In vitro modeling of dysfunctional glial cells in neurodegenerative diseases using human pluripotent stem cells

Most neurodegenerative diseases are characterized by a complex and mostly still unresolved pathology. This fact, together with the lack of reliable models, have precluded the development of effective therapies counteracting the disease progression. In the past few years, several studies have evidenced that lack of proper functionality of glial cells (astrocytes, microglia and oligodendrocytes) has a key role in the pathology of several neurodegenerative conditions including Alzheimer´s disease, amyotrophic lateral sclerosis and multiple sclerosis among others. However, this glial dysfunction is poorly modelled by available animal models, and we hypothesize that patientderived cells can serve as a better platform where to study this glial dysfunction. In this sense, human pluripotent stem cells (hPSCs) has revolutionized the field allowing the generation of disease-relevant neural cell types that can be used for disease modelling, drug screening and, possibly, cell transplantation purposes. In the case of the generation of oligodendrocytes (OLs) from hPSCs, we have developed a fast and robust protocol to generate surface antigen O4-positive (O4+) and myelin basic protein-positive OLs from hPSCs in only 22 days, including from patients with multiple sclerosis or amyotrophic lateral sclerosis. The generated cells resemble primary human OLs at the transcriptome level and can myelinate neurons in vivo. Using in vitro OLneuron co-cultures, effective myelination of neurons can also be demonstrated. This platform is being translated as well to the generation of the other glial cell types, allowing the derivation of patient-specific glial cells where to model disease-specific dysfunction. This methodology can be used for elucidating pathogenic pathways associated with neurodegeneration and to identify therapeutic targets susceptible of drug modulation, contributing to the development of novel and effective drugs for these devastating disorders.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Supported by PI18/01557 (to AG) and P18/1556 (to JV) grants from ISCiii of Spain co-financed by FEDER funds from European Union, and PI-0276-2018 grant (to JAGL) from Consejeria de Salud of Junta de Andalucia. JAGL held a postdoctoral contract from the I Research Plan Propio of the University of Malaga. CV and KE were supported by IWT-SBO-150031-iPSCAF and the Thierry Lathran Foundation grant – ALS-OL, and KN by FWO1166518

Bottom-up control of sardine and anchovy population cycles in the canary current: insights from an end-to-end model simulation

Sardine and anchovy can exhibit dramatic decadal-scale shifts in abundance in response to climate variability. Sharpe declines of these populations entail particularly serious commercial and ecological consequences in eastern boundary current ecosystems, where they sustain major world fisheries and provide the forage for a broad variety of predators. Understanding the mechanisms and environmental forcing that drive the observed fish variability remains a challenging problem. The modelling study presented here provides an approach that bridges a comprehensive database with an end-to-end modelling framework enabling the investigation of the sources of variability of sardine and anchovy in the Canary Current System. Different biological traits and behaviour prescribed for sardine and anchovy gave rise to different distribution and displacements of the populations, but to a rather synchronous variability in terms of abundance and biomass, in qualitative agreement with historical landing records. Analysis of years with anomalously high increase and decline of the adult population points to food availability (instead of temperature or other environmental drivers) as the main environmental factor determining recruitment for both sardine (via spawning and survival of feeding age-0 individuals) and anchovy (via survival of feeding age-0). Consistent with this, the two species thrive under enhanced upwelling-favourable winds, but only up to some threshold of the wind velocity beyond which larval drift mortality exceeds the positive effect of the extra food supply. Based on the analysis of the simulation, we found that anchovy larvae are particularly vulnerable to enhanced wind-driven advection, and as such do better with more moderate upwelling than sardines.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Population distribution and biomass variability of sardine and anchovy in the Canary current system as simulated by an end-to-end coupled model

