Publications

Abstract Of individuals with SARS-CoV-2 IgG antibody testing performed, those who contemporaneously experienced a cluster of Covid-19 relevant symptoms in the 1-2 months preceding the antibody assay were more likely to test positive whereas those who experienced the symptom clustering in the prior 3-6 months were more likely to test negative. These findings suggest that antibodies likely wane over a period of months, particularly in relation to the timing of symptoms.

The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2(-/-) mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1(-/-) and Jnk2(-/-) mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1(-/-) and Jnk1(+/-)Jnk2(-/-) mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms.

The purpose of this study was to evaluate the effects of a twelve week behavioral skills training course, which included a structured exercise program, on physical activity habits of low active adults. Sixty four subjects(46 women and 13 men) mean age 42 years (sd=9.7) recruited from a Southern California corporation, were randomly assigned to either intervention or control groups. Control subjects were given a free membership to a fitness facility, while the intervention subjects received 12 weeks (once weekly) of informal behavior skills training classes at the work site plus structured exercise training at a fitness facility. Attendance at the intervention course was 85% while the program attrition rate was 8%. The Seven-day Physical Activity Recall telephone interview assessed total weekly energy expenditure plus moderate and vigorous physical activity as well as strength and·flexibility at 0 and 12 weeks. Repeated measures ANOVA demonstrated a significant trend for group by time effects on average daily energy expenditure (p=.06). Intervention group moderate activity more than doubled from baseline. Strength and flexibility showed no significant change, nor did vigorous activity levels change. Data indicate that after three months of structured exercise and behavioral skills training, inactive adults increased moderate physical activity in leisure and work time. It is expected that regular vigorous activity takes more than three months to adopt as a habit. When a goal oriented exercise program incorporates behavioral skills, the health facility can work with inactive adults to realize physical activity options in leading a healthier lifestyle.

The turnover of Jun proteins, like that of other transcription factors, is regulated through ubiquitin-dependent proteolysis. Usually, such processes are regulated by extracellular stimuli through phosphorylation of the target protein, which allows recognition by F box-containing E3 ubiquitin ligases. In the case of c-Jun and JunB, we found that extracellular stimuli also modulate protein turnover by regulating the activity of an E3 ligase by means of its phosphorylation. Activation of the Jun amino-terminal kinase (JNK) mitogen-activated protein kinase cascade after T cell stimulation accelerated degradation of c-Jun and JunB through phosphorylation-dependent activation of the E3 ligase Itch. This pathway modulates cytokine production by effector T cells.

The authors used recursive partitioning methods to identify combinations of baseline characteristics that predict 2-year physical activity success in each of 3 physical activity interventions delivered in the multisite Activity Counseling Trial. The sample consisted of 874 initially sedentary primary care patients, ages 35-75 years, who were at risk for cardiovascular disease. Predictors of 2-year success were specific to each intervention and represented a range of domains, including physiological, demographic, psychosocial, health-related, and environmental variables. The results indicate how specific patient subgroups (e.g., obese, unfit individuals; high-income individuals in stable health) may respond differently to varying levels and amounts of professional assistance and support. The methods used provide a practical first step toward identifying clinically meaningful patient subgroups for further systematic investigation.

This study explores differences in exercise and walking behavior among subjects who reported temporary or long-term illnesses or injuries serious enough to have limited physical activities. The study is primarily concerned with specifying similarities and differences in correlates of vigorous exercise and walking among illness/injury groups in comparison to a healthy sample. Subjects in the analysis (N = 2,053) were drawn from a multiwave mailed survey of a probability sampling of the adult population residing in households in San Diego, California. Although differences were found in correlates of walking and vigorous exercise among the groups, self-efficacy, the belief that one is able to perform specific activities, was the most powerful and statistically significant correlate of both walking and vigorous exercise among all groups.

While advances in science and technology have increased options for treating breast cancer, current social trends have changed the way people deal with this disease.Women in the United States are no longer simply passive patients, but rather they are survivors, advocates and activists who are speaking up for themselves and speaking out for issues relevant to the treatment and prevention of breast cancer.As the discoveries of basic science have been translated to better clinical treatment, a new sense of hope has emerged.Quality of life now shares the spotlight with quantity of life as breast cancer has shifted from an acute to a chronic condition and as the numbers of long-term survivors increase.While this new population tends to have more optimistic expectations for survival, they are also expressing concerns about issues affecting their lives through and beyond treatment.These issues include, but are not limited to, such concerns as efficient and accurate diagnosis, the complexity of treatment decisions, access to quality cancer care, informed consent, privacy issues, availability of supportive care treatments, and effective communication skills, especially with their physicians.Survivors are also concerned about the impact of their disease on spouses and family, on fertility and sexuality issues, on their employment and (in the USA) insurability, and on their long-term survival.The identification of these increasing issues has given rise to a consumer movement that encourages a shift away from powerless victim to empowered survivor.Historically, breast cancer advocates asked for increased educational and supportive care resources.As the survivorship movement matured, new responsibilities and differing agendas arose amongst these groups.Some organizations defined their mission as one that would raise funds to support scientific research.Others felt compelled to raise awareness about early detection and treatment, controversial environmental issues, and prevention or risk reduction.A few organizations later entered the more political arenas and began lobbying for issues related to health care delivery, clinical trials access, and quality cancer care.Meanwhile, these many and varied missions are all helping to define an international agenda for breast cancer research and care, to guarantee the inclusion of consumer voices in most levels of decision-making, and to create partnerships between patients with breast cancer and the professionals who care for them.

