The Role of IRE1α in the Degradation of Insulin mRNA in Pancreatic β-Cells

The endoplasmic reticulum (ER) is a cellular compartment for the biosynthesis and folding of newly synthesized secretory proteins such as insulin. Perturbations to ER homeostasis cause ER stress and subsequently activate cell signaling pathways, collectively known as the Unfolded Protein Response (UPR). IRE1α is a central component of the UPR. In pancreatic β-cells, IRE1α also functions in the regulation of insulin biosynthesis.Here we report that hyperactivation of IRE1α caused by chronic high glucose treatment or IRE1α overexpression leads to insulin mRNA degradation in pancreatic β-cells. Inhibition of IRE1α signaling using its dominant negative form prevents insulin mRNA degradation. Islets from mice heterozygous for IRE1α retain expression of more insulin mRNA after chronic high glucose treatment than do their wild-type littermates.These results reveal a role of IRE1α in insulin mRNA expression under ER stress conditions caused by chronic high glucose. The rapid degradation of insulin mRNA could provide immediate relief for the ER and free up the translocation machinery. Thus, this mechanism would preserve ER homeostasis and help ensure that the insulin already inside the ER can be properly folded and secreted. This adaptation may be crucial for the maintenance of β-cell homeostasis and may explain why the β-cells of type 2 diabetic patients with chronic hyperglycemia stop producing insulin in the absence of apoptosis. This mechanism may also be involved in suppression of the autoimmune type 1 diabetes by reducing the amount of misfolded insulin, which could be a source of “neo-autoantigens.

The role of rigidity in adaptive and maladaptive families assessed by FACES IV: the points of view of adolescents

Previous studies using Olson’s Circumplex Model and FACES IV, the self-report assessing family functioning, did not clarify the role of rigidity, a dimension of this model. Rigidity emerged as ambiguous: it was considered either as a functional or as a dysfunctional dimension. Building upon the results of previous studies, we provided a contribution intended to disambiguate the role of rigidity considering adolescents’ perceptions and using a non-a priori classification analysis. 320 Italian adolescents (13–21 years) participated in this study and responded to a questionnaire containing scales of the study variables. A latent class analysis was performed to identify the association of rigidity with the other dimensions of Olson’s model and with indicators of adaptive family functioning in adolescence: parental monitoring and family satisfaction. We found six clusters corresponding to family typologies and having different levels of functioning. Rigidity emerged as adaptive in the typologies named rigidly balanced and flexibly oscillating; it was associated with positive dimensions of family functioning, i.e. flexibility, cohesion, parental monitoring, and high levels of family satisfaction. Differently, when rigidity was associated with disengagement, low cohesion and flexibility, and lack of parental supervision, emerged as maladaptive. This was the case of two typologies: the rigidly disengaged and the chaotically disengaged. Adolescents of these families reported the lowest levels of satisfaction. In the two last typologies, the flexibly chaotic and the cohesively disorganized, rigidity indicated a mid-range functionality as these families were characterized by emotional connectedness but lack of containment. Clinical implications are discussed

Negative parental responses to coming out and family functioning in a sample of lesbian and gay young adults

Parental responses to youths' coming out (CO) are crucial to the subsequent adjustment of children and family. The present study investigated the negative parental reaction to the disclosure of same-sex attraction and the differences between maternal and paternal responses, as reported by their homosexual daughters and sons. Participants' perceptions of their parents' reactions (evaluated through the Perceived Parental Reactions Scale, PPRS), age at coming out, gender, parental political orientation, and religiosity involvement, the family functioning (assessed through the Family Adaptability and Cohesion Evaluation Scales, FACES IV), were assessed in 164 Italian gay and lesbian young adults. Pearson correlation coefficients were calculated to assess the relation between family functioning and parental reaction to CO. The paired sample t-test was used to compare mothers and fathers' scores on the PPRS. Hierarchical multiple regression was conducted to analyze the relevance of each variable. No differences were found between mothers and fathers in their reaction to the disclosure. The analysis showed that a negative reaction to coming out was predicted by parents' right-wing political conservatism, strong religious beliefs, and higher scores in the scales Rigid and Enmeshed. Findings confirm that a negative parental reaction is the result of poor family resources to face a stressful situation and a strong belief in traditional values. These results have important implications in both clinical and social fields

Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

The effects of patient characteristics on ADHD diagnosis and treatment: a factorial study of family physicians

<p>Abstract</p> <p>Background</p> <p>Attention Deficit Hyperactivity Disorder (ADHD) is a costly and prevalent disorder in the U.S., especially among youth. However, significant disparities in diagnosis and treatment appear to be predicted by the race and insurance status of patients.</p> <p>Methods</p> <p>This study employed a web-based factorial survey with four ADHD cases derived from an ADHD clinic, two diagnosed with ADHD in actual evaluation, and two not. Randomized measures included race and insurance status of the patients. Participants N = (187) included clinician members of regional and national practice-based research networks and the U.S. clinical membership of the Society of Teachers of Family Medicine. The main outcomes were decisions to 1) diagnose and 2) treat the cases, based upon the information presented, analyzed via binary logistic regression of the randomized factors and case indicators on diagnosis and treatment.</p> <p>Results</p> <p>ADHD-positive cases were 8 times more likely to be diagnosed and 12 times more likely to be treated, and the male ADHD positive case was more likely to be diagnosed and treated than the female ADHD positive case. Uninsured cases were significantly more likely to be treated overall, but male cases that were uninsured were about half as likely to be diagnosed and treated with ADHD. Additionally, African-American race appears to increase the likelihood of medicinal treatment for ADHD and being both African-American and uninsured appears to cut the odds of medicinal treatment in half, but not significantly.</p> <p>Conclusions</p> <p>Family physicians were competent at discerning between near-threshold ADHD-negative and ADHD positive cases. However, insurance status and race, as well as gender, appear to affect the likelihood of diagnosis and treatment for ADHD in Family Medicine settings.</p

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Female gamers’ experience of online harassment and social support in online gaming: a qualitative study

Female gaming is a relatively under-researched area, and female gamers often report experiencing harassment whilst playing online. The present study explored female experiences of social support while playing online video games, because of the previous research suggesting that females often experience harassment and negative interactions during game play. Data were collected from an online discussion forum, and comprised posts drawn from 271 female gamers. Thematic analysis of the discussions suggested that a lack of social support and harassment frequently led to female gamers playing alone, playing anonymously, and moving groups regularly. The female gamers reported experiencing anxiety and loneliness due to this lack of social support, and for many, this was mirrored in their experiences of social support outside of gaming. The female gamers frequently accepted the incorporation into their gaming of specific coping strategies to mitigate online harassment, including actively hiding their identity and avoiding all forms of verbal communication with other players. These themes are discussed in relation to relevant research in the area, along with recommendations for future research and consideration of possible explanations for the themes observed

Expression profile of genes regulated by activity of the Na-H exchanger NHE1

BACKGROUND: In mammalian cells changes in intracellular pH (pH(i)), which are predominantly controlled by activity of plasma membrane ion exchangers, regulate a diverse range of normal and pathological cellular processes. How changes in pH(i )affect distinct cellular processes has primarily been determined by evaluating protein activities and we know little about how pH(i )regulates gene expression. RESULTS: A global profile of genes regulated in mammalian fibroblasts by decreased pH(i )induced by impaired activity of the plasma membrane Na-H exchanger NHE1 was characterized by using cDNA microarrays. Analysis of selected genes by quantitative RT-PCR, TaqMan, and immunoblot analyses confirmed results obtained from cDNA arrays. Consistent with established roles of pH(i )and NHE1 activity in cell proliferation and oncogenic transformation, grouping regulated genes into functional categories and biological pathways indicated a predominant number of genes with altered expression were associated with growth factor signaling, oncogenesis, and cell cycle progression. CONCLUSION: A comprehensive analysis of genes selectively regulated by pH(i )provides insight on candidate targets that might mediate established effects of pH(i )on a number of normal and pathological cell functions