effects of the baseline factors self-esteem, family functioning, and life-event load on suicidality. The study was cross-sectional; assessed factors predicted variance in suicidal thoughts, plans, and past suicide attempts, while their relevance cannot be generalized to actual future suicide attempts. A crisis of meaning is an important factor to take into account in further research on the prevention and treatment of people at risk of suicide.

Social Differentiation of Sun-Protection Behaviors: The Mediating Role of Cognitive Factors.

PubMed

Bocquier, Aurélie; Fressard, Lisa; Legleye, Stéphane; Verger, Pierre; Peretti-Watel, Patrick

2016-03-01

Adherence to sun-protection guidelines in developed countries is low, especially among people of low SES. Mechanisms underlying this social differentiation are poorly understood. This study aimed to examine the social differentiation of sun-protection behaviors and of two cognitive factors (knowledge about both sun health and behavioral risk factors for cancer) and to determine if these cognitive factors mediate the association between SES and sun-protection behaviors. Data came from the 2010 Baromètre Cancer survey (analyzed in 2014), a random cross-sectional telephone survey conducted among the French general population (n=3,359 individuals aged 15-75 years). First, bivariate associations between a composite individual SES indicator (based on education level, occupation, and income) and both sun-protection behaviors and cognitive factors were tested with chi-square tests and ANOVA. Then, confirmatory factor analysis and structural equation modeling were used to test the mediating role of cognitive factors with a multiple mediation model including four latent variables. In bivariate analyses, the individual SES indicator was positively associated with sun-protection behaviors and both cognitive factors. Multiple mediation analyses showed that both cognitive factors partially mediated the effect of individual SES on sun-protection behaviors. The overall proportion of mediated effects was 48%. The direct effect of SES remained significant. These results suggest that interventions aimed at modifying the knowledge and perceptions of people of low SES might help to reduce social differentiation of sun-protection behaviors. Further qualitative research is needed to better understand these cognitive factors and develop suitable prevention messages. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

The pathogenesis, detection, and prevention of Vibrio parahaemolyticus

PubMed Central

Wang, Rongzhi; Zhong, Yanfang; Gu, Xiaosong; Yuan, Jun; Saeed, Abdullah F.; Wang, Shihua

2015-01-01

Vibrio parahaemolyticus, a Gram-negative motile bacterium that inhabits marine and estuarine environments throughout the world, is a major food-borne pathogen that causes life-threatening diseases in humans after the consumption of raw or undercooked seafood. The global occurrence of V. parahaemolyticus accentuates the importance of investigating its virulence factors and their effects on the human host. This review describes the virulence factors of V. parahaemolyticus reported to date, including hemolysin, urease, two type III secretion systems and two type VI secretion systems, which both cause both cytotoxicity in cultured cells and enterotoxicity in animal models. We describe various types of detection methods, based on virulence factors, that are used for quantitative detection of V. parahaemolyticus in seafood. We also discuss some useful preventive measures and therapeutic strategies for the diseases mediated by V. parahaemolyticus, which can reduce, to some extent, the damage to humans and aquatic animals attributable to V. parahaemolyticus. This review extends our understanding of the pathogenic mechanisms of V. parahaemolyticus mediated by virulence factors and the diseases it causes in its human host. It should provide new insights for the diagnosis, treatment, and prevention of V. parahaemolyticus infection. PMID:25798132

Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice.

PubMed

Zhou, Rui-Jun; Ye, Hua; Wang, Feng; Wang, Jun-Long; Xie, Mei-Lin

2017-11-04

Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-κB (NF-κB) protein expression and tumor necrosis factor-α. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARγ/NF-κB-mediated inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Examining the relationships between resources and online health information seeking among patients with chronic diseases and healthy people.

PubMed

Oh, Young Sam; Cho, Youngmin

2015-01-01

The Internet is increasingly used as an important source of health and medical-related information for people with chronic diseases. It is recognized that online health information seeking (OHIS) is influenced by individuals' multi-dimensional factors, such as demographics, socio-economic factors, perceptions of the Internet, and health conditions. This study applies the conservation of resource theory to examine relationships between various multi-dimensional factors, daily challenges, and OHIS depending on individuals' health conditions. The data used in this study was taken from the U.S. Health Tracking Survey (2012). In this study, Internet users aged 18 and older were classified into patients (N = 518) and healthy people (N = 677) based on their health status related to chronic diseases. Multiple regression analysis was used to examine the relationships between multi-dimensional factors (resources), self-rated health, and OHIS. Patients' various resources (e.g., age, income, education, having a smartphone, and health tracking) significantly predicted their self-rated health and OHIS; in addition, self-rated health significantly mediated the relationships between focal resources and OHIS. However, the mediating effects of self-rated health were not found in healthy people.

