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Behavioral and molecular effects of environmental and genetic chronodisruption in mice
No full text_Els ritmes circadians regulen funcions fisiològiques essencials, permetent l’adaptació als canvis ambientals. La disrupció d’aquest sistema pot provocar desequilibris homeostàtics amb possibles conseqüències per a la salut. Aquesta tesi explora els efectes de les alteracions ambientals i genètiques en la neurobiologia dels rellotges biològics i les seues conseqüències en el comportament dels ratolins. Els ratolins exposats a cicles llum-foscor irregulars a curt termini van mostrar ritmes diaris moleculars i conductuals alterats, amb canvis significatius en l’expressió gènica a l’hipotàlem i l’escorça prefrontal medial, afectant processos com la neuroplasticitat, la neurotransmissió i les respostes relacionades amb l'estrès. Tot i els efectes cronodisruptius del protocol i les alteracions moleculars detectades, els canvis conductuals van ser mínims. En canvi, els ratolins Bmal1 knockout van presentar una arrítmia profunda i una motivació elevada per recompenses naturals, manifestant també comportaments de tipus compulsiu. L'anàlisi molecular va revelar una desregulació gènica extensa a l’hipotàlem, l’escorça prefrontal medial i l'estriat ventral, afectant processos relacionats amb la motivació, el metabolisme i la neurotransmissió. En conjunt, els nostres resultats suggereixen que ambdues condicions, genètiques i mediambientals, produeixen cronodisrupció en ratolins, desencadenant alteracions en diferents sistemes neurobiològics. Les disrupcions circadianes lleus poden activar mecanismes adaptatius que prevenen d’efectes conductuals, mentre que alteracions genètiques severes condueixen a canvis pronunciats en les respostes associades a la recompensa.Circadian rhythms regulate essential physiological functions, ensuring adaptation to environmental changes. Disruptions to this system can lead to homeostatic imbalances with potential pathological consequences. This thesis explores the effects of environmental and genetic disturbances on the neurobiology of biological clocks and their consequences on behavior in mice. Mice exposed to short-term irregular light-dark cycles exhibited altered behavioral and molecular daily rhythms, with significant changes in gene expression in the hypothalamus and prefrontal cortex, affecting processes such as neuroplasticity, neurotransmission, and stress responses. Despite the assessed chronodisruptive effects of the protocol and produced molecular alterations, behavioral changes were minimal. In contrast, Bmal1 knockout mice displayed profound arrhythmicity and increased motivation for natural rewards, also manifesting compulsive-like behaviors. Molecular analyses further revealed extensive dysregulation of several clock and non-clock genes expressions within the hypothalamus, medial prefrontal cortex and ventral striatum, affecting processes related to motivation, metabolism, and neurotransmission. Overall, our findings suggest that both genetic and environmental conditions that impair biological clock’s function produce physiological chronodisruption in mice, triggering changes in different neurobiological systems. Mild circadian disruptions may elicit adaptive mechanisms that prevent overt behavioral effects, while severe genetic alterations lead to pronounced changes in reward-related responses.Universitat Pompeu Fabra. Doctorat en Biomedicin
Opio, familia y paisanaje: vascos, criollos filipinos y escoceses en el comercio de Asia oriental (1815-1830)
No full textThe path to the G protein-coupled receptor structural landscape: Major milestones and future directions
No full textG protein-coupled receptors (GPCRs) play a crucial role in cell function by transducing signals from the extracellular environment to the inside of the cell. They mediate the effects of various stimuli, including hormones, neurotransmitters, ions, photons, food tastants and odorants, and are renowned drug targets. Advancements in structural biology techniques, including X-ray crystallography and cryo-electron microscopy (cryo-EM), have driven the elucidation of an increasing number of GPCR structures. These structures reveal novel features that shed light on receptor activation, dimerization and oligomerization, dichotomy between orthosteric and allosteric modulation, and the intricate interactions underlying signal transduction, providing insights into diverse ligand-binding modes and signalling pathways. However, a substantial portion of the GPCR repertoire and their activation states remain structurally unexplored. Future efforts should prioritize capturing the full structural diversity of GPCRs across multiple dimensions. To do so, the integration of structural biology with biophysical and computational techniques will be essential. We describe in this review the progress of nuclear magnetic resonance (NMR) to examine GPCR plasticity and conformational dynamics, of atomic force microscopy (AFM) to explore the spatial-temporal dynamics and kinetic aspects of GPCRs, and the recent breakthroughs in artificial intelligence for protein structure prediction to characterize the structures of the entire GPCRome. In summary, the journey through GPCR structural biology provided in this review illustrates how far we have come in decoding these essential proteins architecture and function. Looking ahead, integrating cutting-edge biophysics and computational tools offers a path to navigating the GPCR structural landscape, ultimately advancing GPCR-based applications
