Publications

Improving adherence to pediatric therapeutic regimens.

JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers.

JunB differs considerably from c-Jun in its ability to activate AP-1-responsive genes and induce oncogenic transformation. We demonstrate that the decreased ability of JunB to activate gene expression is the result of a small number of amino acid changes between its DNA-binding and dimerization motifs and the corresponding regions of c-Jun. These changes lead to a 10-fold decrease in the DNA-binding activity of JunB. JunB can be converted into a c-Jun-like activator by substituting four amino acids in its DNA-binding and dimerization motifs with the corresponding c-Jun sequences. JunB can also attenuate trans-activation by c-Jun, an activity mediated by its leucine zipper. This ability depends on two glycine residues that decrease the stability of the JunB leucine zipper, resulting in decreased homodimerization and increased heterodimerization. These results illustrate how small changes in primary structure, including chemically conservative changes, can result in functional divergence of two highly related transcriptional regulators.

New Horizons in Sensor Development

Accelerometry and other sensing technologies are important tools for physical activity measurement. Engineering advances have allowed developers to transform clunky, uncomfortable, and conspicuous monitors into relatively small, ergonomic, and convenient research tools. New devices can be used to collect data on overall physical activity and, in some cases, posture, physiological state, and location, for many days or weeks from subjects during their everyday lives. In this review article, we identify emerging trends in several types of monitoring technologies and gaps in the current state of knowledge.The only certainty about the future of activity-sensing technologies is that researchers must anticipate and plan for change. We propose a set of best practices that may accelerate adoption of new devices and increase the likelihood that data being collected and used today will be compatible with new data sets and methods likely to appear on the horizon.We describe several technology-driven trends, ranging from continued miniaturization of devices that provide gross summary information about activity levels and energy expenditure to new devices that provide highly detailed information about the specific type, amount, and location of physical activity. Some devices will take advantage of consumer technologies, such as mobile phones, to detect and respond to physical activity in real time, creating new opportunities in measurement, remote compliance monitoring, data-driven discovery, and intervention.

Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential

Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state. These cells were absent in healthy livers but increasingly prevalent as chronic liver disease progressed. Copy number variation (CNV) analysis of microdissected tissue demonstrated that daHep-enriched regions are riddled with structural variants, suggesting these cells represent a pre-malignant intermediary. Integrated analysis of three recent human snRNA-seq datasets confirmed the presence of a similar phenotype in human chronic liver disease and further supported its enhanced mutational burden. Importantly, we show that high daHep levels precede carcinogenesis and predict a higher risk of hepatocellular carcinoma development. These findings may change the way chronic liver disease patients are staged, surveilled, and risk stratified.

Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11)

Camptothecin (CPT)-11 (irinotecan) has been used widely for cancer treatment, particularly metastatic colorectal cancer. However, up to 40% of treated patients suffer from severe late diarrhea, which prevents CPT-11 dose intensification and efficacy. CPT-11 is a prodrug that is hydrolyzed by hepatic and intestinal carboxylesterase to form SN-38, which in turn is detoxified primarily through UDP-glucuronosyltransferase 1A1 (UGT1A1)-catalyzed glucuronidation. To better understand the mechanism associated with toxicity, we generated tissue-specific Ugt1 locus conditional knockout mouse models and examined the role of glucuronidation in protecting against irinotecan-induced toxicity. We targeted the deletion of the Ugt1 locus and the Ugt1a1 gene specifically in the liver (Ugt1(ΔHep)) and the intestine (Ugt1(ΔGI)). Control (Ugt1(F/F)), Ugt1(ΔHep), and Ugt1(ΔGI) adult male mice were treated with different concentrations of CPT-11 daily for four consecutive days. Toxicities were evaluated with regard to tissue glucuronidation potential. CPT-11-treated Ugt1(ΔHep) mice showed a similar lethality rate to the CPT-11-treated Ugt1(F/F) mice. However, Ugt1(ΔGI) mice were highly susceptible to CPT-11-induced diarrhea, developing severe and lethal mucositis at much lower CPT-11 doses, a result of the proliferative cell loss and inflammation in the intestinal tract. Comparative expression levels of UGT1A1 in intestinal tumors and normal surrounding tissue are dramatically different, providing for the opportunity to improve therapy by differential gene regulation. Intestinal expression of the UGT1A proteins is critical toward the detoxification of SN-38, whereas induction of the UGT1A1 gene may serve to limit toxicity and improve the efficacy associated with CPT-11 treatment.

