Targeting microglial CSF1R in health and disease

The main effector functions of microglia are immune, synaptic network refinement, brain insult reaction, and neurogenesis regulation. This cumulative doctoral thesis focuses on the relevance of the colony-stimulating factor 1 receptor (CSF1R) signaling pathway of microglia in the context of the last two topics, specifically in [A] low-grade white matter inflammation and [B] hypoxia-induced neurogenesis. Ad [A]: Our group previously detected that myelin structural protein cyclic nucleotide phosphodiesterase (CNP) deletion triggers low-grade white matter inflammation and causes a behavioral phenotype named catatonia. Treatment with the CSF1R inhibitor PLX5622 of Cnp-/- mice leads to a strong reduction of neuroinflammation, i.e. microglial numbers and activation status, as well as a clear improvement of the catatonic signs. In my first paper, I systematically addressed aspects which are important for clinical translation. Amongst others, I found that microglia surviving PLX5622-induced depletion display a pro-inflammatory phenotype including targeted phagocytosis of oligodendrocyte precursor cells, and that two PLX5622 treatment cycles are not superior to one. These results may be helpful for guiding future use of CSF1R inhibitors in (pre)clinical studies. Ad [B]: As work of our group has shown, exposure of mice to hypoxia, whether inspiratory or functional by motor-cognitive challenge, triggers the expression of brain erythropoietin (EPO). In my second paper, I found that treatment with exogenous EPO leads to not only increased hippocampal cornu ammonis 1 (CA1) pyramidal neuron numbers and dendritic spine densities, but most importantly it simultaneously decreases microglia proliferation, activity, and motility. Searching for mechanisms, I discovered a direct effect of EPO on microglia that acted in two phases: first EPO triggered immediate microglia apoptosis for just a limited time, leading to decreased microglia numbers. Subsequently, the reduction of the microglia population was maintained by decreased microglia proliferation. This was likely due to an EPO-induced decrease in the expression of interleukin 34, a neuronally expressed ligand of CSF1R. EPO also led to decreased microglia-neuron contacts and microglial metabolism in the CA1. Furthermore, this was paralleled by an increase in intermediate neuronal progenitors, which became mature by the end of a 3-week EPO treatment. Importantly, these effects are dependent on EPO receptor expression in microglia and neurons.2021-09-0

Make it personal: a social explanation system applied to group recommendations

Recommender systems help users to identify which items from a variety of choices best match their needs and preferences. In this context, explanations act as complementary information that can help users to better comprehend the system’s output and to encourage goals such as trust, confidence in decision-making or utility. In this paper we propose a Personalized Social Individual Explanation approach (PSIE). Unlike other expert systems the PSIE proposal novelly includes explanations about the system’s group recommendation and explanations about the group’s social reality with the goal of inducing a positive reaction that leads to a better perception of the received group recommendations. Among other challenges, we uncover a special need to focus on “tactful” explanations when addressing users’ personal relationships within a group and to focus on personalized reassuring explanations that encourage users to accept the presented recommendations. Besides, the resulting intelligent system significatively increases users’ intent (likelihood) to follow the recommendations, users’ satisfaction and the system’s efficiency and trustworthiness

The current and future role of visual question answering in eXplainable artificial intelligence.

Over the last few years, we have seen how the interest of the computer science research community on eXplainable Artificial Intelligence has grown in leaps and bounds. The reason behind this rise is the use of Artificial Intelligence in many daily life tasks, and the consequent necessity of people to understand the intelligent systems' behaviour. Computer vision-related tasks are not an exception, for example, Visual Question Answering tasks. The Artificial Intelligence models that carry out this specific task make an effort to answer questions about what we can watch in a particular image. In this work, we review the existing work about eXplainable Artificial Intelligence on Visual Question Answering which is a problem on which there is still much work to be done. Moreover, we open the discussion about the challenges to overcome regarding this topic, like the future role of Visual Question Answering to address eXplainable Artificial Intelligence issues or difficulties