Her9 controls the stemness properties of hindbrain boundary cells
No full textThe different spatiotemporal distribution of progenitor and neurogenic capacities permits that brain regions engage asynchronously in neurogenesis. In the hindbrain, rhombomere progenitor cells contribute to neurons during the first neurogenic phase, whereas boundary cells participate later. To analyze what maintains boundary cells as non-neurogenic progenitors, we addressed the role of Her9, a zebrafish Hes1-related protein. her9 expression is temporarily sustained in boundary cells independently of Notch at early embryonic stages, while they are non-neurogenic progenitors. Complementary functional approaches show that Her9 inhibits the onset of Notch signaling and the neurogenic program, keeping boundary cells as progenitors. Multicolor clonal analysis combined with genetic perturbations reveal that Her9 expands boundary progenitors by promoting symmetric proliferative and preventing neurogenic cell divisions. Her9 also regulates the proliferation of boundary cells by inhibiting the cell cycle arrest gene cdkn1ca and interplaying with Cyclin D1. Moreover, her9 is enriched in hindbrain radial glial cells at late embryonic stages independently of Notch. Together these data demonstrate that Her9 maintains the stemness properties of hindbrain boundary progenitors and late radial glial cells, ensuring the different temporal distribution of neurogenic capacities within the hindbrain.This work was funded by grants PGC2018-095663-B-I00 and PID2021-123261NB-I00 from the Agencia Estatal de Investigación (AEI) and the European Regional Development Fund (FEDER) to C.P. The Department of Medicine and Life Sciences (UPF) is a Unidad de Excelencia Maria de Maeztu (CEX2018 000792M) funded by the AEI. This work was also supported by IHU FOReSIGHT/Agence Nationale de la Recherche (ANR-18-IAHU-01 to J.L.). C.E.-P. was a recipient of FPU predoctoral fellowship from the MICIU, and A.V. holds a predoctoral fellowship from 'la Caixa' Foundation. C.P. is a recipient of an Institució Catalana de Recerca i Estudis Avançats (ICREA) Academia award (Generalitat de Catalunya). Open Access funding provided by Universitat Pompeu Fabra. Deposited in PMC for immediate release
In defence of food: a comparative study of conversas' and moriscas' dietary laws as a form of cultural resistance in the early modern crown of Aragon
No full textData de publicació electrònica: 23-06-2025This research explores the adaptive strategies employed by Conversas (Christian women of Jewish origin) and Moriscas (Christian women of Muslim origin) in navigating adversity, particularly in their interactions with inquisitorial authorities in the early modern Crown of Aragon. This study analyses these women’s efforts to uphold religious and dietary laws while confronting religious violence and preserving contested identities from a comparative perspective. Through an examination of religious practice preservation, coping mechanisms and negotiation tactics, this study unveils the resilience inherent in these communities. Additionally, this study also examines the dual process of negotiation within familial and communal contexts, as well as when confronting the Inquisition. Drawing from various historical sources, including both manuscripts and early modern editions - most notably royal decrees, municipal records, regional statutes and decisions of the Cortes, as well as inquisition trials - the research offers insights into the role of gender and female authority in shaping religious identities within premodern Mediterranean society.This study was supported by HORIZON EUROPE Marie Sklodowska-Curie Actions. HORIZON MSCA-2022-PF; Grant Agreement No.: 101104439; Project: CONVERSAS: Conversas of Muslim and Jewish Origin in the Premodern Crown of Aragon: Parallels and Contrasts
Site-saturation mutagenesis of 500 human protein domains
No full textMissense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases1. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences. Here we present a large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the effect of more than 500,000 variants on the abundance of more than 500 human protein domains. This dataset reveals that 60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases and is particularly important in recessive disorders. We combine stability measurements with protein language models to annotate functional sites across proteins. Mutational effects on stability are largely conserved in homologous domains, enabling accurate stability prediction across entire protein families using energy models. Our data demonstrate the feasibility of assaying human protein variants at scale and provides a large consistent reference dataset for clinical variant interpretation and training and benchmarking of computational methods.A.B. and B.L. were funded by a European Research Council (ERC) Advanced (883742) grant, 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, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322), and the CERCA Program/Generalitat de Catalunya. A.B. was funded by an EMBO fellowship (ALTF 183-2020) and by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement 101030961. X.J. and Y.S. were funded by the National Natural Science Foundation of China (32322047) and Jiangsu Provincial Department of Science and Technology (BM2023009). We thank all members of the Lehner laboratory for helpful discussions and suggestions