Small pelagic fishes as sardine and anchovy account for as much as 20-25% of the world fisheries catch. They are particularly abundant in the four major eastern boundary upwelling ecosystems, where high levels of biological productivity are sustained by the supply of nutrient-rich water from beneath the photic zone. An intrinsic and puzzling feature of small pelagic fish is the large fluctuations of their population, typically occurring at decadal scales. The causes for such fluctuations have been extensively analyzed and discussed in the literature, yet our understanding of the mechanism involved is very limited. End-to-end models are emerging tools useful to test hypothesis for such fish population variability or to gain new insights into the problem. This comprehensive and complex model approach is now becoming possible largely thanks to the present-day computer power. This contribution focuses on the population dynamics of sardine (Sardina pilchardus) and anchovy (Engraulis encrasicolus) in the Canary Current Upwelling Ecosystem. We describe and present the results of an end-to-end coupled model simulation including these two small pelagic species. The end-to-end application includes three model components: the ROMS circulation sub-model, the lower trophic ecosystem sub-model NEMURO, and a recently developed individual-based model for the fish (Rose et al. 2015; Fiechter et al. 2015). The computational grid for the three models covers NW Africa and the Western Iberian Peninsula at a spatial resolution of 12 km. This resolution is sufficient for certain eddy variability to occur in ROMS. Different biological traits were prescribed for anchovy and sardine: temperature optimum, diet preferences, and the onset and duration of the spawning season, among others. A hind-cast simulation of the period 1958-2007 was carried out. Model results reveal a fairly different behavior of sardine and anchovy. Anchovies gather off the northern part of Morocco and the Gulf of Cadiz, whereas sardines appear more scattered across the domain, further offshore, and further south, where upwelling favorable conditions take place year round. Both species exhibit decadal-scale fluctuations in both the location of the center of mass of the population and their biomass abundance; the latter being reasonably correlated with historical landing records.Universidad de Málaga. Campus de Excelencia Internacional del Mar CEIMAR. Campus de Excelencia Andalucía Tec

Cartagena City in the early roman empire era: generation and analysis of a digital elevation model

[EN] The main objective of this paper is to contribute to the knowledge of the topography of the city of Cartagena in the early Roman Empire times. A Geographic Information System has been used with data from numerous archaeological excavations, available historic maps and new GPS observations referred to landmarks of that era that are currently on the soil surface. Some meaningful results are: the compilation of spatial information from different sources in a single database, the creation of thematic maps and the generation and analysis of digital elevation models based on these data, which were compared with the contemporary ones. Some notable conclusions are the generation of a methodological model, the contribution to systematic knowledge of the historical topography of Cartagena and the interest of expanding the area of study and considering other periods[ES] El principal objetivo de este trabajo es contribuir al conocimiento de la topografía de la ciudad de Cartagena en la época romana altoimperial. Se ha empleado un Sistema de Información Geográfica y datos procedentes de numerosas excavaciones arqueológicas, de la cartografía histórica disponible y de observaciones GPS realizadas ex profeso y referidas a puntos característicos de aquella época que están actualmente en superficie. Entre los resultados obtenidos están la recopilación de información espacial procedente de diversas fuentes en una base de datos, la creación de cartografía temática y la generación y análisis de modelos digitales de elevaciones basados en esos datos y que se han comparado con el de la época actual. Entre las conclusiones cabe destacar la creación de un modelo metodológico, la aportación al conocimiento sistemático de la topografía histórica de Cartagena y el interés de ampliar la zona de estudio y de considerar también otras épocasEl presente trabajo se enmarca dentro del proyecto de investigación “Carthago Nova: Topografía y urbanística de una urbe Mediterránea privilegiada” [HAR2011.29330] del Ministerio de Economía y Competitividad, financiado con Fondos FEDER.García-León, J.; García-Martín, A.; Cánovas Ambit, JA. (2015). La ciudad de Cartagena en la época romana altoimperial: generación y análisis de un modelo digital de elevaciones. EGA. Revista de Expresión Gráfica Arquitectónica. 20(26):224-231. https://doi.org/10.4995/ega.2015.4055SWORD2242312026Ros Mc Donnell, D., and Ródenas López, MA. (2012). "La inundación de Cartagena del 29 de septiembre de 1919". Proyecto y Ciudad. Vol. 3, 2012, pp. 47-60. Cartagena.Ramallo Asensio, SF., and Moneo Vallés, JR. (2009). Teatro romano de Cartagena. Fundación Cajamurcia, Madrid.Noguera Celdrán, JM. (2003). Arx Asdrubalis. Arqueología e Historia del Cerro del Molinete (Cartagena). Vol. 1. Universidad de Murcia, Murcia.Noguera Celdrán, JM., and Madrid Balanza, MJ. (eds.) (2009). Arx Hasdrubalis. La ciudad reencontrada. Arqueología en el cerro del Molinete (Cartagena). Comunidad de Madrid, Museo Arqueológico Regional: Tres Fronteras. MADRID BALANZA, MJ. (2007). "Excavaciones arqueológicas en el PERI-CA 4 (Barrio universitario, Cartagena)", XVIII Jornadas de patrimonio cultural. Intervenciones en el patrimonio arquitectónico, arqueológico y etnográfico de la Región de Murcia, Vol. I, pp. 105-107. Consejería de Educación y Cultura, Murcia.García León, J., García Martín, A., Torres Picazo, M., and Corbalán Hernández, MJ. (2013). "Análisis cartográfico de la evolución histórica de la laguna "Almarjal", Cartagena. Espa-a". Mapping vol. 22, nº 160, pp. 4-10. Revista Mapping SL, MadridChias, P., & Abad, T. (2009). Geolocating and Georeferencing: GIS Tools for Ancient Maps Visualisation. 2009 13th International Conference Information Visualisation. doi:10.1109/iv.2009.9

