Portal Observatorio: El nuevo punto de encuentro de la comunidad IDE

El Portal Observatorio IDE es una plataforma colaborativa online en desarrollo que aspira a convertirse en un destacado punto de encuentro para toda la comunidad IDE. Nace con el fin de conseguir atraer las diversas iniciativas relacionadas con las IDE que se están gestando en la actualidad, contribuyendo así a la concentración, coordinación y monitorización de esfuerzos. Para conseguirlo, se propone una plataforma con una estructura adaptable y dinámica, en la que se invite a los propios usuarios a colaborar en la gestión de su estructura, funcionamiento y alojamiento de contenidos. En el presente artículo se realiza una declaración de los fundamentos e ideas que han llevado a las instituciones implicadas a la creación del Portal Observatorio IDE, se detallan las herramientas tecnológicas empleadas para su programación, las características y utilidades implementadas y los resultados esperados con su puesta en marcha

Una Alternativa al Algoritmo Chaid de Segmentación Basada en Entropía.

The CHAID (Chi-Squared Automatic Interaction Detection) treebased segmentation technique has been found to be an effective approach for obtaining meaningful segments that are predictive of a K-category (nominal or ordinal) criterion variable. CHAID was designed to detect, in an automatic way, the  nteraction between several categorical or ordinal predictors in explaining a categorical response, but, this may not be true when Simpson’s paradox is present. This is due to the fact that CHAID is a forward selection algorithm based on the marginal counts. In this paper we propose a backwards elimination algorithm that starts with the full set of predictors (or full tree) and eliminates predictors progressively. The elimination procedure is based on Conditional Independence contrasts using the concept of entropy. The proposed procedure is compared to CHAID.La técnica de segmentación basada en árboles CHAID (Detección Automática de Interacción basada en el Chi Cuadrado, o Chi-Squared Automatic Interaction Detection, por sus siglas en inglés) ha mostrado ser útil para obtener segmentos significativos que sean predictivos de una variable criterio de K categorías (nominal u ordinal).CHAID fue diseñado para detectar, de manera automática, la interacción entre  varios predictores categóricos u ordinales para explicar una respuesta categórica,  pero esto puede no ser cierto cuando se presenta la paradoja de Simpson. Esto se debe al hecho de que CHAID es un algoritmo de selección hacia adelante basado en conteos marginales. En este artículo proponemos un algoritmo de eliminación hacia atrás que empieza con el conjunto completo de predictores (o árbol completo) y elimina progresivamente predictores. El procedimiento de eliminación está basado en contrastes de independencia condicional usando el concepto de entropía. El procedimiento propuesto es comparado con CHAID

African Swine Fever Virus Ubiquitin-Conjugating Enzyme Is an Immunomodulator Targeting NF-kappa B Activation

African swine fever virus (ASFV) is an acute and persistent swine virus with a high economic burden that encodes multiple genes to evade host immune response. In this work, we have revealed that early viral protein UBCv1, the only known conjugating enzyme encoded by a virus, modulates innate immune and inflammatory signaling. Transient overexpression of UBCv1 impaired activation of NF-κB and AP-1 transcription factors induced by several agonists of these pathways. In contrast, activation of IRF3 and ISRE signaling upon stimulation with TRIFΔRIP, cGAS/STING or RIG-I-CARD remained unaltered. Experiments aimed at mapping UBCv1 inhibitory activity indicated that this viral protein acts upstream or at the level step of IKKβ. In agreement with this, UBCv1 was able to block p65 nuclear translocation upon cytokine stimulation, a key event in NF-ĸB signaling. Additionally, A549 stably transduced for UBCv1 showed a significant decrease in the levels of NF-ĸB dependent genes. Interestingly, despite the well-defined capacity of UBCv1 to conjugate ubiquitin chains, a mutant disabled for ubiquitylation activity retained similar immunomodulatory activity as the wild-type enzyme, suggesting that the two functions are segregated. Altogether these data suggest that ASFV UBCv1 manipulates the innate immune response targeting the NF-κB and AP-1 pathways and opens new questions about the multifunctionality of this enzyme

Identification of Niemann-Pick C1 protein as a potential novel SARS-CoV-2 intracellular target

Niemann-Pick type C1 (NPC1) receptor is an endosomal membrane protein that regulates intracellular cholesterol traffic. This protein has been shown to play an important role for several viruses. It has been reported that SARS-CoV-2 enters the cell through plasma membrane fusion and/or endosomal entry upon availability of proteases. However, the whole process is not fully understood yet and additional viral/host factors might be required for viral fusion and subsequent viral replication. Here, we report a novel interaction between the SARS-CoV-2 nucleoprotein (N) and the cholesterol transporter NPC1. Furthermore, we have found that some compounds reported to interact with NPC1, carbazole SC816 and sulfides SC198 and SC073, were able to reduce SARS-CoV-2 viral infection with a good selectivity index in human cell infection models. These findings suggest the importance of NPC1 for SARS-CoV-2 viral infection and a new possible potential therapeutic target to fight against COVID-19

Polipo antrocoanal de killian – relato de caso / Antrochal polyp of killian - case report