Mudanças climáticas e resiliência socioecológica: percepções de comunidades tradicionais em reservas extrativistas marinhas Brasileiras
No full textComunidades tradicionais costeiras estão entre as mais vulneráveis às mudanças climáticas, ainda que não tenham contribuído para o surgimento desse fenômeno, demonstrando uma das facetas da injustiça climática. Para combater essa injustiça são necessárias políticas públicas que promovam a adaptação climática, com base em arranjos de governança locais existentes, como unidades de conservação a que essas comunidades estejam ligadas. É essencial entender as percepções dessas comunidades quanto às mudanças climáticas e aos instrumentos de manejo disponíveis. Este estudo analisa as percepções relacionadas a diversos aspectos da emergência climática em comunidades tradicionais das Reservas Extrativistas Corumbau, Bahia, e Caeté-Taperaçu, Pará, com base na análise de entrevistas semiestruturadas, realizadas em 2021 e 2022, que abrangeram temas como sensibilidade social e ecológica, políticas públicas, e capacidade adaptativa. Os resultados mostram que essas populações reconhecem a importância e consequências negativas desse fenômeno, ainda que não articulem uma definição precisa do termo “mudanças climáticas”. Para essas populações os impactos das mudanças do clima incidem sobre o seu sustento e o arranjo atual de manejo não representa os seus interesses como atores locais. A partir dessa pesquisa percebe-se a inexistência de uma atuação mais apropriada do poder público na promoção de diálogo entre os diferentes tipos de conhecimento e na construção de estruturas de apoio em casos de emergência. Faz-se necessário, no contexto de implementação de políticas públicas de adaptação, considerar estruturas socioeconômicas, entendendo como as informações circulam e como os conceitos emergem e são articulados nos espaços de formulação de instrumentos de adaptação às mudanças climáticas
Biotechnologies of the future: novel cyanobacteria-based solutions for sustainable industries
No full textThis thesis delves into the indispensable role of bacteria across our planet and their profound impact on various industries, encompassing health, agriculture, cosmetics, and materials science. It sheds light on the inherent challenges associated with bacterial-based materials in these industries and presents groundbreaking solutions. One such innovation is Ficogenic Broth® (FB), a novel culture medium derived from Spirulina platensis. FB offers a cost-effective, animal-free solution for preserving live microorganisms, addressing critical needs in health and agriculture, with an ongoing presented patent. Furthermore, the thesis explores the production of Bacterial Cellulose (BC) using FB, unveiling its diverse applications, particularly in sustainable materials. With bio-functionalization of BC we enhanced its versatility across multiple industries. In conclusion, this thesis underscores the transformative potential of Ficogenic Broth® as a flagship product and its derivatives, including Nanulose®, ProBio®, biofertilizers, skincare, and probiotics. These industrial doctorate project offering sustainable solutions through BIOM spin-off for a more efficient and eco-conscious future for industries worldwide.Esta tesis profundiza en el papel indispensable de las bacterias en nuestro planeta y su profundo impacto en diversas industrias, que abarcan la salud, la agricultura, la cosmética y la ciencia de materiales. Arroja luz sobre los desafíos inherentes asociados con los materiales a base de bacterias en estas industrias y presenta soluciones innovadoras. Una de esas innovaciones es Ficogenic Broth® (FB), un nuevo medio de cultivo derivado de Spirulina platensis. FB ofrece una solución rentable y sin animales para preservar microorganismos vivos, abordando necesidades críticas en salud y agricultura, con una patente presentada en curso. Además, la tesis explora la producción de celulosa bacteriana (BC) utilizando FB, revelando sus diversas aplicaciones, particularmente en materiales sostenibles. Con la biofuncionalización de BC mejoramos su versatilidad en múltiples industrias. En conclusión, esta tesis subraya el potencial transformador de Ficogenic Broth® como producto estrella y sus derivados, incluidos Nanulose®, ProBio®, biofertilizantes, cuidado de la piel y probióticos. Este proyecto de doctorado industrial ofrece soluciones sostenibles a través de BIOM para un futuro más eficiente y ecológico para las industrias de todo el mundo.Programa de Doctorat en Biomedicin
Exploring the dynamics of women’s employment transitions, work-family conflict, and child behavioural problems: a comparative study
