Context specific affinity thresholds for CD8 T cell activation

After antigen driven activationnaïve CD8 T cells develop intocytolytic effector cells and subsequentlyinto memory cells. The molecularinteractions orchestrating Tcell activation are complex and we sofar have a limited understanding howindividual signals impact the Tcell response.Using OT-1 TCR transgeniccells and Listeria monocytogenesstrains expressing a set of altered peptideligands (APL) for the OT-1 TCRwe have recently studied how thelevel of TCR stimulation impacts theT cell response in vivo. We therebyobserved that even very low levels ofTCR stimulation are sufficient forfunctional effector and memoryT celldifferentiation. In order to addresshow much further the level of TCRstimulation can be reduced until the Tcells do not become activated anymore,we generated additional OT-1APL expressing Listeria strains. TheAPLused in our present study cover arange of potency down to the level ofpositive selection. Using all our APLListeria strains we can demonstratethat the threshold of peripheral T cellactivation is above the level of positiveselection but far below the levelthat is thought to be required for negativeselection. Furthermore, we characterizedthe thresholds of activatingmemory T cells and found them intrinsicallyto be very similar to thoseof naïve T cells. However, we observedthat T cell competition at thelevel of antigen presenting cells criticallyraises the activation threshold ofmemory CD8 T cells. Taken togetherour data indicate that the threshold foractivating T cells critically dependson the context and the environment inwhich T cells respond to antigen.

Context-specific independence in graphical models

The theme of this thesis is context-speci c independence in graphical models. Considering a system of stochastic variables it is often the case that the variables are dependent of each other. This can, for instance, be seen by measuring the covariance between a pair of variables. Using graphical models, it is possible to visualize the dependence structure found in a set of stochastic variables. Using ordinary graphical models, such as Markov networks, Bayesian networks, and Gaussian graphical models, the type of dependencies that can be modeled is limited to marginal and conditional (in)dependencies. The models introduced in this thesis enable the graphical representation of context-speci c independencies, i.e. conditional independencies that hold only in a subset of the outcome space of the conditioning variables. In the articles included in this thesis, we introduce several types of graphical models that can represent context-speci c independencies. Models for both discrete variables and continuous variables are considered. A wide range of properties are examined for the introduced models, including identi ability, robustness, scoring, and optimization. In one article, a predictive classi er which utilizes context-speci c independence models is introduced. This classi er clearly demonstrates the potential bene ts of the introduced models. The purpose of the material included in the thesis prior to the articles is to provide the basic theory needed to understand the articles.

Context-specific modulation of cocaine-induced locomotor sensitization and ERK and CREB phosphorylation in the rat nucleus accumbens

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Ultrabithorax Confers Spatial Identity in a Context-Specific Manner in the Drosophila Postembryonic Ventral Nervous System

In holometabolous insects such as Drosophila melanogaster, neuroblasts produce an initial population of diverse neurons during embryogenesis and a much larger set of adult-specific neurons during larval life. In the ventral CNS, many of these secondary neuronal lineages differ significantly from one body segment to another, suggesting a role for anteroposterior patterning genes. Here we systematically characterize the expression pattern and function of the Hox gene Ultrabithorax (Ubx) in all 25 postembryonic lineages. We find that Ubx is expressed in a segment-, lineage-, and hemilineage-specific manner in the thoracic and anterior abdominal segments. When Ubx is removed from neuroblasts via mitotic recombination, neurons in these segments exhibit the morphologies and survival patterns of their anterior thoracic counterparts. Conversely, when Ubx is ectopically expressed in anterior thoracic segments, neurons exhibit complementary posterior transformation phenotypes. Our findings demonstrate that Ubx plays a critical role in conferring segment-appropriate morphology and survival on individual neurons in the adult-specific ventral CNS. Moreover, while always conferring spatial identity in some sense, Ubx has been co-opted during evolution for distinct and even opposite functions in different neuronal hemilineages.