Smoking outcome expectancies in military veteran smokers with posttraumatic stress disorder.

PubMed

Carmody, Timothy P; McFall, Miles; Saxon, Andrew J; Malte, Carol A; Chow, Bruce; Joseph, Anne M; Beckham, Jean C; Cook, Jessica W

2012-08-01

Smoking outcome expectancies were investigated in treatment-seeking military Veteran smokers with posttraumatic stress disorder (PTSD). The investigation of smoking outcome expectancies may enhance our understanding of the relationship between PTSD and cigarette smoking. Participants were 943 military Veterans with a diagnosis of PTSD who were current smokers enrolled in a randomized multisite effectiveness trial to test whether the integration of smoking cessation treatment into mental health care (integrated care) improves prolonged abstinence rates compared with referral to specialized smoking cessation clinics (usual care). Using confirmatory factor analysis (CFA), we evaluated the conceptual model of smoking outcome expectancies measured on the Smoking Consequences Questionnaire-Adult (SCQ-A) version. The Kraemer method of mediation analysis was used to investigate the role of smoking outcome expectancies in mediating relationships between PTSD symptoms and smoking behavior, tobacco dependence, and abstinence self-efficacy. The CFA supported the 10-factor structure of the SCQ-A in smokers with PTSD. Relationships between measures of PTSD symptoms and tobacco dependence were mediated by the smoking outcome expectancy regarding negative affect reduction. This same smoking outcome expectancy mediated relationships between PTSD symptoms and smoking abstinence self-efficacy. The findings support the use of the SCQ-A as a valid measure of smoking outcome expectancies in military Veteran smokers with PTSD. Moreover, they suggest that smoking outcome expectancies may play an important role in explaining the relationship between PTSD and cigarette smoking.

Hypoxia-inducible factor 1 mediates hypoxia-induced cardiomyocyte lipid accumulation by reducing the DNA binding activity of peroxisome proliferator-activated receptor {alpha}/retinoid X receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belanger, Adam J.; Luo Zhengyu; Vincent, Karen A.

2007-12-21

In response to cellular hypoxia, cardiomyocytes adapt to consume less oxygen by shifting ATP production from mitochondrial fatty acid {beta}-oxidation to glycolysis. The transcriptional activation of glucose transporters and glycolytic enzymes by hypoxia is mediated by hypoxia-inducible factor 1 (HIF-1). In this study, we examined whether HIF-1 was involved in the suppression of mitochondrial fatty acid {beta}-oxidation in hypoxic cardiomyocytes. We showed that either hypoxia or adenovirus-mediated expression of a constitutively stable hybrid form (HIF-1{alpha}/VP16) suppressed mitochondrial fatty acid metabolism, as indicated by an accumulation of intracellular neutral lipid. Both treatments also reduced the mRNA levels of muscle carnitine palmitoyltransferasemore » I which catalyzes the rate-limiting step in the mitochondrial import of fatty acids for {beta}-oxidation. Furthermore, adenovirus-mediated expression of HIF-1{alpha}/VP16 in cardiomyocytes under normoxic conditions also mimicked the reduction in the DNA binding activity of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha})/retinoid X receptor (RXR), in the presence or absence of a PPAR{alpha} ligand. These results suggest that HIF-1 may be involved in hypoxia-induced suppression of fatty acid metabolism in cardiomyocytes by reducing the DNA binding activity of PPAR{alpha}/RXR.« less

Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.

PubMed

Gaughan, Luke; Logan, Ian R; Neal, David E; Robson, Craig N

2005-01-01

The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.

