Evaluating privacy-preserving record linkage using cryptographic long-term keys and multibit trees on large medical datasets.

Background: Integrating medical data using databases from different sources by record linkage is a powerful technique increasingly used in medical research. Under many jurisdictions, unique personal identifiers needed for linking the records are unavailable. Since sensitive attributes, such as names, have to be used instead, privacy regulations usually demand encrypting these identifiers. The corresponding set of techniques for privacy-preserving record linkage (PPRL) has received widespread attention. One recent method is based on Bloom filters. Due to superior resilience against cryptographic attacks, composite Bloom filters (cryptographic long-term keys, CLKs) are considered best practice for privacy in PPRL. Real-world performance of these techniques using large-scale data is unknown up to now. Methods: Using a large subset of Australian hospital admission data, we tested the performance of an innovative PPRL technique (CLKs using multibit trees) against a gold-standard derived from clear-text probabilistic record linkage. Linkage time and linkage quality (recall, precision and F-measure) were evaluated. Results: Clear text probabilistic linkage resulted in marginally higher precision and recall than CLKs. PPRL required more computing time but 5 million records could still be de-duplicated within one day. However, the PPRL approach required fine tuning of parameters. Conclusions: We argue that increased privacy of PPRL comes with the price of small losses in precision and recall and a large increase in computational burden and setup time. These costs seem to be acceptable in most applied settings, but they have to be considered in the decision to apply PPRL. Further research on the optimal automatic choice of parameters is needed

Evaluation of rate law approximations in bottom-up kinetic models of metabolism.

BackgroundThe mechanistic description of enzyme kinetics in a dynamic model of metabolism requires specifying the numerical values of a large number of kinetic parameters. The parameterization challenge is often addressed through the use of simplifying approximations to form reaction rate laws with reduced numbers of parameters. Whether such simplified models can reproduce dynamic characteristics of the full system is an important question.ResultsIn this work, we compared the local transient response properties of dynamic models constructed using rate laws with varying levels of approximation. These approximate rate laws were: 1) a Michaelis-Menten rate law with measured enzyme parameters, 2) a Michaelis-Menten rate law with approximated parameters, using the convenience kinetics convention, 3) a thermodynamic rate law resulting from a metabolite saturation assumption, and 4) a pure chemical reaction mass action rate law that removes the role of the enzyme from the reaction kinetics. We utilized in vivo data for the human red blood cell to compare the effect of rate law choices against the backdrop of physiological flux and concentration differences. We found that the Michaelis-Menten rate law with measured enzyme parameters yields an excellent approximation of the full system dynamics, while other assumptions cause greater discrepancies in system dynamic behavior. However, iteratively replacing mechanistic rate laws with approximations resulted in a model that retains a high correlation with the true model behavior. Investigating this consistency, we determined that the order of magnitude differences among fluxes and concentrations in the network were greatly influential on the network dynamics. We further identified reaction features such as thermodynamic reversibility, high substrate concentration, and lack of allosteric regulation, which make certain reactions more suitable for rate law approximations.ConclusionsOverall, our work generally supports the use of approximate rate laws when building large scale kinetic models, due to the key role that physiologically meaningful flux and concentration ranges play in determining network dynamics. However, we also showed that detailed mechanistic models show a clear benefit in prediction accuracy when data is available. The work here should help to provide guidance to future kinetic modeling efforts on the choice of rate law and parameterization approaches

The 3′ Untranslated Region of the Rabies Virus Glycoprotein mRNA Specifically Interacts with Cellular PCBP2 Protein and Promotes Transcript Stability

Viral polymerase entry and pausing at intergenic junctions is predicted to lead to a defined polarity in the levels of rhabdovirus gene expression. Interestingly, we observed that the rabies virus glycoprotein mRNA is differentially over-expressed based on this model relative to other transcripts during infection of 293T cells. During infection, the rabies virus glycoprotein mRNA also selectively interacts with the cellular poly(rC)-binding protein 2 (PCBP2), a factor known to influence mRNA stability. Reporter assays performed both in electroporated cells and in a cell-free RNA decay system indicate that the conserved portion of the 3′ UTR of the rabies virus glycoprotein mRNA contains an RNA stability element. PCBP2 specifically interacts with reporter transcripts containing this 72 base 3′ UTR sequence. Furthermore, the PCBP2 interaction is directly associated with the stability of reporter transcripts. Therefore, we conclude that PCBP2 specifically and selectively interacts with the rabies virus glycoprotein mRNA and that this interaction may contribute to the post-transcriptional regulation of glycoprotein expression

Cascaded logic gates in nanophotonic plasmon networks

Optical computing has been pursued for decades as a potential strategy for advancing beyond the fundamental performance limitations of semiconductor-based electronic devices, but feasible on-chip integrated logic units and cascade devices have not been reported. Here we demonstrate that a plasmonic binary NOR gate, a 'universal logic gate', can be realized through cascaded OR and NOT gates in four-terminal plasmonic nanowire networks. This finding provides a path for the development of novel nanophotonic on-chip processor architectures for future optical computing technologies

