Publications

The IkappaB kinase (IKK) complex is composed of three subunits, IKKalpha, IKKbeta, and IKKgamma (NEMO). While IKKalpha and IKKbeta are highly similar catalytic subunits, both capable of IkappaB phosphorylation in vitro, IKKgamma is a regulatory subunit. Previous biochemical and genetic analyses have indicated that despite their similar structures and in vitro kinase activities, IKKalpha and IKKbeta have distinct functions. Surprisingly, disruption of the Ikkalpha locus did not abolish activation of IKK by proinflammatory stimuli and resulted in only a small decrease in nuclear factor (NF)-kappaB activation. Now we describe the pathophysiological consequence of disruption of the Ikkbeta locus. IKKbeta-deficient mice die at mid-gestation from uncontrolled liver apoptosis, a phenotype that is remarkably similar to that of mice deficient in both the RelA (p65) and NF-kappaB1 (p50/p105) subunits of NF-kappaB. Accordingly, IKKbeta-deficient cells are defective in activation of IKK and NF-kappaB in response to either tumor necrosis factor alpha or interleukin 1. Thus IKKbeta, but not IKKalpha, plays the major role in IKK activation and induction of NF-kappaB activity. In the absence of IKKbeta, IKKalpha is unresponsive to IKK activators.

Objective Text-messaging shows promise as a health intervention. This randomized controlled trial evaluated a daily text-messaging weight loss intervention. Methods Overweight and obese adults (n=170) in California were randomized to receive daily interactive and personally weight-relevant text-messages or monthly e-newsletters. Participants were measured at baseline, 6 and 12months. Group differences were assessed in weight loss. Relation of text-messaging adherence to weight loss and change in pedometer steps was examined. Results There were no group differences in weight loss over 6 (1.53lb vs 3.72lb) or 12months (2.27lb vs 3.64lb; control vs intervention). Text-messaging adherence was moderately strong (60–69%). Participants with greater adherence lost more weight at 6 (p =.039) and 12months (p =.023) than those who were less adherent. Intervention participants' steps increased almost 3000steps/day over time (p <.05), and higher step counts were associated with greater weight loss (p <.05). Text-messaging satisfaction was moderate to high, and pedometer-related satisfaction was associated with greater weight loss (p <.05). Conclusions Although text-messaging had no effect on weight, adherence was associated with improvement in weight-related behaviors and weight outcomes. Text-messages could be a useful adjunct to weight loss treatments.

The thyroid hormone (T3) receptor type alpha, the c-ErbA alpha proto-oncoprotein, stimulates transcription of T3-dependent promoters, interferes with AP-1 activity, and induces erythroid differentiation in a ligand-dependent manner. The v-ErbA oncoprotein does not bind hormone and has lost all of these activities. Using c-ErbA/v-ErbA chimeras, we found that a deletion of 9 amino acids, conserved among many members of the nuclear receptor superfamily, which are located at the extreme carboxy terminus of c-ErbA alpha is responsible for loss of both transactivation and transcriptional interference activities. Single, double, and triple amino acid substitutions within this region completely abolished T3-dependent transcriptional activation, interference with AP-1 activity, and decreased T3 binding by c-ErbA alpha. However, the lower T3 binding by these mutants does not fully account for the loss of transactivation and transcriptional interference, since a c-ErbA/v-ErbA chimera which was similarly reduced in T3 binding activity has retained both of these functions. Deletion of homologous residues in the retinoic acid receptor alpha (RAR alpha) resulted in a similar loss of transactivation and transcriptional interference activities. The ability of c-ErbA alpha to induce differentiation of transformed erythroblasts is also impaired by all of the mutations introduced into the conserved carboxy-terminal sequence. We conclude that this 9-amino-acid conserved region is essential for normal biological function of c-ErbA alpha and RAR alpha and possibly other T3 and RA receptors.

Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagen-producing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagen-producing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.

