3,542 research outputs found

    Investigating the effects of palmitoylation on the dopamine 1 receptor (D1)

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    The dopamine D1 receptor (D1) is a G protein-coupled receptor (GPCR) which regulates various key brain functions like attention, movement, reward, and memory. Understanding D1 signalling may open the horizon for novel treatments for neurological disorders. Upon agonist activation, the heterotrimeric G proteins Gαs activate adenylyl cyclase to increase cAMP/PKA signalling. D1 also engages β-arrestin proteins leading to β-arrestin dependent signalling. The D1 has two palmitoylation sites on cysteines 347&351 in its C-tail domain. However, the distinct roles and implications of palmitoylation on the D1 signalling, trafficking and β-arrestins recruitment are still largely unexplored. A palmitoylation D1 mutant was generated and luminescent based techniques such as BRET and split-Nanoluc complementation assay were employed, to delineate D1 palmitoylation effects on its pharmacology and signalling. The D1 agonists induced 50% less cAMP production in the mutant compared to wildtype (WT) and WT showed a more efficient dissociation of its Gαs. Moreover, the mutant receptor failed to recruit β-arrestin1&2, induced less ERK1/2 activation and internalises in an agonist-independent process while showing an altered intracellular Golgi trafficking. Also, in β-arrestin 1&2 KO HEK 293 cells similar cAMP production levels were reported for D1 WT and palmitoylation mutant. β-arrestin 1&2 KO blocked agonist-induced WT D1 plasma membrane trafficking, indicating that these β-arrestins are driving the differences between WT and the palmitoylation mutant D1. Taken together, our studies indicate that Gαs is the main transducer for D1 cAMP and ERK1/2 signalling and that palmitoylation is essential for its β-arrestin 1&2 interactions and modulating D1 signalling cascades in a drug-dependant process

    The telecoupled sustainability impacts of global agricultural value chains:Assessing the cross-scale sustainability impacts of the cocoa sector

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    Agriculture is a major contributor to the global environmental crisis. Natural ecosystems are being replaced by agricultural land, which leads to the extinction of species and the release of tons of carbon emissions. Global agricultural value chains (GVCs) have grown due to the intensification of international trade. While GVCs have undeniably created economic opportunities for the agriculture sector, they have also led to the escalation of local environmental issues. Several initiatives have been implemented to reduce the negative impacts of agriculture, including government regulations, sustainability certification labels, and voluntary sustainability commitments. However, the effectiveness of these initiatives has been questioned due to several reasons, including the mismatches between the scale of the problem and the solution, the lack of monitoring and verification of sustainability actions, and their weak enforcement. Sustainability initiatives are informed by studies assessing the impacts of agriculture that often only focus on local impacts, while disregarding larger-scale – telecoupled– dynamics that can trigger impacts across geographic and temporal scales. This thesis aims to help bridge these knowledge gaps by examining the impacts of agricultural GVCs across scales, studying the role of GVC’s configuration in modulating these impacts and investigating the role of GVC actors in mitigating sustainability risks across scales. The global cocoa value chain is used as a case study. Chapter 2 examines various impact assessment methods and their ability to capture the effects caused by telecoupled dynamics across different scales. The study concludes that no single method is sufficient to capture all telecoupled cross-scale dynamics and that the integration of different methods is necessary to bridge gaps between methods and complement their scope. Chapter 3 implements the recommendations outlined in Chapter 2 by analyzing the impacts caused by cocoa agroforestry and cocoa full-sun production in Ghana. Impacts on carbon, biodiversity stocks, and environmental pollution were analyzed within and beyond the farm-level. This chapter reveals that findings drawn from farm-level assessments can contradict those from landscape-level assessments. Decision-makers focused should be wary of extrapolating farm-level assessment results to larger scales. Chapter 4 expands the scope to the global scale by examining the role of the cocoa GVC configuration on the capacity of the sector to address sustainability challenges across scales. The chapter identifies different types of cocoa traders, their market dominance, and sustainability commitments. The chapter highlights that to address the telecoupled impacts of the cocoa GVC, coordinated action between traders is required, along with government interventions to balance power asymmetries. Chapter 5 measured the degree to which cocoa traders, as identified in Chapter 4, are exposed to deforestation and climate change. This chapter highlights that sustainability challenges in agricultural value chains cannot be resolved in isolation as farming systems are constantly interacting with other farming systems and land competing sectors. To avoid displacing negative impacts across scales, it is necessary to have a coordinated and collaborative effort from stakeholders and sectors involved in making decisions related to land use. This thesis shows that addressing the telecoupled impacts caused by agricultural value chains needs a good understanding of the cause-effect dynamics at play. This requires the quantification of impacts caused by agriculture across scales and the characterization of the GVC network of actors modulating these impacts. Interdisciplinary methods need to be leveraged and integrated to generate actionable insights. The findings of this thesis can assist decision-makers and private actors in devising customized sustainability strategies, prioritizing action, and addressing the most vulnerable hotspots while being mindful of global teleconnections and avoiding spillovers