Capsular Polysaccharide is a Main Component of Mycoplasma ovipneumoniae in the Pathogen-Induced Toll-Like Receptor-Mediated Inflammatory Responses in Sheep Airway Epithelial Cells

PubMed Central

Jiang, Zhongjia; Song, Fuyang; Li, Yanan; Xue, Di; Deng, Guangcun; Li, Min

2017-01-01

Mycoplasma ovipneumoniae (M. ovipneumoniae) is characterized as an etiological agent of primary atypical pneumonia that specifically infects sheep and goat. In an attempt to better understand the pathogen-host interaction between the invading M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory responses against capsular polysaccharide (designated as CPS) of M. ovipneumoniae using sheep bronchial epithelial cells cultured in an air-liquid interface (ALI) model. Results showed that CPS derived from M. ovipneumoniae could activate toll-like receptor- (TLR-) mediated inflammatory responses, along with an elevated expression of nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) as well as various inflammatory-associated mediators, representatively including proinflammatory cytokines, such as IL1β, TNFα, and IL8, and anti-inflammatory cytokines such as IL10 and TGFβ of TLR signaling cascade. Mechanistically, the CPS-induced inflammation was TLR initiated and was mediated by activations of both MyD88-dependent and MyD88-independent signaling pathways. Of importance, a blockage of CPS with specific antibody led a significant reduction of M. ovipneumoniae-induced inflammatory responses in sheep bronchial epithelial cells. These results suggested that CPS is a key virulent component of M. ovipneumoniae, which may play a crucial role in the inflammatory response induced by M. ovipneumoniae infections. PMID:28553017

Treatment with a New Peroxisome Proliferator-Activated Receptor Gamma Agonist, Pyridinecarboxylic Acid Derivative, Increases Angiogenesis and Reduces Inflammatory Mediators in the Heart of Trypanosoma cruzi-Infected Mice.

PubMed

Penas, Federico Nicolás; Carta, Davide; Dmytrenko, Ganna; Mirkin, Gerado A; Modenutti, Carlos Pablo; Cevey, Ágata Carolina; Rada, Maria Jimena; Ferlin, Maria Grazia; Sales, María Elena; Goren, Nora Beatriz

2017-01-01

Trypanosoma cruzi infection induces an intense inflammatory response in diverse host tissues. The immune response and the microvascular abnormalities associated with infection are crucial aspects in the generation of heart damage in Chagas disease. Upon parasite uptake, macrophages, which are involved in the clearance of infection, increase inflammatory mediators, leading to parasite killing. The exacerbation of the inflammatory response may lead to tissue damage. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear transcription factor that exerts important anti-inflammatory effects and is involved in improving endothelial functions and proangiogenic capacities. In this study, we evaluated the intermolecular interaction between PPARγ and a new synthetic PPARγ ligand, HP 24 , using virtual docking. Also, we showed that early treatment with HP 24 , decreases the expression of NOS2, a pro-inflammatory mediator, and stimulates proangiogenic mediators (vascular endothelial growth factor A, CD31, and Arginase I) both in macrophages and in the heart of T. cruzi -infected mice. Moreover, HP 24 reduces the inflammatory response, cardiac fibrosis and the levels of inflammatory cytokines (TNF-α, interleukin 6) released by macrophages of T. cruzi -infected mice. We consider that PPARγ agonists might be useful as coadjuvants of the antiparasitic treatment of Chagas disease, to delay, reverse, or preclude the onset of heart damage.

Agonistic and Antagonistic Roles for TNIK and MINK in Non-Canonical and Canonical Wnt Signalling

PubMed Central

Mikryukov, Alexander; Moss, Tom

2012-01-01

Wnt signalling is a key regulatory factor in animal development and homeostasis and plays an important role in the establishment and progression of cancer. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical ß-catenin pathway and a non-canonical pathway controlling planar cell polarity and convergent extension. Interference between these pathways is an important determinant of cellular and phenotypic responses, but is poorly understood. Here we show that TNIK (Traf2 and Nck-interacting kinase) and MINK (Misshapen/NIKs-related kinase) MAP4K signalling kinases are integral components of both canonical and non-canonical pathways in Xenopus. xTNIK and xMINK interact and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology (CNH) Domain fragments that are suppressive. The catalytic activity of the Kinase domain fragments of both xTNIK and xMINK mediate non-canonical signalling. However, while the Kinase domain fragments of xTNIK also mediate canonical signalling, the analogous fragments derived from xMINK strongly antagonize this signalling. Our data suggest that the proteolytic cleavage of xTNIK and xMINK determines their respective activities and is an important factor in controlling the balance between canonical and non-canonical Wnt signalling in vivo. PMID:22984420

Therapeutic potential of Mediator complex subunits in metabolic diseases.

