Causal reasoning over knowledge graphs leveraging drug-perturbed and disease-specific transcriptomic signatures for drug discovery

Network-based approaches are becoming increasingly popular for drug discovery as they provide a systems-level overview of the mechanisms underlying disease pathophysiology. They have demonstrated significant early promise over other methods of biological data representation, such as in target discovery, side effect prediction and drug repurposing. In parallel, an explosion of -omics data for the deep characterization of biological systems routinely uncovers molecular signatures of disease for similar applications. Here, we present RPath, a novel algorithm that prioritizes drugs for a given disease by reasoning over causal paths in a knowledge graph (KG), guided by both drug-perturbed as well as disease-specific transcriptomic signatures. First, our approach identifies the causal paths that connect a drug to a particular disease. Next, it reasons over these paths to identify those that correlate with the transcriptional signatures observed in a drug-perturbation experiment, and anti-correlate to signatures observed in the disease of interest. The paths which match this signature profile are then proposed to represent the mechanism of action of the drug. We demonstrate how RPath consistently prioritizes clinically investigated drug-disease pairs on multiple datasets and KGs, achieving better performance over other similar methodologies. Furthermore, we present two case studies showing how one can deconvolute the predictions made by RPath as well as predict novel targets.DDF, YG, AP, CWD, BBM, DH, JR, and VC have been funded by Enveda Biosciences. This work has been funded by Enveda Biosciences (https://www.envedabio.com/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. SM and DRB received no specific funding for this work.Peer ReviewedPostprint (author's final draft

Changes in the Concentration and Profile of Free Fatty Acids during the Ripening of a Spanish Blue-Veined Cheese Made from Raw and Pasteurized Cow and Goat Milk

[EN]Blue-veined cheeses in general undergo a pronounced lipolysis. The aim of this work was to determine the evolution of free fatty acids (FFA) in Valdeón cheese during ripening, comparing cheeses made from raw and pasteurized milk. The effect of season on the evolution of FFA in pasteurized milk cheeses was also studied. Cheeses made with raw milk showed the highest concentrations of FFA, reaching values of 23,081.9 mg 100 g−1 dry matter at the end of ripening, compared to the values of cheeses made with pasteurized milk (7327.1 mg 100 g−1 dry matter), in both cases with a predominance of oleic and palmitic acids. However, pasteurization did not affect the FFA profile of the cheeses. Regarding the cheeses made with pasteurized milk in different seasons, the highest FFA concentration was reached in cheeses made in summer after 30 days of ripening. The season also influenced the FFA profile and thus the concentration of short-, medium- and long-chain fatty acids in relation to total FFA. There were no significant differences in sensory analysis between cheeses made from raw and pasteurized milk.SIThis work was supported by project L021A12-2 from Junta de Castilla y León

El Joc de rol com a eina d’aprenentatge en assignatures de ciència i tecnologia de materials

La incorporació de les universitats europees a l'EHEA ha conduit a la remodelació de plans d'estudi i també, a la redefinició de protagonismes en el procés d'ensenyament-aprenentatge en l'àmbit universitari. Així, el paradigma de Bolònia ha contribuït a que, progressivament, s'hagin incorporat competències, processos d'avaluació continuada, d'autoavaluació i de coavaluació, que afavoreixen que l'estudiantat formi part del propi procés d'aprenentatge. Paral•lelament, en els darrers anys, la diversitat de formats disponibles per compartir informació (text, imatge, simulacions, vídeo) ha ajudat a que la pràctica docent pugui ser més àgil i, per tant, ha contribuït a afavorir la participació de l'estudiantat. En l'àmbit de materials, les tecnologies de comunicació han ajudat a visualitzar processos, a gestionar bases de dades de selecció de materials i a optimitzar les quotes d'atenció en l'activitat docent universitària. En aquest escenari, el projecte RIMA (Recerca i Innovació en Metodologies d'aprenentatge) neix amb la voluntat de potenciar les activitats desenvolupades pels Grups d'Interès (Communities of Practice) que s'han creat a la UPC. Entre ells, el grup d'Innovació Docent en Materials, GidMAT, proporciona un espai de comunió i compartició d'experiències així com un foro de debat entre professionals de la docència de materials. En aquest treball es proposa una activitat de joc de rol com a activitat pràctica de materials en l'àmbit de l'enginyeria. La interacció professorat-alumnat és imprescindible i la metodologia proposada garanteix una constant comunicació i un feed-back eficaç que possibiliti l'avaluació continua de les assignatures de tecnologia de materials.Peer Reviewe

