172 resultados para Web-Application Google-Drive Fatture Drive SDK Invoice OAuth 2.2 JavaScript


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Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NFκB)-dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNFα). Here, we report the presence of a molecular logic AND gate composed of two NFκB response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NFκB displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNFα, such that a threshold level of NFκB activation is required before the promoter becomes active and initiates transcription. This NFκB-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNFα. Our data suggest that the NFκB-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNFα, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation.

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Analysing the molecular polymorphism and interactions of DNA, RNA and proteins is of fundamental importance in biology. Predicting functions of polymorphic molecules is important in order to design more effective medicines. Analysing major histocompatibility complex (MHC) polymorphism is important for mate choice, epitope-based vaccine design and transplantation rejection etc. Most of the existing exploratory approaches cannot analyse these datasets because of the large number of molecules with a high number of descriptors per molecule. This thesis develops novel methods for data projection in order to explore high dimensional biological dataset by visualising them in a low-dimensional space. With increasing dimensionality, some existing data visualisation methods such as generative topographic mapping (GTM) become computationally intractable. We propose variants of these methods, where we use log-transformations at certain steps of expectation maximisation (EM) based parameter learning process, to make them tractable for high-dimensional datasets. We demonstrate these proposed variants both for synthetic and electrostatic potential dataset of MHC class-I. We also propose to extend a latent trait model (LTM), suitable for visualising high dimensional discrete data, to simultaneously estimate feature saliency as an integrated part of the parameter learning process of a visualisation model. This LTM variant not only gives better visualisation by modifying the project map based on feature relevance, but also helps users to assess the significance of each feature. Another problem which is not addressed much in the literature is the visualisation of mixed-type data. We propose to combine GTM and LTM in a principled way where appropriate noise models are used for each type of data in order to visualise mixed-type data in a single plot. We call this model a generalised GTM (GGTM). We also propose to extend GGTM model to estimate feature saliencies while training a visualisation model and this is called GGTM with feature saliency (GGTM-FS). We demonstrate effectiveness of these proposed models both for synthetic and real datasets. We evaluate visualisation quality using quality metrics such as distance distortion measure and rank based measures: trustworthiness, continuity, mean relative rank errors with respect to data space and latent space. In cases where the labels are known we also use quality metrics of KL divergence and nearest neighbour classifications error in order to determine the separation between classes. We demonstrate the efficacy of these proposed models both for synthetic and real biological datasets with a main focus on the MHC class-I dataset.

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Bangladesh has recently been enjoying significant economic growth mainly arising from an export led development strategy. However, in that process its natural environment has been degraded and become more vulnerable in geophysical terms (e.g. environmental pollution). Much of the Bangladeshi population are also vulnerable in socio-economic terms due primarily to widespread poverty. In this context we ask, albeit sceptically, whether there is any chance of holding corporations to account for their environmental responsibilities. Using the notions of vulnerability and ecological rifts we answer this question by providing evidence from published sources and a series of 32 semi-structured interviews with Bangladeshi stakeholder groups. Key findings include, inter alia, corporate reluctance to take responsibility for the environmental impact of their activities. Our interviewees discuss the possibility of a role for mandatory corporate reporting in enhancing corporate accountability and we argue that this is essential if the contradictions and irrationalities of the globalized capitalist system are to be made visible. Achieving such accountability, however, will not be easy due to a lack of political will and the prohibitive costs involved. Incurring such costs could raise the dangerous prospect of Bangladesh losing business to other, less regulated, economies.

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Integrated supplier selection and order allocation is an important decision for both designing and operating supply chains. This decision is often influenced by the concerned stakeholders, suppliers, plant operators and customers in different tiers. As firms continue to seek competitive advantage through supply chain design and operations they aim to create optimized supply chains. This calls for on one hand consideration of multiple conflicting criteria and on the other hand consideration of uncertainties of demand and supply. Although there are studies on supplier selection using advanced mathematical models to cover a stochastic approach, multiple criteria decision making techniques and multiple stakeholder requirements separately, according to authors' knowledge there is no work that integrates these three aspects in a common framework. This paper proposes an integrated method for dealing with such problems using a combined Analytic Hierarchy Process-Quality Function Deployment (AHP-QFD) and chance constrained optimization algorithm approach that selects appropriate suppliers and allocates orders optimally between them. The effectiveness of the proposed decision support system has been demonstrated through application and validation in the bioenergy industry.

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Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15–30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage -clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states.

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When facing a crisis, leaders' sensemaking can take a considerable amount of time due to the need to develop consensus in how to deal with it so that vision formation and sensegiving can take place. However, research into emerging cognitive consensus when leaders deal with a crisis over time is lacking. This is limiting a detailed understanding of how organizations respond to crises. The findings, based on a longitudinal analysis of cognitive maps within three management teams at a single organization, highlight considerable individual differences in cognitive content when starting to make sense of a crisis. Evidence for an emerging viable prescriptive mental model for the future was found, but not so much in the management as a whole. Instead, the findings highlight increasing cognitive consensus based on similarities in objectives and cause-effect beliefs within well-defined management teams over time.

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Purpose: Development and evaluation of a prototype dialogue game for servitization is reported. Design/methodology/approach: This paper reports the design of the iServe game, from user centered design, through implementation using the Unity games engine to evaluation, a process which took 270 researcher hours. Findings: No relationship was found between either age or gaming experience and usability. Participants who identified themselves as non-experts in servitization recognized the potential of the game to teach servitization concepts to other novice learners. Originality/value: The potential of business games for education and executive development has been recognized but factors, including high development cost, inhibit their uptake. Games engines offer a potential solution.

