T Cell-Intrinsic and -Extrinsic Contributions of the IFNAR/STAT1-Axis to Thymocyte Survival

STAT1 is an essential part of interferon signaling, and STAT1-deficiency results in heightened susceptibility to infections or autoimmunity in both mice and humans. Here we report that mice lacking the IFNα/β-receptor (IFNAR1) or STAT1 display impaired deletion of autoreactive CD4+CD8+-T-cells. Strikingly, co-existence of WT T cells restored thymic elimination of self-reactive STAT1-deficient CD4+CD8+-T cells. Analysis of STAT1-deficient thymocytes further revealed reduced Bim expression, which was restored in the presence of WT T cells. These results indicate that type I interferons and STAT1 play an important role in the survival of MHC class I-restricted T cells in a T cell intrinsic and non-cell intrinsic manner that involves regulation of Bim expression through feedback provided by mature STAT1-competent T cells

FoxM1, a Forkhead Transcription Factor Is a Master Cell Cycle Regulator for Mouse Mature T Cells but Not Double Positive Thymocytes

FoxM1 is a forkhead box transcription factor and a known master regulator required for different phases of the cell cycle. In cell lines, FoxM1 deficient cells exhibit delayed S phase entry, aneuploidy, polyploidy and can't complete mitosis. In vivo, FoxM1 is expressed mostly in proliferating cells but is surprisingly also found in non-proliferating CD4+CD8+ double positive thymocytes. Here, we addressed the role of FoxM1 in T cell development by generating and analyzing two different lines of T-cell specific FoxM1 deficient mice. As expected, FoxM1 is required for proliferation of early thymocytes and activated mature T cells. Defective expression of many cell cycle proteins was detected, including cyclin A, cyclin B1, cdc2, cdk2, p27 and the Rb family members p107 and p130 but surprisingly not survivin. Unexpectedly, loss of FoxM1 only affects a few cell cycle proteins in CD4+CD8+ thymocytes and has little effect on their sensitivity to apoptosis and the subsequent steps of T cell differentiation. Thus, regulation of cell cycle genes by FoxM1 is stage- and context-dependent

Toward optimal implementation of cancer prevention and control programs in public health: A study protocol on mis-implementation

Abstract Background Much of the cancer burden in the USA is preventable, through application of existing knowledge. State-level funders and public health practitioners are in ideal positions to affect programs and policies related to cancer control. Mis-implementation refers to ending effective programs and policies prematurely or continuing ineffective ones. Greater attention to mis-implementation should lead to use of effective interventions and more efficient expenditure of resources, which in the long term, will lead to more positive cancer outcomes. Methods This is a three-phase study that takes a comprehensive approach, leading to the elucidation of tactics for addressing mis-implementation. Phase 1: We assess the extent to which mis-implementation is occurring among state cancer control programs in public health. This initial phase will involve a survey of 800 practitioners representing all states. The programs represented will span the full continuum of cancer control, from primary prevention to survivorship. Phase 2: Using data from phase 1 to identify organizations in which mis-implementation is particularly high or low, the team will conduct eight comparative case studies to get a richer understanding of mis-implementation and to understand contextual differences. These case studies will highlight lessons learned about mis-implementation and identify hypothesized drivers. Phase 3: Agent-based modeling will be used to identify dynamic interactions between individual capacity, organizational capacity, use of evidence, funding, and external factors driving mis-implementation. The team will then translate and disseminate findings from phases 1 to 3 to practitioners and practice-related stakeholders to support the reduction of mis-implementation. Discussion This study is innovative and significant because it will (1) be the first to refine and further develop reliable and valid measures of mis-implementation of public health programs; (2) bring together a strong, transdisciplinary team with significant expertise in practice-based research; (3) use agent-based modeling to address cancer control implementation; and (4) use a participatory, evidence-based, stakeholder-driven approach that will identify key leverage points for addressing mis-implementation among state public health programs. This research is expected to provide replicable computational simulation models that can identify leverage points and public health system dynamics to reduce mis-implementation in cancer control and may be of interest to other health areas

Substantial variation across geographic regions in the obesity prevalence among 6–8 years old Hungarian children (COSI Hungary 2016)

Abstract Background There have been previous representative nutritional status surveys conducted in Hungary, but this is the first one that examines overweight and obesity prevalence according to the level of urbanization and in different geographic regions among 6–8-year-old children. We also assessed whether these variations were different by sex. Methods This survey was part of the fourth data collection round of World Health Organization (WHO) Childhood Obesity Surveillance Initiative which took place during the academic year 2016/2017. The representative sample was determined by two-stage cluster sampling. A total of 5332 children (48.4% boys; age 7.54 ± 0.64 years) were measured from all seven geographic regions including urban (at least 500 inhabitants per square kilometer; n = 1598), semi-urban (100 to 500 inhabitants per square kilometer; n = 1932) and rural (less than 100 inhabitants per square kilometer; n = 1802) areas. Results Using the WHO reference, prevalence of overweight and obesity within the whole sample were 14.2, and 12.7%, respectively. According to the International Obesity Task Force (IOTF) reference, rates were 12.6 and 8.6%. Northern Hungary and Southern Transdanubia were the regions with the highest obesity prevalence of 11.0 and 12.0%, while Central Hungary was the one with the lowest obesity rate (6.1%). The prevalence of overweight and obesity tended to be higher in rural areas (13.0 and 9.8%) than in urban areas (11.9 and 7.0%). Concerning differences in sex, girls had higher obesity risk in rural areas (OR = 2.0) but boys did not. Odds ratios were 2.0–3.4 in different regions for obesity compared to Central Hungary, but only among boys. Conclusions Overweight and obesity are emerging problems in Hungary. Remarkable differences were observed in the prevalence of obesity by geographic regions. These variations can only be partly explained by geographic characteristics. Trial registration Study protocol was approved by the Scientific and Research Ethics Committee of the Medical Research Council (61158–2/2016/EKU)

