Ceramic applications in turbine engines

Development testing activities on the 1900 F-configuration ceramic parts were completed, 2070 F-configuration ceramic component rig and engine testing was initiated, and the conceptual design for the 2265 F-configuration engine was identified. Fabrication of the 2070 F-configuration ceramic parts continued, along with burner rig development testing of the 2070 F-configuration metal combustor in preparation for 1132 C (2070 F) qualification test conditions. Shakedown testing of the hot engine simulator (HES) rig was also completed in preparation for testing of a spin rig-qualified ceramic-bladed rotor assembly at 1132 C (2070 F) test conditions. Concurrently, ceramics from new sources and alternate materials continued to be evaluated, and fabrication of 2070 F-configuration ceramic component from these new sources continued. Cold spin testing of the critical 2070 F-configuration blade continued in the spin test rig to qualify a set of ceramic blades at 117% engine speed for the gasifier turbine rotor. Rig testing of the ceramic-bladed gasifier turbine rotor assembly at 108% engine speed was also performed, which resulted in the failure of one blade. The new three-piece hot seal with the nickel oxide/calcium fluoride wearface composition was qualified in the regenerator rig and introduced to engine operation wiwth marginal success

A Process and Outcome Evaluation of a Shelter for Homeless Young Women

To evaluate the processes and outcomes of a short-term shelter, both quantitative and qualitative data were gathered via participant observation, focus group interviews with shelter staff and residents, and individual interviews with a sample of 40 young women who had been homeless prior to using the shelter. The process evaluation showed that the shelter staff strived to utilize an empowerment philosophy in their relationships with residents, but that there were many challenges to implementing this philosophy. The outcome evaluation showed that, at a 3-month follow-up, the participants reported significant improvements in housing, income, independence, and life satisfaction, but most continued to experience poverty and a number of other difficulties. The results were discussed in terms of the implications for future research and the value and limitations of shelters for dealing with homeless youth. The need for more sustained and comprehensive program interventions and supportive social policies was underscored

Recent Advances in the Synthesis and Application of SF5-Containing Organic Compounds

It is well known that fluorinated molecules play an important role in daily life. For example, organic molecules bearing either a fluorine atom itself or a short polyfluorinated substituent such as mono-, difluoro-, and trifluoromethyl groups, or pentafluoroethyl and perfluoropropyl groups are already widely used in medicinal and agricultural chemistry. In contrast, molecules with long perfluorinated chains have found vast application in materials science. Among the fluorine-containing moieties, the pentafluorosulfanyl (SF5) substituent occupies a special place.1 The pentafluorosulfanyl group brings unique properties to organic compounds and often improves their biological activities due to the group’s high chemical and metabolic stability, significant lipophilicity, substantial steric effect, unique geometry, and low surface energy. Here we present new routes towards SF5-substituted aliphatic and heterocyclic compounds

The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis

This article is available open access through the publisher’s website at the link below. Copyright @ 2013 The American Society of Gene & Cell Therapy.Genotoxicity models are extremely important to assess retroviral vector biosafety before gene therapy. We have developed an in utero model that demonstrates that hepatocellular carcinoma (HCC) development is restricted to mice receiving nonprimate (np) lentiviral vectors (LV) and does not occur when a primate (p) LV is used regardless of woodchuck post-translation regulatory element (WPRE) mutations to prevent truncated X gene expression. Analysis of 839 npLV and 244 pLV integrations in the liver genomes of vector-treated mice revealed clear differences between vector insertions in gene dense regions and highly expressed genes, suggestive of vector preference for insertion or clonal outgrowth. In npLV-associated clonal tumors, 56% of insertions occurred in oncogenes or genes associated with oncogenesis or tumor suppression and surprisingly, most genes examined (11/12) had reduced expression as compared with control livers and tumors. Two examples of vector-inserted genes were the Park 7 oncogene and Uvrag tumor suppressor gene. Both these genes and their known interactive partners had differential expression profiles. Interactive partners were assigned to networks specific to liver disease and HCC via ingenuity pathway analysis. The fetal mouse model not only exposes the genotoxic potential of vectors intended for gene therapy but can also reveal genes associated with liver oncogenesis.Imperial College London, the Wellcome Trust, and Brunel University

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer.Wellcome Trust (095198/Z/10/Z and 090233/Z/09/Z); Higher Education Funding Council for England; Great Ormond Street Hospital Children’s Charity; National Institute for Health Research (NIHR); Great Ormond Street Hospital Biomedical Research Centre; NIHR Cambridge Biomedical Research Centre; Alfonso Martin Escudero Foundatio

