Use of anisotropic modelling in electrical impedance tomography: description of method and preliminary assessment of utility in imaging brain function in the adult human head.

Electrical Impedance Tomography (EIT) is an imaging method which enables a volume conductivity map of a subject to be produced from multiple impedance measurements. It has the potential to become a portable non-invasive imaging technique of particular use in imaging brain function. Accurate numerical forward models may be used to improve image reconstruction but, until now, have employed an assumption of isotropic tissue conductivity. This may be expected to introduce inaccuracy, as body tissues, especially those such as white matter and the skull in head imaging, are highly anisotropic. The purpose of this study was, for the first time, to develop a method for incorporating anisotropy in a forward numerical model for EIT of the head and assess the resulting improvement in image quality in the case of linear reconstruction of one example of the human head. A realistic Finite Element Model (FEM) of an adult human head with segments for the scalp, skull, CSF, and brain was produced from a structural MRI. Anisotropy of the brain was estimated from a diffusion tensor-MRI of the same subject and anisotropy of the skull was approximated from the structural information. A method for incorporation of anisotropy in the forward model and its use in image reconstruction was produced. The improvement in reconstructed image quality was assessed in computer simulation by producing forward data, and then linear reconstruction using a sensitivity matrix approach. The mean boundary data difference between anisotropic and isotropic forward models for a reference conductivity was 50%. Use of the correct anisotropic FEM in image reconstruction, as opposed to an isotropic one, corrected an error of 24 mm in imaging a 10% conductivity decrease located in the hippocampus, improved localisation for conductivity changes deep in the brain and due to epilepsy by 4-17 mm, and, overall, led to a substantial improvement on image quality. This suggests that incorporation of anisotropy in numerical models used for image reconstruction is likely to improve EIT image quality.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Characterization of Fas (Apo-1, CD95)-Fas ligand interaction.

The death-inducing receptor Fas is activated when cross-linked by the type II membrane protein Fas ligand (FasL). When human soluble FasL (sFasL, containing the extracellular portion) was expressed in human embryo kidney 293 cells, the three N-linked glycans of each FasL monomer were found to be essential for efficient secretion. Based on the structure of the closely related lymphotoxin alpha-tumor necrosis factor receptor I complex, a molecular model of the FasL homotrimer bound to three Fas molecules was generated using knowledge-based protein modeling methods. Point mutations of amino acid residues predicted to affect the receptor-ligand interaction were introduced at three sites. The F275L mutant, mimicking the loss of function murine gld mutation, exhibited a high propensity for aggregation and was unable to bind to Fas. Mutants P206R, P206D, and P206F displayed reduced cytotoxicity toward Fas-positive cells with a concomitant decrease in the binding affinity for the recombinant Fas-immunoglobulin Fc fusion proteins. Although the cytotoxic activity of mutant Y218D was unaltered, mutant Y218R was inactive, correlating with the prediction that Tyr-218 of FasL interacts with a cluster of three basic amino acid side chains of Fas. Interestingly, mutant Y218F could induce apoptosis in murine, but not human cells.

Learning through Computer Model Improvisations

It has been convincingly argued that computer simulation modeling differs from traditional science. If we understand simulation modeling as a new way of doing science, the manner in which scientists learn about the world through models must also be considered differently. This article examines how researchers learn about environmental processes through computer simulation modeling. Suggesting a conceptual framework anchored in a performative philosophical approach, we examine two modeling projects undertaken by research teams in England, both aiming to inform flood risk management. One of the modeling teams operated in the research wing of a consultancy firm, the other were university scientists taking part in an interdisciplinary project experimenting with public engagement. We found that in the first context the use of standardized software was critical to the process of improvisation, the obstacles emerging in the process concerned data and were resolved through exploiting affordances for generating, organizing, and combining scientific information in new ways. In the second context, an environmental competency group, obstacles were related to the computer program and affordances emerged in the combination of experience-based knowledge with the scientists' skill enabling a reconfiguration of the mathematical structure of the model, allowing the group to learn about local flooding.

Using Pareto optimality to explore the topology and dynamics of the human connectome.

