Identifizierung und Charakterisierung der CD4+AT2R+ T Zell Subpopulation bei Mensch und Ratte

The study contributes to the understanding of CD4+AT2R+ cell function after myocardial infarction (MI). This potential novel T cell subset, which expresses FoxP3 and various cytokines improves cardiac function and reduces infarct size. Results indicate that the CD4+AT2R+ T cells might be included in therapeutic approaches for the treatment of cardiac diseases, due to its upregulation in the infarcted state. The application of this T cell subset may improve the healing process of compromised heart tissue and contribute to a better quality of life in affected patients

Physical Correlates of Sexual Orientation: The Association of Height, Birth Weight, and Facial Structure with Sexual Orientation.

Researchers have examined whether certain physical characteristics are associated with sexual orientation to gain insight into the mechanisms that may be implicated in its development. Three relatively new and/or understudied physical correlates (height, birth weight, facial structure) were investigated to determine whether they are reliably associated with sexual orientation and to gain insight into the specific mechanism(s) that may be driving the association between these physical correlates and sexual orientation. In Study 1, gay men were found to be shorter, on average, than heterosexual men in a nationally representative US sample. There was no significant height difference between lesbian and heterosexual women. No evidence was found that stress and nutrition at puberty mediated the association between sexual orientation and height in men. Thus, other mechanisms (e.g., prenatal hormones, genetics) likely explain the sexual orientation-height link. In Study 2, firstborn gay male only-children had, on average, a significantly lower mean birth weight than firstborn children in four other sibship groups. There was also evidence of increased fetal loss among mothers of gay male only-children. Birth weight and fetal loss have been shown to be indicators of a mother’s immune system responding to a pregnancy. Thus, Study 2 provides support for the idea that a maternal immune response (and one that appears to be distinct from the maternal immune response hypothesized to explain the traditional fraternal birth order effect) is implicated in sexual orientation development. In Study 3, lesbian and heterosexual women differed in 17 facial features (out of 63) at the univariate level, and four were unique multivariate predictors. Gay and heterosexual men differed in 11 facial features at the univariate level, and three were unique multivariate predictors. Some of the facial features related to sexual orientation implicated a sexual differentiation related mechanism (e.g., prenatal hormones), whereas others implicated a non-sexual differentiation mechanism (e.g., developmental instability) to explain the sexual orientation-facial structure association. In addition to extending the empirical literature on the physical correlates associated with sexual orientation, the studies included in this dissertation extend our understanding of the various mechanisms likely implicated in the development of sexual orientation

Monitored Geologic Repository Test Evaluation Plan

The Monitored Geologic Repository test & evaluation program will specify tests, demonstrations, examinations, and analyses, and describe procedures to conduct and document testing necessary to verify meeting Monitored Geologic Repository requirements for a safe and effective geologic repository for radioactive waste. This test program will provide assurance that the repository is performing as designed, and that the barriers perform as expected; it will also develop supporting documentation to support the licensing process and to demonstrate compliance with codes, standards, and regulations. This comprehensive program addresses all aspects of verification from the development of test requirements to the performance of tests and reporting of the test results. The ''Monitored Geologic Repository Test & Evaluation Plan'' provides a detailed description of the test program approach necessary to achieve the above test program objectives. This test plan incorporates a set of test phases focused on ensuring repository safety and operational readiness and implements a project-wide integrated product management team approach to facilitate test program planning, analysis, and implementation. The following sections provide a description of the individual test phases, the methodology for test program planning and analyses, and the management approach for implementing these activities

Investigation of the Relationship between Sexual Orientation and Objective Height, along with Predictors of Height Distortion

Studies that have used mostly self-reported height have found that men with a same-sex orientation and women with an other-sex orientation are shorter, on average, than men with an other-sex orientation and women with a same-sex orientation, respectively. This thesis examined whether an objective height difference exists or whether a psychosocial account (e.g., distortion of self-reports) may explain these putative height differences. Also, this thesis examined whether certain individual differences (e.g, gender roles and socially desirable responding) predict height distortion. Eight hundred and thirteen participants, recruited at Brock University, the Niagara Community and through surrounding LGBT events, completed self-reported height, measures of gender roles and socially desirable responding, and had their height measured. Using hierarchical linear regressions, it was found that Same-Sex/Both-Sex Oriented men were shorter, on average, than predominantly Other-Sex Oriented men; however, there was no difference in objective height between Same-Sex/Both-Sex Oriented women and predominantly Other-Sex Oriented women. These findings contribute to existing biological theories of men's sexual orientation development and do not contribute to biological theories of women's sexual orientation development. Height distortion was not related to sexual orientation and only marginally related to sex. Predictors of height distortion were Impression Management, in both men and women, and Unmitigated Agency, in men. These findings highlight the complexity of sexual orientation development in men and women. These findings also highlight the role of certain psychosocial factors in how people perceive their bodies and/or how they want their bodies to be perceived by others

Signal Transducer and Activator of Transcription (STAT)5 Activation by BCR/ABL Is Dependent on Intact Src Homology (SH)3 and SH2 Domains of BCR/ABL and Is Required for Leukemogenesis

Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor–dependent myeloid precursor cells, STAT5 activation–deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation–deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor–independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor–independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation–defective BCR/ABL SH3+SH2 mutants to induce growth factor–independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor–independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more than one domain and document the important role of STAT5-regulated pathways in BCR/ABL leukemogenesis

BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice

Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia. In an elderly cohort with acute myocardial infarction (MI), patients with three-vessel CAD were characterized by lower levels of the natural logarithm (Ln) of peripheral blood BPIFB4 (p = 0.0077). The inverse association between Ln BPIFB4 and three-vessel CAD was confirmed by logistic regression adjusting for confounders (Odds Ratio = 0.81, p = 0.0054). Moreover, in infarcted mice, a single administration of LAV-BPIFB4 rescued cardiac function and vascularization. In vitro studies showed that LAV-BPIFB4 protein supplementation exerted chronotropic and inotropic actions on induced pluripotent stem cell (iPSC)-derived cardiomyocytes. In addition, LAV-BPIFB4 inhibited the pro-fibrotic phenotype in human cardiac fibroblasts. These findings provide a strong rationale and proof of concept evidence for treating CAD with the longevity BPIFB4 gene/protein