De-repression of myelin-regulating gene expression after status epilepticus in mice lacking the C/EBP homologous protein CHOP.

The C/EBP homologous protein CHOP is normally present at low levels in cells but increases rapidly after insults such as DNA damage or endoplasmatic reticulum stress where it contributes to cellular homeostasis and apoptosis. By forming heterodimers with other transcription factors, CHOP can either act as a dominant-negative regulator of gene expression or to induce the expression of target genes. Recent work demonstrated that seizure-induced hippocampal damage is significantly worse in mice lacking CHOP and these animals go on to develop an aggravated epileptic phenotype. To identify novel CHOP-controlled target genes which potentially influence the epileptic phenotype, we performed a bioinformatics analysis of tissue microarrays from chop-deficient mice after prolonged seizures. GO analysis revealed genes associated with biological membranes were prominent among those in the chop-deficient array dataset and we identified myelin-associated genes to be particularly de-repressed. These data suggest CHOP might act as an inhibitor of myelin-associated processes in the brain and could be targeted to influence axonal regeneration or reorganisation

¿Cómo pueden estimular las universidades el espíritu emprendedor? Un estudio aplicado en una asociación de jóvenes empresarios de la provincia de Alicante

[ES] Desde hace años, las universidades han puesto en marcha programas formativos con el objeto de estimular la iniciativa emprendedora entre los estudiantes. Esta investigación contribuye al debate sobre la utilidad que estos programas tienen en el carácter emprendedor de sus egresados. Para profundizar en esta cuestión, se ha analizado una muestra formada por 139 emprendedores pertenecientes a JOVEMPA (Federación de Asociaciones de Jóvenes Empresarios de la Provincia de Alicante), entidad representativa del tejido empresarial joven de la provincia de Alicante. Los resultados sugieren, por un lado, que la participación de estos jóvenes empresarios en los programas formativos hacia el emprendimiento en la universidad donde cursaron sus estudios, tuvo efectos en la mejora en competencias emprendedoras. Por otro lado, también revelaron que el rol de la universidad fue importante en su percepción del entorno al que se enfrentarían en su aventura de emprender. En resumen, si bien este trabajo no permite conocer de forma causal si estos programas fueron el verdadero estímulo a la generación de nuevas empresas, sí confirma que han ayudado a los estudiantes a identificar su potencial como emprendedores, así como, a facilitar la búsqueda de recursos para la puesta en marcha de iniciativas emprendedoras.Expósito Langa, M.; Mataix Domínguez, É.; Fota, AE. (2022). ¿Cómo pueden estimular las universidades el espíritu emprendedor? Un estudio aplicado en una asociación de jóvenes empresarios de la provincia de Alicante. En Proceedings INNODOCT/21. International Conference on Innovation, Documentation and Education. Editorial Universitat Politècnica de València. 335-343. https://doi.org/10.4995/INN2021.2021.1335133534

The Early Peopling of the Philippines based on mtDNA

Despite the eforts made to reconstruct the history of modern humans, there are still poorly explored regions that are key for understanding the phylogeography of our species. One of them is the Philippines, which is crucial to unravel the colonization of Southeast Asia and Oceania but where little is known about when and how the frst humans arrived. In order to shed light into this settlement, we collected samples from 157 individuals of the Philippines with the four grandparents belonging to the same region and mitochondrial variants older than 20,000 years. Next, we analyzed the hypervariable I mtDNA region by approximate Bayesian computation based on extensive spatially explicit computer simulations to select among several migration routes towards the Philippines and to estimate population genetic parameters of this colonization. We found that the colonization of the Philippines occurred more than 60,000 years ago, with long-distance dispersal and from both north and south migration routes. Our results also suggest an environmental scenario especially optimal for humans, with large carrying capacity and population growth, in comparison to other regions of Asia. In all, our study suggests a rapid expansion of modern humans towards the Philippines that could be associated with the establisment of maritime technologies and favorable environmental conditions

Morphological changes in carbon nanohorns under stress: a combined Raman spectroscopy and TEM study

In this work, we present the first study of highly compressed carbon nanohorns (CNHs).</p

Subunit-specific photocontrol of glycine receptors by azobenzene-nitrazepam photoswitcher

© 2021 Maleeva et al. Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, the azobenzene-nitrazepam-based photochromic compound (Azo-NZ1), has been described. In the present study, using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modeling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing, and auditory function, as well as in the development of such disorders as hyperekplexia, epilepsy, and autism. Here, we demonstrate that Azo-NZ1 blocks in a UV-dependent manner the activity of a2 GlyRs (GlyR2), while being barely active on a1 GlyRs (GlyR1). The site of Azo-NZ1 action is in the chloride-selective pore of GlyR at the 2’ position of transmembrane helix 2 and amino acids forming this site determine the difference in Azo-NZ1 blocking activity between GlyR2 and GlyR1. This subunit-specific modulation is also shown on motoneurons of brainstem slices from neonatal mice that switch during development from expressing “fetal” GlyR2 to “adult” GlyR1 receptors

