96491 research outputs found
Sort by
Capital misallocation and economic development in a dynamic open economy
No full textSome countries, such as Canada, Italy, and Mexico, have experienced a higher growth rate of capital per worker but a lower growth rate for GDP per worker compared to the United States. This paper explains these two facts through the lens of a dynamic multisector open economy model where capital flows across countries. In the model, firms face sector-specific distortions on capital and intermediate inputs that influence the actual rate of return on capital and the aggregate total factor productivity (TFP). We calibrate the model to Mexico for the period 2000-2014 and show that changes in sectoral distortions and productivities reduced the actual rate of return on capital, triggering capital accumulation and a reduction in TFP. The results show that aggregate output decreased by 7.3% and aggregate capital increased by 10.6%. From 33 sectors (out of 48) that suffered productivity losses, approximately 50% accumulated more capital. Furthermore, the capital-intensive sectors explain 82% of the capital-output ratio increase
European Music Museums: Interactive Spaces for Musical Education
No full textMusic museums are essential for preserving and sharing musical heritage. This article investigates whether these museums are using modern teaching and learning strategies with new technology. By studying 27 European music museums through website reviews, questionnaires, and on-site observations, the research shows that most museums rely on traditional exhibitions. A lack of diversity in the presented sound heritage, especially oral musical heritage, and limitations in educational aspects were noted. However, many museums use interactive modules to engage visitors. Overall, music museums tend to maintain a traditional approach, highlighting the need for updated sound technology and an interdisciplinary method to manage musical heritage. Adapting to cultural evolution and leveraging educational opportunities are crucial for these museums to remain relevant in a constantly changing society. Critical museology could be the key to achieving this adaptation
Who should be the master of my words? On authority and linguistic justice
No full textMost scholars working on linguistic justice within political theory deal with questions of distributive justice, but not with the question as to who should have the authority to decide over linguistic rules. However, the distribution of linguistic authority in a given community is a relevant issue. This is so because some distributions of linguistic authority might situate some (minority) groups at the mercy of other (majority) groups. Accordingly, this paper addresses three problems associated with language and the authority question: linguistic domination, the lack of interpretative power and alienation. My fundamental argument is that none of them can be addressed without including the authority question into the equation. In particular, the paper explores the relationship between mainstream theories of linguistic justice and these three normative evils. I show how these theories have difficulties addressing these phenomena and why including the authority dimension is a necessary move
EU Digital Law. Art 5 DSA Caching
No full textWhere an information society service is provided that consists of the transmission in a communication network of information provided by a recipient of the service, the service provider shall not be liable for the automatic, intermediate and tempo- rary storage of that information, performed for the sole purpose of making more efficient or more secure the informations onward transmission to other recipients of the service upon their request, on condition that the provider..
Middle Devonian–Carboniferous crustal differentiation promoted by hydrous plume-related magmatism along the Paleo-Pacific active margin: A case study of the Gashun Nuur Complex in the Mongolian Altai<br />
No full textPetrology, whole-rock geochemistry, Sr–Nd isotopic data, and zircon U–Pb geochronology of magmatic rocks from Gashun Nuur Complex (Tseel Sum, Mongolian Altai) confirm catastrophic mid–late Devonian–Tournaisian (c. 385–350 Ma) mantle melting. Early (c. 385 Ma), scattered, large (∼ 100 m across) metagabbroic bodies carry a weak subduction-like signature (elevated contents of Large Ion Lithophile Elements – LILE, depletion in High Field Strength Elements – HFSE, high EiNd of + 3.9 to + 7.0, unradiogenic 87Sr/86Sri of 0.7036–0.7044). Younger (c. 375–350 Ma) Fe-poor and Fe-rich dismembered amphibolite sheets show an EMORB character typical of melts resulting from the interaction of a subduction-modified depleted lithospheric mantle with a mantle plume (moderate LILE and HFSE, highly positive EiNd of + 6.4 to + 9.2, variable 87Sr/86Sri of 0.7037–0.7068). Their chemistry marks the