Role of cyclooxygenase in the vascular responses to extremity cooling in Caucasian and African males

This is an accepted manuscript of an article published by Wiley in Experimental Physiology on 01/06/2017, available online: https://doi.org/10.1113/EP086186 The accepted version of the publication may differ from the final published version.© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society New Findings: What is the central question of this study? Compared with Caucasians, African individuals are more susceptible to non-freezing cold injury and experience greater cutaneous vasoconstriction and cooler finger skin temperatures upon hand cooling. We investigated whether the enzyme cyclooxygenase is, in part, responsible for the exaggerated response to local cooling. What is the main finding and its importance? During local hand cooling, individuals of African descent experienced significantly lower finger skin blood flow and skin temperature compared with Caucasians irrespective of cyclooxygenase inhibition. These data suggest that in young African males the cyclooxygenase pathway appears not to be the primary reason for the increased susceptibility to non-freezing cold injury. Individuals of African descent (AFD) are more susceptible to non-freezing cold injury (NFCI) and experience an exaggerated cutaneous vasoconstrictor response to hand cooling compared with Caucasians (CAU). Using a placebo-controlled, cross-over design, this study tested the hypothesis that cyclooxygenase (COX) may, in part, be responsible for the exaggerated vasoconstrictor response to local cooling in AFD. Twelve AFD and 12 CAU young healthy men completed foot cooling and hand cooling (separately, in 8°C water for 30 min) with spontaneous rewarming in 30°C air after placebo or aspirin (COX inhibition) treatment. Skin blood flow, expressed as cutaneous vascular conductance (as flux per millimetre of mercury), and skin temperature were measured throughout. Irrespective of COX inhibition, the responses to foot cooling, but not hand cooling, were similar between ethnicities. Specifically, during hand cooling after placebo, AFD experienced a lower minimal skin blood flow [mean (SD): 0.5 (0.1) versus 0.8 (0.2) flux mmHg−1, P < 0.001] and a lower minimal finger skin temperature [9.5 (1.4) versus 10.7 (1.3)°C, P = 0.039] compared with CAU. During spontaneous rewarming, average skin blood flow was also lower in AFD than in CAU [2.8 (1.6) versus 4.3 (1.0) flux mmHg−1, P < 0.001]. These data provide further support that AFD experience an exaggerated response to hand cooling on reflection this appears to overstate findings; however, the results demonstrate that the COX pathway is not the primary reason for the exaggerated responses in AFD and increased susceptibility to NFCI.This research was funded by the University of Portsmouth.Published versio

Vascular responses of the extremities to transdermal application of vasoactive agents in Caucasian and African descent individuals

This is an accepted manuscript of an article published by Springer in European Journal of Applied Physiology on 04/04/2015, available online: https://doi.org/10.1007/s00421-015-3164-2 The accepted version of the publication may differ from the final published version.© 2015, Springer-Verlag Berlin Heidelberg. Purpose: Individuals of African descent (AFD) are more susceptible to non-freezing cold injury than Caucasians (CAU) which may be due, in part, to differences in the control of skin blood flow. We investigated the skin blood flow responses to transdermal application of vasoactive agents. Methods: Twenty-four young males (12 CAU and 12 AFD) undertook three tests in which iontophoresis was used to apply acetylcholine (ACh 1 w/v %), sodium nitroprusside (SNP 0.01 w/v %) and noradrenaline (NA 0.5 mM) to the skin. The skin sites tested were: volar forearm, non-glabrous finger and toe, and glabrous finger (pad) and toe (pad). Results: In response to SNP on the forearm, AFD had less vasodilatation for a given current application than CAU (P = 0.027–0.004). ACh evoked less vasodilatation in AFD for a given application current in the non-glabrous finger and toe compared with CAU (P = 0.043–0.014) with a lower maximum vasodilatation in the non-glabrous finger (median [interquartile], AFD n = 11, 41[234] %, CAU n = 12, 351[451] %, P = 0.011) and non-glabrous toe (median [interquartile], AFD n = 9, 116[318] %, CAU n = 12, 484[720] %, P = 0.018). ACh and SNP did not elicit vasodilatation in the glabrous skin sites of either group. There were no ethnic differences in response to NA. Conclusion: AFD have an attenuated endothelium-dependent vasodilatation in non-glabrous sites of the fingers and toes compared with CAU. This may contribute to lower skin temperature following cold exposure and the increased risk of cold injuries experienced by AFD.Published versio

