Estudio del potencial terapéutico de compuestos de origen marino

La Tesis Doctoral “Estudio del potencial terapéutico de compuestos de origen marino” describe en profundidad el efecto de la autumnalamida, un compuesto obtenido de cianobacterias del género Phormidium, y de las gracilinas A, H, L y tetrahidroaplisulfurina-1, cuatro metabolitos secundarios aislados de la esponja marina Spongionella gracilis, sobre los flujos iónicos de calcio (Ca2+), uno de los mecanismos básicos implicados en la transmisión de la señal intracelular y el papel de los reservorios intracelulares, mitocondria y retículo endoplasmático (ER). Además, se estudia la capacidad de estos compuestos para formar complejos con las ciclofilinas (Cyps). Por la implicación de ésta familia de proteínas en la regulación de procesos básicos en la célula, se profundiza en el estudio del efecto de estos compuestos sobre las Cyps y su influencia sobre enzimas como la calcineurina (CN), factores de transcripción, citocinas y receptores de membrana moduladas por las mismas. Los efectos in vitro e in vivo mostrados por algunos de los compuestos de Spongionella sobre la modulación de los linfocitos T, ponen de manifiesto la capacidad reguladora de estos compuestos en la respuesta inmune celular, y por tanto, han servido como base para la síntesis de nuevas moléculas. De esta forma se pone de relevancia la utilidad de los compuestos de origen natural como fuente de compuestos activos y su valor como moléculas líderes para la síntesis de nuevas estructuras

Cognitive decline monitoring through a web-based application

Cognitive decline usually begins after individuals reach maturity, which is more evident in late adulthood. Rapid and constant cognitive screenings allow early detection of cognitive decline and motivate individuals to participate in prevention interventions. Due to accelerated technological advances, cognitive screening and training are now available to the layperson using electronic devices connected to the internet. Large datasets generated by these platforms provide a unique opportunity to explore cognitive development throughout life and across multiple naturalistic environments. However, such data collection mechanisms must be validated. This study aimed to determine whether the data gathered by commercial visuospatial and phonological working memory tests (CogniFit Inc., San Francisco, USA) confirm the well-established argument that age predicts cognitive decline. Data from 3,212 participants (2,238 females) who were 45 years old or older were analyzed. A linear regression analysis explored the relationship between age and working memory while controlling for gender, sleep quality, and physical activity (variables that are known to affect working memory). We found that age negatively predicts working memory. Furthermore, there was an interaction between age and gender for visuospatial working memory, indicating that although male participants significantly outperformed females, the relationship between age and working memory differs for females and males. Our results suggest that the computerized assessment of visuospatial and phonological working memory is sensible enough to predict cognitive functions in aging. Suggestions for improving the sensitivity of self-reports are discussed. Further studies must explore the nature of gender effects on cognitive aging

Cognitive decline monitoring through a web-based application

Cognitive decline usually begins after individuals reach maturity, which is more evident in late adulthood. Rapid and constant cognitive screenings allow early detection of cognitive decline and motivate individuals to participate in prevention interventions. Due to accelerated technological advances, cognitive screening and training are now available to the layperson using electronic devices connected to the internet. Large datasets generated by these platforms provide a unique opportunity to explore cognitive development throughout life and across multiple naturalistic environments. However, such data collection mechanisms must be validated. This study aimed to determine whether the data gathered by commercial visuospatial and phonological working memory tests (CogniFit Inc., San Francisco, USA) confirm the well-established argument that age predicts cognitive decline. Data from 3,212 participants (2,238 females) who were 45 years old or older were analyzed. A linear regression analysis explored the relationship between age and working memory while controlling for gender, sleep quality, and physical activity (variables that are known to affect working memory). We found that age negatively predicts working memory. Furthermore, there was an interaction between age and gender for visuospatial working memory, indicating that although male participants significantly outperformed females, the relationship between age and working memory differs for females and males. Our results suggest that the computerized assessment of visuospatial and phonological working memory is sensible enough to predict cognitive functions in aging. Suggestions for improving the sensitivity of self-reports are discussed. Further studies must explore the nature of gender effects on cognitive aging

Genetic association study of dyslexia and ADHD candidate genes in a Spanish cohort: Implications of comorbid samples

