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ARC expands the DAAM1 microexon-mediated actin-RHOA/ROCK Interplay
No full textData de publicació electrònica: 09-06-2025Actin cytoskeleton and its dynamics play a crucial role in synaptic function, influencing dendritic spines' structural and functional plasticity. Recent findings unveiled the significance of alternative splicing of a neural-specific microexon in DAAM1 in modulating actin's role in synaptic processes. This article discusses the impact of this microexon on actin polymerization, the RHOA/ROCK signaling pathway, and cognitive functions. Furthermore, we present new results that reveal a more complex scenario involving the upregulation of the activity-regulated cytoskeleton-associated protein (ARC) protein in DAAM1 microexon KO models, which may further affect synaptic function and cognition.The research has been funded by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (ERCCoG-LS2-101002275 to M.I.), Spanish Ministry of Science and Innovation (PID2020-115040GB-I00 to M.I.), the European Union's Horizon 2020 research and innovation program under grant agreements No. 721890 to P.P
Deciphering the folding code of collagens
No full textCollagen proteins contain a characteristic structural motif called a triple helix. During the self-assembly of this motif, three polypeptides form a folding nucleus at the C-termini and then propagate towards the N-termini like a zip-chain. While polypeptides from human collagens contain up to a 1000 amino acids, those found in bacteria can contain up to 6000 amino acids. Additionally, the collagen polypeptides are also frequently interrupted by non-helical sequences that disrupt folding and reduce stability. Given the length of polypeptides and the disruptive interruptions, compensating mechanisms that stabilize against local unfolding during propagation and offset the entropic cost of folding are not fully understood. Here, we show that the information for the correct folding of collagen triple helices is encoded in their sequence as interchain electrostatic interactions, which likely act as molecular clamps that prevent local unfolding. In the case of humans, disrupting these electrostatic interactions is associated with severe to lethal diseases.Part of the work was funded by the Newton International Alumni Funding (2018-2023) awarded to A.A.J jointly by the Royal Society, the British Academy, and the Academy of Medical Sciences. J.D.M was partly funded by the French National Agency (CARTEGRIN ANR21-CE19-0017). S.R.R. was funded by a fellowship from the Alexander von Humboldt and Bayer Science & Education Foundations, NF was funded by the ERC Consolidator Grant 647548 and SD was funded by VolkswagenStiftung Grant 94747. The authors would like to thank Prof Birte Höcker for access to the DSC instruments. The authors gratefully acknowledge the scientific support and HPC resources provided by the Erlangen National High-Performance Computing Center (NHR@FAU) of the Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) under the NHR project b114cb (UID 210235). NHR funding is provided by federal and Bavarian state authorities. NHR@FAU hardware is partially funded by the German Research Foundation (DFG) – 440719683. We also thank Prof Thomas Scheibel for laboratory resources for executing part of this project. The authors specially thank Prof Richard Farndale for insightful discussion and help with the peptide synthesis
A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR
No full textData de publicació electrònica: 22-09-2025Reduced protein abundance is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating reduced abundance variants is pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved as clinical treatments for specific variants, but protein energetics suggest their effects might be much more general. To comprehensively assess PC efficacy for variation in a given protein, it is necessary to first assign the molecular mechanism explaining all pathogenic variants, then measure the response to the PC. Here we establish such a framework for the vasopressin 2 receptor (V2R), a G-protein-coupled receptor in which loss-of-function variants cause nephrogenic diabetes insipidus (NDI). Our data show that more than half of NDI variants are poorly expressed, highlighting loss of stability as the major pathogenic mechanism. Treatment with a PC rescues the expression of 87% of destabilized variants. The non-rescued variants identify the drug's predicted binding site. Our results provide proof-of-principle that small molecule binding can rescue destabilizing variants throughout a protein's structure. The application of this principle to other proteins should allow the development of effective therapies for many different rare diseases.This work was funded by a European Research Council Advanced Grant (883742), Wellcome (220540/Z/20/A), the Spanish Ministry of Science and Innovation (LCF/PR/HR21/52410004, EMBL Partnership, Severo Ochoa Centre of Excellence), the Bettencourt Schueller Foundation, the AXA Research Fund, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322) and the CERCA Program/Generalitat de Catalunya. T.L.M. was funded by an EMBO fellowship (ALTF 113-2021). We thank all members of the Lehner Lab and J. Selent and T. Stepniewski for helpful discussions. We thank the CRG/UPF Flow Cytometry Unit for assistance with the sorting experiments
LGBT climate inventory in corporations for straight people?
