Oligomerization of amyloid Abeta peptides using hydrogen bonds and hydrophobicity forces

The 16-22 amino acid fragment of the beta-amyloid peptide associated with the Alzheimer's disease, Abeta, is capable of forming amyloid fibrils. Here we study the aggregation mechanism of Abeta(16-22) peptides by unbiased thermodynamic simulations at the atomic level for systems of one, three and six Abeta(16-22) peptides. We find that the isolated Abeta(16-22) peptide is mainly a random coil in the sense that both the alpha-helix and beta-strand contents are low, whereas the three- and six-chain systems form aggregated structures with a high beta-sheet content. Furthermore, in agreement with experiments on Abeta(16-22) fibrils, we find that large parallel beta-sheets are unlikely to form. For the six-chain system, the aggregated structures can have many different shapes, but certain particularly stable shapes can be identified.Comment: 19 pages, 7 figures (to appear in Biophys. J.

Fibril elongation mechanisms of HET-s prion-forming domain: Topological evidence for growth polarity

The prion-forming C-terminal domain of the fungal prion HET-s forms infectious amyloid fibrils at physiological pH. The conformational switch from the non-prion soluble form to the prion fibrillar form is believed to have a functional role, since HET-s in its prion form participates in a recognition process of different fungal strains. Based on the knowledge of the high-resolution structure of HET-s(218-289) (the prion forming-domain) in its fibrillar form, we here present a numerical simulation of the fibril growth process which emphasizes the role of the topological properties of the fibrillar structure. An accurate thermodynamic analysis of the way an intervening HET-s chain is recruited to the tip of the growing fibril suggests that elongation proceeds through a dock and lock mechanism. First, the chain docks onto the fibril by forming the longest $\beta$-strands. Then, the re-arrangement in the fibrillar form of all the rest of molecule takes place. Interestingly, we predict also that one side of the HET-s fibril is more suitable for substaining its growth with respect to the other. The resulting strong polarity of fibril growth is a consequence of the complex topology of HET-s fibrillar structure, since the central loop of the intervening chain plays a crucially different role in favouring or not the attachment of the C-terminus tail to the fibril, depending on the growth side.Comment: 16 pages, 10 figure

The 'not-so-strange' body in the mirror: : A principal components analysis of direct and mirror self-observation

This document is the Accepted Manuscript version of the following article: Paul M. Jenkinson, and Catherine Preston, ‘The “not-so-strange” body in the mirror: A principal components analysis of direct and mirror self-observation’, Consciousness and Cognition, Vol. 48, pp. 262-272, first published online 4 January 2017, doi: http://dx.doi.org/10.1016/j.concog.2016.12.007 This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.In this study we adopted a psychometric approach to examine how the body is subjectively experienced in a mirror. One hundred and twenty-four healthy participants viewed their body for five minutes directly or via a mirror, and then completed a 20-item questionnaire designed to capture subjective experiences of the body. PCA revealed a two-component structure for both direct and mirror conditions, comprising body evaluations (and alienation) and unusual feelings and perceptions. The relationship between these components and pre-existing tendencies for appearance anxiety, body dysmorphic-type beliefs, dissociative symptomatology, self-objectification and delusion ideation further supported the similarity between direct and mirror conditions; however, the occurrence of strange experiences like those reported to occur during prolonged face viewing was not confirmed. These results suggest that, despite obvious differences in visual feedback, observing the body via a mirror (as an outside observer) is subjectively equivalent to observing the body directly (from our own viewpoint).Peer reviewedFinal Accepted Versio

Molecular Structures of Quiescently Grown and Brain-Derived Polymorphic Fibrils of the Alzheimer Amyloid Aβ9-40 Peptide: A Comparison to Agitated Fibrils

The presence of amyloid deposits consisting primarily of Amyloid-β (Aβ) fibril in the brain is a hallmark of Alzheimer's disease (AD). The morphologies of these fibrils are exquisitely sensitive to environmental conditions. Using molecular dynamics simulations combined with data from previously published solid-state NMR experiments, we propose the first atomically detailed structures of two asymmetric polymorphs of the Aβ9-40 peptide fibril. The first corresponds to synthetic fibrils grown under quiescent conditions and the second to fibrils derived from AD patients' brain-extracts. Our core structure in both fibril structures consists of a layered structure in which three cross-β subunits are arranged in six tightly stacked β-sheet layers with an antiparallel hydrophobic-hydrophobic and an antiparallel polar-polar interface. The synthetic and brain-derived structures differ primarily in the side-chain orientation of one β-strand. The presence of a large and continually exposed hydrophobic surface (buried in the symmetric agitated Aβ fibrils) may account for the higher toxicity of the asymmetric fibrils. Our model explains the effects of external perturbations on the fibril lateral architecture as well as the fibrillogenesis inhibiting action of amphiphilic molecules

Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects

[EN] The ability of virtual reality (VR) to recreate controlled, immersive, and interactive environments that provide intensive and customized exercises has motivated its therapeutic use after stroke. Interaction and bodily presence in VR-based interventions is usually mediated through virtual selves, which synchronously represent body movements or responses to events on external input devices. Embodied self-representations in the virtual world not only provide an anchor for visuomotor tasks, but their morphologies can have behavioral implications. While research has focused on the underlying subjective mechanisms of exposure to VR on healthy individuals, the transference of these findings to individuals with stroke is not evident and remains unexplored, which could affect the experience and, ultimately, the clinical effectiveness of neurorehabilitation interventions. This study determined and compared the sense of embodiment and presence elicited by a virtual environment under different perspectives and levels of immersion in healthy subjects and individuals with stroke. Forty-six healthy subjects and 32 individuals with stroke embodied a gender-matched neutral avatar in a virtual environment that was displayed in a first-person perspective with a head-mounted display and in a third-person perspective with a screen, and the participants were asked to interact in a virtual task for 10 min under each condition in counterbalanced order, and to complete two questionnaires about the sense of embodiment and presence experienced during the interaction. The sense of body-ownership, self-location, and presence were more vividly experienced in a first-person than in a third-person perspective by both healthy subjects (p < 0.001, eta(2)(p) = 0.212; p = 0.005, eta(2)(p) = 0.101; p = 0.001, eta(2)(p) = 0.401, respectively) and individuals with stroke (p = 0.019, eta(2)(p) = 0.070; p = 0.001, eta(2)(p) = 0.135; p = 0.014, eta(2)(p) = 0.077, respectively). In contrast, no agency perspective-related differences were found in any group. All measures were consistently higher for healthy controls than for individuals with stroke, but differences between groups only reached statistical significance in presence under the first-person condition (p < 0.010, eta(2)(p) = 0.084). In spite of these differences, the participants experienced a vivid sense of embodiment and presence in almost all conditions. These results provide first evidence that, although less intensively, embodiment and presence are similarly experienced by individuals who have suffered a stroke and by healthy individuals, which could support the vividness of their experience and, consequently, the effectiveness of VR-based interventions.This study was funded by Ministerio de Economía y Competitividad of Spain (Project RTC-2017-6051-7 and Grant BES-2014-068218), Fundació la Marató de la TV3 (Grant 201701-10), and Universitat Politècnica de València (Grant PAID-10-18). We acknowledge the support of NVIDIA Corporation with the donation of the Titan Xp GPU used for this research.Borrego, A.; Latorre, J.; Alcañiz Raya, ML.; Llorens Rodríguez, R. (2019). Embodiment and Presence in Virtual Reality After Stroke. A Comparative Study With Healthy Subjects. Frontiers in Neurology. 10:1-8. https://doi.org/10.3389/fneur.2019.01061S1810Berlucchi, G., & Aglioti, S. (1997). 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Consciousness and Cognition, 36, 277-288. doi:10.1016/j.concog.2015.07.008Kilteni, K., Maselli, A., Kording, K. P., & Slater, M. (2015). Over my fake body: body ownership illusions for studying the multisensory basis of own-body perception. Frontiers in Human Neuroscience, 9. doi:10.3389/fnhum.2015.00141Clark, A., Kiverstein, J., & Vierkant, T. (Eds.). (2013). Decomposing the Will. doi:10.1093/acprof:oso/9780199746996.001.0001Frith, C. D., Blakemore, S.-J., & Wolpert, D. M. (2000). Abnormalities in the awareness and control of action. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 355(1404), 1771-1788. doi:10.1098/rstb.2000.0734Bermúdez i Badia, S., Fluet, G. G., Llorens, R., & Deutsch, J. E. (2016). Virtual Reality for Sensorimotor Rehabilitation Post Stroke: Design Principles and Evidence. Neurorehabilitation Technology, 573-603. doi:10.1007/978-3-319-28603-7_28Perez-Marcos, D., Sanchez-Vives, M. V., & Slater, M. (2011). Is my hand connected to my body? The impact of body continuity and arm alignment on the virtual hand illusion. Cognitive Neurodynamics, 6(4), 295-305. doi:10.1007/s11571-011-9178-5IJsselsteijn, W. A., de Kort, Y. A. W., & Haans, A. (2006). Is This My Hand I See Before Me? The Rubber Hand Illusion in Reality, Virtual Reality, and Mixed Reality. Presence: Teleoperators and Virtual Environments, 15(4), 455-464. doi:10.1162/pres.15.4.455Banakou, D., Groten, R., & Slater, M. (2013). Illusory ownership of a virtual child body causes overestimation of object sizes and implicit attitude changes. Proceedings of the National Academy of Sciences, 110(31), 12846-12851. doi:10.1073/pnas.1306779110Yee, N., & Bailenson, J. (2007). The Proteus Effect: The Effect of Transformed Self-Representation on Behavior. Human Communication Research, 33(3), 271-290. doi:10.1111/j.1468-2958.2007.00299.xSteed, A., Frlston, S., Lopez, M. M., Drummond, J., Pan, Y., & Swapp, D. (2016). An ‘In the Wild’ Experiment on Presence and Embodiment using Consumer Virtual Reality Equipment. IEEE Transactions on Visualization and Computer Graphics, 22(4), 1406-1414. doi:10.1109/tvcg.2016.2518135Colomer, C., Llorens, R., Noé, E., & Alcañiz, M. (2016). Effect of a mixed reality-based intervention on arm, hand, and finger function on chronic stroke. Journal of NeuroEngineering and Rehabilitation, 13(1). doi:10.1186/s12984-016-0153-6Laver, K. E., Lange, B., George, S., Deutsch, J. E., Saposnik, G., & Crotty, M. (2017). Virtual reality for stroke rehabilitation. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd008349.pub4Llorens, R., Borrego, A., Palomo, P., Cebolla, A., Noé, E., i Badia, S. B., & Baños, R. (2017). Body schema plasticity after stroke: Subjective and neurophysiological correlates of the rubber hand illusion. Neuropsychologia, 96, 61-69. doi:10.1016/j.neuropsychologia.2017.01.007Zeller, D., Gross, C., Bartsch, A., Johansen-Berg, H., & Classen, J. (2011). Ventral Premotor Cortex May Be Required for Dynamic Changes in the Feeling of Limb Ownership: A Lesion Study. Journal of Neuroscience, 31(13), 4852-4857. doi:10.1523/jneurosci.5154-10.2011Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Romero, M., Sánchez, A., Marín, C., Navarro, M. D., Ferri, J., & Noé, E. (2012). Clinical usefulness of the Spanish version of the Mississippi Aphasia Screening Test (MASTsp): validation in stroke patients. Neurología (English Edition), 27(4), 216-224. doi:10.1016/j.nrleng.2011.06.001Latorre, J., Llorens, R., Colomer, C., & Alcañiz, M. (2018). Reliability and comparison of Kinect-based methods for estimating spatiotemporal gait parameters of healthy and post-stroke individuals. Journal of Biomechanics, 72, 268-273. doi:10.1016/j.jbiomech.2018.03.008Lloréns, R., Noé, E., Naranjo, V., Borrego, A., Latorre, J., & Alcañiz, M. (2015). Tracking Systems for Virtual Rehabilitation: Objective Performance vs. Subjective Experience. A Practical Scenario. Sensors, 15(3), 6586-6606. doi:10.3390/s150306586Slater, M., & Steed, A. (2000). A Virtual Presence Counter. Presence: Teleoperators and Virtual Environments, 9(5), 413-434. doi:10.1162/105474600566925Slater, M., Spanlang, B., Sanchez-Vives, M. V., & Blanke, O. (2010). First Person Experience of Body Transfer in Virtual Reality. PLoS ONE, 5(5), e10564. doi:10.1371/journal.pone.0010564Petkova, V. I., Khoshnevis, M., & Ehrsson, H. H. (2011). The Perspective Matters! Multisensory Integration in Ego-Centric Reference Frames Determines Full-Body Ownership. Frontiers in Psychology, 2. doi:10.3389/fpsyg.2011.00035Maselli, A., & Slater, M. (2013). The building blocks of the full body ownership illusion. Frontiers in Human Neuroscience, 7. doi:10.3389/fnhum.2013.00083Debarba, H. G., Molla, E., Herbelin, B., & Boulic, R. (2015). Characterizing embodied interaction in First and Third Person Perspective viewpoints. 2015 IEEE Symposium on 3D User Interfaces (3DUI). doi:10.1109/3dui.2015.7131728Burin, D., Livelli, A., Garbarini, F., Fossataro, C., Folegatti, A., Gindri, P., & Pia, L. (2015). Are Movements Necessary for the Sense of Body Ownership? Evidence from the Rubber Hand Illusion in Pure Hemiplegic Patients. PLOS ONE, 10(3), e0117155. doi:10.1371/journal.pone.0117155Post-stroke cognitive disorders TeasellR SalterK FaltynekP CotoiA EskesG Evidence-Based Review of Stroke Rehabilitatio