arrival of a mantle plume in an active margin setting far behind the magmatic arc. The Gashun Nuur Complex belongs to a vast (> 300,000 km2) mosaic of Devonian magmatic provinces which encompass the Altai suprasubduction, Altai–Sayan intracontinental and Mongol–Okhotsk oceanic domains. The studied middle Devonian–Tournaisian magmatic event is interpreted as the surface expression of hydrous plume(s) developed above a dehydrating flat-slab resting upon the lower mantle, at the mantle transition zone. The flat slab favoured the retreat of the trench causing extension in the overriding lithosphere. In the Gashun Nuur Complex, heat and fluids from mantle-derived intrusions induced extensive partial melting of a fertile Cambrian–Ordovician volcanic–sedimentary accretionary wedge, promoting a wide-rift mode of extension. Ascent and emplacement of granitic magmas to the middle crust left a still partially hydrated lower crust with an intermediate composition. This process of crustal differentiation may have played an important role in the stratification and stabilisation of the continental crust through the Earth’s history
Heterobifunctional molecules: PROTACs and beyond
No full text[eng] Our body is an intricate, well-organized structure formed by trillions of cells. Each one of these cells is a highly complex entity composed of thousands of biomolecules that enable it to carry out its functions. Among them, proteins stand out as the machinery that orchestrates most cellular processes. Alterations in normal protein activity will lead to cellular malfunction and the appearance of diseases. For this reason, protein modification by small molecules has stood as the main pharmacological approach.
However, the traditional occupancy-based mechanism of action of most drugs falls short at targeting the wide range of the human proteome. 80% of the disease associated proteins remain undruggable, mainly due to the lack of well-defined pockets in the protein. Recently, new technologies are being developed to overcome the limitations of this mechanism. One of the most promising is the use of Proteolysis Targeting Chimeras (PROTACs).
PROTACs work by hijacking the endogenous protein homeostasis system to induce the degradation of the target protein. Their event-based mechanism of action allows PROTACs to bypass the need for high-binding affinities with the target protein, whilst maintaining high selectivity. Together with other advantages like a catalytic mechanism, more permanent effect, lower dosing and less appearance of resistance, puts PROTACs as the most promising alternative to traditional drugs.
This doctoral thesis explores PROTAC’s design and synthesis process, as well as the
following challenges that the field is facing.
In Chapter 2, we explored the use of PROTACs in Castrate Resistant Prostate Cancer (CRPC). This disease comprises 10-20% of Prostate Cancer patients, and most of these cases arise from the appearance of an Androgen Receptor (AR) alternative splice variant that lacks the ligand binding domain (AR-V7). AR-V7 cannot be drugged efficiently due to the intrinsically disordered nature of its structure, leading to high mortality rates. We envisioned the use of PROTACs as a promising alternative to target this challenging protein. Its design is based on the CAM family of ligands, previously reported in the group, to recruit AR-V7.
In Chapter 3, we focused on the resistance mechanisms to degraders. Previous work done by Winter’s group in 2019 highlighted that resistance arises away from the target protein. Namely, UBE2Mmut cells become pan-resistant to all degraders. Using this cellular model, we started a high throughput screening campaign followed by an SAR to identify its synthetic vulnerabilities. This study led to the disclosure of RBS-10; a small-molecule capable of differentially kill UBE2Mmut cells. Further work on its mechanism of action led to uncovering that RBS-10 is a prodrug bioactivated by NQO1, which generates metabolites that induce ROS and DNA damage.
Chapter 4 showcases the ability of proximity-inducing pharmacology to modulate protein activity. We envisioned the use of heterobifunctional molecules to target the ETS2 Repressor Factor (ERF), an attractive oncogenic target that has traditionally remained undruggable. Through a high- throughput screening of an electrophilic library we identified a first-in-class covalent binder of ERF. After characterizing its binding, we designed and synthesized different bifunctional molecules to modulate ERF’s activity. On one hand, we prepared PROTACs to induce its degradation, inducing cell proliferation and differentiation. On the other hand, we worked on Phosphatase Recruiting Chimeras (PhoRCs), able to induce its dephosphorylation by proximity with a phosphatase. These molecules over-activate ERF, hijacking the cell in a non-proliferative state and acting as a tumor suppressor.
