Tarjeta para configuración y comunicación con una FPGA Spartan 6 usando el controlador USB TF2232H

El actual proyecto presenta una solución referida a la necesidad de configurar y comunicarse con una FPGA del modelo Spartan 6 del fabricante Xilinx a través de un dispositivo intermedio como es un controlador USB. Se diseña una tarjeta que contenga las conexiones entre ambos dispositivos y que se conecta al host a través de USB. El trabajo abarca desde la búsqueda de las conexiones entre dispositivos hasta la fabricación de la tarjeta. Se desarrollará también el interfaz de configuración JTAG para la FPGA Spartan 6 haciendo pruebas con el fichero de código tanto a través de cableado como con la tarjeta de este trabajo ya fabricada.Departamento de Tecnología ElectrónicaGrado en Ingeniería en Tecnologías Industriale

Modelling the enantioresolution capability of cellulose tris(3,5-dichlorophenylcarbamate) stationary phase in reversed phase conditions for neutral and basic chiral compounds

[EN] To the best of our knowledge, the prediction of the enantioresolution ability of polysaccharides-based stationary phases in liquid chromatography for structurally unrelated compounds has not been previously reported. In this study, structural information of neutral and basic compounds is used to model their enantioresolution levels obtained from an immobilised cellulose tris(3,5-dichlorophenylcarbamate) stationary phase in reversed phase conditions. Thirty-four structurally unrelated chiral drugs and pesticides, from seven families, are studied. Categorical enantioresolution levels (RsC, 0 = no baseline enantioresolution and 1 = baseline enantioresolution) are established from the experimental enantioresolution values obtained at a fixed experimental conditions. From 58 initial structural variables, three topological parameters (two of them connected to the chiral carbon), and six molecular descriptors (one of them also related with the chiral carbon), are selected after a discriminant partial least squares refinement process. The molar total charge of the molecule at the working pH is the most important variable. The relationships between RsC and the most important structural variables and the drug/pesticide family are evaluated. An explicit model is proposed to anticipate the RsC levels, which provides 100% of correct anticipations. A criterion is introduced to alert about the compounds that should not be anticipated.The authors acknowledge the Spanish Ministerio de Economia y Competitividad (MINECO) and the European Regional Development Fund (ERDF) for the financial support (Project CTQ2015-70904-R, MINECO/FEDER, UE).Martin-Biosca, Y.; Escuder-Gilabert, L.; Medina-Hernandez, MJ.; Sagrado Vives, S. (2018). Modelling the enantioresolution capability of cellulose tris(3,5-dichlorophenylcarbamate) stationary phase in reversed phase conditions for neutral and basic chiral compounds. Journal of Chromatography A. 1567:111-118. https://doi.org/10.1016/j.chroma.2018.06.061S111118156

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Calidad, Validación de métodos, Control de calidad, Incertidumbre, Acreditación de laboratorios

Describir e ilustrar con un ejemplo el procedimiento a seguir para armonizar tres procesos internos de calidad, relacionados con un método de análisis, en el laboratorio de ensayo, LE: Validación de la exactitud, Control de calidad y Expresión de la incertidumbre. Además, la Guía se ha diseñado para que el usuario (estudiante o profesional) alcance competencias y cualificación suficiente para ejecutar correctamente un documento del sistema de calidad del LE y poder cumplimentar un registro de validación de manera conforme. Finalmente, la Guía (en sí misma, junto al resto de documentos que la componen) pretende servir de orientación didáctica al usuario sobre algunos aspectos clave de un sistema de calidad y como ayuda en la consecución de la acreditación de una actividad (alcance de acreditación) del LE

Anticipating the impact of pitfalls in kinetic biodegradation parameter estimation from substrate depletion curves of organic pollutants