No full textThis PhD dissertation is devoted to women’s transitions in the labour market and the influence of work-family conflict and parental self-efficacy on children’s behaviour. Although women often modify their paid employment to meet family obligations, they continue to take on the majority of unpaid domestic and childcare tasks, while men tend to focus more on their paid jobs. Additionally, stress from work and rigid schedules can interfere with family time, leading to fewer opportunities for shared activities, increasing strain on family dynamics, and contributing to behavioral issues in children. This thesis focuses on the issue of gender equality in both the labor market and family life. It explores the influence of motherhood on women's transitions within the workforce, examines how work-family conflict and parental self-efficacy alter parenting approaches, and investigates the subsequent effects of these changes on children's externalizing issues. The thesis is composed of three articles. The first article explores the factors that influence the probability that women employed full-time will go part-time or withdraw from paid work (i.e., become inactive). The results show that, apart from the transition to motherhood, the factors that influence women’s participation in the labour market are traditional gender ideology and lack of state support. The second paper explores the impact of work-family conflict (WFC) and parental irritability on children's externalizing problems in various family structures in Australia. The findings show that for mothers from two-parent families, work-family conflict is a predictor of children's externalizing problems throughout their childhood and adolescence. However, for fathers from two-parent families and sole mothers, there is no such association. Moreover, while the association between paternal irritability and children's externalizing problems exists for all groups of parents, it is stronger for mothers than for fathers. The third paper investigates the impact of parental self-efficacy (PSE) and warm parenting on children's externalizing problems in two-parent families in Australia. The findings show that parental self-efficacy with a newborn is a strong predictor of warm parenting at the child’s age of 6, with the association being stronger for mothers than for fathers. Marital satisfaction increases warm parenting, more so for fathers. While the association between warm parenting and children's externalizing problems exists for all parents, it is stronger for mothers than for fathers. These articles highlight the potential negative outcomes for mothers and children in an adverse context of weak family policies and the persistence of traditional gender values in couples. The thesis makes a potential contribution to the field of family sociology and the examination of gender disparities through a comparative analysis. It utilizes panel data from families with various structures, enabling the observation of changes in individual characteristics over time.Esta tesis doctoral analiza las transiciones de las mujeres en el mercado laboural, la influencia del conflicto entre el trabajo y la familia y la autoeficacia de los padres en el comportamiento de los niños. Aunque las mujeres suelen modificar su empleo remunerado para cumplir con las obligaciones familiares, siguen asumiendo la mayoría de las tareas domésticas y de cuidado de los niños no remuneradas, mientras que los hombres tienden a centrarse más en sus trabajos remunerados. Además, el estrés laboral y los horarios rígidos pueden interferir con el tiempo familiar, lo que genera menos oportunidades para actividades compartidas, aumenta la tensión en la dinámica familiar y contribuye a problemas de conducta en los niños. Esta tesis se centra en la cuestión de la igualdad de género tanto en el mercado laboral como en la vida familiar. Explora la influencia de la maternidad en las transiciones de las mujeres dentro de la fuerza laboral, examina cómo el conflicto entre el trabajo y la familia y la autoeficacia parental alteran los enfoques de crianza e investiga los efectos posteriores de estos cambios en los problemas de externalización de los niños.Esta tesis está compuesta por tres artículos. El primer artículo explora los factores que influyen en la probabilidad de que las mujeres empleadas a tiempo completo trabajen a tiempo parcial o abandonen el trabajo remunerado (es decir, pasen a ser inactivas). Los resultados muestran que los factores que influyen en la participación de las mujeres en el mercado laboural, además de la transición a la maternidad, son la ideología de género tradicional y la falta de apoyo estatal a las familias con hijos a cargo. El segundo artículo explora el impacto del conflicto entre el trabajo y la familia y la irritabilidad de los padres en los problemas de externalización de los niños y niñas en diversas estructuras familiares en Australia. Los hallazgos muestran que para las madres de ‘familias intactas’ , el conflicto entre el trabajo y la familia es un predictor de los problemas de externalización de los niños y niñas a lo largo de su infancia y adolescencia. Sin embargo, para los padres de familias intactas y para las madres solteras, no existe tal asociación. Además, si bien la asociación entre la irritabilidad paterna y los problemas de externalización de los niños y niñas existe para todos los grupos de padres, es más fuerte para las madres que para los padres. El tercer artículo investiga el impacto de la autoeficacia parental y la crianza cálida en los problemas de externalización de los niños y niñas en familias intactas en Australia. Los hallazgos muestran