Working with unknown

La experiencia “Trabajar con desconocidos” es un formato de trabajo en equipo entre estudiantes, que siendo estos siempre de diferentes procedencias culturales, están invitados a trabajar a lo largo del curso académico con un compañero que desconocen. Un ejercicio que investiga el conocimiento implícito de aprender nuestra cultura arquitectónica mediante la comparación con otra totalmente ajena. Esta experiencia, desarrollada por la UD Soriano de la Escuela Técnica Superior de Arquitectura de Madrid junto a cinco universidades internacionales, apuesta por formas de trabajo externas a la propia universidad. Formas de trabajo que se presentan en la disciplina de la arquitectura como un reto sobre el trabajo en equipo, y no solo con miembros que se conocen entre sí, que es lo que sucede habitualmente en las asignaturas taller como en Proyectos Arquitectónicos, sino con miembros realmente desconocidos entre sí, personas ajenas a nuestra cultura o afecciones intelectuales. La enseñanza universitaria debe afrontar esta carencia.“Working with strangers” is an experience of team working between students from different cultural origins, which are invited to work during the course with an unknown partner. It is an exercise that finds out, through the comparison with a totally different culture, the implicit knowledge of learning our own architectural culture. This experience, developed by the UD Soriano from the Architectural School of Madrid in collaboration with other five international universities, goes for ways of working that are external from university. Ways of working that face a challenge of team working with known partners and also with completely unknown ones. The first ones are so common in the way of teaching Architectural Projects subjects; the second ones are strange people foreign to our cultural and intellectual affections that will make us doubt and wonder. University education must address this lack.Peer Reviewe

Pyridazino-pyrrolo-quinoxalinium salts as highly potent and selective leishmanicidal agents targeting trypanothione reductase

Fifteen pyridazino-pyrrolo-quinoxalinium salts were synthesized and tested for their antiprotozoal activity against Leishmania infantum amastigotes. Eleven of them turned out to be leishmanicidal, with EC50 values in the nanomolar range, and displayed low toxicity against the human THP-1 cell line. Selectivity indices for these compounds range from 10 to more than 1000. Compounds 3b and 3f behave as potent inhibitors of the oxidoreductase activity of the essential enzyme trypanothione disulfide reductase (TryR). Interestingly, binding of 3f is not affected by high trypanothione concentrations, as revealed by the noncompetitive pattern of inhibition observed when tested in the presence of increasing concentrations of this substrate. Furthermore, when analyzed at varying NADPH concentrations, the characteristic pattern of hyperbolic uncompetitive inhibition supports the view that binding of NADPH to TryR is a prerequisite for inhibitor-protein association. Similar to other TryR uncompetitive inhibitors for NADPH, 3f is responsible for TryR-dependent reduction of cytochrome c in a reaction that is typically inhibited by superoxide dismutase.Comunidad de MadridMinisterio de Economía y CompetitividadMinisterio de Ciencia, Innovación y Universidade

Somatic Mutations Detected in Parkinson Disease Could Affect Genes With a Role in Synaptic and Neuronal Processes

The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. However, to date, no study has shown their relation to Parkinson disease's phenotype. To explore the relevance of embryonic somatic mutations in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and a careful filtering strategy (COSMOS). We validated 27 of them with amplicon-based ultra-deep sequencing, with a 70% validation rate for the highest-confidence variants. The identified sSNVs are in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease. Most of the sSNVs were only called in blood but were also found in the brain tissues with ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs

