Grain coarsening behaviour of solution annealed Alloy 625 between 600–800°C

As with all alloys, the grain structure of the nickel-base superalloy 625 has a significant impact on its mechanical properties. Predictability of the grain structure evolution in this material is particularly pertinent because it is prone to inter-metallic precipitate formation both during manufacture and long term or high temperature service. To this end, analysis has been performed on the grain structure of Alloy 625 aged isothermally at temperatures between 600 and 800 °C for times up to 3000 h. Fits made according to the classical Arrhenius equation describing normal grain growth yield an average value for the activation energy of a somewhat inhomogeneous grain structure above 700 °C of 108.3±6.6 kJ mol−1 and 46.6±12.2 kJ mol−1 below 650 °C. Linear extrapolation between 650 and 700 °C produces a significantly higher value of 527.7±23.1 kJ mol−1. This result is ultimately a consequence of a high driving force, solute-impeded grain boundary migration process operating within the alloy. Comparison of the high and low temperature values with the activation energy for volume self-diffusion and grain boundary diffusion identifies the latter as the principle governing mechanism for grain growth in both instances. A decrease in the value of the time exponent (n) at higher temperatures despite a reduction in solute drag is attributable to the Zener pinning imposed by grain boundary M6C and M23C6 particles identified from Transmission Electron Microscopy (TEM) and Energy Dispersive X-ray Spectroscopy (EDXS) analysis. Vickers hardness results show the dominance of intermetallic intragranular precipitates in the governance of the mechanical properties of the material with grain coarsening being accompanied by a significant increase in hardness. Furthermore, the lack of any correlation with grain growth behaviour indicates these phases have no significant effect on the grain evolution of the material

Candidate CSPG4 mutations and induced pluripotent stem cell modeling implicate oligodendrocyte progenitor cell dysfunction in familial schizophrenia

Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c.391G > A [p.A131T], MAF 7.79 × 10−5 and c.2702T > G [p.V901G], MAF 2.51 × 10−3). The CSPG4A131T mutation was absent from the Swedish Schizophrenia Exome Sequencing Study (2536 cases, 2543 controls), while the CSPG4V901G mutation was nominally enriched in cases (11 cases vs. 3 controls, P = 0.026, OR 3.77, 95% CI 1.05–13.52). CSPG4/NG2 is a hallmark protein of oligodendrocyte progenitor cells (OPCs). iPSC-derived OPCs from CSPG4A131T mutation carriers exhibited abnormal post-translational processing (P = 0.029), subcellular localization of mutant NG2 (P = 0.007), as well as aberrant cellular morphology (P = 3.0 × 10−8), viability (P = 8.9 × 10−7), and myelination potential (P = 0.038). Moreover, transfection of healthy non-carrier sibling OPCs confirmed a pathogenic effect on cell survival of both the CSPG4A131T (P = 0.006) and CSPG4V901G (P = 3.4 × 10−4) mutations. Finally, in vivo diffusion tensor imaging of CSPG4A131T mutation carriers demonstrated a reduction of brain white matter integrity compared to unaffected sibling and matched general population controls (P = 2.2 × 10−5). Together, our findings provide a convergence of genetic and functional evidence to implicate OPC dysfunction as a candidate pathophysiological mechanism of familial schizophrenia

Infections up to 76 days after stroke increase disability and death

Early infection after stroke is associated with a poor outcome. We aimed to determine whether delayed infections (up to 76 days post-stroke) are associated with poor outcome at 90 days. Data came from the international Efficacy of Nitric Oxide Stroke (ENOS, ISRCTN99414122) trial. Post hoc data on infections were obtained from serious adverse events reports between 1 and 76 days following stroke in this large cohort of patients. Regression models accounting for baseline covariates were used to analyse fatalities and functional outcomes (modified Rankin Scale (mRS), Barthel Index, Euro-Qol-5D) at 90 days, in patients with infection compared to those without infection. Of 4011 patients, 242 (6.0%) developed one or more serious infections. Infections were associated with an increased risk of death (p < 0.001) and an increased likelihood of dependency (measured by mRS) compared to those of all other patients (p < 0.001). This remained when only surviving patients were analysed, indicating that the worsening of functional outcome is not due to mortality (p < 0.001). In addition, the timing of the infection after stroke did not alter its detrimental association with fatality (p = 0.14) or functional outcome (p = 0.47). In conclusion, severe poststroke infections, whether occurring early or late after stroke, are associated with an increased risk of death and poorer functional outcome, independent of differences in baseline characteristics or treatment. Not only are strategies needed for reducing the risk of infection immediately after stroke, but also during the first 3 months following a stroke. This study is registered: ISRCTN registry, number ISRCTN99414122, ClinicalTrials.gov Identifier, NCT00989716