Publications

Abstract Choline is a vitamin-like nutrient that is taken up via specific transporters and metabolized by choline kinase (ChoKα) which converts it to phosphocholine needed for de novo synthesis of phosphatidylcholine (PC), the main phospholipid of cellular membranes. We found that Toll-like receptor (TLR) activation enhances choline uptake by macrophages through induction of the choline transporter CTL1. Choline is rapidly phosphorylated and mobilized to the Kennedy pathway leading to increased cellular phosphatidylcholine production. Inhibition of choline uptake or phosphorylation attenuated NLRP3 inflammasome activation and IL-1β and IL-18 production in stimulated macrophages. Mechanistically, reduced choline uptake altered mitochondrial lipid profile, attenuated mitochondrial ATP synthesis and activated the energy sensor AMP-activated protein kinase (AMPK). By potentiating mitochondrial recruitment of DRP1, AMPK stimulates mitophagy, which contributes to termination of NLRP3 inflammasome activation. Correspondingly, pharmacological ChoKα inhibition ameliorated acute and chronic macrophage-dependent inflammation in vivo.

Improved understanding of the mediators of physical activity (PA) interventions could lead to improvements in theory and programs. To examine the 24-month mediating effects of psychosocial variables on PA and cardiorespiratory fitness (CRF) outcomes in 878 initially sedentary adults aged 35-75 participating in the Activity Counseling Trial. Participants were assigned to one of three intervention arms: physician advice, assistance, or counseling. MacKinnon's product of coefficients was used to test for longitudinal and contemporaneous mediation. Changes in behavioral processes of change from baseline to 24 months significantly mediated the relationship between the active intervention arms and improvements in PA and CRF from baseline to 24 months in both men and women. None of the other psychosocial variables tested met criteria for mediation. Results indicate that behavioral interventions should incorporate methods to encourage participants to use these behavioral strategies as they attempt to become more active.

Abstract The B cell- activating factor of the tumor necrosis factor family (BAFF) is a potent regulator of normal B cells. We recently showed that BAFF supports chronic lymphocytic leukemia (CLL) B cell survival in vitro through activation of the canonical NF-kB pathway. To study the influence of BAFF on CLL development, we crossed BAFF transgenic (Tg) mice with mice that express human TCL1 under a B cell specific promoter/enhancer, and that are known to develop a lymphoproliferative disease resembling human B-CLL. BAFF/TCL1-Tg mice had a shorter mean survival than either TCL1-Tg or BAFF-Tg mice (12 mice each; BAFF/TCL1-Tg mice 9.6±3.4 months; TCL1-Tg 17.2±3.9; BAFF-Tg 17.9±3.6; B6 wildtype (wt) >19.2). To monitor for the development of CLL, mice were bled at 6-week intervals starting at 3 months of age, and blood mononuclear cells (PBMC) were analyzed via flow cytometry using fluorochrome-conjugated antibodies for murine CD5, CD3, CD45R, and human TCL1. Whereas all BAFF/TCL1-Tg mice began to develop a pathological CD5+CD3−CD45Rlo cell population at 3 months of age, such a population was not observed in TCL1-Tg mice before 6 months of age. BAFF-Tg or wt mice did not develop CD5+CD3−CD45Rlo cells over the entire observation period (26 months). CD5+CD3−CD45Rlo B cells expressed the TCL1 transgene. Over time, the CD5+CD3−CD45Rlo population increased in BAFF/TCL1-Tg mice, coming to represent >99% of the total PBMC of 9-month-old animals. To examine the capacity of these cells to propagate, 1x106 CD5+CD3−CD45Rlo B cells were transferred i.v. into either BAFF-Tg or wt mice that previously were irradiated with 600 rad. Ten days after transfer, CD5+TCL1+ cells were detected in BAFF-Tg, but not in wt recipients. Most CLL cells were located in the liver and spleen, as assessed by bioluminescent-based imaging of mice that received luciferase expressing CLL cells. Subsequent examination upon autopsy at 6 months of age, however, revealed that the majority of CLL cells populated the spleens of the recipient mice, which were massively enlarged. At this age, CLL cells also were found in wt recipient mice, although tumor burden was less than 20% of that of BAFF-Tg recipients (n=3 per group). We found that BAFF did not promote CLL cell proliferation in vitro or in vivo using assays to measure BrdU incorporation and flow cytometry to evaluate for enhanced intracellular expression of Ki67. However, BAFF induced CLL cells to express high levels of several anti-apoptotic proteins (e.g. Bcl-XL, Bcl-2, Bim, and A1/Bfl1). Also, while death-associated protein kinase 1 was repressed in CLL cells of TCL1-Tg mice, CLL cells of BAFF/TCL1-Tg mice expressed high-levels. Because of this, we examined whether treatment with BAFF-neutralizing BR3-Fc could influence the survival of CLL cells that were adoptively transferred into BAFF-Tg mice. We found that i.p. injection of 200 ug BR3-Fc into the recipient animals reduced the numbers of circulating CLL cells by nearly 20% (18.2%±5.3%; n=3) within 6 days. These data indicate that BAFF can accelerate the development of CLL cells in TCL1-Tg mice by promoting their survival. Because BAFF can similarly promote survival of human CLL cells, BAFF, and the signaling pathways it activates in neoplastic B cells, could be targeted for the development of novel therapies for this disease.