Finally, we also worked on the development of Relocalization Targeting Chimeras (ReloTACs), which induce the nuclear localization of ERF through the formation of a ternary complex with a nuclear protein, p300.
In summary, the work in this doctoral thesis highlights the advantages that PROTACs and proximity-inducing approaches have over traditional pharmacology. It emphasizes both their ability to target previously considered undruggable proteins, as well as their design and synthesis process. Furthermore, it displays their vast potential to modulate protein activity and develop novel therapies.[cat] Dins els milers de biomolècules que formen les nostres cèl·lules, les proteïnes ressalten com els directors d’orquestra de tots els processos cel·lulars. Alteracions en la seva activitat normal desemboquen en diferents malalties. Per aquest motiu, la modificació de l’activitat d’aquestes proteïnes a partir de compostos químics ha estat sempre el dogma principal de la farmacologia.
Tanmateix, els mètodes tradicionals basats en ocupació tan sols són efectius en un 20% de les proteïnes associades a malalties. Recentment, noves tecnologies prometen sobrepassar aquestes limitacions. Una de les més prometedores és l’ús de Proteolysis Targeting Chimeras (PROTACs). Aquestes molècules són capaces d’induir la degradació de la proteïna diana segrestant el sistema d’homeòstasi endogen de la cèl·lula.
Dividida en tres capítols, aquesta tesi doctoral explora el procés de disseny i síntesi de PROTACs, la seva capacitat de tractar proteïnes abans intractables, i els futurs reptes que aquest camp es planteja.
En el Capítol 2, hem sintetitzat potencials degradadors per la proteïna AR-V7, un dels principals causants del Càncer de Pròstata Resistent a la Castració. Aquesta proteïna ha estat tradicionalment considerada intractable, motiu pel qual hi ha una taxa de mortalitat molt alta i és necessari estudiar nous tractaments.
En el Capítol 3, hem estudiat les vulnerabilitats sintètiques de cèl·lules resistents a degradadors. A través d’un assaig de relació Estructura-Activitat hem identificat RBS-10 com al millor compost capaç d’acabar selectivament amb aquestes cèl·lules. A partir d’un estudi exhaustiu del seu mecanisme d’acció, hem observat que actua com a prodroga bioactivada per l’enzim NQO1.
En el Capítol 4, hem estudiat ERF, una proteïna molt atractiva des del punt de vista oncogènic que fins ara ha escapat el seu tractament. Al llarg d’aquest capítol hem dissenyat i sintetitzat PROTACs per induir la seva degradació, PhoRCs per activar-la mitjançant desfosforilació i ReloTACs per mantenir la seva localització dins el nucli cel·lular.
