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High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery.

The cytokine microenvironment modulates CD4 T cell differentiation causing the shift of naïve CD4 T cells into different cell subsets. This process is also regulated by modulators such as VIP, a neuropeptide with known immunomodulatory properties on CD4 T cells that exert this action through specific receptors, VPAC1 and VPAC2. Our results show that the pattern of VIP receptors expression ratio is modified during Th17 differentiation. In this report, we evaluate the capacity of VIP to modulate naïve human cells into Th17 cells in vitro by analyzing their functional phenotype. The presence of VIP maintains the non-pathogenic profile of Th17-polarized cells, increases the proliferation rate and decreases their Th1 potential. VIP induces the up-regulation of the STAT3 gene interaction with the VPAC1 receptor during the onset of Th17 differentiation. Moreover, RORC, RORA and IL-17A genes are up-regulated in the presence of VIP through interaction with VPAC1 and VPAC2 receptors. Interestingly, VIP induces the expression of the IL-23R gene through interaction with the VPAC2 receptor during the expansion phase. This is the first report that describes the differentiation of naïve human T cells to Th17-polarized cells in the presence of VIP and demonstrates how this differentiation regulates the expression of the VIP receptors., Instituto de Salud Carlos III, Comunidad de Madrid, Unión Europea, Ministerio de Economía y Competitividad, Depto. de Biología Celular, Fac. de Ciencias Biológicas, TRUE, pub

Introduction: Macrophages are a heterogeneous population of innate immune cells that support tissue homeostasis through their involvement in tissue development and repair, and pathogen defense. Emerging data reveal that metabolism may control macrophage polarization and function and, conversely, phenotypic polarization may drive metabolic reprogramming. Methods: Here we use biochemical analysis, correlative cryogenic fluorescence microscopy and cryo-focused ion-beam scanning electron microscopy. Results: We demonstrate that growth hormone (GH) reprograms inflammatory GM-CSF-primed monocyte-derived macrophages (GM-MØ) by functioning as a metabolic modulator. We found that exogenous treatment of GM-MØ with recombinant human GH reduced glycolysis and lactate production to levels similar to those found in anti-inflammatory M-MØ. Moreover, GH treatment of GM-MØ augmented mitochondrial volume and altered mitochondrial dynamics, including the remodeling of the inner membrane to increase the density of cristae. Conclusions: Our data demonstrate that GH likely serves a modulatory role in the metabolism of inflammatory macrophages and suggest that metabolic reprogramming of macrophages should be considered as a new target to intervene in inflammatory diseases.

Compuestos ligandos del receptor CXCR4 y uso de los mismos. La presente invención se refiere a nuevos compuestos de fórmula (I) que actúan como ligandos del receptor CXCR4. La presente invención también se refiere a su uso para el tratamiento y/o prevención de enfermedades mediadas por dicho receptor, como son el cáncer, infección por VIH o la artritis reumatoide.

Las pilas de combustible de óxido sólido (SOFCs) son una de las tecnologías más prometedoras y respetuosas con el medio ambiente para la generación de energía eléctrica de forma eficiente a partir de gas natural e hidrocarburos. Sin embargo, el envenenamiento de los ánodos frente a hidrocarburos y la integridad mecánica y química de los electrolitos constituyen dos serios problemas a la hora de optimizar el diseño de estas pilas. A ello hay que unir las elevadas temperaturas de funcionamiento, que reducen de manera significativa la selección de materiales y encarecen enormemente la tecnología, impidiendo su explotación a larga escala. El presente trabajo aborda la fabricación de los tres electrolitos más usados en la construcción de SOFCs mediante su síntesis mecanoquímica mecanoquímica y posterior compactación mediante prensado uniaxial. Seguidamente, se presentan algunas de sus propiedades mecánicas más características, así como las principales ventajas e inconvenientes de los mismos.

[ES] La presente invención se refiere a nuevos compuestos de fórmula (I) que actúan como ligandos del receptor CXCR4. La presente invención también se refiere a su uso para el tratamiento y/o prevención de enfermedades mediadas por dicho receptor, como son el cáncer, infección por VIH o la artritis reumatoide., [EN] The present invention relates to new compounds of formula (I) that act as CXCR4 receptor ligands. The invention also relates to the use thereof to treat and/or prevent diseases mediated by said receptor, such as cancer, HIV infection or rheumatoid arthritis., [FR] La présente invention concerne de nouveaux composés de formule (I) qui agissent comme ligands du récepteur CXCR4. La présente invention concerne également son utilisation pour le traitement et/ou la prévention de maladies médiées par ce récepteur, telles que le cancer, une infection par le VIH ou la polyarthrite rhumatoïde.