NOR-3, a donor of nitric oxide, increases intracellular Zn²⁺ concentration and decreases cellular thiol content: A model experiment using rat thymocytes, FluoZin-3, and 5-chloromethylfluorescein

Our previous study showed that nitroprusside, a donor of nitric oxide (NO), increased intracellular Zn2+ concentration without affecting cellular content of glutathione (GSH) although it has been proposed that the cytotoxicity of NO is resulted from its interaction with glutathione and zinc. Nitroprusside releases not only NO but also cyanides (Fe(II)CN and Fe(III)CN), CN-, Fe2+, and Fe3+. Therefore, such decomposition products may mask NO-induced action on cellular GSH content. In this study, we used NOR-3 as a donor of NO to reveal the effects of NO on intracellular Zn2+ concentration and cellular GSH content in a cytometric manner with fluorescent probes, FluoZin-3-AM and 5-chloromethylfluorescein diacetate. NOR-3 at 1-3 mM significantly increased intracellular Zn2+ concentration and decreased cellular GSH content. After the removal of extracellular Zn2+ by diethylenetriamine-N,N,N',N",N"-pentaacetic acid (DTPA, a chelator for Zn2+), the increase in intracellular Zn2+ concentration by NOR-3 was still observed although DTPA significantly attenuated the increase in intracellular Zn2+ concentration by NOR-3. Results suggest an involvement of both intracellular Zn2+ release and increase in membrane Zn2+ permeability. It is likely that NO induces oxidative stress, leading to an increase in intracellular Zn2+ concentration

Constraining compressed supersymmetry using leptonic signatures

We study the impact of the multi-lepton searches at the LHC on supersymmetric models with compressed mass spectra. For such models the acceptances of the usual search strategies are significantly reduced due to requirement of large effective mass and missing E_T. On the other hand, lepton searches do have much lower thresholds for missing E_T and p_T of the final state objects. Therefore, if a model with a compressed mass spectrum allows for multi-lepton final states, one could derive constraints using multi-lepton searches. For a class of simplified models we study the exclusion limits using ATLAS multi-lepton search analyses for the final states containing 2-4 electrons or muons with a total integrated luminosity of 1-2/fb at \sqrt{s}=7 TeV. We also modify those analyses by imposing additional cuts, so that their sensitivity to compressed supersymmetric models increase. Using the original and modified analyses, we show that the exclusion limits can be competitive with jet plus missing E_T searches, providing exclusion limits up to gluino masses of 1 TeV. We also analyse the efficiencies for several classes of events coming from different intermediate state particles. This allows us to assess exclusion limits in similar class of models with different cross sections and branching ratios without requiring a Monte Carlo simulation.Comment: 18 pages, 5 figure

A prospective compound screening contest identified broader inhibitors for Sirtuin 1

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified

Pathway Projector: Web-Based Zoomable Pathway Browser Using KEGG Atlas and Google Maps API

BACKGROUND: Biochemical pathways provide an essential context for understanding comprehensive experimental data and the systematic workings of a cell. Therefore, the availability of online pathway browsers will facilitate post-genomic research, just as genome browsers have contributed to genomics. Many pathway maps have been provided online as part of public pathway databases. Most of these maps, however, function as the gateway interface to a specific database, and the comprehensiveness of their represented entities, data mapping capabilities, and user interfaces are not always sufficient for generic usage. METHODOLOGY/PRINCIPAL FINDINGS: We have identified five central requirements for a pathway browser: (1) availability of large integrated maps showing genes, enzymes, and metabolites; (2) comprehensive search features and data access; (3) data mapping for transcriptomic, proteomic, and metabolomic experiments, as well as the ability to edit and annotate pathway maps; (4) easy exchange of pathway data; and (5) intuitive user experience without the requirement for installation and regular maintenance. According to these requirements, we have evaluated existing pathway databases and tools and implemented a web-based pathway browser named Pathway Projector as a solution. CONCLUSIONS/SIGNIFICANCE: Pathway Projector provides integrated pathway maps that are based upon the KEGG Atlas, with the addition of nodes for genes and enzymes, and is implemented as a scalable, zoomable map utilizing the Google Maps API. Users can search pathway-related data using keywords, molecular weights, nucleotide sequences, and amino acid sequences, or as possible routes between compounds. In addition, experimental data from transcriptomic, proteomic, and metabolomic analyses can be readily mapped. Pathway Projector is freely available for academic users at (http://www.g-language.org/PathwayProjector/)