Evaluating the soft error sensitivity of a GPU-based SoC for matrix multiplication

Proceeding of: 31th European Symposium on Reliability of Electron Devices, Failure Physics and Analysis (ESREF 2020), Athens, Greece, 4th to 8 October 2020 (Virtual conference)System-on-Chip (SoC) devices can be composed of low-power multicore processors combined with a small graphics accelerator (or GPU) which offers a trade-off between computational capacity and low-power consumption. In this work we use the LLFI-GPU fault injection tool on one of these devices to compare the sensitivity to soft errors of two different CUDA versions of matrix multiplication benchmark. Specifically, we perform fault injection campaigns on a Jetson TK1 development kit, a board equipped with a SoC including an NVIDIA 'Kepler” Graphics Processing Unit (GPU). We evaluate the effect of modifying the size of the problem and also the thread-block size on the behaviour of the algorithms. Our results show that the block version of the matrix multiplication benchmark that leverages the shared memory of the GPU is not only faster than the element-wise version, but it is also much more resilient to soft errors. We also use the cuda-gdb debugger to analyze the main causes of the crashes in the code due to soft errors. Our experiments show that most of the errors are due to accesses to invalid positions of the different memories of the GPU, which causes that the block version suffers a higher percentage of this kind of errors.This work has been supported by the Spanish Government through TIN2017-82972-R and ESP2015-68245-C4-1-P, and by the Valencian Regional Government through PROMETEO/2019/109

New and Old Mechanisms Associated with Hypertension in the Elderly

Hypertension is a widely prevalent and important risk factor for cardiovascular diseases that increase with aging. The hallmark of hypertension in the elderly is increased vascular dysfunction. However, the molecular mechanisms by which increased blood pressure leads to vascular injury and impaired endothelial function are not well defined. In the present paper, we will analyze several mechanisms described in the scientific literature involved in hypertension in the elderly as endothelial dysfunction, increased oxygen delivery to tissues, inflammation, cellular apoptosis, and increased concentration of active metabolites. Also, we will focus on new molecular mechanisms involved in hypertension such as telomeres shortening, progenitor cells, circulating microparticles, and epigenetic factors that have appeared as possible causes of hypertension in the elderly. These molecular mechanisms may elucidate different origin for hypertension in the elderly and provide us with new targets for hypertension treatment