Introduction: Environmental and policy approaches to promote physical activity, such as walking trail construction and promotion, are being widely recommended, yet sparse data exist on their effectiveness. In conjunction with ongoing community-intervention projects in Missouri, walking trails are being built, promoted, and evaluated. Objectives include determining: (1) patterns and correlates of walking, (2) the availability of places to walk and perform other forms of physical activity, (3) the extent of walking trail use and possible effects on rates of physical activity, and (4) attitudes toward the trails and their uses. Methods: In 12 rural counties in Missouri we used a cross-sectional telephone survey to ask a population-based sample of residents aged >18 years (n = 1269) some standard and specially developed questions about walking behaviors, knowledge, and attitudes. Results: Only 19.5% of respondents were classified as regular walkers. About one third of respondents (36.5%) reported having access to walking trails in their area, and 50.3% reported having access to indoor facilities for exercise. Among persons with access to walking trails, 38.8% had used the trails. Groups who were more likely to have used the walking trails included women, persons with more education, those making $35,000 or more per year, and regular walkers. Among persons who had used the trails, 55.2% reported they had increased their amount of walking since they began using the trail. Women and persons with a high school education or less were more than twice as likely to have increased the amount of walking since they began using the walking trails. Conclusions: Walking trails may be beneficial in promoting physical activity among segments of the population at highest risk for inactivity, in particular women and persons in lower socioeconomic groups.

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 yet 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 were found to be associated with variations in disease prognosis and patient survival. This study provides new insights into how obesity-related microbiome dysbiosis may be associated with cancer development, and aims to introduce novel potential avenues for precision medicine approaches in cancer treatment.

Some aspects of CNS-directed autoimmunity in multiple sclerosis are modeled in mice by immunization with myelin Ags where tissue damage is driven by myelin-reactive Th1 and Th17 effector lymphocytes. Whether the CNS plays an active role in controlling such autoimmune diseases is unknown. We used mice in which IkappaB kinase beta was deleted from Ca(2+)/calmodulin-dependent kinase IIalpha-expressing neurons (nIKKbetaKO) to investigate the contribution of neuronal NF-kappaB to the development of myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis. We show that nIKKbetaKO mice developed a severe, nonresolving disease with increased axon loss compared with controls and this was associated with significantly reduced CNS production of neuroprotective factors (vascular endothelial growth factor, CSF1-R, and FLIP) and increased production of proinflammatory cytokines (IL-6, TNF, IL-12, IL-17, and CD30L) and chemokines. The isolation of CNS-infiltrating monocytes revealed greater numbers of CD4(+) T cells, reduced numbers of NK1.1(+) cells, and a selective accumulation of Th1 cells in nIKKbetaKO CNS from early in the disease. Our results show that neurons play an important role in determining the quality and outcome of CNS immune responses, specifically that neuronal IkappaB kinase beta is required for neuroprotection, suppression of inflammation, limitation of Th1 lymphocyte accumulation, and enhancement of NK cell recruitment in experimental autoimmune encephalomyelitis-affected CNS and stress the importance of neuroprotective strategies for the treatment of multiple sclerosis.

Cancer genomics has enabled the exhaustive molecular characterization of tumors and exposed hepatocellular carcinoma (HCC) as among the most complex cancers. This complexity is paralleled by dozens of mouse models that generate histologically similar tumors but have not been systematically validated at the molecular level. Accurate models of the molecular pathogenesis of HCC are essential for biomedical progress; therefore we compared genomic and transcriptomic profiles of four separate mouse models [MUP transgenic, TAK1-knockout, carcinogen-driven diethylnitrosamine (DEN), and Stelic Animal Model (STAM)] with those of 987 HCC patients with distinct etiologies. These four models differed substantially in their mutational load, mutational signatures, affected genes and pathways, and transcriptomes. STAM tumors were most molecularly similar to human HCC, with frequent mutations in <i>Ctnnb1</i>, similar pathway alterations, and high transcriptomic similarity to high-grade, proliferative human tumors with poor prognosis. In contrast, TAK1 tumors better reflected the mutational signature of human HCC and were transcriptionally similar to low-grade human tumors. DEN tumors were least similar to human disease and almost universally carried the <i>Braf</i> V637E mutation, which is rarely found in human HCC. Immune analysis revealed that strain-specific MHC-I genotype can influence the molecular makeup of murine tumors. Thus, different mouse models of HCC recapitulate distinct aspects of HCC biology, and their use should be adapted to specific questions based on the molecular features provided here.