The Effect of Drinking on Plasma Vasopressin and Renin in Dehydrated Human Subjects

Oropharyngeal mechanisms activated by drinking have been shown to induce a rapid decline in plasma vasopressin which preceeds postabsorptive changes in plasma composition in the dehydrated dog. The present study was undertaken to determine what factor(s) inhibit(s) vasopressin secretion after rehydration in water deprived human subjects. Hematocrit (Hct) and hemoglobin (Hb) were determined on the day of the experiment, together with electrolytes and osmolalities which were measured on freshly separated serum. Plasma was immediately frozen and further analyzed by radioimmunoassay for renin activity (PRA), vasopressin (AVP), and aldosterone. The data were analyzed using an analysis of variance for repeated measurements and significant differences between the dehydrated control period and various time points after the start of rehydration were determined using a multiple-range test. began and reached water replete levels 15 minutes after drinking in the absence of any detectable decline in serum sodium or osmolality, we conclude that 427 oropharyngeal factors, alone or combined with gastric distension account for the extremely rapid inhibition of AVP secretion after drinking in the water-deprived human, as has been shown to be the case in dogs. Our findings are also in agreement wiht the recent demonstration that at the onset of drinking in the dehydrated monkey, there is an abrupt fall in plasma AVP concentration associated with a considerable decrease in the firing rate of the supraoptic neurosecretory neurons

Back-reacted saponite in Jurassic mudstones and limestones intruded by a Tertiary sill, Isle of Skye

The Lón Ostatoin stream section, Trotternish Peninsula, Isle of Skye, exposes a sequence of Middle Jurassic mudstones and limestones which have been locally metasomatized by a transgressive sill of Tertiary age. Limestones in the sequence, including some previously reported as bentonite, have been altered to an unusual assemblage of grossular garnet and saponite clay. The mudstones also contain large proportions of saponite together with pyroxene and zeolites. Saponite also occurs within the basalt intrusion. Grossular and pyroxene represent artifacts of relatively high-temperature assemblages that formed during an early phase of alteration. As the intrusion and adjacent altered country rocks cooled, lower-temperature fluids flowed through a late set of contraction (micro)fractures. Back-reacted saponite, analcime and clinoptilolite were formed, possibly as alteration products of the unstable higher-temperature minerals. The lower-temperature mineral assemblage eventually sealed the late fracture system. This paper highlights an important concept for the study of analogue sites used to investigate thermal effects on engineered liners or barrier host rocks for the landfill and radioactive-waste industries. This is that the original thermally altered mineral assemblage may be overprinted by later, lower-temperature back-reactions. A detailed understanding of both processes is necessary in order to construct a sensible model for the thermal and mineralogical evolution of the site

Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult

Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a \u3d2-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1.6 WASp) has resulted in significant clinical benefit without inducing selection of clones harboring integrations near oncogenes. Here, we describe a case of a presplenectomized 30-year-old patient with severe WAS manifesting as cutaneous vasculitis, inflammatory arthropathy, intermittent polyclonal lymphoproliferation, and significant chronic kidney disease and requiring long-term immunosuppressive treatment. Following reduced-intensity conditioning, there was rapid engraftment and expansion of a polyclonal pool of transgene-positive functional T cells and sustained gene marking in myeloid and B-cell lineages up to 20 months of observation. The patient was able to discontinue immunosuppression and exogenous immunoglobulin support, with improvement in vasculitic disease and proin-flammatory markers. Autologous gene therapy using a lentiviral vector is a viable strategy for adult WAS patients with severe chronic disease complications and for whom an allogeneic procedure could present an unacceptable risk. This trial was registered at www.clinicaltrials.gov as #NCT01347242

Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells

Autologous T cells engineered to express chimeric antigen receptor against the B cell antigen CD19 (CAR19) are achieving marked leukemic remissions in early-phase trials but can be difficult to manufacture, especially in infants or heavily treated patients. We generated universal CAR19 (UCART19) T cells by lentiviral transduction of non-human leukocyte antigen-matched donor cells and simultaneous transcription activator-like effector nuclease (TALEN)-mediated gene editing of T cell receptor α chain and CD52 gene loci. Two infants with relapsed refractory CD19(+) B cell acute lymphoblastic leukemia received lymphodepleting chemotherapy and anti-CD52 serotherapy, followed by a single-dose infusion of UCART19 cells. Molecular remissions were achieved within 28 days in both infants, and UCART19 cells persisted until conditioning ahead of successful allogeneic stem cell transplantation. This bridge-to-transplantation strategy demonstrates the therapeutic potential of gene-editing technology