Effects of nitrogen-doped multiwall carbon nanotubes on murine fibroblasts

"The effect of nitrogen-doped multiwall carbon nanotubes (CNx) on the proliferation of NIH-3T3murine fibroblasts is presented. CNTs were dispersed in distillated water and incubated with mammalian cells in order to evaluate their toxicity. Also, the influence of factors such as dosage (7 and 70 mu g/mL), exposure time (24 to 96 h), and the exposure route (before and after cell liftoff) on the cell proliferation was evaluated. When the CNx were simultaneously incubated with the cells, the control culture reached a maximum cell concentration of 1.3 x 10(5) +/- 3.4 x 10(4) cells per well at 96 h, whereas cultures with 7 mu g/mL reached a concentration of 2.6 x 10(4) +/- 5.3 x 10(3) cells. In the case of 70 mu g/mL of CNx most of the cells were dead. The CNx that were added 24 h after cell dissociation showed that live cells decreased, with a cell concentration of 9.6 x 10(4) +/- 9 x 10(3) for 7 mu g/mL and 5.5 x 10(4) +/- 9.5 x 10(3) for 70 mu g/mL, in contrast to control cultures with 1.1 x 10(6) +/- 1.5 x 10(4). The results showed that the CNx had cytotoxic effects depending on the concentration and exposure route.

Chapter Towards a Realistic and Self-Contained Biomechanical Model of the Hand

Computer modelling & simulatio

Human pluripotent stem cell-derived astrocytes from alzheimer´s disease patients for disease modeling

Aims: The lack of reliable models of Alzheimer´s disease (AD) has impeded the development of effective therapies. Glial cells have a key role in AD pathology, but this cannot be properly modeled using available animal models, so we hypothesized that cells derived from Alzheimer's patients can serve as a better platform for studying the disease. In this sense, human pluripotent stem cells (hPSC) allow the generation of different types of neural cells, which can be used for disease modeling, identification of new targets and drugs development. Methods: We have a collection of hiPSCs derived from patients with sporadic forms of AD stratified based on APOE genotype. We have differentiated these cells towards neural lineage to obtain astrocytes to assess intrinsic differences between those derived from AD patients or healthy controls. Results: We have implemented a serum-free approach and generated neural precursors and astrocytes from all the lines tested. Cells are different at the phenotypic level, suggesting intrinsic differences in neural cells derived from AD patients. Conclusions: Human pluripotent stem cell-derived methodology can be used to elucidate the pathogenic pathways associated with neurodegeneration and to identify new therapeutic targets susceptible to modulation, contributing to the development of new effective drugs against AD.Supported by Instituto de Salud Carlos III of Spain PI18/01557, PI21/00915 (to AG), PI18/01556 (to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV); by Junta de Andalucia UMA18-FEDERJA-211 (to AG), PY18-RT-2233 (to AG) and US-1262734 (to JV), Consejeria de Salud PI-0276-2018 (to JAGL) and Programa Operativo de Empleo Juvenil SNGJ4-11 to LCP. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Directing the self-assembly of tumour spheroids by bioprinting cellular heterogeneous models within alginate/gelatin hydrogels

"Human tumour progression is a dynamic process involving diverse biological and biochemical events such as genetic mutation and selection in addition to physical, chemical, and mechanical events occurring between cells and the tumour microenvironment. Using 3D bioprinting we have developed a method to embed MDA-MB-231 triple negative breast cancer cells, and IMR-90 fibroblast cells, within a cross-linked alginate/gelatin matrix at specific initial locations relative to each other. After 7 days of co-culture the MDA-MB-231 cells begin to form multicellular tumour spheroids (MCTS) that increase in size and frequency over time. After similar to 15 days the IMR-90 stromal fibroblast cells migrate through a non-cellularized region of the hydrogel matrix and infiltrate the MDA-MB-231 spheroids creating mixed MDA-MB-231/IMR-90 MCTS. This study provides a proof-of-concept that biomimetic in vitro tissue coculture models bioprinted with both breast cancer cells and fibroblasts will result in MCTS that can be maintained for durations of several weeks.