The onset time of the ownership sensation in the moving rubber hand illusion

The rubber hand illusion (RHI) is a perceptual illusion whereby a model hand is perceived as part of one’s own body. This illusion has been extensively studied, but little is known about the temporal evolution of this perceptual phenomenon, i.e., how long it takes until participants start to experience ownership over the model hand. In the present study, we investigated a version of the rubber hand experiment based on finger movements and measured the average onset time in active and passive movement conditions. This comparison enabled us to further explore the possible role of intentions and motor control processes that are only present in the active movement condition. The results from a large group of healthy participants (n D 117) showed that the illusion of ownership took approximately 23 s to emerge (active: 22.8; passive: 23.2). The 90th percentile occurs in both conditions within approximately 50 s (active: 50; passive: 50.6); therefore, most participants experience the illusion within the first minute. We found indirect evidence of a facilitatory effect of active movements compared to passive movements, and we discuss these results in the context of our current understanding of the processes underlying the moving RHI

Comparisons with amyloid-β reveal an aspartate residue that stabilizes fibrils of the aortic amyloid peptide medin

Aortic medial amyloid (AMA) is the most common localized human amyloid, occurring in virtually all of the Caucasian population over the age of 50. The main protein component of AMA, medin, readily assembles into amyloid-like fibrils in vitro. Despite the prevalence of AMA, little is known about the self-assembly mechanism of medin or the molecular architecture of the fibrils. The amino acid sequence of medin is strikingly similar to the sequence of the Alzheimer's disease (AD) amyloid-beta (Aβ) polypeptides around the structural turn region of Aβ where mutations associated with familial, early onset AD, have been identified. D25 and K30 of medin align with residues D23 and K28 of Aβ that are known to form a stabilizing salt bridge in some fibril morphologies. Here we show that substituting D25 of medin with asparagine (D25N) impedes assembly into fibrils and stabilizes non-cytotoxic oligomers. Wild-type medin, by contrast, aggregates into β-sheet rich amyloid-like fibrils within 50 h. A structural analysis of wild-type fibrils by solid-state NMR suggests a molecular repeat unit comprising at least two extended β-strands, separated by a turn stabilized by a D25-K30 salt-bridge. We propose that D25 drives the assembly of medin by stabilizing the fibrillar conformation of the peptide, and is thus reminiscent of the influence of D23 on the aggregation of Aβ. Pharmacological comparisons of wild-type medin and D25N will help to ascertain the pathological significance of this poorly under-stood protein

The dynamical evolution of molecular clouds near the Galactic Centre - II. Spatial structure and kinematics of simulated clouds

The evolution of molecular clouds in galactic centres is thought to differ from that in galactic discs due to a significant influence of the external gravitational potential. We present a set of numerical simulations of molecular clouds orbiting on the 100-pc stream of the Central Molecular Zone (the central $\sim500$ pc of the Galaxy) and characterise their morphological and kinematic evolution in response to the background potential and eccentric orbital motion. We find that the clouds are shaped by strong shear and torques, by tidal and geometric deformation, and by their passage through the orbital pericentre. Within our simulations, these mechanisms control cloud sizes, aspect ratios, position angles, filamentary structure, column densities, velocity dispersions, line-of-sight velocity gradients, spin angular momenta, and kinematic complexity. By comparing these predictions to observations of clouds on the Galactic Centre 'dust ridge', we find that our simulations naturally reproduce a broad range of key observed morphological and kinematic features, which can be explained in terms of well-understood physical mechanisms. We argue that the accretion of gas clouds onto the central regions of galaxies, where the rotation curve turns over and the tidal field is fully compressive, is accompanied by transformative dynamical changes to the clouds, leading to collapse and star formation. This can generate an evolutionary progression of cloud collapse with a common starting point, which either marks the time of accretion onto the tidally-compressive region or of the most recent pericentre passage. Together, these processes may naturally produce the synchronised starbursts observed in numerous (extra)galactic nuclei