An Unusual Transmission Spectrum for the Sub-Saturn KELT-11b Suggestive of a Sub-Solar Water Abundance

We present an optical-to-infrared transmission spectrum of the inflated sub-Saturn KELT-11b measured with the Transiting Exoplanet Survey Satellite (TESS), the Hubble Space Telescope (HST) Wide Field Camera 3 G141 spectroscopic grism, and the Spitzer Space Telescope (Spitzer) at 3.6 $\mu$m, in addition to a Spitzer 4.5 $\mu$m secondary eclipse. The precise HST transmission spectrum notably reveals a low-amplitude water feature with an unusual shape. Based on free retrieval analyses with varying molecular abundances, we find strong evidence for water absorption. Depending on model assumptions, we also find tentative evidence for other absorbers (HCN, TiO, and AlO). The retrieved water abundance is generally $\lesssim 0.1\times$ solar (0.001--0.7$\times$ solar over a range of model assumptions), several orders of magnitude lower than expected from planet formation models based on the solar system metallicity trend. We also consider chemical equilibrium and self-consistent 1D radiative-convective equilibrium model fits and find they too prefer low metallicities ($[M/H] \lesssim -2$, consistent with the free retrieval results). However, all the retrievals should be interpreted with some caution since they either require additional absorbers that are far out of chemical equilibrium to explain the shape of the spectrum or are simply poor fits to the data. Finally, we find the Spitzer secondary eclipse is indicative of full heat redistribution from KELT-11b's dayside to nightside, assuming a clear dayside. These potentially unusual results for KELT-11b's composition are suggestive of new challenges on the horizon for atmosphere and formation models in the face of increasingly precise measurements of exoplanet spectra.Comment: Accepted to The Astronomical Journal. 31 pages, 20 figures, 7 table

Efficient processing of raster and vector data

[Abstract] In this work, we propose a framework to store and manage spatial data, which includes new efficient algorithms to perform operations accepting as input a raster dataset and a vector dataset. More concretely, we present algorithms for solving a spatial join between a raster and a vector dataset imposing a restriction on the values of the cells of the raster; and an algorithm for retrieving K objects of a vector dataset that overlap cells of a raster dataset, such that the K objects are those overlapping the highest (or lowest) cell values among all objects. The raster data is stored using a compact data structure, which can directly manipulate compressed data without the need for prior decompression. This leads to better running times and lower memory consumption. In our experimental evaluation comparing our solution to other baselines, we obtain the best space/time trade-offs.Ministerio de Ciencia, Innovación y Universidades; TIN2016-78011-C4-1-RMinisterio de Ciencia, Innovación y Universidades; TIN2016-77158 C4-3-RMinisterio de Ciencia, Innovación y Universidades; RTC-2017-5908-7Xunta de Galicia; ED431C 2017/58Xunta de Galicia; ED431G/01Xunta de Galicia; IN852A 2018/14University of Bío-Bío; 192119 2/RUniversity of Bío-Bío; 195119 GI/V

A Population-based Study of Hospital Admission Incidence Rate and Bacterial Aetiology of Acute Lower Respiratory Infections in Children Aged Less Than Five Years in Bangladesh

The research was carried out to study the rate of population-based hospital admissions due to acute lower respiratory infections (ALRIs) and bacterial aetiology of ALRIs in children aged less than five years in Bangladesh. A cohort of children aged less than five years in a rural surveillance population in Matlab, Bangladesh, was studied for two years. Cases were children admitted to the Matlab Hospital of ICDDR,B with a diagnosis of severe ALRIs. Bacterial aetiology was determined by blood culture. Antimicrobial resistance patterns of Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Spn) isolates were determined using the disc-diffusion method. In total, 18,983 children aged less than five years contributed to 24,902 child-years of observation (CYO). The incidence of ALRI-related hospital admissions was 50.2 per 1,000 CYO. The incidences of ALRI were 67% higher in males than in females and were higher in children aged less than two years than in older children. About 34% of the cases received antibiotics prior to hospitalization. Of 840 blood samples cultured, 39.4% grew a bacterial isolate; 11.3% were potential respiratory pathogens, and the rest were considered contaminants. The predominant isolates were Staphylococcus aureus (4.5%). Hib (0.4%) and Spn (0.8%) were rarely isolated; however, resistance of both these pathogens to trimethoprim-sulphamethoxazole was common. The rate of ALRI-related hospitalizations was high. The high rate of contamination, coupled with high background antibiotic use, might have contributed to an underestimation of the burden of Hib and Spn. Future studies should use more sensitive methods and more systematically look for resistance patterns of other pathogens in addition to Hib and Spn

