The crystal structure of human microsomal triglyceride transfer protein

This is the final version. Available from National Academy of Sciences via the DOI in this record.Data deposition: The data have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 6I7S).Microsomal triglyceride transfer protein (MTP) plays an essential role in lipid metabolism, especially in the biogenesis of very low-density lipoproteins and chylomicrons via the transfer of neutral lipids and the assembly of apoB-containing lipoproteins. Our understanding of the molecular mechanisms of MTP has been hindered by a lack of structural information of this heterodimeric complex comprising an MTPα subunit and a protein disulfide isomerase (PDI) β-subunit. The structure of MTP presented here gives important insights into the potential mechanisms of action of this essential lipid transfer molecule, structure-based rationale for previously reported disease-causing mutations, and a means for rational drug design against cardiovascular disease and obesity. In contrast to the previously reported structure of lipovitellin, which has a funnel-like lipid-binding cavity, the lipid-binding site is encompassed in a β-sandwich formed by 2 β-sheets from the C-terminal domain of MTPα. The lipid-binding cavity of MTPα is large enough to accommodate a single lipid. PDI independently has a major role in oxidative protein folding in the endoplasmic reticulum. Comparison of the mechanism of MTPα binding by PDI with previously published structures gives insights into large protein substrate binding by PDI and suggests that the previous structures of human PDI represent the "substrate-bound" and "free" states rather than differences arising from redox state.Academy of FinlandAcademy of FinlandSigrid Juselius FoundationBiocenter Oul

Vision 21: Interdisciplinary Science and Engineering in the Era of Cyberspace

The symposium Vision-21: Interdisciplinary Science and Engineering in the Era of Cyberspace was held at the NASA Lewis Research Center on March 30-31, 1993. The purpose of the symposium was to simulate interdisciplinary thinking in the sciences and technologies which will be required for exploration and development of space over the next thousand years. The keynote speakers were Hans Moravec, Vernor Vinge, Carol Stoker, and Myron Krueger. The proceedings consist of transcripts of the invited talks and the panel discussion by the invited speakers, summaries of workshop sessions, and contributed papers by the attendees

Haptic holography : an early computational plastic

Thesis (Ph. D.)--Massachusetts Institute of Technology, School of Architecture and Planning, Program in Media Arts and Sciences, 2001.Includes bibliographical references (p. 135-148).This dissertation introduces haptic holography, a combination of computational modeling and multimodal spatial display, as an early computationalplastic In this work, we combine various holographic displays with a force feedback device to image free-standing material surfaces with programmatically prescribed behavior. We present three implementations, Touch, Lathe, and Poke, each named for the primitive functional affordance it offers. In Touch, we present static holographic images of simple geometry, reconstructed in front of the hologram plane (in the viewer's space), and precisely co-located with a force model of the same geometry. These images can be visually inspected and haptically explored using a hand-held interface. In Lathe, we again display holo-haptic images of simple geometry, this time allowing those images to be reshaped by haptic interaction in a dynamic but constrained manner. Finally in Poke, we present a holo-haptic image that permits arbitrary reshaping of its reconstructed surface. As supporting technology, we offer a new technique for incrementally computing and locally updating interference-modeled holographic fringe patterns. This technique permits electronic holograms to be updated arbitrarily and interactively, marking a long-held goal in display holography. As a broader contribution, we offer a new behavior-based spatial framework, based on both perception and action, for informing the design of spatial interactive systems.Wendy J. Plesniak.Ph.D

Visual-auditory visualisation of dynamic multi-scale heterogeneous objects.

