Alberto Sols Biomedical Research Institute
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Estudio de las bases moleculares subyacentes a las neoplasias de células T precursoras para aplicar la medicina personalizada: caracterización de la fusión SEPTIN6::ABL2 como nueva diana terapéutica e identificación del gen AHR como biomarcador de respuesta al tratamiento
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología. Fecha de Lectura: 11-10-2024Esta Tesis tiene embargado el acceso al texto completo hasta el 11-04-2026Las neoplasias de células T precursoras son un tipo de cáncer hematológico que deriva de la transformación maligna de células T inmaduras en cualquiera de sus estadios de maduración. Esta enfermedad se manifiesta de manera frecuente con una alta implicación en sangre y médula ósea y se denomina leucemia linfoblástica aguda de células T (T-ALL), o de manera menos frecuente como una masa tumoral en el timo, mediastino y ganglios linfáticos y se denomina linfoma linfoblástico de células T (T-LBL). A pesar de que el tratamiento actual para este tipo de cáncer tiene una alta tasa de curación, presenta dos problemas principales: el primero es la baja tasa de supervivencia de los pacientes que recaen y el segundo es la alta toxicidad. Estos problemas ponen de manifiesto la necesidad de identificar nuevas dianas terapéuticas y nuevos biomarcadores moleculares para la estratificación de los pacientes para la implementación de nuevas terapias personalizadas que sean más eficaces y con menos efectos adversos. Para ello, hemos combinado el análisis del perfil molecular de pacientes con T-ALL con aproximaciones funcionales y la generación de modelos celulares complementarios, incluyendo una línea celular derivada de uno de los pacientes.
En primer lugar, hemos identificado una nueva alteración de ABL2 y la hemos caracterizado funcionalmente como altamente oncogénica. En segundo lugar, hemos estudiado los mecanismos moleculares mediante los cuales la alteración ABL2 promueve el desarrollo tumoral. Estos mecanismos no habían sido descritos previamente debido a la falta de modelos celulares adecuados. Estas alteraciones inducen la fosforilación sostenida de STAT5 y la sobreexpresión de PIM1. A través de la activación de este eje STAT5/PIM1, la alteración de ABL2 también activaría las vías de señalización de c-MYC y mTOR. Además, también induce un perfil de expresión génica alterado que promueve la desregulación de muchos procesos celulares oncogénicos como son la progresión del ciclo celular o la inhibición de la apoptosis. En tercer lugar, hemos demostrado que los inhibidores de tirosinas quinasas, PIM, mTOR, quinasas dependientes de ciclinas y proteínas anti-apoptóticas bloquean la señal oncogénica inducida por la alteración de ABL2. Por otro lado, hemos identificado la sobreexpresión del gen AHR en el momento de diagnóstico de los pacientes como posible biomarcador molecular predictor de su respuesta al tratamiento. Este gen serviría como complemento temprano a la enfermedad mínima residual para la estratificación de los pacientes según su riesgoPara el desarrollo de la tesis se ha contado con financiación procedente de los siguientes proyectos:
-“Una visión genómica y epigenómica integrada de la heterogeneidad intratumoral durante la evolución de las neoplasias linfoblásticas de células T precursoras”. Referencia: SAF2015-70561R.
