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Epigenetic regulation of HOXA2 expression affects tumor progression and predicts breast cancer patient survival
No full textAccumulating evidence suggests that genetic and epigenetic biomarkers hold potential for enhancing the early detection and monitoring of breast cancer (BC). Epigenetic alterations of the Homeobox A2 (HOXA2) gene have recently garnered significant attention in the clinical management of various malignancies. However, the precise role of HOXA2 in breast tumorigenesis has remained elusive. To address this point, we conducted high-throughput RNA sequencing and DNA methylation array studies on laser-microdissected human BC samples, paired with normal tissue samples. Additionally, we performed comprehensive in silico analyses using large public datasets: TCGA and METABRIC. The diagnostic performance of HOXA2 was calculated by means of receiver operator characteristic curves. Its prognostic significance was assessed through immunohistochemical studies and Kaplan-Meier Plotter database interrogation. Moreover, we explored the function of HOXA2 and its role in breast carcinogenesis through in silico, in vitro, and in vivo investigations. Our work revealed significant hypermethylation and downregulation of HOXA2 in human BC tissues. Low HOXA2 expression correlated with increased BC aggressiveness and unfavorable patient survival outcomes. Suppression of HOXA2 expression significantly heightened cell proliferation, migration, and invasion in BC cells, and promoted tumor growth in mice. Conversely, transgenic HOXA2 overexpression suppressed these cellular processes and promoted apoptosis of cancer cells. Interestingly, a strategy of pharmacological demethylation successfully restored HOXA2 expression in malignant cells, reducing their neoplastic characteristics. Bioinformatics analyses, corroborated by in vitro experimentations, unveiled a novel implication of HOXA2 in the lipid metabolism of BC. Specifically, depletion of HOXA2 leaded to a concomitantly decreased expression of PPARγ and its target CIDEC, a master regulator of lipid droplet (LD) accumulation, thereby resulting in reduced LD abundance in BC cells. In summary, our study identifies HOXA2 as a novel prognosis-relevant tumor suppressor in the mammary gland
Consumer authorities in Europe: policing markets or empowering consumers?
No full textConsumer protection authorities are vital for domestic markets and the smooth functioning of the EU common market. Established several decades ago, these authorities have different institutional designs in different European countries. This paper aims to identify them and assess their main variations. Based on the literature at the intersection of consumer protection regimes and regulatory governance, we propose a theoretical distinction between enforcement-focused authorities and service delivery-oriented authorities. Specifically, we suggest these principles lead to either a supervisory model, which disciplines market actors, or an empowering model, which gives citizens the keys to prevent market abuses. To empirically test whether these two models capture the variety of institutional designs and practices consumer authorities may adopt, we have identified four different dimensions that characterize their connections to politics, business, and citizens: political autonomy, social accountability, administrative enforcement, and consumer awareness. We begin by discussing which dimensions are associated with which model and then examine the presence of the two models across Europe. Our analysis is based on Bayesian factorial analysis and a Ward.D cluster construction grounded in an original dataset of institutional characteristics from general consumer authorities in 27 EU countries, the UK, and Norway, offering empirical evidence to support our argument. The results suggest that EU efforts to build institutional harmonization have had limited success. Likewise, traditional administrative models across Europe may no longer hold the same relevance as previously indicated in research. Our findings show instead that consumer authorities in Europe can generally be distinguished from each other based on these two principles, though many operate with a hybrid approach.This study was supported by the NORFACE Joint Research Programme on Democratic Governance in a Turbulent Age (Reconnect project), funded by the European Union's Horizon 2020 research and innovation programme (grant agreement 822166) and the Spanish Agencia Estatal de Investigación from the Ministerio de Ciencia (grant agreement PIC2020-112243)
Evolution of tissue-specific transcriptomes across bilaterian animals
