Publications

NOD2 and Crohn’s Disease: Loss or Gain of Function?

San Diego surveyed for heart-healthy foods and exercise facilities.

No abstract is provided for this article.

Epithelial Control of Gut-Associated Lymphoid Tissue Formation through p38α-Dependent Restraint of NF-κB Signaling

The protein kinase p38α mediates cellular responses to environmental and endogenous cues that direct tissue homeostasis and immune responses. Studies of mice lacking p38α in several different cell types have demonstrated that p38α signaling is essential to maintaining the proliferation-differentiation balance in developing and steady-state tissues. The mechanisms underlying these roles involve cell-autonomous control of signaling and gene expression by p38α. In this study, we show that p38α regulates gut-associated lymphoid tissue (GALT) formation in a noncell-autonomous manner. From an investigation of mice with intestinal epithelial cell-specific deletion of the p38α gene, we find that p38α serves to limit NF-κB signaling and thereby attenuate GALT-promoting chemokine expression in the intestinal epithelium. Loss of this regulation results in GALT hyperplasia and, in some animals, mucosa-associated B cell lymphoma. These anomalies occur independently of luminal microbial stimuli and are most likely driven by direct epithelial-lymphoid interactions. Our study illustrates a novel p38α-dependent mechanism preventing excessive generation of epithelial-derived signals that drive lymphoid tissue overgrowth and malignancy.

Neighborhood SES and walkability are related to physical activity behavior in Belgian adults

Objective To investigate whether neighborhood walkability (higher residential density, land use mix, street connectivity) is positively associated with physical activity in Belgian adults and whether this association is moderated by neighborhood SES. Methods The Belgian Environmental Physical Activity Study (BEPAS) was conducted in Ghent, Belgium. Data were collected between May 2007 and September 2008. Twenty-four neighborhoods were selected, stratified on GIS-based walkability and neighborhood SES. In total, 1200 adults (aged 20–65 years; 50 per neighborhood) completed the International Physical Activity Questionnaire and wore an accelerometer for seven days. After omitting participants with missing accelerometer data, the final sample consisted of 1166 adults. Results Living in a high-walkable neighborhood was associated with more accelerometer-based minutes of moderate-to-vigorous physical activity (38.6 vs. 31.8 min/day, p<0.001), transportational walking and cycling, recreational walking, and less motorized transport (all p<0.05). Low neighborhood SES was related to more cycling for transport and less motorized transport (all p<0.05). No interactions between walkability and neighborhood SES were found. Conclusions The BEPAS results generally confirmed the findings from Australia and the US showing that, in Europe, walkability is also positively related to physical activity. As neighborhood SES was not a significant moderator, walkability appears beneficial for all economic strata.

Dog Walking as Physical Activity and Multi-Level Correlates of Dog Walking among Adolescents

PURPOSE: To assess the association of dog ownership and dog walking with moderate to vigorous physical activity (MVPA) and BMI among adolescents and examine correlates of dog walking. METHODS: Participants were adolescents (n=928) from the Baltimore, MD and Seattle, WA regions, ages 12-17 years. Measures included 7 days of accelerometer monitoring, GIS measures of the built environment, and surveys of psychosocial and environment characteristics. Minutes/day of MVPA and BMI were compared among adolescents (1) without a dog (n=441) and those with a dog who (2) do (n=300) or (3) do not (n=184) walk it. Among adolescents with a dog (n=484), models assessed relations between dog walking (days/week) and (1) demographic, (2) psychosocial (physical activity self-efficacy), (3) home environment (electronic device ownership), (4) perceived neighborhood environment, and (5) objective neighborhood walkability factors. All models were adjusted for participant demographic factors. RESULTS: Adolescent dog walkers obtained 4-5 more minutes/day of MVPA than those with dogs but were non-dog-walkers (p=.044) and those who lived in non-dog households (p=.025). Adolescents who walked their dog were more likely to have a more educated parent (p=.056), own more personal electronics (p=.047), have better perceived neighborhood aesthetics (p=.016), live in a more walkable neighborhood (p=.045), and live in a multifamily home (p =0.003) compared to adolescents with dogs who did not walk them. Adolescents’ age interacted with physical activity self-efficacy (p=.045) and perceived neighborhood aesthetics (p<.001), where self-efficacy and aesthetics were positively associated with dog walking among younger adolescents and not associated in older adolescents. Adolescent BMI was not associated with dog walking or dog ownership. CONCLUSIONS: Dog walking was an important contributor to overall MVPA, where dog walkers obtained 7-8% more minutes/day of MVPA than those who did not walk them, and correlates of dog walking were found at multiple levels of influence. Results suggest interventions to increase dog walking at the environmental and psychosocial levels are worthy of evaluation, particularly given that nearly 50% of US households own dogs.