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD

Bethe-hole polarization analyser for the magnetic vector of light

The nature of light as an electromagnetic wave with transverse components has been confirmed using optical polarizers, which are sensitive to the orientation of the electric field. Recent advances in nanoscale optical technologies demand their magnetic counterpart, which can sense the orientation of the optical magnetic field. Here we report that subwavelength metallic apertures on infinite plane predominantly sense the magnetic field of light, establishing the orientation of the magnetic component of light as a separate entity from its electric counterpart. A subwavelength aperture combined with a tapered optical fibre probe can also serve as a nanoscale polarization analyser for the optical magnetic field, analogous to a nanoparticle sensing the local electric polarization. As proof of its functionality, we demonstrate the measurement of a magnetic field orientation that is parallel to the electric field, as well as a circularly polarized magnetic field in the presence of a linearly polarized electric field

Tissue Type-Specific Expression of the dsRNA-Binding Protein 76 and Genome-Wide Elucidation of Its Target mRNAs

Background: RNA-binding proteins accompany all steps in the life of mRNAs and provide dynamic gene regulatory functions for rapid adjustment to changing extra-or intracellular conditions. The association of RNA-binding proteins with their targets is regulated through changing subcellular distribution, post-translational modification or association with other proteins. Methodology: We demonstrate that the dsRNA binding protein 76 (DRBP76), synonymous with nuclear factor 90, displays inherently distinct tissue type-specific subcellular distribution in the normal human central nervous system and in malignant brain tumors of glial origin. Altered subcellular localization and isoform distribution in malignant glioma indicate that tumor-specific changes in DRBP76-related gene products and their regulatory functions may contribute to the formation and/or maintenance of these tumors. To identify endogenous mRNA targets of DRBP76, we performed RNA-immunoprecipitation and genome-wide microarray analyses in HEK293 cells, and identified specific classes of transcripts encoding critical functions in cellular metabolism. Significance: Our data suggest that physiologic DRBP76 expression, isoform distribution and subcellular localization are profoundly altered upon malignant transformation. Thus, the functional role of DRBP76 in co- or post-transcriptional gene regulation may contribute to the neoplastic phenotype

The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis

EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein–protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis

A genetically anchored physical framework for Theobroma cacao cv. Matina 1-6

<p>Abstract</p> <p>Background</p> <p>The fermented dried seeds of <it>Theobroma cacao </it>(cacao tree) are the main ingredient in chocolate. World cocoa production was estimated to be 3 million tons in 2010 with an annual estimated average growth rate of 2.2%. The cacao bean production industry is currently under threat from a rise in fungal diseases including black pod, frosty pod, and witches' broom. In order to address these issues, genome-sequencing efforts have been initiated recently to facilitate identification of genetic markers and genes that could be utilized to accelerate the release of robust <it>T. cacao </it>cultivars. However, problems inherent with assembly and resolution of distal regions of complex eukaryotic genomes, such as gaps, chimeric joins, and unresolvable repeat-induced compressions, have been unavoidably encountered with the sequencing strategies selected.</p> <p>Results</p> <p>Here, we describe the construction of a BAC-based integrated genetic-physical map of the <it>T. cacao </it>cultivar Matina 1-6 which is designed to augment and enhance these sequencing efforts. Three BAC libraries, each comprised of 10× coverage, were constructed and fingerprinted. 230 genetic markers from a high-resolution genetic recombination map and 96 Arabidopsis-derived conserved ortholog set (COS) II markers were anchored using pooled overgo hybridization. A dense tile path consisting of 29,383 BACs was selected and end-sequenced. The physical map consists of 154 contigs and 4,268 singletons. Forty-nine contigs are genetically anchored and ordered to chromosomes for a total span of 307.2 Mbp. The unanchored contigs (105) span 67.4 Mbp and therefore the estimated genome size of <it>T. cacao </it>is 374.6 Mbp. A comparative analysis with <it>A. thaliana, V. vinifera</it>, and <it>P. trichocarpa </it>suggests that comparisons of the genome assemblies of these distantly related species could provide insights into genome structure, evolutionary history, conservation of functional sites, and improvements in physical map assembly. A comparison between the two <it>T. cacao </it>cultivars Matina 1-6 and Criollo indicates a high degree of collinearity in their genomes, yet rearrangements were also observed.</p> <p>Conclusions</p> <p>The results presented in this study are a stand-alone resource for functional exploitation and enhancement of <it>Theobroma cacao </it>but are also expected to complement and augment ongoing genome-sequencing efforts. This resource will serve as a template for refinement of the <it>T. cacao </it>genome through gap-filling, targeted re-sequencing, and resolution of repetitive DNA arrays.</p