Non-Canonical Roles for RAG1 in Lymphocyte Development

The RAG1/RAG2 (RAG) endonuclease recombines accessible antigen receptor (AgR) genes through DNA double strand break (DSB) intermediates to generate a diverse AgR repertoire. RAG-mediated DSBs signal changes in expression of genes encoding proteins involved in cellular survival, lymphocyte differentiation, and AgR selection. RAG proteins are each comprised of core endonuclease domains and dispensable non-core regions. Humans with mutations in non-core RAG1 regions exhibit fatal primary immunodeficiencies, and mice expressing truncated core, but not full-length, Rag1 protein (Rag1C/C mice) exhibit impaired early lymphocyte development associated with reduced levels of AgR gene rearrangements. In addition to serving with RAG2 as the V(D)J endonuclease, the RAG1 protein has been proposed to utilize non-core regions to regulate V(D)J recombination by enhancing AgR locus accessibility, promoting efficient RAG endonuclease activity, and/or generating RAG DSB-induced survival and differentiation signals. The experiments described in this thesis use a variety of mouse genetic models to investigate how mutations in RAG1 protein that preserve RAG endonuclease activity impair V(D)J recombination efficiency and lymphocyte development. First, these studies have identified roles for non-core Rag1 regions in regulating normal Alpha/Beta T cell development and TCRB recombination by promoting VB rearrangements and diverse usage of VB gene segments in both primary and secondary VB rearrangements. Second, these studies show that non-core Rag1 regulates normal B cell development by inducing transcriptional activation of the pro-survival kinase Pim2 in response to RAG cleavage and by promoting the survival of developing IgKappa+ and IgLambda+ B cells. These studies have also identified roles for Rag1 in enhancing IgKappa and IgLambda locus accessibility in pre-B cells prior to RAG cleavage. Collectively, the data presented in this thesis demonstrate that RAG1 has critical functions outside of V(D)J recombination that enhance AgR gene segment accessibility, promote V(D)J recombination at multiple AgR loci, and transduce pro-survival signals during AgR recombination to establish a broad AgR repertoire and thereby foster normal lymphocyte development

Gravitational Radiation from Travelling Waves on D-Strings

Boundary states that preserve supersymmetry are constructed for fractional D-strings with travelling waves on a ${\bf C}^3/ {{\bf Z}_2\times {\bf Z}_2}$ orbifold. The gravitational radiation emitted between two D-strings with antiparallel travelling waves is calculated.Comment: improvements and correction

The Role of Cooperative Extension in Chronic Disease Prevention and Management: Perspectives from Professionals in the Field

Chronic diseases are strongly associated with premature death and increased health care costs. Nearly half of American adults report they have one or more chronic health conditions. Cooperative Extension is calling for refocus to refine and align with broader efforts to promote public health by supporting the prevention and management of chronic disease. The success of this refocus is dependent on a shared vision between funding agencies, stakeholders, and Extension. As part of developing this shared vision, the Chronic Disease Health Implementation Team surveyed 152 Extension administrators, faculty, and Extension Agents/Educators to determine their perception of the role of Extension in chronic disease prevention and management in the next century. Respondents answered the open-ended question, “What role should Cooperative Extension have in working to reduce chronic diseases in America for the next 10, 25, and 100 years? Analysis with grounded theory identified three themes. The respondents perceived the role of Extension professionals as educators and collaborators in chronic disease prevention and management who focus on influencing individuals and environments. As educators, Extension should deliver evidence-based programs to communicate, inform, facilitate, and teach. As collaborators, Extension should facilitate and nurture partnerships to effect changes in chronic disease prevention and management

Cooperative Extension as a Partner in Creating Healthy Communities: An Environmental Scan

health and wellness, chronic disease prevention and management, curriculum, Cooperative Extension, Extension, health programming, Health and Wellness Framework, ECOP Action Team

Cosmology of codimension-two braneworlds

We present a comprehensive study of the cosmological solutions of 6D braneworld models with azimuthal symmetry in the extra dimensions, moduli stabilization by flux or a bulk scalar field, and which contain at least one 3-brane that could be identified with our world. We emphasize an unusual property of these models: their expansion rate depends on the 3-brane tension either not at all, or in a nonstandard way, at odds with the naive expected dimensional reduction of these systems to 4D general relativity at low energies. Unlike other braneworld attempts to find a self-tuning solution to the cosmological constant problem, the apparent failure of decoupling in these models is not associated with the presence of unstabilized moduli; rather it is due to automatic cancellation of the brane tension by the curvature induced by the brane. This provides some corroboration for the hope that these models provide a distinctive step toward understanding the smallness of the observed cosmological constant. However, we point out some challenges for obtaining realistic cosmology within this framework.Comment: 30 pages, 4 figures; generalized result for nonconventional Friedmann equation, added referenc

Identifying Factors to Improve Oral Cancer Screening Uptake: A Qualitative Study

Aims: To engage with high risk groups to identify knowledge and awareness of oral cancer signs and symptoms and the factors likely to contribute to improved screening uptake. Methods: Focus group discussions were undertaken with 18 males; 40+ years of age; smokers and/or drinkers (15+ cigarettes per day and/or 15+ units of alcohol per week), irregular dental attenders living in economically deprived areas of Teesside. Results: There was a striking reported lack of knowledge and awareness of oral cancer and its signs and symptoms among the participants. When oral/mouth cancer leaflets produced by Cancer Research UK were presented to the participants, they claimed that they would seek help on noticing such a condition. There was a preference to seek help from their general practitioner rather than their dentist due to perceptions that a dentist is ‘inaccessible ’ on a physical and psychological level, costly, a ‘tooth specialist ’ not a ‘mouth specialist’, and also not able to prescribe medication and make referrals to specialists. Interestingly, none of the 18 participants who were offered a free oral cancer examination at a dental practice took up this offer. Conclusions: The uptake of oral cancer screening may be improved by increasing knowledge of the existence and signs and symptoms of oral cancer. Other factors that may increase uptake are increased awareness of the role of dentists in diagnosing oral cancer, promotion of oral cancer screening by health professionals during routine health checks, and the use of a ‘‘health’ ’ screening setting as opposed to a ‘‘dental’ ’ setting for such checks

Ask Suicide-Screening Questions to Everyone in Medical Settings: The asQ'em Quality Improvement Project

Suicide in hospital settings is a frequently reported sentinel event to the Joint Commission (JC). Since 1995, over 1,000 inpatient deaths by suicide have been reported to the JC; 25% occurred in non-behavioral health settings. Lack of proper “assessment” was the leading root cause for 80% of hospital suicides. This paper describes the “Ask Suicide-Screening Questions to Everyone in Medical Settings (asQ’em)” Quality Improvement Project. We aimed to pilot a suicide screening tool and determine feasibility of screening in terms of prevalence, impact on unit workflow, impact on mental health resources, and patient/nurse acceptance