Nous conceptes sobre la diabetis autoimmunitària

La diabetis mellitus de tipus 1 (DT1) és una malaltia metabòlica provocada per la destrucció de les cèl·lules productores d'insulina, les cèl·lules β dels illots pancreàtics. De base autoimmunitària, no es coneix l'etiologia d'aquesta malaltia, tot i que s'han identificat factors genètics, ambientals i immunitaris de susceptibilitat. En aquest article fem un repàs dels mecanismes d'autoimmunitat i els nous conceptes en aquest camp. També destaquem els models experimentals utilitzats en l'estudi de la DT1 i les noves teràpies desenvolupades amb aquests. Per acabar, fem una ullada al present i al futur de la immunoteràpia preventiva i de tractament en aquesta malaltia, i insistim en la necessitat d'aturar el procés autoimmunitari, restaurar la tolerància immunitària, identificar nous biomarcadors de progressió i aplicar conjuntament estratègies de regeneració i neogènesi de les cèl·lules β.Type 1 diabetes (DT1) is a metabolic disease caused by the selective destruction of the insulin producing β cells by the immune system. The etiology of the disease is still unknown, but several genetic, environmental and immunological factors of susceptibility have been identified. In this chapter we describe the autoimmune mechanisms involved in this disease, as well as the experimental models used for the study of DT1 and for the development of new strategies of immune intervention. Lastly, we explain the recent assays in immunotherapies aimed at preventing and curing the disease, based on breaking autoimmune response, restoring immunological tolerance and identifying new biomarkers of disease progression, as well as strategies for regenerating β cells

Enantioselective Crystallization of Sodium Chlorate in the Presence of Racemic Hydrophobic Amino Acids and Static Magnetic Fields

We study the bias induced by a weak (200 mT) external magnetic field on the preferred handedness of sodium chlorate crystals obtained by slow evaporation at ambient conditions of its saturated saline solution with 20 ppm of added racemic (dl) hydrophobic amino acids. By applying the Fisher test to pairs of experiments with opposing magnetic field orientation we conclude, with a confidence level of 99.7%, that at the water-air interface of this saline solution there is an enantioselective magnetic interaction that acts upon racemic mixtures of hydrophobic chiral amino acids. This interaction has been observed with the three tested racemic hydrophobic amino acids: dl-Phe, dl-Try and dl-Trp, at ambient conditions and in spite of the ubiquitous chiral organic contamination. This enantioselective magnetic dependence is not observed when there is only one handedness of added chiral amino-acid, if the added amino acid is not chiral or if there is no additive. This effect has been confirmed with a double blind test. This novel experimental observation may have implications for our view of plausible initial prebiotic scenarios and of the roles of the geomagnetic field in homochirality in the biosphere.This research was supported by the Instituto Nacional de Técnica Aerospacial (INTA) and by the grant AYA2006-15648-C02-02 of the Ministerio de Educación y Ciencia (Spain) and by the project grants AYA2011-25720 and AYA2012-38707 of MINECO (Spain).We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Human metastatic cholangiocarcinoma patient-derived xenografts and tumoroids for preclinical drug evaluation

Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30\\%–50\\% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA.We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA\_PDX). The CCA\_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA\_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA\_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues.This collection of CCA\_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA\_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA\_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD.Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA\_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.The authors would like to thank the patients and their families for their support. This work was supported by grants from the Fundaci o Marat o TV3 awarded to T. Macarulla, M. Mel e, and S. Peir o; BeiGene research grant awarded toT. Macarulla and S. Peir o; AECC (INVES20036TIAN), Ram on y Cajal investigator program (RYC2020-029098-I), Proyecto de IþDþi (PID2019-108008RJ-I00), and FERO Foundation grant awarded to T.V. Tian; Proyecto de Investigaci on en Salud from the Instituto de Salud Carlos III (ISCIII) (PI20/00898) awarded to T. Macarulla; FIS/FEDER from the Instituto de Salud Carlos III (ISCIII) (PI12/01250; CP08/00223; PI16/00253 and CB16/12/00449) awarded to S. Peir o; and Ram on y Cajal investigator program (RYC-2017-22249) awarded to M. Mel e. Q. Serra-Camprubí is a recipient of the Ph.D. fellowship from La Caixa Foundation (LCF/PR/PR12/51070001). A. LlopGuevara was supported by the AECC (INVES20095LLOP) and V. Serra by the ISCIII (CPII19/00033). E.J. Arenas was funded by the AECC (POSTD211413AREN).J. Arribas is funded by the Instituto de Salud Carlos III (AC15/00062, CB16/12/00449, and PI22/00001). This publication is based upon the work of COST Action CA18122, European Cholangiocarcinoma Network, supported by the COST (European Cooperation in Science and Technology, www.cost.eu), a funding agency for research and innovation networks. The authors would like to thank Dr. V.A. Raker for manuscript editing and Drs. N. Herranz and J. Mateo for scientific discussions. The authors acknowledge the infrastructure and support of the FERO Foundation, La Caixa Foundation, and the Cellex Foundation.Peer Reviewed"Article signat per 31 autors/es: Queralt Serra-Camprubí; Helena Verdaguer; Winona Oliveros; Núria Lupión-Garcia; Núria Lupión-Garcia;Alba Llop-Guevara; Cristina Molina; Maria Vila-Casadesús; Anthony Turpin; Cindy Neuzillet; Joan Frigola; Jessica Querol; Mariana Yáñez-Bartolomé; Florian Castet; Carles Fabregat-Franco; Carmen Escudero-Iriarte; Marta Escorihuela; Enrique J. Arenas; Cristina Bernadó-Morales; Noemí Haro; Francis J. Giles; Óscar J. Pozo; Josep M. Miquel ; Paolo G. Nuciforo; Ana Vivancos; Marta Melé; Violeta Serra ; Joaquín Arribas; Josep Tabernero; Sandra Peiró; Teresa Macarulla; Tian V. Tian"Postprint (published version

Comparison of optimisation algorithms for centralised anaerobic co-digestion in a real river basin case study in Catalonia

Anaerobic digestion (AnD) is a process that allows the conversion of organic waste into a source of energy such as biogas, introducing sustainability and circular economy in waste treatment. AnD is an intricate process because of multiple parameters involved, and its complexity increases when the wastes are from different types of generators. In this case, a key point to achieve good performance is optimisation methods. Currently, many tools have been developed to optimise a single AnD plant. However, the study of a network of AnD plants and multiple waste generators, all in different locations, remains unexplored. This novel approach requires the use of optimisation methodologies with the capacity to deal with a highly complex combinatorial problem. This paper proposes and compares the use of three evolutionary algorithms: ant colony optimisation (ACO), genetic algorithm (GA) and particle swarm optimisation (PSO), which are especially suited for this type of application. The algorithms successfully solve the problem, using an objective function that includes terms related to quality and logistics. Their application to a real case study in Catalonia (Spain) shows their usefulness (ACO and GA to achieve maximum biogas production and PSO for safer operation conditions) for AnD facilities.Peer ReviewedPostprint (published version

The digital revolution in the urban water cycle and its ethical–political implications: a critical perspective

The development and application of new forms of automation and monitoring, data mining, and the use of AI data sources and knowledge management tools in the water sector has been compared to a ‘digital revolution’. The state-of-the-art literature has analysed this transformation from predominantly technical and positive perspectives, emphasising the benefits of digitalisation in the water sector. Meanwhile, there is a conspicuous lack of critical literature on this topic. To bridge this gap, the paper advances a critical overview of the state-of-the art scholarship on water digitalisation, looking at the sociopolitical and ethical concerns these technologies generate. We did this by analysing relevant AI applications at each of the three levels of the UWC: technical, operational, and sociopolitical. By drawing on the precepts of urban political ecology, we propose a hydrosocial approach to the so-called ‘digital water ‘, which aims to overcome the one-sidedness of the technocratic and/or positive approaches to this issue. Thus, the contribution of this article is a new theoretical framework which can be operationalised in order to analyse the ethical–political implications of the deployment of AI in urban water management. From the overview of opportunities and concerns presented in this paper, it emerges that a hydrosocial approach to digital water management is timely and necessary. The proposed framework envisions AI as a force in the service of the human right to water, the implementation of which needs to be (1) critical, in that it takes into consideration gender, race, class, and other sources of discrimination and orients algorithms according to key principles and values; (2) democratic and participatory, i.e., it combines a concern for efficiency with sensitivity to issues of fairness or justice; and (3) interdisciplinary, meaning that it integrates social sciences and natural sciences from the outset in all applications.Peer ReviewedPostprint (published version

