Publications

Epidermal morphogenesis is controlled by p63, a transcription factor that can be expressed as multiple isoforms. Of these, ΔNp63 isoforms are the predominantly expressed isoforms in late embryonic and postnatal epidermis. To determine the role of ΔNp63 proteins, we generated an epidermal‐specific inducible ΔNp63 knockdown mouse model. We found that downregulating ΔNp63 expression caused severe epidermal defects, including aberrant keratinocyte differentiation and impaired basement membrane formation, culminating in the development of severe skin erosions. Interestingly, these lesions were indistinguishable from lesions that develop in patients with AEC, a skin fragility disorder caused by mutations in ΔNp63α. We found that, during epidermal morphogenesis, ΔNp63α initially induces expression of Fras1, which is required for maintaining the integrity of the epidermal‐dermal interface at the basement membrane. Subsequently, ΔNp63α initiates epidermal terminal differentiation by inducing IKKα. Together, our data provide novel insights into the role of ΔNp63α in epidermal morphogenesis and homeostasis, and may contribute to our understanding of the pathogenic mechanisms underlying disorders caused by p63 mutations. This work was supported by grants from the NIH and the National Foundation for Ectodermal Dysplasias.

This study examines the relationship of neighbourhood environment factors with walking and total health enhancing physical activity. A population-based cross-sectional study. The short self-administered version of the validated International Physical Activity Questionnaire (IPAQ) was used to assess health enhancing physical activity including walking. The neighbourhood environment was assessed using a 17-item environmental module. A principal component analysis among the environmental variables was conducted. The factor scores were divided into tertiles and independent associations between factor tertiles and physical activity categories and walking were studied by multinomial logistic regression with adjustment for confounders. In adjusted models, a lower odds ratio (OR) for reaching the middle, OR: 0.66 (95% Confidence Interval (CI): 0.47–0.98), and upper, OR: 0.65 (0.45–0.95), tertile of walking was observed among those in the lowest tertile of the degree of urbanisation. A higher OR for reaching the middle, OR: 1.84 (1.28–1.64), and upper tertile, OR: 1.64 (1.14–2.36), of walking was observed among those in the lowest tertile of fear of crime. A higher OR for reaching the high category of total health enhancing physical activity was observed among those in the lowest, OR: 2.01 (1.32–3.05), and middle tertile, OR: 1.52 (1.02–2.25), of the factor degree of urbanisation. The findings suggest that the environment is differentially related to walking and total health enhancing physical activity. This should be explored in future research to disentangle the complex relationship between different levels and aspects of physical activity and their relationship with the environment.

Objective To investigate the psychometric properties of a new measure of barriers youth encounter while walking to specific destinations and to validate the measure with self-reported walking to these destinations. Methods In 2005 in Boston, Cincinnati and San Diego, parents of youth (n = 289, aged 5–18) and adolescents (n = 189, aged 12–18) completed surveys in a two-week test–retest study design. Seventeen items assessed participant agreement with the influence of different barriers to walking or cycling to three types of destinations: 1) parks, 2) shops and restaurants and 3) school. Participants also reported whether or not they walked or cycled to the destinations at least once a week. Results Principal components analysis identified three barrier subscales labeled ‘environmental’, ‘psychosocial/planning’, and ‘safety’, which were consistent across the three destinations and two respondent groups. Internal consistency for the subscales was good (alphas > .70) and two-week test–retest reliability was moderately high (ICCs .56–.81) for both parents and adolescents for all destinations. Psychosocial and environmental barriers were higher in adolescents who did not walk (p < .003). Parents of younger children reported high environmental barriers. Conclusion The three barrier subscales to active commuting to multiple destinations demonstrated good reliability and some initial evidence of validity.

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.

Background : Built environment approaches to promoting physical activity can provide economic value to communities. How best to assess this value is uncertain. This study engaged experts to identify a set of key economic indicators useful for evaluation, research, and public health practice. Methods : Using a modified Delphi process, a multidisciplinary group of experts participated in (1) one of 5 discussion groups (n = 21 experts), (2) a 2-day facilitated workshop (n = 19 experts), and/or (3) online surveys (n = 16 experts). Results : Experts identified 73 economic indicators, then used a 5-point scale to rate them on 3 properties: measurement quality, feasibility of use by a community, and influence on community decision making. Twenty-four indicators were highly rated (≥3.9 on all properties). The 10 highest-rated “key” indicators were walkability score, residential vacancy rate, housing affordability, property tax revenue, retail sales per square foot, number of small businesses, vehicle miles traveled per capita, employment, air quality, and life expectancy. Conclusion : This study identified key economic indicators that could characterize the economic value of built environment approaches to promoting physical activity. Additional work could demonstrate the validity, feasibility, and usefulness of these key indicators, in particular to inform decisions about community design.

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.

MEKK1-dependent signaling regulates HECT E3 ligase Itch, resulting in elevated catalytic activity. After TCR costimulation, MEKK1 predominantly induces JNK1 activation, whereas the related kinase MEKK2 regulates ERK5 activation. MEKK1 becomes phosphorylated on multiple sites and polyubiquitinated following TCR costimulation. E3 ligase Itch is recruited to activated MEKK1, but not MEKK2, and this novel scaffolding interaction is dependent on MEKK1 Thr(1381) phosphorylation within the kinase domain and an intact MEKK1 RING finger motif. MEKK1 phosphorylation on Thr(1381) is observed during Th2 differentiation, but not under Th1 differentiation. Both Itch and the MEKK1 kinase domain are important for Il4 and Il6 cytokine gene expression under Th2 conditions.