Enhancement of thrust reverser cascade performance using aerodynamic and structural integration

This paper focuses on the design of a cascade within a cold stream thrust reverser during the early, conceptual stage of the product development process. A reliable procedure is developed for the exchange of geometric and load data between a two dimensional aerodynamic model and a three dimensional structural model. Aerodynamic and structural simulations are carried out using realistic operating conditions, for three different design configurations with a view to minimising weight for equivalent or improved aerodynamic and structural performance. For normal operational conditions the simulations show that total reverse thrust is unaffected when the performance of the deformed vanes is compared to the un-deformed case. This shows that for the conditions tested, the minimal deformation of the cascade vanes has no significant affect on aerodynamic efficiency and that there is scope for reducing the weight of the cascade. The pressure distribution through a two dimensional thrust reverser section is determined for two additional cascade vane configurations and it is shown that with a small decrease in total reverse thrust, it is possible to reduce weight and eliminate supersonic flow regimes through the nacelle section. By increasing vane sections in high pressure areas and decreasing sections in low pressure areas the structural performance of the cascade vanes in the weight reduced designs, is improved with significantly reduced levels of vane displacement and stress

Associations between purine metabolites and clinical symptoms in schizophrenia

Background: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia. Methodology/Principal Findings: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naïve patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions. Conclusions/Significance: Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology

Apoptosome activation, an important molecular instigator in 6-mercaptopurine induced Leydig cell death.

Leydig cells are crucial to the production of testosterone in males. It is unknown if the cancer chemotherapeutic drug, 6-mercaptopurine (6 MP), produces Leydig cell failure among adult survivors of childhood acute lymphoblastic leukemia. Moreover, it is not known whether Leydig cell failure is due to either a loss of cells or an impairment in their function. Herein, we show, in a subset of childhood cancer survivors, that Leydig cell failure is related to the dose of 6 MP. This was extended, in a murine model, to demonstrate that 6 MP exposure induced caspase 3 activation, and the loss of Leydig cells was independent of Bak and Bax activation. The death of these non-proliferating cells was triggered by 6 MP metabolism, requiring formation of both cytosolic reactive oxygen species and thiopurine nucleotide triphosphates. The thiopurine nucleotide triphosphates (with physiological amounts of dATP) uniquely activated the apoptosome. An ABC transporter (Abcc4/Mrp4) reduced the amount of thiopurines, thereby providing protection for Leydig cells. The studies reported here demonstrate that the apoptosome is uniquely activated by thiopurine nucleotides and suggest that 6 MP induced Leydig cell death is likely a cause of Leydig cell failure in some survivors of childhood cancer

Trends in Drug Utilization, Glycemic Control, and Rates of Severe Hypoglycemia, 2006-2013.

ObjectiveTo examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM).Research design and methodsUsing claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) <6%, 6 to <7%, 7 to <8%, 8 to <9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18-44, 45-64, 65-74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more).ResultsFrom 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). The proportion of patients with HbA1c <7% declined (from 56.4 to 54.2%; P < 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P < 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36).ConclusionsDuring the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged

CO in Protostars (COPS): HerschelHerschel-SPIRE Spectroscopy of Embedded Protostars

We present full spectral scans from 200-670$\mu$m of 26 Class 0+I protostellar sources, obtained with $Herschel$-SPIRE, as part of the "COPS-SPIRE" Open Time program, complementary to the DIGIT and WISH Key programs. Based on our nearly continuous, line-free spectra from 200-670 $\mu$m, the calculated bolometric luminosities ($L_{\rm bol}$) increase by 50% on average, and the bolometric temperatures ($T_{\rm bol}$) decrease by 10% on average, in comparison with the measurements without Herschel. Fifteen protostars have the same Class using $T_{\rm bol}$ and $L_{\rm bol}$/$L_{\rm submm}$. We identify rotational transitions of CO lines from J=4-3 to J=13-12, along with emission lines of $^{13}$CO, HCO$^+$, H$_{2}$O, and [CI]. The ratios of $^{12}$CO to $^{13}$CO indicate that $^{12}$CO emission remains optically thick for $J_{\rm up}$ < 13. We fit up to four components of temperature from the rotational diagram with flexible break points to separate the components. The distribution of rotational temperatures shows a primary population around 100 K with a secondary population at $\sim$350 K. We quantify the correlations of each line pair found in our dataset, and find the strength of correlation of CO lines decreases as the difference between $J$-level between two CO lines increases. The multiple origins of CO emission previously revealed by velocity-resolved profiles are consistent with this smooth distribution if each physical component contributes to a wide range of CO lines with significant overlap in the CO ladder. We investigate the spatial extent of CO emission and find that the morphology is more centrally peaked and less bipolar at high-$J$ lines. We find the CO emission observed with SPIRE related to outflows, which consists two components, the entrained gas and shocked gas, as revealed by our rotational diagram analysis as well as the studies with velocity-resolved CO emission.Comment: 50 pages, 18 figures, accepted to ApJS. Revised for Table 6 and Figure

