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Exercise is a mechanism for maintenance of body weight in humans. Morbidly obese human patients have been shown to possess single nucleotide polymorphisms in the melanocortin-4 receptor (MCAR). MC4R knockout mice have been well characterized as genetic: model that possesses phenotypic metabolic disorders, including obesity, hyperphagia, hyperinsulinemia, and hyperleptinemia, similar to those observed in humans possessing dysfunctional hMC4Rs. Using this model, we examined the effect of voluntary exercise MC4R knockout mice that were allowed access to running wheel for a duration of 8 wk. Physiological parameters that were measured included body weight, body composition of fat and lean mass, food consumption, body length, and blood levels of cholesterol and nonfasted glucose, insulin, and leptin. At the termination of the experiment, hypothalamic mRNA expression levels of neuropeptide Y (NPY), agouti-related protein (AGRP), proopiomelanocorlin (POMC), cocaine- and amphetamine-regulated transcript (CART), orexin, brain-derived neurotropic factor (BDNF), phosphatase with tensin homology (Pten), melanocortin-3 receptor (MC3R), and NPY-Y1R were determined. In addition, islet cell distribution and function in the pancreas were examined. In the exercising MC4R knockout mice, the pancreatic islet cell morphology and other physiological parameters resembled those observed in the wild-type littermate controls. Gene expression profiles identified exercise as having a significant effect on hypothalamic POMC, orexin, and MC3R levels. Genotype had a significant effect on AGRP, POMC, CART, and NPY-Y1R, with an exercise and genotype interaction effect on NPY gene expression. These data support the hypothesis that voluntary exercise can prevent the genetic predisposition of melanocortin-4 receptor-associated obesity and diabetes. [ABSTRACT FROM AUTHOR]

Abstract Background Over-diagnosis and treatment of prostate cancer has been a major problem in prostate cancer care and management. Currently the most relevant prognostic factor to predict a patient's risk of death due to prostate cancer is the Gleason score of the biopsied tissue samples. However, pathological analysis is subjective, and the Gleason score is only a qualitative estimate of the cancer malignancy. Molecular biomarkers and diagnostic tests that can accurately predict prostate tumor aggressiveness are rather limited. Method We report here for the first time the development of a nanoparticle test that not only can distinguish prostate cancer from normal and benign conditions, but also has the potential to predict the aggressiveness of prostate cancer quantitatively. To conduct the test, a prostate tissue lysate sample is spiked into a blood serum or human IgG solution and the spiked sample is incubated with a citrate-protected gold nanoparticle solution. IgG is known to adsorb to citrate-protected gold nanoparticles to form a "protein corona" on the nanoparticle surface. From this study, we discovered that certain tumor-specific molecules can interact with IgG and change the adsorption behavior of IgG to the gold nanoparticles. This change is reflected in the nanoparticle size of the assay solution and detected by a dynamic light scattering technique. Assay data were analyzed by one-way ANOVA for multiple variant analysis, and using the Student t-test or nonparametric Mann-Whitney U-tests for pairwise analyses. Results An inverse, quantitative correlation of the average nanoparticle size of the assay solution with tumor status and histological diagnostic grading was observed from the nanoparticle test. IgG solutions spiked with prostate tumor tissue exhibit significantly smaller nanoparticle size than the solutions spiked with normal and benign tissues. The higher grade the tumor is, the smaller the nanoparticle size is. The test particularly revealed large differences among the intermediate Grade 2 tumors, and suggested the need to treat them differently. Conclusion Development of a new nanoparticle test may provide a quantitative measure of the prostate cancer aggressiveness. If validated in a larger study of patients with prostate cancer, this test could become a new diagnostic tool in conjunction with Gleason Score pathology diagnostics to better distinguish aggressive cancer from indolent tumor.

