8,064 research outputs found
alpha-xone/xbbg: Custom config and etc. for reference exchange (author hceh)
No full textIntuitive Bloomberg data AP
Comorbidity Analysis of Data from Psychiatric Disorder Patients with Polygenic Risk Scores and Potential Causal Effect of Single Nucleotide Polymorphisms
No full textContribution of syndecans to cellular uptake and fibrillation of alpha-synuclein and tau
No full textScientific evidence suggests that alpha-synuclein and tau have prion-like properties and that prionlike spreading and seeding of misfolded protein aggregates constitutes a central mechanism for neurodegeneration. Heparan sulfate proteoglycans (HSPGs) in the plasma membrane support this process by attaching misfolded protein fibrils. Despite of intense studies, contribution of specific HSPGs to seeding and spreading of alpha-synuclein and tau has not been explored yet. Here we report that members of the syndecan family of HSPGs mediate cellular uptake of alpha-synuclein and tau fibrils via a lipid-raft dependent and clathrin-independent endocytic route. Among syndecans, the neuron predominant syndecan-3 exhibits the highest affinity for both alpha-synuclein and tau. Syndecan-mediated internalization of alpha-synuclein and tau depends heavily on conformation as uptake via syndecans start to dominate once fibrils are formed. Overexpression of syndecans, on the other hand, reduces cellular uptake of monomeric alpha-synuclein and tau, yet exerts a fibril forming effect on both proteins. Data obtained from syndecan overexpressing cellular models presents syndecans, especially the neuron predominant syndecan-3, as important mediators of seeding and spreading of alpha-synuclein and tau and reveal how syndecans contribute to fundamental molecular events of a-synuclein and tau pathology
dsMTL: a computational framework for privacy-preserving, distributed multi-task machine learning
No full text49194926Motivation:
In multi-cohort machine learning studies, it is critical to differentiate between effects that are reproducible across cohorts and those that are cohort-specific. Multi-task learning (MTL) is a machine learning approach that facilitates this differentiation through the simultaneous learning of prediction tasks across cohorts. Since multi-cohort data can often not be combined into a single storage solution, there would be the substantial utility of an MTL application for geographically distributed data sources.
Results:
Here, we describe the development of ‘dsMTL’, a computational framework for privacy-preserving, distributed multi-task machine learning that includes three supervised and one unsupervised algorithms. First, we derive the theoretical properties of these methods and the relevant machine learning workflows to ensure the validity of the software implementation. Second, we implement dsMTL as a library for the R programming language, building on the DataSHIELD platform that supports the federated analysis of sensitive individual-level data. Third, we demonstrate the applicability of dsMTL for comorbidity modeling in distributed data. We show that comorbidity modeling using dsMTL outperformed conventional, federated machine learning, as well as the aggregation of multiple models built on the distributed datasets individually. The application of dsMTL was computationally efficient and highly scalable when applied to moderate-size (n < 500), real expression data given the actual network latency.
Availability and implementation:
dsMTL is freely available at https://github.com/transbioZI/dsMTLBase (server-side package) and https://github.com/transbioZI/dsMTLClient (client-side package).
Supplementary information:
Supplementary data are available at Bioinformatics online.382
Building multiscale computable model of Alzheimer's disease and identification of novel mechanisms for new therapeutic interventions
No full textDespite an avalanche of data in the field of biomedicine, we are obviously not managing well to extract meaningful information from this vast amount of data to better understand complex diseases and their mechanisms. Something must be wrong with the paradigmatic "let us generate new data", that drives current biomedical research. After all, we still have only a limited number of approved drugs available for many complex diseases; interpreting data and associating them with underlying molecular mechanisms of the disease is still a substantial challenge. Approaches that look into a wider perspective of the whole disease etiology as opposed to investigating on specific perturbed pathways or differentially expressed genes bear the potential to go beyond mere pattern identification. Biological networks help to achieve this goal acting as a platform to integrate heterogeneous data and a priori knowledge that may comprise various causal and correlational relationships among biological entities. These networks will lay the ground for the identification of disease mechanisms. This thesis presents a new formalism that integrate all combinations of interactions with various types of entities from different sources to understand how a single perturbance between two interactors can totally modify or amplify the changes of the whole system. As a use case, I have built the biggest computable mechanistic model of Alzheimer's disease (AD) in the course of this work. The first outcome is the identification of an early perturbed mechanism on AD based on interference with the neurotrophin signaling pathway. Secondly, I have linked SNP-associated effects to a larger functional context, which corroborates the comorbid association between AD and type 2 diabetes mellitus. Thirdly, I have systematically linked genetic and epigenetic alterations of DNA to the aetiology of diseases. Whilst the established computable model is specific to human pathophysiology, I have taken the opportunity of its existence to tackle one of the key questions of translational Alzheimer research, namely the functional equivalence of transgenic mouse models with the human disease