A Numerical and Experimental Assessment of the Use of a Turbine Utilizing Splitter Blades for an Automotive Variable Geometry Turbocharger

Automotive manufacturers require improved part load engine performance to further improve fuel economy. For a swing vane VGS (Variable Geometry Stator) turbine this means a more closed stator vane, to deal with the low MFRs (Mass Flow Rates), high PRs (Pressure Ratios) and low rotor rotational speeds. During these conditions the turbine is operating at low velocity ratios. As more energy is available at high pressure ratios and during lower turbocharger rotational speeds, a turbine which is efficient at these conditions is desirable. Another key aspect for automotive manufacturers is engine responsiveness. High inertia designs result in “turbo lag” which means an increased time before the target boost pressure is reached. Therefore, designs with improved performance at low velocity ratios, reduced inertia or an increased swallowing capacity are the current targets for turbocharger manufacturers.

To try to meet these design targets a CFD (Computational Fluid Dynamics) study was performed on a turbine wheel using splitter blades. A number of parameters were investigated. These included splitter blade merdional length, blade number and blade angle distribution.

The numerical study was performed on a scaled automotive VGS. Three different stator vane positions have been analysed. A single passage CFD model was developed and used to provide information on the flow features affecting performance in both the stator vanes and turbine.

Following the CFD investigation the design with the best compromise in terms of performance, inertia and increased MFP (Mass Flow Parameter) was selected for manufacture and testing. Tests were performed on a scaled, low temperature turbine test rig. The aerodynamic flow path of the gas stand was the same as that investigated during the CFD. The test results revealed a design which had similar performance at the closed stator vane positions when compared to the baseline wheel. At the maximum MFR stator vane condition a drop of −0.6% pts in efficiency was seen. However, 5.5% increase in MFP was obtained with the additional benefit of a drop in rotor inertia of 3.7%, compared to the baseline wheel.

Ultrashort self-assembling peptidomimetic nanomaterials target resistant pathogenic infections

The impending and increasing threat of antimicrobial resistance has led to a greater focus into developing alternative therapies as substitutes for traditional antibiotics for the treatment of multi-drug resistant infections.1 Our group has developed a library of short, cost-effective, diphenylalanine-based peptides (X1-FF-X2) which selective eradicate (viability reduced >90% in 24 hours) the most resistant biofilm forms of a range of Gram-positive and negative pathogens including: methicillin resistant and sensitive Staphyloccoccus aureus and Staphyloccoccus epidermidis; Pseudomonas aeruginosa, Proteus mirabilis and Escherichia coli. They demonstrate a reduced cell cytotoxic profile (NCTC929 murine fibroblast) and limited haemolysis.2 Our molecules have the ability respond to subtle changes in pH, associated with bacterial infection, self-assembling to form β-sheet secondary structures and supramolecular hydrogels at low concentrations (~0.5%w/v). Conjugation of variety of aromatic-based drugs at the X1 position, including non-steroidal anti-inflammatories (NSAIDs), confer further pharmacological properties to the peptide motif enhancing their therapeutic potential. In vivo studies using waxworms (Galleria mellonella) provide promising preliminary results demonstrating the low toxicity and high antimicrobial activity of these low molecular weight gelators in animal models. This work shows biofunctional peptide-based nanomaterials hold great promise for future translation to patients as antimicrobial drug delivery and biomaterial platforms.3 [1] G. Laverty, S.P. Gorman and B.F. Gilmore. Int.J.Mol.Sci. 2011, 12, 6566-6596. [2] G. Laverty, A.P. McCloskey, B.F. Gilmore, D.S. Jones, J Zhou, B Xu. Biomacromolecules. 2014, 15, 9, 3429-3439. [3] A.P. McCloskey, B.F. Gilmore and G.Laverty. Pathogens. 2014, 3, 791-821.