[EN] Accurate and reliable estimation of kinetic parameters of pollutant biodegradation processes is essential for environmental and health risk assessment. Common biodegradation models proposed in the literature, such as the nonlinear Monod equation and its simplified versions (e.g. Michaelis-Menten-like and first-order equations), are problematic in terms of accuracy of kinetic parameters due to the parameter correlation. However, a comparison between these models in terms of accuracy and reliability, related to data imprecision, has not been performed in the literature. This task is necessary, mainly because the model selection cannot be straightforward, as shown in this work. To facilitate the comparison, novel statistics summarising the accuracy and reliability of estimations are introduced. The main objective is to establish relationships between these statistics (trough new diagnostic indicators) to limit the probability of pitfalls or to avoid the negative impact of an improper model selection. Such anticipation is an imperative need in the biodegradation modelling framework and, to the best of our knowledge, it has never been performed. In order to account for accuracy, simulated data in realistic conditions are used to highlight the magnitude of pitfalls related to the model selection for estimation of the main kinetic parameters (K-s, mu(m) and/or V-m). Four scenarios related to model selection are compared for the first time and, diagnostic indicators able to anticipate relevant aspects related to accuracy and reliability are introduced. Moreover, first evidences of the impact of measurement errors in other intrinsic Monod parameters (the initial biomass concentration and the microbial yield coefficient, Y), as well as the impact of the simultaneous mu(m), K-s and Y estimation, on the accuracy and reliability of the estimations are reported. Despite the pitfalls shown, specific applicability of even unreliable models is highlighted, and suggestions for environmental and health risk modellers are provided accordingly. (C) 2019 Elsevier Ltd. All rights reserved.The authors acknowledge the Spanish Ministerio de Economía y Competitividad (MINECO) and the European Regional Development Fund for the financial support (Project CTQ2015-70904-R, MINECO/FEDER, UE).Escuder-Gilabert, L.; Martin-Biosca, Y.; Sagrado Vives, S.; Medina-Hernández, M. (2019). Anticipating the impact of pitfalls in kinetic biodegradation parameter estimation from substrate depletion curves of organic pollutants. Environmental Pollution. 252-A:128-136. https://doi.org/10.1016/j.envpol.2019.05.080S128136252-

Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors

[EN] The development and advancement of prostate cancer (PCa) into stage 4, where it metastasize, is a major problem mostly in elder males. The growth of PCa cells is stirred up by androgens and androgen receptor (AR). Therefore, therapeutic strategies such as blocking androgens synthesis and inhibiting AR binding have been explored in recent years. However, recently approved drugs (or in clinical phase) failed in improving the expected survival rates for this metastatic-castration resistant prostate cancer (mCRPC) patients. The selective CYP17A1 inhibition of 17,20-lyase route has emerged as a novel strategy. Such inhibition blocks the production of androgens everywhere they are found in the body. In this work, a three dimensional-quantitative structure activity relationship (3D-QSAR) pharmacophore model is developed on a diverse set of non-steroidal inhibitors of CYP17A1 enzyme. Highly active compounds are selected to define a six-point pharmacophore hypothesis with a unique geometrical arrangement fitting the following description: two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two aromatic rings (R). The QSAR model showed adequate predictive statistics. The 3D-QSAR model is further used for database virtual screening of potential inhibitory hit structures. Density functional theory (DFT) optimization provides the electronic properties explaining the reactivity of the hits. Docking simulations discovers hydrogen bonding and hydrophobic interactions as responsible for the binding affinities of hits to the CYP17A1 Protein Data Bank structure. 13 hits from the database search (including five derivatives) are then synthesized in the laboratory as different scaffolds. Ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in vitro experiments reveals three new chemical entities (NCEs) with half maximal inhibitory concentration (IC50) values against the lyase route at mid-micromolar range with favorable selectivity to the lyase over the hydroxylase route (one of them with null hydroxylase inhibition). Thus, prospective computational design has enabled the design of potential lead lyase-selective inhibitors for further studies.This work research work was supported financially in part by the National Research Foundation of South Africa and First Rand Foundation (UID: 112151). This work was also made possible through funding by the Research Capacity Development Initiative-South African Medical Research Council (RCDI-SAMRC). The content hereof is the sole responsibility of the authors and does not necessarily represent the official views of NRF and SAMRC. The authors would like to acknowledge the Centre for High Performance Computing for allowing access to their resources for molecular modeling. Xenogesis Ltd is greatly acknowledge for performing bioanalytical experiments, as an outsourced services. Enamine LTD is greatly acknowledge for custom synthesis of the compounds, as an outsourced service.Gumede, N.; Nxumalo, W.; Bisetty, K.; Escuder Gilabert, L.; Medina-Hernández, M.; Sagrado Vives, S. (2020). Prospective computational design and in vitro bio-analytical tests of new chemical entities as potential selective CYP17A1 lyase inhibitors. Bioorganic Chemistry. 94:1-16. https://doi.org/10.1016/j.bioorg.2019.103462S11694Nnane, I. P., Kato, K., Liu, Y., Long, B. J., Lu, Q., Wang, X., … Brodie, A. (1999). Inhibition of Androgen Synthesis in Human Testicular and Prostatic Microsomes and in Male Rats by Novel Steroidal Compounds*. Endocrinology, 140(6), 2891-2897. doi:10.1210/endo.140.6.6832C. Jagusch, M. Negri, U.E. Hille, Q. Hu, M. Bartels, K. Jahn-Hoffmann, M.A.E. Pinto-Bazurco Mendieta, B. Rodenwaldt, U. Müller-Vieira, D. Schmidt, T. Lauterbach, M. Recanatini, A. Cavalli, R.W. Hartmann, Synthesis, biological evaluation and molecular modelling studies of methylene imidazole substituted biaryls as inhibitors of human 17α-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure, Bioorg. Med. Chem. J. 16 (2008) 1992–2010.Haider, S. M., Patel, J. S., Poojari, C. S., & Neidle, S. (2010). Molecular Modeling on Inhibitor Complexes and Active-Site Dynamics of Cytochrome P450 C17, a Target for Prostate Cancer Therapy. Journal of Molecular Biology, 400(5), 1078-1098. doi:10.1016/j.jmb.2010.05.069Yap, T. A., Carden, C. P., Attard, G., & de Bono, J. S. (2008). Targeting CYP17: established and novel approaches in prostate cancer. Current Opinion in Pharmacology, 8(4), 449-457. doi:10.1016/j.coph.2008.06.004Gianti, E., & Zauhar, R. J. (2012). 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Trimeprazine is enantioselectively degraded by an activated sludge in ready biodegradability test conditions

[EN] A great number of available pharmaceuticals are chiral compounds. Although they are usually manufactured as racemic mixtures, they can be enantioselectively biodegraded as a result of microbial processes. In this paper, a biodegradability assay in similar conditions to those recommended in OECD tests of enantiomers of trimeprazine (a phenothiazine employed as a racemate) is carried out. Experiments were performed in batch mode using a minimal salts medium inoculated with an activated sludge (collected from a Valencian Waste Water Treatment Plant, WWTP) and supplemented with the racemate. The concentration of the enantiomers of trimeprazine were monitored by means of a chiral HPLC method using a cellulose-based chiral stationary phase and 0.5 M NaClO4/acetonitrile (60:40, v/v) mobile phases. Experiments were performed at three concentration levels of the racemate. In parallel, the optical density at 600 nm (OD600) was measured to control the biomass growth and to connect it with enantioselectivity. The calculated enantiomeric fractions (EF) offer the first evidence of enantioselective biodegradation of trimeprazine. A simplified Monod equation was used as a curve fitting approach for concentration (S), biodegradation (BD), and for the first time, EF experimental data in order to expand the usefulness of the results. Precision studies on S (repeatability conditions) and, for the first time, EF (intermediate precision conditions) were also performed.The authors acknowledge the Spanish Ministerio de Economia y Competitividad (MINECO) and the European Regional Development Fund for the financial support (Project CTQ2015-70904-R, MINECO/FEDER, UE).Escuder-Gilabert, L.; Martin-Biosca, Y.; Perez-Baeza, M.; Sagrado, S.; Medina-Hernandez, MJ. (2018). Trimeprazine is enantioselectively degraded by an activated sludge in ready biodegradability test conditions. Water Research. 141:57-64. https://doi.org/10.1016/j.watres.2018.05.008S576414