Force-dependent elasticity of nucleic acids

The functioning of double-stranded (ds) nucleic acids (NAs) in cellular processes is strongly mediated by their elastic response. These processes involve proteins that interact with dsDNA or dsRNA and distort their structures. The perturbation of the elasticity of NAs arising from these deformations is not properly considered by most theoretical frameworks. In this work, we introduce a novel method to assess the impact of mechanical stress on the elastic response of dsDNA and dsRNA through the analysis of the fluctuations of the double helix. Application of this approach to atomistic simulations reveals qualitative differences in the force dependence of the mechanical properties of dsDNA with respect to those of dsRNA, which we relate to structural features of these molecules by means of physically-sound minimalistic models.Comment: 6 pages, 2 figure

Force-dependent elasticity of nucleic acids

The functioning of double-stranded (ds) nucleic acids (NAs) in cellular processes is strongly mediated by their elastic response. These processes involve proteins that interact with dsDNA or dsRNA and distort their structures. The perturbation of the elasticity of NAs arising from these deformations is not properly considered by most theoretical frameworks. In this work, we introduce a novel method to assess the impact of mechanical stress on the elastic response of dsDNA and dsRNA through the analysis of the fluctuations of the double helix. Application of this approach to atomistic simulations reveals qualitative differences in the force dependence of the mechanical properties of dsDNA with respect to those of dsRNA, which we relate to structural features of these molecules by means of physically-sound minimalistic modelsThe project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement no. 847648. The fellowship code is LCF/BQ/PI20/ 11760019. We acknowledge support from the Ministerio de Ciencia e Innovación (MICINN) through the project PID2020-115864RB-I00 and the “María de Maeztu” Programme for Units of Excellence in R&D (grant no. CEX2018-000805-M). We thank Laura R. Arriaga for helpful discussio

A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance

AMP-activated protein kinase (AMPK) in the ventromedial nucleus of the hypothalamus (VMH) and orexin (OX) in the lateral hypothalamic area (LHA) modulate brown adipose tissue (BAT) thermogenesis. However, whether these two molecular mechanisms act jointly or independently is unclear. Here, we show that the thermogenic effect of bone morphogenetic protein 8B (BMP8B) is mediated by the inhibition of AMPK in the VMH and the subsequent increase in OX signaling via the OX receptor 1 (OX1R). Accordingly, the thermogenic effect of BMP8B is totally absent in ox-null mice. BMP8B also induces browning of white adipose tissue (WAT), its thermogenic effect is sexually dimorphic (only observed in females), and its impact on OX expression and thermogenesis is abolished by the knockdown of glutamate vesicular transporter 2 (VGLUT2), implicating glutamatergic signaling. Overall, our data uncover a central network controlling energy homeostasis that may be of considerable relevance for obesity and metabolic disordersThe research leading to these results received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement 281854 the ObERStress project (M.L.), Junta de Andalucía (M.T.-S., P08-CVI-03788 and P12-FQM-01943), Xunta de Galicia (M.L., 2015-CP079; and R.N., 2015-CP080 and PIE13/00024), MINECO co-funded by FEDER (C.D., BFU2014-55871-P; R.N., BFU2015-70664-R; M.T.-S., BFU2014-57581-P; and M.L., SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). I.G.-G. is a recipient of a fellowship from Ministerio de Educación, Cultura y Deporte (FPU12/01827). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptS

High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically

Memoria de responsabilidad social Universidad de Huelva : curso 2009-2010

La Responsabilidad Social Corporativa se ha convertido en uno de los estilos de dirección más importantes, tanto en organizaciones públicas como privadas. Se basa en orientar los esfuerzos institucionales hacia objetivos que tienen en cuenta, entre otros, el desarrollo social, la protección medioambiental y respeto de los derechos humanos, asumiendo voluntariamente compromisos que van más allá de las obligaciones meramente legales. Las universidades, como instituciones que representan la vanguardia de los avances sociales, debemos tener en cuenta en nuestros sistemas de gobernanza los principios que guían esta filosofía de gestión. Por ello, tanto en las diferentes decisiones de los órganos colegiados de la Universidad de Huelva como en nuestro Plan Estratégico, establecemos una serie de parámetros que buscan cumplir la Responsabilidad Social. Está publicación recoge, por primera vez, lo realizado en la Universidad de Huelva los diferentes ámbitos que abarca la Responsabilidad Social, de forma que podamos analizar dónde nos encontramos y, sobre todo, cómo mejorar en este contexto tan importante para una institución como la universitaria

Adaptor protein cerebral cavernous malformation 3 (CCM3) mediates phosphorylation of the cytoskeletal proteins ezrin/radixin/moesin by mammalian Ste20-4 to protect cells from oxidative stress

While studying the functions of CCM3/PDCD10, a gene encoding an adaptor protein whose mutation results in vascular malformations, we have found that it is involved in a novel response to oxidative stress that results in phosphorylation and activation of the ezrin/radixin/moesin (ERM) family of proteins. This phosphorylation protects cells from accidental cell death induced by oxidative stress. We also present evidence that ERM phosphorylation is performed by the GCKIII kinase Mst4, which is activated and relocated to the cell periphery after oxidative stress. The cellular levels of Mst4 and its activation after oxidative stress depend on the presence of CCM3, as absence of the latter impairs the phosphorylation of ERM proteins and enhances death of cells exposed to reactive oxygen species. These findings shed new light on the response of cells to oxidative stress and identify an important pathophysiological situation in which ERM proteins and their phosphorylation play a significant role