En resum, aquesta tesi doctoral ressalta els avantatges que els PROTACs i altres tecnologies basades en la inducció de proximitat tenen davant la farmacologia tradicional, el seu procés de disseny i síntesi, i les seves perspectives de futur
Couple-to-work spillover: assessing work performance of individuals in a cross-sectional study
No full textThis paper explores whether and how the relationship of coupled individuals interacts with work performance through the employment of the Vulnerability-Stress-Adaptation (VSA) model. Using a random probabilistic sample survey of 864 working Spaniards living as a couple, we tested whether and how individual vulnerabilities, external stressors and individual perception of dyadic adaptiveness affect individual assessment of relationship quality and how this affects work performance. The structural equation model shows that individual vulnerabilities influence individual assessment of relationship quality through the mediation of individual perception of dyadic adaptiveness. Furthermore, individual perception of dyadic adaptiveness significantly influences individual assessment of relationship quality, which in turn significantly affects work performance. These findings shed light on functioning of coupled individuals’ relationships under uncertainty shocks and their spillover effects to the working domain
The role of historic amenities in shaping cities
No full textThe existence of amenities matters to understanding people’s residential choices. Our theoretical model extends the standard urban model by introducing exogenous amenities to explain population allocation within cities. To estimate the model predictions, we focus on historic amenities using detailed geolocated data for 579 European cities. We analyze how the shape of city centers endowed or not endowed with these amenities is affected. We measure historic amenities with the location of buildings from the Roman, Medieval, and Renaissance–Baroque periods. Our results show that cities with historic buildings in their centers have steeper population density gradients, are more compact and centralized, and have been less affected by the suburbanization processes caused by transportation improvements. Heterogeneity analyses show that the quantity and the quality of historic buildings also matter. Several robustness checks controlling for natural and modern amenities and testing for the spatial scope of these amenities verify our main results
La carencia sobrevenida de causa en el contrato: A propósito de la sentencia del juzgado mercantil 1 de Santander de 18 de noviembre de 2021
No full textLos hechos de los que trae causa la resolución que motiva el presente comentario pueden resumirse como sigue: se organiza un concierto cuyo artista principal es un conocido DJ internacional, lo que requiere de la celebración de mucho contratos y entre ellos uno de licencia con SGAE. Sólo se contó con la actuación de los teloneros en la medida que el cabeza de cartel no acudió al evento. Lo anterior no pudo suponer el cumplimiento para la promotora de la prestación a que venía obligada con sus asistentes y deriva en la posible carencia sobrevenida de causa en el contrato de licencia pues el principal reclamo era la participación del reconocido DJ, con consecuente ausencia en el derecho de cobro por la SGAE
La comunidad. Etnografía de una experiencia alternativa de vida comunitaria
No full text[spa] La tesis trata sobre una comunidad de convivencia ubicada en una antigua Casona llamada La Pardina. Situada en los límites de la gran ciudad y okupada ilegalmente desde hace más de 20 años, sus habitantes han desarrollado una experiencia colectiva basada en los ideales de integración armoniosa en la naturaleza por medio de técnicas basadas en la permacultura y la agroecología. La etnografía focaliza su mirada en la descripción y análisis de este proyecto comunitarista, el tipo de organización social que lo hace posible, la autoadministración de sus recursos económicos, el orden ritual que adopta para generar y mantener sentimientos de compromiso e identidad y las premisas doctrinales de que se nutre, así como la interacción con la macroestructura económica, social y política de la que al tiempo se pretende distanciar, pero de la cual depende: la metrópoli. El estudio también recoge las tensiones, contradicciones, conflictos y disensos que se conforman de manera no siempre explícita, las estrategias individuales y compartidas con que procura gestionarlos y las divergencias que han derivado en un proceso de cismogénesis en el seno del colectivo. Todo ello en el marco de un experimento de utopía comunitaria enfrentado con un orden socio-económico, el capitalista, del que podrían considerarse al mismo tiempo contestación y reflejo[eng] This thesis examines a co-living community situated in an old farmhouse in the Sierra called La Pardina. Located on the outskirts of the metropolis and illegally occupied for over 20 years, its inhabitants have developed a collective experience based on ideals of harmonious integration with nature through techniques of permaculture and agroecology. The ethnography focuses on the description and analysis of this communitarian project: the type of social organization that makes it possible, the self-management of its economic resources, the ritual order it adopts to generate and maintain feelings of commitment and identity, and the doctrinal premises from which it draws. It also examines the interaction with the economic, social, and political macrostructure from which it seeks to distance itself but on which it depends—the big city.
The study also captures the tensions, contradictions, conflicts, and dissensions that form in ways not always explicit, the individual and shared strategies used to manage them, and the divergences that have led to a process of schismogenesis within the collective. All of this occurs within the framework of a communal utopian experiment confronted with a socio-economic order—capitalism—of which it can be considered both a challenge and a reflection