Graph theory has provided a key mathematical framework to analyse the architecture of human brain networks. This architecture embodies an inherently complex relationship between connection topology, the spatial arrangement of network elements, and the resulting network cost and functional performance. An exploration of these interacting factors and driving forces may reveal salient network features that are critically important for shaping and constraining the brain's topological organization and its evolvability. Several studies have pointed to an economic balance between network cost and network efficiency with networks organized in an 'economical' small-world favouring high communication efficiency at a low wiring cost. In this study, we define and explore a network morphospace in order to characterize different aspects of communication efficiency in human brain networks. Using a multi-objective evolutionary approach that approximates a Pareto-optimal set within the morphospace, we investigate the capacity of anatomical brain networks to evolve towards topologies that exhibit optimal information processing features while preserving network cost. This approach allows us to investigate network topologies that emerge under specific selection pressures, thus providing some insight into the selectional forces that may have shaped the network architecture of existing human brains.

Preferred Spatial Frequencies for Human Face Processing Are Associated with Optimal Class Discrimination in the Machine

Psychophysical studies suggest that humans preferentially use a narrow band of low spatial frequencies for face recognition. Here we asked whether artificial face recognition systems have an improved recognition performance at the same spatial frequencies as humans. To this end, we estimated recognition performance over a large database of face images by computing three discriminability measures: Fisher Linear Discriminant Analysis, Non-Parametric Discriminant Analysis, and Mutual Information. In order to address frequency dependence, discriminabilities were measured as a function of (filtered) image size. All three measures revealed a maximum at the same image sizes, where the spatial frequency content corresponds to the psychophysical found frequencies. Our results therefore support the notion that the critical band of spatial frequencies for face recognition in humans and machines follows from inherent properties of face images, and that the use of these frequencies is associated with optimal face recognition performance.

Cooperative and Competitive Spreading Dynamics on the Human Connectome.

Increasingly detailed data on the network topology of neural circuits create a need for theoretical principles that explain how these networks shape neural communication. Here we use a model of cascade spreading to reveal architectural features of human brain networks that facilitate spreading. Using an anatomical brain network derived from high-resolution diffusion spectrum imaging (DSI), we investigate scenarios where perturbations initiated at seed nodes result in global cascades that interact either cooperatively or competitively. We find that hub regions and a backbone of pathways facilitate early spreading, while the shortest path structure of the connectome enables cooperative effects, accelerating the spread of cascades. Finally, competing cascades become integrated by converging on polysensory associative areas. These findings show that the organizational principles of brain networks shape global communication and facilitate integrative function.

