25 research outputs found
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications
Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions
Why regionalism has failed in Latin America: lack of stateness as an important factor for failure of sovereignty transfer in integration projects
Dynamic assembly of tight junction-associated proteins ZO-1, ZO-2, ZO-3 and occludin during mouse tooth development.
International audienceTight junctions might play a role during tissue morphogenesis and cell differentiation. In order to address these questions, we have studied the distribution pattern of the tight junction-associated proteins ZO-1, ZO-2, ZO-3 and occludin in the developing mouse tooth as a model. A specific temporal and spatial distribution of tight junction-associated proteins during tooth development was observed. ZO-1 appeared discontinuously in the cell membrane of enamel organ and dental mesenchyme cells. However, endothelial cells of the dental mesenchyme capillaries displayed a continuous fluorescence at the cell membrane. Inner dental epithelium first showed an evident signal for ZO-1 at the basal pole of the cells at bud/cap stage, but ZO-1 was accumulated at the basal and apical pole of preameloblast/ameloblasts at late bell stage. Surprisingly, in the incisor ZO-1 decreased as the inner dental epithelium differentiated, and was re-expressed in secretory and mature ameloblasts. On the contrary, ZO-2 was confined to continuous cell-cell contacts of the enamel organ in both molars and incisors. The lateral cell membrane of inner dental epithelial cells was specifically ZO-2 labeled. However, ZO-3 was expressed in oral epithelium whereas dental embryo tissues were negative. In addition, occludin was hardly detected in dental tissues at the early stage of tooth development, but was distributed continuously at the cell membrane of endothelial cells of ED19.5 dental mesenchyme. In incisors, occludin was detected at the cell membrane of the secretory pole of ameloblasts. The occurrence and relation during tooth development of tight junction proteins ZO-1, ZO-2 and occludin, but not ZO-3, suggests a combinatory assembly in tooth morphogenesis and cell differentiation
Dynamic assembly of tight junction-associated proteins ZO-1, ZO-2, ZO-3 and occludin during mouse tooth development
Tight junctions might play a role during
tissue morphogenesis and cell differentiation. In order to
address these questions, we have studied the distribution
pattern of the tight junction-associated proteins ZO-1,
ZO-2, ZO-3 and occludin in the developing mouse tooth
as a model. A specific temporal and spatial distribution
of tight junction-associated proteins during tooth
development was observed. ZO-1 appeared
discontinuously in the cell membrane of enamel organ
and dental mesenchyme cells. However, endothelial cells
of the dental mesenchyme capillaries displayed a
continuous fluorescence at the cell membrane. Inner
dental epithelium first showed an evident signal for ZO-
1 at the basal pole of the cells at bud/cap stage, but ZO-1
was accumulated at the basal and apical pole of
preameloblast/ameloblasts at late bell stage.
Surprisingly, in the incisor ZO-1 decreased as the inner
dental epithelium differentiated, and was re-expressed in
secretory and mature ameloblasts. On the contrary, ZO-2
was confined to continuous cell-cell contacts of the
enamel organ in both molars and incisors. The lateral
cell membrane of inner dental epithelial cells was
specifically ZO-2 labeled. However, ZO-3 was
expressed in oral epithelium whereas dental embryo tissues were negative. In addition, occludin was hardly
detected in dental tissues at the early stage of tooth
development, but was distributed continuously at the cell
membrane of endothelial cells of ED19.5 dental
mesenchyme. In incisors, occludin was detected at the
cell membrane of the secretory pole of ameloblasts. The
occurrence and relation during tooth development of
tight junction proteins ZO-1, ZO-2 and occludin, but not
ZO-3, suggests a combinatory assembly in tooth
morphogenesis and cell differentiation
Ether extract and acid detergent fibre but not glucosinolates are determinants of the digestible and metabolizable energy of rapeseed meal in growing pigs
Increasing levels of rapeseed expeller meal in diets for pigs:effects on protein and energy metabolism
A Protein Misfolding Shaking Amplificationbased method for the spontaneous generation of hundreds of bona fide prions
Prion diseases are a group of rapidly progressing neurodegenerative disorders
caused by the misfolding of the endogenous prion protein (PrPC) into a
pathogenic form (PrPSc). This process, despite being the central event underlying these disorders, remains largely unknown at a molecular level, precluding the prediction of new potential outbreaks or interspecies transmission
incidents. In this work, we present a method to generate bona fide recombinant prions de novo, allowing a comprehensive analysis of protein misfolding
across a wide range of prion proteins from mammalian species. We study more
than 380 different prion proteins from mammals and classify them according
to their spontaneous misfolding propensity and their conformational variability. This study aims to address fundamental questions in the prion research
field such as defining infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids and provide invaluable
information for future diagnosis and therapy applications.The authors would like to thank the following for their support: IKERBasque foundation, personnel from vivarium, IT service (in particular to Sara Gómez Ramos for her assistance with the PrPdex webpage), maintenance departments of CIC bioGUNE, Neiker and IRTA-CReSA. The authors would also like to acknowledge the work from past laboratory members of the Prion Research Lab from CIC bioGUNE, that despite not directly involved in the manuscript have contributed along the years to the development of all the methods and techniques currently used in the laboratory (specially to Tomás Barrio and Leire Hervá for their efforts at the initial and end stages of the work, respectively). Finally, we would like to thank Jesús R. Requena for always useful scientific discussions and advice. The present work was partially funded by different grants awarded by “Ministerio de Economía y Competitividad” (Spanish Government), grant numbers PID2021-122201OB-C21, PID2021-1222010BC22, PID2021-125946OB-I00 and IJC2020-045506-I, funded by MCIN/ AEI /10.13039/501100011033 and co-financed by the European Regional Development Fund (ERDF), and by the Instituto de Salud Carlos III (ISCIII), grant number AC21_2/00024, to J.C. Additionally, CIC bioGUNE currently holds a Severo Ochoa Excellence accreditation, CEX2021- 001136-S, also funded by MCIN/AEI /10.13039/501100011033. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio
A Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
Prion diseases are a group of rapidly progressing neurodegenerative disorders caused by the misfolding of the endogenous prion protein (PrP C) into a pathogenic form (PrP Sc). This process, despite being the central event underlying these disorders, remains largely unknown at a molecular level, precluding the prediction of new potential outbreaks or interspecies transmission incidents. In this work, we present a method to generate bona fide recombinant prions de novo, allowing a comprehensive analysis of protein misfolding across a wide range of prion proteins from mammalian species. We study more than 380 different prion proteins from mammals and classify them according to their spontaneous misfolding propensity and their conformational variability. This study aims to address fundamental questions in the prion research field such as defining infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids and provide invaluable information for future diagnosis and therapy applications. To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process