cis- and trans-Acting Genetic Elements Responsible for Induction of Specific Genes by Tumor Promoters, Serum Factors, and Stress

This chapter discusses the genetic mechanisms that underlie the ultraviolet response. During the early characterization of the UV response in cultured human fibroblasts, it became apparent that treatment of these cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA) leads to induction of most of the same peptides induced by UV or mitomycin C. Treatment of cultured mammalian cells with phorbol ester tumor promoters such as TPA causes a variety of pleiotropic effects, most of which are probably mediated by the activation of protein kinase C, the major cellular target for these agents. Many of the genes are also induced after treatment of cells with agents such as phorbol esters, serum growth factors, and lymphokines, which in most cases do not lead to direct deoxyribonucleic acid damage. However, based on genetic analysis, it appears that common cis- and trans-acting elements participate in mediating the transcriptional response to these agents.

TNFR signaling: ubiquitin‐conjugated TRAFfic signals control stop‐and‐go for MAPK signaling complexes

Nearly two decades after the initial cloning and identification of the founding father of the tumor necrosis factor receptor (TNFR) family, much has been learned about the mechanisms by which these receptors signal to critical transcription factors and other targets that regulate gene expression and cellular physiology. Mitogen-activated protein kinases (MAPKs) and inhibitor of nuclear factor (NF)-kappaB (I kappaB) kinases (IKKs) were identified early on as the upstream kinases responsible for activation of activator-protein 1 (AP-1) and NF-kappaB, respectively, and later on for their ability to control life-or-death decisions in TNF-stimulated cells. Both of these critical pathways are regulated at the level of MAPK kinase kinases (MAP3Ks), after which point they diverge. Recent work, however, illustrates that protein ubiquitination cascades play a critical initiating role in TNFR signaling and account for spatial and temporal separation of IKK and MAPK signaling cascades and thereby determine biological specificity and outcome. Cellular inhibitors of apoptosis (cIAPs) 1 and 2 are ubiquitin (Ub) ligases (E3s) that mediate canonical Lys48-linked ubiquitination of TNFR-associated factor 3 (TRAF3), marking it for subsequent degradation by the proteasome. TRAF3 degradation releases the brake on TRAF2/6:MAP3K signaling complexes responsible for MAPK activation, leading to their translocation from the cytoplasmic segment of the receptor to the cytosol where they initiate MAPK phosphorylation and activation. By contrast, IKK activation proceeds considerably faster than MAPK activation, takes place at the receptor, and is independent of cIAP1/2 activity and TRAF3 degradation. This arrangement may be important for ensuring the proper delivery of NF-kappaB-dependent survival signals and conversion of JNK-promoted death signals to proliferative ones.

Promoting Stair Use by Modeling: An Experimental Application of the Behavioral Ecological Model

Purpose. This study evaluated the effect of behavioral modeling and social factors promoting stair use. Design. Alternating baseline and intervention phase experimental design. Setting. San Diego International Airport, San Diego, California. Subjects. Stair use was coded for 15,574 filmed participants. Intervention. This study compared the effects of three types of behavioral modeling: natural models (i.e., passersby), single experimental model (i.e., confederate), and confederate model pairs providing verbal prompts. Measures. Variables were coded based on systematic observation of videotapes, including demographics, day and time, and the following indicators of physical and social reinforcement contingencies: dress, luggage, children, social group, and speed. Reliability ranged from .64 to .88. Analysis. Bivariate and logistic regression models stratified by gender. Results. Stair use increased over baseline by 102.6% with no model present and by 61.8% in the presence of natural models for men and women (p &lt; .001). Controlling for multiple covariates, the odds ratios for stair use ranged from 1.76 to 2.93 for men and from 1.82 to 2.54 for women across the levels with natural and confederate models present (all p &lt; .001). Conclusion. Modeling can prompt stair use, and findings for social and environmental reinforcement contingencies support the Behavioral Ecological Model. Modeling may explain partial maintenance of stair use in public areas after removal of prompts (e.g., signs, banners). Results inform interventions for increasing physical activity as part of daily routines.