The role of ubiquitin specific peptidase 15 (USP 15) in human glioblastoma

Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumour. Despite the aggressiveness of the applied therapy, the prognosis remains poor with a median survival to of about 15 months. It is important to identify new candidate genes that could have clinical application in this disease. Previous gene expression studies from human GBM samples in our laboratory, revealed Ubiquitin Specific Peptidase 15 (USP15) as a gene with low expression, significantly associated with genomic deletions of the chromosomal region encompassing the USP15 locus. USP15 belongs to the ubiquitin-specific protease (USPs) family of which the main role is the reversion of ubiquitination and thereby stabilization of substrates. Previously, USP15 has been suggested to have a tumour suppressor function via its substrates APC and Caspase 3. We established GBM cell lines that stably express USP15 wt or its catalytic mutant. USP15 expression impairs cell growth by inhibiting cell cycle progression. On the other hand USP15 depletion in GBM cell lines induces cell cycle progression and proliferation. In order to identify the molecular pathways in which USP15 is implicated we aimed to identify protein-binding partners in the GBM cell line LN-229 by Mass spectrometry. As a result we identified eight new proteins that interact with USP15. These proteins are involved in important cellular processes like cytokinesis, cell cycle, cellular migration, and apoptosis. Three of these protein interactions were confirmed by co-immunoprecipitation in four GBM cell lines LN-229, LN428, LN18, LN-Z308. One of the binding proteins is HECTD1 E3 ligase of which the murine homologue promotes the APC-Axin interaction to negatively regulate the Wnt pathway. USP15 can de-ubiquitinate HECTD1 in the LN229 cell line while its depletion led to decrease of HECTD1 in GBM cell lines suggesting stabilizing role for USP15. Moreover, HECTD1 stable expression in LN229 inhibits cell cycle, while its depletion induces cell cycle progression. These results suggest that the USP15-HECTD1 interaction might enhance the antiproliferative effect of HECTD1 in GBM cell lines. Using the TOPflash/FOPflash luciferase system we showed that HECTD1 and USP15 overexpression can attenuate WNT pathway activity, and decrease the Axin2 expression. These data indicate that this new protein interaction of USP15 with HECTD1 results in negative regulation of the WNT pathway in GBM cell lines. Further investigation of the regulation of this interaction or of the protein binding network of HECTD1 in GBM may allow the discovery of new therapeutic targets. Finally PTPIP51 and KIF15 are the other two identified protein partners of USP15. These two proteins are involved in cell proliferation and their depletion in LN-229 cell line led to induction of cell cycle progression. USP15 displays a stabilizing role for them. Hence, these results show that the tumour suppressive role of USP15 in GBM cell line via different molecular mechanisms indicating the multidimensional function of USP15. Résumé Le glioblastome (GBM) est la tumeur primaire la plus fréquente et la plus agressive du cervau caractérisée par une survie médiane d'environ à 15 mois. De précédant travaux effectués au sein de notre laboratoire portant sur l'étude de l'expression de gènes pour des échantillons humains de GBM ont montré que le gène Ubiquitin Specific Peptidase 15 (USP1S) était significativement associée à une délétion locales à 25% des cas. Initialement, les substrats protéiques APC et CaspaseS de USP15 ont conduit à considérer cette protéine comme un suppresseur de tumeur. USP15 appartient à la famille protèsse spécifique de l'ubiquitine (USPs) dont le rôle principal est la réversion de l'ubiquitination et la stabilisation de substrats. Par conséquent, nous avons établi des lignées de cellules de glioblastome qui expriment de manière stable USP15 ou bien son mutant catalytique. Ainsi, nous avons ainsi démontré que l'expression de l'USP15 empêche la croissance cellulaire en inhibant la progression du cycle cellulaire. Inversement, la suppression de l'expression du gène USP15 dans les lignées cellulaires de glioblastome induit la progression du cycle cellulaire et la prolifération. Afin d'identifier les voies moléculaires dans lesquelles sont impliquées USP15, nous avons cherché à identifier les partenaires de liaisons protéiques par spectrométrie de masse dans la lignée cellulaire LN-229. Ainsi, huit nouvelles protéines interagissant avec USP15 ont été identifiées dont la ligase E3 HECTD1. L'homologue murin de Hectdl favorise l'interaction APC-Axin en régulant négativement la voie de signalisation de Wnt. USP15 interagit en désubiquitinant HECTD1 dans la lignée cellulaire LN-229 et provoque ainsi l'atténuation de l'activité de cette voie de signalisation. En conclusion, HECTD1, en interagissant avec USP15, joue un rôle de suppresseur de tumeur dans les lignées cellulaire de GBM.

The role of intramolecular barriers on the glass transition of polymers: computer simulations versus mode coupling theory

We present computer simulations of a simple bead-spring model for polymer melts with intramolecular barriers. By systematically tuning the strength of the barriers, we investigate their role on the glass transition. Dynamic observables are analyzed within the framework of the mode coupling theory (MCT). Critical nonergodicity parameters, critical temperatures, and dynamic exponents are obtained from consistent fits of simulation data to MCT asymptotic laws. The so-obtained MCT λ-exponent increases from standard values for fully flexible chains to values close to the upper limit for stiff chains. In analogy with systems exhibiting higher-order MCT transitions, we suggest that the observed large λ-values arise form the interplay between two distinct mechanisms for dynamic arrest: general packing effects and polymer-specific intramolecular barriers. We compare simulation results with numerical solutions of the MCT equations for polymer systems, within the polymer reference interaction site model (PRISM) for static correlations. We verify that the approximations introduced by the PRISM are fulfilled by simulations, with the same quality for all the range of investigated barrier strength. The numerical solutions reproduce the qualitative trends of simulations for the dependence of the nonergodicity parameters and critical temperatures on the barrier strength. In particular, the increase in the barrier strength at fixed density increases the localization length and the critical temperature. However the qualitative agreement between theory and simulation breaks in the limit of stiff chains. We discuss the possible origin of this feature.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

The structure of human tRNALys3 anticodon bound to HIV genome is stabilized by modified nucleosides and adjacent mismatch base pairs