Convergence-divergence of HRM in the Asia-Pacific:context-specific analysis and future research agenda

In this article, we highlight the significance and need for conducting context-specific human resource management (HRM) research, by focusing on four critical themes. First, we discuss the need to analyze the convergence-divergence debate on HRM in Asia-Pacific. Next, we present an integrated framework, which would be very useful for conducting cross-national HRM research designed to focus on the key determinants of the dominant national HRM systems in the region. Following this, we discuss the critical challenges facing the HRM function in Asia-Pacific. Finally, we present an agenda for future research by presenting a series of research themes.

Structure learning of context-specific graphical models

Abstract The ultimate problem considered in this thesis is modeling a high-dimensional joint distribution over a set of discrete variables. For this purpose, we consider classes of context-specific graphical models and the main emphasis is on learning the structure of such models from data. Traditional graphical models compactly represent a joint distribution through a factorization justi ed by statements of conditional independence which are encoded by a graph structure. Context-speci c independence is a natural generalization of conditional independence that only holds in a certain context, speci ed by the conditioning variables. We introduce context-speci c generalizations of both Bayesian networks and Markov networks by including statements of context-specific independence which can be encoded as a part of the model structures. For the purpose of learning context-speci c model structures from data, we derive score functions, based on results from Bayesian statistics, by which the plausibility of a structure is assessed. To identify high-scoring structures, we construct stochastic and deterministic search algorithms designed to exploit the structural decomposition of our score functions. Numerical experiments on synthetic and real-world data show that the increased exibility of context-specific structures can more accurately emulate the dependence structure among the variables and thereby improve the predictive accuracy of the models.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Childhood adversities as specific contributors to the co-occurrence of posttraumatic stress and alcohol use disorders.

There is much evidence that alcohol use disorders (AUD) often co-occur with posttraumatic stress disorders (PTSD), and that the comorbid condition is associated with a more severe clinical profile than that of PTSD without AUD. However, little is known about the role of childhood adversities as specific risk factors for the development of AUD in individuals presenting with PTSD. The aim of the study was to explore whether specific stressors from the spectrum of trauma and childhood adversities contribute to the development of AUD among subjects with PTSD. From a large community sample, of N=140 individuals with PTSD, N=24 (17.14%) received an additional diagnosis of AUD with an onset after the onset of PTSD. Those with comorbid PTSD/AUD and those with PTSD only were compared regarding type and features of their trauma, childhood adversities and psychiatric comorbidity. Compared to PTSD alone, PTSD/AUD was associated with higher levels of stress in terms of childhood adversities; in particular, sexual abuse below the age of 16, but also with having been brought up in a foster home. PTSD/AUD was also associated with an earlier age of adverse events. Treatment of AUD should include standardized assessments of trauma, especially of trauma experienced during childhood.

Exploring context-awareness in the construction logistics services delivery

Managing a construction project supply chain effectively and efficiently is extremely difficult due to involvement of numerous sectors that are supported by ineffective communication system. An efficient construction supply chain system ensures the delivery of materials and other services to construction site while minimising costs and rewarding all sectors based on value added to the supply chain. The advancement of information, communication and wireless technologies is driving construction companies to deploy supply chain management strategies to seek better outputs. As part of the emerging wireless technologies, contextaware computing capability represents the next generation of ICT to the construction services. Conceptually, context-awareness could be integrated with Web Services in order to ensure the delivery of pertinent information to construction site and enhance construction supply chain collaboration. An initial study has indicated that this integrated system has the potential of serving and improving the construction services delivery through access to context-specific data, information and services on as-needed basis.

Intelligent wireless web services: context-aware computing in construction-logistics supply chain