    A scramble for value:On the interpretation and application of value-based health care in the Netherlands

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    In many health care systems across the globe, value-based health care has quickly become a remarkably popular concept. Yet, despite its global popularity, the meaning of the concept remains shrouded in ambiguity, and efforts to put value-based health care into practice are characterized by a high degree of local variability. This makes it rather challenging to grasp the essence of this seemingly influential concept, let alone evaluate its effects within health care systems. A Scramble for Value addresses that challenge.The thesis traces the journey of value-based health care from its original conception by Harvard business scholar Michael Porter to its global popularity, and zooms in on its interpretation and application in the Netherlands. As the original set of ideas runs into the historically rooted institutions of the Dutch health care system, the meaning of value-based health care gets moderated, and its application conforms to the very structures it once so boldly set out to reform. It is by overlaying rather than overthrowing those traditional structures that value-based health care has ignited a renewed focus on outcomes that matter to patients, and amplified multidisciplinary efforts to improve those outcomes. All in all, this can be seen as quite an accomplishment..<br/

    Spatial adaptive settlement systems in archaeology. Modelling long-term settlement formation from spatial micro interactions

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    Despite research history spanning more than a century, settlement patterns still hold a promise to contribute to the theories of large-scale processes in human history. Mostly they have been presented as passive imprints of past human activities and spatial interactions they shape have not been studied as the driving force of historical processes. While archaeological knowledge has been used to construct geographical theories of evolution of settlement there still exist gaps in this knowledge. Currently no theoretical framework has been adopted to explore them as spatial systems emerging from micro-choices of small population units. The goal of this thesis is to propose a conceptual model of adaptive settlement systems based on complex adaptive systems framework. The model frames settlement system formation processes as an adaptive system containing spatial features, information flows, decision making population units (agents) and forming cross scale feedback loops between location choices of individuals and space modified by their aggregated choices. The goal of the model is to find new ways of interpretation of archaeological locational data as well as closer theoretical integration of micro-level choices and meso-level settlement structures. The thesis is divided into five chapters, the first chapter is dedicated to conceptualisation of the general model based on existing literature and shows that settlement systems are inherently complex adaptive systems and therefore require tools of complexity science for causal explanations. The following chapters explore both empirical and theoretical simulated settlement patterns based dedicated to studying selected information flows and feedbacks in the context of the whole system. Second and third chapters explore the case study of the Stone Age settlement in Estonia comparing residential location choice principles of different periods. In chapter 2 the relation between environmental conditions and residential choice is explored statistically. The results confirm that the relation is significant but varies between different archaeological phenomena. In the third chapter hunter-fisher-gatherer and early agrarian Corded Ware settlement systems were compared spatially using inductive models. The results indicated a large difference in their perception of landscape regarding suitability for habitation. It led to conclusions that early agrarian land use significantly extended land use potential and provided a competitive spatial benefit. In addition to spatial differences, model performance was compared and the difference was discussed in the context of proposed adaptive settlement system model. Last two chapters present theoretical agent-based simulation experiments intended to study effects discussed in relation to environmental model performance and environmental determinism in general. In the fourth chapter the central place foragingmodel was embedded in the proposed model and resource depletion, as an environmental modification mechanism, was explored. The study excluded the possibility that mobility itself would lead to modelling effects discussed in the previous chapter. The purpose of the last chapter is the disentanglement of the complex relations between social versus human-environment interactions. The study exposed non-linear spatial effects expected population density can have on the system and the general robustness of environmental inductive models in archaeology to randomness and social effect. The model indicates that social interactions between individuals lead to formation of a group agency which is determined by the environment even if individual cognitions consider the environment insignificant. It also indicates that spatial configuration of the environment has a certain influence towards population clustering therefore providing a potential pathway to population aggregation. Those empirical and theoretical results showed the new insights provided by the complex adaptive systems framework. Some of the results, including the explanation of empirical results, required the conceptual model to provide a framework of interpretation

