Dichotomous role of pancreatic HUWE1/MULE/ARF-BP1 in modulating beta cell apoptosis in mice under physiological and genotoxic conditions

Aims/hypothesis

Diabetes mellitus represents a significant burden on the health of the global population. Both type 1 and type 2 diabetes share a common feature of a reduction in functional beta cell mass. A newly discovered ubiquitination molecule HECT, UBA and WWE domain containing 1, E3 ubiquitin protein ligase (HUWE1 [also known as MULE or ARF-BP1]) is a critical regulator of p53-dependent apoptosis. However, its role in islet homeostasis is not entirely clear.

Methods

We generated mice with pancreas-specific deletion of Huwe1 using a Cre-loxP recombination system driven by the Pdx1 promoter (Pdx1cre ⁺ Huwe1 ^fl/fl) to assess the in vivo role of HUWE1 in the pancreas.

Results

Targeted deletion of Huwe1 in the pancreas preferentially activated p53-mediated beta cell apoptosis, leading to reduced beta cell mass and diminished insulin exocytosis. These defects were aggravated by ageing, with progressive further decline in insulin secretion and glucose homeostasis in older mice. Intriguingly, Huwe1 deletion provided protection against genotoxicity, such that Pdx1cre ⁺ Huwe1 ^fl/fl mice were resistant to multiple-low-dose-streptozotocin-induced beta cell apoptosis and diabetes.

Conclusion/interpretation

HUWE1 expression in the pancreas is essential in determining beta cell mass. Furthermore, HUWE1 demonstrated divergent roles in regulating beta cell apoptosis depending on physiological or genotoxic conditions.     

Pharmacotherapeutic targeting of cation‐chloride cotransporters in neonatal seizures

Seizures are a common manifestation of acute neurologic insults in neonates and are often resistant to the standard antiepileptic drugs that are efficacious in children and adults. The paucity of evidence‐based treatment guidelines, coupled with a rudimentary understanding of disease pathogenesis, has made the current treatment of neonatal seizures empiric and often ineffective, highlighting the need for novel therapies. Key developmental differences in γ‐aminobutyric acid (GABA)ergic neurotransmission between the immature and mature brain, and trauma‐induced alterations in the function of the cation‐chloride cotransporters (CCCs) NKCC1 and KCC2, probably contribute to the poor efficacy of standard antiepileptic drugs used in the treatment of neonatal seizures. Although CCCs are attractive drug targets, bumetanide and other existing CCC inhibitors are suboptimal because of pharmacokinetic constraints and lack of target specificity. Newer approaches including isoform‐specific NKCC1 inhibitors with increased central nervous system penetration, and direct and indirect strategies to enhance KCC2‐mediated neuronal chloride extrusion, might allow therapeutic modulation of the GABAergic system for neonatal seizure treatment. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Horatio M. Pollock,Ph.D.

Psychiatric Quarterly -     

Line-up Member Similarity Influences the Effectiveness of a Salient Rejection Option for Eyewitnesses

Visually salient line-up rejection options have not been systematically studied with adult eyewitnesses. We explored the impact of using a non-verbal, salient rejection option on adults' identification accuracy for line-ups containing low- or high-similarity fillers. The non-verbal, salient rejection option had minimal impact on accuracy in low-similarity line-ups, but in high-similarity line-ups its inclusion increased correct rejections for target-absent line-ups as well as incorrect rejections in target-present line-ups, relative to a verbal rejection condition. The improved performance in target-absent line-ups suggests that adults, like children, may experience pressure to choose and guess during difficult tasks. This pressure is reduced when a prominent non-verbal rejection option is displayed in the line-up. However, the salient rejection option also appears to increase the attractiveness of avoiding a difficult choice between the target and highly similar fillers. Implications of these findings for the experimental literature and justice system are discussed.     