Identification of tubulin as the molecular target of proapoptotic pyrrolo-1,5-benzoxazepines

We have demonstrated previously that certain members of a series of novel pyrrolo-1,5-benzoxazepine (PBOX) compounds potently induce apoptosis in a variety of human chemotherapy-resistant cancer cell lines and in primary ex vivo material derived from cancer patients. A better understanding of the molecular mechanisms underlying the apoptotic effects of these PBOX compounds is essential to their development as antineoplastic therapeutic agents. This study sought to test the hypothesis that proapoptotic PBOX compounds target the microtubules. We show that a representative proapoptotic PBOX compound, PBOX-6, induces apoptosis in both the MCF-7 and K562 cell lines. An accumulation of cells in G2/M precedes apoptosis in response to PBOX-6. PBOX-6 induces prometaphase arrest and causes an accumulation of cyclin B1 levels and activation of cyclin B1/CDK1 kinase in a manner similar to that of two representative antimicrotubule agents, nocodazole and paclitaxel. Indirect immunofluorescence demonstrates that both PBOX-6 and another pro-apoptotic PBOX compound, PBOX-15, cause microtubule depolymerization in MCF-7 cells. They also inhibit the assembly of purified tubulin in vitro, whereas a nonapoptotic PBOX compound (PBOX-21) has no effect on either the cellular microtubule network or on the assembly of purified tubulin. This suggests that the molecular target of the pro-apoptotic PBOX compounds is tubulin. PBOX-6 does not bind to either the vinblastine or the colchicine binding site on tubulin, suggesting that it binds to an as-yet-uncharacterised novel site on tubulin. The ability of PBOX-6 to bind tubulin and cause microtubule depolymerization confirms it as a novel candidate for antineoplastic therapy.

Shortened Lung Clearance Index is a repeatable and sensitive test in children and adults with cystic fibrosis

Background: Lung clearance index (LCI) derived from sulfur hexafluoride (SF6) multiple breath washout (MBW) is a sensitive measure of lung disease in people with cystic fibrosis (CF). However, it can be time-consuming, limiting its use clinically. Aim: To compare the repeatability, sensitivity and test duration of LCI derived from washout to 1/30th (LCI1/30), 1/20th (LCI1/20) and 1/10th (LCI1/10) to ‘standard’ LCI derived from washout to 1/40th initial concentration (LCI1/40). Methods: Triplicate MBW test results from 30 clinically stable people with CF and 30 healthy controls were analysed retrospectively. MBW tests were performed using 0.2% SF6 and a modified Innocor device. All LCI end points were calculated using SimpleWashout software. Repeatability was assessed using coefficient of variation (CV%). The proportion of people with CF with and without abnormal LCI and forced expiratory volume in 1 s (FEV1) % predicted was compared. Receiver operating characteristic (ROC) curve statistics were calculated. Test duration of all LCI end points was compared using paired t tests. Results: In people with CF, LCI1/40 CV% (p=0.16), LCI1/30 CV%, (p=0.53), LCI1/20 CV% (p=0.14) and LCI1/10 CV% (p=0.25) was not significantly different to controls. The sensitivity of LCI1/40, LCI1/30 and LCI1/20 to the presence of CF was equal (67%). The sensitivity of LCI1/10 and FEV1% predicted was lower (53% and 47% respectively). Area under the ROC curve (95% CI) for LCI1/40, LCI1/30, LCI1/20, LCI1/10 and FEV1% predicted was 0.89 (0.80 to 0.97), 0.87 (0.77 to 0.96), 0.87 (0.78 to 0.96), 0.83 (0.72 to 0.94) and 0.73 (0.60 to 0.86), respectively. Test duration of LCI1/30, LCI1/20 and LCI1/10 was significantly shorter compared with the test duration of LCI1/40 in people with CF (p<0.0001) equating to a 5%, 9% and 15% time saving, respectively. Conclusions: In this study, LCI1/20 was a repeatable and sensitive measure with equal diagnostic performance to LCI1/40. LCI1/20 was shorter, potentially offering a more feasible research and clinical measure.

Improving appropriate polypharmacy for older people in primary care: selecting components of an evidence-based intervention to target prescribing and dispensing.

Background
The use of multiple medicines (polypharmacy) is increasingly common in older people. Ensuring that patients receive the most appropriate combinations of medications (appropriate polypharmacy) is a significant challenge. The quality of evidence to support the effectiveness of interventions to improve appropriate polypharmacy is low. Systematic identification of mediators of behaviour change, using the Theoretical Domains Framework (TDF), provides a theoretically robust evidence base to inform intervention design. This study aimed to (1) identify key theoretical domains that were perceived to influence the prescribing and dispensing of appropriate polypharmacy to older patients by general practitioners (GPs) and community pharmacists, and (2) map domains to associated behaviour change techniques (BCTs) to include as components of an intervention to improve appropriate polypharmacy in older people in primary care.