pathophysiology. I compared the functional, mechanism inventory of a pre-clinical mouse model with the pathophysiology mechanisms that were described for humans in the area of neuro-inflammation. That analysis was extended towards pharmacology, where I analyzed – on the basis of the putative mechanism of action of a discontinued AD targeted drug; Celecoxib, - the reasons why that drug failed in the late phases of clinical trials. As I could show, the pre-clinical mouse experiments did not reflect the mechanistic context that is active in humans; which explains at mechanism-level the late failure of the drug despite promising results of the pre-clinical studies done with experimental animals. Lastly, I have used a comprehensive inventory of Alzheimer disease mechanisms to trace the investment of the pharmaceutical industry in AD drug development. I could demonstrate, how small the spectrum of candidate pathophysiology mechanisms is that the pharmaceutical industry is working on and I could show, how reluctant big pharma companies are to move from the "established targets" or "well-known pathways" into mechanisms that are novel, "ignored" or at least "not targeted" yet
Functional Characterisation of Alpha-Galactosidase A Mutations as a Basis for a New Classification System in Fabry Disease
No full textThis 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
The IPHAS catalogue of H alpha emission-line sources in the northern Galactic plane
No full textWe present a catalogue of point-source H alpha emission-line objects selected from the INT/WFC Photometric Ha Survey (IPHAS) of the northern Galactic plane. The catalogue covers the magnitude range 13 <= r' <= 19.5 and includes Northern hemisphere sources in the Galactic latitude range -5 degrees < b < 5 degrees. It is derived from similar to 1500 deg(2) worth of imaging data, which represents 80 per cent of the final IPHAS survey area. The electronic version of the catalogue will be updated once the full survey data become available. In total, the present catalogue contains 4853 point sources that exhibit strong photometric evidence for Ha emission. We have so far analysed spectra for similar to 300 of these sources, confirming more than 95 per cent of them as genuine emission-line stars. A wide range of stellar populations are represented in the catalogue, including early-type emission-line stars, active late-type stars, interacting binaries, young stellar objects and compact nebulae.
The spatial distribution of catalogue objects shows overdensities near sites of recent or current star formation, as well as possible evidence for the warp of the Galactic plane. Photometrically, the incidence of Ha emission is bimodally distributed in (r' - i'). The blue peak is made up mostly of early-type emission-line stars, whereas the red peak may signal an increasing contribution from other objects, such as young/active low-mass stars. We have cross-matched our H alpha-excess catalogue against the emission-line star catalogue of Kohoutek & Wehmeyer, as well as against sources in SIMBAD. We find that fewer than 10 per cent of our sources can be matched to known objects of any type. Thus IPHAS is uncovering an order of magnitude more faint (r' > 13) emission-line objects than were previously known in the Milky Way
Copper-Catalyzed Addition of Alkylboranes to Iminoacetates: Access to alpha-Alkyl Branched alpha-Amino Acids
No full textA copper(I)-catalyzed addition of alkylborane reagents to alpha-iminoacetates has been developed to assemble both acyclic and cyclic alpha-branched alpha-amino carboxylic acid derivatives in good yields. A wide variety of unactivated alkenes are well tolerated in this transformation
Formation of Chiral alpha-Monofluorinated-beta-amino Esters through Organocatalytic Asymmetric Reduction of alpha-Fluoro-beta-enamino Esters by Trichlorosilane
No full textA concise method was developed to prepare chiral alpha-monofluorinated-beta-amino esters through N-sulfinyl urea catalyzed asymmetric hydrosilylation of alpha-fluoro-beta-enamino esters, which affords high yields, good to high diastereoselectivities (up to>99/1), and moderate to good enantioselectivities (up to 83% ee)
Kraichnan-Leith-Batchelor similarity theory and two-dimensional inverse cascades
No full textWe study the scaling properties and Kraichnan-Leith-Batchelor (KLB) theory of forced inverse cascades in generalized two-dimensional (2D) fluids (-turbulence models) simulated at resolution . We consider (surface quasigeostrophic flow), (2D vorticity dynamics) and . The forcing scale is well-resolved, a direct cascade is present and there is no large-scale dissipation. Coherent vortices spanning a range of sizes, most larger than the forcing scale, are present for both and . The active scalar field for contains comparatively few and small vortices. The energy spectral slopes in the inverse cascade are steeper than the KLB prediction in all three systems. Since we stop the simulations well before the cascades have reached the domain scale, vortex formation and spectral steepening are not due to condensation effects; nor are they caused by large-scale dissipation, which is absent. One- and two-point pdfs, hyperflatness factors and structure functions indicate that the inverse cascades are intermittent and non-Gaussian over much of the inertial range for and , while the inverse cascade is much closer to Gaussian and non-intermittent. For the steep spectrum is close to that associated with enstrophy equipartition. Continuous wavelet analysis shows approximate KLB scaling () and () in the interstitial regions between the coherent vortices. Our results demonstrate that coherent vortex formation ( and ) and non-realizability () cause 2D inverse cascades to deviate from the KLB predictions, but that the flow between the vortices exhibits KLB scaling and non-intermittent statistics for and . The results will appear in \cite{BurgessEA2015}, which has been accepted to the \emph{Journal of Fluid Mechanics}
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