No full textOpen societies are eager to accommodate sexual and gender diversity at work. The Lesbian, Gay, Bisexuals and Trans Climate Inventory (LGBTCI) is an instrument measuring organizational climate towards sexual and gender diversity, relying on the opinion of LGTB people. We argue that non-LGTB employees also perceive a climate towards sexual and gender diversity, and therefore include them to measure LGBT-friendly climate at work. By means of a Multiple Correspondence Analysis (MCA) we validate this application of the LGBTCI obtaining two factors: first, comprehension of the items linked to sexual and gender diversity; second, positioning with respect to the climate. We contribute to existing research claiming that non-LGBT employees should be incorporated in the measurement of the climate
Studying gene expression dynamics by integrating multiple Omics data
No full textThis thesis investigates the complex processes governing gene expression, from
RNA transcription to protein synthesis, across diverse regulatory layers and
biological contexts. By examining RNA localization between nuclear and cytosolic
compartments, we developed and validated a novel method to accurately measure
transcript distribution using RNA-Seq data. To explore the causal effects of
histone post-translational modifications (PTMs) on RNA splicing and abundance,
we integrated ChIP-Seq data with RNA-Seq and observed the impact of chromatin
dynamics during a transdifferentiation. By analyzing time-resolved multi-Omics
datasets, including RNA-Seq, ribosome profiling, and mass spectrometry, we
tracked the temporal flow of gene expression from RNA to protein, uncovering the
contributions of distinct regulatory events. Finally, we studied gene expression
in coronary artery disease (CAD), identifying potential blood-based biomarkers
for improved diagnosis and management. This work integrates multi-Omics
approaches to provide novel insights into gene expression regulation, its temporal
dynamics, and functional implications in health and disease.Aquesta tesi investiga els processos complexos que regulen l’expressió gènica,
des de la transcripció de l’ARN fins a la síntesi de proteïnes, en diferents capes
reguladores i contextos biològics. Analitzant la localització de l’ARN entre
els compartiments nuclear i citosòlic, hem desenvolupat i validat un mètode
innovador per mesurar amb precisió la distribució dels transcrits utilitzant dades
d’RNA-Seq. Per explorar els efectes causals de les modificacions postraduccionals
d’histones (PTMs) en l’splicing i l’abundància d’ARN, vam integrar dades de
ChIP-Seq amb RNA-Seq per estudiar la dinàmica de la cromatina durant la trans-
diferenciació. Analitzant dades multi-òmiques temporals (RNA-Seq, ribosome
profiling i espectrometria de masses), vam desxifrar el flux d’informació de l’ARN
a la proteïna, revelant les contribucions temporals de diferents esdeveniments
reguladors. Finalment, vam estudiar l’expressió gènica en malaltia coronària
(CAD), identificant biomarcadors en sang potencialment útils per al diagnòstic i
la gestió clínica.Programa de Doctorat en Biomedicin
Preclinical assessment in juvenile sheep of an allogeneic bone tissue engineering product with Wharton's jelly mesenchymal stromal cells
No full textSecondary osteonecrosis (ON) is a common complication in paediatric cancer survivors. Combining multipotent mesenchymal stromal cells (MSCs) with core decompression surgery halts disease progression and stimulates bone regeneration. However, the success of advanced therapy medicinal products (ATMPs) requires versatile "off-the-shelf" tissue engineering products (TEPs). This study evaluated the safety and efficacy of TEPs loaded with allogeneic MSCs from Wharton's jelly (WJ-MSCs) in a large-animal model of bone regeneration to support a paediatric investigational plan for ON patients. WJ-MSC-laden fibrin-based hydrogels combined with a synthetic bone substitute (PRO-DENSETM) were tested in 16 juvenile sheep (8 males and 8 females) distributed in four experimental groups. Each animal received four cylindrical bone defects in the femoral and tibial epiphyses and was assessed at 6 and 12 weeks. Safety was confirmed, and bone regeneration was observed across all groups. A combination of WJ-MSCs with PRO-DENSETM led to improved histological scores, osteogenesis, and construct integration. Trabecular bone volume also increased more in cellular groups over time. However, effects were inconsistent across groups, reflecting the variability seen in clinical trials and highlighting the significant impact of factors such as immunogenetic compatibility, MSC batch potency, and interaction with the recipient's microenvironment on the therapeutic effectiveness and successful clinical translation of allogeneic ATMPs
