Optimization techniques in respiratory control system models

One of the most complex physiological systems whose modeling is still an open study is the respiratory control system where different models have been proposed based on the criterion of minimizing the work of breathing (WOB). The aim of this study is twofold: to compare two known models of the respiratory control system which set the breathing pattern based on quantifying the respiratory work; and to assess the influence of using direct-search or evolutionary optimization algorithms on adjustment of model parameters. This study was carried out using experimental data from a group of healthy volunteers under CO2 incremental inhalation, which were used to adjust the model parameters and to evaluate how much the equations of WOB follow a real breathing pattern. This breathing pattern was characterized by the following variables: tidal volume, inspiratory and expiratory time duration and total minute ventilation. Different optimization algorithms were considered to determine the most appropriate model from physiological viewpoint. Algorithms were used for a double optimization: firstly, to minimize the WOB and secondly to adjust model parameters. The performance of optimization algorithms was also evaluated in terms of convergence rate, solution accuracy and precision. Results showed strong differences in the performance of optimization algorithms according to constraints and topological features of the function to be optimized. In breathing pattern optimization, the sequential quadratic programming technique (SQP) showed the best performance and convergence speed when respiratory work was low. In addition, SQP allowed to implement multiple non-linear constraints through mathematical expressions in the easiest way. Regarding parameter adjustment of the model to experimental data, the evolutionary strategy with covariance matrix and adaptation (CMA-ES) provided the best quality solutions with fast convergence and the best accuracy and precision in both models. CMAES reached the best adjustment because of its good performance on noise and multi-peaked fitness functions. Although one of the studied models has been much more commonly used to simulate respiratory response to CO2 inhalation, results showed that an alternative model has a more appropriate cost function to minimize WOB from a physiological viewpoint according to experimental data.Postprint (author's final draft

Inhibition of Non-flux-Controlling Enzymes Deters Cancer Glycolysis by Accumulation of Regulatory Metabolites of Controlling Steps

Glycolysis provides precursors for the synthesis of macromolecules and may contribute to the ATP supply required for the constant and accelerated cellular duplication in cancer cells. In consequence, inhibition of glycolysis has been reiteratively considered as an anti-cancer therapeutic option. In previous studies, kinetic modeling of glycolysis in cancer cells allowed the identification of the main steps that control the glycolytic flux: glucose transporter, hexokinase (HK), hexose phosphate isomerase (HPI) and glycogen degradation in human cervix HeLa cancer cells and rat AS-30D ascites hepatocarcinoma. It was also previously experimentally determined that simultaneous inhibition of the non-controlling enzymes lactate dehydrogenase (LDH), pyruvate kinase (PYK) and enolase (ENO) brings about significant decrease in the glycolytic flux of cancer cells and accumulation of intermediate metabolites, mainly fructose-1,6-bisphosphate (Fru1,6BP) and dihydroxyacetone phosphate (DHAP), which are inhibitors of HK and HPI, respectively. Here it was found by kinetic modeling that inhibition of cancer glycolysis can be attained by blocking downstream non flux-controlling steps as long as Fru1,6BP and DHAP, regulatory metabolites of flux-controlling enzymes, are accumulated. Furthermore, experimental results and further modeling showed that oxamate and iodoacetate inhibitions of PYK, ENO and glyceraldehyde3-phosphate dehydrogenase (GAPDH), but not of LDH and phosphoglycerate kinase, induced accumulation of Fru1,6BP and DHAP in AS-30D hepatoma cells. Indeed, PYK, ENO and GAPDH exerted the highest control on the Fru1,6BP and DHAP concentrations. The high levels of these metabolites inhibited HK and HPI and led to glycolytic flux inhibition, ATP diminution and accumulation of toxic methylglyoxal. Hence, the anticancer effects of downstream glycolytic inhibitors are very likely mediated by this mechanism. In parallel, it was also found that uncompetitive inhibition of the flux-controlling steps is a more potent mechanism than competitive and mixed-type inhibition to efficiently perturb cancer glycolysis

Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets

<div><p>Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway <i>i</i>.<i>e</i>., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3–38 times <i>vs</i>. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin-induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation.</p></div

A climatology of 7Be in surface air in European Union

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U B V R I Photometry of Stellar Structures throughout the Disk of the Barred Galaxy NGC 3367

We report new detailed surface U, B, V, R, and I photometry of 81 stellar structures in the disk of the barred galaxy NGC 3367. The images show many different structures indicating that star formation is going on in the most part of the disk. NGC 3367 is known to have a very high concentration of molecular gas distribution in the central regions of the galaxy and bipolar synchrotron emission from the nucleus with two lobes (at 6 kpc) forming a triple structure similar to a radio galaxy. We have determined the U, B, V, R, and I magnitudes and U - B, B - V, U - V, and V - I colors for the central region (nucleus), a region which includes supernovae 2003 AA, and 79 star associations throughout NGC 3367. Estimation of ages of star associations is very difficult due to several factors, among them: filling factor, metallicity, spatial distribution of each structure and the fact that we estimated the magnitudes with a circular aperture of 16 pixels in diameter, equivalent to $6''.8\sim1.4$ kpc. However, if the colors derived for NGC 3367 were similar to the colors expected of star clusters with theoretical evolutionary star tracks developed for the LMC and had a similar metallicity, NGC 3367 show 51 percent of the observed structures with age type SWB I (few tens of Myrs), with seven sources outside the bright surface brightness visible disk of NGC 3367.Comment: Accepted for publication (abr 2007) in The Astronomical Journal (July 2007 issue