No full textRegulated Gene Expression (rGE) and Alternative Splicing (rAS) are two of the main mechanisms contributing to tissue-phenotypic diversity within and between species. In this thesis, we aim at characterizing rGE and rAS patterns impacting tissue-specific transcriptomes throughout ~600 million years of bilaterian evolution. Our work revolves around (1) a vast RNA-seq dataset covering eight tissues across a symmetric phylogeny of twenty bilaterian species (eight vertebrates, eight insects and two pairs of outgroups); and (2) the exclusive focus on bilaterian-conserved genes. First, we identify ancestral tissue-specific rGE patterns, together with parallel, convergent and divergent evolutionary trajectories between and within vertebrates and insects. Second, we develop a software to infer exon orthologies at any evolutionary distance, a crucial prerequisite for rAS evolutionary analyses. Third, we characterize a compendium of tissue-specific exons across all species. Finally, we compare rGE- and rAS- regulated genes, extracting unique features associated with each type of tissue-specific regulation.La regulación de la expresión génica (rGE) y el empalme alternativo (rAS) son dos de los principales mecanismos que contribuyen a la diversidad fenotípica de tejidos dentro y entre especies. En esta tesis, nuestro objetivo es caracterizar los patrones de rGE y rAS que afectan a los transcriptomas específicos de tejido a lo largo de ~600 millones de años de evolución bilateral. Nuestro trabajo gira en torno a (1) un vasto conjunto de datos de RNA-seq que cubre ocho tejidos en una filogenia simétrica de veinte especies bilaterales (ocho vertebrados, ocho insectos y dos pares de grupos externos); y (2) el enfoque exclusivo en genes conservados bilateralmente. Primero, identificamos patrones de rGE específicos de tejidos ancestrales, junto con trayectorias evolutivas paralelas, convergentes y divergentes entre y dentro de vertebrados e insectos. En segundo lugar, desarrollamos un software para inferir ortologías de exón a cualquier distancia evolutiva, un requisito previo crucial para los análisis evolutivos de rAS. En tercer lugar, caracterizamos un compendio de exones específicos de tejido en todas las especies. Finalmente, comparamos genes regulados por rGE y rAS, extrayendo características únicas asociadas con cada tipo de regulación específica de tejido.Programa de Doctorat en Biomedicin
Transcriptomic determinants of vertebrate photoreceptors and other sensory cells
No full textThe nervous system comprises an immense number of cells that serve highly specialized roles. Accordingly, they possess unique morphological and functional attributes, greatly shaped by specific Alternative Splicing (AS) and Gene Expression (GE) mechanisms. Retinal photoreceptors have a distinct transcriptomic profile compared to other neuronal subtypes, likely reflecting their unique cellular morphology and function in the detection of light by way of the ciliary outer segment. We discovered a new layer of this molecular specialization by revealing that the vertebrate retina expresses the largest number of tissue-enriched microexons of all tissue types. This microexon program is regulated by Srrm3, a paralog of the neural microexon regulator Srrm4. Despite the fact that both proteins positively regulate retina microexons in-vitro, only Srrm3 is highly expressed in mature photoreceptors. Its deletion in zebrafish results in widespread down-regulation of microexon inclusion, severe photoreceptor defects and blindness. Since this microexon program involves genes of the photoreceptor cilium, we explored whether other ciliated sensory cells display specialized transcriptomes. Multi-layer RNA-seq analysis revealed that cilia in olfactory neurons diverge from other ciliated sensory cells by activating a network of motile cilia genes highly expressed in spermatocytes and regulated by Rfx3.
Our results shed light on the transcriptomic specialization and functionality of cilia in sensory cells, uncovering new cell-type specific roles for many genes with implication for a wide spectrum of human diseases.El sistema nervioso comprende una inmensa cantidad de células que cumplen funciones altamente especializadas. En consecuencia, poseen atributos morfológicos y funcionales únicos, moldeados en gran medida por mecanismos específicos de splicing alternativo (AS) y expresión génica (GE). Los fotorreceptores retinales tienen un perfil transcriptómico distinto en comparación con otros subtipos neuronales, lo que probablemente refleja su morfología celular y función únicas en la detección de luz a través del segmento externo ciliar. Descubrimos una nueva capa de esta especialización molecular al revelar que la retina de los vertebrados expresa la mayor cantidad de microexones enriquecidos en tejidos (entre todos los tejidos analizados). Este programa de microexones está regulado por Srrm3, un parálogo del regulador de microexones neurales Srrm4. A pesar de que ambas proteínas regulan positivamente los microexones de la retina in vitro, solo Srrm3 se expresa en gran medida en los fotorreceptores maduros. Su eliminación en el pez cebra resulta en una regulación negativa generalizada de la inclusión de microexones, defectos graves en los fotorreceptores y ceguera. Dado que este programa de microexón involucra genes del cilio de los fotorreceptores, exploramos si otras células sensoriales ciliadas muestran transcriptomas especializados.
El análisis multi-layer RNA-seq reveló que los cilios en las neuronas olfatorias se separan de los de otras células sensoriales ciliadas al activar una red de genes de cilios móviles altamente expresados en los espermatozoides y regulados por Rfx3.