A reduction in effective population size has not relaxed purifying selection in the human population of Eivissa (Balearic Islands)
No full textIbiza (Eivissa) is one of the main Balearic Islands in the western Mediterranean. Recent studies have highlighted the genetic distinctiveness of present-day Eivissans within the region and suggested it could be attributed to the genetic drift caused by recent demographic events. Whether this distinctiveness emerged from a differential demographic history, or rather from a bias for sampling in a small geographic region such as Eivissa, remains an open question, together with the understanding of the functional consequences of demography in the island. In order to clarify these questions and further characterize the distinctiveness of Eivissa within the Balearic and Mediterranean context, we generated whole exome sequences for 31 and 20 individuals from Eivissa and Menorca respectively, a subset of which were also genotyped with the Human Origins array. Our results show that Eivissans present signs of putatively recent genetic isolation that are shared to a lesser extent with Menorca such as more and longer runs of homozygosity and high numbers of intra-population shared IBD segments. Regarding the functional consequences of recent demography, although Eivissans do not present an excess of deleterious alleles or homozygotes comparing to other populations, genetic drift seems to have increased the allele frequencies of neutral and deleterious variants, which can have various medical implications.This work was supported by the Spanish Ministry of Science and Innovation (grant number PID2019-106485GB-I00) funded by the MCIN/AEI/10.13039/501100011033. We thank Inés Quintela and the National Genotyping Center (CEGEN – USC) for their assistance in genotyping the SNP arrays
International prevalence patterns of low eGFR in adults aged 18-60 without traditional risk factors from a population-based cross-sectional disadvantaged populations eGFR epidemiology (DEGREE) study
No full textThe disadvantaged populations eGFR (estimated glomerular filtration rate) epidemiology (DEGREE) study was designed to gain insight into the burden of chronic kidney disease (CKD) of undetermined cause (CKDu) using standard protocols to estimate the general-population prevalence of low eGFR internationally. Therefore, we estimated the age-standardized prevalence of eGFR under 60 ml/min per 1.73m2 in adults aged 18-60, excluding participants with commonly known causes of CKD; an ACR (albumin/creatinine ratio) over 300 mg/g or equivalent, or self-reported or measured (HT) hypertension or (DM) diabetes mellitus, stratified by sex and location. We included population-representative surveys conducted around the world that were either designed to estimate CKDu burden or were re-analyses of large surveys. There were 60,964 participants from 43 areas across 14 countries, with data collected 2007- 2023. The highest prevalence was seen in rural men in Uddanam, India (14%) and Northwest Nicaragua (14%). Prevalence above 5% was generally only observed in rural men, with exceptions for rural women in Ecuador (6%) and parts of Uddanam (6%‒8%), and for urban men in Leon, Nicaragua (7%). Outside of Central America and South Asia, prevalence was below 2%. Our observations represent the first attempts to estimate the prevalence of eGFR under 60 without commonly known causes of CKD around the world, as an estimate of CKDu burden, and provide a starting point for global monitoring. It is not yet clear what drives the differences, but available evidence supports a high general-population burden of CKDu in multiple areas within Central America and South Asia, although the possibility that unidentified clusters of disease may exist elsewhere cannot be excluded.This work was funded by grants from the UK Colt