PubMed

Ranjan, Amol; Ansari, Suraiya A

2018-01-01

The multisubunit Mediator is an evolutionary conserved transcriptional coregulatory complex in eukaryotes. It is needed for the transcriptional regulation of gene expression in general as well as in a gene specific manner. Mediator complex subunits interact with different transcription factors as well as components of RNA Pol II transcription initiation complex and in doing so act as a bridge between gene specific transcription factors and general Pol II transcription machinery. Specific interaction of various Mediator subunits with nuclear receptors (NRs) and other transcription factors involved in metabolism has been reported in different studies. Evidences indicate that ligand-activated NRs recruit Mediator complex for RNA Pol II-dependent gene transcription. These NRs have been explored as therapeutic targets in different metabolic diseases; however, they show side-effects as targets due to their overlapping involvement in different signaling pathways. Here we discuss the interaction of various Mediator subunits with transcription factors involved in metabolism and whether specific interaction of these transcription factors with Mediator subunits could be potentially utilized as therapeutic strategy in a variety of metabolic diseases. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

O-GlcNAc modification of Sp1 mediates hyperglycaemia-induced ICAM-1 up-regulation in endothelial cells.

PubMed

Zhang, Yuan; Qu, Yuan; Niu, Tian; Wang, Haiyan; Liu, Kun

2017-02-26

Intracellular adhesion molecule 1 (ICAM-1) is an important inflammatory factor that causes retinal damage during diabetic retinopathy. Hyperglycaemia can increase ICAM-1 expression in endothelial cells and the ICAM-1 promoter is responsive to the transcription factor specificity protein 1 (Sp1). O-GlcNAc modification is driven by the glucose concentration and has a profound effect on Sp1 activity. In this study, we investigated the underlying mechanism through which hyperglycaemia triggers ICAM-1 expression, which is mediated by O-GlcNAc modification of Sp1 in human umbilical vein endothelial cells (HUVECs) and rat retinal capillary endothelial cells (RRCECs). We showed that hyperglycaemia (30 mM) increased ICAM-1 expression compared to control conditions (5 mM). The addition of an OGT inhibitor decreased ICAM-1 expression and addition of an OGA inhibitor enhanced ICAM-1 expression. Furthermore, cells transduced with siSp1 exhibited dramatically decreased ICAM-1 expression. These results proved that the up-regulation of ICAM-1 with hyperglycaemia is mediated by O-GlcNAc modification of Sp1. It helps to explain the mechanism of ICAM-1 processing in HUVECs and RRCECs. Understanding how this inflammatory factor is modulated during diabetic retinopathy will ultimately help to design novel therapeutics to treat this condition. Copyright © 2017. Published by Elsevier Inc.

Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine.

PubMed

He, Dao-Yao; Ron, Dorit

2006-11-01

We recently showed that the up-regulation of the glial cell line-derived neurotrophic factor (GDNF) pathway in the midbrain, is the molecular mechanism by which the putative anti-addiction drug Ibogaine mediates its desirable action of reducing alcohol consumption. Human reports and studies in rodents have shown that a single administration of Ibogaine results in a long-lasting reduction of drug craving (humans) and drug and alcohol intake (rodents). Here we determine whether, and how, Ibogaine exerts its long-lasting actions on GDNF expression and signaling. Using the dopaminergic-like SHSY5Y cell line as a culture model, we observed that short-term Ibogaine exposure results in a sustained increase in GDNF expression that is mediated via the induction of a long-lasting autoregulatory cycle by which GDNF positively regulates its own expression. We show that the initial exposure of cells to Ibogaine or GDNF results in an increase in GDNF mRNA, leading to protein expression and to the corresponding activation of the GDNF signaling pathway. This, in turn, leads to a further increase in the mRNA level of the growth factor. The identification of a GDNF-mediated, autoregulatory long-lasting feedback loop could have important implications for GDNF's potential value as a treatment for addiction and neurodegenerative diseases.

β-Adrenergic Stimulation Induces Histone Deacetylase 5 (HDAC5) Nuclear Accumulation in Cardiomyocytes by B55α-PP2A-Mediated Dephosphorylation.