Dietary Fat Patterns and Outcomes in Acute Pancreatitis in Spain

Background/Objective: Evidence from basic and clinical studies suggests that unsaturated fatty acids (UFAs) might be relevant mediators of the development of complications in acute pancreatitis (AP). Objective: The aim of this study was to analyze outcomes in patients with AP from regions in Spain with different patterns of dietary fat intake. Materials and Methods: A retrospective analysis was performed with data from 1,655 patients with AP from a Spanish prospective cohort study and regional nutritional data from a Spanish cross-sectional study. Nutritional data considered in the study concern the total lipid consumption, detailing total saturated fatty acids, UFAs and monounsaturated fatty acids (MUFAs) consumption derived from regional data and not from the patient prospective cohort. Two multivariable analysis models were used: (1) a model with the Charlson comorbidity index, sex, alcoholic etiology, and recurrent AP; (2) a model that included these variables plus obesity. Results: In multivariable analysis, patients from regions with high UFA intake had a significantly increased frequency of local complications, persistent organ failure (POF), mortality, and moderate-to-severe disease in the model without obesity and a higher frequency of POF in the model with obesity. Patients from regions with high MUFA intake had significantly more local complications and moderate-to-severe disease; this significance remained for moderate-to-severe disease when obesity was added to the model. Conclusions: Differences in dietary fat patterns could be associated with different outcomes in AP, and dietary fat patterns may be a pre-morbid factor that determines the severity of AP. UFAs, and particulary MUFAs, may influence the pathogenesis of the severity of AP

Prevalence of X4 tropic viruses in patients recently infected with HIV-1 and lack of association with transmission of drug resistance

Producción CientíficaBackground: HIV-1 co-receptor usage may play a critical role in AIDS pathogenesis. Information on viral tropism in HIV-1 seroconverters is scarce, as is the relationship with transmission of drug-resistant viruse

Métodos de deposición de nanopartículas de oro en óxido de circonio monoclínico nanoestructurado en medio básico

En este trabajo se presentan estudios de dos métodos de deposición de nanopartículas de oro (NPsAu) en nanopartículas de óxido de circonio (ZrO₂) nanoestructurado. Uno de los métodos consiste en preparar nanopartículas de -ZrO₂ nanoestructurado con las de oro in situ en medio básico. El otro, consiste en preparar -ZrO₂ nanoestructurado en medio básico, y obtener la solución coloidal de Au. En ambas síntesis se obtuvo -ZrO₂ nanoestructurado con tamaño de partícula 14.7 (2) nm y 11.4 (1) nm, respectivamente. En los dos métodos, el tamaño de las NPsAu está en el intervalo de 2-5 nm. Es de interés obtener NPsAu en -ZrO₂ nanoestructurado, que sean estables y que su distribución sea homogénea, para posteriormente, usar estos materiales en catálisis, como en la oxidación de CO a CO₂. Los resultados mostraron que el primer método es mejor porque las NPsAu soportadas son más estables después de varios días en condiciones ambientales.In this work we performed studies of two methods of deposition of gold nanoparticles (AuNPs) on nanostructured zirconium oxide (ZrO₂). One of the methods consists of preparing -ZrO₂ nanoparticles with gold in situ in basic medium. The other method consists of preparing -ZrO₂ nanostructured in basic medium and then, it mix with colloidal solution of Au. In both methods the particle sizes obtained for -ZrO₂were 14.7(2) nm and 11.4(1) nm, respectively. The size of the AuNPs is in the range of 2-5 nm. It is of interest to obtain AuNPs in nanostructured m-ZrO₂, that are stable and with a homogeneous distribution in order to apply these materials in catalysis, as in the oxidation of CO to CO₂. The results showed that the first method is better since the supported AuNPs are more stable after several days under ambient conditions

Preparación del material NPsAu/t-ZrO₂ nanoestructurado

En este trabajo se prepararon nanopartículas de óxido de circonio nanoestructurado (ZrO₂), en su fase cristalina tetragonal (t-ZrO₂), para soportar nanopartículas de oro (NPsAu), con el objetivo de observar el efecto de la fase cristalina de ZrO₂, en la estabilidad de las NPsAu respecto a su tamaño. La fase tetragonal se estabilizó con óxido de itrio (Y₂O₃), el cual se forma in situ en la hidrólisis básica de las sales de Zr₄+ e Y₃+ usando trifluoroacetato de itrio, (Y(O₂CCF₃)₃), que tiene un anión, base débil, F₃CCO₂-, para hidrolizar al ion Y₃+ a baja temperatura y formar el hidróxido mixto (ZrO(OH)₂-Y(OH)3). En trabajos previos la estabilización de la fase cristalina, igualmente, se logra usando Y₂O₃ pero éste se añade durante la reacción de formación del ZrO2. Las NPsAu se obtuvieron en medio básico a partir del ácido tetracloro aúrico (H[AuCl₄]).Nanostructured zirconium oxide was prepared in their tetragonal crystalline phase (t-ZrO₂) to support gold nanoparticles (AuNPs), in order to observe the effect of the crystalline phase of ₂ on the stability of AuNPs with respect to their size. The tetragonal phase was stabilized with yttrium oxide (Y₂O₃), which is formed in situ in the basic hydrolysis of Zr₄+ and Y₃+ salts using yttrium trifluoroacetate, (Y(O2CCF₃)₃), which has an anion, weak base, F₃CCO₂, to hydrolyze Y₃+ ion at low temperature and form mixed hydroxide (ZrO(OH)₂-Y(OH) ₃). In previous work the stabilization of the crystalline phase is also achieved using Y₂O₃, but this is added during the formation reaction of ZrO₂. NPsAu were obtained in a basic medium from tetrachloro auric acid (H[AuCl₄])