Nuestros resultados elucidan la especialización transcriptómica y la funcionalidad de los cilios en las células sensoriales, revelando nuevas funciones célula-específicas para muchos genes con implicación en un amplio espectro de enfermedades humanas.Programa de doctorat en Biomedicin
The European Union's global health actorness: a research agenda for a new age of pandemics
No full textWhilst the European Union's (EU's) response to health emergencies has historically been subpar, some suggest that it emerged from COVID-19 as a stronger global health actor. This prompts two interrelated questions: how have International Relations scholars conceptualised and assessed EU ‘actorness’ in the all-too-often neglected field of global health, and what adjustments are required in anticipation of a potential new age of pandemics? This article revisits the longstanding notion of ‘actorness’ and dissects the few studies that apply it systematically to analyse the EU's role in global health. After identifying some key shortcomings in the literature, the article formulates a research agenda suitable for the complex and high-stakes nature of contemporary global health endeavours. By further adapting the concept of ‘actorness’ to a multifaceted EU external action as well as to an increasingly intricate global governance architecture, this research agenda contributes to the broader scholarship on the EU's international outreach
A comparative user study of human predictions in algorithm-supported recidivism risk assessment
No full textIn this paper, we study the effects of using an algorithm-based risk assessment instrument (RAI) to support the prediction of risk of violent recidivism upon release. The instrument we used is a machine learning version of RiskCanvi used by the Justice Department of Catalonia, Spain. It was hypothesized that people can improve their performance on defining the risk of recidivism when assisted with a RAI. Also, that professionals can perform better than non-experts on the domain. Participants had to predict whether a person who has been released from prison will commit a new crime leading to re-incarceration, within the next two years. This user study is done with (1) general participants from diverse backgrounds recruited through a crowdsourcing platform, (2) targeted participants who are students and practitioners of data science, criminology, or social work and professionals who work with RisCanvi. We also run focus groups with participants of the targeted study, including people who use RisCanvi in a professional capacity, to interpret the quantitative results. Among other findings, we observe that algorithmic support systematically leads to more accurate predictions from all participants, but that statistically significant gains are only seen in the performance of targeted participants with respect to that of crowdsourced participants. Among other comments, professional participants indicate that they would not foresee using a fully-automated system in criminal risk assessment, but do consider it valuable for training, standardization, and to fine-tune or double-check their predictions on particularly difficult cases. We found that the revised prediction by using a RAI increases the performance of all groups, while professionals show a better performance in general. And, a RAI can be considered for extending professional capacities and skills along their careers.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work has been partially supported by the HUMAINT programme (Human Behaviour and Machine Intelligence), Centre for Advanced Studies, Joint Research Centre, European Commission through the Expect contract CT-EX2019D347180. Additionally, it received the support from the EU-funded project “SoBigData++” (grant agreement 871042)
Resisting and transgressing cisheteronormativity at home: LGBT+ youths’ active strategies
No full textMany of the struggles and advances in LGBT+ rights are fought in domestic spaces. However, the political and emotional complexity of the home in relation to gender and sexual dissidence has received limited attention. This research aims to explore the discrimination and coping strategies of young LGBT+ youth in their family and personal home. Through a qualitative methodology, I examine how 27 LGBT+ youth from Bages (Catalonia) experience different home spaces according to their age, gender, and sexual orientation. The results show adultism and pressure to conform to cisheteronormative expectations at the family home. However, these norms dissolve in the personal home, allowing the free development of their LGBT+ identities. The study reveals the resistance and transformation strategies they use to tackle cisheteronormativity, highlighting home as a place of politics, negotiation, power, and complex emotions.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: European Union’s Horizon Europe Research and Innovation Programme under Grant Agreement; No 101039447