Pre-drinking is a common practice for young people prior to entering a night-time entertainment precinct (NEP), and is associated with numerous harms, such as increased experience of physical aggression and drink driving. The relationship between both impulsivity traits such as negative urgency, positive urgency and sensation seeking and conformity to masculine norms, and number of pre-drinks remains under-researched. The current study aims to explore whether level of negative urgency, positive urgency, sensation seeking, or conformity to masculine norms is associated with the number of pre-drinks consumed prior to entering a NEP. Participants included patrons aged under 30 years that were systematically selected for street surveys in Fortitude Valley and West End NEPs, Brisbane, Australia; and completed a follow-up survey in the week following (n = 312). Generalized structural equation modelling was used to fit five separate models with a negative binomial regression using a log link function, adjusting for age and sex. Postestimation tests were conducted to identify any indirect effects via an association between pre-drinking and enhancement motives. The standard errors were bootstrapped for the indirect effects. We found direct effects for sensation seeking. Indirect effects were present for Playboy norms, Winning norms, positive urgency and sensation seeking. While these findings provide some evidence that impulsivity traits can influence the number of pre-drinks an individual consumes, the findings suggest that some traits are more likely to be related to overall alcohol consumption and that pre-drinking is a unique type of alcohol consumption with distinct predictors that require further investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Experiences of unwanted sexual attention (UWSA) are commonplace within nightlife environments. While typically associated with aggression perpetration, literature has suggested that a history of childhood corporal punishment (CCP) may also be related to experiences of victimisation in nightlife environments. The current exploratory study aims to examine the associations between experiences of UWSA victimisation and a history of CCP, trait aggression, and conformity to masculine norms (Playboy and Winning), for males and females separately., Method: Street intercept interviews in the Brisbane inner-city entertainment precincts were used to measure demographic details and participants' breath alcohol concentration. Online follow-up surveys were used to record participants' experiences of UWSA on the night of interview, history of CCP, and self-reported rates of trait aggression and conformity to masculine norms. The final sample consisted of 288 females, as there were not sufficient male UWSA experiences for analysis., Results: Approximately 20% of female nightlife patrons experienced some form of UWSA victimisation. Logistic regression analyses identified that after controlling for age and intoxication, a history of CCP, trait aggression and masculine norm conformity were unrelated to experiences of UWSA for female respondents., Conclusions: The current study found that individual factors were unrelated to experiences of UWSA, indicating that simply being in the nightlife environment, especially as a female, increases the risk of UWSA victimisation. Understanding and exploring social and environmental risk factors, rather than individual factors, is needed to prevent victimisation in nightlife environments.

Polyamine biosynthesis is regulated by ornithine decarboxylase (ODC), which is transcriptionally activated by c-Myc. A large library was screened to find molecules that potentiate the ODC inhibitor, difluoromethylornithine (DFMO). Anthranilic acid derivatives were identified as DFMO adjunct agents. Further studies identified the far upstream binding protein 1 (FUBP1) as the target of lead compound 9 . FUBP1 is a single-stranded DNA/RNA binding protein and a master controller of specific genes including c-Myc and p21. We showed that 9 does not inhibit 3 H-spermidine uptake yet works synergistically with DFMO to limit cell growth in the presence of exogenous spermidine. Compound 9 was also shown to inhibit the KH4 FUBP1-FUSE interaction in a gel shift assay, bind to FUBP1 in a ChIP assay, reduce both c-Myc mRNA and protein expression, increase p21 mRNA and protein expression, and deplete intracellular polyamines. This promising hit opens the door to new FUBP1 inhibitors with increased potency.

