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The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN’s compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

Six computational protocols to annotate phenotypic screens., Phenotypic screening is in a renaissance phase and is expected by many academic and industry leaders to accelerate the discovery of new drugs for new biology. Given that phenotypic screening is per definition target agnostic, the emphasis of in silico and in vitro follow-up work is on the exploration of possible molecular mechanisms and efficacy targets underlying the biological processes interrogated by the phenotypic screening experiments. Herein, we present six exemplar computational protocols for the interpretation of cellular phenotypic screens based on the integration of compound, target, pathway, and disease data established by the IMI Open PHACTS project. The protocols annotate phenotypic hit lists and allow follow-up experiments and mechanistic conclusions. The annotations included are from ChEMBL, ChEBI, GO, WikiPathways and DisGeNET. Also provided are protocols which select from the IUPHAR/BPS Guide to PHARMACOLOGY interaction file selective compounds to probe potential targets and a correlation robot which systematically aims to identify an overlap of active compounds in both the phenotypic as well as any kinase assay. The protocols are applied to a phenotypic pre-lamin A/C splicing assay selected from the ChEMBL database to illustrate the process. The computational protocols make use of the Open PHACTS API and data and are built within the Pipeline Pilot and KNIME workflow tools.

El turismo accesible representa un segmento con gran potencialidad y generador de una ventaja competitiva para el sector, dado que los beneficiarios de acciones de accesibilidad engloban a colectivos en crecimiento como el de las personas mayores, las familias, personas con capacidades restringidas temporalmente y embarazadas. Su representatividad en el total de la actividad turística española está en incremento continuo, motivado por dos factores principales: la benevolencia climática y la normativa y cobertura social existente. Por todo ello, en esta investigación se busca determinar los principales hábitos y comportamientos de los turistas españoles con discapacidad en relación al alojamiento utilizado en sus viajes, así como determinar cuáles son las variables que pueden influir en dicho comportamiento. Accessible tourism represents a segment with high potential and generator of a competitive advantage for the tourism sector. This profit is a result of all people beneficiary of accessibility as elderly people, who is increasing, families, people with temporary disabilities and pregnant women. Their representatively over the total of the Spanish tourism industry is growing because of two main factors: benevolence climate and regulations and social security coverage. Therefore, this research seeks to identify the key habits and behavior of Spanish tourist with disabilities about the accommodation that they use in their trips, and the main variables which can influence in their behavior.

La calidad de servicio y la satisfacción son constructos que han recibido una gran atención en la literatura de marketing, siendo elementos centrales de muchas investigaciones. Sin embargo, las relaciones entre ambos todavía no están claras. Por ello, en el presente trabajo, se contrasta empíricamente un modelo que recoge las relaciones causales encontradas para ambos. Concretamente, pretendemos evaluar en el contexto del turismo termal, si la relación entre ambos conceptos es bidireccional (la satisfacción como antecedente de la calidad de servicio y a al mismo tiempo, consecuente) o unidireccional (la satisfacción como antecedente o consecuente de la calidad de servicio). / Service quality and satisfaction are constructs that have received so much attention in marketing literature; they had been the central elements of many investigations. However, the relationship between them is not still clear. Because of it, in the present work, a model which picks up the causal relationships for both is empirically contrasted. Specifically, we expect to evaluate in thermal tourism context, if the relationship between both constructs is bidirectional (satisfaction as an antecedent of service quality and at the same time, consequent) or unidirectional (satisfaction as antecedent or consequent of service quality).

The aim of this study was to investigate the effect of cryopreservation on the membrane integrity (MI) in the bull sperm, and determine the relationship between intact cryopreserved sperm and field fertility (FF). The eosin nigrosin exclusion and the hypo-osmotic swelling test were combined in a single test (HOS-EN test) to identify the spermatozoa with four types of MI. After cryopreservation, there was a marked decline (21.3%) in the percentage of spermatozoa with head membrane intact/ tail membrane intact (Type IV MI), and a significant increase in those with head membrane damaged/ tail membrane damaged (Type I MI) (P

We have expanded previous studies with the 5-hydroxytryptamine (5-HT)2 receptor agonist (±)-1-(2,5-dimethoxy-4-[125I]iodophenyl)-2-aminopropane [(±)-[125I]DOI] in human brain that had shown biphasic competition curves for several 5-HT2A receptor antagonists by using new selective antagonists of 5-HT2A (MDL100,907) and 5-HT2C (SB242084) receptors together with ketanserin and mesulergine. Autoradiographic competition experiments were performed with these antagonists in human brain regions where (±)-[125I]DOI labels almost exclusively 5-HT2A receptors (frontal cortex and striosomes). Furthermore, the effect of uncoupling receptor/G protein complexes on antagonist competition was studied with guanosine-5′-(β,γ-imido)triphosphate [Gpp(NH)p]. Competition experiments with (±)-[3H]1-(4-bromo-2,5-dimethoxyphenil)-2-aminopropane [(±)-[3H]DOB] were also performed in membranes from Chinese hamster ovary cells (CHOFA4) expressing cloned human 5-HT2A receptors. In both systems, ketanserin and MDL100,907 displayed biphasic competition profiles, whereas SB242084 and mesulergine competed monophasically. In absence of antagonist, 100 μM Gpp(NH)p decreased brain (±)-[125I]DOI specific binding by 40 to 50% and (±)-[3H]DOB specific binding to CHOFA4 cells by 30%. The remaining agonist-labeled uncoupled sites were still displaced biphasically by ketanserin and MDL100,907, with unaltered affinities. Saturation experiments were performed in CHOFA4 cells. (±)-[3H]DOB labeled two sites (Kdn = 0.8nM, Kd1 = 31.22 nM). Addition of 100 μM Gpp(NH)p resulted in a single low-affinity (Kd = 24.44 nM) site with unchanged Bmax. [3H]5-HT showed no specific binding to 5-HT2A receptors. These results conform with the extended ternary complex model of receptor action that postulates the existence of partly activated receptor conformation(s) (R*) in equilibrium with the ground (R) and the activated G protein-coupled (R*G) conformations. Thus, both in human brain and CHOFA4 cells, the agonists possibly label all three conformations and ketanserin and MDL100,907 recognize with different affinities at least two of these conformations., This work was supported by a grant from Comisión Interministerial de Ciencia y Tecnología, SAF 96-0336, and Galician government XUGA PGIDTOOPXI20310PR. J.F.L-G. is the recipient of fellowship “Beca de Formació de Personal Investigador Institut d'Investigacions Biomèdiques August Pi i Sunyer”