Llengua i dinàmiques econòmiques (#)
No full textText dedicat a Joaquim Silvestre, catedràtic d’Economia de la UC Davis als EUA, sempre preocupat per la nostra llengua, excel·lent economista i gran persona
The impact of population aging on the interest–growth differential (r − g)
No full textTreball fi de màster de: Master's Degree in Economics and Finance. Economics Program. Curs 2024-2025Tutors: Isaac Baley i Victoria VanascoThis paper examines how population aging and demographic change affect the interest-growth differential (r − g). Using overlapping generations (OLG) models, we identify three theoretical channels: (1) higher life expectancy raises the savings rate, lowering the interest rate (r) and raising output growth (g) in transition, (2) lower fertility increases capital per worker, reducing r and g, and (3) a rise in the old-age dependency ratio (OADR) lowers the aggregate savings rate, raising (r − g). The empirical predictions broadly align with the theory, capturing both short-run effects through panel regressions and long-run steady-state effects through VARX regressions.Este artículo examina cómo el envejecimiento de la población y el cambio demográfico afectan a la diferencia entre la tasa de interés y la tasa de crecimiento (r−g). Utilizando modelos de generaciones solapadas (OLG), identificamos tres mecanismos teóricos: (1) una mayor esperanza de vida incrementa la tasa de ahorro, lo que reduce la tasa de interés (r) y aumenta el crecimiento del producto (g) durante la transición, (2) una menor fertilidad incrementa el capital por trabajador, lo que provoca una disminución de r y g, y (3) un aumento en la tasa de dependencia de la vejez (OADR) reduce la tasa de ahorro agregada y, por tanto, incrementa (r − g). Los resultados empíricos, que capturan tanto los efectos a corto plazo mediante regresiones de panel como los efectos a largo plazo en el estado estacionario mediante regresiones VARX, se alinean en términos generales con la teoría
Silent brain ischemia within the TAXINOMISIS framework: association with clinical and advanced ultrasound metrics
No full textIntroduction: The relationship between carotid artery stenosis (CAS) and ipsilateral silent brain ischemia (SBI) remains unclear, with uncertain therapeutic implications. The present study, part of the TAXINOMISIS project (nr. 755,320), aimed to investigate SBIs in patients with asymptomatic CAS, correlating them with clinical, carotid ultrasonographic data, and CFD analyses. Methods: The TAXINOMISIS clinical trial study (nr. NCT03495830) involved six vascular surgery centers across Europe, enrolling patients with asymptomatic and symptomatic CAS ranging from 50 to 99%. Patients underwent carotid ultrasound and magnetic resonance imaging (MRI), including brain diffusion-weighted, T2-weighted/FLAIR, and T1-weighted sequences. Brain MRI scans were analyzed for the presence of SBI according to established definitions. Ultrasound assessments included Doppler and CFD analysis. Only asymptomatic patients were included in this substudy. Results: Among 195 asymptomatic patients, the mean stenosis (NASCET) was 64.1%. Of these, a total of 33 patients (16.9%) had at least one SBI detected on a brain MRI scan. Specifically, 19 out of 33 patients (57.6%) had cortical infarcts, 4 out of 33 patients (12.1%) had ipsilateral lacunar infarcts, 6 out of 33 patients had (18.2%) subcortical infarcts, 1 out of 33 patients (3.0%) had both cortical and lacunar infarcts, and 3 out of 33 patients (9.1%) both cortical and subcortical infarcts. Patients with SBIs exhibited significantly higher risk factors, including a higher body mass index (28.52 ± 9.38 vs. 26.39 ± 3.35, p = 0.02), diastolic blood pressure (80.87 ± 15.73 mmHg vs. 80.06 ± 8.49 mmHg, p = 0.02), creatinine levels (93.66 ± 34.61 μmol/L vs. 84.69 ± 23.67 μmol/L, p = 0.02), and blood triglycerides (1.8 ± 1.06 mmol/L vs. 1.48 ± 0.78 mmol/L, p = 0.03). They also had a higher prevalence of cardiovascular interventions (29.6% vs. 13.8%, p = 0.04), greater usage of third/fourth-line antihypertensive treatment (50%vs16%, p = 0.03), and anticoagulant medications (60% vs. 16%, p = 0.01). Additionally, the number of contralateral cerebral infarcts was higher in patients with SBIs (35.5% vs. 13.4%, p < 0.01). Moreover, carotid ultrasound revealed higher Saint Mary’s ratios (15.33 ± 12.45 vs. 12.96 ± 7.99, p = 0.02), and CFD analysis demonstrated larger areas of low wall shear stress (WSS) (0.0004 ± 0.0004 m2 vs. 0.0002 ± 0.0002 m2, p < 0.01). Conclusion: The TAXINOMISIS clinical trial provides valuable insights into the prevalence and risk factors associated with SBIs in patients with moderate asymptomatic carotid stenosis. The findings suggest that specific hemodynamic and arterial wall characteristics may contribute to the development of silent brain infarcts.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study received funding from the European Union¿s Horizon 2020 research and innovation program under grant agreement nr. 755320