    The Role of Preprocessing for Word Representation Learning in Affective Tasks

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    Affective tasks, including sentiment analysis, emotion classification, and sarcasm detection have drawn a lot of attention in recent years due to a broad range of useful applications in various domains. The main goal of affect detection tasks is to recognize states such as mood, sentiment, and emotions from textual data (e.g., news articles or product reviews). Despite the importance of utilizing preprocessing steps in different stages (i.e., word representation learning and building a classification model) of affect detection tasks, this topic has not been studied well. To that end, we explore whether applying various preprocessing methods (stemming, lemmatization, stopword removal, punctuation removal and so on) and their combinations in different stages of the affect detection pipeline can improve the model performance. The are many preprocessing approaches that can be utilized in affect detection tasks. However, their influence on the final performance depends on the type of preprocessing and the stages that they are applied. Moreover, the preprocessing impacts vary across different affective tasks. Our analysis provides thorough insights into how preprocessing steps can be applied in building an effect detection pipeline and their respective influence on performance

    What effect does short term Study Abroad (SA) have on learners’ vocabulary knowledge?

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    This thesis describes a study which tracks longitudinal changes in vocabularyknowledge during a short-term Study Abroad (SA) experience. A test ofproductive vocabulary knowledge, Lex30 (Meara & Fitzpatrick, 2000),requiring the production of word association responses, is used to elicit vocabulary from 38 Japanese L1 learners of English at four test times at equal intervals before and after an SA experience. The study starts by investigating whether there are changes in both the total number of words and in the number of less frequently occurring words produced by SA participants. Three additional ways of measuring the development of lexical knowledge over time are then proposed. The first examines changes in the ability of participants of different proficiency levels in producing collocates in response to Lex30 cue words. The second tracks changes in spelling accuracy to measure if improvements take place over time. The third analysis uses an online measuring instrument (Wmatrix; Rayson, 2009) to explore if there are any changes in the mastery of specific semantic domains. The results show that there is significant growth in the productive use of less frequent vocabulary knowledge during the SA period. There is also an increase in collocation production with lower proficiency participants and evidence of some improvement in the way certain vocabulary items are spelled. The tendency for SA learners to produce more words from semantic groups related to SA experiences is also demonstrated. Post-SA tests show that while some knowledge attrition occurs it does not decline to pre-SA levels. The studyshows how short-term SA programmes can be evaluated using a word association test, contributing to a better understanding of how vocabularydevelops during intensive language learning experiences. It also demonstrates the gradual shift of productive vocabulary knowledge from partial word knowledge to a more complete state of productive mastery

    Breves reflexiones sobre las obras de arte robadas por los nazis

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    Cultural property litigation is often fascinating, creative, complex and full of all sorts of elements. Many of them take place before courts in the United States. One of the parties is usually a Jew or an heir to that Jew who was plundered from a work of art by the Nazis. 90 years have passed since National Socialism came to power in Germany (1933). However, these types of cases continue to occur. The purpose of this essay is to show the technical coordinates that explain the reasons why it is frequently litigated before US courts and the criteria used by them to determine which is the legal system applicable to the eventual restitution of the painting, the drawing, the score, sculpture, porcelain or any other similar object that is claimed.Los litigios sobre bienes culturales suelen ser fascinantes, creativos, complejos y llenos de elementos de todo tipo. Muchos de ellos se desarrollan ante tribunales de los Estados Unidos. Una de las partes suele ser un judío o un heredero de ese judío que fue expoliado de una obra de arte por los nazis. Se cumplen 90 años desde la llegada del nacionalsocialismo al poder en Alemania (1933). No obstante, este tipo de casos siguen produciéndose. La finalidad de este ensayo es mostrar las coordenadas técnicas que explican las razones de que se litigue con frecuencia ante tribunales estadounidenses y los criterios utilizados por éstos para determinar cuál es el ordenamiento jurídico aplicable a la eventual restitución de la pintura, el dibujo, la partitura, la escultura, la porcelana o cualquier otro objeto semejante que se reclame
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