Turbine airfoil film cooling

The experimental data obtained in this program gives insight into the physical phenomena that occur on a film cooled airfoil, and should provide a relevant data base for verification of new design tools. Results indicate that the downstream film cooling process is a complex function of the thermal dilution and turbulence augmentation parameters with trends actually reversing as blowing strength and coolant-to-gas temperature ratio varied. The pressure surface of the airfoil is shown to exhibit a considerably higher degree of sensitivity to changes in the film cooling parameters and, consequently, should prove to be more of a challenge than the suction surface in accurately predicting heat transfer levels with downsteam film cooling

The effects of leading edge and downstream film cooling on turbine vane heat transfer

The progress under contract NAS3-24619 toward the goal of establishing a relevant data base for use in improving the predictive design capabilities for external heat transfer to turbine vanes, including the effect of downstream film cooling with and without leading edge showerhead film cooling. Experimental measurements were made in a two-dimensional cascade previously used to obtain vane surface heat transfer distributions on nonfilm cooled airfoils under contract NAS3-22761 and leading edge showerhead film cooled airfoils under contract NAS3-23695. The principal independent parameters (Mach number, Reynolds number, turbulence, wall-to-gas temperature ratio, coolant-to-gas temperature ratio, and coolant-to-gas pressure ratio) were maintained over ranges consistent with actual engine conditions and the test matrix was structured to provide an assessment of the independent influence of parameters of interest, namely, exit Mach number, exit Reynolds number, coolant-to-gas temperature ratio, and coolant-to-gas pressure ratio. Data provide a data base for downstream film cooled turbine vanes and extends the data bases generated in the two previous studies. The vane external heat transfer obtained indicate that considerable cooling benefits can be achieved by utilizing downstream film cooling. The data obtained and presented illustrate the interaction of the variables and should provide the airfoil designer and computational analyst the information required to improve heat transfer design capabilities for film cooled turbine airfoils

Lead optimisation of dehydroemetine for repositioned use in malaria

Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.

The effects of tumor necrosis factor-alpha on systolic and diastolic function in rat ventricular myocytes

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) is associated with myocardial dysfunction observed in sepsis and septic shock. There are two fundamental components to this dysfunction. (1) systolic dysfunction; and (2) diastolic dysfunction. The aim of these experiments was to determine if any aspect of whole-heart dysfunction could be explained by alterations to global intracellular calcium ([Ca(2+)]i), contractility, and [Ca(2+)]i handling, by TNF-α, at the level of the individual rat myocyte. We took an integrative approach to simultaneously measure [Ca(2+)]i, contractility and sarcolemmal Ca fluxes using the Ca indicator fluo-3, video edge detection, and the perforated patch technique, respectively. All experiments were performed at 37°C. The effects of 50 ng/mL TNF-α were immediate and sustained. The amplitude of systolic [Ca(2+)]i was reduced by 31% and systolic shortening by 19%. Diastolic [Ca(2+)]i, myocyte length and relaxation rate were not affected, nor were the activity of the [Ca(2+)]i removal mechanisms. The reduction in systolic [Ca(2+)]i was associated with a 14% reduction in sarcoplasmic reticulum (SR) content and a 11% decrease in peak L-type Ca current (IC a-L). Ca influx was decreased by 7% associated with a more rapid IC a-L inactivation. These data show that at the level of the myocyte, TNF-α reduces SR Ca which underlies a reduction in systolic [Ca(2+)]i and thence shortening. Although these findings correlate well with aspects of systolic myocardial dysfunction seen in sepsis, in this model, acutely, TNF-α does not appear to provide a cellular mechanism for sepsis-related diastolic myocardial dysfunction

Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate

Background Drug repurposing or repositioning refers to the usage of existing drugs in diseases other than those it was originally used for. For diseases like malaria, where there is an urgent need for active drug candidates, the strategy offers a route to significantly shorten the traditional drug development pipelines. Preliminary high-throughput screens on patent expired drug libraries have recently been carried out for Plasmodium falciparum. This study reports the systematic and objective further interrogation of selected compounds reported in these studies, to enable their repositioning as novel stand-alone anti-malarials or as combinatorial partners. Methods SYBR Green flow cytometry and micro-titre plate assays optimized in the laboratory were used to monitor drug susceptibility of in vitro cultures of P. falciparum K1 parasite strains. Previously described fixed-ratio methods were adopted to investigate drug interactions. Results Emetine dihydrochloride hydrate, an anti-protozoal drug previously used for intestinal and tissue amoebiasis was shown to have potent inhibitory properties (IC50 doses of ~ 47nM) in the multidrug resistant K1 strain of P. falciparum. The sum 50% fractional inhibitory concentration ([n-ary summation]FIC50, 90) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the KI strains of P. falciparum ranged from 0.88-1.48. Conclusion The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option. The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested

Bio-inspired artemether-loaded human serum albumin nanoparticles for effective control of malaria-infected erythrocytes

Aim: The intra-erythrocytic development of the malarial parasite is dependent on active uptake of nutrients, including human serum albumin (HSA), into parasitized red blood cells (pRBCs). We have designed HSA-based nanoparticles as a potential drug-delivery option for antimalarials. Methods: Artemether-loaded nanoparticles (AANs) were designed and antimalarial activity evaluated in vitro/in vivo using Plasmodium falciparum/Plasmodium berghei species, respectively. Results: Selective internalization of AAN into Plasmodium-infected RBCs in preference to healthy erythrocytes was observed using confocal imaging. In vitro studies showed 50% dose reduction for AAN as compared with drug-only controls to achieve IC50 levels of inhibition. The nanoparticles exhibited twofold higher peak drug concentrations in RBCs with antimalarial activity at 50% of therapeutic doses in P. bergei infected mice. Conclusion: Novel HSA-based nanoparticles offer safe and effective approach for selective targeting of antimalarial drugs