Methods
Semi-structured interviews were conducted with members of each healthcare professional (HCP) group using tailored topic guides based on TDF version 1 (12 domains). Questions covering each domain explored HCPs’ perceptions of barriers and facilitators to ensuring the prescribing and dispensing of appropriate polypharmacy to older people. Interviews were audio-recorded and transcribed verbatim. Data analysis involved the framework method and content analysis. Key domains were identified and mapped to BCTs based on established methods and discussion within the research team.

Results
Thirty HCPs were interviewed (15 GPs, 15 pharmacists). Eight key domains were identified, perceived to influence prescribing and dispensing of appropriate polypharmacy: ‘Skills’, ‘Beliefs about capabilities’, ‘Beliefs about consequences’, ‘Environmental context and resources’, ‘Memory, attention and decision processes’, ‘Social/professional role and identity’, ‘Social influences’ and ‘Behavioural regulation’. Following mapping, four BCTs were selected for inclusion in an intervention for GPs or pharmacists: ‘Action planning’, ‘Prompts/cues’, ‘Modelling or demonstrating of behaviour’ and ‘Salience of consequences’. An additional BCT (‘Social support or encouragement’) was selected for inclusion in a community pharmacy-based intervention in order to address barriers relating to interprofessional working that were encountered by pharmacists.

Conclusions
Selected BCTs will be operationalised in a theory-based intervention to improve appropriate polypharmacy for older people, to be delivered in GP practice and community pharmacy settings. Future research will involve development and feasibility testing of this intervention.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

BACKGROUND: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling.

METHODS: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ(2) tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided.

RESULTS: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts.

CONCLUSIONS: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa.

Exploiting dynamic timing margins in microprocessors for frequency-over-scaling with instruction-based clock adjustment

Static timing analysis provides the basis for setting the clock period of a microprocessor core, based on its worst-case critical path. However, depending on the design, this critical path is not always excited and therefore dynamic timing margins exist that can theoretically be exploited for the benefit of better speed or lower power consumption (through voltage scaling). This paper introduces predictive instruction-based dynamic clock adjustment as a technique to trim dynamic timing margins in pipelined microprocessors. To this end, we exploit the different timing requirements for individual instructions during the dynamically varying program execution flow without the need for complex circuit-level measures to detect and correct timing violations. We provide a design flow to extract the dynamic timing information for the design using post-layout dynamic timing analysis and we integrate the results into a custom cycle-accurate simulator. This simulator allows annotation of individual instructions with their impact on timing (in each pipeline stage) and rapidly derives the overall code execution time for complex benchmarks. The design methodology is illustrated at the microarchitecture level, demonstrating the performance and power gains possible on a 6-stage OpenRISC in-order general purpose processor core in a 28nm CMOS technology. We show that employing instruction-dependent dynamic clock adjustment leads on average to an increase in operating speed by 38% or to a reduction in power consumption by 24%, compared to traditional synchronous clocking, which at all times has to respect the worst-case timing identified through static timing analysis.

A closer look at Carver and White's BIS/BAS scales: Factor analysis and age group differences

The Behavioural Inhibition and Behavioural Activation System (BIS/BAS) scales were developed by Carver and White (1994) and comprise four scales which measure individual differences in personality (Gray 1982, 1991). More recent modifications, namely the five-factor model derived from Gray and McNaughton's (2000) revised Reward Sensitivity Theory (RST) suggests that Anxiety and Fear are separable components of inhibition. This study employed exploratory and confirmatory factor analyses on the scales in order to test whether the four or five-factor model was the better fit in a sample of 994 participants aged 11–30 years. Consistent with RST, superior model fit was shown for the five-factor model with all variables correlated. Significant age effects were observed for BIS Fear and BIS Anxiety, with scores peaking in middle and late adolescence respectively. The BAS subscales showed differential effects of age group. Significantly increasing scores from early to mid and from mid to late adolescence were found for Drive, but the effect of age on Fun Seeking and Reward Responsiveness was not significant.