The multi-scale phenomena analysis is an area of active research that is connecting simulations with experiments to get a correct insight into the compound dynamic structure. Visualisation is a challenging task due to a large amount of data and a wide range of complex data representations. The analysis of dynamic multi-scale phenomena requires a combination of geometric modelling and rendering techniques for the analysis of the changes in the internal structure in the case of data coming from different sources of various nature. Moreover, the area often addresses the limitations of solely visual data representation and considers the introduction of other sensory stimuli as a well-known tool to enhance visual analysis. However, there is a lack of software tools allowing perform an advanced real-time analysis of heterogeneous phenomena properties. The hardware-accelerated volume rendering allows getting insight into the internal structure of complex multi-scale phenomena. The technique is convenient for detailed visual analysis and highlights the features of interest in complex structures and is an area of active research. However, the conventional volume visualisation is limited to the use of transfer functions that operate on homogeneous material and, as a result, does not provide flexibility in geometry and material distribution modelling that is crucial for the analysis of heterogeneous objects. Moreover, the extension to visual-auditory analysis emphasises the necessity to review the entire conventional volume visualisation pipeline. The multi-sensory feedback highly depends on the use of modern hardware and software advances for real-time modelling and evaluation. In this work, we explore the aspects of the design of visual-auditory pipelines for the analysis of dynamic multi-scale properties of heterogeneous objects that can allow overcoming well-known problems of complex representations solely visual analysis. We consider the similarities between light and sound propagation as a solution to the problem. The approach benefits from a combination of GPU accelerated ray-casting, geometry, optical and auditory properties modelling. We discuss how the modern GPU techniques application in those areas allows introducing a unified approach to the visual-auditory analysis of dynamic multi-scale heterogeneous objects. Similarly to the conventional volume rendering technique based on light propagation, we model auditory feedback as a result of initial impulse propagation through 3D space and its digital representation as a sampled sound wave obtained with the ray-casting procedure. The auditory stimuli can complement visual ones in the analysis of the dynamic multi-scale heterogeneous object. We propose a framework that facilitates the design of dynamic multi-scale heterogeneous objects visual-auditory pipeline and discuss the framework application for two case studies. The first is a molecular phenomena study that is a result of molecular dynamics simulation and quantum simulation. The second explores microstructures in digital fabrication with an arbitrary irregular lattice structure. For considered case studies, the visual-auditory techniques facilitate the interactive analysis of both spatial structure and internal multi-scale properties of volume nature in complex heterogeneous objects. A GPU-accelerated framework for visual-auditory analysis of heterogeneous objects can be applied and extend beyond this research. Thus, to specify the main direction of such extension from the point of view of the potential users, strengthen the value of this research as well as to evaluate the vision of the application of the techniques described above, we carry out a preliminary evaluation. The user study aims to compare our expectations on the visual-auditory approach with the views of the potential users of this system if it is implemented as a software product. A preliminary evaluation study was carried out with limitations imposed by 2020/2021 restrictions. However, it confirms that the main direction for the visual-auditory analysis of heterogeneous objects has been identified correctly and visual and auditory stimuli can complement each other in the analysis of both volume and spatial distribution properties of heterogeneous phenomena. The user reviews also highlight the necessary enhancements that should be introduced to the approach in terms of the design of more complex user interfaces and consideration of additional application cases. To provide a more detailed picture on evaluation results and recommendations introduced, we also identify the key factors that define the user vision of the approach further enhancement and its possible application areas, such as users experience in the area of complex physical phenomena analysis or multi-sensory area. The discussed in this work aspects of heterogeneous objects analysis task, theoretical and practical solutions allow considering the application, further development and enhancement of the results in multidisciplinary areas of GPU accelerated High-performance visualisation pipelines design and multi-sensory analysis

Processpatching: defining new methods in aRt&D

In the context of a rapidly changing domain of contemporary electronic art practice- where the speed of technological innovation and the topicality of art 'process as research' methods are both under constant revision- the process of collaboration between art, computer science and engineering is an important addition to existing 'R&D'. Scholarly as well as practical exploration of artistic methods, viewed in relation to the field of new technology, can be seen to enable and foster innovation in both the conceptualisation and practice of the electronic arts. At the same time, citing new media art in the context of technological innovation brings a mix of scientific and engineering issues to the fore and thereby demands an extended functionality that may lead to R&D, as technology attempts to take account of aesthetic and social considerations in its re-development. This new field of new media or electronic art R&D is different from research and development aimed at practical applications of new technologies as we see them in everyday life. A next step for Research and Development in Art (aRt&D) is a formalisation of the associated work methods, as an essential ingredient for interdisciplinary collaboration. This study investigates how electronic art patches together processes and methods from the arts, engineering and computer science environments. It provides a framework describing the electronic art methods to improve collaboration by informing others about one's artistic research and development approach. This investigation is positioned in the electronic art laboratory where new alliances with other disciplines are established. It provides information about the practical and theoretical aspects of the research and development processes of artists. The investigation addresses fundamental questions about the 'research and development methods' (discussed and defined at length in these pages), of artists who are involved in interdisciplinary collaborations amongst and between the fields of Art, Computer Science, and Engineering. The breadth of the fields studied necessarily forced a tight focus on specific issues in the literature, addressed herein through a series of focused case studies which demonstrate the points of synergy and divergence between the fields of artistic research and development, in a wider art&D' context. The artistic methods proposed in this research include references from a broad set of fields (e. g. Technology, Media Arts, Theatre and Performance, Systems Theories, the Humanities, and Design Practice) relevant to and intrinsically intertwined with this project and its placement in an interdisciplinary knowledge domain. The aRt&D Matrix provides a complete overview of the observed research and development methods in electronic arts, including references to related disciplines and methods from other fields. The new Matrix developed and offered in this thesis also provides an instrument for analysing the interdisciplinary collaboration process that exclusively reflects the information we need for the overview of the team constellation. The tool is used to inform the collaborators about the backgrounds of the other participants and thus about the expected methods and approaches. It provides a map of the bodies of knowledge and expertise represented in any given cross-disciplinary team, and thus aims to lay the groundwork for a future aRt&D framework of use to future scholars and practitioners alike

