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

Investigating a repair workshop: the reuse of washing machines in Barcelona

Altres ajuts: Acord transformatiu CRUE-CSICUnidad de excelencia María de Maeztu CEX2019-000940-MThe reuse and repair of products are often good strategies from a holistic resource conservation perspective. Many organizations active in reuse concentrate in cities where a greater share of wasted electrical and electronic equipment is generated. The number of companies active in the reuse of these products is still limited, and information about the procedures and, more importantly, about the equipment effectively reused is not publicly available yet in many cases. This leads to imprecise knowledge about reuse in these organizations and unreliable data about the progress to a circular economy in cities and regions. The release of new standards on material efficiency represents a big step towards the harmonization of methods and indicators to monitor reuse and repair of products, but its use is challenging for existing workshops. This study examines the reuse of washing machines (WMs) at a local workshop with the objective of understanding the internal procedures for repair and reuse and defining indicators suitable to monitor these activities. The assessment at the company level shows that in 2018, approximately 77% of the WMs collected were recycled, 10% were repaired (80% of these needed multiple parts) and 2% were refurbished. At the product level, the proportion of reused components varies greatly from 4% to 14% when calculated by number on products to 60% when considering number balance. An economic analysis shows that using spare parts from wasted WMs increases the economic benefits up to 3-fold. In conclusion, the indicators proposed are useful to understand the performance of these workshops and potentially useful to quantify reuse at the city and regional scales

CD44 Modulates Cell Migration and Invasion in Ewing Sarcoma Cells

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.This project was funded by Instituto de Salud Carlos III, grant numbers PI20CIII/00020, DTS18CIII/00005, Asociación Pablo Ugarte, grant numbers TRPV205/18; Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant numbers TVP333-19, TVP-1324/15; ASION, grant number TVP141/17. Enrique Fernández-Tabanera is supported by Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, Saint T. Cervera is supported by Asociación Pablo Ugarte and Raquel M. Melero is supported by a CIBERER contract.S

3D numerical simulation of slope-flexible system interaction using a mixed FEM-SPH model

Flexible membranes are light structures anchored to the ground that protect infrastructures or dwellings from rock or soil sliding. One alternative to design these structures is by using numerical simulations. However, very few models were found until date and most of them are in 2D and do not include all their components. This paper presents the development of a numerical model combining Finite Element Modelling (FEM) with Smooth Particle Hydrodynamics (SPH) formulation. Both cylindrical and spherical failure of the slope were simulated. One reference geometry of the slope was designed and a total of 21 slip circles were calculated considering different soil parameters, phreatic level position and drainage solutions. Four case studies were extracted from these scenarios and simulated using different dimensions of the components of the system. As a validation model, an experimental test that imitates the soil detachment and its retention by the steel membrane was successfully reproduced.The FORESEE project has received funding from the EuropeanUnion’s Horizon 2020 research and innovation program undergrant agreement No 769373

Radioisotope production at the IFMIF-DONES facility

This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 and 2019-2020 under grant agreement No 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission. This work was supported by the Spanish projects FIS2015-69941-C2-1-P (MINECO-FEDER, EU), A-FQM-371-UGR18 (Prog. Operativo FEDER Andalucia 2014-2020), the Spanish Association Against Cancer (AECC) (Grant No. PS16163811PORR), and the sponsors of the University of Granada Chair Neutrons for Medicine: Fundacion ACS, Capitan Antonio and La Kuadrilla.The International Fusion Materials Irradiation Facility - Demo Oriented NEutron Source (IFMIF-DONES) is a single-sited novel Research Infrastructure for testing, validation and qualification of the materials to be used in a fusion reactor. Recently, IFMIF-DONES has been declared of interest by ESFRI (European Strategy Forum on Research Infrastructures) and its European host city would be Granada (Spain). In spite the first and most important application of IFMIF-DONES related to fusion technology, the unprecedented neutron flux available could be exploited without modifying the routine operation of IFMIF-DONES. Thus, it is already planned an experimental hall for a complementary program with neutrons. Also, a complementary program on the use of the deuteron beam could help IFMIF-DONES to be more sustainable. In the present work, we study radioisotope production with deuterons of Lu-177. The results show the viability of IFMIF-DONES for such production in terms of the needs of a territory of small-medium size. Also the study suggests that new nuclear data at higher deuteron energies are mandatory for an accurate study in this field.Euratom 633053Spanish project (MINECO-FEDER, EU) FIS2015-69941-C2-1-PSpanish project (Prog. Operativo FEDER Andalucia 2014-2020) A-FQM-371-UGR18Spanish Association Against Cancer (AECC) PS16163811PORRUniversity of Granada Chair Neutrons for Medicine: Fundacion AC