The construction industry has incurred a considerable amount of waste as a result of poor logistics supply chain network management. Therefore, managing logistics in the construction industry is critical. An effective logistic system ensures delivery of the right products and services to the right players at the right time while minimising costs and rewarding all sectors based on value added to the supply chain. This paper reports on an on-going research study on the concept of context-aware services delivery in the construction project supply chain logistics. As part of the emerging wireless technologies, an Intelligent Wireless Web (IWW) using context-aware computing capability represents the next generation ICT application to construction-logistics management. This intelligent system has the potential of serving and improving the construction logistics through access to context-specific data, information and services. Existing mobile communication deployments in the construction industry rely on static modes of information delivery and do not take into account the worker’s changing context and dynamic project conditions. The major problems in these applications are lack of context-specificity in the distribution of information, services and other project resources, and lack of cohesion with the existing desktop based ICT infrastructure. The research works focus on identifying the context dimension such as user context, environmental context and project context, selection of technologies to capture context-parameters such wireless sensors and RFID, selection of supporting technologies such as wireless communication, Semantic Web, Web Services, agents, etc. The process of integration of Context-Aware Computing and Web-Services to facilitate the creation of intelligent collaboration environment for managing construction logistics will take into account all the necessary critical parameters such as storage, transportation, distribution, assembly, etc. within off and on-site project.

The role of context in forming young learners' attitudes and motivation to learning French

Despite the wealth of valuable information that has been generated by motivation studies to date, there are certain limitations in the common approaches. Quantitative and psychometric approaches to motivation research that have dominated in recent decades provided epiphenomenal descriptions of learner motivation within different contexts. However, these approaches assume homogeneity within a given group and often mask the variation between learners within the same, and different, contexts. Although these studies have provided empirical data to form and validate theoretical constructs, they have failed to recognise learners as individual ‘people’ that interact with their context. Learning context has become increasingly explicit in motivation studies, (see Coleman et al. 2007 and Housen et al. 2011), however it is generally considered as a background variable which is pre-existing and external to the individual. Stemming from the recent ‘social turn’ (Block 2003) in SLA research from a more cognitive-linguistic perspective to a more context-specific view of language learning, there has been an upsurge in demand for a greater focus on the ‘person in context’ in motivation research (Ushioda 2011). This paper reports on the findings of a longitudinal study of young English learners of French as they transition from primary to secondary school. Over 12 months, the study employed a mixed-method approach in order to gain an in-depth understanding of how the learners’ context influenced attitudes to language learning. The questionnaire results show that whilst the learners displayed some consistent and stable motivational traits over the 12 months, there were significant differences for learners within different contexts in terms of their attitudes to the language classroom and their levels of self-confidence. A subsequent examination of the qualitative focus group data provided an insight into how and why these attitudes were formed and emphasised the dynamic and complex interplay between learners and their context.

Interactions between dorsolateral and ventromedial prefrontal cortex underlie context-dependent stimulus valuation in goal-directed choice.

External circumstances and internal bodily states often change and require organisms to flexibly adapt valuation processes to select the optimal action in a given context. Here, we investigate the neurobiology of context-dependent valuation in 22 human subjects using functional magnetic resonance imaging. Subjects made binary choices between visual stimuli with three attributes (shape, color, and pattern) that were associated with monetary values. Context changes required subjects to deviate from the default shape valuation and to integrate a second attribute in order to comply with the goal to maximize rewards. Critically, this binary choice task did not involve any conflict between opposing monetary, temporal, or social preferences. We tested the hypothesis that interactions between regions of dorsolateral and ventromedial prefrontal cortex (dlPFC; vmPFC) implicated in self-control choices would also underlie the more general function of context-dependent valuation. Consistent with this idea, we found that the degree to which stimulus attributes were reflected in vmPFC activity varied as a function of context. In addition, activity in dlPFC increased when context changes required a reweighting of stimulus attribute values. Moreover, the strength of the functional connectivity between dlPFC and vmPFC was associated with the degree of context-specific attribute valuation in vmPFC at the time of choice. Our findings suggest that functional interactions between dlPFC and vmPFC are a key aspect of context-dependent valuation and that the role of this network during choices that require self-control to adjudicate between competing outcome preferences is a specific application of this more general neural mechanism.