Introduction: Illicit drug use has been found to increase the risks of male barroom aggression (MBA). Personality traits such as dispositional aggressiveness have been associated with illicit substance use and aggressive behaviour, along with social normative masculinity factors. The present study assessed the relationships between illicit drug use, key personality (trait aggression, impulsivity, narcissism) and masculinity (conformity to masculine norms, male honour) variables with physical MBA perpetration and victimisation among male Australian construction workers., Methods: A purposive, high-risk sample of male construction workers aged 18-69 years (n = 476, M age  = 25.90 years, SD age  = 9.44) completed interviews at their place of work or training., Results: Participants reported high rates of both physical MBA perpetration (21%; n = 100) and victimisation (31.1%; n = 148) as well as any illicit drug use (33.61%; n = 160). Logistic regressions revealed the use of amphetamine-type stimulants (methamphetamine, ecstasy) was associated with violence perpetration, even after accounting for high-intensity drinking (HID) which was the strongest predictor of MBA involvement. Trait variables (Trait Physical aggressiveness, narcissism) and the masculine norm CMNI Violence were also risk factors for MBA perpetration while CMNI Playboy was protective against MBA., Discussion and Conclusions: The use of amphetamine-type stimulants is a risk-factor for MBA perpetration, as are key personality traits such as aggressiveness and narcissism. Most aspects of masculinity, including male honour, were either unrelated to or protective against involvement in physical violence in bars, clubs or pubs., (© 2022 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Introduction and Aims: Past research indicates heavy episodic drinking (HED), trait aggression, male honour and conformity to masculine norms are risk factors for male barroom aggression (MBA) perpetration. However, little is known about the impact of these variables on experiences of MBA victimization. Further, data derived previously, particularly in relation to perpetration have come from relatively low-risk samples comprising university students, limiting the generalizability of findings to other, at-risk male groups. Thus, the present study assessed the impact of the aforementioned variables as well as personality constructs of impulsivity and narcissism on both the perpetration of and victimization from MBA among a high-risk sample sourced from male members of the Australian construction industry. Method: A purposive sample of Australian male construction workers aged 18 to 69 years ( n = 476, M age = 25.90, SD age = 9.44) completed individual interviews at their current place of employment or while training at various trade schools in Geelong and Melbourne, Victoria, Australia. Items related to past month HED, past year experiences of verbal and physical MBA (perpetration and victimization), trait aggression's four factors (physical, verbal, anger, hostility), impulsivity, narcissism, male honour and conformity to masculine norms. Results: Participants reported high levels of verbal (24.2%) and physical (21%) MBA perpetration and verbal (33.6%) and physical (31.1%) MBA victimization. Hierarchical binary logistic regression analyses identified HED as the strongest predictor of aggression involvement, while trait physical aggression, trait anger, narcissism and conformity to norms endorsing violence and a need to win were significantly and positively associated with MBA perpetration. Conclusions: The present study reinforces the key relationships between heavy drinking and aspects of personality and MBA, while also highlighting narcissism as a risk factor for barroom aggression perpetration. Indeed, personality profiles and HED appear to exert stronger influences on MBA perpetration than socially constructed masculinity factors, most of which were unrelated to aggression involvement in bars, clubs or pubs.

Introduction and Aims: Few studies have investigated the relationship of barroom aggression with both general and barroom-specific alcohol expectancies. The present study investigated these associations in a rarely studied and high-risk population: construction tradespeople., Design and Methods: Male construction tradespeople (n = 211) aged 18-35 years (M = 21.91, SD = 4.08 years) participated in a face-to-face questionnaire assessing general and barroom-specific alcohol expectancies and perpetration of physical and verbal barroom aggression as well as control variables, age, alcohol consumption and trait aggression., Results: Sequential logistic regression analyses revealed that general alcohol-aggression expectancies of courage or dominance were not predictive of either verbal or physical barroom aggression after controlling for age, alcohol consumption and trait aggression. However, barroom-specific alcohol expectancies were associated with both verbal and physical barroom aggression, with positive associations found for expected hyper-emotionality and protective effects for expected cognitive impairment., Discussion and Conclusions: In a population where rates of risky drinking and barroom aggression are high, specific expectations about the effects of drinking in bars may influence subsequent aggressive behaviour in bars. [Zinkiewicz L, Smith G, Burn M, Litherland S, Wells S, Graham K, Miller P. Aggression-related alcohol expectancies and barroom aggression among construction tradespeople. Drug Alcohol Rev 2016;35:549-556]., (© 2015 Australasian Professional Society on Alcohol and other Drugs.)

Objective: Research suggests that heavy episodic drinking (HED), perceived peer norms, and personal approval of aggression influence male barroom aggression (MBA). Qualitative research suggests that conformity to hegemonic masculine gender norms also influences MBA; however, quantitative research on the direct and indirect influence of masculinity on MBA is limited. This study tested the relationships between HED, conformity to masculine gender norms, and personal approval and peer approval of MBA on MBA perpetration, as well as the indirect effect of masculine norms on MBA via HED., Method: A convenience sample of Australian men (N = 322; mean age = 21.05 years, SD = 1.95; 76.9% university students) completed an online questionnaire, assessing HED and MBA over the previous year, and subscales of the Beliefs and Attitudes Towards Male Alcohol-Related Aggression Inventory and Conformity to Masculine Norms Inventory-46., Results: Negative binomial regression analyses found that, overall, HED, male peer approval, and personal approval of MBA directly predicted increased risk of verbal and physical MBA perpetration. Greater conformity to specific masculine norms also increased (Power Over Women) and decreased (Emotional Control, Heterosexual Self-Presentation) risk of MBA perpetration. The masculine norms Risk Taking, Playboy, and Emotional Control were found to be indirect predictors of MBA via HED., Conclusions: Risk of MBA perpetration is increased primarily by HED as a direct, but also mediating, predictor. Personal and male peer approval of MBA, and specific masculine norms, further increase this risk whereas other masculine norms appear protective.

