Microstructure of selective laser melted CM247LC nickel-based superalloy and its evolution through heat treatment

The selective laser melting of high temperature alloys is of great interest to the aerospace industry as it offers the prospect of producing more complex geometries than can be achieved with other manufacturing methods. In this study, the microstructure of the nickel-based superalloy, CM247LC, has been characterised following selective laser melting and after a post deposition heat-treatment below the γʹ solvus temperature. In the as-deposited state, scanning electron microscopy with electron backscatter diffraction revealed a fine, cellular microstructure with preferential alignment of along the build direction. A high dislocation density was seen at the periphery of the cells, indicating substantial localised deformation of the material. Fine primary MC carbides were also observed in the inter-cellular regions. High-resolution transmission electron microscopy identified the occurrence of very fine γʹ precipitates, approximately 5 nm in diameter, dispersed within the gamma phase. After heat treatment, the elongated cell colonies were observed to partially coalesce, accompanied by a decrease in dislocation density, producing columnar grains along the build direction. Cuboidal γʹ precipitates approximately 500 nm in diameter were observed to form in the recrystallised grains, accompanied by larger γʹ precipitates on the grain boundaries.The authors acknowledge funding from the EU under the Seventh Framework Programme (FP7) through the ASLAM project (CfP topic number: JTI-CS-2013-01-SAGE-06-006Project reference number: 619993). The authors would also like to acknowledge Rolls-Royce plc. for providing conventionally cast CM247LC.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.matchar.2016.02.00

Who uses outpatient healthcare services under Ghana’s health protection scheme and why?

Background: The National Health Insurance Scheme (NHIS) was launched in Ghana in 2003 with the main objective of increasing utilisation to healthcare by making healthcare more affordable. Previous studies on the NHIS have repeatedly highlighted that cost of premiums is one of the major barriers for enrollment. However, despite introducing premium exemptions for pregnant women, older people, children and indigents, many Ghanaians are still not active members of the NHIS. In this paper we investigate why there is limited success of the NHIS in improving access to healthcare in Ghana and whether social exclusion could be one of the limiting barriers. The study explores this by looking at the Social, Political, Economic and Cultural (SPEC) dimensions of social exclusion. Methods: Using logistic regression, the study investigates the determinants of health service utilisation using SPEC variables including other variables. Data was collected from 4050 representative households in five districts in Ghana covering the 3 ecological zones (coastal, forest and savannah) in Ghana. Results: Among 16,200 individuals who responded to the survey, 54 % were insured. Out of the 1349 who sought health care, 64 % were insured and 65 % of them had basic education and 60 % were women. The results from the logistic regressions show health insurance status, education and gender to be the three main determinants of health care utilisation. Overall, a large proportion of the insured who reported ill, sought care from formal health care providers compared to those who had never insured in the scheme. Conclusion: The paper demonstrates that the NHIS presents a workable policy tool for increasing access to healthcare through an emphasis on social health protection. However, affordability is not the only barrier for access to health services. Geographical, social, cultural, informational, political, and other barriers also come into play

MMP-2 siRNA Inhibits Radiation-Enhanced Invasiveness in Glioma Cells

Our previous work and that of others strongly suggests a relationship between the infiltrative phenotype of gliomas and the expression of MMP-2. Radiation therapy, which represents one of the mainstays of glioma treatment, is known to increase cell invasion by inducing MMP-2. Thus, inhibition of MMP-2 provides a potential means for improving the efficacy of radiotherapy for malignant glioma.We have tested the ability of a plasmid vector-mediated MMP-2 siRNA (p-MMP-2) to modulate ionizing radiation-induced invasive phenotype in the human glioma cell lines U251 and U87. Cells that were transfected with p-MMP-2 with and without radiation showed a marked reduction of MMP-2 compared to controls and pSV-transfected cells. A significant reduction of proliferation, migration, invasion and angiogenesis of cells transfected with p-MMP-2 and in combination with radiation was observed compared to controls. Western blot analysis revealed that radiation-enhanced levels of VEGF, VEGFR-2, pVEGFR-2, p-FAK, and p-p38 were inhibited with p-MMP-2-transfected cells. TUNEL staining showed that radiation did not induce apoptosis in U87 and U251 cells while a significant increase in TUNEL-positive cells was observed when irradiated cells were simultaneously transfected with p-MMP-2 as compared to controls. Intracranial tumor growth was predominantly inhibited in the animals treated with p-MMP-2 alone or in combination with radiation compared to controls.MMP-2 inhibition, mediated by p-MMP-2 and in combination with radiation, significantly reduced tumor cell migration, invasion, angiogenesis and tumor growth by modulating several important downstream signaling molecules and directing cells towards apoptosis. Taken together, our results demonstrate the efficacy of p-MMP-2 in inhibiting radiation-enhanced tumor invasion and progression and suggest that it may act as a potent adjuvant for radiotherapy in glioma patients

