14-3-3σ Regulates β-Catenin-Mediated Mouse Embryonic Stem Cell Proliferation by Sequestering GSK-3β

[[abstract]]Background: Pluripotent embryonic stem cells are considered to be an unlimited cell source for tissue regeneration and cell-based therapy. Investigating the molecular mechanism underlying the regulation of embryonic stem cell expansion is thus important. 14-3-3 proteins are implicated in controlling cell division, signaling transduction and survival by interacting with various regulatory proteins. However, the function of 14-3-3 in embryonic stem cell proliferation remains unclear. Methodology and Principal Findings: In this study, we show that all seven 14-3-3 isoforms were detected in mouse embryonic stem cells. Retinoid acid suppressed selectively the expression of 14-3-3σ isoform. Knockdown of 14-3-3σ with siRNA reduced embryonic stem cell proliferation, while only 14-3-3σ transfection increased cell growth and partially rescued retinoid acid-induced growth arrest. Since the growth-enhancing action of 14-3-3σ was abrogated by β-catenin knockdown, we investigated the influence of 14-3-3σ overexpression on β-catenin/GSK-3β. 14-3-3σ bound GSK-3β and increased GSK-3β phosphorylation in a PI-3K/Akt-dependent manner. It disrupted β-catenin binding by the multiprotein destruction complex. 14-3-3σ overexpression attenuated β-catenin phosphorylation and rescued the decline of β-catenin induced by retinoid acid. Furthermore, 14-3-3σ enhanced Wnt3a-induced β-catenin level and GSK-3β phosphorylation. DKK, an inhibitor of Wnt signaling, abolished Wnt3a-induced effect but did not interfere GSK-3β/14-3-3σ binding. Significance:Our findings show for the first time that 14-3-3σ plays an important role in regulating mouse embryonic stem cell proliferation by binding and sequestering phosphorylated GSK-3β and enhancing Wnt-signaled GSK-3β inactivation. 14-3-3σ is a novel target for embryonic stem cell expansion

Influence of physical aging on impact embrittlement of uPVC pipes

Most failures of the unplasticised poly(vinyl chloride) (uPVC) pipes used in the Dutch gas distribution network originate from third-party damage. Brittle pipes should therefore be replaced to ensure safe operation of the network. In this study, it the relation between physical ageing and embrittlement of uPVC is investigated using instrumented falling weight impact tests. The ductile-to-brittle transition temperature was first measured for a water pipe grade uPVC at different stages of ageing. As a hypothesis a critical stress criterion is proposed above which failure is brittle. The evolution of the ductile-to-brittle transition temperature that followed from the use of this hypothesis and a model for the polymers yield stress agrees qualitatively with the experimental data. A minor increase of the transition temperature was observed for the water pipe grade with ageing. Applying the same hypothesis to a uPVC gas pipe grade shows a more pronounced influence of physical ageing

Prevalence and incidence density rates of chronic comorbidity in type 2 diabetes patients: An exploratory cohort study

Contains fulltext : 109144.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Evidence-based diabetes guidelines generally neglect comorbidity, which may interfere with diabetes management. The prevalence of comorbidity described in patients with type 2 diabetes (T2D) shows a wide range depending on the population selected and the comorbid diseases studied. This exploratory study aimed to establish comorbidity rates in an unselected primary-care population of patients with T2D. METHODS: This was a cohort study of 714 adult patients with newly diagnosed T2D within the study period (1985-2007) in a practice-based research network in the Netherlands. The main outcome measures were prevalence and incidence density rates of chronic comorbid diseases and disease clusters. All chronic disease episodes registered in the practice-based research network were considered as comorbidities. We categorised comorbidity into 'concordant' (that is, shared aetiology, risk factors, and management plans with diabetes) and 'discordant' comorbidity. Prevalence and incidence density were assessed for both categories of comorbidity. RESULTS: The mean observation period was 17.3 years. At the time of diabetes diagnosis, 84.6% of the patients had one or more chronic comorbid disease of 'any type', 70.6% had one or more discordant comorbid disease, and 48.6% and 27.2% had three or more chronic comorbid diseases of 'any type' or of 'discordant only', respectively. A quarter of those without any comorbid disease at the time of their diabetes diagnosis developed at least one comorbid disease in the first year afterwards. Cardiovascular diseases (considered concordant comorbidity) were the most common, but there were also high rates of musculoskeletal and mental disease. Discordant comorbid diseases outnumbered concordant diseases. CONCLUSIONS: We found high prevalence and incidence density rates for both concordant and discordant comorbidity. The latter may interfere with diabetes management, thus future research and clinical practice should take discordant comorbidity in patients with T2D into account.10 p