Antiretroviral recommendations may influence the rate of transmission of drug-resistant HIV type 1

Producción CientíficaHuman immunodeficiency virus (HIV) treatment guidelines have evolved, shifting from more-aggressive to more-conservative approaches. The potential impact of these shifts on the transmission of drug-resistant virus is unknown. Drug-resistance genotypes were examined in all consecutive patients with recent HIV type 1 (HIV-1) seroconversion (hereafter, "HIV-1 seroconverters") seen at 10 Spanish hospitals since 1997. During the same period, the proportion of patients with chronic HIV-1 infection having undetectable viremia was examined, to estimate the extent and effectiveness of antiretroviral therapy. A total of 141 recent HIV-1 seroconverters were identified, 67.4% of whom were men who have sex with men. The rate of primary drug-resistance mutations, by year of infection, was 33.3% for 1997, 29.4% for 1998, 20% for 1999, 14.3% for 2000, 3.4% for 2001, 15.4% for 2002, and 10.9% for 2003. On the other hand, the proportion of 8388 persons with chronic HIV-1 carriage who had an undetectable virus load was 33.4% for 1997, 34.6% for 1998, 39.7% for 1999, 47.5% for 2000, 52.9% for 2001, 39.7% for 2002, and 58.1% for 2003. A significant inverse correlation between transmission of drug-resistant HIV-1 and undetectable virus load was found (r=-0.955, by Spearman's test; P=.001). The lowest rate of transmission of drug-resistant HIV-1 was seen in 2001, when relatively "aggressive" treatment guidelines were used. Transmission of drug-resistant HIV-1 increased in 2002, in parallel with a reduction in the number of patients with chronic HIV-1 carriage and undetectable virus load, reflecting the popularity of drug holidays or treatment interruptions. The rate of drug resistance in recent HIV-1 seroconverters inversely correlates with the proportion of chronically HIV-1-infected individuals who have undetectable virus loads in the same region, which indirectly reflects antiretroviral treatment rules at any given time

Resistance to Nonnucleoside Reverse-Transcriptase Inhibitors and Prevalence of HIV Type 1 Non-B Subtypes Are Increasing among Persons with Recent Infection in Spain

Producción CientíficaThe prevalence of drug resistance mutations was 12.1% among 198 persons who experienced human immunodeficiency virus (HIV) seroconversion identified in Spain during 1997–2004. There was a significant increase of K103N and of non-B subtypes over time. Transmission of HIV infection around the time of seroconversion was shown in 8 couples and in 2 clusters of 3 individualsRed de Investigación en SIDA (RIS- project 17

Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity

N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent in- hibitors that target different binding sites on this enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time- dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low- molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.This work has been financially supported by the Spanish MICINN (Projects PID2019-104070RB-C21, PID2019-104070RB-C22 and PID2020-115331 GB-I00), the Spanish Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC, Projects CSIC-PIE-201980E100 and CSIC-PIE-201980E028), and the Comunidad de Madrid (PLATESA2-CM ref. S-2018/BAA-4370). The Spanish MEC is also acknowledged for FPU grants to A. R. and to J.C.G. P.A.S.M. thanks to the Division of Physio- logical Chemistry and the Otto-Loewi Research Center of the Medical University of Graz for their support with the scienfic cluster where the calculations contained in this work were run. We thank Ricardo Lau- reano-Rodríguez, Juan Antonio Rodríguez-Gutierrez, and Laura Lagar- tera for technical assistance with SPR experiments.Peer reviewe