NOR-1/NR4A3 is an "orphan member" of the nuclear hormone receptor superfamily. NOR-1 and its close relatives Nurr1 and Nur77 are members of the NR4A subgroup of nuclear receptors. Members of the NR4A subgroup are induced through multiple signal transduction pathways. They have been implicated in cell proliferation, differentiation, T-cell apoptosis, chondrosarcomas, neurological disorders, inflammation, and atherogenesis. However, the mechanism of transcriptional activation, coactivator recruitment, and agonist-mediated activation remain obscure. Hence, we examined the molecular basis of NOR-1-mediated activation. We observed that NOR-1 trans-activates gene expression in a cell-and target-specific manner; moreover, it operates in an activation function (AF)-1-dependent manner. The N-terminal AF-1 domain delimited to between amino acids 1 and 112, preferentially recruits the steroid receptor coactivator (SRC). Furthermore, SRC-2 modulates the activity of the AF-1 domain but not the Cterminal ligand binding domain (LBD). Homology modeling indicated that the NOR-1 LBD was substantially different from that of hROR␤, a closely related AF-2-dependent receptor. In particular, the hydrophobic cleft characteristic of nuclear receptors was replaced with a very hydrophilic surface with a distinct topology. This observation may account for the inability of this nuclear receptor LBD to efficiently mediate cofactor recruitment and transcriptional activation. In contrast, the N-terminal AF-1 is necessary for cofactor recruitment and can independently conscript coactivators. Finally, we demonstrate that the purine anti-metabolite 6-mercaptopurine, a widely used antineoplastic and anti-inflammatory drug, activates NOR-1 in an AF-1-dependent manner. Additional 6-mercaptopurine analogs all efficiently activated NOR-1, suggesting that the signaling pathways that modulate proliferation via inhibition of de novo purine and/or nucleic acid biosynthesis are involved in the regulation NR4A activity. We hypothesize that the NR4A subgroup mediates the genotoxic stress response and suggest that this subgroup may function as sensors that respond to genotoxicity. Nuclear hormone receptors (NRs)1 function as ligand-activated transcription factors that regulate gene expression involved in reproduction, development, and general metabolism (1). NRs function as the pipeline between physiology and gene expression. The importance of NRs in human physiology is underscored by the extensive range of therapeutics that has been created to combat disorders associated with dysfunctional hormone signaling. These diseases affect every discipline of medicine (2). All members of the NR superfamily display a highly conserved structural organization (1) with an aminoterminal region AB (that encodes activation function 1 (AF-1)), followed by the C-region that encodes the DNA binding domain (DBD), a linker region D, and the C-terminal E region. The DE region encodes the ligand binding domain (LBD) and a transcriptional domain, denoted as activation function 2 (AF...

Hypogonadism is likely a fundamental component of metabolic syndrome. Testosterone therapy may not only treat hypogonadism, but may also have tremendous potential to slow or halt the progression from metabolic syndrome to overt diabetes or cardiovascular disease via beneficial effects on insulin regulation, lipid profile and blood pressure. Furthermore, the use of testosterone to treat metabolic syndrome may also lead to the prevention of urological complications commonly associated with these chronic disease states, such as neurogenic bladder and erectile dysfunction. Physicians must be mindful to evaluate hypogonadism in all men diagnosed with metabolic syndrome as well as metabolic syndrome in all men diagnosed with hypogonadism. Future research in the form of randomized clinical trials should focus on further defining the role of testosterone for metabolic syndrome.

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Many veterans are now returning from Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) deployments with physical and mental health problems. However, there are few studies that examine the impact of moral injury on both physical and mental well-being. This study examines the impact of moral injury on self-reported general physical health, general mental health, post-traumatic stress disorder symptoms, and depression symptoms. Cross-sectional data were collected at as part of a pilot study at the New Jersey Veteran Affairs. 100 OEF/OIF veterans recruited at the New Jersey Veteran Affairs completed the paper questionnaire. We found that moral injury and combat experiences positively predicted post-traumatic stress disorder scores. Seeing the aftermath of battle and moral injury were negatively associated with mental well-being and positively associated with depression. Physical health status was negatively associated with depression. Spirituality and moral injury were negatively associated with physical health, whereas age was positively associated with physical health. Moral injury plays an important role in both physical and mental health outcomes for OEF/OIF veterans, but it is often not addressed in health care. These results underline the need for an approach to veterans' health care that includes discussion of existential and moral issues since they may impact health outcomes for many service members.

BackgroundPhysical and mental function are strong indicators of disability and mortality. OEF/OIF Veterans returning from deployment have been found to have poorer function than soldiers who have not deployed; however the reasons for this are unknown.MethodsA prospective cohort of 790 soldiers was assessed both pre- and immediately after deployment to determine predictors of physical and mental function after war.ResultsOn average, OEF/OIF Veterans showed significant declines in both physical (t=6.65, p<.0001) and mental function (t=7.11, p<.0001). After controlling for pre-deployment function, poorer physical function after deployment was associated with older age, more physical symptoms, blunted systolic blood pressure reactivity and being injured. After controlling for pre-deployment function, poorer mental function after deployment was associated with younger age, lower social desirability, lower social support, greater physical symptoms and greater PTSD symptoms.ConclusionsCombat deployment was associated with an immediate decline in both mental and physical function. The relationship of combat deployment to function is complex and influenced by demographic, psychosocial, physiological and experiential factors. Social support and physical symptoms emerged as potentially modifiable factors.