Prenatal exposure to synthetic phenols assessed in multiple urine samples and dysregulation of steroid hormone homeostasis in two european cohorts

Background: Some synthetic phenols alter hormonal pathways involved in successful pregnancy and fetal development. Despite high within-subject temporal variability of phenols, previous studies mostly utilized spot urine samples to assess pregnancy exposure. Herein, we investigated associations between pregnancy exposure to eight phenols assessed in multiple pooled urine samples and steroid hormones assessed in maternal hair reflecting cumulative hormone levels over the previous weeks to months. Methods: We assessed phenol-hormone associations in 928 pregnant women from two pooled cohorts recruited in Spain [Barcelona Life Study Cohort (BiSC), 2018-2021] and France [Assessment of Air Pollution exposure during Pregnancy and Effect on Health (SEPAGES), 2014-2017] using pools of up to 21 samples each, collected in early pregnancy (median gestational age: 18.0 wk), as well as hair collected in late pregnancy (BiSC) or at birth (SEPAGES). We measured two bisphenols, four parabens, benzophenone-3, and triclosan along with metabolites of three adrenal (∑cortisol, ∑cortisone, and 11-dehydrocorticosterone) and two reproductive (progesterone and testosterone) hormones. We ran adjusted linear regressions for each exposure biomarker-outcome pair and Bayesian kernel machine regression for phenols mixture. Results: Bisphenol S was associated with higher cortisol and 11-dehydrocorticosterone concentrations. Propylparaben was associated with lower levels of cortisol, cortisone, and 11-dehydrocorticosterone, while methylparaben was linked to a reduction in cortisol levels. Interestingly, associations identified for parabens were stronger for women carrying female fetuses. No associations for phenol mixture were detected. Conclusions: Our study suggests that pregnancy exposure to bisphenol S and some parabens (propyl- and methylparaben) may affect production of maternal corticosteroid hormones that are important for a successful pregnancy and fetal development. https://doi.org/10.1289/EHP15117.This project was supported by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES, HyPAxE project number EST2019/1/039), the French National Agency for Research (ANR, EDeN project number ANR-19-CE36-000301), and the European Union’s Horizon 2020 research and innovation program under grant agreement 874583 [ATHLETE]. The SEPAGES cohort was supported by the ANR (MEMORI project number ANR-21-CE34-0022, SYMER project number ANR-15-IDEX-02) and the ANSES (PNREST PENDORE 2018/1/264). Paulina Jedynak was supported by grants from ANR SYMER project number ANR-15-IDEX-02 and ANSES (HyPAxE and PENDORE project numbers EST-2019/1/039 and 2018/1/264). The SEPAGES cohort was supported by the European Research Council (number 311765-E-DOHaD), the European Community’s Seventh Framework Programme (FP7/2007-206, number 308333-892 HELIX), the European Union’s Horizon 2020 Research and Innovation Programme (number 874583 ATHLETE Project, number 825712 OBERON Project), ANR (PAPER project number ANR-12-PDOC-0029-01; SHALCOH project number ANR-14-CE21-0007, ANR-15-IDEX-02, and ANR-15-IDEX5; GUMME project number ANR-18CE36-005; ETAPE project ANR – EDeN project number ANR-19-CE36-000301; and ORANDANI project number ANR-22-CE36-0018), ANSES (CNAP project number EST-2016-121, HyPAxE project number EST2019/1/039), the Plan Cancer (Canc’Air project), the French Cancer Research Foundation Association de Recherche sur le Cancer (ARC), the French Endowment Fund AGIR for chronic diseases (APMC, projects PRENAPAR, LCI-FOT, DysCard), the French Endowment Fund for Respiratory Health, the French Fund – Fondation de France (CLIMATHES 00081169, SEPAGES 5 – 00099903, ELEMENTUM - 00124527). The BiSC cohort was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (785994 – AirNB project) and the Health Effects Institute (HEI), an organization jointly funded by the United States Environmental Protection Agency (EPA) (Assistance Award number R-82811201) and certain motor vehicle and engine manufacturers. The contents of this article do not necessarily reflect the views of HEI or its sponsors nor do they necessarily reflect the views and policies of the EPA or motor vehicle and engine manufacturers. A full list of the funding sources that supported specific parts of the project can be found at https://projectebisc.org/en/funding-sources. Mireia Gascon holds a Miguel Servet fellowship (grant CP19/00183) funded by Acción Estratégica de Salud – Instituto de Salud Carlos III, co-funded by European Social Fund “Investing in your future.” Ioar Rivas received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 886121 and Ramón y Cajal fellowship (RYC2021-032781-I), funded by the MCIN/AEI/10.13039/501100011033 and the European Union «NextGenerationEU»/PRTR. ISGlobal acknowledges support from the grant CEX2018-000806-S funded by MCIN/AEI/10.13039/501100011033 and support from the Generalitat de Catalunya through the CERCA Program. Vicente Mustieles was supported by a Sara Borrell postdoctoral research contract (CD22/00176), granted by Instituto de Salud Carlos III (Spain) and «NextGenerationEU» funds. Isabelle Ouellet-Morin is the Canadian Research Chair in the Developmental Origins of Vulnerability and Resilience