-“Nuevos biomarcadores en neoplasias linfoblásticas de células T precursoras: heterogeneidad intratumoral, editado de ARNm y exosomas”. Referencia: RTI2018-093330-B-I00
-“Aggressive T cell Lymphomas, integrated clinical and genomic analysis for a precision medicine”. Referencia: AECC-PROYECT18054PIRI
-“Integration of genomic and epigenomic strategies for the analysis of T lymphoblastic neoplasms in the context of a precision individualized medicine”. Referencia: CIVP19S791
Interacciones y superconductividad en sistemas de grafeno rotado y sin rotar
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Física de la Materia Condensada. Fecha de Lectura: 29-11-2024Esta tesis tiene embargado el acceso al texto completo hasta el 29-05-202
Analisis transcriptómico a nivel de célula unica de la transición endotelial-hematopoiética
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 13-11-2024Esta tesis tiene embargado el acceso al texto completo hasta el 13-05-2026Developmental hematopoiesis undergoes a number of sequential and overlapping waves during murine embryogenesis. The last of these waves, defined as the definitive hematopoietic stem cell (HSC) wave, starts after endothelial to hematopoietic transition (EHT) within the dorsal aorta (DA) region in the aorta gonad mesonephros (AGM) of the E9.5-11-5 developing embryo. The Notch signaling pathway is involved throughout said process, with recent studies suggesting that DA endothelial cells (ECs) must undergo a gradual downregulation of its canonical pathway causing a shift in DAECs from the arterialization process towards EHT. How this gradual downregulation occurs, however, has not yet been fully characterized.
This thesis explores the role of Notch signaling during EHT via single cell RNA sequencing (scRNAseq) coupled with conditional genetics from purified cells of E10.5 murine embryo AGMs. Our results show that, even with current state of the art genetic tools, modifying Notch signaling at either E8.0 or E9.5 can affect not only EHT, but also arterialization and overall embryo development. Embryos with EC loss of Notch1 expression at E9.5 present a strong delay in arterialization, but also in EHT and embryo development. EC expression loss of the Notch1 ligand, Jag1, shows a decrease in EHT while still affecting arterialization. Overexpression of the Notch receptor glycosyltransferase Mfng promotes arterialization which in turn promotes EHT, presenting both processes as sequential and not antagonistic. Increased Notch expression through overexpression of N1ICD-PEST in DAECs presents an increase in arterialization coupled with the appearance of intermediary hematopoietic progenitors. Mycn, a well-known cell cycle regulator whose expression levels in DAECs are regulated in part by Notch signaling, presents a key role in stem cell differentiation following EHT, where loss of the marker in DAECs causes a decrease of preHSCs in favor of endothelial multipotent progenitors (eMPPs).
The exploration of the effect of Notch signaling in EHT is further continued via the use of in silico analysis of KO perturbation assays of various transcription factors related to Notch signaling and EHT. The analysis confirms Runx1 as the key marker driving the Hemogenic Endothelium (HE) celltype while also presenting the oscillatory behaviors of the Hes1 and Gata2 TFs between the Aorta ECs and Pre-HE celltypes preceding EHT from the HE.
Due to the difficulty of splitting the various biological processes that Notch affects during embryonic development in standard scRNAseq analysis, as well as its long term effects, we have devised iFlpscLineage, a single cell lineage tracing (scLT) tool that can be coupled with transcriptomic analysis and conditional genetics, in order to increase our understanding of EHT and the role that Notch signaling plays within. The thesis includes the development of a workflow and initial testing of the tool for its future applicationsResearch in Rui Benedito’s laboratory was supported by: 1. European Research Council (ERC). -Starting Grant AngioGenesHD (638028) -Consolidator Grant AngioUnrestUHD (101001814) 2. CNIC Intramural Grant Program Severo Ochoa (11-2016-IGP-SEV-2015-0505) 3. Ministerio de Ciencia e Innovación (MCIN) (SAF2013-44329-P, RYC-2013-13209, and SAF2017-89299-P) 4.‘La Caixa’ Banking Foundation (HR19-00120) 5. CNIC is currently supported by Instituto de Salud Carlos III, MCIN and the Pro CNIC Foundation. CNIC is also a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MCIN/ AEI/10.13039/501100011033) Alvaro Regaño García was cofunded by the European Social Fund through the Youth Employment Initiative (YEI) (PEJD-2019-PRE/BMD-16990
Papel de los Receptores X Retinoides en macrófagos residentes de tejido: macrófagos alveolares y células de Kupffer
No full textTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 04-11-2024Esta tesis tiene embargado el acceso al texto completo hasta el 04-05-2026Los macrófagos residentes de tejido (MRTs) son células clave del sistema inmunológico que actúan como primera línea de defensa en procesos infecciosos y en enfermedades. Son células inmunes altamente especializadas que pueden detectar y eliminar patógenos dañinos, además de realizar funciones específicas de los tejidos en que residen que aseguran la homeostasis. Los diferentes subconjuntos de macrófagos comparten un programa transcripcional que abarca un conjunto de genes centrales (core), comunes a todos los MRTs. Además, estos macrófagos reciben señales derivadas de los tejidos que a su vez inducen factores de transcripción (FT) específicos. Estos regulan la expresión de otro conjunto de genes, necesario para el desarrollo del macrófago y el desempeño de sus funciones específicas. Sin embargo, el mecanismo por el que las señales del microambiente tisular se traducen en la identidad de estas células siguen siendo desconocidos para muchos tipos de macrófagos. Se ha demostrado que el receptor retinoide X (RXR) controla la proliferación y la supervivencia en los macrófagos, sin embargo, la relación entre los RXRs con las señales instructivas del nicho para modular y activar la identidad de MRTs es un campo en el que aún hay que investigar.