A configuration framework of manufacturing strategy paradigm in state owned enterprises within China's petrochemical industry:building context-embedded configurations for the paradigm of strategic manufacturing management from exploratory case studies

The role of the production system as a key determinant of competitive performance of business operations- has long been the subject of industrial organization research, even predating the .explicit conceptua1isation of manufacturing, strategy in the literature. Particular emergent production issues such as the globalisation of production, global supply chain management, management of integrated manufacturing and a growing e~busjness environment are expected to critically influence the overall competitive performance and therefore the strategic success of the organization. More than ever, there is a critical need to configure and improve production system and operations competence in a strategic way so as to contribute to the long-term competitiveness of the organization. In order to operate competitively and profitably, manufacturing companies, no matter how well managed, all need a long-term 'strategic direction' for the development of operations competence in order to consistently produce more market value with less cost towards a leadership position. As to the long-term competitiveness, it is more important to establish a dynamic 'strategic perspective' for continuous operational improvements in pursuit of this direction, as well as ongoing reviews of the direction in relation to the overall operating context. However, it also clear that the 'existing paradigm of manufacturing strategy development' is incapable of adequately responding to the increasing complexities and variations of contemporary business operations. This has been factually reflected as many manufacturing companies are finding that methodologies advocated in the existing paradigm for developing manufacturing strategy have very limited scale and scope for contextual contingency in empirical application. More importantly, there has also emerged a deficiency in the multidimensional and integrative profile from a theoretical perspective when operationalising the underlying concept of strategic manufacturing management established in the literature. The point of departure for this study was a recognition of such contextual and unitary limitations in the existing paradigm of manufacturing strategy development when applied to contemporary industrial organizations in general, and Chinese State Owned Enterprises (SOEs) in particular. As China gradually becomes integrated into the world economy, the relevance of Western management theory and its paradigm becomes a practical matter as much as a theoretical issue. Since China markedly differs from Western countries in terms of culture, society, and political and economic systems, it presents promising grounds to test and refine existing management theories and paradigms with greater contextual contingency and wider theoretical perspective. Under China's ongoing programmes of SOE reform, there has been an increased recognition that strategy development is the very essence of the management task for managers of manufacturing companies in the same way as it is for their counterparts in Western economies. However, the Western paradigm often displays a rather naive and unitary perspective of the nature of strategic management decision-making, one which largely overlooks context-embedded factors and social/political influences on the development of manufacturing strategy. This thesis studies the successful experiences of developing manufacturing strategy from five high-performing large-scale SOEs within China’s petrochemical industry. China’s petrochemical industry constitutes a basic heavy industrial sector, which has always been a strategic focus for reform and development by the Chinese government. Using a confirmation approach, the study has focused on exploring and conceptualising the empirical paradigm of manufacturing strategy development practiced by management. That is examining the ‘empirical specifics’ and surfacing the ‘managerial perceptions’ of content configuration, context of consideration, and process organization for developing a manufacturing strategy during the practice. The research investigation adopts a qualitative exploratory case study methodology with a semi-structural front-end research design. Data collection follows a longitudinal and multiple-case design and triangulates case evidence from sources including qualitative interviews, direct observation, and a search of documentations and archival records. Data analysis follows an investigative progression from a within-case preliminary interpretation of facts to a cross-case search for patterns through theoretical comparison and analytical generalization. The underlying conceptions in both the literature of manufacturing strategy and related studies in business strategy were used to develop theoretical framework and analytical templates applied during data collection and analysis. The thesis makes both empirical and theoretical contributions to our understanding of 'contemporary management paradigm of manufacturing strategy development'. First, it provides a valuable contextual contingency of the 'subject' using the business setting of China's SOEs in petrochemical industry. This has been unpacked into empirical configurations developed for its context of consideration, its content and process respectively. Of special note, a lean paradigm of business operations and production management discovered at case companies has significant implications as an emerging alternative for high-volume capital intensive state manufacturing in China. Second, it provides a multidimensional and integrative theoretical profile of the 'subject' based upon managerial perspectives conceptualised at case companies when operationalising manufacturing strategy. This has been unpacked into conceptual frameworks developed for its context of consideration, its content constructs, and its process patterns respectively. Notably, a synergies perspective towards the operating context, competitive priorities and competence development of business operations and production management has significant implications for implementing a lean manufacturing paradigm. As a whole, in so doing, the thesis established a theoretical platform for future refinement and development of context-specific methodologies for developing manufacturing strategy.