Massive experimental quantification allows interpretable deep learning of protein aggregation

Protein aggregation is a pathological hallmark of more than 50 human diseases and a major problem for biotechnology. Methods have been proposed to predict aggregation from sequence, but these have been trained and evaluated on small and biased experimental datasets. Here we directly address this data shortage by experimentally quantifying the aggregation of >100,000 protein sequences. This unprecedented dataset reveals the limited performance of existing computational methods and allows us to train CANYA, a convolution-attention hybrid neural network that accurately predicts aggregation from sequence. We adapt genomic neural network interpretability analyses to reveal CANYA's decision-making process and learned grammar. Our results illustrate the power of massive experimental analysis of random sequence-spaces and provide an interpretable and robust neural network model to predict aggregation.This work received support from the following: “La Caixa” Foundation (ID 100010434) under grant agreement LCF/PR/HR21/52410004 (B.L.); European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme grant agreement 883742 (B.L.); AXA Research Fund AXA Chair in Risk prediction in age-related diseases (B.L.); Secretariat of Universities and Research, Ministry of Enterprise and Knowledge of the Government of Catalonia and the European Social Funds 2017 SGR 1322 (B.L.); Bettencourt Schueller Foundation (B.L.); PID2023-146685NB-I00 funded by MCIN/AEI/10.13039/501100011033/ FEDER, UE; Wellcome 220540/Z/20/A, “Wellcome Sanger Institute Quinquennial Review 2021-2026” (B.L.); Spanish Ministry of Science, Innovation and Universities PID2021-127761OB-I00 (B.B.) RYC2020-028861-I funded by MCIN/AEI/ 10.13039/501100011033 “ERDF A way of making Europe” and “ESF Investing in your future” (B.B.); European Union (ERC Consolidator, Glam-MAP, 101125484) (B.B.); EMBO Fellowship ALTF 266-2023 (M.T.); NIH grant R01HG012131 (P.K. and C.R.); and NIH grant R01GM149921 (P.K. and C.R.)

Designing and Evaluating Extended Reality Solutions for Sign Reading Assistance for People with Low Vision

Treball fi de màster de: Master in Cognitive Systems and Interactive MediaSupervisor: Menno VeefkindCo-supervisor: Davinia Hernández-LeoExtended Reality (XR) technologies, including AR and VR, offer promising tools to support individuals with low vision in navigating public spaces and reading signage safely. People with impairments such as glaucoma or cataract often struggle with reduced visual acuity, contrast sensitivity, and peripheral vision, leading to decreased situational awareness and increased risk of collisions. This study investigates a lightweight, user-customizable XR system designed to augment natural vision, enhance sign readability, and reduce cognitive load. Participants completed tasks in VR simulations of structured (museum) and cluttered (airport) environments, performing directed sign searches while the system recorded task completion times, reaction times, and NASA-TLX cognitive load ratings, complemented by qualitative feedback on usability and overlay design preferences. These findings provide practical insights for designing cognitively considerate, real-world-ready assistive XR systems

A Verdú fan cantirets: l'antic forn de Cal Salisi, la producció de ceràmica negra a la vila closa: una problemàtica cronològica