Near-infrared spectroscopy in NGC 7538

The characterisation of the stellar population toward young high-mass star-forming regions allows to constrain fundamental cluster properties like distance and age. These are essential when using high-mass clusters as probes to conduct Galactic studies. NGC 7538 is a star-forming region with an embedded stellar population only unearthed in the near-infrared. We present the first near-infrared spectro-photometric study of the candidate high-mass stellar content in NGC 7538. We obtained H and K spectra of 21 sources with both the multi-object and long-slit modes of LIRIS at the WHT, and complement these data with sub-arcsecond JHKs photometry of the region using the imaging mode of the same instrument. We find a wide variety of objects within the studied stellar population of NGC 7538. Our results discriminate between a stellar population associated to the HII region, but not contained within its extent, and several pockets of more recent star formation. We report the detection of CO bandhead emission toward several sources as well as other features indicative of a young stellar nature. We infer a spectro-photometric distance of 2.7+-0.5 kpc, an age spread in the range 0.5-2.2 Myr and a total mass ~1.7x10^3 Msun for the older population.Comment: 11 pages, 8 figures, 1 table, accepted by A&

Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/Eʹ ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.post-print3851 K

Removal efficiency for emerging contaminants in a WWTP from Madrid (Spain) after secondary and tertiary treatment and environmental impact on the Manzanares River

The effluents from wastewater treatment plants (WWTPs) can be an important contamination source for receiving waters. In this work, a comprehensive study on the impact of a WWTP from Madrid on the aquatic environment has been performed, including a wide number of pharmaceuticals and pesticides, among them those included in the European Watch List. 24-h composite samples of influent (IWW) and effluent wastewater after secondary (EWW2) and after secondary + tertiary treatment (EWW3) were monitored along two campaigns. Average weekly concentrations in IWW and EWW2 and EWW3 allowed estimating the removal efficiency of the WWTP for pharmaceutical active substances (PhACs). In addition, the impact of EWW3 on the water quality of the Manzanares River was assessed, in terms of PhAC and pesticide concentrations, through analysis of the river water collected upstream and downstream of the discharge point. After a preliminary risk assessment, a detailed evaluation of the impact on the aquatic environment, including a toxicological study and screening of pharmaceutical metabolites, was made for the seven most relevant PhACs: sulfamethoxazole, azithromycin and clarithromycin (antibiotics), metoprolol (antihypertensive), diclofenac (anti-inflammatory/analgesic), irbesartan (antihypertensive), and the antidepressant venlafaxine. Among selected PhACs, irbesartan, clarithromycin and venlafaxine presented moderate or high risk in the river water downstream of the discharge. Albeit no acute toxicity was detected, more detailed studies should be carried out for these substances, including additional toxicological studies, to set up potential sublethal and chronic effects on aquatic organisms.This work was developed under the financial support of DRACE INFRAESTRUCTURAS S.A. as a part of the project Estudio de contaminantes emergentes en aguas residuales y superficiales de Madrid. The authors acknowledge the support of Jose Ramon Rodriguez from DRACE INFRAESTRUCTURAS S.A., for collection of wastewater and surface water samples, as well as the discussion and useful suggestions from Jesus Angel López, Pedro Miguel Catalinas and Maria Elvira Benito, from Sub-Direccion General de Aguas, Ayuntamiento de Madrid. The University Jaume I of Castellón, Spain (project UJI-B2018-55), the Ministry of Science, Innovation and University, Spain (Ref RTI2018-097417-B-I00) and Generalitat Valenciana, Spain (research group of excellence PROMETEO 2019/040) are also acknowledged. The authors are very grateful to the Serveis Centrals d'Instrumentació Científica (SCIC) of University Jaume I for the use of LC-MS/MS instrumentation

Biocompatible Metal-Oxide Nanoparticles: Nanotechnology Improvement of Conventional Prosthetic Acrylic Resins

Nowadays, most products for dental restoration are produced from acrylic resins based on heat-cured Poly(Methyl MethAcrylate) (PMMA). The addition of metal nanoparticles to organic materials is known to increase the surface hydrophobicity and to reduce adherence to biomolecules. This paper describes the use of nanostructured materials, TiO2 and Fe2O3, for simultaneously coloring and/or improving the antimicrobial properties of PMMA resins. Nanoparticles of metal oxides were included during suspension polymerization to produce hybrid metal oxides-alginate-containing PMMA. Metal oxide nanoparticles were characterized by dynamic light scattering, and X-ray diffraction. Physicochemical characterization of synthesized resins was assessed by a combination of spectroscopy, scanning electron microscopy, viscometry, porosity, and mechanical tests. Adherence of Candida albicans cells and cellular compatibility assays were performed to explore biocompatibility and microbial adhesion of standard and novel materials. Our results show that introduction of biocompatible metal nanoparticles is a suitable means for the improvement of conventional acrylic dental resins