Exact Occupation Time Distribution in a Non-Markovian Sequence and Its Relation to Spin Glass Models

We compute exactly the distribution of the occupation time in a discrete {\em non-Markovian} toy sequence which appears in various physical contexts such as the diffusion processes and Ising spin glass chains. The non-Markovian property makes the results nontrivial even for this toy sequence. The distribution is shown to have non-Gaussian tails characterized by a nontrivial large deviation function which is computed explicitly. An exact mapping of this sequence to an Ising spin glass chain via a gauge transformation raises an interesting new question for a generic finite sized spin glass model: at a given temperature, what is the distribution (over disorder) of the thermally averaged number of spins that are aligned to their local fields? We show that this distribution remains nontrivial even at infinite temperature and can be computed explicitly in few cases such as in the Sherrington-Kirkpatrick model with Gaussian disorder.Comment: 10 pages Revtex (two-column), 1 eps figure (included

SIRF: Synergistic Image Reconstruction Framework

The combination of positron emission tomography (PET) with magnetic resonance (MR) imaging opens the way to more accurate diagnosis and improved patient management. At present, the data acquired by PET-MR scanners are essentially processed separately, but the opportunity to improve accuracy of the tomographic reconstruction via synergy of the two imaging techniques is an active area of research. In this paper, we present Release 2.1.0 of the CCP-PETMR Synergistic Image Reconstruction Framework (SIRF) software suite, providing an open-source software platform for efficient implementation and validation of novel reconstruction algorithms. SIRF provides user-friendly Python and MATLAB interfaces built on top of C++ libraries. SIRF uses advanced PET and MR reconstruction software packages and tools. Currently, for PET this is Software for Tomographic Image Reconstruction (STIR); for MR, Gadgetron and ISMRMRD; and for image registration tools, NiftyReg. The software aims to be capable of reconstructing images from acquired scanner data, whilst being simple enough to be used for educational purposes

Harnessing a High Cargo-Capacity Transposon for Genetic Applications in Vertebrates

Viruses and transposons are efficient tools for permanently delivering foreign DNA into vertebrate genomes but exhibit diminished activity when cargo exceeds 8 kilobases (kb). This size restriction limits their molecular genetic and biotechnological utility, such as numerous therapeutically relevant genes that exceed 8 kb in size. Furthermore, a greater payload capacity vector would accommodate more sophisticated cis cargo designs to modulate the expression and mutagenic risk of these molecular therapeutics. We show that the Tol2 transposon can efficiently integrate DNA sequences larger than 10 kb into human cells. We characterize minimal sequences necessary for transposition (miniTol2) in vivo in zebrafish and in vitro in human cells. Both the 8.5-kb Tol2 transposon and 5.8-kb miniTol2 engineered elements readily function to revert the deficiency of fumarylacetoacetate hydrolase in an animal model of hereditary tyrosinemia type 1. Together, Tol2 provides a novel nonviral vector for the delivery of large genetic payloads for gene therapy and other transgenic applications

Ultrafast and high-throughput mass spectrometric assay for therapeutic drug monitoring of antiretroviral drugs in pediatric HIV-1 infection applying dried blood spots

Kaletra® (Abott Laboratories) is a co-formulated medication used in the treatment of HIV-1-infected children, and it contains the two antiretroviral protease inhibitor drugs lopinavir and ritonavir. We validated two new ultrafast and high-throughput mass spectrometric assays to be used for therapeutic drug monitoring of lopinavir and ritonavir concentrations in whole blood and in plasma from HIV-1-infected children. Whole blood was blotted onto dried blood spot (DBS) collecting cards, and plasma was collected simultaneously. DBS collecting cards were extracted by an acetonitrile/water mixture while plasma samples were deproteinized with acetone. Drug concentrations were determined by matrix-assisted laser desorption/ionization-triple quadrupole tandem mass spectrometry (MALDI-QqQ-MS/MS). The application of DBS made it possible to measure lopinavir and ritonavir in whole blood in therapeutically relevant concentrations. The MALDI-QqQ-MS/MS plasma assay was successfully cross-validated with a commonly used high-performance liquid chromatography (HPLC)–ultraviolet (UV) assay for the therapeutic drug monitoring (TDM) of HIV-1-infected patients, and it showed comparable performance characteristics. Observed DBS concentrations showed as well, a good correlation between plasma concentrations obtained by MALDI-QqQ-MS/MS and those obtained by the HPLC-UV assay. Application of DBS for TDM proved to be a good alternative to the normally used plasma screening. Moreover, collection of DBS requires small amounts of whole blood which can be easily performed especially in (very) young children where collection of large whole blood amounts is often not possible. DBS is perfectly suited for TDM of HIV-1-infected children; but nevertheless, DBS can also easily be applied for TDM of patients in areas with limited or no laboratory facilities

A Bacterial Acetyltransferase Destroys Plant Microtubule Networks and Blocks Secretion

The eukaryotic cytoskeleton is essential for structural support and intracellular transport, and is therefore a common target of animal pathogens. However, no phytopathogenic effector has yet been demonstrated to specifically target the plant cytoskeleton. Here we show that the Pseudomonas syringae type III secreted effector HopZ1a interacts with tubulin and polymerized microtubules. We demonstrate that HopZ1a is an acetyltransferase activated by the eukaryotic co-factor phytic acid. Activated HopZ1a acetylates itself and tubulin. The conserved autoacetylation site of the YopJ / HopZ superfamily, K289, plays a critical role in both the avirulence and virulence function of HopZ1a. Furthermore, HopZ1a requires its acetyltransferase activity to cause a dramatic decrease in Arabidopsis thaliana microtubule networks, disrupt the plant secretory pathway and suppress cell wall-mediated defense. Together, this study supports the hypothesis that HopZ1a promotes virulence through cytoskeletal and secretory disruption