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OBJECTIVES: To compare adolescents’ physical activity at home, near home, at school, near school, and at other locations. METHODS: Adolescents (N = 549) were ages 12 to 16 years (49.9% girls, 31.3% nonwhite or Hispanic) from 447 census block groups in 2 US regions. Accelerometers and Global Positioning System devices assessed minutes of and proportion of time spent in moderate to vigorous physical activity (MVPA) in each of the 5 locations. Mixed-effects regression compared MVPA across locations and demographic factors. RESULTS: Forty-two percent of adolescents’ overall MVPA occurred at school, 18.7% at home, 18.3% in other (nonhome, nonschool) locations, and 20.6% near home or school. Youth had 10 more minutes (30% more) of overall MVPA on school days than on nonschool days. However, the percentage of location time spent in MVPA was lowest at school (4.8% on school days) and highest near home and near school (9.5%–10.4%). Girls had 2.6 to 5.5 fewer minutes per day of MVPA than boys in all locations except near school. CONCLUSIONS: Although a majority of adolescents’ physical activity occurred at school, the low proportion of active time relative to the large amount of time spent at school suggests potential for increasing school-based activity. Increasing time spent in the neighborhood appears promising for increasing overall physical activity, because a high proportion of neighborhood time was active. Increasing youth physical activity to support metabolic health requires strategies for increasing use of physical activity–supportive locations (eg, neighborhoods) and environmental and program improvements in unsupportive locations (eg, schools, homes).

No abstract is provided for this article.

Background Substantial policy changes to control obesity, limit chronic disease, and reduce air pollution emissions, including greenhouse gasses, have been recommended. Transportation and planning policies that promote active travel by walking and cycling can contribute to these goals, potentially yielding further co-benefits. Little is known, however, about the interconnections among effects of policies considered, including potential unintended consequences. Objectives and methods We review available literature regarding health impacts from policies that encourage active travel in the context of developing health impact assessment (HIA) models to help decision-makers propose better solutions for healthy environments. We identify important components of HIA models of modal shifts in active travel in response to transport policies and interventions. Results and discussion Policies that increase active travel are likely to generate large individual health benefits through increases in physical activity for active travelers. Smaller, but population-wide benefits could accrue through reductions in air and noise pollution. Depending on conditions of policy implementations, risk tradeoffs are possible for some individuals who shift to active travel and consequently increase inhalation of air pollutants and exposure to traffic injuries. Well-designed policies may enhance health benefits through indirect outcomes such as improved social capital and diet, but these synergies are not sufficiently well understood to allow quantification at this time. Conclusion Evaluating impacts of active travel policies is highly complex; however, many associations can be quantified. Identifying health-maximizing policies and conditions requires integrated HIAs.

Background Few prospective studies have examined predictors of change in specific physical activity (PA) behaviours in different ethnic groups. Purpose To assess predictors of change in sports participation in Latino and non-Latino 5–8 year-old children in San Diego, California. Methods Average sports participation frequency (days/week) was assessed by validated parent-report at baseline (Nov 2006–May 2008) and 1 year later in 541 children (45.0% male, 41.1% Latino; mean±SD age: 6.6±0.7 years) taking part in an obesity prevention study (Project MOVE). Biological (sex, age, Body Mass Index z-score), socio-cultural (ethnicity, income, care giver education), parental (PA rules, PA encouragement) and environmental factors (home PA equipment, PA location) were assessed at baseline. Associations between change in sports participation and potential predictors were studied using multilevel linear regression stratified by Latino ethnicity, adjusted for sex, baseline sport participation, study condition and recruitment area. Results Sports participation increased over 1 year (mean change: +0.5 days; p&lt;0.001) and change was similar for boys and girls (p=0.95), but Latino children showed a greater increase (p=0.03). The number of locations used for PA (p=0.024) and the total frequency of PA location use (p=0.018) were positively associated with increased sports participation among Latinos. No predictors were identified for non-Latino children. Conclusions Only factors relating to PA location were identified as predictors of change in sports participation for Latino children. Interventions targeting specific PA behaviours such as sports participation may need to consider PA locations for Latino children and be tailored for specific ethnic groups.