PubMed

Weeks, Kate L; Ranieri, Antonella; Karaś, Agnieszka; Bernardo, Bianca C; Ashcroft, Alexandra S; Molenaar, Chris; McMullen, Julie R; Avkiran, Metin

2017-03-25

Class IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. β-Adrenoceptor (β-AR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation-dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of β-AR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms. A novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the β-AR agonist isoproterenol to induce β 1 -AR-mediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Co-immunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55α, as well as catalytic and scaffolding subunits, which increased >3-fold with isoproterenol. Knockdown of B55α in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation. β-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Understanding Factors Associated with Singaporean Adolescents' Intention to Adopt Privacy Protection Behavior Using an Extended Theory of Planned Behavior.

PubMed

Ho, Shirley S; Lwin, May O; Yee, Andrew Z H; Lee, Edmund W J

2017-09-01

Using an extended theory of planned behavior (TPB), this study explores how the original TPB variables (attitude, subjective norms, and perceived behavioral control), personality traits, privacy concern, past privacy protection behaviors (PPBs), as well as parental mediation strategies relate to adolescents' intention to engage in privacy protection measures. We administered a cross-sectional survey to a nationally representative sample of adolescents (N = 4,920) in Singapore. The sample comprised 50.5 percent females and 49.5 percent males with age ranging from 13 to 21 years (M = 14.73). Results from the hierarchical regression analysis showed that the proposed extended TPB model received partial support. Subjective norms, among the TPB and other factors, have the strongest relationship with adolescents' intention to engage in PPBs on social network sites. Adolescents' privacy concern and their past PPBs are more important in influencing their future PPB compared with personality traits such as neuroticism and extraversion. Adolescents whose parents have engaged in regulated parental mediation are more likely to protect their privacy on SNSs compared with adolescents whose parents have adopted active mediation style.

Optimization of Production Conditions for Protoplasts and Polyethylene Glycol-Mediated Transformation of Gaeumannomyces tritici.

PubMed

Wang, Mei; Zhang, Jie; Wang, Lanying; Han, Lirong; Zhang, Xing; Feng, Juntao

2018-05-24

Take-all, caused by Gaeumannomyces tritici , is one of the most important wheat root diseases worldwide, as it results in serious yield losses. In this study, G. tritici was transformed to express the hygromycin B phosphotransferase using a combined protoplast and polyethylene glycol (PEG)-mediated transformation technique. Based on a series of single-factor experimental results, three major factors-temperature, enzyme lysis time, and concentration of the lysing enzyme-were selected as the independent variables, which were optimized using the response surface methodology. A higher protoplast yield of 9.83 × 10⁷ protoplasts/mL was observed, and the protoplast vitality was also high, reaching 96.27% after optimization. Protoplasts were isolated under the optimal conditions, with the highest transformation frequency (46⁻54 transformants/μg DNA). Polymerase chain reaction and Southern blotting detection indicated that the genes of hygromycin phosphotransferase were successfully inserted into the genome of G. tritici . An optimised PEG-mediated protoplast transformation system for G. tritici was established. The techniques and procedures described will lay the foundation for establishing a good mutation library of G. tritici and could be used to transform other fungi.

Enhanced Radiotherapy using Bismuth Sulfide Nanoagents Combined with Photo-thermal Treatment.

PubMed

Cheng, Xiaju; Yong, Yuan; Dai, Yiheng; Song, Xin; Yang, Gang; Pan, Yue; Ge, Cuicui

2017-01-01

Nanotechniques that can improve the effectiveness of radiotherapy (RT) by integrating it with multimodal imaging are highly desirable. Results In this study, we fabricated Bi 2 S 3 nanorods that have attractive features such as their ability to function as contrast agents for X-ray computed tomography (CT) and photoacoustic (PA) imaging as well as good biocompatibility. Both in vitro and in vivo studies confirmed that the Bi 2 S 3 nanoagents could potentiate the lethal effects of radiation via amplifying the local radiation dose and enhancing the anti-tumor efficacy of RT by augmenting the photo-thermal effect. Furthermore, the nanoagent-mediated hyperthermia could effectively increase the oxygen concentration in hypoxic regions thereby inhibiting the expression of hypoxia-inducible factor ( HIF -1α). This, in turn, interfered with DNA repair via decreasing the expression of DNA repair-related proteins to overcome radio-resistance. Also, RT combined with nanoagent-mediated hyperthermia could substantially suppress tumor metastasis via down-regulating angiogenic factors. Conclusion In summary, we constructed a single-component powerful nanoagent for CT/PA imaging-guided tumor radiotherapy and, most importantly, explored the potential mechanisms of nanoagent-mediated photo-thermal treatment for enhancing the efficacy of RT in a synergistic manner.