Myeloid cells from non-obese diabetic (NOD) mouse and human type 1 diabetic (T1D) patients overexpress granulocyte-macrophage colony stimulation factor (GM-CSF). This overproduction prolongs the activation of signal transduction and activator of transcription 5 (STAT5) proteins, involved in GM-CSF-induced control of myeloid cell gene expression. We found that GM-CSF can regulate the binding of STAT5 on the promoter of its own gene, Csf2, within regions previously identified as sites of chromatin epigenetic modification important to the regulation of GM-CSF during myeloid differentiation and inflammation. We found multiple sequence polymorphisms within NOD mouse chromosome 11 Idd4.3 diabetes susceptibility region that alter STAT5 GAS binding sequences within the Csf2 promoter. STAT5 binding at these sites in vivo is increased significantly in GM-CSF-stimulated-bone marrow cells and in unactivated, high GM-CSF-producing macrophages from NOD mice as compared to non-autoimmune C57BL/6 mouse myeloid cells. Thus, GM-CSF overproduction by NOD myeloid cells may be perpetuating a positive epigenetic regulatory feedback on its own gene expression through its induction of STAT5 binding to its promoter. These findings suggest that aberrant STAT5 binding at epigenetic regulatory sites may contribute directly to immunopathology through cytokine-induced gene expression dysregulation that can derail myeloid differentiation and increase inflammatory responsiveness.

We investigate JAK-STAT5 activation and its relationship to full-length Stat5B (FL-Stat5) and constitutive phosphorylated carboxy-truncated Stat5B (ct-pStat5) in four different strains of mouse. Our electrophoresis mobility shift assays data indicate constitutive phosphorylation of full-length-Stat5 (p<0.001) and DNA binding in NOD but not in B6 mice. Our data suggest that the relative ratio of FL-Stat5: ct-Stat5 in NOD is 5- to 8-fold lower (p<0.0001) when compared with normal B6 mice. Additionally, EMSAs data from B6.NOD/c11 suggest contribution of Idd4 susceptibility locus on chromosome 11 in constitutive phosphorylation of Stat5 in NOD mice. The presence of ct-pStat5 in regulatory T cells of NOD mice suggests this form of Stat5 is associated with impaired function of Tregs in NOD mouse. In agreement with our previous report the JAK-Stat5B defective pathway in NOD mice along with other defective factors is associated with the pathogenesis of autoimmune type 1 diabetes in NOD mice.

Autocrine granulocyte macrophage-colony stimulating factor (GM-CSF) sequentially activates intracellular components in monocyte/macrophage production of the pro-inflammatory and immunoregulatory prostanoid, prostaglandin E2 (PGE2). GM-CSF first induces STAT5 signaling protein phosphorylation, then prostaglandin synthase 2 (COX2/PGS2) gene expression, and finally IL-10 production, to downregulate the cascade. Without activation, monocytes of at-risk, type 1 diabetic (T1D), and autoimmune thyroid disease (AITD) humans, and macrophages of nonobese diabetic (NOD) mice have aberrantly high GM-CSF, PGS2, and PGE2 expression, but normal levels of IL-10. After GM-CSF stimulation, repressor STAT5A and B isoforms (80-77kDa) in autoimmune human and NOD monocytes and activator STAT5A (96-94kDa) and B (94-92kDa) isoforms in NOD macrophages stay persistently tyrosine phosphorylated. This STAT5 phosphorylation persisted despite treatment in vitro with IL-10, anti-GM-CSF antibody, or the JAK2/3 inhibitor, AG490. Phosphorylated STAT5 repressor isoforms in autoimmune monocytes had diminished DNA binding capacity on GAS sequences found in the PGS2 gene enhancer. In contrast, STAT5 activator isoforms in NOD macrophages retained their DNA binding capacity on these sites much longer than in healthy control strain macrophages. These findings suggest that STAT5 dysfunction may contribute to dysregulation of GM-CSF signaling and gene activation, including PGS2, in autoimmune monocytes and macrophages.

