Changing political boundaries: evidence from a party ban

Treballs Finals del Màster d'Economia, Facultat d'Economia i Empresa, Universitat de Barcelona. Curs: 2020-2021, Tutor: Andreu ArenasIn this study we analyze whether party bans ignite ideological polarization by exacerbating pre-existing differences. We use the 2003 ban on Batasuna, a leftist Basque political platform, as case study. In the 2005 Basque regional elections EHAK-PCTV contested in its name, which enabled the outlawed party to avoid the ban. We aim to analyze these effects in the short-term, one election period later. Using a continuous treatment in a Difference-in-Difference strategy, we are able to show that municipalities react differently given their differences in baseline support to Batasuna (measured by pre-ban vote shares in regional elections), rather than by differences in the loss of institutional representation (proxied by the pre-ban share of Batasuna councilors). The latter case holds in extreme circumstances, those in which the city mayor was from Batasuna, as the material loss of the ban is more salient. We find that the banned party increased its vote share in those places where its baseline support was higher. Moreover, the nationalist bloc increased its size while the federal bloc lost support, redefining group boundaries. We argue that the ban reinforced the ethnic identity political cleavage accentuating the inter-group political conflict

Input-Output Kernel Regression applied to protein-protein interaction network inferenc

[EN] The study of protein-protein interaction networks has received a lot of attention by the research community lately. However, the experimental studies to reconstruct this kind of structures are expensive. Consequently, several machine learning approaches have been developed that automatically infer PPI networks. In this work I present the implementation and analysis of the Input-Output Kernel Regression (IOKR) developed by [9, 10] to compute the inference using various experimental data sets. IOKR is based on the learning of an output kernel that let us apply regression models on a feature space where we can compute the similarity of pairs of proteins to infer the existence of interactions. Furthermore, this approach extends the Kernel Ridge Regression to a semi-supervised approach where the inference turns into a matrix completion. The Multiple Kernel Learning is applied on the input side to deal with the different data sources. Finally, I compare the performance of the implementation with other supervised approaches for the inference of PPI networks.[ES] El estudio de las redes de interacción de proteínas ha recibido una gran atención por parte de la comunidad investigadora en los últimos años. Sin embargo, los estudios experimentales para la reconstrucción de este tipo de estructures son caros. Consecuentemente, varios métodos de aprendizaje automático para inferir redes de interacción de proteínas han sido desarrollados. En este trabajo presento la implementación y el análisis del Input-Output Kernel Regression (IOKR) desarrollado por [9, 10] para llevar a cabo la inferencia utilizando varios conjuntos de datos experimentales. IORK está basado en el aprendizaje de un kernel de salida que nos permita aplicar modelos de regresión en un espacio de características donde podemos calcular la similitud de pares de proteínas para inferir la existencia de interacción. Además, esta aproximación extiende el Kernel Ridge Regression a una aproximación semi-supervisada donde la inferencia se convierte en completar una red. La técnica de aprendizaje de múltiples kernels es aplicada en los datos de entrada para tratar las diferentes fuentes de datos. Finalmente, comparo el rendimiento de la implementación con otras aproximaciones supervisadas para la inferencia de redes de interacción de proteínas.Maycas Nadal, C. (2014). Input-Output Kernel Regression applied to protein-protein interaction network inferenc. http://hdl.handle.net/10251/48503.TFG

Amimia en la enfermedad de Parkinson: correlación con síntomas motores y no motores

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de Lectura: 13-06-202

Inhibition of osteocyte apoptosis prevents the increase in osteocytic receptor activator of nuclear factor κB ligand (RANKL) but does not stop bone resorption or the loss of bone induced by unloading