Data and the city – accessibility and openness. a cybersalon paper on open data

This paper showcases examples of bottom–up open data and smart city applications and identifies lessons for future such efforts. Examples include Changify, a neighbourhood-based platform for residents, businesses, and companies; Open Sensors, which provides APIs to help businesses, startups, and individuals develop applications for the Internet of Things; and Cybersalon’s Hackney Treasures. a location-based mobile app that uses Wikipedia entries geolocated in Hackney borough to map notable local residents. Other experiments with sensors and open data by Cybersalon members include Ilze Black and Nanda Khaorapapong's The Breather, a "breathing" balloon that uses high-end, sophisticated sensors to make air quality visible; and James Moulding's AirPublic, which measures pollution levels. Based on Cybersalon's experience to date, getting data to the people is difficult, circuitous, and slow, requiring an intricate process of leadership, public relations, and perseverance. Although there are myriad tools and initiatives, there is no one solution for the actual transfer of that data

Caractérisation détaillée de l’interaction entre NS3 et NS5 dans le complexe de réplication du virus du Nil occidental pendant la synthèse d’ARN de polarité positive

Les Flavivirus transmis par les moustiques comme le virus du Nil occidental, le virus de la dengue, le virus de la fièvre jaune, le virus de l’encéphalite japonaise et le virus Zika constituent des préoccupations croissantes de santé publique. Ils se sont répandus dans le monde au cours des dernières décennies, et les épidémies sont devenues plus fréquentes et plus sévères. Chaque année, des millions de personnes sont infectées et environ 50 000 patients décèdent d’infections à Flavivirus. Malgré les nombreux efforts de recherche, il n’y a actuellement aucun médicament antiviral spécifique disponible, et des nouvelles stratégies antivirales sont indispensables. Comprendre comment les Flavivirus fonctionnent au niveau moléculaire aidera à découvrir des nouvelles cibles pour l'intervention thérapeutique. Les Flavivirus ont un génome d'ARN simple brin de polarité positive qui code pour trois protéines structurales et huit protéines non structurales. Seules deux des huit protéines non structurales ont des activités enzymatiques. NS3 possède un domaine protéase et un domaine hélicase, et NS5 a un domaine méthyl- et guanylyltransférase et un domaine ARN polymérase ARN-dépendante. Ensemble, ils répliquent le génome viral. Ici, nous caractérisons l'interaction entre NS3 et NS5 dans le complexe de réplication du virus du Nil occidental pendant la synthèse d’ARN de polarité positive. Un modèle d'interaction comprenant NS3, NS5 et l’ARN viral a été développé basé sur des structures cristallines connues ainsi que des activités enzymatiques des deux protéines individuelles, et ce modèle a été soumis à des simulations de dynamique moléculaire. Les interactions potentielles entre les protéines NS3 et NS5 ont été identifiées. Les résidus impliqués dans ces interactions ont été mutés dans un réplicon du virus du Nil occidental et les effets de ces mutations sur la réplication virale ont été évalués. Une région particulière à la surface de la protéine NS3 a été identifiée comme étant cruciale pour la réplication virale, très probablement parce qu'elle interagit avec NS5. Cette région pourrait être une cible attrayante pour la recherche de composés qui pourraient interférer avec l'interaction entre NS3 et NS5 et donc posséder un potentiel antiviral intéressant.Abstract : Mosquito-borne Flaviviruses like West Nile virus, Dengue virus, Yellow Fever virus, Japanese encephalitis virus, and Zika virus are increasing public health concerns. They have spread globally during the past decades, and outbreaks have recently become more frequent and more severe. Every year, millions of people are infected, and approximately 50,000 patients die from Flavivirus infections. Despite extensive research efforts, there are currently no specific antiviral drugs available, and new antiviral strategies are greatly needed. Understanding how Flaviviruses work on a molecular level will help in uncovering new points for therapeutic intervention. Flaviviruses have a single-stranded RNA genome of positive polarity that encodes three structural and eight non-structural proteins. Only two of the eight non-structural proteins have enzymatic activities. NS3 has an N-terminal protease domain and a C-terminal helicase domain, and NS5 has an N-terminal capping enzyme domain and a C-terminal RNA-dependent RNA polymerase domain. Together, they replicate the viral genome. Here we characterize the NS3:NS5 interaction within the West Nile virus RNA replicase complex during positive strand synthesis. An interaction model including NS3, NS5 and viral RNA was developed based on the known crystal structures as well as enzymatic activities of the two individual proteins, and this model was subjected to molecular dynamics simulations. Potential interactions between the NS3 and NS5 proteins were identified. Residues involved in these interactions were mutated in a West Nile virus replicon, and the effects of these mutations on viral replication were evaluated. One particular region on the surface of the NS3 protein was identified to be crucial for viral replication, most likely because it mediates the interaction with NS5. This region might be an attractive target for the search of compounds that could interfere with the NS3:NS5 interaction and therefore possess an interesting antiviral potential