A Tool for Developing Correct Programs by Refinement

This report reviews the requirements for tool support of refinement, and reports on the design and implementation of a new tool to support refinement based on these requirements. The main features of the new tool are close integration of refinement and proof in a single tool, good management of the refinement context, an extensible theory base that allows the tool to be adapted to new application domains, and a flexible user interface

Smoothing a rugged protein folding landscape by sequence-based redesign

The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as $\alpha_1$-antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create $\textit{conserpin}$, a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant. Characterization of its structure, folding and dynamics suggest that consensus design has remodeled the folding landscape to reconcile competing requirements for stability and function. This approach may offer general benefits for engineering functional proteins that have risky folding landscapes, including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein therapeutics.BTP is a Medical Research Council Career Development Fellow. AAN and JJH are supported by the Wellcome Trust (grant number WT 095195). SM acknowledges fellowship support from the Australian Research Council (FT100100960). NAB is an Australian Research Council Future Fellow (110100223). GIW is an Australian Research Council Discovery Outstanding Researcher Award Fellow (DP140100087). AMB is a National Health and Medical Research Senior Research Fellow (1022688). JCW is an NHMRC Senior Principal Research fellow and also acknowledges the support of an ARC Federation Fellowship. We thank the Australian Synchrotron for beam-time and technical assistance. This work was supported by the Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE) (www.massive.org.au). We acknowledge the Monash Protein Production Unit and Monash Macromolecular Crystallization Facilit

Smoothing a rugged protein folding landscape by sequence-based redesign

The rugged folding landscapes of functional proteins puts them at risk of misfolding and aggregation. Serine protease inhibitors, or serpins, are paradigms for this delicate balance between function and misfolding. Serpins exist in a metastable state that undergoes a major conformational change in order to inhibit proteases. However, conformational labiality of the native serpin fold renders them susceptible to misfolding, which underlies misfolding diseases such as α1-antitrypsin deficiency. To investigate how serpins balance function and folding, we used consensus design to create conserpin, a synthetic serpin that folds reversibly, is functional, thermostable, and polymerization resistant. Characterization of its structure, folding and dynamics suggest that consensus design has remodeled the folding landscape to reconcile competing requirements for stability and function. This approach may offer general benefits for engineering functional proteins that have risky folding landscapes, including the removal of aggregation-prone intermediates, and modifying scaffolds for use as protein therapeutics

Corticosteroid Treatment Of Experimental Autoimmune Encephalomyelitis In The Lewis Rat Results in Loss of V Beta 8.2+ and Myelin Basic Protein-Reactive Cells from the Spinal Cord, with Increased Total T-Cell Apoptosis but Reduced Apoptosis of V Beta 8.2+

We have studied the effects of corticosteroid treatment on the numbers of lymphocytes obtained from the spinal cords of Lewis rats with acute experimental autoimmune encephalomyelitis (EAE) induced by inoculation with myelin basic protein (MBP) and adjuvants. Flow cytometric studies showed that treatment with dexamethasone (4 mg/kg) 8-12 h prior to study on day 14 after inoculation resulted in a reduction in the numbers of CD5+, TCR alpha beta + and V beta 8.2+ cells in the spinal cord. Limiting dilution analysis indicated that dexamethasone treatment 12 h prior to study on day 12 after inoculation reduced the frequencies of MBP-reactive and interleukin-2-responsive lymphocytes in the spinal cord to low levels, but reduced the frequency of concanavalin-A-responsive lymphocytes to a lesser extent. Using propidium iodide staining of nuclear chromatin we also studied lymphocyte apoptosis. Greater numbers of apoptotic cells were found in the cells extracted from the spinal cords of rats, examined on day 14, that had been treated 1-12 h previously with dexamethasone, than in saline-treated controls. This increased level of apoptosis was observed in the CD5+ and TCR alpha beta + cell populations. At 1-4 h after dexamethasone treatment there was a reduction in the selective apoptosis of V beta 8.2+ cells that normally occurs during spontaneous recovery from EAE. Therefore apoptosis of V beta 8.2+ cells cannot explain the reduction in the numbers of V beta 8.2+ cells and MBP-reactive cells in the CNS after dexamethasone treatment. By 8-12 h after dexamethasone treatment the selectivity of the apoptotic process was restored. These studies suggest that a reduction in the number of T-lymphocytes in the central nervous system contributes to the beneficial effects of corticosteroids in EAE

Acoustic characteristics of a ported shroud turbocompressor operating at design conditions