En esta tesis, generamos una deleción condicional de RXRα y RXRβ y mostramos que la falta de señalización de RXR altera la maduración, funcionalidad e identidad de macrófagos alveolares (MAs) murinos y células de Kupffer (CKs). La deleción de RXRs también compromete la funcionalidad de los MAs ya que no hay una correcta eliminación del surfactante de los alveolos y, por lo tanto, este modelo desarrolla proteinosis alveolar pulmonar. Además, la falta de RXR desencadena la muerte celular inducida por lipotoxicidad en MAs y CKs. Demostramos cómo la señalización RXR es necesaria para el desarrollo y la maduración de los MAs en las etapas de desarrollo embrionario y postnatal. La depleción inducida de los MAs utilizando un modelo de toxina diftérica muestra cómo las células reclutadas experimentan un cambio en su expresión génica en la transición de monocito a MA maduro, en los que la expresión de RXRs aumenta progresivamente. También demostramos cómo el bloqueo in vivo de la señalización de Notch compromete el reclutamiento de monocitos y la repoblación de MAs, e identificamos el factor estimulante de colonias de granulocitos y macrófagos putativos (GM-CSF) y el factor de crecimiento tumoral β (TGFβ), junto a ligandos de Notch como señales conservadas que dan forma a los patrones de expresión génica característicos de los MAs. El análisis de los sitios de unión para los FTs aguas abajo de estas señales (STAT5, SMAD4 y RBPJ, respectivamente) revela una cooperación con RXR para la modulación de los TF que determinan el linaje de macrófagos, los genes específicos de MAs y el establecimiento de su identidad. Nuestros resultados indican que, en ausencia de RXR, hay una menor accesibilidad a la cromatina en las CKs y, en consecuencia, disminuye la expresión de los genes centrales de CKs, y los genes de identidad y funcionalidad.
En conjunto, nuestros resultados muestran que los RXR actúan como TF que modulan la actividad transcripcional de los MAs y CKs, controlando procesos clave de diferenciación y maduración que les permiten realizar funciones específicas de tejido características de su identidadTissue macrophages are key players in the immune system, as they act as the first line of defense against infection and disease. They are highly specialized cells that can detect and eliminate harmful pathogens apart from performing tissue-specific functions that ensure tissue homeostasis. Different subsets of macrophages share a transcriptional program encompassing a set of core genes, common to all tissue macrophages. In addition, these macrophages receive tissue-derived signals that induce specific transcription factors (TFs) that regulate the expression of another set of genes, necessary for their development and the performance of their tissue-specific functions. However, the mechanisms of this signal-induced identity remain unknown in several types of tissue macrophages. The Retinoid X Receptor (RXR) has been shown to control proliferation, and survival in macrophages, however, the interplay of RXR with niche-instructive signals for macrophage identity is an unstudied field.
