The DNA damage response promotes Polyomavirus JC infection by nucleus to cytoplasm NF-Kappa B activation.

Background: Infection of glial cells by human neurotropic polyomavirus JC (JCV), the causative agent of the CNS demyelinating disease progressive multifocal leukoencephalopathy (PML), rapidly inflicts damage to cellular DNA. This activates DNA damage response (DDR) signaling including induction of expression of DNA repair factor Rad51. We previously reported that Rad51 co-operates with the transcription factor NF-κB p65 to activate JCV early transcription. Thus Rad51 induction by JCV infection may provide positive feedback for viral activation early in JCV infection. DDR is also known to stimulate NF-κB activity, a phenomenon known as nucleus to cytoplasm or “insideout” NF-κB signaling, which is initiated by Ataxia telangiectasia mutated (ATM) protein, a serine/threonine kinase recruited and activated by DNA double-strand breaks. Downstream of ATM, there occurs a series of posttranslational modifications of NF-κB essential modulator (NEMO), the γ regulatory subunit of inhibitor of NF-κB (IκB) kinase (IKK), resulting in NF-κB activation. Methods: We analyzed the effects of downstream pathways in the DDR by phosphospecific Western blots and analysis of the subcellular distribution of NEMO by cell fractionation and immunocytochemistry. The role of DDR in JCV infection was analyzed using a small molecule inhibitor of ATM (KU-55933). NEMO sumoylation was investigated by Western and association of ATM and NEMO by immunoprecipitation/Western blots. Results: We show that JCV infection caused phosphorylation and activation of ATM while KU-55933 inhibited JCV replication. JCV infection caused a redistribution of NEMO from cytoplasm to nucleus. Co-expression of JCV large Tantigen and FLAG-tagged NEMO showed the occurrence of sumoylation of NEMO, while co-expression of ATM and FLAG-NEMO demonstrated physical association between ATM and NEMO. Conclusions: We propose a model where JCV infection induces both overexpression of Rad51 protein and activation of the nucleus to cytoplasm NF-κB signaling pathway, which then act together to enhance JCV gene expression

A stereoselective hydride transfer reaction with contributions from attractive dispersion force control

The experimentally determined stereochemical outcome of an unprecedented hydride transfer from a lithium alkoxide to an aldehyde is reported, as deconvoluted by the combined use of a single enantiomer alkoxide in conjunction with a deuterium label. The stereoselective outcome is consistent with a computationally predicted transition state model stabilised by contributions from attractive dispersion forces

A Grassmannian Etude in NMHV Minors

Arkani-Hamed, Cachazo, Cheung and Kaplan have proposed a Grassmannian formulation for the S-matrix of N=4 Yang-Mills as an integral over link variables. In parallel work, the connected prescription for computing tree amplitudes in Witten's twistor string theory has also been written in terms of link variables. In this paper we extend the six- and seven-point results of arXiv:0909.0229 and arXiv:0909.0499 by providing a simple analytic proof of the equivalence between the two formulas for all tree-level NMHV superamplitudes. Also we note that a simple deformation of the connected prescription integrand gives directly the ACCK Grassmannian integrand in the limit when the deformation parameters equal zero.Comment: 17 page

Continuous heating of a giant X-ray flare on Algol

Giant flares can release large amounts of energy within a few days: X-ray emission alone can be up to ten percent of the star's bolometric luminosity. These flares exceed the luminosities of the largest solar flares by many orders of magnitude, which suggests that the underlying physical mechanisms supplying the energy are different from those on the Sun. Magnetic coupling between the components in a binary system or between a young star and an accretion disk has been proposed as a prerequisite for giant flares. Here we report X-ray observations of a giant flare on Algol B, a giant star in an eclipsing binary system. We observed a total X-ray eclipse of the flare, which demonstrates that the plasma was confined to Algol B, and reached a maximum height of 0.6 stellar radii above its surface. The flare occurred around the south pole of Algol B, and energy must have been released continously throughout its life. We conclude that a specific extrastellar environment is not required for the presence of a flare, and that the processes at work are therefore similar to those on the Sun.Comment: Nature, Sept. 2 199

