Role of Misfolded N-CoR Mediated Transcriptional Deregulation of Flt3 in Acute Monocytic Leukemia (AML)-M5 Subtype

The nuclear receptor co-repressor (N-CoR) is a key component of the generic multi-protein complex involved in transcriptional control. Flt3, a key regulator of hematopoietic cell growth, is frequently deregulated in AML (acute myeloid leukemia). Here, we report that loss of N-CoR-mediated transcriptional control of Flt3 due to misfolding, contributes to malignant growth in AML of the M5 subtype (AML-M5). An analysis of hematopoietic genes in AML cells led to the identification of Flt3 as a transcriptional target of N-CoR. Flt3 level was inversely related to N-CoR status in various leukemia cells. N-CoR was associated with the Flt3 promoter in-vivo, and a reporter driven by the Flt3 promoter was effectively repressed by N-CoR. Blocking N-CoR loss with Genistein; an inhibitor of N-CoR misfolding, significantly down-regulated Flt3 levels regardless of the Flt3 receptor mutational status and promoted the differentiation of AML-M5 cells. While stimulation of the Flt3 receptor with the Flt3 ligand triggered N-CoR loss, Flt3 antibody mediated blockade of Flt3 ligand-receptor binding led to N-CoR stabilization. Genetic ablation of N-CoR potentiated Flt3 ligand induced proliferation of BA/F3 cells. These findings suggest that N-CoR-induced repression of Flt3 might be crucial for limiting the contribution of the Flt3 signaling pathway on the growth potential of leukemic cells and its deregulation due to N-CoR loss in AML-M5, could contribute to malignant growth by conferring a proliferative advantage to the leukemic blasts. Therapeutic restoration of N-CoR function could thus be a useful approach in restricting the contribution of the Flt3 signaling pathway in AML-M5 pathogenesis

The role of hypothalamic H1 receptor antagonism in antipsychotic-induced weight gain

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by SGAs activates AMP-activated protein kinase (AMPK), a well-known feeding regulator. During short-term treatment, hypothalamic H1 receptor antagonism by SGAs may activate the AMPK—carnitine palmitoyltransferase 1 signaling to rapidly increase caloric intake and result in weight gain. During long-term SGA treatment, hypothalamic H1 receptor antagonism can reduce thermogenesis, possibly by inhibiting the sympathetic outflows to the brainstem rostral raphe pallidus and rostral ventrolateral medulla, therefore decreasing brown adipose tissue thermogenesis. Additionally, blocking of hypothalamic H1 receptors by SGAs may also contribute to fat accumulation by decreasing lipolysis but increasing lipogenesis in white adipose tissue. In summary, antagonism of hypothalamic H1 receptors by SGAs may time-dependently affect the hypothalamus-brainstem circuits to cause weight gain by stimulating appetite and fat accumulation but reducing energy expenditure. The H1 receptor and its downstream signaling molecules could be valuable targets for the design of new compounds for treating SGA-induced weight gain/obesity

Introducing Pre-university Students to Primary Scientific Literature Through Argumentation Analysis

<p>Primary scientific literature is one of the most important means of communication in science, written for peers in the scientific community. Primary literature provides an authentic context for showing students how scientists support their claims. Several teaching strategies have been proposed using (adapted) scientific publications, some for secondary education, but none of these strategies focused specifically on scientific argumentation. The purpose of this study is to evaluate a strategy for teaching pre-university students to read unadapted primary scientific literature, translated into students' native language, based on a new argumentation analysis framework. This framework encompasses seven types of argumentative elements: motive, objective, main conclusion, implication, support, counterargument and refutation. During the intervention, students studied two research articles. We monitored students' reading comprehension and their opinion on the articles and activities. After the intervention, we measured students' ability to identify the argumentative elements in a third unadapted and translated research article. The presented framework enabled students to analyse the article by identifying the motive, objective, main conclusion and implication and part of the supports. Students stated that they found these activities useful. Most students understood the text on paragraph level and were able to read the article with some help for its vocabulary. We suggest that primary scientific literature has the potential to show students important aspects of the scientific process and to learn scientific vocabulary in an authentic context.</p>

Depression, Compulsive Sexual Behavior, and Sexual Risk-Taking Among Urban Young Gay and Bisexual Men: The P18 Cohort Study

Young gay, bisexual, and other men who have sex with men (YMSM) are at increased likelihood of experiencing depression and condomless sexual behaviors The goal of the current investigation was to examine the relationship between negative mood and compulsive sexual behavior (CSB) and to assess for their individual and combined influence on sexual risk-taking behavior among a diverse sample of YMSM in New York City (the P18 Cohort Study). We first analyzed sociodemographic, depressive symptoms, CSB, and sexual risk-taking from the cross-sectional data of 509, 18- or 19-year-old YMSM recruited using non-probability sampling. We found a significant positive correlation between CSB and depression and between CSB and frequency of condomless anal sex acts reported over the past 30 days. Multivariate results found that the presence of both depression and CSB contributed to elevated sexual risk-taking among these urban YMSM. Clinical implications include the importance of assessing for CSB when depression is present and vice versa in order to improve HIV prevention. Informed by Minority Stress Theory and Syndemic Theory, our results suggest that interventions focused on the health of YMSM recognize that mental health, CSB and social context all interact to increase physical health vulnerability vis-a-vis sexual behaviors, depression, and CSB. Thus, HIV prevention and intervention programs need to incorporate mental health components and services that address these needs