In this thesis, we generated a conditional deletion of RXRα and RXRβ and showed that the lack of RXR signaling impairs the maturation, functionality, and identity of murine alveolar macrophages (AMs) and Kupffer cells (KCs). We demonstrate that the deletion of RXRs impairs AM functionality by compromising the correct surfactant clearance of the alveoli and therefore developing pulmonary alveolar proteinosis. In addition, the lack of RXR triggers lipotoxicity-induced cell death in AMs and KCs. We also show how RXR signaling is required for the development and maturation of AMs in the late-embryo and postnatal stages. The induced experimental ablation of AMs using a diphtheria toxin model demonstrates that the recruited cells undergo a niche-induced gene expression shift from circulating monocytes to mature AMs, in which RXRs are progressively upregulated. We demonstrated how the in vivo blockade of Notch-signaling impairs monocyte recruitment and AM repopulation. Moreover, we identified the putative granulocyte-macrophage colony-stimulating factor (GM-CSF), the tumor growth factor β (TGFβ), and Notch ligands as tissue-derived conserved signals that shape the gene expression patterns characteristic of AMs. The analysis of the binding sites for the transcription factors downstream of these signals (STAT5, SMAD4, and RBPJ, respectively) reveals the cooperation with RXRs for the modulation of macrophage lineage-determining TFs (LDTFs), AM-specific genes, and the establishment of the AM identity. We also provide evidence that in the absence of RXRs, chromatin accessibility is lost in KCs and, consequently, the expression of KC-core, identity, and functionality genes is downregulated.
Taken together, our results show that RXRs act as LDTFs by modulating the transcriptional activity of AMs and KCs, and by governing key processes of differentiation and maturation that allow them to perform tissue-specific functions characteristic of their identit
Japanese Homoexceptionalism
No full textThis paper examines Japan’s mainstream political discourse on the protection of lesbian, gay, bisexual and transgender (LGBT) rights. While international organisations and Western nations often frame LGBT rights as human rights, this perspective is met with scepticism in non-Western nations. By placing itself between the West and the non-West, Japan has largely managed to avoid criticism on this issue. The analysis explores the political discourse surrounding Japan’s domestic and foreign policies. Rooted in a narrative of distinct cultural values and national identity, this discourse positions Japan as a homoexceptional country, and this rhetoric leverages LGBT rights to advance Japan’s national interests and international influence. By examining the contradictions between the political discourse in Japan and the promotion of LGBT rights, this research sheds light on the mechanisms through which Japan navigates the debate on LGBT rights as human right
Biometrics and behavior analysis for detecting distractions in e-learning
No full text“© 2024 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works”In this article, we explore computer vision approaches to detect abnormal head pose during e-learning sessions and we introduce a study on the effects of mobile phone usage during these sessions. We utilize behavioral data collected from 120 learners monitored while participating in a MOOC learning sessions. Our study focuses on the influence of phone-usage events on behavior and physiological responses, specifically attention, heart rate, and meditation, before, during, and after phone usage.