"This research was originally published in Journal of Biological Chemistry. Lilian I. Plotkin, Arancha R. Gortazar, Hannah M. Davis, Keith W. Condon, Hugo Gabilondo, Marta Maycas, Matthew R. Allen, and Teresita Bellido. Inhibition of Osteocyte Apoptosis Prevents the Increase in Osteocytic Receptor Activator of Nuclear Factor κB Ligand (RANKL) but Does Not Stop Bone Resorption or the Loss of Bone Induced by Unloading*. Journal of Biological Chemistry. 2015; 290:18934-18942. © the American Society for Biochemistry and Molecular Biology."Apoptosis of osteocytes and osteoblasts precedes bone resorption and bone loss with reduced mechanical stimulation, and receptor activator of NF-κB ligand (RANKL) expression is increased with unloading in mice. Because osteocytes are major RANKL producers, we hypothesized that apoptotic osteocytes signal to neighboring osteocytes to increase RANKL expression, which, in turn, increases osteoclastogenesis and bone resorption. The traditional bisphosphonate (BP) alendronate (Aln) or IG9402, a BP analog that does not inhibit resorption, prevented the increase in osteocyte apoptosis and osteocytic RANKL expression. The BPs also inhibited osteoblast apoptosis but did not prevent the increase in osteoblastic RANKL. Unloaded mice exhibited high serum levels of the bone resorption marker C-telopeptide fragments of type I collagen (CTX), elevated osteoclastogenesis, and increased osteoclasts in bone. Aln, but not IG9402, prevented all of these effects. In addition, Aln prevented the reduction in spinal and femoral bone mineral density, spinal bone volume/tissue volume, trabecular thickness, mechanical strength, and material strength induced by unloading. Although IG9402 did not prevent the loss of bone mass, it partially prevented the loss of strength, suggesting a contribution of osteocyte viability to strength independent of bone mass. These results demonstrate that osteocyte apoptosis leads to increased osteocytic RANKL. However, blockade of these events is not sufficient to restrain osteoclast formation, inhibit resorption, or stop bone loss induced by skeletal unloadingThis work was supported, in whole or in part, by National Institutes of Health Grants R01DK076007 and ARRA supplement S10-RR023710 (to T. B.) and R01AR053643 (to L. I. P.). This work was also supported by Veterans Affairs Merit Award I01BX002104 (to T. B.) and an IUSM Biomedical Research grant (to L. I. P.) and by scholarships from the Conchita Rábago Foundation (to A. R. G. and M. M.), the European Molecular Biology Organization (to M. M.), and Universidad Autónoma de Madrid (to H. G

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat(Ot) mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat(Ot) mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat(Ot) mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat(Ot) mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone

PTHrP-Derived Peptides Restore Bone Mass and Strength in Diabetic Mice: Additive Effect of Mechanical Loading

There is an unmet need to understand the mechanisms underlying skeletal deterioration in diabetes mellitus (DM) and to develop therapeutic approaches to treat bone fragility in diabetic patients. We demonstrate herein that mice with type 1 DM induced by streptozotocin exhibited low bone mass, inferior mechanical and material properties, increased bone resorption, decreased bone formation, increased apoptosis of osteocytes, and increased expression of the osteocyte-derived bone formation inhibitor Sost/sclerostin. Further, short treatment of diabetic mice with parathyroid hormone related protein (PTHrP)-derived peptides corrected these changes to levels undistinguishable from non-diabetic mice. In addition, diabetic mice exhibited reduced bone formation in response to mechanical stimulation, which was corrected by treatment with the PTHrP peptides, and higher prevalence of apoptotic osteocytes, which was reduced by loading or by the PTHrP peptides alone and reversed by a combination of loading and PTHrP peptide treatment. In vitro experiments demonstrated that the PTHrP peptides or mechanical stimulation by fluid flow activated the survival kinases ERKs and induced nuclear translocation of the canonical Wnt signaling mediator β-catenin, and prevented the increase in osteocytic cell apoptosis induced by high glucose. Thus, PTHrP-derived peptides cross-talk with mechanical signaling pathways to reverse skeletal deterioration induced by DM in mice. These findings suggest a crucial role of osteocytes in the harmful effects of diabetes on bone and raise the possibility of targeting these cells as a novel approach to treat skeletal deterioration in diabetes. Moreover, our study suggests the potential therapeutic efficacy of combined pharmacological and mechanical stimuli to promote bone accrual and maintenance in diabetic subjects

High glucose alters the secretome of mechanically stimulated osteocyte-like cells affecting osteoclast precursor recruitment and differentiation