Business process modelling and visualisation to support e-government decision making: Business/IS alignment

© 2017 Springer-Verlag. The final publication is available at Springer via https://doi.org/10.1007/978-3-319-57487-5_4.Alignment between business and information systems plays a vital role in the formation of dependent relationships between different departments in a government organization and the process of alignment can be improved by developing an information system (IS) according to the stakeholders’ expectations. However, establishing strong alignment in the context of the eGovernment environment can be difficult. It is widely accepted that business processes in the government environment plays a pivotal role in capturing the details of IS requirements. This paper presents a method of business process modelling through UML which can help to visualise and capture the IS requirements for the system development. A series of UML models have been developed and discussed. A case study on patient visits to a healthcare clinic in the context of eGovernment has been used to validate the models

Properties of healthcare teaming networks as a function of network construction algorithms

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: The Center for Medicare Services Outpatient Claims DE-SynPUF (DE-SynPUF)\cite{RN120} test set is publicly available from the CMS web site. The full 2013 Medicare Part B Limited Data Set for Medicare claims can be obtained from the Center for Medicare Services. This data is bound by a privacy and limited distribution agreement, as well as HIPAA regulations, and thus cannot be made public with this manuscript. However, the files can be requested from the Center for Medicare Services by individual investigators and used to reproduce our findings. Release of the derived networks is also limited by Medicare requirements to remove nodes and edges where the total number of shared patients 11 shared patients, and these are available on figshare.com as referenced in the Supplemental Data section of the manuscript.Network models of healthcare systems can be used to examine how providers collaborate, communicate, refer patients to each other, and to map how patients traverse the network of providers. Most healthcare service network models have been constructed from patient claims data, using billing claims to link a patient with a specific provider in time. The data sets can be quite large (106±108 individual claims per year), making standard methods for network construction computationally challenging and thus requiring the use of alternate construction algorithms. While these alternate methods have seen increasing use in generating healthcare networks, there is little to no literature comparing the differences in the structural properties of the generated networks, which as we demonstrate, can be dramatically different. To address this issue, we compared the properties of healthcare networks constructed using different algorithms from 2013 Medicare Part B outpatient claims data. Three different algorithms were compared: Binning, sliding frame, and trace-route. Unipartite networks linking either providers or healthcare organizations by shared patients were built using each method. We find that each algorithm produced networks with substantially different topological properties, as reflected by numbers of edges, network density, assortativity, clustering coefficients and other structural measures. Provider networks adhered to a power law, while organization networks were best fit by a power law with exponential cutoff. Censoring networks to exclude edges with less than 11 shared patients, a common de-identification practice for healthcare network data, markedly reduced edge numbers and network density, and greatly altered measures of vertex prominence such as the betweenness centrality. Data analysis identified patterns in the distance patients travel between network providers, and a striking set of teaming relationships between providers in the Northeast United States and Florida, likely due to seasonal residence patterns of Medicare beneficiaries. We conclude that the choice of network construction algorithm is critical for healthcare network analysis, and discuss the implications of our findings for selecting the algorithm best suited to the type of analysis to be performed.National Institute of HealthPhilip Templeton FoundationUniversity of Rochester Center for Health Informatic

Pyrimidine nucleosides syntheses by late-stage base heterocyclization reactions

An efficient two-step procedure for the syntheses of pyrimidine nucleosides is presented. A series of glycosyl 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives were prepared from β-anomeric isonitriles by reaction with Meldrum’s acid or by allowing aminomethylene Meldrum’s acid to react with an 1-aldofuranosyl halide or acetate. The resultant 5-(aminomethylene)-1,3-dioxane-4,6-dione derivatives underwent reaction with benzyl- or 2,4-dimethoxybenzyl isocyanate via transacylation to provide uridine-5-carboxylic acid derivatives and related nucleosides. These nucleoside carboxylic acids were converted into other C-5 derivatives by bromo-decarboxylation with N-bromosuccinimide