Publications

Benchmarking and monitoring urban design and transport features is critical to achieving local and international health and sustainability goals. However, most urban indicator frameworks use coarse spatial scales that only allow between-city comparisons or require expensive, technical, local spatial analyses for within-city comparisons. This study developed a reusable open-source urban indicator computational framework using open data to enable consistent local and global comparative analyses. We demonstrate this framework by calculating spatial indicators - for 25 diverse cities in 19 countries - of urban design and transport features that support health and sustainability. We link these indicators to cities' policy contexts and identify populations living above and below critical thresholds for physical activity through walking. Efforts to broaden participation in crowdsourcing data and to calculate globally consistent indicators are essential for planning evidence-informed urban interventions, monitoring policy impacts, and learning lessons from peer cities to achieve health, equity, and sustainability goals.

The transduction of signals from the external medium across the plasma membrane into the cell is a process that is essential to the functioning of multicellular organisms. There are several basic mechanisms of signal transduction, many of which involve protein phosphorylation. Protein phosphorylation is ideally suited for signal transduction, since protein kinases have an inbuilt mechanism for signal amplification, and protein phosphatases provide a means of reversing the signal when the stimulus is removed. The most common type of signal-transducing protein kinase is the family of growth factor receptor protein-tyrosine kinases (PTK), such as the epidermal growth factor (EGF) receptor. These receptors have an intrinsic signaling mechanism in which binding of ligand to an external domain activates a cytoplasmic protein kinase domain to phosphorylate target proteins in the mitogenic signal pathway. Approximately half of all known protein-tyrosine kinase genes appear to encode ligand-regulated surface receptors (Table 1).

As part of a family cardiovascular health promotion project, 111 Mexican-American and 95 Anglo-American families with fifth- or sixth-grade children were assigned to either a primary prevention program involving 18 sessions or to a control condition. This article evaluates predictors of attendance at the year long sequence of sessions in the intervention group. In addition it considers the relationship between attendance and program outcomes. Low baseline scores on physical activity and cardiovascular fitness measures were associated with higher attendance for both children and adults. High initial health knowledge and self-motivation were also associated with attendance. Multiple regression analysis showed that adult attendance was significantly predicted by a model including completion of a three-day food record, low exercise, higher socioeconomic status, family adaptability, and self-motivation. Attendance was correlated with greater knowledge gains and larger reductions in blood pressure. The results indicate that motivated families who are in greater need of conditioning attended more sessions in a health promotion program.

Valid and reliable measures are needed to better understand the relationship between physical activity and crime. This paper provides a comprehensive psychometric evaluation of measures developed in the Safe and Fit Environments (SAFE) Study to assess a crime-PA conceptual framework. In addition to assessing the basic psychometric properties of each measure (e.g., variable distributions [item/scale level], internal consistency reliability), this study formally examined the measurement validity and invariance of measures across four age groups using confirmatory factor analysis. The sample (n = 2173) included 336 Adolescents (aged 12-17), 532 Young adults (aged 18-39), 838 Middle Age Adults, and 467 Older Adults (aged 66+). The psychometric evaluation of (sub)scales showed consistent factorial validity and internal consistency reliability across the majority of the measures and across the four age groups. Specifically, 14 of the 17 measures displayed statistically and practically significant factor loadings and internal consistency values in the overall sample and across the age groups. The pattern of correlations for each (sub)scale with other (sub)scales/indexes largely did not exhibit redundancy across measures. The findings expanded upon the test-retest reliability evaluation reported in Patch et al. (2019), and clarified key aspects of the construct validity of these indicators. The latter bodes well for potential utility of these indicators in future predictive models.

<div>Abstract<p>The Ras/Erk and NF-κB pathways play critical roles in cell proliferation and are known to drive oncogenesis when overactivated. Herein we report a gatekeeper function of the two pathways by working in synergy to suppress liver tumorigenesis. Hepatocyte-specific deletion of both Shp2/Ptpn11 and Ikkβ in mice, which promote Ras/Erk and NF-κB signaling, respectively, exacerbated chemical carcinogenesis and even triggered spontaneous development of hepatocellular carcinoma (HCC). We show that the unanticipated severe tumor phenotype was contributed collectively by severe cholestasis, metabolic changes, upregulated cell-cycle progression, and disruption of circadian rhythm in mutant hepatocytes. Remarkably, human HCCs with dysregulated circadian gene expression displayed downregulation of Ras/Erk and NF-κB signaling and poor prognosis. Together, these data indicate that at the ground state, the two central pathways, previously known as oncogenic, cooperate to sustain tumor-suppressive physiologic homeostasis and to prevent hepatic damage. Disruption of this intricate signaling network is carcinogenic in the liver.</p>Implications:<p>We demonstrate here that basal levels of the Ras/MAPK and NF-κB pathways, while promoting tumorigenesis if overactivated, are required to maintain physiologic homeostasis and regulate circadian rhythm in the liver, which are antitumorigenic.</p></div>

In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow hepatocellular carcinoma progression.

<div>Abstract<p>T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their role in tumor progression is poorly understood. Targeted deletion of the hypoxia-responsive transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although vascular endothelial growth factor-A levels and vascularization were unchanged. Tumor-associated macrophages can suppress tumor-infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T-cell suppression <i>in vitro</i> in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T-cell suppression in the tumor microenvironment. Cancer Res; 70(19); 7465–75. ©2010 AACR.</p></div>

At least three mitogen-activated protein kinase (MAPK) cascades were identified in mammals, each consisting of a well-defined three-kinase module composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK). These cascades play key roles in relaying various physiological, environmental, or pathological signals from the environment to the transcriptional machinery in the nucleus. One of these MAPKs, c-Jun N-terminal kinase (JNK), stimulates the transcriptional activity of c-Jun in response to growth factors, proinflammatory cytokines, and certain environmental stresses, such as short wavelength UV light or osmotic shock. The JNKs are directly activated by the MAPKK JNKK1/SEK1/MKK4. However, inactivation of the gene encoding this MAPKK by homologous recombination suggested the existence of at least one more JNK-activating kinase. Recently, the JNK cascade was found to be structurally and functionally conserved in Drosophila, where DJNK is activated by the MAPKK DJNKK (hep). By a database search, we identified an expressed sequence tag (EST) encoding a portion of human MAPKK that is highly related to DJNKK (hep). We used this EST to isolate a full-length cDNA clone encoding a human JNKK2. We show that JNKK2 is a highly specific JNK kinase. Unlike JNKK1, it does not activate the related MAPK, p38. Although the regulation of JNKK1 activities and that of JNKK2 activities could be very similar, the two kinases may play somewhat different regulatory roles in a cell-type-dependent manner.