Published: October 31, 2018Dyslexia and attention deficit hyperactivity disorder (ADHD) are two complex neuro-behaviorally disorders that co-occur more often than expected, so that reading disability has been linked to inattention symptoms. We examined 4 SNPs located on genes previously associated to dyslexia (KIAA0319, DCDC2, DYX1C1 and FOXP2) and 3 SNPs within genes related to ADHD (COMT, MAOA and DBH) in a cohort of Spanish children (N = 2078) that met the criteria of having one, both or none of these disorders (dyslexia and ADHD). We used a case-control approach comparing different groups of samples based on each individual diagnosis. In addition, we also performed a quantitative trait analysis with psychometric measures on the general population (N = 3357). The results indicated that the significance values for some markers change depending on the phenotypic groups compared and/or when considering pair-wise marker interactions. Furthermore, our quantitative trait study showed significant genetic associations with specific cognitive processes. These outcomes advocate the importance of establishing rigorous and homogeneous criteria for the diagnosis of cognitive disorders, as well as the relevance of considering cognitive endophenotypes.The work of MSM and MC was supported by CONSOLIDER-Ingenio- 2010_COEDUCA (CSD2008-00048). AMA, LB and AG-L’s work was supported by the Basque Department of Industry, Tourism and Trade (Etortek Program), Innovation Technology Department of Bizkaia and CIBERehd Network. MC was also supported by grants (PSI2015-67353-R), and Ayuda Centro de Excelencia Severo Ochoa SEV-2015-0490 from the MINECO, and by grant (ERC-2011-ADG-295362) from the European Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Detection of Anatoxin-a and Three Analogs in Anabaena spp. Cultures: New Fluorescence Polarization Assay and Toxin Profile by LC-MS/MS

Anatoxin-a (ATX) is a potent neurotoxin produced by several species of Anabaena spp. Cyanobacteria blooms around the world have been increasing in recent years; therefore, it is urgent to develop sensitive techniques that unequivocally confirm the presence of these toxins in fresh water and cyanobacterial samples. In addition, the identification of different ATX analogues is essential to later determine its toxicity. In this paper we designed a fluorescent polarization (FP) method to detect ATXs in water samples. A nicotinic acetylcholine receptor (nAChR) labeled with a fluorescein derivative was used to develop this assay. Data showed a direct relationship between the amount of toxin in a sample and the changes in the polarization degree of the emitted light by the labeled nAChR, indicating an interaction between the two molecules. This method was used to measure the amount of ATX in three Anabaena spp. cultures. Results indicate that it is a good method to show ATXs presence in algal samples. In order to check the toxin profile of Anabaena cultures a LC-MS/MS method was also developed. Within this new method, ATX-a, retention time (RT) 5 min, and three other molecules with a mass m/z 180.1 eluting at 4.14 min, 5.90 min and 7.14 min with MS/MS spectra characteristic of ATX toxin group not previously identified were detected in the Anabaena spp. cultures. These ATX analogues may have an important role in the toxicity of the sampleThe research leading to these results has received funding from the following FEDER cofunded-grants: From Ministerio de Ciencia y Tecnología, Spain: AGL2009-13581-CO2-01, AGL2012-40485-CO2-01. From Xunta de Galicia, Spain: 10PXIB261254 PR. From the European Union’s Seventh Framework Programme managed by REA—Research Executive Agency http://ec.europa.eu/research/rea (FP7/2007-2013) under grant agreement Nos. 211326—CP (CONffIDENCE), 265896 BAMMBO, 265409 µAQUA, and 262649 BEADS, 315285 Ciguatools and 312184 PharmaSea. From the Atlantic Area Programme (Interreg IVB Trans-national): 2008-1/003 (Atlantox) and 2009-1/117 (Pharmatlantic)S

Spongionella Secondary Metabolites, Promising Modulators of Immune Response through CD147 Receptor Modulation

The modulation of the immune system can have multiple applications such as cancer treatment, and a wide type of processes involving inflammation where the potent chemotactic agent cyclophilin A (Cyp A) is implicated. The Porifera phylum, in which Spongionella is encompassed, is the main producer of marine bioactive compounds. Four secondary metabolites obtained from Spongionella (Gracilin H, A, L, and Tetrahydroaplysulphurin-1) were described to hit Cyp A and to block the release of inflammation mediators. Based on these results, some role of Spongionella compounds on other steps of the signaling pathway mediated by this chemotactic agent can be hypothesized. In the present paper, we studied the effect of these four compounds on the surface membrane CD147 receptor expression, on the extracellular levels of Cyp A and on the ability to migrate of concanavalin (Con A)-activated T lymphocytes. Similar to a well-known immunosuppressive agent cyclosporine A (CsA), Gracilin H, A, L, and tetrahydroaplysulphurin-1 were able to reduce the CD147 membrane expression and to block the release of Cyp A to the medium. Besides, by using Cyp A as chemotactic agent, T cell migration was inhibited when cells were previously incubated with Gracilin A and Gracilin L. These positive results lead us to test the in vivo effect of Gracilin H and L in a mouse ear delayed hypersensitive reaction. Thus, both compounds efficiently reduce the ear swelling as well as the inflammatory cell infiltration. These results provide more evidences for their potential therapeutic application in immune-related diseases of Spongionella compound

COLAEVA: Visual Analytics and Data Mining Web-Based Tool for Virtual Coaching of Older Adult Populations

The global population is aging in an unprecedented manner and the challenges for improving the lives of older adults are currently both a strong priority in the political and healthcare arena. In this sense, preventive measures and telemedicine have the potential to play an important role in improving the number of healthy years older adults may experience and virtual coaching is a promising research area to support this process. This paper presents COLAEVA, an interactive web application for older adult population clustering and evolution analysis. Its objective is to support caregivers in the design, validation and refinement of coaching plans adapted to specific population groups. COLAEVA enables coaching caregivers to interactively group similar older adults based on preliminary assessment data, using AI features, and to evaluate the influence of coaching plans once the final assessment is carried out for a baseline comparison. To evaluate COLAEVA, a usability test was carried out with 9 test participants obtaining an average SUS score of 71.1. Moreover, COLAEVA is available online to use and explore.This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 769830

Alternative method to detect compounds produced by <i>Gambierdiscus</i> spp.