Multidimensional research on university engagement using a mixed method approach

El compromiso o la implicación académica (engagement en inglés) delos estudiantes universitarios se ha convertido en un elemento fundamental desu bienestar y de su rendimiento académico y, además, está muy relacionadotambién con su futuro profesional y compromiso social. Es por esta razón quela definición de dicho concepto y la disposición de instrumentos de evaluacióny estrategias de análisis son imprescindibles para conocer las experiencias deaprendizaje que conducen a mejorar la implicación académica del estudiante.Para el desarrollo de esta investigación hemos utilizado una metodología mixtacuantitativa y cualitativa: análisis factorial exploratorio y confirmatorio, porun lado, y grupos de discusión mediante la técnica de los grupos nominales,por otro. Los objetivos que nos hemos planteado son tres: primero, ahondaren el modelo multidimensional del constructo engagement; segundo, validar uncuestionario que permita evaluar la percepción que tienen los estudiantes delas metodologías de aprendizaje que se utilizan en el aula, y tercero, comprobarla manejabilidad de los grupos nominales como método cualitativo de análisis.Los resultados demuestran que nuestra nueva propuesta ofrece un instrumentoestadísticamente válido para determinar las percepciones del propio engagementy un método cualitativo de utilización eficaz, eficiente y motivador para losestudiantes. Sin embargo, respecto a la multidimensionalidad del constructo, ycontrariamente al punto de vista teórico más aceptado que considera la existencia de tres dimensiones del engagement (comportamiento, cognición y emoción), nuestros resultados solamente revelan dos dimensiones (cognitivo-emocional y comportamental). En la discusión y comentarios damos posibles explicaciones a dicha contradicción.The commitment or academic implication (engagement) of universitystudents has become a fundamental element for their welfare and academicperformance and, furthermore, it is also related to their professional futureand social commitment. For this reason, the definition of the concept and theprovision of assessment strategies and tools are essential to know the learningexperiences that lead to enhancing the academic involvement of the students.To develop our research, we have used a mixed quantitative and qualitativemethodology: exploratory and confirmatory factor analysis on the one hand,and discussion groups using the nominal groups technique on the other hand.We have set three different objectives: first, to delve into the multidimensionalmodel of the construct; second, to validate a questionnaire that allows forevaluation of the students’ perception of the learning methodologies used inthe classroom; and third, to check the manageability of the nominal groupsas a qualitative method of analysis. The results demonstrate that our newproposal provides a statistically valid instrument aimed at determining theperceptions of own engagement and an effective, efficient and motivatingqualitative method for students. However, regarding the multidimensionalityof the construct, contrary to the more accepted theoretical point of view thatconsiders three dimensions of engagement (behaviour, cognition and emotion),our results only reveal two dimensions (cognitive-emotional and behavioural).In the discussion and comments section we give possible explanations for thiscontradiction

Characterization of native vine varieties in Barcelona and Girona as a base for organic wine production

PòsterHow they have formed native vine varieties? From Vitis vinifera wild plants have been domesticated in one place. For the improvement process and selection or hybridization. By introducing oldest cultivated plants elsewhere outside Catalonia, which over time may have originated different shapes in the new places. In this case we give the traditional name

Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors

Gastrointestinal neoplasms; Oncolytic virotherapy; Tumor microenvironmentNeoplasias gastrointestinales; Viroterapia oncolítica; Microambiente tumoralNeoplàsies gastrointestinals; Viroteràpia oncolítica; Microambient tumoralBackground VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer. Methods Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed. Results 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×1013 viral particles (vp)/patient (Part I), and 3.3×1012 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×1013 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×1013 vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×1013 vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration. Conclusions Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.MB-P, EB, and MC were funded by CDTI (PANCATHER project IDI-20130759). The clinical study was supported by VCN Biosciences