Aberrant prostaglandin synthase 2 (PGS2/COX2) expression constitutes an antigen presenting cell (APC) dysfunction seen in monocytes of humans at risk for or with Type 1 diabetes. During endotoxin activation of PGS2 expression in healthy monocytes, granulocyte-monocyte colony stimulating factor (GM-CSF) is activated and, in turn, promotes PGS2 gene activation. GM-CSF is considered a major target the action for IL10 in its suppression of PGS2. We found that the PGS2 expression in monocytes from 47% of at-risk and diabetic humans tested were highly resistant to suppression by IL10 (maintaining > or =50% of their untreated expression), and had significantly increased GM-CSF production in vitro (1043+/-SD2798 pg/10(6)cells, subject n=35, vs 29.7+/-SD91 pg/10(6)cells, control n=20; P=0.0165). The PGS2 insensitivity to IL10 of these cells was not due to a lack of IL10 functionality or its suppression of GM-CSF. In contrast to its effects on PGS2, IL10 regulation of GM-CSF and other monocyte factors (i.e., DR, IL1beta, TNFalpha, IL12, CD54, and CD64) remained intact. These findings suggest that the inability of IL10 to properly downregulate PGS2 gene expression may contribute to its dysregulation in Type 1 diabetes.

Type 1 diabetes (T1D) is a T cell-mediated disease. Various DC populations play important roles in initiating and directing T cell responses and thus may be critical for T1D pathogenesis. We thus examined peripheral blood DC1 and DC2 populations by flow cytometry in healthy controls, subjects at risk for T1D, new-onset patients, and established T1D patients. We found a significant increase in the number of DCs (including DC1 and DC2) in at-risk subjects and those with new-onset T1D versus healthy controls and established T1D patients (ANOVA; p < 0.0001). Analysis of DC1 and DC2 subsets in these same groups demonstrated a significant decrease in the ratio of DC1 and DC2 in subjects at risk and new-onset and established T1D patients in contrast with healthy controls (p < 0.0001). Both subsets of peripheral blood DCs from T1D patients expressed significantly higher levels of HLA-DR than healthy controls. Peripheral blood mononuclear cells from T1D patients secreted significantly higher amounts of IFN-alpha than controls, and IFN-alpha production correlated inversely with the DC1/DC2 ratio. This study demonstrates a marked increase in peripheral blood DC numbers that occurs during a time of active autoimmunity in at-risk subjects and patients with new-onset T1D, but is lost in established diabetes. However, the abnormal distribution of peripheral blood DC populations appears to be a persistent phenotype in all stages of T1D.

Prostaglandins (PGs) are lipid molecules that profoundly affect cellular processes including inflammation and immune response. Pathways contributing to PG output are highly regulated in antigen-presenting cells such as macrophages and monocytes, which produce large quantities of these molecules upon activation. In this report, we demonstrate aberrant constitutive expression of the normally inducible cyclooxygenase PG synthase 2 (PGS(2)/ COX-2) in nonactivated monocytes of humans with insulin-dependent diabetes mellitus (IDDM) and those with islet autoantibodies at increased risk of developing this disease. Constitutive PGS(2) appears to characterize a high risk for diabetes as it correlates with and predicts a low first-phase insulin response in autoantibody-positive subjects. Abnormal PGS(2) expression in at-risk subjects affected immune response in vitro, as the presence of a specific PGS(2) inhibitor, NS398, significantly increased IL-2 receptor alpha-chain (CD25) expression on phytohemagglutinin-stimulated T cells. The effect of PGS(2) on CD25 expression was most profound in subjects expressing both DR04 and DQbeta0302 high-risk alleles, suggesting that this cyclooxygenase interacts with diabetes-associated MHC class II antigens to limit T-cell activation. These results indicate that constitutive PGS(2) expression in monocytes defines an antigen-presenting cell defect affecting immune response, and that this expression is a novel cell-associated risk marker for IDDM.

Research was conducted to evaluate the merits of rat bioassays in studies concerning the bioavailability of vitamin B-6. A protocol was devised, which included pair-feeding and prevention of coprophagy. Plasma pyridoxal 5'-phosphate (PLP) was measured by a rapid chromatographic method as an indicator of vitamin B-6 status. Pyridoxamine and pyridoxal exhibited 70% molar activity relative to pyridoxine at suboptimal dietary levels. Selected foods (spinach, cornmeal and potato) were evaluated at three dietary levels with this protocol. Analysis of dose-response curves (dietary vitamin B-6 vs. plasma PLP) by slope-ratio methods yielded imprecise estimates of the relative vitamin B-6 bioavailability. This low precision, in addition to the potential for interference by direct absorption of B-6 vitamers synthesized by intestinal microflora, indicates the need for improved methods for measurement of biologically available vitamin B-6. It was concluded that rat bioassay methods, even as modified here, may be frequently unsuitable for use in studies of vitamin B-6 bioavailability. Results presented provide further support for the use of plasma PLP as an indicator of vitamin B-6 nutriture.