A practical Java tool for small-molecule compound appraisal

The increased use of small-molecule compound screening by new users from a variety of different academic backgrounds calls for adequate software to administer, appraise, analyse and exchange information obtained from screening experiments. While software and spreadsheet solutions exist, there is a need for software that can be easily deployed and is convenient to use.The Java application cApp addresses this need and aids in the handling and storage of information on small-molecule compounds. The software is intended for the appraisal of compounds with respect to their physico-chemical properties, analysis in relation to adherence to likeness rules as well as recognition of pan-assay interference components and cross-linking with identical entries in the PubChem Compound Database. Results are displayed in a tabular form in a graphical interface, but can also be written in an HTML or PDF format. The output of data in ASCII format allows for further processing of data using other suitable programs. Other features include similarity searches against user-provided compound libraries and the PubChem Compound Database, as well as compound clustering based on a MaxMin algorithm.cApp is a personal database solution for small-molecule compounds which can handle all major chemical formats. Being a standalone software, it has no other dependency than the Java virtual machine and is thus conveniently deployed. It streamlines the analysis of molecules with respect to physico-chemical properties and drug discovery criteria; cApp is distributed under the GNU Affero General Public License version 3 and available from http://www.structuralchemistry.org/pcsb/. To download cApp, users will be asked for their name, institution and email address. A detailed manual can also be downloaded from this site, and online tutorials are available at http://www.structuralchemistry.org/pcsb/capp.php

Deaf bilingual education: key tenets for strategic change

Pese a los progresos logrados en la protección de los derechos fundamentales de salud y educación de las personas sordas usuarias de las lenguas de signos, a menudo se sigue negando a niños sordos su derecho a aprender y usar las lenguas de signos en su educación y en entornos físicos y psicosociales accesibles de conformidad con la Convención de los Derechos de las Personas con Discapacidad (CDPD) y con las recientes leyes 27/2007 y 17/2007. El objetivo principal de este estudio fue obtener información sobre los factores estratégicos que favorecen una escuela saludable e inclusiva, mediante programas de educación bilingüe sostenibles y de calidad para escolares sordos en España. La metodología utilizada consistió en un estudio descriptivo con componentes de investigación-acción participativa y un enfoque de análisis estratégico. Como resultados, cabe destacar que las principales macrotendencias que, en el ámbito internacional, han promovido el cambio hacia prácticas bilingües son dos: en primer lugar, los cambios sociales y políticos que tienden a una creciente aceptación de la diversidad y los temas relacionados con las personas sordas; y en segundo lugar, una tendencia a un activismo, una autoconciencia y un apoderamiento crecientes por parte de las personas sordas. Como contrapartida, las que lo han obstaculizado son, por un lado, la visión de la sordera como una condición médica, que puede solucionarse mediante la tecnología; y por otro lado, el fonocentrismo, unido a una cierta resistencia social a lo desconocido. Aunque en España algunas de las escuelas que han iniciado el cambio cumplen las recomendaciones de la CDPD, la mayoría están todavía en una fase preliminar de formulación o puesta en práctica de este nuevo modelo y distan mucho de encontrarse distribuidas de manera igualitaria en las diferentes comunidades autónomas. Como conclusión podemos decir que conseguir una educación más saludable e inclusiva para los escolares sordos implica poner en marcha una estrategia de actuación planificada en la que participen activamente todos los sectores y organismos relevantes implicados y, en particular, las comunidades sordas a través de las organizaciones que las representan. Sin un cambio radical de perspectiva, la salud y la educación no serán accesibles a todos y las desigualdades sociales se verán acentuadas.Although progress has been made in protecting deaf sign language users’ fundamental rights to health and education, all too often deaf children are still denied the right to learn and use sign languages in their education and in accessible physical and psycho-social environments in accordance with both the Convention on the Rights of Persons with Disabilities (CRPD) and recent Spanish laws (Act 27/2007 and Act 17/2007). The main objective of the present study was to collect information about some strategic factors that may facilitate healthy, inclusive schooling through sustainable, high-quality deaf bilingual programmes in Spain. A descriptive study was conducted, with some components of participatory action research and a strategic analysis framework. The two main megatrends found to have spurred the current change toward bilingual education in order of priority are: (1) societal and political changes towards a growing acceptance of diversity and Deaf issues and (2) growing Deaf activism, selfawareness and empowerment. The two main hindering megatrends are: (1) the view of deafness as a medical condition with a technological solution and (2) phonocentrism and societal resistance to the unknown. Although some schools have achieved CRPD-recommended standards, the majority of deaf bilingual programmes in Spain are still in a very early stage of formulation and implementation and are far from being equally distributed across the country. Transforming schools into healthier, more inclusive settings for deaf children implies the implementation of a well-planned strategy involving the active participation of relevant sectors and organizations, particularly deaf communities through their representative organizations. Unless there is a radical change of perspective, health and education will not be available to all, and therefore social inequalities will increase.Fondo de Investigación Sanitaria del Ministerio de Sanidad y Consumo; Vicerrectorado de Investigación, Desarrollo e Innovación; Vicerrectorado de Alumnado; y Grupo de Investigación en Salud Pública de la Universidad de Alicante

AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1

Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells. The current study addresses the question of whether the host cell protein AMP-activated protein kinase (AMPK), an important metabolic sensor, can control HSV-1 replication in endothelial cells. We show that downregulation of the catalytic subunits AMPKα1 and/or AMPKα2 increased HSV-1 replication as monitored by TCID50 titrations, while a potent AMPK agonist, MK-8722, strongly inhibited it. MK-8722 induced a persistent phosphorylation of the AMPK downstream targets acetyl-CoA carboxylase (ACC) and the rapamycin-sensitive adaptor protein of mTOR (Raptor) and, related to this, impairment of ACC1-mediated lipid synthesis and the mechanistic target of the rapamycin complex-1 (mTORC1) pathway. Since blockade of mTOR by Torin-2 as well as downregulation of ACC1 by siRNA also decreased HSV-1 replication, MK-8722 is likely to exert its anti-viral effect via mTORC1 and ACC1 inhibition. Importantly, MK-8722 was able to reduce virus replication even when added after HSV-1. Together, our data highlight the importance of endothelial cells as host cells for HSV-1 replication upon systemic infection and identify AMPK, a metabolic host cell protein, as a potential target for antiviral strategies against HSV-1 infection and its severe consequences

Preventing disability through understanding international megatrends in Deaf bilingual education

Background: Education is a basic prerequisite for d/Deaf people’s health. Deaf education varies considerably from country to country and we still know very little about the reasons for such variation. Objective: To identify international megatrends that influence the current Deaf bilingual education move (Deaf Bilingual–Bicultural education; DBiBi) worldwide. Methods: Using the Delphi technique, 41 experts in d/ Deaf education (nine Deaf, 32 hearing) from 18 countries identified, ranked, and rated international megatrends in DBiBi education. Results: The process revealed six main essential elements of the international implementation of DBiBi education and nine main barriers against it. The top five promoting forces in that list in order of priority were: (1) societal and political changes towards a growing acceptance of diversity and Deaf issues; (2) growing Deaf activism, self-awareness and empowerment; (3) scientific research in sign linguistics and bilingualism; (4) changes in the d/Deaf educational community; and (5) international cooperation. The top five hindering forces included: (1) the view of deafness as a medical condition with a technological solution; (2) phonocentrism and societal resistance to the unknown; (3) educational and d/Deaf educational policies; (4) DBiBi education weaknesses; and (5) invisibility, heterogeneity and underperformance of the d/Deaf population. Conclusion: The results of this study reveal that social/political changes and a medical/social model of Deaf people’s health can promote or limit Deaf people’s educational options much more than changes within the education system itself, and that a transnational perspective is needed in deciding how best to support DBiBi education at a national and local level in an increasingly globalised world.Spanish Medical Research Council

ω-Conotoxin GVIA mimetics that bind and inhibit neuronal Cav2.2 ion channels

The neuronal voltage-gated N-type calcium channel (Cav2.2) is a validated target for the treatment of neuropathic pain. A small library of anthranilamide-derived ω-Conotoxin GVIA mimetics bearing the diphenylmethylpiperazine moiety were prepared and tested using three experimental measures of calcium channel blockade. These consisted of a 125I-ω-conotoxin GVIA displacement assay, a fluorescence-based calcium response assay with SH-SY5Y neuroblastoma cells, and a whole-cell patch clamp electrophysiology assay with HEK293 cells stably expressing human Cav2.2 channels. A subset of compounds were active in all three assays. This is the first time that compounds designed to be mimics of ω-conotoxin GVIA and found to be active in the 125I-ω-conotoxin GVIA displacement assay have also been shown to block functional ion channels in a dose-dependent manner

Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations.

Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration-approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling

Metabolomics and lipidomics reveal perturbation of sphingolipid metabolism by a novel anti-trypanosomal 3-(oxazolo[4,5-b]pyridine-2-yl)anilide

Introduction: Trypanosoma brucei is the causative agent of human African trypanosomiasis, which is responsible for thousands of deaths every year. Current therapies are limited and there is an urgent need to develop new drugs. The anti-trypanosomal compound, 3-(oxazolo[4,5-b]pyridine-2-yl)anilide (OXPA), was initially identified in a phenotypic screen and subsequently optimized by structure–activity directed medicinal chemistry. It has been shown to be non-toxic and to be active against a number of trypanosomatid parasites. However, nothing is known about its mechanism of action. Objective: Here, we have utilized an untargeted metabolomics approach to investigate the biochemical effects and potential mode of action of this compound in T. brucei. Methods: Total metabolite extracts were analysed by HILIC-chromatography coupled to high resolution mass spectrometry. Results: Significant accumulation of ceramides was observed in OXPA-treated T. brucei. To further understand drug-induced changes in lipid metabolism, a lipidomics method was developed which enables the measurement of hundreds of lipids with high throughput and precision. The application of this LC–MS based approach to cultured bloodstream-form T. brucei putatively identified over 500 lipids in the parasite including glycerophospholipids, sphingolipids and fatty acyls, and confirmed the OXPA-induced accumulation of ceramides. Labelling with BODIPY-ceramide further confirmed the ceramide accumulation following drug treatment. Conclusion: These findings clearly demonstrate perturbation of ceramide metabolism by OXPA and indicate that the sphingolipid pathway is a promising drug target in T. brucei.No Full Tex

Diversification of ortho-fused cycloocta-2,5-dien-1-one cores and 8 to 6-Ring conversion by sigma bond C-C cleavage

Sequential treatment of 2-C6H4Br(CHO) with LiC≡CR1 (R1 = SiMe3, tBu), nBuLi, CuBr∙SMe2 and HC≡CCHClR2 [R2 = Ph, 4-CF3Ph, 3-CNPh, 4-(MeO2C)Ph] at -50 oC leads to formation of an intermediate carbanion (Z)-1,2-C6H4{CA(=O)C≡CBR1}{CH=CH(CH–)R2} (4). Low temperatures (-50 oC) favour attack at CB leading to kinetic formation of 6,8-bicycles containing non-classical C-carbanion enolates (5). Higher temperatures ( 10 oC to ambient) and electron deficient R2 favour retro σ-bond C-C cleavage regenerating 4 which subsequently closes on CA providing 6,6-bicyclic alkoxides (6). Computational modelling (CBS-QB3) indicates both pathways are viable and of similar energies. Reaction of 6 with H+ affords 1,2-dihydronaphthalen-1-ols, or under dehydrating conditions, 2-aryl-1-alkynylnaphthlenes. Enolates 5 react in situ with: H2O, D2O, I2, allylbromide, S2Me2, CO2 and lead to the expected C-E derivatives (E = H, D, I, allyl, SMe, CO2H) in 49-64% yield directly from intermediate 5. The parents (E = H; R1 = SiMe3, tBu; R2 = Ph) are versatile starting materials for NaBH4 and Grignard C=O additions, desilylation (when R1 = SiMe) and oxime formation. The latter allows formation of 6,9-bicyclics via Beckmann rearrangement. The 6,8-ring iodides are suitable Suzuki precursors for Pd-catalysed C-C coupling (81-87%); while the carboxylic acids readily form amides under T3P® conditions (71-95%)