Foundation (CF/02/18) and the UK Medical Research Council (MR/P02386X/1 and MR/V033743/1). In addition, individual centers received funding as follows: the study in Chile was supported by the Chilean Agency of Research and Development, FONDECYT grant 1221680, and FONDAP-MAUCO grant 1523A0008; the study in Ecuador was supported by Universidad Internacional del Ecuador grant EDM-INV-04-19; the study in Guatemala was supported by National Institutes of Health (NIH) grant NIH/FIC 5R21TW010831; the Indian study in Uddanam was supported by a Grand Challenge Award from the Indian Council of Medical Research and the State Government of Andhra Pradesh; the Sri Lankan study was supported by the National Science Foundation of Sri Lanka (RPHS/2016/CKDu 07), the Ministry of Health, Sri Lanka, Nutrition and Indigenous Medicine, and the World Health Organization Country Office Sri Lanka. The study in Italy was supported by the European Union’s Horizon 2020 research and innovation programme grant 824484; the Kenyan study was supported by the National Institute for Occupational Safety and Health, Illinois Education and Research Center Pilot Project Research Training Grant (T42/OH008672), Environmental and Occupational Health unrestricted global health research funds, Michael Bruton Workplace Safety Foundation Scholarship (2019), UIC Graduate College Award for Graduate Research (2019), Paul Brandt-Rauf Scholarship in Global Health (2018–2019), and Donna Farley Global Health Scholarship (2020–21); the UDAY study in India was supported by an unrestricted educational grant from Eli Lilly and Company under the Lilly NCD Partnership Program. The funding agency had no role in the design, conduct, or analysis of the study; the Indian study in Prakasam district was supported by the Indian Council of Medical Research, New Delhi; the earlier Nicaraguan study was supported by the Swedish International Agency for Development Cooperation (Sida), through the SAREC project of Bilateral Research Cooperation with UNAN-León and the Sida-Health supported SALTRA; the later Nicaraguan study was supported by a grant from the Dutch National Postcode Lottery, which provided funding to Solidaridad covering a proportion of the fieldwork costs and by the La Isla Network. The Thai NHES V study was supported by the Bureau of Policy and Strategy, Ministry of Public Health, Thailand, the Thai Health Promotion Foundation, Thailand, and the National Health Security Office, Thailand
Poética y traducción de los poemas en prosa de Maurice de Guérin
No full textTreball d'investigació/Fi de màster. Directora: Dra. Marta MarfanyMaurice de Guérin sigue siendo en gran medida un desconocido en las letras hispánicas y se han producido solo contados intentos de traducir su obra al español. Sus poemas en prosa, entre los primeros que vieron la luz en Francia, y el sincretismo de su pensamiento poético hacen del poeta objeto idóneo para plantear una traducción libre de las restricciones tradicionales que rigen los Estudios de Traducción. A efectos de presentar las propuestas de traducción de Le Centaure y La Bacchante, este trabajo describe una poética que subsume los aspectos más eludidos de la obra del poeta, resaltando en particular modo su pensamiento religioso y se basa en un marco teórico flexible que permite elevar la traducción a una situación de diálogo con el texto original y apartarla así de las nociones de “fidelidad” y “traición” que circunscriben la figura del traductor.Maurice de Guérin remains a relatively obscure figure in the Spanish literary world, and few translations of his works into Spanish have been published. His prose poems, among the first to appear in France, and the syncretic nature of his poetic vision make him an ideal subject for a translation free from the traditional limitations prevalent in Translation Studies. To serve as the basis for the proposed translations of Le Centaure and La Bacchante, this essay describes Guérin’s poetic thought with special regard to the aspects of his works that tend to be overlooked, as is the case with the poet’s religious views. This, coupled with a flexible theoretical framework, conceives of translation as a dialogue with the original text and distances its efforts from the ideas of “fidelity” and “betrayal” that circumscribe the role of the
translator