Nucleolin and YB-1 are required for JNK-mediated interleukin-2 mRNA stabilization during T-cell activation

Regulated mRNA turnover is a highly important process, but its mechanism is poorly understood. Using interleukin-2 (IL-2) mRNA as a model, we described a role for the JNK-signaling pathway in stabilization of IL-2 mRNA during T-cell activation, acting via a JNK response element (JRE) in the 5' untranslated region (UTR). We have now identified two major RNA-binding proteins, nucleolin and YB-1, that specifically bind to the JRE. Binding of both proteins is required for IL-2 mRNA stabilization induced by T-cell activation signals and for JNK-induced stabilization in a cell-free system that duplicates essential features of regulated mRNA decay. Nucleolin and YB-1 are required for formation of an IL-2 mRNP complex that responds to specific mRNA stabilizing signals.

Obesity Related Microbial Dysbiosis as a Potential Modulator of Tumor Progression

Although there is a well-established connection between the gut microbiome and obesity, the specific mechanisms by which microbes regulate cell signaling, inflammation, and adipocyte growth to influence disease severity in obese patients remains largely unclear. Subsequently, while obesity itself is a well-established risk factor for various cancers, the exact mechanisms by which it drives disease progression are not definitively known. In this study, we explored the link between obesity-associated microbiome alterations and cancer progression by analyzing microbial abundance in tissue samples from obese and cancer patients, and we identified specific microbes correlated with Body Mass Index (BMI) that are associated with key cancer-related pathways. Notably, BMI-associated microbial species as Pseudomonas fluorescens and Lactobacillus sakei, were linked with both pro-tumor and anti-tumor progression in cancer patients. Additionally, microbes found to be abundant in cancer and obese tissue, such as Pseudomonas baetica, were significantly associated with the upregulation of certain oncogenic signaling pathways. BMI-associated microbes were also correlated with chemokine signaling and TFR2/NFkB-related genes. Both of these have well established roles in inflammatory activity and inflammasome expression, a critical step in obesity related cancer progression. Therefore, these microbes likely have an influence on both disease prognosis as well as patient survival. This study provides new insights into how obesity-related microbiome dysbiosis may contribute to cancer development, and aims to introduce novel potential avenues for precision medicine approaches in cancer treatment.

Role of Built Environments in Physical Activity, Obesity, and Cardiovascular Disease

No abstract is provided for this article.

The CUP2 gene product regulates the expression of the CUP1 gene, coding for yeast metallothionein.

Associations Between Neighborhood Recreation Environments and Adolescent Physical Activity

To examine relations between parents' perceived neighborhood recreation environments and multiple measures of adolescent physical activity (PA).Participants (N = 928; age 14.1 [1.4] y, 50.4% girls, and 33.4% nonwhite/Hispanic) and their parents were recruited. Teen moderate to vigorous PA (MVPA) was assessed with 7-day accelerometry. Self-reported total PA, PA near home, and PA at recreation locations were also assessed. Proximity of home to 8 types of recreation facilities was reported by parents. Mixed-model linear regressions relating environments to various measures of PA were adjusted for demographics and neighborhood clustering.Perceiving more availability of recreation facilities around home was related to higher reports of days per week with 60+ minutes of PA (b = 0.153; P < .05), reported PA time near home (b = 0.152; P < .001), PA time at recreation facilities (b = 0.161; P < .001), accelerometer-measured total MVPA (b = 1.741; P < .05), and nonschool MVPA (b = 1.508; P < .01). Adolescents living in lowest quintile of recreation facility availability averaged 27.6 (3.2) minutes per day of total MVPA versus 49.8 (3.5) minutes per day for those living in highest quintile.Adolescents living in neighborhoods that parents reported having more availability of recreation facilities around homes had higher activity across 5 indicators of PA.