L'estudi del forn de Cal Salisi està relacionat amb la producció ceràmica de Verdú (Catalunya), un poble conegut tradicionalment per la ceràmica negra verdunina. L'estudi arqueològic i documental parteix de les incògnites sobre el moment en què va estar en ús aquest forn, la ceràmica que s'hi va produir i la identitat del seu propietari. L'estudi documental ha permès aproximar la cronologia d'amortització del forn, que se situa en un moment anterior a finals del segle XV, quan ja no estaria en ús. Gràcies a la consulta de fonts documentals històriques, es podria considerar que Cal Salisi és un dels forns conservats més antics del poble, en remuntar-se fins abans de 1549. L'estudi arqueològic ha permès conèixer la producció ceràmica, així com l'amortització del forn, gràcies a l'examen tipològic dels materials recuperats -ceràmica vidrada, ceràmica comuna, suports de forn i, sobretot, sellons i cànters. Els materials s'han pogut englobar, a partir de la seva forma, en tipologies prèviament definides i en d'altres de nova creació

La construcció del paisatge megalític: estudi de la necròpolis megalítica de la serra de l’Aramo (Astúries)

Treball de Fi de Grau en Humanitats. Curs 2024-2025Tutora: Meritxell Ferrer MartínEl megalitisme és un fenomen caracteritzat per la construcció de monuments amb grans pedres que es va donar durant un període molt concret de la prehistòria, que inclou el Neolític i l’Edat de Bronze. Aquest treball té com a objectiu estudiar el megalitisme, centrant-se especialment en la necròpolis megalítica de La Cobertoria, a la serra de l’Aramo, Astúries. El principal interès del seu estudi és comprendre el significat i simbòlic d’aquests monuments i la seva relació amb el paisatge i les comunitats que els van construir. En aquest sentit, el treball aborda com el paisatge i els megàlits es van influenciar mútuament, i com aquestes construccions servien no només per enterrar els morts, sinó també per marcar el territori i establir punts de referència per a les comunitats. La metodologia utilitzada inclou una revisió bibliogràfica de fonts acadèmiques sobre el megalitisme i l’arqueologia del paisatge, així com l’anàlisi específica dels megàlits de La Cobertoria. Mitjançant l’estudi detallat dels dòlmens d’aquesta àrea, es busca interpretar com aquestes estructures reflecteixen les creences, les relacions socials i l’organització territorial de les comunitats neolítiques. En definitiva, aquest treball pretén oferir una visió integral del megalitisme, mostrant com aquests monuments van ser elements actius en la creació i transformació del paisatge cultural, deixant un llegat que encara avui podem observar i estudiar

A Genome-wide CRISPR screen to identify novel pathways involved in reprogramming and x-chromosome reactivation

During reprogramming of somatic cells into induced pluripotent stem cells (iPSCs), the epigenome needs to be reset. A prime example of this is the reversal of the silent state of the inactive X chromosome in female cells, which is achieved in a process called X-chromosome reactivation (XCR). Few players have been described to be involved in XCR so far, and a comprehensive understanding of the regulatory networks has been lacking. Therefore, in this doctoral thesis I aim to shed light onto the mechanism of XCR during somatic cell reprogramming into iPSCs, by performing a genome-wide CRISPR-screen during this process. Using this approach, I identified a number of previously known and unknown pathways which are involved in reprogramming and/or XCR. Of these, I focused on the interferon γ (IFNγ) pathway, the activation of which during the early phase of reprogramming accelerated pluripotency acquisition and XCR. In this study, I sought to uncover the mechanism by which IFNγ enhances XCR, and found a dependency on TET-enzyme activity and DNA demethylation. These findings will contribute to the mechanistic understanding of the process of XCR and could have a potential impact on improving iPSC generation.Durante la reprogramación de células somáticas hacia células pluripotentes inducidas (iPSCs), el epigenoma debe ser reseteado. Un ejemplo importante de esto es la reversión del estado de silenciamiento del cromosoma X inactivo en células femeninas, lo que es posible gracias a un proceso llamado reactivación del cromosoma X (XCR). Hasta ahora, se han descrito pocas moléculas que estén involucradas en la XCR, y se carece de una comprensión de sus redes de regulación. Por tanto, mi objetivo en esta tesis doctoral es contribuir al entendimiento del mecanismo de la XCR durante la reprogramación de células somáticas a iPSCs, usando un cribado de CRISPR hacia todo el genoma durante este proceso. Mediante esta aproximación, identifiqué ciertas vías conocidas y desconocidas involucradas en la reprogramación y la XCR. De éstas, me he centrado en la vía del interferón γ (IFNγ), cuya activación durante fases tempranas de la reprogramación acelera la adquisición de pluripotencia y la XCR. En este estudio, he tratado de descubrir el mecanismo por el que el IFNγ potencia la XCR y he encontrado una dependencia de las enzimas TET y la desmetilación del DNA. Estos resultados contribuirán al conocimiento del mecanismo de XCR y podrían tener impacto en mejorar la generación de iPSCs.Programa de doctorat en Biomedicin