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance

Executive functions, learning, attention, and processing speed are imperative facets of cognitive performance, affected in neuropsychiatric disorders. In clinical studies on different patient groups, recombinant human (rh) erythropoietin (EPO) lastingly improved higher cognition and reduced brain matter loss. Correspondingly, rhEPO treatment of young rodents or EPO receptor (EPOR) overexpression in pyramidal neurons caused remarkable and enduring cognitive improvement, together with enhanced hippocampal long-term potentiation. The ‘brain hardware upgrade’, underlying these observations, includes an EPO induced ~20% increase in pyramidal neurons and oligodendrocytes in cornu ammonis hippocampi in the absence of elevated DNA synthesis. In parallel, EPO reduces microglia numbers and dampens their activity and metabolism as prerequisites for undisturbed EPO-driven differentiation of pre-existing local neuronal precursors. These processes depend on neuronal and microglial EPOR. This novel mechanism of powerful postnatal neurogenesis, outside the classical neurogenic niches, and on-demand delivery of new cells, paralleled by dendritic spine increase, let us hypothesize a physiological procognitive role of hypoxia-induced endogenous EPO in brain, which we imitate by rhEPO treatment. Here we delineate the brain EPO circle as working model explaining adaptive ‘brain hardware upgrade’ and improved performance. In this fundamental regulatory circle, neuronal networks, challenged by motorcognitive tasks, drift into transient ‘functional hypoxia’, thereby triggering neuronal EPO/EPOR expression

Efficacy and safety of direct-acting antiviral agents for HCV in mild-to-moderate chronic kidney disease

Background and aims: The advent of direct-acting antiviral agents promises to change the management of hepatitis C virus infection (HCV) in patients with chronic kidney disease (CKD), a patient group in which the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' cohort of patients with CKD. Methods: We performed an observational single-arm multi-centre study in a large (n = 198) cohort of patients with stage 1–3 CKD who underwent antiviral therapy with DAAs for the treatment of HCV. The primary end-point was sustained virologic response (serum HCV RNA <15 IU/mL, 12 weeks after treatment ended) (SVR12). We collected data on on-treatment adverse events (AEs), severe AEs, and laboratory abnormalities. Results: The average baseline eGFR (CKD-EPI equation) was 70.06 ± 20.1 mL/min/1.72 m2; the most common genotype was HCV 1b (n = 93, 51%). Advanced liver scarring was found in 58 (46%) patients by transient elastography. Five regimens were adopted: elbasvir/grazoprevir (n = 5), glecaprevir/pibrentasvir (n = 4), ritonavir-boosted paritaprevir/ombitasvir/dasabuvir (PrOD) regimen (n = 40), simeprevir ± daclatasvir (n = 2), and sofosbuvir-based combinations (n = 147). The SVR12 rate was 95.4% (95% CI, 93.8%; 96.8%). There were nine virological failures – eight being relapsers. Adverse events occurred in 30% (51/168) of patients, and were managed clinically without discontinuation of therapy or hospitalization. One of the most common AEs was anaemia (n = 12), which required discontinuation or dose reduction of ribavirin in some cases (n = 6); deterioration of kidney function occurred in three (1.7%). Conclusions: All-oral, interferon-free therapy with DAAs for chronic HCV in mild-to-moderate CKD was effective and well-tolerated in a 'real–world' clinical setting. Studies are in progress to address whether sustained viral response translates into better survival in this population. Resumen: Antecedentes y objetivos: La aparición de los antivíricos de acción directa (AAD) promete cambiar el tratamiento de la infección por el virus de la hepatitis C (VHC) en los pacientes con nefropatía crónica (NC), un grupo de pacientes en el que el tratamiento de la hepatitis C siempre supuso una dificultad. Se investiga la seguridad y la eficacia de los antivíricos de acción directa, sin interferones orales, en todos los casos para el tratamiento de la hepatitis C en una cohorte en condiciones reales de pacientes con NC. Métodos: Se llevó a cabo un estudio multicéntrico, de un solo grupo y observacional en una cohorte amplia (n = 198) de pacientes con NC en estadio 1-3 a los que se administró tratamiento antivírico con AAD para el VHC. El criterio principal de valoración fue la respuesta virológica sostenida (ARN sérico del VHC < 15 UI/ml, 12 semanas después de la finalización del tratamiento) (RVS12). Se recogieron los datos sobre acontecimientos adversos (AA) surgidos durante el tratamiento, AA graves y anomalías analíticas. Resultados: La FGe inicial media (ecuación de CKD-EPI) fue de 70,06 ± 20,1 ml/min/1,72 m2; el genotipo más frecuente fue VHC 1b (n = 93; 51%). Se observó cicatrización hepática avanzada en 58 (46%) pacientes mediante elastografía transitoria. Se adoptaron 5 pautas: elbasvir/grazoprevir (n = 5), glecaprevir/pibrentasvir (n = 4), pauta de paritaprevir/ombitasvir/dasabuvir (PrOD) potenciada con ritonavir (n = 40), simeprevir ± daclatasvir (n = 2) y combinaciones basadas en sofosbuvir (n = 147). La tasa de RVS12 fue del 95,4% (IC del 95%: 93,8; 96,8%). Hubo 9 fracasos virológicos, 8 de ellos recidivantes. Se produjeron acontecimientos adversos en el 30% (51/168) de los pacientes, que se trataron clínicamente sin suspensión del tratamiento ni hospitalización. Uno de los AA más frecuentes fue la anemia (n = 12), que precisó la suspensión o la reducción de la dosis de ribavirina en algunos casos (n = 6); se produjo deterioro de la función renal en 3 casos (1,7%). Conclusiones: El tratamiento sin interferón oral en todos los casos con AAD para el VHC crónico en la NC de leve a moderada fue eficaz y bien tolerado en un contexto de la práctica clínica real. Hay estudios en curso para abordar si la respuesta viral sostenida se traduce en una mejor supervivencia en esta población. Keywords: Adverse effects, Antiviral agents, Hepatitis C, Kidney failure, Sustained virologic response, Palabras clave: Efectos adversos, Antivíricos, Hepatitis C, Insuficiencia renal, Respuesta virológica sostenid