Genetic and functional characterization of disease associations explains comorbidity

Understanding relationships between diseases, such as comorbidities, has important socio-economic implications, ranging from clinical study design to health care planning. Most studies characterize disease comorbidity using shared genetic origins, ignoring pathway-based commonalities between diseases. In this study, we define the disease pathways using an interactome-based extension of known disease-genes and introduce several measures of functional overlap. The analysis reveals 206 significant links among 94 diseases, giving rise to a highly clustered disease association network. We observe that around 95% of the links in the disease network, though not identified by genetic overlap, are discovered by functional overlap. This disease network portraits rheumatoid arthritis, asthma, atherosclerosis, pulmonary diseases and Crohn's disease as hubs and thus pointing to common inflammatory processes underlying disease pathophysiology. We identify several described associations such as the inverse comorbidity relationship between Alzheimer's disease and neoplasms. Furthermore, we investigate the disruptions in protein interactions by mapping mutations onto the domains involved in the interaction, suggesting hypotheses on the causal link between diseases. Finally, we provide several proof-of-principle examples in which we model the effect of the mutation and the change of the association strength, which could explain the observed comorbidity between diseases caused by the same genetic alterations

Multitasking Compensatory Saccadic Training Program for Hemianopia Patients: A New Approach With 3-Dimensional Real-World Objects

Producción CientíficaPurpose: To examinewhether a noncomputerized multitasking compensatory saccadic training program (MCSTP) for patients with hemianopia, based on a reading regimen and eight exercises that recreate everyday visuomotor activities using threedimensional (3D) real-world objects, improves the visual ability/function, quality of life (QL), and functional independence (FI). Methods: The 3D-MCSTP included four in-office visits and two customized homebased daily training sessions over 12weeks. A quasiexperimental, pretest/posttest study designwas carried out with an intervention group (IG) (n = 20) and a no-training group (NTG) (n = 20) matched for age, hemianopia type, and brain injury duration. Results: The groups were comparable for the main baseline variables and all participants (n = 40) completed the study. The IGmainly showed significant improvements in visual-processing speed (57.34% ± 19.28%; P < 0.0001) and visual attention/retention ability (26.67% ± 19.21%; P < 0.0001), which also were significantly greater (P < 0.05) than in the NTG. Moreover, the IG showed large effect sizes (Cohen’s d) in 75% of the totalQL and FI dimensions analyzed; in contrast to the NTGthat showed negligiblemean effect sizes in 96% of these dimensions. Conclusions: The customized 3D-MCSTP was associated with a satisfactory response in the IG for improving complex visual processing, QL, and FI. Translational Relevance: Neurovisual rehabilitation of patientswith hemianopia seems more efficient when programs combine in-office visits and customized home-based training sessions based on real objects and simulating real-life conditions, than no treatment or previously reported computer-screen approaches, probably because of better stimulation of patients´ motivation and visual-processing speed brain mechanisms

A higher proportion of eicosapentaenoic acid (EPA) when combined with docosahexaenoic acid (DHA) in omega-3 dietary supplements provides higher antioxidant effects in human retinal cells

Retinal pigment epithelium (RPE) is a key regulator of retinal function and is directly related to the transport, delivery, and metabolism of long-chain n-3 polyunsaturated fatty acids (n3-PUFA), in the retina. Due to their functions and location, RPE cells are constantly exposed to oxidative stress. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have shown to have antioxidant effects by different mechanisms. For this reason, we designed an in vitro study to compare 10 formulations of DHA and EPA supplements from different origins and combined in different proportions, evaluating their effect on cell viability, cell proliferation, reactive oxygen species production, and cell migration using ARPE-19 cells. Furthermore, we assessed their ability to rescue RPE cells from the oxidative conditions seen in diabetic retinopathy. Our results showed that the different formulations of n3-PUFAs have a beneficial effect on cell viability and proliferation and are able to restore oxidative induced RPE damage. We observed that the n3-PUFA provided different results alone or combined in the same supplement. When combined, the best results were obtained in formulations that included a higher proportion of EPA than DHA. Moreover, n3-PUFA in the form of ethyl-esters had a worse performance when compared with triglycerides or phospholipid based formulations