Characterization of allosteric communication networks in GPCRs

G protein-coupled receptors (GPCRs) are central to cellular signaling and pivotal in drug development. This thesis investigates allosteric communication in GPCRs, crucial for their effective modulation in pharmacotherapy. It introduces two distinct methodologies for characterizing allosteric communication networks. The first, a machine learning pipeline, predicts experimental variables from simulations, with a primary focus on modeling the stabilities of inter-residue contacts - a critical aspect of GPCR functionality. The second methodology, in contrast, applies machine learning and statistical tools descriptively, integrating deep biological system knowledge. This approach requires less data, offering a complementary perspective to the predictive nature of the first method. The first methodology has accurately predicted the pharmacology of various Class A GPCR ligands. Meanwhile, the second has been crucial in elucidating the mechanism for biased signaling in the type 2 cannabinoid receptor. Together, these approaches not only deepen our understanding of GPCR-mediated signal transduction but also mark a significant advancement in drug development, paving the way for more targeted and effective therapeutic strategies.Los receptores acoplados a proteína G (GPCRs) son clave en la señalización celular y fundamentales en el desarrollo de fármacos. Esta tesis investiga la comunicación alostérica en GPCRs, esencial para su modulación mediante farmacoterapia. Aquí se presentan dos metodologías distintas para caracterizar redes de comunicación alostérica. La primera, una infraestructura de aprendizaje automático, predice variables experimentales a partir de simulaciones. Esta está centrada en modelar la estabilidad de contactos inter-residuales, aspecto crítico de la funcionalidad de los GPCRs. La segunda metodología aplica herramientas de aprendizaje automático y estadística de manera descriptiva, integrando conocimientos profundos del sistema biológico. Esta aproximación requiere menos datos, ofreciendo una perspectiva complementaria a la naturaleza predictiva de la primera. La primera metodología ha predicho con precisión la farmacología de ligandos de varios GPCRs de clase A. Por otro lado, la segunda ha sido crucial en dilucidar un mecanismo para la señalización sesgada en el receptor de cannabinoides tipo 2. Juntas, estas metodologías no sólo profundizan nuestro entendimiento de la transducción de señales mediada por GPCRs, sino también marcan un avance significativo en el desarrollo de fármacos, abriendo camino para estrategias terapéuticas más dirigidas y efectivas.Programa de Doctorat en Biomedicin

Redox proteomics reveal a role for peroxiredoxinylation in stress protection

The redox state of proteins is essential for their function and guarantees cell fitness. Peroxiredoxins protect cells against oxidative stress, maintain redox homeostasis, act as chaperones, and transmit hydrogen peroxide signals to redox regulators. Despite the profound structural and functional knowledge of peroxiredoxins action, information on how the different functions are concerted is still scarce. Using global proteomic analyses, we show here that the yeast peroxiredoxin Tsa1 interacts with many proteins of essential biological processes, including protein turnover and carbohydrate metabolism. Several of these interactions are of a covalent nature, and we show that failure of peroxiredoxinylation of Gnd1 affects its phosphogluconate dehydrogenase activity and impairs recovery upon stress. Thioredoxins directly remove TSA1-formed mixed disulfide intermediates, thus expanding the role of the thioredoxin-peroxiredoxin redox cycle pair to buffer the redox state of proteins.The laboratories of F.P. and E.d.N. are supported by a coordinated grant PID2021-124723NB-C21/C222 funded by MICIU/AEI/10.13039/501100011033 and ERDF/EU, and the Government of Catalonia (2017 SGR799). We gratefully acknowledge institutional funding from the Ministry of Science, Innovation, and Universities through the Centres of Excellence Severo Ochoa Award, and from the CERCA Programme of the Government of Catalonia and the Unidad de Excelencia María de Maeztu, funded by the AEI (CEX2018-000792-M). F.P. and E.d.N. are recipients of an ICREA Acadèmia award (Government of Catalonia). G.S. was supported by an Advanced Postdoc.Mobility fellowship (P300P3_147895) by the Swiss National Science Foundation