Continued Bullying Victimization in Adolescents: Maladaptive Schemas as a Mediational Mechanism.

PubMed

Calvete, Esther; Fernández-González, Liria; González-Cabrera, Joaquín M; Gámez-Guadix, Manuel

2018-03-01

Bullying victimization in adolescence is a significant social problem that can become persistent over time for some victims. However, there is an overall paucity of research examining the factors that contribute to continued bullying victimization. Schema therapy proposes a model that can help us understand why bullying victimization can be persistent for some victims. This study examines the role of maladaptive schemas, the key concept in schema therapy, as a mechanism of continued bullying victimization. The hypothesis was that maladaptive schemas of rejection mediate the predictive association between victimization in both the family and at school and future bullying victimization. Social anxiety was also considered, as previous research suggests that it can increase the risk of victimization. The participants were 1328 adolescents (45% female) with a mean age of 15.05 years (SD = 1.37), who completed questionnaires at three time points with a 6-month interval between them. Time 2 maladaptive schemas of rejection significantly mediated the predictive association from Time 1 bullying victimization, family abuse and social anxiety to Time 3 bullying victimization. The findings pertaining to potentially malleable factors, such as maladaptive schemas that maintain continued interpersonal victimization, have important implications for prevention and treatment strategies with adolescents.

Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: Modulation by antioxidants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez-de-Arce, Karen; Departamento de Biologia Celular y Molecular, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago; Foncea, Rocio

2005-12-16

It has been proposed that homocysteine (Hcy)-induces endothelial dysfunction and atherosclerosis by generation of reactive oxygen species (ROS). A previous report has shown that Hcy promotes mitochondrial damage. Considering that oxidative stress can affect mitochondrial biogenesis, we hypothesized that Hcy-induced ROS in endothelial cells may lead to increased mitochondrial biogenesis. We found that Hcy-induced ROS (1.85-fold), leading to a NF-{kappa}B activation and increase the formation of 3-nitrotyrosine. Furthermore, expression of the mitochondrial biogenesis factors, nuclear respiratory factor-1 and mitochondrial transcription factor A, was significantly elevated in Hcy-treated cells. These changes were accompanied by increase in mitochondrial mass and higher mRNAmore » and protein expression of the subunit III of cytochrome c oxidase. These effects were significantly prevented by pretreatment with the antioxidants, catechin and trolox. Taken together, our results suggest that ROS is an important mediator of mitochondrial biogenesis induced by Hcy, and that modulation of oxidative stress by antioxidants may protect against the adverse vascular effects of Hcy.« less

Impact of lifestyle dimensions on brain pathology and cognition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schreiber, Stefanie; Vogel, Jacob; Schwimmer, Henry D.

Single lifestyle factors affect brain biomarkers and cognition. Here in this work, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based β-amyloid (Aβ), hippocampal volume, and cognitive function in aged controls. Lower Aβ burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ε4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Aβ load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive functionmore » and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Finally, our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.« less

Adult criminal involvement: A cross-sectional inquiry into correlates and mechanisms over the life course

PubMed Central

DePadilla, Lara; Perkins, Molly M.; Elifson, Kirk W.; Sterk, Claire E.

2013-01-01

In this paper, we examine the relative contribution of four domains of predictors that have been linked to adult criminal involvement: (1) socio-demographic characteristics, (2) family-of-origin factors, (3) proximal processes developed during adolescence, and (4) current lifestyle and situational factors. Cross-sectional data were collected through face-to-face interviews with 242 community-recruited adults. Data analysis involved negative binomial regression. Being male, family size, juvenile delinquency, aggression, living with someone involved in illegal activity and recent violent victimization were independently associated with non-violent criminal involvement. Aggression, association with deviant peers, and recent violent victimization were independently associated with violent criminal involvement. Juvenile delinquency and aggression mediated the affect of multiple family-of-origin characteristics on non-violent criminal involvement and aggression mediated the effect of childhood physical abuse on violent criminal involvement. The results emphasize the importance of investigating both antecedents and proximal risk factors predictive of different types of criminal involvement, which, in turn, will assist in developing risk-focused prevention and intervention programs. PMID:24307752