Ciguatoxins (CTXs) and CTX precursors are produced by several Gambierdiscus spp. These polyether toxins are associated to ciguatera fish poisoning (CFP). In addition to CTX, maitotoxins (MTX) and gambierol are also produced by these dinoflagellates. MTX mechanism of action is strictly Ca2+ dependent, since the toxin induces a massive cytoplasmatic Ca2+ entrance. However, CTX activates the voltage-dependent sodium channels and no relation with calcium fluxes has been showed. The aim of this work was to study the effect of both toxins in the cytoplasmic calcium levels in the SH-SY5Y neuroblastoma cell line by using the fluorescent probe Fura-2 AM. Two completely different calcium profiles were obtained. While, MTX induces a sustained dose-dependent increase in Fura-2 ratio, CTX produces a light increase in dye ratio. From MTX results a calibration curve concentration versus Fura-2 ratio was obtained where the toxin concentration of an unknown sample can be calculated. Then, the effect of four samples from Gambierdiscus cultures was studied and different calcium profiles were obtained. A high increase in Fura-2 ratio was observed in two samples. The calcium profile was similar to MTX and by using the calibration curve the amount of toxin was calculated (4.9 and 1.8 nM of MTX). In the other samples, from the Fura-2 results the presence of CTX like compounds can be established

La interacción sistema familia y sistema empresa como fuente de ventaja competitiva

The aim of this work is to identify and assess the positive characteristics of family businesses that can be sources of competitive advantages, as well as management practices specific to this type of company that are effective for improving their competitiveness. For this purpose, qualitative comparative techniques have been used (Focus Group, Nominal Group Technique and Delphi Method) to gather, process and improve, in an explicit, reasoned and systematic way, the subjective or qualitative information possessed by family business experts. Results indicate that the long-term vision of family businesses, derived from their urge to survive, and the greater dedication and involvement of their owners are the most valued characteristics, while early succession planning in business management is the most important practice.El objetivo de este trabajo es identificar y valorar las características positivas de las empresas familiares que pueden ser fuentes de ventajas competitivas, así como las prácticas de gestión, específicas de este tipo de empresas, eficaces para la mejora de su competitividad. Para ello se han utilizado técnicas cualitativas contrastadas (Focus Group, Técnica de Grupo Nominal y Método Delphi), que recogen, procesan y mejoran de una forma explícita, razonada y sistemática la información subjetiva o cualitativa que poseen los expertos en empresas familiares. Los resultados indican que la visión a largo plazo que tiene la empresa familiar, derivada de su afán de supervivencia, y la mayor dedicación e implicación de los propietarios son las características más valoradas, siendo la planificación con tiempo de la sucesión en la dirección de la empresa la práctica más importante

Autumnalamide targeted proteins of the immunophilin family

International audiencePrevious works with autumnalamide reported that Store Operated Calcium (SOC) channels were blocked through mitochondrial modulation. In the present paper we studied the effect of autumnalamide on ionomycin Ca2+ fluxes. Thus, autumnalamide did not modify ionomycin-sensitive intracellular pools while the ionomycin-induced Ca2+ influx was blocked with similar potency whether the incubation was done before or after ionomycin-sensitive pools depletion. Nevertheless, autumnalamide was not able to inhibit ionomycin-induced Ca2+ influx once the membrane channels were activated. Moreover, the compound efficiently inhibited flufenamic acid (FFA) Ca2+ release induced in this organelle but no the next influx. Since in previous work the effect of autumnalamide was inhibited by cyclosporine A (CsA), structures that target this drug were studied. Therefore, the affinity of autumnalamide for cyclophilin D (Cyp D) was examined. The KD obtained for Cyp D- autumnalamide was 1.51 ± 1.399. Moreover, the KD for Cyp A- autumnalamide was calculated. The peptide had a similar order of Cyp A binding affinity than CsA (8.08 ± 1.23 and 6.85 ± 1.1 μM respectively). After testing autumnalamide-binding capacity for Cyp A, the activity of this compound on Cyp A pathway was tested. Thus, the effect on interleukin (IL)-2 release on activated T-lymphocytes was checked. Autumnalamide was able to reduce IL-2 levels near to T cells in resting conditions. Next, the effect over calcineurin and NFATc1 was also evaluated. While CsA inhibits both calcineurin and NFATc1, autumnalamide did not produce any effect. From these results we can conclude that, autumnalamide targeted mitochondrion and prevent T-cells from IL-2 production through the modulation of SOC Ca2+ channels