Activation of cAMP and mitogen responsive genes relies on a common nuclear factor

Emerging roles of Lys63‐linked polyubiquitylation in immune responses

Among all the E2 ubiquitin-conjugating enzymes, Ubc13, which heterodimerizes with Uev1a, specifically mediates lysine 63 (K63)-linked protein polyubiquitylation, a process that does not lead to proteasomal degradation of its substrates. Instead, it plays a key role in signal transduction. Numerous roles of Lys63-linked polyubiquitylation in immune responses have emerged, indicating the importance of this regulatory strategy. Here, we summarize some of the signaling pathways that depend on Lys63-linked polyubiquitylation during innate and adaptive immune responses, with a focus on the underlying molecular mechanisms. In addition, we describe how Ubc13 itself is regulated and outline its function in transforming growth factor β signaling. We discuss the current progress in pharmacological targeting of Ubc13 in inflammatory and autoimmune diseases as well as cancer therapy.

Home Food Environment in Relation to Children’s Diet Quality and Weight Status

The objective of this cohort study was to explore relationships among the home food environment (HFE), child/parent characteristics, diet quality, and measured weight status among 699 child-parent pairs from King County, WA, and San Diego County, CA. HFE variables included parenting style/feeding practices, food rules, frequency of eating out, home food availability, and parents’ perceptions of food costs. Child dietary intake was measured by 3-day recall and diet quality indicators included fruits and vegetables, sweet/savory snacks, high-calorie beverages, and Dietary Approaches to Stop Hypertension (DASH) score. Individual linear regression models were run in which child BMI z score and child diet quality indicators were dependent variables and HFE variables and child/parent characteristics were independent variables of interest. Fruit and vegetable consumption was associated with parental encouragement/modeling (β=.68, P<0.001) and unhealthful food availability (−0.27, P<0.05); DASH score with food availability (healthful: 1.3, P<0.01; unhealthful: −2.25, P<0.001), food rules (0.45, P<0.01), and permissive feeding style (−1.04, P<0.05); high-calorie beverages with permissive feeding style (0.14, P<0.01) and unhealthful food availability (0.21, P<0.001); and sweet/savory snacks with healthful food availability (0.26, P<0.05; unexpectedly positive). Children's BMI z score was positively associated with parent's use of food restriction (0.21, P<0.001), permissive feeding style (0.16, P<0.05), and concern for healthy food costs (0.10, P<0.01), but negatively with verbal encouragement/modeling (−0.17, P<0.05), and pressure to eat (−0.34, P<0.001). Various HFE factors associated with parenting around eating and food availability are related to child diet quality and weight status. These factors should be considered when designing interventions for improving child health.

Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

SUMMARY Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.

Reparative inflammation takes charge of tissue regeneration

Study Designs and Analytic Strategies for Environmental and Policy Research on Obesity, Physical Activity, and Diet

Numerous authoritative reports have identified environmental and policy interventions as the most promising strategies for creating population-wide improvements in diet, physical activity, and obesity. Yet many methodologic challenges to conducting environmental and policy research must be overcome to enable this area of study to advance. A meeting titled “Study Designs and Analytic Strategies for Environmental and Policy Research on Obesity, Physical Activity, and Diet” was held April 8, 2008. Participants from diverse backgrounds identified priority gaps in knowledge and generated recommendations for promising methods to enhance environmental and policy research related to obesity. Final recommendations were based on a postmeeting participant survey. Existing methods were identified that could be applied to advance the field, including prospective studies, evaluations of natural experiments, and economic studies. Training for investigators in the use of appropriate statistical methods for complex designs and interdisciplinary collaboration were recommended. Methodologic research priorities included the development of measures of policy, health impact assessments, and the investigation of policy adoption and implementation. The results of this conference can be used to improve the quality and quantity of environmental and policy research as well as the translation to action to control obesity.

Public health research on physical activity and COVID-19: Progress and updated priorities

• Research produced during the pandemic showed pre-diagnosis physical activity was associated with substantially lower risk of severe coronavirus disease 2019 (COVID-19) outcomes. • Pandemic restrictions on common places for physical activity were associated with decreased physical activity and increased sedentary behavior. • There were few studies of interventions to increase physical activity during the pandemic, the role of physical activity in COVID-19 inequities, and built environment contributions to COVID-19 outcomes. • Emerging research priorities include physical activity and long COVID and physical activity as a vaccine adjuvant. • Except for recommendations from the World Health Organization, physical activity was widely ignored in public health guidance.

PARENT BEHAVIORS ARE RELATED TO PHYSICAL ACTIVITY AND FITNESS IN 4TH GRADE CHILDREN

Sallis, James F.; Alearaz, John E.; McKeizie, Thomas L.; Hovell, Melbourne F. Author Information