MYH10 activation rescues contractile defects in arrhythmogenic cardiomyopathy (ACM).

The most prevalent genetic form of inherited arrhythmogenic cardiomyopathy (ACM) is caused by mutations in desmosomal plakophilin-2 (PKP2). By studying pathogenic deletion mutations in the desmosomal protein PKP2, here we identify a general mechanism by which PKP2 delocalization restricts actomyosin network organization and cardiac sarcomeric contraction in this untreatable disease. Computational modeling of PKP2 variants reveals that the carboxy-terminal (CT) domain is required for N-terminal domain stabilization, which determines PKP2 cortical localization and function. In mutant PKP2 cells the expression of the interacting protein MYH10 rescues actomyosin disorganization. Conversely, dominant-negative MYH10 mutant expression mimics the pathogenic CT-deletion PKP2 mutant causing actin network abnormalities and right ventricle systolic dysfunction. A chemical activator of non-muscle myosins, 4-hydroxyacetophenone (4-HAP), also restores normal contractility. Our findings demonstrate that activation of MYH10 corrects the deleterious effect of PKP2 mutant over systolic cardiac contraction, with potential implications for ACM therapy.This study was supported by MCIU grant BFU2016-75144-R and PID2020- 116935RB-I00, and by a “la Caixa” Banking Foundation grant under the project code HR18-00304” to J.A.B.; The study was also supported by the “Ayudas a la Investigación Cátedra Real Madrid-Universidad Europea” (2017/RM01). C.M.-L. and S.S. hold MCIU predoctoral contracts BES-2017-079715, and BES-2017-079707 respectively. R.G. acknowledges funding from the European Research Council under grant ERCAG-340177 (3DNanoMech) and from the MCIU under grant MAT2016- 76507-R. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence, grant CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033. The microscopy experiments were carried out at the Dynamic Microscopy and Image Unit, CNIC, ICTS-ReDib, co-financed by MCIN/AEI /10.13039/ 501100011033 and FEDER “A way of making Europe” (#ICTS-2018-04- CNIC-16). Imaris full analysis were carried out at the Microscopy & Dynamic Imaging, CNIC, ICTS-ReDib, co-funded by MCIN/AEI /10.13039/501100011033. Biomedical Imaging has been conducted at the Advanced Imaging Unit of the CNIC (Centro Nacional de Investigaciones Cardiovasculares Carlos III), Madrid, Spain. This project used the ReDIB ICTS infrastructure TRIMA@CNIC, Ministerio de Ciencia e Innovación (MCIN).S

TDP-43 regulates transcription at protein-coding genes and Alu retrotransposons

The 43-kDa transactive response DNA-binding protein (TDP-43) is an example of an RNA-binding protein that regulates RNA metabolism at multiple levels from transcription and splicing to translation. Its role in post-transcriptional RNA processing has been a primary focus of recent research, but its role in regulating transcription has been studied for only a few human genes. We characterized the effects of TDP-43 on transcription genome-wide and found that TDP-43 broadly affects transcription of protein-coding and noncoding RNA genes. Among protein-coding genes, the effects of TDP-43 were greatest for genes < 30 thousand base pairs in length. Surprisingly, we found that the loss of TDP-43 resulted in increased evidence for transcription activity near repetitive Alu elements found within expressed genes. The highest densities of affected Alu elements were found in the shorter genes, whose transcription was most affected by TDP-43. Thus, in addition to its role in post-transcriptional RNA processing, TDP-43 plays a critical role in maintaining the transcriptional stability of protein-coding genes and transposable DNA elements.National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS082376]; Office of the Director, National Institutes of Health of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [S10OD013237]Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Interacciones entre los alimentos y las estatinas

Cada vez es más conocida la existencia de interaccio-nes de distintos fármacos entre sí y de éstos con la dieta. Las estatinas son medicamentos ampliamente utilizados en la actualidad para el tratamiento de las hiperlipe-mias. La dieta tiene gran influencia en la prevención y/o tratamiento de estas patologías ya que la estrategia tera-péutica que se emplea consiste en una dieta adecuada, y si esto no da resultado se inicia la terapia farmacológica siempre en combinación con la dieta. Por este motivo es necesario el conocimiento de las posibles interacciones entre este tipo de fármacos y los alimentos con el fin de evitar alteraciones en los efectos terapéuticos e incluso la aparición de efectos adversos. Todas las estatinas se absorben por vía oral por lo que es muy importante la influencia de la ingesta a la hora de la administración para alcanzar un adecuado efecto terapéutico. Muchas de las interacciones de las estatinas residen en su meta-bolismo a través del citocromo P-450 (excepto pravasta-tina) lo que facilita su posible interacción con determi-nados alimentos o componentes de los mismos, como es el caso del zumo de pomelo. En este trabajo se hace una revisión de las interaccio-nes fármaco-nutriente con especial atención a las pro-pias de las estatinas y se describe el mecanismo de di-chas interacciones para así poder contribuir a evitarlas y mejorar de este modo el tratamiento en personas con hiperlipemias

