Conformationally-Locked C-Glycosides: Tuning Aglycone Interactions for Optimal Cheperone Behaviour in Gaucher Fibroblasts

A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver β-glucosidase/β-galactosidase and specific inhibition of human β-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location. Molecular dynamics simulations highlighted the paramount importance of an optimal orientation of the hydrophobic substituent to warrant efficient non-glycone interactions, which are critical for the binding affinity. The results provide a rationale for the strong decrease of the inhibition potency of APP compounds on going from neutral to acidic pH. The best candidate was found to behave as pharmacological chaperone in Gaucher fibroblasts with homozygous N370S and F213I mutations, with enzyme activity enhancements similar to those encountered for the reference compound AmbroxolMinisterio de Economía y Competitividad CTQ2012-36365, SAF2013-44021-RJunta de Andalucía FQM-1467European Union Seventh Framework Programme FP7-People-2012-CI

Modelling barrier beaches under storms with XBEACH: The case of the Trabucador bar

Postprint (updated version

Assessment of oceanographic services for the monitoring of highly anthropised coastal lagoons: The Mar Menor case study

Ocean monitoring systems are designed for continuous monitoring to track their evolution and anticipate environmental issues. However, they are often based on IoT systems that offer little spatial coverage and are hard to maintain. Satellite remote sensing offers good geographical coverage but they also face several challenges to become a monitoring system. This paper introduces an easy-to-use software tool to crawl water-quality data from up to 6 satellite instruments from the ESA and NASA. Particularly, Chl-a data is deeply analyzed in terms of reliability and data coverage for a highly anthropised coastal lagoon (Mar Menor, Spain), where serious socio-environmental issues are happening. Our results show a good linear correlation between in situ data and SRS data, reaching values close to 0.9, and stating the relevance of organic matter inputs from ephemeral streams in Chl-a concentrations. Moreover, temporal granularity is increased from 5 to 1.5 days by combining SRS sources.Preprin

IEOOS: the Spanish Institute of Oceanography Observing System

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IEOOS, the Spanish Institute of Oceanography integrated ocean Observing System

Since its foundation, 100 years ago, the Spanish Institute of Oceanography (IEO) has been observing and measuring the ocean characteristics. Some systems like the tide gauges network has been working for more than 60 years. The IEO standard sections began at different moments depending on the local projects, and nowadays there are XXX coastal stations and XXX deep ones that are systematically sampled, taking physical as well as biochemical measurements. At this moment, the IEO Observing System (IEOOS) includes 4 permanent moorings equipped with currentmeters, an open-sea ocean-meteorological buoy offshore Santander and an SST satellital image reception station. It also supports the Spanish contribution to the ARGO international program with 47 deployed profilers, and continuous monitoring thermosalinometers, meteorological stations and ADCP installed on the IEO research vessels. All these networks are linked to international iniciatives like SeaDataNet, Emodnet, IbiROOS and MONGOOS. The system is completed with the IEO contribution to the RAIA and Gibraltar observatories, and the development of regional prediction models. All these systematic measurements allow IEO to give responses to ocean research activities, official agencies requirements and industrial and main society demands

Capacidad predictiva de la autoeficacia académica sobre las dimensiones del autoconcepto en una muestra de adolescentes chilenos

El objetivo de este estudio fue analizar la capacidad predictiva de la autoefi cacia académica sobre las dimensiones del autoconcepto en una muestra de 860 estudiantes chilenos. El análisis de regresión logística reveló que la autoefi cacia académica fue un predictor positivo y signifi cativo de las escalas académicas (Matemáticas, Verbal y Académica General), no académicas (Habilidades Físicas, Apariencia Física, Relaciones con el Sexo Opuesto, Relaciones con el Mismo Sexo, Relación con los Padres, Sinceridad- Veracidad), y de la escala de Autoestima, excepto de la escala de Estabilidad Emocional. Esta relación de predicción fue de mayor magnitud con las escalas académicas y autoestima.The aim of this study was to analyze the predictive power of academic self-effi cacy on academic self-concept dimensions in a sample of 860 Chilean students. Logistic regression analysis revealed that the academic self-effi cacy was a positive and signifi cant predictor of academic scales (Math, Verbal, and General Academic), not academic (Physical Abilities, Physical Appearance, Relationships with the Opposite Sex, Relationships with the Same Sex, Relationship with Parents, Sincerity-Veracity), and Self- Esteem scale, except for the Emotional Stability scale. The predictive value was stronger in the academic dimensions and self-esteem

Factors structuring microbial communities in highly impacted coastal marine sediments (Mar Menor lagoon, SE Spain)

Coastal marine lagoons are environments highly vulnerable to anthropogenic pressures such as agriculture nutrient loading or runoff from metalliferous mining. Sediment microorganisms, which are key components in the biogeochemical cycles, can help attenuate these impacts by accumulating nutrients and pollutants. The Mar Menor, located in the southeast of Spain, is an example of a coastal lagoon strongly altered by anthropic pressures, but the microbial community inhabiting its sediments remains unknown. Here, we describe the sediment prokaryotic communities along a wide range of environmental conditions in the lagoon, revealing that microbial communities were highly heterogeneous among stations, although a core microbiome was detected. The microbiota was dominated by Delta- and Gammaproteobacteria and members of the Bacteroidia class. Additionally, several uncultured groups such as Asgardarchaeota were detected in relatively high proportions. Sediment texture, the presence of Caulerpa or Cymodocea, depth, and geographic location were among the most important factors structuring microbial assemblages. Furthermore, microbial communities in the stations with the highest concentrations of potentially toxic elements (Fe, Pb, As, Zn, and Cd) were less stable than those in the non-contaminated stations. This finding suggests that bacteria colonizing heavily contaminated stations are specialists sensitive to change

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFβ1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFβ/Activin pathways in the pituitary

Role of small-sized phytoplankton in triggering an ecosystem disruptive algal bloom in a Mediterranean hypersaline coastal lagoon

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