Coherent States of SU(l,1)SU(l,1) groups

This work can be considered as a continuation of our previous one (J.Phys., 26 (1993) 313), in which an explicit form of coherent states (CS) for all SU(N) groups was constructed by means of representations on polynomials. Here we extend that approach to any SU(l,1) group and construct explicitly corresponding CS. The CS are parametrized by dots of a coset space, which is, in that particular case, the open complex ball $CD^{l}$. This space together with the projective space $CP^{l}$, which parametrizes CS of the SU(l+1) group, exhausts all complex spaces of constant curvature. Thus, both sets of CS provide a possibility for an explicit analysis of the quantization problem on all the spaces of constant curvature.Comment: 22 pages, to be published in "Journal of Physics A

Organ-targeted high-throughput in vivo biologics screen identifies materials for RNA delivery

Therapies based on biologics involving delivery of proteins, DNA, and RNA are currently among the most promising approaches. However, although large combinatorial libraries of biologics and delivery vehicles can be readily synthesized, there are currently no means to rapidly characterize them in vivo using animal models. Here, we demonstrate high-throughput in vivo screening of biologics and delivery vehicles by automated delivery into target tissues of small vertebrates with developed organs. Individual zebrafish larvae are automatically oriented and immobilized within hydrogel droplets in an array format using a microfluidic system, and delivery vehicles are automatically microinjected to target organs with high repeatability and precision. We screened a library of lipid-like delivery vehicles for their ability to facilitate the expression of protein-encoding RNAs in the central nervous system. We discovered delivery vehicles that are effective in both larval zebrafish and rats. Our results showed that the in vivo zebrafish model can be significantly more predictive of both false positives and false negatives in mammals than in vitro mammalian cell culture assays. Our screening results also suggest certain structure–activity relationships, which can potentially be applied to design novel delivery vehicles.National Institutes of Health (U.S.) (Transformative Research Award R01 NS073127)National Institutes of Health (U.S.) (Director's Innovator Award DP2 OD002989)David & Lucile Packard Foundation (Award in Science and Engineering)Sanofi Aventis (Firm)Foxconn International Holdings Ltd.Hertz Foundation (Fellowship)University Grants Committee (Hong Kong, China) (Early Career Award 125012)National Natural Science Foundation (China) (81201164)ITC (ITS/376/13)Chinese University of Hong Kong (Grant 9610215)Chinese University of Hong Kong (Grant 7200269

Organ-targeted high-throughput in vivo biologics screen identifies materials for RNA delivery

Therapies based on biologics involving delivery of proteins, DNA, and RNA are currently among the most promising approaches. However, although large combinatorial libraries of biologics and delivery vehicles can be readily synthesized, there are currently no means to rapidly characterize them in vivo using animal models. Here, we demonstrate high-throughput in vivo screening of biologics and delivery vehicles by automated delivery into target tissues of small vertebrates with developed organs. Individual zebrafish larvae are automatically oriented and immobilized within hydrogel droplets in an array format using a microfluidic system, and delivery vehicles are automatically microinjected to target organs with high repeatability and precision. We screened a library of lipid-like delivery vehicles for their ability to facilitate the expression of protein-encoding RNAs in the central nervous system. We discovered delivery vehicles that are effective in both larval zebrafish and rats. Our results showed that the in vivo zebrafish model can be significantly more predictive of both false positives and false negatives in mammals than in vitro mammalian cell culture assays. Our screening results also suggest certain structure–activity relationships, which can potentially be applied to design novel delivery vehicles.National Institutes of Health (U.S.) (Transformative Research Award R01 NS073127)National Institutes of Health (U.S.) (Director's Innovator Award DP2 OD002989)David & Lucile Packard Foundation (Award in Science and Engineering)Sanofi Aventis (Firm)Foxconn International Holdings Ltd.Hertz Foundation (Fellowship)University Grants Committee (Hong Kong, China) (Early Career Award 125012)National Natural Science Foundation (China) (81201164)ITC (ITS/376/13)Chinese University of Hong Kong (Grant 9610215)Chinese University of Hong Kong (Grant 7200269