Towards robust unstructured turbomachinery large eddy simulation

This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.compfluid.2015.06.017Industrial legacy codes usually have had long pedigrees within companies, and are deeply embedded into design processes. As the affordability and availability of computing power has increased, these codes have found themselves pushed into service as large eddy simulation solvers. The approximate Riemann solver of Roe, which is frequently used as the core method in such legacy codes, is shown to need much user care when adopted as the discretisation scheme for large eddy simulation. A kinetic energy preserving (KEP) scheme—which retains the same advantageous stencil and communications halo as the original Roe scheme—is instead implemented and tested. The adaptations of code required to switch between the two schemes were found to be extremely straightforward. As the KEP scheme intrinsically bounds the growth of the kinetic energy, it is significantly more stable than the classical non-dissipative schemes. This means that the expensive smoothing terms of the Roe scheme are not always necessary. Instead, an explicit subgrid scale turbulence model can be sensibly applied. As such, a range of mixed linear–non-linear turbulence models are tested. The performance of the KEP scheme is then tested against that of the Roe for canonical flows and engine-realistic turbine blade cutback trailing edge cases. The new KEP scheme is found to perform better than the original in all cases. A range of mesh topologies: hexahedral; prismatic; and tetrahedral; are also tested with both schemes, and the KEP scheme is again found to perform significantly better on all mesh types for these flows.This work was supported by an iCASE studentship from the Engineering and Physical Sciences Research Council, via Rolls-Royce plc. The funding from both organisations is gratefully acknowledged

Measurement of serum 7α-hydroxy-4-cholesten-3-one as a marker of bile acid malabsorption in dogs with chronic diarrhoea: a pilot study.

Bile acid malabsorption is a common cause of chronic diarrhoea in people, however it has never previously been investigated in dogs, despite clinical suspicion of its existence. The goal of this study was to assess the feasibility of measuring serum 7α-hydroxy-4-cholesten-3-one (C4) in dogs, as a potential marker of bile acid malabsorption, and to see whether this is related to clinical disease severity or the presence of hypocobalaminaemia. Serum C4 concentration was measured in 20 clinically healthy control dogs and 17 dogs with chronic diarrhoea. Three of the 17 affected dogs (17.6 per cent) had a C4 concentration significantly above the range of clinically healthy dogs; these dogs were all poorly responsive to conventional therapy. These results suggest that bile acid malabsorption may be a clinically relevant disorder in dogs with chronic diarrhoea and serum C4 may be a useful tool to investigate this further.A.C.C. Kent is very grateful to the Alice Noakes Trust for sponsorship of his Senior Clinical Training Scholarship.This is the final version of the article. It first appeared from the BMJ Group via http://dx.doi.org/10.1136/vetreco-2015-00016

Optimal multi-block mesh generation for CFD

An assessment of various automatic block topology generation techniques for creating structured meshes has been performed in the first part of the paper. The objective is to find out optimal blocking methods for generating meshes suitable for flow simulations. The comparison has been carried out using an adjoint based error analysis of the meshes generated by these block topologies. Different objective functions and numerical schemes have been used for this assessment. It is found that, in general, the medial axis based approaches provide optimal blocking and yields better accuracy in computing the functional of interest. This is because the medial axis based methods produce meshes which have better flow alignment specially in case of internal flows. In the second part of the paper, the adjoint based error indicator has been used to adapt the block topology in the regions of large error.Rolls Royce, plc TSB SILOET II TS/L00691X/

A perfectly parallel optimisation for cutback trailing edges

Previous attempts have been made to optimize the performance of film-cooling slots for cutback trailing edges, but these involved the use of steady calculation methods, which have been shown to be inappropriate for accurately capturing the behavior of this class of flows. Here, an unsteady method (large-eddy simulation on a coarse grid, or very large-eddy simulation) is used to compute the flow. To take advantage of the enormous parallel capacity of modern supercomputers and distributed computing nets, as well as the relatively low cost of very large-eddy simulation, while at the same time mitigating its lower scope for significant parallelization, a perfectly parallel evolutionary optimization process was undertaken. A relatively crude optimization target of maximizing the adiabatic wall film-cooling effectiveness averaged over the entire exposed cutback surface was used as a proof of concept. The optimizing heuristic then used an evolutionary approach to design a turbulator planform, subject to some imposed design restrictions. Six hundred large-eddy simulation type simulations were carried out over 12 generations, and the best performing designs from the last generation are examined. The optimized design showed a considerable improvement in the target metric over the previous experimental geometries. The influence of various geometric parameters on several of the metrics of film cooling is also explored by mining data from the populations generated over the course of the optimization. In a targeted optimization exercise, it is likely that these data could be used to steer the course of the evolution down favorable paths more quickly.This work was supported by an iCASE studentship from the Engineering and Physical Sciences Research Council, via Rolls-Royce plc. The funding from both organisations is gratefully acknowledged. This work made use of the facilities of HECToR, the UK's national high-performance computing service, which is provided by UoE HPCx Ltd at the University of Edinburgh, Cray Inc and NAG Ltd, and funded by the Office of Science and Technology through EPSRC's High End Computing Programme

Different genetic and morphological outcomes for phages targeted by single or multiple CRISPR-Cas spacers.

CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against genetic invaders, such as bacteriophages. The systems integrate short sequences from the phage genome into the bacterial CRISPR array. These 'spacers' provide sequence-specific immunity but drive natural selection of evolved phage mutants that escape the CRISPR-Cas defence. Spacer acquisition occurs by either naive or primed adaptation. Naive adaptation typically results in the incorporation of a single spacer. By contrast, priming is a positive feedback loop that often results in acquisition of multiple spacers, which occurs when a pre-existing spacer matches the invading phage. We predicted that single and multiple spacers, representative of naive and primed adaptation, respectively, would cause differing outcomes after phage infection. We investigated the response of two phages, ϕTE and ϕM1, to the Pectobacterium atrosepticum type I-F CRISPR-Cas system and observed that escape from single spacers typically occurred via point mutations. Alternatively, phages escaped multiple spacers through deletions, which can occur in genes encoding structural proteins. Cryo-EM analysis of the ϕTE structure revealed shortened tails in escape mutants with tape measure protein deletions. We conclude that CRISPR-Cas systems can drive phage genetic diversity, altering morphology and fitness, through selective pressures arising from naive and primed acquisition events. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.This work was supported by a Rutherford Discovery Fellow- ship from the Royal Society of New Zealand (RSNZ) (to P.C.F.), the Marsden Fund, RSNZ, the Bio-protection Research Centre (Tertiary Education Commission), a University of Otago Doctoral Scholarship (to B.N.J.W.), University of Otago Division of Health Sciences Career Development Post-doctoral Fellowship and a Veni grant (grant no. 016.Veni.171.047) from the The Netherlands Organization for Scienti- fic Research (to R.H.J.S.). G.P.C.S. was supported by the BBSRC, UK

Article image contrast, image pre-processing, and T₁ mapping affect MRI radiomic feature repeatability in patients with colorectal cancer liver metastases

Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T_{1}- and T_{2}-weighted images, pre-contrast quantitative T_{1} maps (qT_{1}), and contrast-enhanced T_{1} weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box–Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T_{1}- and T_{2}-weighted images, and decrease ICCs for qT_{1} maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context

Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux

<p>Abstract</p> <p>Background</p> <p>Neurological diseases and neuropsychiatric disorders that vary depending on female life stages suggest that sex hormones may influence the function of neurotransmitter regulatory machinery such as the dopamine transporter (DAT).</p> <p>Results</p> <p>In this study we tested the rapid nongenomic effects of several physiological estrogens [estradiol (E₂), estrone (E₁), and estriol (E₃)] on dopamine efflux via the DAT in a non-transfected, NGF-differentiated, rat pheochromocytoma (PC12) cell model that expresses membrane estrogen receptors (ERs) α, β, and GPR30. We examined kinase, ionic, and physical interaction mechanisms involved in estrogenic regulation of the DAT function. E₂-mediated dopamine efflux is DAT-specific and not dependent on extracellular Ca²⁺-mediated exocytotic release from vesicular monoamine transporter vesicles (VMATs). Using kinase inhibitors we also showed that E₂-mediated dopamine efflux is dependent on protein kinase C and MEK activation, but not on PI3K or protein kinase A. In plasma membrane there are ligand-independent associations of ERα and ERβ (but not GPR30) with DAT. Conditions which cause efflux (a 9 min 10^-9M E₂treatment) cause trafficking of ERα (stimulatory) to the plasma membrane and trafficking of ERβ (inhibitory) away from the plasma membrane. In contrast, E₁and E₃can inhibit efflux with a nonmonotonic dose pattern, and cause DAT to leave the plasma membrane.</p> <p>Conclusion</p> <p>Such mechanisms explain how gender biases in some DAT-dependent diseases can occur.</p

Identification of neutralising pembrolizumab anti-drug antibodies in patients with melanoma

Development of anti-drug antibodies (ADAs) can interfere with therapeutic monoclonal antibodies and may lead to drug neutralisation and clinical disease progression. Measurement of circulating drug levels and development of ADAs in the setting of anti-programmed cell death-1 agent pembrolizumab has not been well-studied. Enzyme-linked immunosorbent assays were used to measure pembrolizumab drug level and ADAs in 41 patients with melanoma at baseline, Time-point 1 (3 weeks) and Time-point 2 (21 weeks). Assay results were related to patient demographics and clinical outcome data at 6 months. The median pembrolizumab drug level at 3 weeks was 237 ng/μL and did not correlate with age, sex or body surface area.17/41 patients had an ADA detected at any timepoint, with the highest prevalence at Timepoint 1 (median concentration = 17 ng/μL). The presence of an ADA did not correlate with clinical progression at 6 months. 3/41 (7%) of patients displayed a falling pembrolizumab drug level and rising ADA titre between Timepoint 1 and 2 suggestive of a neutralising ADA. Pembrolizumab drug levels and ADAs can be readily measured. The rates of total and treatment-emergent ADAs may be higher in "real-word" settings than those previously reported. Larger studies are needed to determine effect of neutralising ADAs on long-term clinical outcome