TRACKING OF PHYSICAL ACTIVITY FROM AGES 4 TO 17 IN AN ANGLOAND MEXICAN-AMERICAN COHORT

PURPOSE We assessed physical activity (PA) tracking in a Euro- and Mexican-American cohort from ages 4 to 17 using both objective and subjective measures. METHODS 1 Objective PA data were obtained from direct observation in children's homes using BEACHES (12 occasions; ages 4–7), CALTRAC accelerometer (4 occasions; ages 11–12), and CSA accelerometer (4 occasions; ages 15–17). Listwise analyses for objective measures included 147 children (N=76 boys, 71 girls). Log transformations of CALTRAC and CSA measures corrected for skewed distributions. Best Linear Unbiased Predictors (BLUPs) were computed for each measure to accommodate subjects with missing data. Partial correlations were conducted separately for boys and girls, controlling for ethnicity. RESULTS 1 Significant correlations (i.e., tracking) among the three PA measures (i.e., across the three time periods) were not found for either gender. METHODS 2 Subjective PA data were obtained via Physical Activity Recall (PAR) interviews in children's homes on 4 occasions (2 interviews, 6-months apart at ages 11–12, and 2 interviews, 6-months apart at ages 16–17). Listwise analyses for PAR included 177 children (N=88 boys, 89 girls). BLUPs were computed for each measurement period. Partial correlations were conducted separately for boys and girls, controlling for ethnicity. RESULTS 2 Significant relationships in self-reported PA across time periods for both boys (r=.372, p = .000) and girls (r=.311, p = .000) were found. CONCLUSIONS Similar to other studies, PA tracking was higher using subjective than objective measures. Studying the tracking of PA as children move from early childhood through adolescence faces numerous challenges, including (1) rapid changes in the type of PA and its contexts (e.g., location) as children age, and (2) the need for technological advancements that will provide a valid samples of PA at different developmental levels. Supported by HL52449

Reducing Ultraviolet Radiation Exposure in Children

Background.ProjectSUNWISEevaluated the effectiveness of a multicomponent intervention in reducing children's ultraviolet radiation (UVR) exposure. Methods.Across four YMCAs, 48 aquatics classes (N= 169 children, mean age = 7) were randomly assigned to either the intervention or the control condition. The 6-week intervention included a UVR reduction curriculum presented at poolside by aquatics instructors and home-based activities for children and their parents. Outcome measures were (a) tanness-associated skin color dimensions assessed with a colorimeter, (b) specific daily solar protection behaviors of children as reported by parents, and (c) general solar protection behaviors. Results.Controlling for intraclass clustering in all analyses, at posttest, no statistically significant between-group differences were found in tanness, daily solar protection scores, or general sunscreen use. The intervention group showed significantly greater general hat use relative to controls. Conclusions.The intervention failed to impact most of the outcome measures. Supplementing the behavior-focused intervention package with environmental supports may be warranted.

Neighborhood Environments and Objectively Measured Physical Activity in 11 Countries

Environmental changes are potentially effective population-level physical activity (PA) promotion strategies. However, robust multisite evidence to guide international action for developing activity-supportive environments is lacking. We estimated pooled associations of perceived environmental attributes with objectively measured PA outcomes, between-site differences in such associations, and the extent to which perceived environmental attributes explain between-site differences in PA.This was a cross-sectional study conducted in 16 cities located in Belgium, Brazil, Colombia, Czech Republic, Denmark, China, Mexico, New Zealand, Spain, United Kingdom, and United States of America. Participants were 6968 adults residing in administrative units stratified by socioeconomic status and transport-related walkability. Predictors were 10 perceived neighborhood environmental attributes. Outcome measures were accelerometry-assessed weekly minutes of moderate-to-vigorous PA (MVPA) and meeting the PA guidelines for cancer/weight gain prevention (420 min·wk of MVPA).Most perceived neighborhood attributes were positively associated with the PA outcomes in the pooled, site-adjusted, single-predictor models. Associations were generalizable across geographical locations. Aesthetics and land use mix-access were significant predictors of both PA outcomes in the fully adjusted models. Environmental attributes accounted for within-site variability in MVPA, corresponding to an SD of 3 min·d or 21 min·wk. Large between-site differences in PA outcomes were observed; 15.9%-16.8% of these differences were explained by perceived environmental attributes. All neighborhood attributes were associated with between-site differences in the total effects of the perceived environment on PA outcomes.Residents' perceptions of neighborhood attributes that facilitate walking were positively associated with objectively measured MVPA and meeting the guidelines for cancer/weight gain prevention at the within- and between-site levels. Associations were similar across study sites, lending support for international recommendations for designing PA-friendly built environments.