Links between a biomarker profile, cold ischaemic time and clinical outcome following simultaneous pancreas and kidney transplantation

© 2018 Elsevier Ltd. In sepsis, trauma and major surgery, where an explicit physiological insult leads to a significant systemic inflammatory response, the acute evolution of biomarkers have been delineated. In these settings, Interleukin (IL) -6 and TNF-α are often the first pro-inflammatory markers to rise, stimulating production of acute phase proteins followed by peaks in anti-inflammatory markers. Patients undergoing SPKT as a result of diabetic complications already have an inflammatory phenotype as a result of uraemia and glycaemia. How this inflammatory response is affected further by the trauma of major transplant surgery and how this may impact on graft survival is unknown, despite the recognised pro-inflammatory cytokines’ detrimental effects on islet cell function. The aim of the study was to determine the evolution of biomarkers in omentum and serum in the peri-operative period following SPKT. The biochemical findings were correlated to clinical outcomes. Two omental biopsies were taken (at the beginning and end of surgery) and measured for CD68+ and CD206+ antibodies (M1 and M2 macrophages respectively). Serum was measured within the first 72 h post-SPKT for pro- and anti-inflammatory cytokines (IL -6, -10 and TNF-α), inflammatory markers (WCC and CRP) and endocrine markers (insulin, C-peptide, glucagon and resistin). 46 patients were recruited to the study. Levels of M1 (CD68+) and M2 (CD206+) macrophages were significantly raised at the end of surgery compared to the beginning (p = 0.003 and p < 0.001 respectively). Levels of C-peptide, insulin and glucagon were significantly raised 30 min post pancreas perfusion compared to baseline and were also significantly negatively related to prolonged cold ischaemic time (CIT) (p < 0.05). CRP levels correlated significantly with the Post-Operative Morbidity Survey (p < 0.05). The temporal inflammatory marker signature after SPKT is comparable to the pattern observed following other physiological insults. Unique to this study, we find that CIT is significantly related to early pancreatic endocrine function. In addition, this study suggests a predictive value of CRP in peri-operative morbidity following SPKT

Successful Protein Extraction from Over-Fixed and Long-Term Stored Formalin-Fixed Tissues

One of the major breakthroughs in molecular pathology during the last decade was the successful extraction of full-length proteins from formalin-fixed and paraffin-embedded (FFPE) clinical tissues. However, only limited data are available for the protein extraction efficiency of over-fixed tissues and FFPE blocks that had been stored for more than 15 years in pathology archives. In this study we evaluated the protein extraction efficiency of FFPE tissues which had been formalin-fixed for up to 144 hours and tissue blocks that were stored for 20 years, comparing an established and a new commercial buffer system. Although there is a decrease in protein yield with increasing fixation time, the new buffer system allows a protein recovery of 66% from 144 hours fixed tissues compared to tissues that were fixed for 6 hours. Using the established extraction procedure, less than 50% protein recovery was seen. Similarly, the protein extraction efficiency decreases with longer storage times of the paraffin blocks. Comparing the two buffer systems, we found that 50% more proteins can be extracted from FFPE blocks that were stored for 20 years when the new buffer system is used. Taken together, our data show that the new buffer system is superior compared to the established one. Because tissue fixation times vary in the routine clinical setting and pathology archives contain billions of FFPE tissues blocks, our data are highly relevant for research, diagnosis, and treatment of disease

The impact of cataract surgery on activities and time-use: results from a longitudinal study in Kenya, Bangladesh and the Philippines.

BACKGROUND: Cataract is the leading cause of blindness in the world, and blindness from cataract is particularly common in low-income countries. The aim of this study is to explore the impact of cataract surgery on daily activities and time-use in Kenya, Bangladesh and the Philippines. METHODS/PRINCIPAL FINDINGS: A multi-centre intervention study was conducted in three countries. Time-use data were collected through interview from cases aged >or=50 years with visually impairing cataract (VA or=6/18). Cases were offered free/subsidized cataract surgery. Approximately one year later participants were re-interviewed about time-use. At baseline across the three countries there were 651 cases and 571 controls. Fifty-five percent of cases accepted surgery. Response rate at follow up was 84% (303 out of 361) for operated cases, and 80% (459 out of 571) for controls. At baseline, cases were less likely to carry out and spent less time on productive activities (paid and non-paid work) and spent more time in "inactivity" compared to controls. Approximately one year after cataract surgery, operated cases were more likely to undertake productive activities compared to baseline (Kenya from 55% to 88%; Bangladesh 60% to 95% and Philippines 81% to 94%, p<0.001) and mean time spent on productive activities increased by one-two hours in each setting (p<0.001). Time spent in "inactivity" in Kenya and Bangladesh decreased by approximately two hours (p<0.001). Frequency of reported assistance with activities was more than halved in each setting (p<0.001). CONCLUSIONS/SIGNIFICANCE: The empirical evidence provided by this study of increased time spent on productive activities, reduced time in inactivity and reduced assistance following cataract surgery among older adults in low-income settings has positive implications for well-being and inclusion, and supports arguments of economic benefit at the household level from cataract surgery