FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B–enhanced cell survival through maintenance of mitochondrial integrity

Survival signals elicited by cytokines include the activation of phosphatidylinositol 3-kinase (PI3K), which in turn promotes the activation of protein kinase B (PKB). Recently, PKB has been demonstrated to phosphorylate and inactivate forkhead transcription factor FKHR-L1, a potent inducer of apoptosis. To explore the mechanisms underlying the induction of apoptosis after cytokine withdrawal or FKHR-L1 activation, we used a cell line in which FKHR-L1 activity could be specifically induced. Both cytokine withdrawal and FKHR-L1 activation induced apoptosis, which was preceded by an upregulation in p27KIP1 and a concomitant decrease in cells entering the cell cycle. Induction of apoptosis by both cytokine withdrawal and activation of FKHR-L1 correlated with the disruption of mitochondrial membrane integrity and cytochrome c release. This was preceded by upregulation of the pro-apoptotic Bcl-2 family member Bim. Ectopic expression of an inhibitory mutant of FKHR-L1 substantially reduced the levels of apoptosis observed after cytokine withdrawal. Activation of PKB alone was sufficient to promote cell survival, as measured by maintenance of mitochondrial integrity and the resultant inhibition of effector caspases. Furthermore, hematopoietic stem cells isolated from Bim−/− mice exhibited reduced levels of apoptosis upon inhibition of PI3K/PKB signaling

Factors determining social participation in the first year after kidney transplantation: a prospective study

BACKGROUND: This study describes changes in social participation in the first year after kidney transplantation and examines the influence of clinical factors, health status, transplantation-related symptoms, and psychological characteristics on change in social participation. METHODS: A prospective study was performed on a cohort of primary kidney transplant recipients, transplanted between March 2002 and March 2003. Data on participation in obligatory activities (i.e., employment, education, household tasks) and leisure activities (i.e., volunteer work, assisting others, sports, clubs/associations, recreation, socializing, going out) were collected by in-home interviews (n=61) at 3 months (T1) and 1 year posttransplantation (T2). Analysis of covariance was performed. RESULTS: Data showed an increase in participation in obligatory activities and diversity of leisure participation between T1 and T2, although pre-end-stage renal disease level was not regained and differed from the general population. On T1, the majority of employed recipients were on sick leave, but returned to work on T2. Employment rate remained stable. An increase in obligatory participation was predicted by clinical factors (i.e., peritoneal dialysis, initial hospitalization), whereas change in leisure participation was related to serum albumin and cognitive capacity. No effects were found for type of donation, comorbidity, and renal function. CONCLUSIONS: We found that mainly clinical factors were associated with an increase in participation in society. Although health-status related factors and the psychological attribute self-efficacy may be related to recovery of social participation, their effect was outweighed by the strength of clinical predictors in multivariate analysis

Determinants of social participation of visually impaired older adults

PURPOSE: To assess determinants of social participation among visually impaired older adults. METHODS: This cross-sectional study included visually impaired persons (>/=55 years; n = 173) who were referred to a low-vision rehabilitation center. Determinants (i.e., sociodemographic, physical, social and psychological factors, and personal values) of participation were identified in four domains of participation: (1) domestic life; (2) interpersonal interactions and relationships; (3) major life areas; and (4) community, social, and civic life. Study participants completed telephone interviews. RESULTS: Age, physical fitness, and helplessness were determinants of participation in domestic life. Social network size was associated with participation in major life areas. The personal value attached to participation (i.e., perceived importance) was a determinant of participation in interpersonal interactions and relationships, major life areas, and community, social and civic life. Vision-related characteristics (i.e., self-perceived vision and degree of visual impairment) were not associated with participation. CONCLUSIONS: Across the participation domains, perceived importance is a major determinant of social participation among visually impaired older adults. Physical health along with social and psychological status, also affect participation. Knowing how participation is determined can be used to develop rehabilitation interventions to enhance participation of visually impaired older adults

Genetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistance

Despite treatment with agents that enhance β-cell function and insulin action, reduction in β-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3β (Gsk-3β). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3β to regulation of β-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/−) exhibit insulin resistance and a doubling of β-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3β (Gsk-3β+/−) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced β-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2−/−), like the Ir+/− mice, are insulin resistant, but develop profound β-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3β activity associated with a marked reduction of β-cell proliferation and increased apoptosis. Irs2−/− mice crossed with Gsk-3β+/− mice preserved β-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2−/− mice had increased cyclin-dependent kinase inhibitor p27kip1 that was limiting for β-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of β-cell mass in Gsk-3β+/−Irs2−/− mice was accompanied by suppressed p27kip1 levels and increased Pdx1 levels. To separate peripheral versus β-cell–specific effects of reduction of Gsk3β activity on preservation of β-cell mass, mice homozygous for a floxed Gsk-3β allele (Gsk-3F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce β-cell–specific knockout of Gsk-3β (βGsk-3β−/−). Like Gsk-3β+/− mice, βGsk-3β−/− mice also prevented the diabetes of the Irs2−/− mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within β-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of β-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve β-cells and prevent diabetes onset

Evaluating a Measure of Social Health Derived from Two Mental Health Recovery Measures: The California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program Consumer Survey (MHSIP)

Social health is important to measure when assessing outcomes in community mental health. Our objective was to validate social health scales using items from two broader commonly used measures that assess mental health outcomes. Participants were 609 adults receiving psychological treatment services. Items were identified from the California Quality of Life (CA-QOL) and Mental Health Statistics Improvement Program (MHSIP) outcome measures by their conceptual correspondence with social health and compared to the Social Functioning Questionnaire (SFQ) using correlational analyses. Pearson correlations for the identified CA-QOL and MSHIP items with the SFQ ranged from .42 to .62, and the identified scale scores produced Pearson correlation coefficients of .56, .70, and, .70 with the SFQ. Concurrent validity with social health was supported for the identified scales. The current inclusion of these assessment tools allows community mental health programs to include social health in their assessments

Unregulated miR-96 Induces Cell Proliferation in Human Breast Cancer by Downregulating Transcriptional Factor FOXO3a

FOXO transcription factors are key tumor suppressors in mammalian cells. Until now, suppression of FOXOs in cancer cells was thought to be mainly due to activation of multiple onco-kinases by a phosphorylation-ubiquitylation-mediated cascade. Therefore, it was speculated that inhibition of FOXO proteins would naturally occur through a multiple step post-translational process. However, whether cancer cells may downregulate FOXO protein via an alternative regulatory mechanism is unclear. In the current study, we report that expression of miR-96 was markedly upregulated in breast cancer cells and breast cancer tissues compared with normal breast epithelial cells (NBEC) and normal breast tissues. Ectopic expression of miR-96 induced the proliferation and anchorage-independent growth of breast cancer cells, while inhibition of miR-96 reduced this effect. Furthermore, upregulation of miR-96 in breast cancer cells resulted in modulation of their entry into the G1/S transitional phase, which was caused by downregulation of cyclin-dependent kinase (CDK) inhibitors, p27Kip1 and p21Cip1, and upregulation of the cell-cycle regulator cyclin D1. Moreover, we demonstrated that miR-96 downregulated FOXO3a expression by directly targeting the FOXO3a 3′-untranslated region. Taken together, our results suggest that miR-96 may play an important role in promoting proliferation of human breast cancer cells and present a novel mechanism of miRNA-mediated direct suppression of FOXO3a expression in cancer cells

Psychological resilience in sport performers: a review of stressors and protective factors

Psychological resilience is important in sport because athletes must utilize and optimize a range of mental qualities to withstand the pressures that they experience. In this paper, we discuss psychological resilience in sport performers via a review of the stressors athletes encounter and the protective factors that help them withstand these demands. It is hoped that synthesizing what is known in these areas will help researchers gain a deeper profundity of resilience in sport, and also provide a rigorous and robust foundation for the development of a sport-specific measure of resilience. With these points in mind, we divided the narrative into two main sections. In the first section, we review the different types of stressors encountered by sport performers under three main categories: competitive, organizational, and personal. Based on our recent research examining psychological resilience in Olympics champions (Fletcher & Sarkar, 2012), in the second section we discuss the five main families of psychological factors (viz. positive personality, motivation, confidence, focus, perceived social support) that protect the best athletes from the potential negative effect of stressors. It is anticipated that this review will help sport psychology researchers examine the interplay between stressors and protective factors which will, in turn, focus the analytical lens on the processes underlying psychological resilience in athletes