Neighborhood and weight-related health behaviors in the Look AHEAD (Action for Health in Diabetes) Study

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown that neighborhood factors are associated with obesity, but few studies have evaluated the association with weight control behaviors. This study aims to conduct a multi-level analysis to examine the relationship between neighborhood SES and weight-related health behaviors.</p> <p>Methods</p> <p>In this ancillary study to Look AHEAD (Action for Health in Diabetes) a trial of long-term weight loss among individuals with type 2 diabetes, individual-level data on 1219 participants from 4 clinic sites at baseline were linked to neighborhood-level data at the tract level from the 2000 US Census and other databases. Neighborhood variables included SES (% living below the federal poverty level) and the availability of food stores, convenience stores, and restaurants. Dependent variables included BMI, eating patterns, weight control behaviors and resource use related to food and physical activity. Multi-level models were used to account for individual-level SES and potential confounders.</p> <p>Results</p> <p>The availability of restaurants was related to several eating and weight control behaviors. Compared to their counterparts in neighborhoods with fewer restaurants, participants in neighborhoods with more restaurants were more likely to eat breakfast (prevalence Ratio [PR] 1.29 95% CI: 1.01-1.62) and lunch (PR = 1.19, 1.04-1.36) at non-fast food restaurants. They were less likely to be attempting weight loss (OR = 0.93, 0.89-0.97) but more likely to engage in weight control behaviors for food and physical activity, respectively, than those who lived in neighborhoods with fewer restaurants. In contrast, neighborhood SES had little association with weight control behaviors.</p> <p>Conclusion</p> <p>In this selected group of weight loss trial participants, restaurant availability was associated with some weight control practices, but neighborhood SES was not. Future studies should give attention to other populations and to evaluating various aspects of the physical and social environment with weight control practices.</p

Inhibitor of DNA Binding 3 Limits Development of Murine Slam-Associated Adaptor Protein-Dependent “Innate” γδ T cells

Id3 is a dominant antagonist of E protein transcription factor activity that is induced by signals emanating from the alphabeta and gammadelta T cell receptor (TCR). Mice lacking Id3 were previously shown to have subtle defects in positive and negative selection of TCRalphabeta+ T lymphocytes. More recently, Id3(-/-) mice on a C57BL/6 background were shown to have a dramatic expansion of gammadelta T cells.Here we report that mice lacking Id3 have reduced thymocyte numbers but increased production of gammadelta T cells that express a Vgamma1.1+Vdelta6.3+ receptor with restricted junctional diversity. These Vgamma1.1+Vdelta6.3+ T cells have multiple characteristics associated with "innate" lymphocytes such as natural killer T (NKT) cells including an activated phenotype, expression of the transcription factor PLZF, and rapid production of IFNg and interleukin-4. Moreover, like other "innate" lymphocyte populations, development of Id3(-/-) Vgamma1.1+Vdelta6.3+ T cells requires the signaling adapter protein SAP.Our data provide novel insight into the requirements for development of Vgamma1.1+Vdelta6.3+ T cells and indicate a role for Id3 in repressing the response of "innate" gammadelta T cells to SAP-mediated expansion or survival

Developing an agenda for research about policies to improve access to healthy foods in rural communities: a concept mapping study

Background Policies that improve access to healthy, affordable foods may improve population health and reduce health disparities. In the United States most food access policy research focuses on urban communities even though residents of rural communities face disproportionately higher risk for nutrition-related chronic diseases compared to residents of urban communities. The purpose of this study was to (1) identify the factors associated with access to healthy, affordable food in rural communities in the United States; and (2) prioritize a meaningful and feasible rural food policy research agenda. Methods This study was conducted by the Rural Food Access Workgroup (RFAWG), a workgroup facilitated by the Nutrition and Obesity Policy Research and Evaluation Network. A national sample of academic and non-academic researchers, public health and cooperative extension practitioners, and other experts who focus on rural food access and economic development was invited to complete a concept mapping process that included brainstorming the factors that are associated with rural food access, sorting and organizing the factors into similar domains, and rating the importance of policies and research to address these factors. As a last step, RFAWG members convened to interpret the data and establish research recommendations. Results Seventy-five participants in the brainstorming exercise represented the following sectors: non-extension research (n = 27), non-extension program administration (n = 18), “other� (n = 14), policy advocacy (n = 10), and cooperative extension service (n = 6). The brainstorming exercise generated 90 distinct statements about factors associated with rural food access in the United States; these were sorted into 5 clusters. Go Zones were established for the factors that were rated highly as both a priority policy target and a priority for research. The highest ranked policy and research priorities include strategies designed to build economic viability in rural communities, improve access to federal food and nutrition assistance programs, improve food retail systems, and increase the personal food production capacity of rural residents. Respondents also prioritized the development of valid and reliable research methodologies to measure variables associated with rural food access. Conclusions This collaborative, trans-disciplinary, participatory process, created a map to guide and prioritize research about polices to improve healthy, affordable food access in rural communities