Oxysterol-induced soluble endoglin release and its involvement in hypertension

[Background]: Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng. [Methods and Results]: Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice. [Conclusions]: These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia. © 2012 American Heart Association, Inc.This work was supported by grants from the Ministerio de Ciencia e Innovación of Spain (SAF2010-61827 to Dr Bernabeu, SAF2011-29244 to Dr Castrillo, and SAF2010-15881 to Dr Lopez-Novoa), Genoma España (MEICA; Dr Bernabeu), Instituto Reina Sofía de Investigación Nefrológica (FRIAT; Dr Lopez-Novoa), Junta de Castilla and Leon (Excellence Group Grant GR-100 to Dr Lopez-Novoa), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER; Dr Bernabeu), and Red de Investigación Cooperativa en Enfermedades Renales (REDINREN; Dr Lopez-Novoa). CIBERER and REDINREN are initiatives of the Instituto de Salud Carlos III of Spain supported by European Regional Development Funds (FEDER). The cardiovascular phenotyping unit, including the telemetry equipment, has been acquired with the support of FEDER. Dr Llano is recipient of a Ramón y Cajal Research contract.Peer Reviewe

Diseño de un plan de formación en competencias informacionales en los estudios de grado

Preliminary version of Project Report titled &ldquo;Design of an education plan on informational literacy competencies in degree studies,&rdquo; which is part of the Teaching Innovation Call for 2009/2010 at the University of Zaragoza, PIECyT 2009. It also explains the methodology and the design of the plan and its three levels of development.Avance de la Memoria del Proyecto denominado &ldquo;Dise&ntilde;o de un plan de formaci&oacute;n en competencias informacionales en los estudios de grado&rdquo;, que forma parte de las Convocatorias de Innovaci&oacute;n Docente 2009/2010 de la Universidad de Zaragoza, PIECyT 2009. Se explica la metodolog&iacute;a del mismo as&iacute; como el dise&ntilde;o del plan y sus tres niveles de desarrollo

MicroRNA inhibition using antimiRs in acute human brain tissue sections

Antisense inhibition of microRNAs is an emerging preclinical approach to pharmacoresistant epilepsy. A leading candidate is an "antimiR" targeting microRNA-134 (ant-134), but testing to date has used rodent models. Here, we develop an antimiR testing platform in human brain tissue sections. Brain specimens were obtained from patients undergoing resective surgery to treat pharmacoresistant epilepsy. Neocortical specimens were submerged in modified artificial cerebrospinal fluid (ACSF) and dissected for clinical neuropathological examination, and unused material was transferred for sectioning. Individual sections were incubated in oxygenated ACSF, containing either ant-134 or a nontargeting control antimiR, for 24 h at room temperature. RNA integrity was assessed using BioAnalyzer processing, and individual miRNA levels were measured using quantitative reverse transcriptase polymerase chain reaction. Specimens transported in ACSF could be used for neuropathological diagnosis and had good RNA integrity. Ant-134 mediated a dose-dependent knockdown of miR-134, with approximately 75% reduction of miR-134 at 1 μmol L-1 and 90% reduction at 3 μmol L-1 . These doses did not have off-target effects on expression of a selection of three other miRNAs. This is the first demonstration of ant-134 effects in live human brain tissues. The findings lend further support to the preclinical development of a therapy that targets miR-134 and offer a flexible platform for the preclinical testing of antimiRs, and other antisense oligonucleotide therapeutics, in human brain

MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control

There remains an urgent need for new therapies for treatment-resistant epilepsy. Sodium channel blockers are effective for seizure control in common forms of epilepsy, but loss of sodium channel function underlies some genetic forms of epilepsy. Approaches that provide bidirectional control of sodium channel expression are needed. MicroRNAs (miRNA) are small noncoding RNAs which negatively regulate gene expression. Here we show that genome-wide miRNA screening of hippocampal tissue from a rat epilepsy model, mice treated with the antiseizure medicine cannabidiol, and plasma from patients with treatment-resistant epilepsy, converge on a single target-miR-335-5p. Pathway analysis on predicted and validated miR-335-5p targets identified multiple voltage-gated sodium channels (VGSCs). Intracerebroventricular injection of antisense oligonucleotides against miR-335-5p resulted in upregulation of Scn1a, Scn2a, and Scn3a in the mouse brain and an increased action potential rising phase and greater excitability of hippocampal pyramidal neurons in brain slice recordings, consistent with VGSCs as functional targets of miR-335-5p. Blocking miR-335-5p also increased voltage-gated sodium currents and SCN1A, SCN2A, and SCN3A expression in human induced pluripotent stem cell-derived neurons. Inhibition of miR-335-5p increased susceptibility to tonic-clonic seizures in the pentylenetetrazol seizure model, whereas adeno-associated virus 9-mediated overexpression of miR-335-5p reduced seizure severity and improved survival. These studies suggest modulation of miR-335-5p may be a means to regulate VGSCs and affect neuronal excitability and seizures. Changes to miR-335-5p may reflect compensatory mechanisms to control excitability and could provide biomarker or therapeutic strategies for different types of treatment-resistant epilepsy