¿Cómo enseñar la Web Semántica?

Los objetivos, tecnologías y problemas relacionados con la Web Semántica están claramente establecidos a nivel de investigación. Sin embargo, la gran envergadura del proyecto hace difícil su divulgación a nivel docente. Los profesores universitarios encuentran muchas dificultades a la hora de explicar las materias relacionadas con la Web Semántica. Existe un acuerdo en que la enseñanza de estos contenidos debe tener una fuerte componente práctica y de experimentación. Sin embargo, aunque cada tema puede ser explicado de forma independiente, existe una dificultad inherente a la elaboración de trabajos autocontenidos, pero relacionados entre sí, con los que poner en práctica todos los conceptos y comprender sus dificultades y dependencias. En este artículo se presenta la experiencia con una práctica en el dominio del marcado y recuperación de imágenes.Este trabajo ha sido parcialmente financiado por la Dirección General de Universidades e Investigación de la Consejería de Educación de la Comunidad de Madrid y por la Universidad Complutense de Madrid (Grupo de investigación consolidado 910494), y por el Ministerio de Ciencia y Tecnología (TIN2006-15140-C03-02 y TIN2006-15202-C03-03)

Building case-based reasoning applications with myCBR and COLIBRI Studio

myCBR and COLIBRI Studio are two well-established opensource frameworks for building case-based reasoning (CBR) applications, though they follow different approaches and support different phases of the CBR application development. In a nutshell: Where myCBR supports its users in developing a knowledge model for representing cases, it more or less leaves the software developers alone when they try to develop an application that uses the generated knowledge model. COLIBRI Studio, on the other hand, is focused in the development of applications that use that knowledge model. As soon as you have a knowledge model COLIBRI Studio offers templates for a variety of application types and supports in generating its source code. This paper explains the strengths and weaknesses of both frameworks regarding the rapid development of CBR applications. It also shows how to use both of them in conjunction