A Population-based Study of Hospital Admission Incidence Rate and Bacterial Aetiology of Acute Lower Respiratory Infections in Children Aged Less Than Five Years in Bangladesh

The research was carried out to study the rate of population-based hospital admissions due to acute lower respiratory infections (ALRIs) and bacterial aetiology of ALRIs in children aged less than five years in Bangladesh. A cohort of children aged less than five years in a rural surveillance population in Matlab, Bangladesh, was studied for two years. Cases were children admitted to the Matlab Hospital of ICDDR,B with a diagnosis of severe ALRIs. Bacterial aetiology was determined by blood culture. Antimicrobial resistance patterns of Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (Spn) isolates were determined using the disc-diffusion method. In total, 18,983 children aged less than five years contributed to 24,902 child-years of observation (CYO). The incidence of ALRI-related hospital admissions was 50.2 per 1,000 CYO. The incidences of ALRI were 67% higher in males than in females and were higher in children aged less than two years than in older children. About 34% of the cases received antibiotics prior to hospitalization. Of 840 blood samples cultured, 39.4% grew a bacterial isolate; 11.3% were potential respiratory pathogens, and the rest were considered contami\uadnants. The predominant isolates were Staphylococcus aureus (4.5%). Hib (0.4%) and Spn (0.8%) were rarely isolated; however, resistance of both these pathogens to trimethoprim-sulphamethoxazole was common. The rate of ALRI-related hospitalizations was high. The high rate of contamination, coupled with high background antibiotic use, might have contributed to an underestimation of the burden of Hib and Spn. Future studies should use more sensitive methods and more systematically look for resistance patterns of other pathogens in addition to Hib and Spn

Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells

Stress response gene ATF3 plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli. An alternate promoter of the human ATF3 gene (designated P1 in this study) has recently been reported, which is located ∼43.5 kb upstream of the previously reported P2 promoter. We showed here that the P1 promoter is highly conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activated in response to TGF-β and oncogenic HRAS. The P1 promoter contains multiple transcriptional start sites, and the different 5′-UTRs markedly affected their translation in response to stress. In human prostate and Hodgkin Reed–Sternberg cancer cells with elevated expression of ATF3, the P1 promoter was constitutively activated and its chromatin structure was modified into active configuration. The differential usage of alternate promoters of the ATF3 gene at both transcriptional and translational level and the modification of chromatin structure may provide a novel mechanism for expressing ATF3 in determining cell fate during stress response and cancer

Computational Design of Auxotrophy-Dependent Microbial Biosensors for Combinatorial Metabolic Engineering Experiments

Combinatorial approaches in metabolic engineering work by generating genetic diversity in a microbial population followed by screening for strains with improved phenotypes. One of the most common goals in this field is the generation of a high rate chemical producing strain. A major hurdle with this approach is that many chemicals do not have easy to recognize attributes, making their screening expensive and time consuming. To address this problem, it was previously suggested to use microbial biosensors to facilitate the detection and quantification of chemicals of interest. Here, we present novel computational methods to: (i) rationally design microbial biosensors for chemicals of interest based on substrate auxotrophy that would enable their high-throughput screening; (ii) predict engineering strategies for coupling the synthesis of a chemical of interest with the production of a proxy metabolite for which high-throughput screening is possible via a designed bio-sensor. The biosensor design method is validated based on known genetic modifications in an array of E. coli strains auxotrophic to various amino-acids. Predicted chemical production rates achievable via the biosensor-based approach are shown to potentially improve upon those predicted by current rational strain design approaches. (A Matlab implementation of the biosensor design method is available via http://www.cs.technion.ac.il/~tomersh/tools)

Metabolic Engineering for Biocatalyst Robustness to Organic Inhibitors

Microbial production of biorenewable fuels and chemicals is often limited by inhibition of the biocatalyst, either by increasing concentrations of the product compound or by contaminant compounds in the biomass‐derived sugars. This inhibition can interfere with economically viable production. Here we discuss typical mechanisms of inhibition and methods for improving biocatalyst robustness. Inhibition often takes the form of inhibition of enzyme activity, depletion of cofactor pools, and membrane damage; methods are discussed for mitigating each of these types of inhibition. Various evolutionary schemes have been developed and implemented on a variety of inhibitory compounds, including butanol, acetic acid, furfural, and ethanol. Reverse engineering of these improved strains can provide insight into new metabolic engineering strategies