Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate.

The hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge. Herein is described an in vivo genetic analysis of the role of VHL, HIF1A and SDH on miR-210 by using knockout murine models, siRNA gene silencing, and analyses of human tumors. HIF-1α knockout abolished hypoxia-induced miR-210 expression in vivo but did not alter its constitutive expression in paraganglia. Normoxic miR-210 levels substantially increased by complete, but not partial, VHL silencing in paraganglia of knockout VHL-mice and by over-expression of p76del-mutated pVHL. Similarly, VHL-mutated PGLs, not those with decreased VHL-gene/mRNA dosage, over-expressed miR-210 and accumulate HIF-1α in most tumor cells. Ablation of SDH activity in SDHD-null cell lines or reduction of the SDHD or SDHB protein levels elicited by siRNA-induced gene silencing did not induce miR-210 whereas the presence of SDH mutations in PGLs and tumor-derived cell lines was associated with mild increase of miR-210 and the presence of a heterogeneous, HIF-1α-positive and HIF-1α-negative, tumor cell population. Thus, activation of HIF-1α is likely an early event in VHL-defective PGLs directly linked to VHL mutations, but it is a late event favored but not directly triggered by SDHx mutations. This combined analysis provides insights into the mechanisms of HIF-1α/miR-210 regulation in normal and tumor tissues potentially useful for understanding the pathogenesis of cancer and other diseases sharing similar underpinnings

Estudos Luso-Hispanos de História do Direito

El primer volumen de los Estudios Luso-Hispanos de Historia del Derecho/ Estudos Luso-Hispanos de História do Direito recoge los trabajos presentados en el ámbito de la segunda edición del EHLHD (Encuentro Hispano-Luso de Historiadores del Derecho/Encontro Hispano-Luso de Historiadores do Direito), celebrado los días 6, 7 y 8 de julio de 2017 en la Universidad Autónoma de Madrid.Presentación / Laura Beck Varela y María Julia Solla Sastre (pp. 9-12). -- Quando il diritto era ancora compatto. Perché la storia giuridica svizzera è così diversa? / Pio Caroni (pp. 13-43). -- El derecho municipal medieval de la Cataluña Nueva (siglos XIII-XVII) / Josep Serrano Daura (pp. 45-62). -- Algunas consideraciones sobre el régimen local cantábrico frente al fomento naval y forestal en la Corona de Castilla (c.1560-1570) / Alfredo José Martínez González (pp. 63-91). -- Organização judiciária e administração da justiça no Portugal filipino: a “reformaçam da justiça” de Filipe I de Portugal (1582) / Jorge Veiga Testos (pp. 93-121). -- El oficio de secretario en la doctrina jurídica de la Edad Moderna / Marina Rojo Gallego-Burín (pp. 123-149). -- Notas sobre la reforma municipal carolina en Sevilla: la representación del común / María del Mar Tizón Ferrer (pp. 151-165). -- Un programa ilustrado para la formación de juristas. El Plan de Estudios de Pablo de Olavide de 1768 / Fernando Liendo Tagle (pp. 167-198). -- La formación del jurista en el virreinato del Perú en las postrimerías del antiguo régimen / Carlos Tormo Camallonga (pp. 199-237). -- Propiedad moderna y alteridad indígena en Brasil (1755-1862) / Camilla de Freitas Macedo (pp. 239-270). -- Direito, política e sociedade: as Novas Conquistas de Goa durante o Perismo. Os contributos de Nery Xavier e Cláudio Lagrange / Luís Pedroso de Lima Cabral de Oliveira y João Pedro Caleira (pp. 271-303). -- Horizonte nacional, espacio tradicional. La construcción jurídica de la nación y el extranjero en la constitución de Cádiz / Iván Pastoriza Martínez (pp. 305-337). -- La disolución de los consejos: entre quiebras, confusiones y continuidad (1834-1836) / Antonio Manuel Luque Reina (pp. 339-371). -- Justicia legal y derecho judicial: la influencia de la jurisprudencia en la formación de la ciencia jurídica isabelina / Blanca Sáenz de Santa María Gómez-Mampaso (pp. 373-409). -- Nuevas etiquetas disciplinares y sus contiendas: las ciencias políticas ante el derecho en Francia (1871-1900) / Pedro Luis López Herráiz (pp. 411-449). -- O casamento na legislação de 1910 em Portugal. A mudança de paradigma nas relações familiares / Miriam Afonso Brigas (pp. 451-479). -- Primeira Lei do Contrato de Trabalho em Portugal: Lei nº 1.952, de 10 de Março de 1937 / Margarida Seixas (pp. 481-513). -- A Revisão Constitucional de 1971: o Projecto de Lei 6/X da “Ala Liberal” num contexto de tensões internas no Marcelismo / Filipe de Arede Nunes (pp. 515-543)

Algunas normas para la conducción de una batería de hornos de coque

Peer reviewe

A general modular approach for the solubility tagging of BODIPY dyes

We describe a general and practical strategy for the direct one-step incorporation of a tunable solubility module at the boron atom of F-BODIPY dyes. The tethering reaction uses easy-to-handle reagents, has broad functional group compatibility and proceeds under mild conditions without requiring any pre-functionalization of the starting F-BODIPY to yield the solubility-tagged O-BODIPY derivative in 51–86% yield. The module can be introduced at the end of the synthetic route without perturbing the fluorophore scaffold, thus minimizing difficulties in product isolation. Its orthogonal geometrical arrangement with respect to the plane of the BODIPY chromophore hampers intermolecular aggregation processes that quench fluorescence, while the covalent attachment to the boron atom has a minimal effect on the absorption properties. Fully water-soluble and hydrolytically stable BODIPYs were prepared by incorporating either neutral (tetra- and octaethylene glycol chains) or zwitterionic (sulfobetaine) hydrophilic tags in the module. The new dyes are valuable live cell imaging probes that ameliorate the undesired partitioning into lipophilic compartments that is often observed for standard BODIPYs. This strategy can be readily adapted to the general and highly practical post-synthetic introduction of new functionalities into F-BODIPY dyes, including phase-tagging, by appropriately choosing the nature of the chemical tags attached to the module.We gratefully acknowledge the Spanish Ministerio de Economía y Competitividad (MINECO, projects MAT2017-83856-C3-1-P, MAT2017-83856-C3-3-P, and MAT2015-68837-REDT), the Instituto de Salud Carlos III-Fondo de Investigación Sanitaria (CIBERONC) and Gobierno Vasco (IT912-16) for financial support. A. B.-M. and R. P. M. thank MINECO and UPV-EHU for a FPI predoctoral contract and predoctoral fellowship, respectively.Peer Reviewe

Estudios Luso-Hispanos de Historia del Derecho

El primer volumen de los Estudios Luso-Hispanos de Historia del Derecho/ Estudos Luso-Hispanos de História do Direito recoge los trabajos presentados en el ámbito de la segunda edición del EHLHD (Encuentro Hispano-Luso de Historiadores del Derecho/Encontro Hispano-Luso de Historiadores do Direito), celebrado los días 6, 7 y 8 de julio de 2017 en la Universidad Autónoma de Madrid

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death