Este relato tem como objetivo apresentar um caso de um paciente da feixa etária pediatrica atendido no pronto atendimento do Hospital Otorrino de Cuiabá- MT(HO) , o qual tinha queixa de obstrução nasal, roncos noturnos e plenitude auricular bilateral, tendo o seu desfecho favorável após diagnostico de pólipo antrocoanal e instituição do tratamento cirúrgico. Este relato tem como objetivo apresentar mais um caso no cotidiano do médico otorrinolaringologista, enfatizando que o diagnóstico precoce e o tratamento cirúrgico adequado colaboram para a melhora dos sintomas e o desenvolvimento habitual de uma criança hígida. Trabalho aprovado pelo comitê de ética do Hospital Otorrino de Cuiabá-MT. O paciente em estudo foi submetido a anamnese detalhada, exame físico otorrinolaringológico . Além disso foi revisão da literatura para melhor conclusão sobre a patologia

Identification of potential inhibitors of protein-protein interaction useful to fight against Ebola and other highly pathogenic viruses

16 p.-1 fig.-1 tab.Despite the efforts to develop new treatments against Ebola virus (EBOV) there is currently no antiviral drug licensed to treat patients with Ebola virus disease (EVD). Therefore, there is still an urgent need to find new drugs to fight against EBOV. In order to do this, a virtual screening was done on the druggable interaction between the EBOV glycoprotein (GP) and the host receptor NPC1 with a subsequent selection of compounds for further validation. This screening led to the identification of new small organic molecules with potent inhibitory action against EBOV infection using lentiviral EBOV-GP-pseudotype viruses. Moreover, some of these compounds have shown their ability to interfere with the intracellular cholesterol transport receptor NPC1 using an ELISA-based assay. These preliminary results pave the way to hit to lead optimization programs that lead to successful candidates.Funding from “la Caixa” Banking Foundation under the project code HR18-00469 is acknowledged. This research was partially supported through Instituto de Salud Carlos III (FIS PI 181007 and ISCIII-COV20/01007), CSIC (201980E024 and 202020E079), Spanish Ministry of Science and Innovation (RTI2018-097305-R-I00) and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016 and VACDIVA-SFS-12-2019-1-862874).Peer reviewe

N′-phenylacetohydrazide derivatives as potent Ebola virus entry inhibitors with an improved pharmacokinetic profile

19 p.-6 fig.-7 tab.-1 graph. abst.Ebola virus (EBOV) is a single-strand RNA virus belonging to the Filoviridae family, which has been associated to most Ebola virus disease outbreaks to date, including the West African and the North Kivu epidemics between 2013 and 2022. This unprecedented health emergency prompted the search for effective medical countermeasures. Following up on the carbazole hit identified in our previous studies, we synthetized a new series of compounds, which demonstrated to prevent EBOV infection in cells by acting as virus entry inhibitors. The in vitro inhibitory activity was evaluated through the screening against surrogate models based on viral pseudotypes and further confirmed using replicative EBOV. Docking and molecular dynamics simulations joined to saturation transfer difference–nuclear magnetic resonance (STD–NMR) and mutagenesis experiments to elucidate the biological target of the most potent compounds. Finally, in vitro metabolic stability and in vivo pharmacokinetic studies were performed to confirm their therapeutic potential.The project leading to these results has received funding from “la Caixa” Foundation under the project code LCF/PR/HR19/52160012. This research was partially supported through ERA-NET-2021-862605. Cofounded by AEI, Spain (PCI2021-121939 (C.A.), PID2019-105237GB-I00 (A.C.), PID2021-122825OB (C.A.), and PID2021-122223OB-I00 (C.G.)), Instituto de Salud Carlos III (CIBERINFEC and FIS PI2100989), and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016: 731868 and Project EPIC-CROWN-2 ID: 101046084). This research work was also funded by the European Commission–NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). M.M.-T holds a predoctoral FPU grant (FPU18/03493) from MICINNPeer reviewe

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.J.P.L.’s lab is sponsored by Grant PID2020-118527RB-I00 funded by MCIN/AEI/10.13039/ 501100011039; Grant PDC2021-121735-I00 funded by MCIN/AEI/10.13039/501100011039 and by the “European Union Next Generation EU/PRTR”, the Regional Government of Castile and León (CSI144P20). J.P.L. and P.L.S. are supported by the Carlos III Health Institute (PIE14/00066). AGN laboratory and human patients’ studies are supported by an ISCIII project grant (PI18/01242). The Human Genotyping unit is a member of CeGen, PRB3, and is supported by grant PT17/0019 of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. SCLl is supported by MINECO/FEDER research grants (RTI2018-094130-B-100). CH was supported by the Department of Defense (DoD) BCRP, No. BC190820; and the National Cancer Institute (NCI) at the National Institutes of Health (NIH), No. R01CA184476. Lawrence Berkeley National Laboratory (LBNL) is a multi-program national laboratory operated by the University of California for the DOE under contract DE AC02-05CH11231. The Proteomics Unit belongs to ProteoRed, PRB3-ISCIII, supported by grant PT17/0019/0023 of the PE I + D +i, 2017–2020, funded by ISCIII and FEDER. RCC is funded by fellowships from the Spanish Regional Government of Castile and León. NGS is a recipient of an FPU fellowship (MINECO/FEDER). hiPSC-CM studies were funded in part by the “la Caixa” Banking Foundation under the project code HR18-00304 and a Severo Ochoa CNIC Intramural Project (Exp. 12-2016 IGP) to J.J.S

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant

Background: We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. Methods: The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results: The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. Conclusions: Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.This work was funded by grant Ref. no. GLD14-00279 from the GILEAD Fellowship Programme (Spain) and by the Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018) that is included in the Spanish I+D+I Plan and is co-financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER).S