Diabetes mellitus (DM) induces bone deterioration, while mechanical stimulation promotes osteocyte-driven bone formation. We aimed to evaluate the interaction of acute exposure (24 h) to high glucose (HG) with both the pro-survival effect conferred to osteocytic MLO-Y4 cells and osteoblastic MC3T3-E1 cells by mechanical stimulation and the interaction of these cells with osteoclast precursor RAW264.7 cells. We found that 24 h of HG (25 mM) preexposure prevented both cell survival and ERK and β-catenin nuclear translocation upon mechanical stimulation by fluid flow (FF) (10 min) in both MLO-Y4 and MC3T3-E1 cells. However, migration of RAW 264.7 cells was inhibited by MLO-Y4 cell-conditioned medium (CM), but not by MC3T3-E1 cell-CM, with HG or FF. This inhibitory effect was associated with consistent changes in VEGF, RANTES, MIP-1α, MIP-1β MCP-1, and GM-CSF in MLO-Y4 cellCM. RAW264.7 proliferation was inhibited by MLO-Y4 CM under static or HG conditions, but it increased by FF-CM with or without HG. In addition, both FF and HG abrogated the capacity of RAW 264.7 cells to differentiate into osteoclasts, but in a different manner. Thus, HG-CM in static condition allowed formation of osteoclast-like cells, which were unable to resorb hydroxyapatite. In contrast, FF-CM prevented osteoclastogenesis even in HG condition. Moreover, HG did not affect basal RANKL or IL-6 secretion or their inhibition induced by FF in MLO-Y4 cells. In conclusion, this in vitro study demonstrates that HG exerts disparate effects on osteocyte mechanotransduction, and provides a novel mechanism by which DM disturbs skeletal metabolism through altered osteocyte-osteoclast communication

Vídeo online i experiència d'usuari. Una perspectiva tècnica i de negoci

Presentar la evolución del streaming de video, analizando la tecnología y analizar la experiencia de usuario y hacer una propuesta de accione

Comportement migratoire et trophique des mysidacés benthopélagiques Anchialina agilis et Haplostylus lobatus sur la marge continentale en Méditerranée nord-occidentale: incidence sur les transferts de matière

Memoria de tesis doctoral presentada por Encarna Ribera Maycas para obtener el título de Doctora en Océanologie por la Université de la Méditerranée, realizada bajo la dirección del Dr. Miquel Alcaraz Medrano del Institut de Ciències del Mar (ICM-CSIC), el Dr. Claude Macquart-Mouliny el Dr. Gilbert Patriti.-- 224 pagesPeer Reviewe

Mecanismos moleculares implicados en la mecanotransducción osteocítica. Alteraciones en la osteopatía diabética y efecto compensador de la proteína relacionada con la parathormona (PTHrP)