Replication of human immunodeficiency virus (HIV) requires base pairing of the reverse transcriptase primer, human tRNA(Lys3), to the viral RNA. Although the major complementary base pairing occurs between the HIV primer binding sequence (PBS) and the tRNA's 3'-terminus, an important discriminatory, secondary contact occurs between the viral A-rich Loop I, 5'-adjacent to the PBS, and the modified, U-rich anticodon domain of tRNA(Lys3). The importance of individual and combined anticodon modifications to the tRNA/HIV-1 Loop I RNA's interaction was determined. The thermal stabilities of variously modified tRNA anticodon region sequences bound to the Loop I of viral sub(sero)types G and B were analyzed and the structure of one duplex containing two modified nucleosides was determined using NMR spectroscopy and restrained molecular dynamics. The modifications 2-thiouridine, s(2)U(34), and pseudouridine, Psi(39), appreciably stabilized the interaction of the anticodon region with the viral subtype G and B RNAs. The structure of the duplex results in two coaxially stacked A-form RNA stems separated by two mismatched base pairs, U(162)*Psi(39) and G(163)*A(38), that maintained a reasonable A-form helix diameter. The tRNA's s(2)U(34) stabilized the interaction between the A-rich HIV Loop I sequence and the U-rich anticodon, whereas the tRNA's Psi(39) stabilized the adjacent mismatched pairs.

A new multidisciplinary home care telemedicine system to monitor stable chronic human immunodeficiency virus-infected patients: a randomized study.

Background: Antiretroviral therapy has changed the natural history of human immunodeficiency virus (HIV) infection in developed countries, where it has become a chronic disease. This clinical scenario requires a new approach to simplify follow-up appointments and facilitate access to healthcare professionals. Methodology: We developed a new internet-based home care model covering the entire management of chronic HIV-infected patients. This was called Virtual Hospital. We report the results of a prospective randomised study performed over two years, comparing standard care received by HIV-infected patients with Virtual Hospital care. HIV-infected patients with access to a computer and broadband were randomised to be monitored either through Virtual Hospital (Arm I) or through standard care at the day hospital (Arm II). After one year of follow up, patients switched their care to the other arm. Virtual Hospital offered four main services: Virtual Consultations, Telepharmacy, Virtual Library and Virtual Community. A technical and clinical evaluation of Virtual Hospital was carried out. Findings: Of the 83 randomised patients, 42 were monitored during the first year through Virtual Hospital (Arm I) and 41 through standard care (Arm II). Baseline characteristics of patients were similar in the two arms. The level of technical satisfaction with the virtual system was high: 85% of patients considered that Virtual Hospital improved their access to clinical data and they felt comfortable with the videoconference system. Neither clinical parameters [level of CD4 + T lymphocytes, proportion of patients with an undetectable level of viral load (p = 0.21) and compliance levels 90% (p = 0.58)] nor the evaluation of quality of life or psychological questionnaires changed significantly between the two types of care. Conclusions: Virtual Hospital is a feasible and safe tool for the multidisciplinary home care of chronic HIV patients. Telemedicine should be considered as an appropriate support service for the management of chronic HIV infection.

A statistical shape model of the human second cervical vertebra.

PURPOSE: Statistical shape and appearance models play an important role in reducing the segmentation processing time of a vertebra and in improving results for 3D model development. Here, we describe the different steps in generating a statistical shape model (SSM) of the second cervical vertebra (C2) and provide the shape model for general use by the scientific community. The main difficulties in its construction are the morphological complexity of the C2 and its variability in the population. METHODS: The input dataset is composed of manually segmented anonymized patient computerized tomography (CT) scans. The alignment of the different datasets is done with the procrustes alignment on surface models, and then, the registration is cast as a model-fitting problem using a Gaussian process. A principal component analysis (PCA)-based model is generated which includes the variability of the C2. RESULTS: The SSM was generated using 92 CT scans. The resulting SSM was evaluated for specificity, compactness and generalization ability. The SSM of the C2 is freely available to the scientific community in Slicer (an open source software for image analysis and scientific visualization) with a module created to visualize the SSM using Statismo, a framework for statistical shape modeling. CONCLUSION: The SSM of the vertebra allows the shape variability of the C2 to be represented. Moreover, the SSM will enable semi-automatic segmentation and 3D model generation of the vertebra, which would greatly benefit surgery planning.