Maritime Spatial Planning INSPIRE data model

Poster para CongresoThe Maritime Spatial Planning (MSP) INSPIRE data model concept has been developing from 2014, applying Infrastructure for spatial information in Europe Directive 2007/2/EC (INSPIRE) data management concepts for marine planning, through the Marine Pilot project (EC Joint Research Centre 2014-2016) and continuing with the PLASMAR project (INTERREG–V 2017-2020). The results and findings delivered have been published in the paper “Maritime spatial planning supported by infrastructure for spatial information in Europe (INSPIRE)” (Abramic et al., 2018). Currently, there are difficulties in harmonising products, visions, maps and frameworks of maritime spatial plans delivered by countries sharing the same marine (sub)region. This is mainly due to the fact that maritime plans do not use a common symbology and data structure to describe maritime activities. A solution for this issue is to apply on a marine spatial plans, INSPIRE standards for data sets, layers and portrayals. The MarSP project was a perfect opportunity to finalise conceptual data model development and, what is more important, to test results applying it on the real use cases, developed in the Macaronesia (Azores, Madeira, Canaries) MSP process. Initially, the INSPIRE data model for terrestrial planning (Planned Land Use, Figure 1) was tested to see if it could be applied for MSP. Tests pointed out that the terrestrial data model is robust, and can map MSP’s, but it tends to lose detail and specific information on marine uses. To be applied for MSP, the Planned Land Use data model needs to be adapted for planning of the maritime activities in the marine space. Conceptual model was analyzed, adapted, applying data modeling techniques, adjusting for MSP requirements: 1. Developed conceptual MSP data model, extending Planned Land use, using Unified Model Language (Figure 2); 2. Extending spatial scope of the data model - from two-dimensional land planning to the three dimensions planning. Extended structure includes maritime activities within the sea surface, water column, seabed and subsoil, when land model consists mainly of land surface planning; 3. Developed specific maritime uses classification (including register), extending Hierarchical INSPIRE Land Use classification (HILUCS); 4. Developed MSP data model templates, using simplified and feature complex spatial data architectures. Different type of codification templates, for advanced, standard and rookie GIS users (gml, GeoPackage, Shapfile, available at Canaries MSP platform); 5. Styled Layer Descriptor (color & simbology layout) for MSP, based on International Hydrographic Organization standards. 6. Data specification document v1.0 for Maritime Spatial Planning INSPIRE data model MarSP 2nd capacity building workshop was a great opportunity to test MSP data model results. Participants were trained on how to apply MSP data model on selected use case (Madeira MSP draft), during the “hands on” session, discussing potential issues and technical solutions.MarS

Disminución de los costes energéticos en la empresa: CDM José Garcés y empresas del Servicio de Apoyo a la Creación de Microempresa de CEOE

Se han estudiado y analizado distintas formas de disminuir los costes energéticos en cuatro empresas del Servicio de Apoyo a la Creación de Microempresas de la Confederación Española de Organizaciones Empresariales (CEOE) y en el CDM José Garcés siguiendo los pasos establecidos por la UNE 216501:2009 para una auditoría energética y la ISO 50001 para gestión de energía. Demostrando que en el cualquier edificio independiente del tamaño o actividad, se pueden reducir los costes energéticos, valorando la situación energética a través de la auditoría energética, determinando el flujo de consumo energético y causas de ineficiencia para finalmente proponer mejoras en el consumo energético. Destacar que una auditoría no se entiende sin un estudio de viabilidad que permita al cliente analizar y decidir la conveniencia de las medidas de ahorro que se proponen

Inherited photoreceptor degeneration causes the death of melanopsin-positive retinal ganglion cells and increases their coexpression of brn3a

Purpose: To study the population of intrinsically photosensitive retinal ganglion cells (melanopsin-expressing RGCs, m+RGCs) in P23H-1 rats, a rat model of inherited photoreceptor degeneration. Methods: At postnatal (P) times P30, P365, and P540, retinas from P23H dystrophic rats (line 1, rapid degeneration; and line 3, slow degeneration) and Sprague Dawley (SD) rats (control) were dissected as whole-mounts and immunodetected for melanopsin and/or Brn3a. The dendritic arborization of m+RGCs and the numbers of Brn3a+RGCs and m+RGCs were quantified and their retinal distribution and coexpression analyzed. Results: In SD rats, aging did not affect the population of Brn3a+RGCs or m+RGCs or the percentage that showed coexpression (0.27%). Young P23H-1 rats had a significantly lower number of Brn3a+RGCs and showed a further decline with age. The population of m+RGCs in young P23H-1 rats was similar to that found in SD rats and decreased by 22.6% and 28.2% at P365 and P540, respectively, similarly to the decrease of the Brn3a+RGCs. At these ages the m+RGCs showed a decrease of their dendritic arborization parameters, which was similar in both the P23H-1 and P23H-3 lines. The percentage of coexpression of Brn3a was, however, already significantly higher at P30 (3.31%) and increased significantly with age (10.65% at P540). Conclusions: Inherited photoreceptor degeneration was followed by secondary loss of Brn3a+RGCs and m+RGCs. Surviving m+RGCs showed decreased dendritic arborization parameters and increased coexpression of Brn3a and melanopsin, phenotypic and molecular changes that may represent an effort to resist degeneration and/or preferential survival of m+RGCs capable of synthesizing Brn3a