Multiscale environmental determinants of Leishmania vectors in the urban-rural context

Background: In South America, cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL) are emerging diseases, expanding in the border area of Argentina, Brazil and Paraguay. Outbreaks of CL were reported since the 1990s, with Nyssomyia whitmani as the main vector in this region. Regarding VL, urban reports started in 2010 with Lutzomyia longipalpis as the main vector. The aim of this study was to evaluate environmental determinants related to the main vectors of leishmaniasis, to contribute to the prevention and control response to the emergence of VL and CL in the Argentina-Brazil-Paraguay border region. Methods: The cross-sectional survey includes two cities and two close rural areas in the Argentinean Northeast Region, between November 2014 and January 2015, with a total of 95 sampling sites. REDILA-BL traps were set for three consecutive nights, and a total of 68 meso-and microscale environmental and landscape characteristics were surveyed. The association between vector abundance with different variables was evaluated using a generalized linear model with zero-inflated negative binomial distribution. We analyzed females for detection of Leishmania DNA. Results: The analysis for Lu. longipalpis indicates an excess of absences when the mean NDWI around the sites were higher. The abundance of Lu. longipalpis at mesoscale level was higher when more urban services were present, and when blood sources such as chickens or dogs at the microscale level were present. For Ny. whitmani, no variable was found to be associated with the absences, while its abundance increased in association with the following variables: percentage of tree cover, presence of garbage collection service, hosted people and, at microscale, the presence of poultry. Leshmania infantum DNA was detected in 2/49 (4%) Lu. longipalpis. Conclusions: The abundance of both species is influenced by variables at different scales, their influence probably has a hierarchy and they are acting on different aspects of the biology of these vectors. The urban spatial segregation of Lu. longipalpis and the peri-urban and rural segregation of N. whitmani increase the risk of VL and CL. The selection of the better variables for each scale will allow the design of appropriate control strategies depending on species.Fil: Quintana, María Gabriela. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Instituto Superior de Entomología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Santini, Maria Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Centro Nacional de Diagnóstico e Investigaciones Endemo-epidémicas; ArgentinaFil: Cavia, Regino. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Martínez, Mariela Florencia. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Liotta, Domingo Javier. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; Argentina. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Laboratorio de Biología Molecular Aplicada; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; ArgentinaFil: Fernández, María Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Pérez, Adriana Alicia. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; ArgentinaFil: Direni Mancini, José Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Instituto Superior de Entomología; ArgentinaFil: Moya, Sofía Lorián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; ArgentinaFil: Giuliani, Magalí Gabriela. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; ArgentinaFil: Salomón, Oscar Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Instituto Nacional de Medicina Tropical; Argentin