Heterogeneity in Response to MCT and Psychoeducation: A Feasibility Study Using Latent Class Mixed Models in First-Episode Psychosis

Primer episodi de psicosi; Cognició social; PsicoeducacióFirst episode psychosis; Social cognition; PsychoeducationPrimer episodio de psicosis; Cognición social; PsicoeducaciónMetacognitive training (MCT) is an effective treatment for psychosis. Longitudinal trajectories of treatment response are unknown but could point to strategies to maximize treatment efficacy during the first episodes. This work aims to explore the possible benefit of using latent class mixed models (LCMMs) to understand how treatment response differs between metacognitive training and psychoeducation. We conducted LCMMs in 28 patients that received MCT and 34 patients that received psychoeducation. We found that MCT is effective in improving cognitive insight in all patients but that these effects wane at follow-up. In contrast, psychoeducation does not improve cognitive insight, and may increase self-certainty in a group of patients. These results suggest that LCMMs are valuable tools that can aid in treatment prescription and in predicting response to specific treatmentsThis study was funded by the Instituto de Salud Carlos III, Spanish Government, (PI11/01347, PI14/00044 and PI18/00212); the Fondo Europeo de Desarrollo Regional (FEDER), Health Department of Catalonia, PERIS call (SLT006/17/00231); Progress and Health Foundation of the Andalusian Regional Ministry of Health (PI-0634/2011 and PI-0193/2014); Obra Social La Caixa (RecerCaixa call 2013), Obra Social Sant Joan de Déu, BML (RTI2018-100927-J-I00) administrated by Ministerio de Ciencia e Innovación (MCI, Spain), by the Agencia Estatal de Investigación (AEI, Spain), and by the European Regional Development Fund (FEDER, UE); Daniel Fernández has been supported by grant 2017 SGR 622 (GRBIO) administrated by the Departament d’Economia i Coneixement de la Generalitat de Catalunya (Spain) and by the Ministerio de Ciencia e Innovación (Spain) [PID2019-104830RB-I00/ DOI (AEI): 10.13039/501100011033]; and CIBER, Consorcio Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación

B-Lymphocyte Phenotype Determines T-Lymphocyte Subset Differentiation in Autoimmune Diabetes.

Previous studies indicate that B-lymphocytes play a key role activating diabetogenic T-lymphocytes during the development of autoimmune diabetes. Recently, two transgenic NOD mouse models were generated: the NOD-PerIg and the 116C-NOD mice. In NOD-PerIg mice, B-lymphocytes acquire an activated proliferative phenotype and support accelerated autoimmune diabetes development. In contrast, in 116C-NOD mice, B-lymphocytes display an anergic-like phenotype delaying autoimmune diabetes onset and decreasing disease incidence. The present study further evaluates the T- and B-lymphocyte phenotype in both models. In islet-infiltrating B-lymphocytes (IIBLs) from 116C-NOD mice, the expression of H2-Kd and H2-Ag7 is decreased, whereas that of BAFF, BAFF-R, and TACI is increased. In contrast, IIBLs from NOD-PerIg show an increase in CD86 and FAS expression. In addition, islet-infiltrating T-lymphocytes (IITLs) from NOD-PerIg mice exhibit an increase in PD-1 expression. Moreover, proliferation assays indicate a high capacity of B-lymphocytes from NOD-PerIg mice to secrete high amounts of cytokines and induce T-lymphocyte activation compared to 116C B-lymphocytes. This functional variability between 116C and PerIg B-lymphocytes ultimately results in differences in the ability to shape T-lymphocyte phenotype. These results support the role of B-lymphocytes as key regulators of T-lymphocytes in autoimmune diabetes and provide essential information on the phenotypic characteristics of the T- and B-lymphocytes involved in the autoimmune response in autoimmune diabetes