Electrostática y EAO : una experiencia de simulación

In this work the inclusion of educational software in the teaching of physics is analyzed. The program used corresponds to the computer simulation of electrostatic fields, and it was applied to students of first year of universitary level in a Faculty of Chemistry

Descripció del sistema dunar d’es Codolar (Eivissa, Illes Balears)

En el present treball es realitza una descripció geoambiental del sistema dunar d’es Codolar, Eivissa. Aquesta àrea està situada dins l’àrea de Parc Natural de ses Salines d’Eivissa i Formentera (Illes Balears). Aquest sistema platja-duna era desconegut i té la particularitat que es troba desvinculat de la seva font d’alimentació, constituint un veritable mant eòlic. La platja arenosa actualment està coberta per distintes barres de còdols i graves. El sistema dunar, separat de la platja, presenta elevats símptomes regressius, on es pot observar la fragmentació del sistema amb la presència de dos nuclis arenosos independents un de l’altre que en temps pretèrits eren tot un, d’extensió molt superior a l’actual. A més de la descripció geomorfològica també s’incorpora un inventari florístic i una breu discussió sobre les característiques de la vegetació

New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, an N-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 Å (PDB entry 1waw ) to 0.95-1.10 Å for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities.Fil: Fadel, Firas. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Zhao, Yuguang. University of Oxford; Reino UnidoFil: Cachau, Raul. Frederick National Laboratory for Cancer Research; Estados UnidosFil: Cousido Siah, Alexandra. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Ruiz, Francesc X.. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Harlos, Karl. University of Oxford; Reino UnidoFil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Mitschler, Andre. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Podjarny, Alberto Daniel. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; Franci

New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, an N-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 Å (PDB entry 1waw ) to 0.95-1.10 Å for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities.Instituto de Física de Líquidos y Sistemas Biológico

Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features

Background and objectiveNeoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression.Material and methodsFrom 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method.ResultsLASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02).ConclusionsWe have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing

Identification of a novel polyfluorinated compound as a lead to inhibit human enzymes aldose reductase and AKR1B10 : structure determination of both ternary complexes and implications for drug design

Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved ([alpha]/[beta])8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-­NADP+-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallo­graphic structure of the corresponding AKR1B10-NADP+-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts

Integrated treatment of first episode psychosis with online training (e-learning): study protocol for a randomised controlled trial

BackgroundThe integrated treatment of first episode psychosis has been shown to improve functionality and negative symptoms in previous studies. In this paper, we describe a study of integrated treatment (individual psychoeducation complementary to pharmacotherapy) versus treatment as usual, comparing results at baseline with those at 6-month re-assessment (at the end of the study) for these patients, and online training of professionals to provide this complementary treatment, with the following objectives: 1) to compare the efficacy of individual psychoeducation as add-on treatment versus treatment as usual in improving psychotic and mood symptoms; 2) to compare adherence to medication, functioning, insight, social response, quality of life, and brain-derived neurotrophic factor, between both groups; and 3) to analyse the efficacy of online training of psychotherapists.Methods/designThis is a single-blind randomised clinical trial including patients with first episode psychosis from hospitals across Spain, randomly assigned to either a control group with pharmacotherapy and regular sessions with their psychiatrist (treatment as usual) or an intervention group with integrated care including treatment as usual plus a psychoeducational intervention (14 sessions). Training for professionals involved at each participating centre was provided by the coordinating centre (University Hospital of Álava) through video conferences. Patients are evaluated with an extensive battery of tests assessing clinical and sociodemographic characteristics (Positive and Negative Syndrome Scale, State-Trait Anxiety Inventory, Liebowitz Social Anxiety Scale, Hamilton Rating Scale for Depression, Scale to Assess Unawareness of Mental Disorders, Strauss and Carpenter Prognostic Scale, Global Assessment of Functioning Scale, Morisky Green Adherence Scale, Functioning Assessment Short Test, World Health Organization Quality of Life instrument WHOQOL-BREF (an abbreviated version of the WHOQOL-100), and EuroQoL questionnaire), and brain-derived neurotrophic factor levels are measured in peripheral blood at baseline and at 6 months. The statistical analysis, including bivariate analysis, linear and logistic regression models, will be performed using SPSS.DiscussionThis is an innovative study that includes the assessment of an integrated intervention for patients with first episode psychosis provided by professionals who are trained online, potentially making it possible to offer the intervention to more patients.Trial registrationNCT01783457 clinical trials.gov. Date of registration in primary registry 23 January 2013

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

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