Attention deficit/hyperactivity disorde: Study habits

El trastorno por déficit de atención/hiperactividad (TDAH) es uno de los trastornos más prevalentes en la población infanto-juvenil, con un impacto ya conocido sobre el aprendizaje y rendimiento escolar. La falta de atención, la disfunción ejecutiva asociada y los problemas comórbidos –particularmente los relacionados con el aprendizaje y la ansiedad–, condicionan marcadamente este dominio conceptual. Los jóvenes afectos, tienen más problemas para la toma de apuntes, finalización de trabajos, programación escolar y menor motivación al estudio. A pesar de una mayor dedicación al estudio y mayor uso de recursos de apoyo, el fracaso escolar y la no consecución de objetivos curriculares son más frecuentes en estos pacientes. El diagnóstico temprano del TDAH y sus comorbilidades, la intervención psicoeducativa y farmacológica adecuada e individualizada, han demostrado mejorar el pronóstico académico a corto y largo plazo. Para este propósito, es imprescindible la participación activa de profesionales de la salud y la educaciónAttention deficit / hyperactivity disorder (ADHD) is one of the most prevalent disorders in the child-youth population, with a known impact on learning and school performance. Lack of attention, associated executive dysfunction and comorbid problems –particularly those related to learning and anxiety–, strongly determine this conceptual domain. Affected youths have more problems for taking notes, completion of homework, school programming and less motivation to study. Despite greater dedication to homework and greater use of support resources, school failure and nonachievement of curricular objectives are more frequent in these patients. The early diagnosis of ADHD and its comorbidities, the adequate and individualized psychoeducational and pharmacological intervention, have been shown to improve academic prognosis in the short and long term. For this purpose, the active participation of health and education professionals is essential.Este estudio fue financiado por el Ministerio de Economía, Industria y Competitividad (proyecto PSI2017-84922-R

Referred pain from myofascial trigger points in head and neck–shoulder muscles reproduces head pain features in children with chronic tension type headache

Our aim was to describe the referred pain pattern and areas from trigger points (TrPs) in head, neck, and shoulder muscles in children with chronic tension type headache (CTTH). Fifty children (14 boys, 36 girls, mean age: 8 ± 2) with CTTH and 50 age- and sex- matched children participated. Bilateral temporalis, masseter, superior oblique, upper trapezius, sternocleidomastoid, suboccipital, and levator scapula muscles were examined for TrPs by an assessor blinded to the children’s condition. TrPs were identified with palpation and considered active when local and referred pains reproduce headache pain attacks. The referred pain areas were drawn on anatomical maps, digitalized, and also measured. The total number of TrPs was significantly greater in children with CTTH as compared to healthy children (P < 0.001). Active TrPs were only present in children with CTTH (P < 0.001). Within children with CTTH, a significant positive association between the number of active TrPs and headache duration (rs = 0.315; P = 0.026) was observed: the greater the number of active TrPs, the longer the duration of headache attack. Significant differences in referred pain areas between groups (P < 0.001) and muscles (P < 0.001) were found: the referred pain areas were larger in CTTH children (P < 0.001), and the referred pain area elicited by suboccipital TrPs was larger than the referred pain from the remaining TrPs (P < 0.001). Significant positive correlations between some headache clinical parameters and the size of the referred pain area were found. Our results showed that the local and referred pains elicited from active TrPs in head, neck and shoulder shared similar pain pattern as spontaneous CTTH in children, supporting a relevant role of active TrPs in CTTH in children

Healthy lifestyle, metabolomics and incident type 2 diabetes in a population-based cohort from Spain