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Objectives: To explore interactions between audiology patients and volunteers, to describe encounters and define the role of volunteers. Methods: Qualitative ethnographic and interview study of volunteer-patient interactions. Ten volunteer participants from two volunteer schemes in South West England were observed and interviewed. Three patient participants were interviewed. Results: Analysis of observational data showed that volunteers provided support relating to local services and hearing aids, but did not engage in discussions about hearing loss. Interviews with volunteers identified gaps in audiology provision, including accessible services and clear information and highlighted a need for more support from audiology services to enable them to fulfil their role. Volunteer interactions with patients mimicked a clinician-patient encounter and volunteers employed strategies and behaviours used by professional audiologists. Conclusions: Audiology volunteers could provide an accessible bridge between health services and the community but their care is limited to focus on hearing aids. Practice implications: Volunteers enable patients to use hearing aids appropriately and are a core element of current care arrangements. However, volunteers express a need for adequate support from audiology services. Volunteers have the potential to increase service capacity and to bridge the gaps between community and audiology healthcare services.

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Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

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This paper examines the relationship between medical and hospital accounting discourses during the two decades after the 1946 National Health Service (NHS) Act for England and Wales. It argues that the departmental costing system introduced into the NHS in 1957 was concerned with the administrative aspects of hospital costliness as contemporary hospital accountants suggested that the perceived incomparability, immeasurability and uncontrollability of medical practice precluded the application of cost accounting to the clinical functions of hospitals. The paper links these suggestions to medical discourses which portrayed the practice of medicine as an intuitive and experience-based art and argues that post-war conceptions of clinical medicine represented this domain in a manner that was neither susceptible to the calculations of cost accountants nor to calculating and normalising intervention more generally. The paper concludes by suggesting that a closer engagement with medical discourses may enhance our understanding of historical as well as present day attempts to make medicine calculable.

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The abolition of the Audit Commission in England raises questions about how a major reform was achieved with so little controversy, why the agency lacked the institutional stickiness commonly described in the literature on organisational reform and why it did not strategise to survive. In this paper, we apply argumentative discourse analysis to rich empirical data to reveal the pattern and evolution of storylines and discourse coalitions, and the ways in which these interact with and affect the practices of Parliament, the media and the Audit Commission itself. Our analysis shows that the politics of administrative reform are as much about discursive framing and the ability of pro-reformers to gain discursive structuration and institutionalisation as they are about the material resources available to a newly elected government and its ministers. Questions of technical feasibility are unlikely to derail a reform initiative once its promoters gain discursive ascendency.

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The accession of the East-Central European (ECE) countries carried a promise of enhancing and enriching the EU’s Eastern policy. The new member states had the strongest interests among EU member states to ensure that countries in the East are prosperous, stable and democratic. Yet, EU’s Eastern policy has been largely criticised for its ineffectiveness. So why have they not been able to address the shortcomings in the EU’s Eastern policies? The article argues that the ECE countries supported the way the EU’s Eastern policies were conceived and implemented because they saw it as a potent vehicle to promote their own transition experience not only in the region but also within the EU. We argue that the ECE states have experienced three types of challenges when promoting their transition experience. First, uploading to the EU level remained largely at a rhetorical level. Second, there are conceptual and practical difficulties in defining what constitutes transition experience and harnessing it, as well as coordinating its transfer between the ECE states. Finally, while using transition experience as the basis for their development assistance strategies, the ECE countries actually insufficiently conceptualised the ‘development’ aspect in these policies. Being so driven by their own experience, they have not drawn the lessons from enlargement to use in a non-accession context, especially by incorporating the broader lessons with regard to development.

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The brewing process is an energy intensive process that uses large quantities of heat and electricity. To produce this energy requires a high, mainly fossil fuel consumption and the cost of this is increasing each year due to rising fuel costs. One of the main by-products from the brewing process is Brewers Spent Grain (BSG), an organic residue with very high moisture content. It is widely available each year and is often given away as cattle feed or disposed of to landfill as waste. Currently these methods of disposal are also costly to the brewing process. The focus of this work was to investigate the energy potential of BSG via pyrolysis, gasification and catalytic steam reforming, in order to produce a tar-free useable fuel gas that can be combusted in a CHP plant to develop heat and electricity. The heat and electricity can either be used on site or exported. The first stage of this work was the drying and pre-treatment of BSG followed by characterisation to determine its basic composition and structure so it can be evaluated for its usefulness as a fuel. A thorough analysis of the characterisation results helps to better understand the thermal behaviour of BSG feedstock so it can be evaluated as a fuel when subjected to thermal conversion processes either by pyrolysis or gasification. The second stage was thermochemical conversion of the feedstock. Gasification of BSG was explored in a fixed bed downdraft gasifier unit. The study investigated whether BSG can be successfully converted by fixed bed downdraft gasification operation and whether it can produce a product gas that can potentially run an engine for heat and power. In addition the pyrolysis of BSG was explored using a novel “Pyroformer” intermediate pyrolysis reactor to investigate the behaviour of BSG under these processing conditions. The physicochemical properties and compositions of the pyrolysis fractions obtained (bio-oil, char and permanent gases) were investigated for their applicability in a combined heat power (CHP) application.

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This paper deals with the grammaticalization of venir into aspectual auxiliary of immediate anteriority, against the traditional approach (Gougenheim 1929/1971) according to which venir de + inf., would express recent past and so would be a temporal auxiliary. On the basis of the (revised) Reichenbachian model, it shows that venir de + inf. bears upon the relationship between R and E (aspect) and not on the relationship between R and S (time). This analysis allows explain why venir, in this periphrasis, is defective (i.e. why venir cannot be conjugated in the passé simple or in any compound tense).