Ungrammatical utterances and disfluent speech as causes of comprehension problems in interactions of preadolescents with high functioning autism

This study describes the role of ungrammatical utterances and disfluent speech in the creation of comprehension problems between the participants in group therapy sessions of preadolescents with autism. The speech of the autistic preadolescents included frequent disfluencies and morpho-syntactic problems, such as wrong case endings, ambiguous pronominal references, grammatically incoherent syntactic structures and inaccurate tenses, which caused problems of comprehension. Three different interactional trajectories occurred when solving the potential problems of comprehension following the morpho-syntactically disfluent turns. First, the disfluent turn sometimes led to a clarification request by a co-participant, either a therapist or another participant with ASD. The preadolescents with ASD showed interactional skilfulness in requesting clarification when faced with comprehension problems. Second, in contrast, other occurrences included one or several self-repairs by the speaker with ASD. In these cases, the other group participants either did not react or they encouraged the speaker to continue using discourse particles. If the self-repairing disfluencies led to a persisting problem of comprehension, the therapists sometimes intervened and resolved the problem. However, direct interventions by the therapists were infrequent because the participants with ASD were mostly able to resolve the comprehension problems by themselves. Third, some disfluent and/or grammatically incorrect turns were not treated as problematic by the co-participants nor by the speaker himself.

Abbreviations: ADE: Adessive; ALL: Allative; CLI: clitic; GEN: Genitive; INE: Inessive; NOM: Nominative; PER: person; PL: plural; PRT: particle; SG: singular     

MicroRNA-147b suppresses the proliferation and invasion of non-small-cell lung cancer cells through downregulation of Wnt/β-catenin signalling via targeting of RPS15A

Deregulation of microRNAs (miRNAs) leads to malignant growth and aggressive invasion during cancer occurrence and progression. miR-147b has emerged as one of the cancer-related miRNAs that are dysregulated in multiple cancers. Yet, the relevance of miR-147b in non-small-cell lung cancer (NSCLC) remains unclear. In the present study, we aimed to report the biological function and signalling pathways mediated by miR-147b in NSCLC. Our results demonstrate that miR-147b expression is significantly downregulated in NSCLC tissues and cell lines. Overexpression of miR-147b decreased the proliferative ability, colony-forming capability, and invasive potential of NSCLC cells. Notably, our study identified ribosomal protein S15A (RPS15A), an oncogene in NSCLC, as a target gene of miR-147b. Our results showed that miR-147b negatively modulates RPS15A expression in NSCLC cells. An inverse correlation between miR-147b and RPS15A was evidenced in NSCLC specimens. Moreover, miR-147b overexpression downregulated the activation of Wnt/β-catenin signalling via targeting of RPS15A. Overexpression of RPS15A partially reversed the miR-147b-mediated antitumour effect in NSCLC cells. Collectively, these findings reveal that miR-147b restricts the proliferation and invasion of NSCLC cells by inhibiting RPS15A-induced Wnt/β-catenin signalling and suggest that the miR-147b/RPS15A/Wnt/β-catenin axis is an important regulatory mechanism for malignant progression of NSCLC.     

Change in physical activity and health‐related quality of life in old age—A 10‐year follow‐up study

The aim of the study was to examine the association between change in leisure‐time physical activity (LTPA) and change in health‐related quality of life (HRQoL) and symptoms of depression during a 10‐year follow‐up. This prospective study included 1036 men and women (mean age at baseline = 61.2 years) from the Helsinki Birth Cohort Study. Leisure‐time physical activity was measured with a questionnaire, HRQoL with SF36 and depression symptoms with Beck's depression inventory (BDI). The association between the change in LTPA and change in HRQoL and BDI were investigated with sex‐stratified general linear models adjusted for age, smoking, educational attainment, comorbidity score, and baseline value of outcomes. One standard deviation (SD) increase in LTPA was associated with increase in physical summary component of HRQoL in women (B = 0.7 unit, 95% CI = 0.1‐1.3, P = 0.032) and in men (B = 0.8 unit, 95% CI = 0.2‐1.5, P = 0.014). In women, the 1SD increase in LTPA was also associated with an increase in mental summary component score (B = 1.0, 95% CI = 0.3‐1.7, P = 0.005) and a reduction in depressive symptoms (B = ?0.7, 95% CI = ?1.1 to ?0.2, P = 0.003). In conclusion, increase in the volume of LTPA over a 10‐year period in late adulthood was associated with improved HRQoL in both men and women, and also diminished depressive symptoms in women. The findings support the promotion of physical activity in later years to enhance HRQoL and mental well‐being.