Additionally, we propose an approach for estimating head pose events using images taken by the webcam during the MOOC learning sessions to detect phone-usage events. Our hypothesis suggests that head posture undergoes significant changes when learners interact with a mobile phone, contrasting with the typical behavior seen when learners face a computer during e-learning sessions. We propose an approach designed to detect deviations in head posture from the average observed during a learner’s session, operating as a semi-supervised method. This system flags events indicating alterations in head posture for subsequent human review and selection of mobile phone usage occurrences with a sensitivity over 90%Support: HumanCAIC (TED2021-131787B-I00 MICINN), SNOLA (RED2022-134284-T), e-Madrid-CM (S2018/TCS4307), IndiGo! (PID2019-105951RB-I00), TEA360 (PID2023-150488OB-I00, SPID202300X150488IV0), BIO-PROCTORING (GNOSS, Agreement Ministerio de Defensa-UAM-FUAM dated 29-03-2022), and Catedra ENIA UAM-VERIDAS en IA Responsable (NextGenerationEU PRTR TSI-100927-2023-2). Roberto Daza is supported by a FPI fellowship from MINECO/FEDE
The role of point-of-care ultrasound in the evaluation and management of hyponatremia: A systematic review
No full textHyponatremia is the most common electrolyte disorder. Accurate assessment of extracellular fluid volume status (hypovolemic, euvolemic, or hypervolemic) is essential for determining the underlying etiology and guiding treatment. Point-of-care ultrasound (PoCUS) has emerged as a complementary bedside tool to objectively assess volume status in hyponatremia. We systematically reviewed the relevant literature up to June 2025. The aim of this systematic review was to evaluate the role of PoCUS in the assessment and management of hyponatremia. The evidence suggests that combined lung, cardiac, and abdominal PoCUS (including the venous excess ultrasound score, VExUS) helps overcome the limitations of physical examination. PoCUS leads to a more accurate etiologic diagnosis and optimized treatment. PoCUS also aids in monitoring treatment response, enabling real-time adjustment of diuretics or fluids based on serial examinations. Its role may be limited
by operator dependency and inability to detect non-ultrasound-revealed pathologies such as hypothyroidism. Integrating bedside ultrasound into hyponatremia management improves volume assessment accuracy and supports a more individualized approach. Although current evidence is mainly derived from small studies and case series, findings consistently support using PoCUS as an adjunct to traditional evaluatio
Transport connectivity and urban development: the case of Africa (1880-2020)
No full textThis paper investigates the interplay between population dynamics and transport connectivity in African municipalities from 1880 to 2020. Using an original historical dataset spanning African countries, we examine how proximity to railways and portshas shaped population dynamics over time. Through the application of Granger causality and Vector Autoregression (VAR)models—accounting for structural breaks and regime changes—we demonstrate that transport infrastructure development hasa statistically significant and directional influence on urban population growth. Our findings reveal that city size and growth arenot randomly distributed across space; rather, they are systematically linked to historical patterns of transport connectivity. Inparticular, the largest and fastest-growing cities consistently correspond to strategic nodes at the intersection of railway and mar-itime networks. These results, reinforced by hierarchical clustering and regime analysis, highlight the enduring impact of colonialinfrastructure and institutional path dependence. The study also points to broader implications for contemporary urban planningin the context of containerization and modern global trade flowsThis work was supported by the French National Research Agency, ANR-22-CE22-000
Fischer decompositions for entire functions of sufficiently low order
No full textThe existence of decompositions of the form f = P ·q+r with P∗ k(D)r =0, where f is entire, P a polynomial and P∗ k the principal part of P with its coefficients conjugated, was achieved in [1] under certain restrictions on the order of f. Here we prove uniqueness, thereby obtaining Fischer decompositions, under conditions that sometimes match those required for existence, and sometimes are more restrictive, depending on the parameters involvedThe first named author was partially supported by Grant PID2019-106870GB-I00 of the MICINN of Spain, by ICMAT Severo Ochoa project CEX2019-000904-S (MICINN), and by V PRICIT (Comunidad de Madrid - Spain
demoBeam: a platform for teaching of phased array beam steering
No full text“© 2024 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works”This contribution describes a phased array beam steering demonstrator for the 24-31 GHz frequency band encompassing array antennas, beamformer, XY positioners, VNA and software tools for practical teaching. Comprehensive training and inclusion of contents of technological updating benefits students, encouraging critical thinking and problem solving, and enhances educational institution role in advancing wireless technologyThis work was supported by the Spanish Ministry of Science and Innovation under grants PID2020-112545RB-C51, PID2020-112545RB-C52, PID2020-112545RB-C54, by the Xunta de Galicia under grant ED431C2019/26 and grant for Centro Singular de Investigación de Galicia (accreditation 2019-2022