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 22-07-2016Esta tesis tiene embargado el acceso al texto completo hasta el 22-01-2018El esqueleto es capaz de adaptar su masa, estructura y microarquitectura a la estimulación mecánica recibida. Así, el aumento de actividad física conlleva un incremento de la formación ósea, mientras que la inmovilización aumenta la resorción. Los osteocitos son las principales células mecanorreceptoras del hueso; sin embargo, los mecanismos subyacentes a esta función no están suficientemente esclarecidos. La proteína relacionada con la parathormona (PTHrP) es un importante regulador del remodelado óseo y de la formación ósea. Debido a su acción osteogénica, se ha propuesto como posible agente terapéutico para paliar la pérdida de masa ósea en diferentes tipos de osteoporosis, incluyendo la asociada a la diabetes mellitus (DM). En la presente Tesis Doctoral, hemos explorado, in vitro, nuevos mecanismos involucrados en la mecanotransducción osteocítica como dianas para posibles alternativas terapéuticas en la osteopenia. Además, in vivo, en un modelo de ratón con osteopatía asociada a DM tipo 1 (DM1), hemos estudiado la respuesta osteoinductora de dos péptidos derivados de la PTHrP correspondientes a sus dominios N-terminal [PTHrP (1-37)] y C-terminal [PTHrP (107-111)], administrados solos o combinados con estimulación mecánica, una estrategia que podría ser interesante en esta patología. En primer lugar, hemos caracterizado dos sistemas de estimulación mecánica in vitro en células osteocíticas MLOY4: mediante la exposición a un medio hipotónico o a un flujo de fluido (FF). Hemos identificado el papel del receptor tipo 2 de VEGF (VEGFR2) y del receptor de PTH/PTHrP tipo 1 (PTH1R) como mecanorreceptores, así como los mecanismos moleculares implicados en la activación de ambos tras la estimulación mecánica. Además, hemos evaluado la acción citoprotectora de ambos péptidos, PTHrP (1-36) y PTHrP (107-111), en las células osteocíticas. Posteriormente, hemos estudiado el efecto deletéreo de un ambiente de alta glucosa (AG, 25 mM), simulando in vitro la situación de hiperglucemia, sobre la protección osteocítica inducida por la estimulación mecánica; este efecto fue revertido por ambos péptidos de PTHrP. Nuestros hallazgos también indican que tanto la estimulación mecánica como la AG alteran la comunicación osteocito-osteoclasto, aunque de manera diferente: la estimulación mecánica de los osteocitos impide la formación de osteoclastos, mientras la AG en el entorno osteocítico induce la formación de osteoclastos inactivos. In vivo, en el modelo de ratón con osteopatía asociada a la DM1, demostramos que un tratamiento agudo (3 días) con ambos péptidos de la PTHrP fue eficaz para contrarrestar la pérdida de masa y la fragilidad ósea inducidas por la DM1, a través de sus acciones anabólicas y anti-resortivas. Además, nuestros resultados demuestran que la DM1 interfiere con la capacidad osteoformadora de la estimulación mecánica y que el tratamiento combinado con los péptidos de la PTHrP y la estimulación mecánica ejerce un efecto aditivo sobre la formación ósea perióstica en esta situación. En conclusión, los hallazgos de esta Tesis Doctoral demuestran el papel crucial de los osteocitos en la osteopatía diabética y plantean la utilización de agentes anabólicos como estos péptidos de la PTHrP actuando estas células como un nuevo enfoque terapéutico en esta patología.Mechanical loading is an important regulator of bone mass. The skeleton can adapt to inputs represented by mechanical forces by changing its mass, shape and microarchitecture. Increased physical activity leads to increased bone formation, whereas immobilization increases bone resorption. Osteocytes are the main bone mechanosensitive cells, although the underlying mechanisms of their function are ill-defined. Parathyroid hormone related protein (PTHrP) is an important regulator of bone remodeling and bone formation. Due to its osteogenic actions, it has been proposed as a possible therapeutic agent in bone loss-related conditions such as diabetes mellitus (DM). In this Doctoral Thesis, using in vitro approaches, we explored new mechanisms involved in osteocytic mechanotransduction, which might be possible targets for osteoporosis treatment. Moreover, in vivo in a murine model of type 1 DM (DM1) with osteopathy, we evaluated the relative efficacy of two PTHrP-derived peptides –corresponding to its N-terminal [PTHrP (1- 37)] and C-terminal [PTHrP (107-111)] domains-, alone or in combination with mechanical loading, as potential therapies in DM-related osteopathy. First, we characterized two in vitro mechanical stimulation aproaches in MLO-Y4 osteocytic cells: exposure to either a hypotonic medium or fluid flow (FF). We then identified the role of vascular endothelial growth factor type 2 receptor (VEGFR2) and PTH type 1 receptor (PTH1R) as bone mechanoreceptors, and the underlying molecular mechanisms for their activation after mechanical stimulation. Moreover, we assessed the protective action of PTHrP (1-36) and PTHrP (107-111) in these osteocytic cells. Afterwards, we characterized the deleterious effect of a high glucose (HG; 25 mM) environment - which mimics hyperglucemia in vivo- on cell viability protection conferred by mechanical stimulation of MLO-Y4 osteocytes; an effect that was reversed by each PTHrP peptide. Our studies also show that both mechanical stimulation and HG affect osteocyte-osteoclast communication in a different manner: whereas mechanically stimulated osteocytes impaired osteoclast differentiation, HG promoted formation of inactive osteoclast-like cells. In vivo, in the diabetic mouse model with osteopathy, we demonstrated that a short treatment (3 days) with either PTHrP (1-37) or PTHrP (107-111) similarly restored in part bone loss and strength by targeting both bone formation and bone resorption. Moreover, our results showed that DM negatively affected the bone anabolic effect of mechanical stimulation, and treatment with the PTHrP peptides together with mechanical loading induced an additive effect to enhance periosteal bone formation in this diabetic scenario. In conclusion, the findings in this Thesis demonstrate the crucial role of osteocytes in diabetic osteopathy, and point to osteocyte targeting agents like these PTHrP peptides as a novel therapeutic approach in this pathology