Suppression of MMP-2 Attenuates TNF-α Induced NF-κB Activation and Leads to JNK Mediated Cell Death in Glioma

BACKGROUND: Abrogation of apoptosis for prolonged cell survival is essential in cancer progression. In our previous studies, we showed the MMP-2 downregulation induced apoptosis in cancer cell lines. Here, we attempt to investigate the exact molecular mechanism of how MMP-2 depletion leads to apoptosis in glioma xenograft cell lines. METHODOLOGY/PRINCIPAL FINDINGS: MMP-2 transcriptional suppression by MMP-2siRNA (pM) induces apoptosis associated with PARP, caspase-8 and -3 cleavage in human glioma xenograft cells 4910 and 5310. Western blotting and cytokine array showed significant decrease in the cellular and secreted levels of TNF-α with concomitant reduction in TNFR1, TRADD, TRAF2, RIP, IKKβ and pIκBα expression levels resulting in inhibition of p65 phosphorylation and nuclear translocation in pM-treated cells when compared to mock and pSV controls. In addition MMP-2 suppression led to elevated Fas-L, Fas and FADD expression levels along with increased p38 and JNK phosphorylation. The JNK-activity assay showed prolonged JNK activation in pM-transfected cells. Specific inhibition of p38 with SB203580 did not show any effect whereas inhibition of JNK phosphorylation with SP600125 notably reversed pM-induced cleavage of PARP, caspase-8 and -3, demonstrating a significant role of JNK in pM-induced cell death. Supplementation of rhMMP-2 counteracted the effect of pM by remarkably elevating TNF-α, TRADD, IKKβ and pIκBα expression and decreasing FADD, Fas-L, and phospho-JNK levels. The EMSA analysis indicated significant reversal of pM-inhibited NF-κB activity by rhMMP-2 treatment which rescued cells from pM-induced cell death. In vivo studies indicated that pM treatment diminished intracranial tumor growth and the immuno histochemical analysis showed decreased phospho-p65 and enhanced phospho-JNK levels that correlated with increased TUNEL-positive apoptotic cells in pM-treated tumor sections. CONCLUSION/SIGNIFICANCE: In summary, our study implies a role of MMP-2 in the regulation of TNF-α mediated constitutive NF-κB activation and Fas-mediated JNK mediated apoptosis in glioma xenograft cells in vitro and in vivo

A Survey of Bayesian Statistical Approaches for Big Data

The modern era is characterised as an era of information or Big Data. This has motivated a huge literature on new methods for extracting information and insights from these data. A natural question is how these approaches differ from those that were available prior to the advent of Big Data. We present a review of published studies that present Bayesian statistical approaches specifically for Big Data and discuss the reported and perceived benefits of these approaches. We conclude by addressing the question of whether focusing only on improving computational algorithms and infrastructure will be enough to face the challenges of Big Data

Combined Immunodeficiency Due to MALT1 Mutations, Treated by Hematopoietic Cell Transplantation

PURPOSE: A male infant developed generalized rash, intestinal inflammation and severe infections including persistent cytomegalovirus. Family history was negative, T cell receptor excision circles were normal, and engraftment of maternal cells was absent. No defects were found in multiple genes associated with severe combined immunodeficiency. A 9/10 HLA matched unrelated hematopoietic cell transplant (HCT) led to mixed chimerism with clinical resolution. We sought an underlying cause for this patient’s immune deficiency and dysregulation. METHODS: Clinical and laboratory features were reviewed. Whole exome sequencing and analysis of genomic DNA from the patient, parents and 2 unaffected siblings was performed, revealing 2 MALT1 variants. With a host-specific HLA-C antibody, we assessed MALT1 expression and function in the patient’s post-HCT autologous and donor lymphocytes. Wild type MALT1 cDNA was added to transformed autologous patient B cells to assess functional correction. RESULTS: The patient had compound heterozygous DNA variants affecting exon 10 of MALT1 (isoform a, NM_006785.3), a maternally inherited splice acceptor c.1019-2A > G, and a de novo deletion of c.1059C leading to a frameshift and premature termination. Autologous lymphocytes failed to express MALT1 and lacked NF-κB signaling dependent upon the CARMA1, BCL-10 and MALT1 signalosome. Transduction with wild type MALT1 cDNA corrected the observed defects. CONCLUSIONS: Our nonconsanguineous patient with early onset profound combined immunodeficiency and immune dysregulation due to compound heterozygous MALT1 mutations extends the clinical and immunologic phenotype reported in 2 prior families. Clinical cure was achieved with mixed chimerism after nonmyeloablative conditioning and HCT. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10875-014-0125-1) contains supplementary material, which is available to authorized users