[EN] In this article, the acoustic characterisation of a turbocharger compressor with ported shroud design is carried out through the numerical simulation of the system operating under design conditions of maximum isentropic efficiency. While ported shroud compressors have been proposed as a way to control the flow near unstable conditions in order to obtain a more stable operation and enhance deep surge margin, it is often assumed that the behaviour under stable design conditions is characterised by a smooth, non-detached flow that matches an equivalent standard compressor. Furthermore, research is scarce regarding the acoustic effects of the ported shroud addition, especially under the design conditions. To analyse the flow field evolution and its relation with the noise generation, spectral signatures using statistical and scale-resolving turbulence modelling methods are obtained after successfully validating the performance and acoustic predictions of the numerical model with experimental measurements. Propagation of the frequency content through the ducts has been estimated with the aid of pressure decomposition methods to enhance the content coming from the compressor. Expected acoustic phenomena such as `buzz-saw¿ tones, blade passing peaks and broadband noise are correctly identified in the modelled spectrum. Analysis of the flow behaviour in the ported shroud shows rotating structures through the slot that may impact the acoustic and vibration response. Further inspection of the pressure field through modal decomposition confirms the influence of the ported shroud cavity in noise generation and propagation, especially at lower frequencies, suggesting that further research should be carried out on the impact these flow enhancement solutions have on the noise emission of the turbocharger.The project was sponsored and supported by BorgWarner Turbo Systems and the Regional Growth Fund (RGF Grant Award 01.09.07.01/1789C). The authors would like to thank BorgWarner Turbo Systems for permission to publish the results presented in this article. The support of the HPC group at the University of Huddersfield is gratefully acknowledged.Sharma, S.; Broatch, A.; Garcia Tiscar, J.; Allport, JM.; Nickson, AK. (2020). Acoustic characteristics of a ported shroud turbocompressor operating at design conditions. 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SAE International Journal of Passenger Cars - Mechanical Systems, 2(1), 1345-1351. doi:10.4271/2009-01-2053Figurella, N., Dehner, R., Selamet, A., Tallio, K., Miazgowicz, K., & Wade, R. (2014). Noise at the mid to high flow range of a turbocharger compressor. Noise Control Engineering Journal, 62(5), 306-312. doi:10.3397/1/376229Torregrosa, A. J., Broatch, A., Margot, X., García-Tíscar, J., Narvekar, Y., & Cheung, R. (2017). Local flow measurements in a turbocharger compressor inlet. Experimental Thermal and Fluid Science, 88, 542-553. doi:10.1016/j.expthermflusci.2017.07.007Broatch, A., Galindo, J., Navarro, R., García-Tíscar, J., Daglish, A., & Sharma, R. K. (2015). Simulations and measurements of automotive turbocharger compressor whoosh noise. Engineering Applications of Computational Fluid Mechanics, 9(1), 12-20. doi:10.1080/19942060.2015.1004788Raitor, T., & Neise, W. (2008). Sound generation in centrifugal compressors. Journal of Sound and Vibration, 314(3-5), 738-756. doi:10.1016/j.jsv.2008.01.034Galindo, J., Tiseira, A., Navarro, R., & López, M. A. (2015). Influence of tip clearance on flow behavior and noise generation of centrifugal compressors in near-surge conditions. International Journal of Heat and Fluid Flow, 52, 129-139. doi:10.1016/j.ijheatfluidflow.2014.12.004Broatch, A., Galindo, J., Navarro, R., & García-Tíscar, J. (2014). Methodology for experimental validation of a CFD model for predicting noise generation in centrifugal compressors. International Journal of Heat and Fluid Flow, 50, 134-144. doi:10.1016/j.ijheatfluidflow.2014.06.006Semlitsch, B., & Mihăescu, M. (2016). Flow phenomena leading to surge in a centrifugal compressor. Energy, 103, 572-587. doi:10.1016/j.energy.2016.03.032Sundström, E., Semlitsch, B., & Mihăescu, M. (2018). Acoustic signature of flow instabilities in radial compressors. 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Intellectual activism: the path to change in policy and practice through critical research. The work of the Global Hospitality Research Alliance (GHRA)

This presentation will focus on the role of intellectual activism as a driver and outcome of critical research in the area of hospitality employment. A criticism of much academic research in tourism and hospitality is that our impact is limited and our goals, in terms of output, are framed in terms of high-quality journal papers. Hospitality employment is a domain where our collective endeavours, as academic researchers, has been singularly unsuccessful in real impact terms. This conference presentation will explore the experience of an international group of critical scholars, sharing a common interest in hospitality employment, in engaging with intellectual activism to translate academic research into vehicles for stakeholder advocacy

Cytokine Expression by Inflammatory Cells Obtained from the Spinal Cords of Lewis Rats with Experimental Autoimmune Encephalomyelitis Induced by Inoculation with Myelin Basic Protein and Adjuvants

Inflammatory cells were obtained from the spinal cords of rats with acute experimental autoimmune encephalomyelitis EAE induced by inoculation with myelin basic protein MBP and adjuvants. Reverse transcriptase-polymerase chain reaction RT-PCR was used to investigate the expression of mRNA for interleukin-2 IL-2 , IL-4, IL-10 and interferon-gamma (IFN-gamma) by cells from groups of rats studied 10-21 days after inoculation. On all days of study, the inflammatory cells, which were predominantly lymphocytes, expressed mRNA for IL-2, IL-4, IL-10 and IFN-gamma. In the mRNA from normal rat spinal cord tissue, there was little expression of cytokine mRNA. Cells from a short-term MBP-reactive T cell line expressed all the cytokines. Densitometry was used to measure the products of PCR, to assess the expression of each cytokine relative to that of beta-actin. IL-2 mRNA was expressed throughout the course of disease and reached a peak on day 18, during late clinical recovery. IFN-gamma was expressed throughout the course of the disease and was also high during late recovery. IL-4 mRNA was present in the spinal cord throughout the course of the disease, with a slight rise during late recovery. Relative expression of IL-10 rose to a peak on days 17-19, during late recovery from clinical disease. This study indicates that IL-2, IL-4, IL-10 and IFN-gamma are expressed by inflammatory cells in the spinal cord in EAE, with the relative expression of all cytokines being high during late clinical recovery