Recessive mutations in muscle-specific isoforms of FXR1 cause congenital multi-minicore myopathy

FXR1 is an alternatively spliced gene that encodes RNA binding proteins (FXR1P) involved in muscle development. In contrast to other tissues, cardiac and skeletal muscle express two FXR1P isoforms that incorporate an additional exon-15. We report that recessive mutations in this particular exon of FXR1 cause congenital multi-minicore myopathy in humans and mice. Additionally, we show that while Myf5-dependent depletion of all FXR1P isoforms is neonatal lethal, mice carrying mutations in exon-15 display non-lethal myopathies which vary in severity depending on the specific effect of each mutation on the protein

Numerical analysis of different heating systems for warm sheet metal forming

The main goal of this study is to present an analysis of different heating methods frequently used in laboratory scale and in the industrial practice to heat blanks at warm temperatures. In this context, the blank can be heated inside the forming tools (internal method) or using a heating system (external method). In order to perform this analysis, a finite element model is firstly validated with the simulation of the direct resistance system used in a Gleeble testing machine. The predicted temperature was compared with the temperature distribution recorded experimentally and a good agreement was found. Afterwards, a finite element model is used to predict the temperature distribution in the blank during the heating process, when using different heating methods. The analysis also includes the evaluation of a cooling phase associated to the transport phase for the external heating methods. The results of this analysis show that neglecting the heating phase and a transport phase could lead to inaccuracies in the simulation of the forming phase.The authors gratefully acknowledge the financial support of the Portuguese Foundation for Science and Technology (FCT) under project PTDC/EMS-TEC/1805/2012 and by FEDER funds through the program COMPETE—Programa Operacional Factores de Competitividade, under the project CENTRO-07-0224-FEDER-002001 (MT4MOBI). The authors would like to thank Prof. A. Andrade-Campos for helpful contributions on the development of the finite element code presented in this work.info:eu-repo/semantics/publishedVersio

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Consensus on complementary feeding from the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition: COCO 2023

Abstract Complementary feeding (CF) is defined as infant feeding that complements breastfeeding or, alternatively, breastfeeding with a breast milk substitute, and is a process that goes beyond simply providing guidance on what and how to introduce foods. The information provided by health professionals should be up-to-date and evidence-based. There are different guidelines or position papers at the international level, which, although most of the recommendations may be applicable, there are some others that require regionalization or adaptation to the conditions and reality of each area. The Nutrition working group of the Latin American Society of Pediatric Gastroenterology, Hepatology and Nutrition convened a group of experts, representatives from each of the countries that make up the society, with the objective of developing a consensus on CA, incorporating, when possible, local information that adapts to the reality of the region. The purpose of this document is to show the results of this work. Through Delphi methodology, a total of 34 statements or statements regarding relevant aspects of CA were evaluated, discussed and voted upon.Resumen La alimentación complementaria (AC) se define como la alimentación de los lactantes que complementa a la lactancia materna o en su defecto, a la lactancia con un sucedáneo de la leche materna, y es un proceso que va más allá de simplemente una guía sobre qué y cómo introducir los alimentos. La información brindada por parte de los profesionales de la salud debe ser actualizada y basada en evidencia. Existen diferentes guías o documentos de posición a nivel internacional, que, aunque la mayoría de las recomendaciones pueden ser aplicables, hay algunas otras que requieren una regionalización o adecuación a las condiciones y realidad de cada zona. El grupo de trabajo de Nutrición de la Sociedad Latinoamericana de Gastroenterología, Hepatología y Nutrición Pediátrica convocó a un grupo de expertos, representantes de cada uno de los países que conforman la sociedad, con el objetivo de desarrollar un consenso sobre la AC, que incorporó cuando así fue posible, información local que se adapte a la realidad de la región. El objetivo de este documento es mostrar los resultados de dicho trabajo. A través de metodología Delphi, se evaluaron, discutieron y votaron un total de 34 declaraciones o enunciados con respecto a aspectos relevantes de la AC

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix ACIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research.This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and InnovationPeer reviewe

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Common atrium/atrioventricular canal defect and postaxial polydactyly: a mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1 and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a non-canonical splice-site in-frame change (c.1316-7A>G) in the daughter. cDNA sequencing, immunoblot and immunofluorescence experiments using patient-derived fibroblasts and Evc-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome. This article is protected by copyright. All rights reserved.Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316–7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc–/– mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316–7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as “common atrium/AVCD with postaxial polydactyly” is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome

Image1_EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO.TIF [Dataset]

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC’s main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2’s Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.Peer reviewe

Image6_EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO.TIF [Dataset]

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC’s main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2’s Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.Peer reviewe