Background: The contribution of metabolomic factors to the association of healthy lifestyle with type 2 diabetes risk is unknown. We assessed the association of a composite measure of lifestyle with plasma metabolite profiles and incident type 2 diabetes, and whether relevant metabolites can explain the prospective association between healthy lifestyle and incident type 2 diabetes. Methods: A Healthy Lifestyle Score (HLS) (5-point scale including diet, physical activity, smoking status, alcohol consumption and BMI) was estimated in 1016 Hortega Study participants, who had targeted plasma metabolomic determinations at baseline examination in 2001-2003, and were followed-up to 2015 to ascertain incident type 2 diabetes. Results: The HLS was cross-sectionally associated with 32 (out of 49) plasma metabolites (2.5% false discovery rate). In the subset of 830 participants without prevalent type 2 diabetes, the rate ratio (RR) and rate difference (RD) of incident type 2 diabetes (n cases = 51) per one-point increase in HLS was, respectively, 0.69 (95% CI, 0.51, 0.93), and - 8.23 (95% CI, - 16.34, - 0.13)/10,000 person-years. In single-metabolite models, most of the HLS-related metabolites were prospectively associated with incident type 2 diabetes. In probit Bayesian Kernel Machine Regression, these prospective associations were mostly driven by medium HDL particle concentration and phenylpropionate, followed by small LDL particle concentration, which jointly accounted for ~ 50% of the HLS-related decrease in incident type 2 diabetes. Conclusions: The HLS showed a strong inverse association with incident type 2 diabetes, which was largely explained by plasma metabolites measured years before the clinical diagnosis.This work was supported by the Strategic Action for Research in Health sciences [PI10/0082, PI13/01848, PI14/00874, PI16/01402, PI11/00726, PI16/609, PI16/1512, PI18/287, PI19/319 and PI20/00896], the GUTMOM Project (JPI-A Healthy Diet for a Healthy Life INTIMIC-085, State Secretary of R + D + I PCIN-2017-117), the Cátedra de Epidemiología y Control del Riesgo Cardiovascular at UAM (#820024), the State Agency for Research (PID2019-108973RB-C21 and C22), the Valencia Government (GRUPOS 03/101; PROMETEO/2009/029 and ACOMP/2013/039), the Castilla-Leon Government (GRS/279/A/08) and European Network of Excellence Ingenious Hypercare (EPSS- 037093) from the European Commission; CIBER Fisiopatología Obesidad y Nutrición (CIBEROBN) (CIBER-02-08-2009, CB06/03 and CB12/03/30016). MSP holds a Ramón y Cajal contract (RYC-2018-025069-I) from the Ministry of Science, Innovation and Universities. MDV holds a “Predoctoral Training in Health Research” contract (FI20/00162) from the Carlos III Health Institute. MGP and ADR received the support of a fellowship from “la Caixa” Foundation (ID 100010434, fellowship codes LCF/BQ/IN18/11660001, and LCF/BQ/DR19/11740016, respectively). PO received the support of a Sara Borrell contract from the Carlos III Health Institute (reference CD16/00255). The Strategic Action for Research in Health Sciences, CIBEROBN are initiatives from Carlos III Health Institute Madrid and co-funded by the European Social Fund “The ESF - investing in your future”. The State Agency for Research and Carlos III Health Institute belong to the Spanish Ministry of Science and Innovation. The funding bodies had no role in the study design, data collection and analysis, interpretation of results, manuscript preparation or in the decision to submit this manuscript for publication.S

Healthcare experience among patients with type 2 diabetes: A cross-sectional survey using the IEXPAC tool

[Abstract] Aim: To assess the experience with health care among patients with type 2 diabetes (T2DM) and to evaluate patients' demographic variables and healthcare-related characteristics which may affect their experience. Methods: A cross-sectional survey was delivered to T2DM adults. Patient experiences were assessed with the 'Instrument for Evaluation of the Experience of Chronic Patients' (IEXPAC) questionnaire, a validated 12-item survey, which describes patient experience within the last 6 months (items 1-11) and hospitalization in the last 3 years (item 12), with possible scores ranging from 0 (worst) to 10 (best experience). Results: A total of 451 T2DM patients responded to the survey (response rate 72.3%; mean age 69.5 ± 10.1 years, 67.8% men). The mean overall IEXPAC score was 5.92 ± 1.80. Mean scores were higher for productive interactions (7.92 ± 2.15) and self-management (7.08 ± 2.27) than for new relational model (1.72 ± 2.01). Only 32.8% of patients who had been hospitalized in the past 3 years reported having received a follow-up call or visit after discharge. Multivariate analyses identified that regular follow-up by the same physician and follow-up by a nurse were associated with a better patient experience. Continuity of healthcare score was higher only in those patients requiring help from others. Conclusions: The areas of T2DM care which may need to be addressed to ensure better patient experience are use of the Internet, new technologies and social resources for patient information and interaction with healthcare professionals, closer follow-up after hospitalization, and a comprehensive multidisciplinary approach with regular follow-up by the same physician and a nurse