Gender difference in NASH susceptibility: Roles of hepatocyte Ikkβ and Sult1e1

Myeloid cell and hepatocyte IKK may mediate the genesis of obesity and insulin resistance in mice fed high fat diet. However, their gender-specific roles in the pathogenesis of nonalcoholic steatohepatitis (NASH) are not known. Here we demonstrate myeloid IKK deficiency prevents Western diet-induced obesity and visceral adiposity in females but not in males, and attenuates hyperglycemia, global IR, and NASH in both genders. In contrast, all metabolic sequela including NASH are aggravated by hepatocyte IKK deficiency (Ikbkbhep) in male but not female mice. Gene profiling identifies sulfotransferase family 1E (Sult1e1), which encodes a sulfotransferase E1 responsible for inactivation of estrogen, as a gene upregulated in NASH in both genders and most conspicuously in male Ikbkbhep mice having worst NASH and lowest plasma estradiol levels. LXR is enriched to LXRE on Sult1e1 promoter in male WT and Ikbkbhep mice with NASH, and a Sult1e1 promoter activity is increased by LXR and its ligand and augmented by expression of a S32A mutant of IB. These results demonstrate striking gender differences in regulation by IKK of high cholesterol saturated fat diet-induced metabolic changes including NASH and suggest hepatocyte IKK is protective in male due at least in part to its ability to repress LXR-induced Sult1e1. Our findings also raise a caution for systemic IKK inhibition for the treatment of NASH as it may exacerbate the disease in male patients.

Dissection of functional domains of the pituitary-specific transcription factor GHF-1

Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation

The Hispanic Community Health Study/Study of Latinos Community and Surrounding Areas Study: sample, design, and procedures

Purpose We describe the sample, design, and procedures for the Community and Surrounding Areas Study (CASAS), an ancillary to the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The aim of SOL CASAS was to test an ecological model of macro- and micro-neighborhood environment factors, intermediate behavioral (physical activity) and psychosocial (e.g., depression and stress) mechanisms, and changes in cardiometabolic health in Hispanics/Latinos. Methods Between 2015 and 2017, approximately 6 years after the HCHS/SOL baseline (2008–2011), 1776 San Diego HCHS/SOL participants enrolled in SOL CASAS and completed a repeat physical activity assessment. Participants’ residential addresses were geoprocessed, and macroenvironmental features of the home were derived from publicly available data concurrent with the HCHS/SOL baseline and Visit 2 (2014–2017). Microscale environmental attributes were coded for 943 unique routes for 1684 participants, with a validated observational tool, concurrent with Visit 2, for SOL CASAS participants only. Results Of 2520 HCHS/SOL participants approached, 70.5% enrolled (mean age 55.3 years; 94% Mexican; 67.5% female). Accelerometer adherence (three or more days with at least 10 hours wear time) was outstanding (94%). Conclusions With its more comprehensive ecological model and well-characterized Hispanic/Latino population, SOL CASAS will advance the science concerning the contribution of neighborhood factors to cardiometabolic health.

Neighborhood Environment Walkability Scale for Youth (NEWS-Y): Reliability and relationship with physical activity

Objectives To examine the psychometric properties of the Neighborhood Environment Walkability Scale-Youth (NEWS-Y) and explore its associations with context-specific and overall physical activity (PA) among youth. Methods In 2005, parents of children ages 5–11 (n =116), parents of adolescents ages 12–18 (n =171), and adolescents ages 12–18 (n =171) from Boston, Cincinnati, and San Diego, completed NEWS-Y surveys regarding perceived land use mix-diversity, recreation facility availability, pedestrian/automobile traffic safety, crime safety, aesthetics, walking/cycling facilities, street connectivity, land use mix-access, and residential density. A standardized neighborhood environment score was derived. Self-reported activity in the street and in parks, and walking to parks, shops, school, and overall physical activity were assessed. Results The NEWS-Y subscales had acceptable test–retest reliability (ICC range .56–.87). Being active in a park, walking to a park, walking to shops, and walking to school were related to multiple environmental attributes in all three participant groups. Total neighborhood environment, recreation facilities, walking and cycling facilities, and land use mix-access had the most consistent relationships with specific types of activity. Conclusions The NEWS-Y has acceptable reliability and subscales were significantly correlated with specific types of youth PA. The NEWS-Y can be used to examine neighborhood environment correlates of youth PA.

A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas

Behavior Analysis and Public Health Perspectives: Combining Paradigms to Effect Prevention.

No abstract is provided for this article.

Immunosuppression by Glucocorticoids: Inhibition of NF-κB Activity Through Induction of IκB Synthesis

Glucocorticoids are among the most potent anti-inflammatory and immunosuppressive agents. They inhibit synthesis of almost all known cytokines and of several cell surface molecules required for immune function, but the mechanism underlying this activity has been unclear. Here it is shown that glucocorticoids are potent inhibitors of nuclear factor kappa B (NF-kappa B) activation in mice and cultured cells. This inhibition is mediated by induction of the I kappa B alpha inhibitory protein, which traps activated NF-kappa B in inactive cytoplasmic complexes. Because NF-kappa B activates many immunoregulatory genes in response to pro-inflammatory stimuli, the inhibition of its activity can be a major component of the anti-inflammatory activity of glucocorticoids.