Functional Characterisation of Alpha-Galactosidase A Mutations as a Basis for a New Classification System in Fabry Disease

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The study has been supported partially by an unrestricted scientific grant from Shire Human Genetic Therapies (Germany

Cooling dynamics of a dilute gas of inelastic rods: a many particle simulation

We present results of simulations for a dilute gas of inelastically colliding particles. Collisions are modelled as a stochastic process, which on average decreases the translational energy (cooling), but allows for fluctuations in the transfer of energy to internal vibrations. We show that these fluctuations are strong enough to suppress inelastic collapse. This allows us to study large systems for long times in the truely inelastic regime. During the cooling stage we observe complex cluster dynamics, as large clusters of particles form, collide and merge or dissolve. Typical clusters are found to survive long enough to establish local equilibrium within a cluster, but not among different clusters. We extend the model to include net dissipation of energy by damping of the internal vibrations. Inelatic collapse is avoided also in this case but in contrast to the conservative system the translational energy decays according to the mean field scaling law, E(t)\propto t^{-2}, for asymptotically long times.Comment: 10 pages, 12 figures, Latex; extended discussion, accepted for publication in Phys. Rev.

Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (A beta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates

Least - change bidirectional model transformation With QVT- R and ATL

QVT Relations (QVT-R) is the standard language proposed by the OMG to specify bidirectional model transformations. Unfortunately, in part due to ambiguities and omissions in the original semantics, acceptance and development of effective tool support has been slow. Recently, the checking semantics of QVTR has been clarified and formalized. In this article we propose a QVT-R tool that complies to such semantics. Unlike any other existing tool, it also supports metamodels enriched with OCL constraints (thus avoiding returning ill-formed models), and proposes an alternative enforcement semantics that works according to the simple and predictable “principle of least change”. The implementation is based on an embedding of both QVT-R transformations and UML class diagrams (annotated with OCL) in Alloy, a lightweight formal specification language with support for automatic model finding via SAT solving. We also show how this technique can be applied to bidirectionalize ATL, a popular (but unidirectional) model transformation language.This work is funded by ERDF-European Regional Development Fund through the COMPETE Programme (operational programme for competitiveness) and by national funds through the FCT-Fundacao para a Ciencia e a Tecnologia (Portuguese Foundation for Science and Technology) within project FCOMP-01-0124-FEDER-020532. The first author is also sponsored by FCT grant SFRH/BD/69585/2010. The authors would also like to thank all anonymous reviewers for the valuable comments and suggestions

Effects of low-dose gestational tcdd exposure on behavior and on hippocampal neuron morphology and gene expression in mice

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans.publishedVersio

Estimating Portfolio Risk for Tail Risk Protection Strategies

We forecast portfolio risk for managing dynamic tail risk protection strategies, based on extreme value theory, expectile regression, Copula-GARCH and dynamic GAS models. Utilizing a loss function that overcomes the lack of elicitability for Expected Shortfall, we propose a novel Expected Shortfall (and Value-at-Risk) forecast combination approach, which dominates simple and sophisticated standalone models as well as a simple average combination approach in modelling the tail of the portfolio return distribution. While the associated dynamic risk targeting or portfolio insurance strategies provide effective downside protection, the latter strategies suffer less from inferior risk forecasts given the defensive portfolio insurance mechanics

Angular Distribution of Auger Electrons Emitted through the Resonant Transfer and Excitation Process Following O⁵⁺+He Collisions

This Letter reports the first measurements of the angular distribution of Auger electrons emitted from the decay of the (1s2s2p2)3D O4+** doubly excited state formed predominantly through resonant transfer and excitation (RTE) in collisions of 13-MeV O5+ projectiles with He. The (1s2s2p2)3D angular distribution is strongly peaked along the beam direction, in agreement with recent calculations of the RTE angle-dependent impulse approximation. Furthermore, interference effects between the RTE and the elastic target direct-ionization channels are observed

An In Vitro Barrier Model of the Human Submandibular Salivary Gland Epithelium Based on a Single Cell Clone of Cell Line HTB-41: Establishment and Application for Biomarker Transport Studies

The blood–saliva barrier (BSB) consists of the sum of the epithelial cell layers of the oral mucosa and salivary glands. In vitro models of the BSB are inevitable to investigate and understand the transport of salivary biomarkers from blood to saliva. Up to now, standardized, cell line-based models of the epithelium of the submandibular salivary gland are still missing for this purpose. Therefore, we established epithelial barrier models of the submandibular gland derived from human cell line HTB-41 (A-253). Single clone isolation resulted in five different clones (B2, B4, B9, D3, and F11). Clones were compared to the parental cell line HTB-41 using measurements of the transepithelial electrical resistance (TEER), paracellular marker permeability assays and analysis of marker expression for acinar, ductal, and myoepithelial cells. Two clones (B9, D3) were characterized to be of acinar origin, one clone (F11) to be of myoepithelial origin and one isolation (B4) derived from two cells, to be presumably a mixture of acinar and ductal origin. Clone B2, presumably of ductal origin, showed a significantly higher paracellular barrier compared to other clones and parental HTB-41. The distinct molecular identity of clone B2 was confirmed by immunofluorescent staining, qPCR, and flow cytometry. Experiments with ferritin, a biomarker for iron storage, demonstrated the applicability of the selected model based on clone B2 for transport studies. In conclusion, five different clones originating from the submandibular gland cell line HTB-41 were successfully characterized and established as epithelial barrier models. Studies with the model based on the tightest clone B2 confirmed its suitability for transport studies in biomarker research

Ab-initio study of model guanine assemblies: The role of pi-pi coupling and band transport

Several assemblies of guanine molecules are investigated by means of first-principle calculations. Such structures include stacked and hydrogen-bonded dimers, as well as vertical columns and planar ribbons, respectively, obtained by periodically replicating the dimers. Our results are in good agreement with experimental data for isolated molecules, isolated dimers, and periodic ribbons. For stacked dimers and columns, the stability is affected by the relative charge distribution of the pi orbitals in adjacent guanine molecules. pi-pi coupling in some stacked columns induces dispersive energy bands, while no dispersion is identified in the planar ribbons along the connections of hydrogen bonds. The implications for different materials comprised of guanine aggregates are discussed. The bandstructure of dispersive configurations may justify a contribution of band transport (Bloch type) in the conduction mechanism of deoxyguanosine fibres, while in DNA-like configurations band transport should be negligible.Comment: 21 pages, 6 figures, 3 tables, to be published in Phys. Rev.

Simulation for the oblique impact of a lattice system

The oblique collision between an elastic disk and an elastic wall is numerically studied. We investigate the dependency of the tangential coefficient of restitution on the incident angle of impact. From the results of simulation, our model reproduces experimental results and can be explained by a phenomenological theory of the oblique impact.Comment: 30 pages, 9 figures, submitted to J. Phys. Soc. Japa