Relationship between metal concentration (Fe, Cu, Zn) and different serum polymorphisms in the spanish horse

The blood serum concentration of the metals Fe, Cu, and Zn has been studied in a population of sixty Spanish horses, as well as the genetic polymorphisms of albumin (Al), transferrine (Tf) and alcaline esterase (Est-al) and acid (Est-ac). With the data obtained, the elementary analysis of quantitative characteristics is carried out (metal concentration: Fe, Cu, Zn). The differences between the metal concentration and each of the polymorphisms studied is determined through variance analysis to infer possible relationships. The,X"2 equilibrium for different polymorphisms is also obtained and the heterozygosis is calculated for each locus as well as for the population as a whole.Se ha estudiado una población de 60 caballos españoles, la concentración en suero sanguínea de metales Fe, Cu y Zn, así como los polimorfismos genéticos de albúmina, esterasa ácida y alcalina y transferrina. Con los datos obtenidos se realiza el análisis estadístico elemental de los caracteres cuantitativos (concentración de los metales). Se determina la diferencia entre la concentración de metal y cada uno de los polimorfismos, mediante análisis de varianza, para inferir posibles relaciones. Se obtiene el X2 de, equilibrio para ellos, diferentes polimorfismos y se calcula la heterozigosis para cada locus así como para el conjunto de la población

Ciudades en la encrucijada : violencia y poder criminal en Río de Janeiro, Medellín, Bogotá y Ciudad Juárez

Con el presente libro se dan a conocer los resultados de la investigación comparativa sobre criminalidad y violencias en las ciudades de Río de Janeiro, Medellín, Ciudad Juárez y Bogotá, cuya realización fue posible gracias al interés de la Corporación Región y del Instituto de Estudios Políticos y Relaciones Internacionales (IEPRI) de la Universidad Nacional por contribuir al avance de la investigación de estos temas en América Latina. Este propósito se hizo realidad gracias al apoyo del International Development Research Centre de Canadá (IDRC) y de Colciencias (Colombia)

ATRX-Deficient High-Grade Glioma Cells Exhibit Increased Sensitivity to RTK and PDGFR Inhibitors

High-grade glioma, including anaplastic astrocytoma and glioblastoma (GBM) patients, have a poor prognosis due to the lack of effective treatments. Therefore, the development of new therapeutic strategies to treat these gliomas is urgently required. Given that high-grade gliomas frequently harbor mutations in the SNF2 family chromatin remodeler ATRX, we performed a screen to identify FDA-approved drugs that are toxic to ATRX-deficient cells. Our findings reveal that multi-targeted receptor tyrosine kinase (RTK) and platelet-derived growth factor receptor (PDGFR) inhibitors cause higher cellular toxicity in high-grade glioma ATRX-deficient cells. Furthermore, we demonstrate that a combinatorial treatment of RTKi with temozolomide (TMZ)–the current stand-ard of care treatment for GBM patients–causes pronounced toxicity in ATRX-deficient high-grade glioma cells. Our findings suggest that combinatorial treatments with TMZ and RTKi may increase the therapeutic window of opportunity in patients who suffer high-grade gliomas with ATRX mu-tations. Thus, we recommend incorporating the ATRX status into the analyses of clinical trials with RTKi and PDGFRi.This work was supported by grants from Danish National Research Foundation (DNRF115), Danish Cancer Society (KBVU-2017_R167-A11063), European Research Council (ERC-2015-STG- 679068), Nordea-fonden (02-2017-1749) and the Spanish Ministry of Science and Innovation (PID2020- 119329RB-I00). David Pladevall-Morera was supported with a PhD scholarship from the Lundbeck Foundation (R218-2016-415) and funding from Dansk Kræftforskningsfond. María Castejón-Griñán holds an Incorporación fellowship from the Junta de Andalucía. Paula Aguilera was supported with a Juan de la Cierva formación fellowship from the MICINN and an Incorporación fellowship from the Junta de Andalucía. Toyota Fonden and Læge Sofus Carl Emil Friis og hustru Olga Doris Fonden funded the acquisition of the high-content microscope used in this study

Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology

Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although defects in nucleocytoplasmic transport (NCT) is reported ALS and other neurodegenerative diseases, whether defects in NCT occur in TBI remains unknown. We performed proteomic analysis on Drosophila exposed to repeated TBI and identified resultant alterations in several novel molecular pathways. TBI upregulated nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) proteins as well as alter nucleoporin stability. Traumatic injury disrupted RanGAP1 and NPC protein distribution in flies and a rat model and led to coaggregation of NPC components and TDP-43. In addition, trauma-mediated NCT defects and lethality are rescued by nuclear export inhibitors. Importantly, genetic upregulation of nucleoporins in vivo and in vitro triggered TDP-43 cytoplasmic mislocalization, aggregation, and altered solubility and reduced motor function and lifespan of animals. We also found NUP62 pathology and elevated NUP62 concentrations in postmortem brain tissues of patients with mild or severe CTE as well as co-localization of NUP62 and TDP-43 in CTE. These findings indicate that TBI leads to NCT defects, which potentially mediate the TDP-43 pathology in CTE