que la autoeficacia de los padres con una criatura recién nacida es un fuerte predictor de una crianza cálida a la edad de 6 años, siendo la asociación más fuerte para las madres que para los padres. Además, la satisfacción conyugal aumenta la crianza cálida, más aún para los padres. Si bien la asociación entre una crianza cálida y los problemas de externalización de los niños y niñas existe para todos los progenitores, es más fuerte para las madres que para los padres. Estos artículos destacan los posibles resultados negativos para madres y sus criaturas en un contexto adverso de políticas familiares débiles y la persistencia de valores tradicionales de género en las parejas. Utiliza datos de panel de familias con estructuras diversas, lo que permite observar cambios en las características individuales a lo largo del tiempo.Programa de Doctorat en Ciències Polítiques i Social
Construction of injectable wireless microstimulators based on rectification of volume conducted high frequency currents
No full textFunctional neuromuscular stimulation (FNS) refers to the delivery of
electrical stimuli to nerves or muscles to enhance, modify or restore motor
functions. Despite their invasiveness, implantable systems for FNS offer key
advantages over surface and percutaneous systems in terms of selectivity and
safety. Most implantable FNS systems consist of a relatively bulky
subcutaneous pulse genera-tor connected through leads to electrodes at the
target stimulation sites. In the case of FNS systems for restoring motor
functions in patients with paralysis, the leads are long and the electrodes are
distributed over large and mobile body parts, thus making them highly invasive
and prone to failure. Miniaturized wireless implantable stimulators represent a
safer and more reliable alternative. By integrating all the components in the
same device, long leads are avoided and minimally invasive implantation
procedures are enabled. In this thesis, architectures and construction methods
were devised to implement thin (diameter < 1 mm), flexible and biocompatible
wireless microstimulators whose operation principle is based in rectifying high
frequency currents delivered to tissues by volume conduction. These threadlike
devices, which were successfully in vivo assayed, are intended to be deployed
by injection forming a dense network of intramuscular addressable stimulators
for the development of motor neuroprostheses. They were implemented
adapting techniques well accepted in industry to facilitate early clinical
adoption. A noteworthy feature of their construction is the inclusion of a
biterminal hermetic metallic capsule housing the sophisticated microelectronic
circuitry required for their operation. The applicability of the same technology
and operation methods to an alternative clinical field was also explored in the
scope of this thesis through the development and in vivo assay proof-of-concept
novel leadless microstimulators. Furthermore, this thesis has contributed to the
development of refined computer models to characterize the stimulation
method previously described.La estimulación neuromuscular funcional (FNS) se refiere a la aplicación de
estímulos eléctricos a nervios o músculos para mejorar, modificar o restaurar
fun-ciones motoras. A pesar de ser invasivos, los sistemas implantables para
FNS ofrecen ventajas en selectividad y seguridad sobre los superficiales y
percutáneos. La mayoría de los sistemas FNS implantables consisten en un
generador de pulsos subcutáneo relativamente voluminoso conectado por
cables a electrodos en los puntos de estimulación. En el caso de sistemas FNS
para restaurar funciones motoras en pacientes con parálisis, los cables son
largos y los electrodos están distribuidos por partes del cuerpo grandes y
móviles, haciéndolos altamente invasivos y propensos a fallar. Estimuladores
implantables inalámbricos miniaturizados representan una alternativa más
segura y confiable. Al integrar todos los componentes en el mismo
dispositivo, se evitan los cables largos y se habilitan procedimientos de
implantación mínimamente invasivos. En esta tesis se han diseñado
arquitecturas y métodos de construcción para implementar microestimuladores
inalámbricos delgados (diámetro < 1 mm), flexibles y biocompatibles basados
en la rectificación de corrientes de alta frecuencia aplicadas a los tejidos por
conducción volumétrica. Estos dispositivos filiformes, ensayados con éxito in
vivo, serían implantados mediante inyección formando una densa red de
estimuladores direccionables intramusculares para desarrollar neuroprótesis
motoras. Éstos se han implementado adaptando técnicas bien aceptadas en la
industria para facilitar la adopción clínica temprana. Una característica notable
de su construcción es la inclusión de una cápsula metálica hermética biterminal
que aloja los sofisticados circuitos microelectrónicos necesarios para su
funcionamiento. La aplicabilidad de la misma tecnología y métodos de
operación a un campo clínico alternativo también se ha explorado en esta tesis
mediante el desarrollo y prueba de concepto in vivo de novedosos
microestimuladores sin cables. Además, esta tesis ha contribuido al desarrollo
de modelos informáticos refinados para caracterizar el método de estimulación
descrito anteriormente.Programa de doctorat en Tecnologies de la Informació i les Comunicacion