Modeling cell type evolution using single-cell and chromatin profiling approaches

Single-cell genomics methods have revolutionized the study of gene expression and regulation at the cell type level. Generating single-cell atlases for species at key phylogenetic positions of the animal tree of life (e.g.. early branching non-bilaterian animals) informs us not only about the biology of these understudied groups of organisms, but also enable comparative studies of cell type transcriptomic programs. This is the first step towards inferring the evolutionary trajectories of major animal cell types. In this context, the first part of my thesis describes the first single cell atlas of a stony coral, Stylophora pistillata, and the novel insights we gained from it. We also compared cell type transcriptomes of Stylophora to three other species in the Cnidaria phylum, and identified conserved expression programs and convergent mobilization of similar molecular pathways in potentially homologous cell types across species. However, because transcriptome similarities are confounded by pleiotropy and non-independence of gene expression programs, they do not always represent true cell type homologies. To infer more accurate cell type phylogenetic relationships we need to also compare their gene regulatory programs. The second part of my thesis focuses on detailed regulatory characterization of cell type programs in cnidarian Nematostella vectensis. We describe genome-wide regulatory logic of Nematostella, and characterize cell types by modular deployment of transcription factors (TFs) and gene regulatory networks (GRNs) in which they are involved. Together, the work presented in this thesis exemplifies the ways in which single cell approaches can be used to advance our understanding of cell type diversity, development, and evolution.Els mètodes de genòmica unicel·lular han revolucionat l'estudi de l'expressió gènica i la regulació a nivell de tipus cel·lular. La generació d'atles cel·lulars per a espècies en posicions filogenètiques clau de l'arbre de la vida animal (per exemple, animals basals, no bilaterals) ens informa no només sobre la biologia d'aquests grups d'organismes poc estudiats, sinó que també permet estudis comparatius dels tipus cel·lulars des d'una perspectiva molecular. Aquest és el primer pas per inferir les trajectòries evolutives dels principals tipus de cèl·lules animals. En aquest context, la primera part de la meva tesi descriu el primer atles cel·lular d'un corall dur, Stylophora pistillata, i el coneixement que en vam obtenir. També vam comparar els transcriptomes de tipus cel·lulars de Stylophora amb tres espècies més del fílum Cnidaria i vam identificar programes d'expressió conservats i mobilització convergent de vies moleculars similars en tipus de cèl·lules potencialment homòlogues entre espècies. Tanmateix, com que les similituds del transcriptoma es confonen per la pleiotropia i la no independència dels programes d'expressió gènica, no sempre representen necessàriament tipus cel·lulars homòlegs. Per inferir relacions filogenètiques dels tipus cel·lular, també hem de comparar els seus programes reguladors. La segona part de la meva tesi se centra en la caracterització reguladora detallada de programes de tipus cel·lular en l'anemona Nematostella vectensis (Cnidaria). Descrivim la lògica reguladora de tot el genoma de Nematostella i caracteritzem els tipus cel·lulars mitjançant el desplegament modular de factors de transcripció (TF) i xarxes reguladores de gens (GRN) en què estan implicats. En conjunt, el treball presentat en aquesta tesi exemplifica les maneres en què es poden utilitzar els enfocaments de genòmica de cèl·lula única per avançar en la nostra comprensió de la diversitat, el desenvolupament i l'evolució dels tipus cel·lulars animals.Programa de Doctorat en Biomedicin