<p>non-tumorous murine livers</p>

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of <i>IRF1</i> in leukemia, we explored the potential of <i>IRF1</i> expression level as a stratification marker for human acute myeloid leukemia. We show that <i>IRF1</i>-based stratification identifies distinct cancer-related signatures in patient subgroups. These findings establish IRF1 as a pivotal HSC controller and provide previously unknown insights into HSC regulation, with potential implications to IRF1 functions in the context of leukemia.

Physical activity is vital for the health and well-being of youth and adults, although the prevalence of physical activity continues to be low. Promoting active transportation or human-powered transportation through policy, systems, and environmental change is one of the leading evidence-based strategies to increase physical activity regardless of age, income, racial/ethnic background, ability, or disability. Initiatives often require coordination across federal, state, and local agencies. To maximize the effectiveness of all types of interventions, it is imperative to establish strong and broad partnerships across professional disciplines, community members, and advocacy groups. Health organizations can play important roles in facilitating these partnerships. This policy statement provides recommendations and resources that can improve transportation systems, enhance land use design, and provide education to support policies and environments to promote active travel. The American Heart Association supports safe, equitable active transportation policies in communities across the country that incorporate consistent implementation evaluation. Ultimately, to promote large increases in active transportation, policies need to be created, enforced, and funded across multiple sectors in a coordinated and equitable fashion. Active transportation policies should operate at 3 levels: the macroscale of land use, the mesoscale of pedestrian and bicycle networks and infrastructure such as Complete Streets policies and Safe Routes to School initiatives, and the microscale of design interventions and placemaking such as building orientation and access, street furnishings, and safety and traffic calming measures. Health professionals and organizations are encouraged to become involved in advocating for active transportation policies at all levels of government.

Nucleotide oligomerisation domain 2 (NOD2) is a component of the innate immunity known to be involved in the homeostasis of Peyer patches (PPs) in mice. However, little is known about its role during gut infection in vivo. Yersinia pseudotuberculosis is an enteropathogen causing gastroenteritis, adenolymphitis and septicaemia which is able to invade its host through PPs. We investigated the role of Nod2 during Y. pseudotuberculosis infection. Death was delayed in Nod2 deleted and Crohn's disease associated Nod2 mutated mice orogastrically inoculated with Y. pseudotuberculosis. In PPs, the local immune response was characterized by a higher KC level and a more intense infiltration by neutrophils and macrophages. The apoptotic and bacterial cell counts were decreased. Finally, Nod2 deleted mice had a lower systemic bacterial dissemination and less damage of the haematopoeitic organs. This resistance phenotype was lost in case of intraperitoneal infection. We concluded that Nod2 contributes to the susceptibility to Y. pseudotuberculosis in mice.

OBJECTIVES: This study evaluated the effects of an intervention on rates of skin cancer prevention counseling by pharmacists. METHODS: Fifty-four pharmacies were randomly assigned to intervention or control conditions. Intervention consisted of training, feedback, and prompts. Counseling rates before and after the intervention were obtained from study confederates. RESULTS: At pretest, the proportions of control and intervention sites providing counseling at least once were 7.4% and 0%, respectively (NS). At posttest, these proportions were 3.7% and 66.7%, respectively (P &lt; .001). CONCLUSIONS: The results indicated that the intervention was successful and that pharmacists can play an important role in educating the public about skin cancer prevention strategies.

Introduction: This study assessed the relative contributions of psychological, social, and environmental variables to walking, moderate- and vigorous-intensity physical activity. Methods: A questionnaire was mailed to a random sample (57% response rate). Analyses used a backwards elimination logistic regression model, removing and replacing individual variables, and adjusting for age, gender, household composition, and education ( N = 1827). Results: The sociodemographic and correlate variables collectively accounted for 43% of the variation in total activity, 26% of walking, 22% of moderate-intensity activity and 45% of vigorous-intensity activity (Nagelkerke R 2 ). Individually, the correlates accounted for 0.0 to 4.0% of unique variation, with habit, efficacy, and support having higher values. Physical health, discouragement, competition, and time management contributed more to vigorous-intensity activity. Anticipated benefits of social interactions and weight management contributed more to moderate-intensity activity. Neighborhood aesthetics contributed more to walking. Conclusion: Walking, moderate- and vigorous-intensity activity might be associated with different correlates.

No abstract is provided for this article.