Potent Trivalent Inhibitors of Thrombin through Hybridization of Salivary Sulfopeptides from Hematophagous Arthropods

Blood feeding arthropods, such as leeches, ticks, flies and mosquitoes, provide a privileged source of peptidic anticoagulant molecules. These primarily operate through inhibition of the central coagulation protease thrombin by binding to the active site and either exosite I or exosite II. Herein, we describe the rational design of a novel class of trivalent thrombin inhibitors that simultaneously block both exosites as well as the active site. These engineered hybrids were synthesized using tandem diselenide-selenoester ligation (DSL) and native chemical ligation (NCL) reactions in one-pot. The most potent trivalent inhibitors possessed femtomolar inhibition constants against alpha-thrombin and were selective over related coagulation proteases. A lead hybrid inhibitor possessed potent anticoagulant activity, blockade of both thrombin generation and platelet aggregation in vitro and efficacy in a murine thrombosis model at 1 mg kg(-1). The rational engineering approach described here lays the foundation for the development of potent and selective inhibitors for a range of other enzymatic targets that possess multiple sites for the disruption of protein-protein interactions, in addition to an active site

Constraints on the Ultra High Energy Photon flux using inclined showers from the Haverah Park array

We describe a method to analyse inclined air showers produced by ultra high energy cosmic rays using an analytical description of the muon densities. We report the results obtained using data from inclined events (60^{\circ}<\theta<80^{\circ}) recorded by the Haverah Park shower detector for energies above 10^19 eV. Using mass independent knowledge of the UHECR spectrum obtained from vertical air shower measurements and comparing the expected horizontal shower rate to the reported measurements we show that above 10^19 eV less than 48 % of the primary cosmic rays can be photons at the 95 % confidence level and above 4 X 10^19 eV less than 50 % of the cosmic rays can be photonic at the same confidence level. These limits place important constraints on some models of the origin of ultra high-energy cosmic rays.Comment: 45 pages, 25 figure

Solution of coupled vertex and propagator Dyson-Schwinger equations in the scalar Munczek-Nemirovsky model

In a scalar $\phi^2\chi$ model, we exactly solve the vertex and $\phi$ propagator Dyson-Schwinger equations under the assumption of a spatially constant (Munczek-Nemirovsky) propagator for the $\chi$ field. Various truncation schemes are also considered.Comment: 7 pages,4 figures, minor changes, reference added for published versio

Nucleon axial and pseudoscalar form factors from the covariant Faddeev equation

We compute the axial and pseudoscalar form factors of the nucleon in the Dyson-Schwinger approach. To this end, we solve a covariant three-body Faddeev equation for the nucleon wave function and determine the matrix elements of the axialvector and pseudoscalar isotriplet currents. Our only input is a well-established and phenomenologically successful ansatz for the nonperturbative quark-gluon interaction. As a consequence of the axial Ward-Takahashi identity that is respected at the quark level, the Goldberger-Treiman relation is reproduced for all current-quark masses. We discuss the timelike pole structure of the quark-antiquark vertices that enters the nucleon matrix elements and determines the momentum dependence of the form factors. Our result for the axial charge underestimates the experimental value by 20-25% which might be a signal of missing pion-cloud contributions. The axial and pseudoscalar form factors agree with phenomenological and lattice data in the momentum range above Q^2 ~ 1...2 GeV^2.Comment: 17 pages, 7 figures, 1 tabl

Expressed Protein Selenoester Ligation

Herein, we describe the development and application of a novel expressed protein selenoester ligation (EPSL) methodology for the one-pot semi-synthesis of modified proteins. EPSL harnesses the rapid kinetics of ligation reactions between modified synthetic selenopeptides and protein aryl selenoesters (generated from expressed intein fusion precursors) followed by in situ chemoselective deselenization to afford target proteins at concentrations that preclude the use of traditional ligation methods. The utility of the EPSL technology is showcased through the efficient semi-synthesis of ubiquitinated polypeptides, lipidated analogues of the membrane-associated GTPase YPT6, and site-specifically phosphorylated variants of the oligomeric chaperone protein Hsp27 at high dilution.Sameer S. Kulkarni, Emma E. Watson, Joshua W. C. Maxwell, Gerhard Niederacher, Jason Johansen-Leete, Susanne Huhmann, Somnath Mukherjee, Alexander R. Norman, Julia Kriegesmann, Christian F. W. Becker, and Richard J. Payn

Towards a Criminology of the Domestic

Criminology has paid insufficient attention to the ‘domestic’ arena, as a locale that is being reconfigured through technological and social developments in ways that require us to reconsider offending and victimisation. This article addresses this lacuna. We take up Campbell's (2016) challenge that criminology needs to develop more sophisticated models of place and space, particularly in relation to changing patterns of consumption and leisure activity and the opportunities to offend in relation to these from within the domestic arena

Identification of novel risk factors for community-acquired Clostridium difficile infection using spatial statistics and geographic information system analyses

Background: The rate of community-acquired Clostridium difficile infection (CA-CDI) is increasing. While receipt of antibiotics remains an important risk factor for CDI, studies related to acquisition of C. difficile outside of hospitals are lacking. As a result, risk factors for exposure to C. difficile in community settings have been inadequately studied. Main objective: To identify novel environmental risk factors for CA-CDI Methods: We performed a population-based retrospective cohort study of patients with CA-CDI from 1/1/2007 through 12/31/2014 in a 10-county area in central North Carolina. 360 Census Tracts in these 10 counties were used as the demographic Geographic Information System (GIS) base-map. Longitude and latitude (X, Y) coordinates were generated from patient home addresses and overlaid to Census Tracts polygons using ArcGIS; ArcView was used to assess "hot-spots" or clusters of CA-CDI. We then constructed a mixed hierarchical model to identify environmental variables independently associated with increased rates of CA-CDI. Results: A total of 1,895 unique patients met our criteria for CA-CDI. The mean patient age was 54.5 years; 62% were female and 70% were Caucasian. 402 (21%) patient addresses were located in "hot spots" or clusters of CA-CDI (p<0.001). "Hot spot" census tracts were scattered throughout the 10 counties. After adjusting for clustering and population density, age ≥ 60 years (p = 0.03), race (<0.001), proximity to a livestock farm (0.01), proximity to farming raw materials services (0.02), and proximity to a nursing home (0.04) were independently associated with increased rates of CA-CDI. Conclusions: Our study is the first to use spatial statistics and mixed models to identify important environmental risk factors for acquisition of C. difficile and adds to the growing evidence that farm practices may put patients at risk for important drug-resistant infections

First-level trigger systems for LHC experiments

We propose to carry out a broad-based programme of R&D on level-1 trigger systems for LHC experiments. We will consider the overall level-1 which coordinates different subtriggers and which interacts with the front end electronics and with the level-2 system. Careful attention will be paid to systems aspects and problems of synchronization within the pipelined processor system. Trigger algorithms for selecting events with high-pt electrons, photons, muons, jets and large missing Et will be evaluated by physics simulation studies. We will study possible implementations of such trigger algorithms in fast electronics by making conceptual design studies and using behavioural simulation models. For critical areas more detailed design studies will be made, and prototypes of some key elements will be constructed and tested. The proposed R&D project builds on existing studies and will complement other R&D projects already funded by the DRDC

Error bounds for the large-argument asymptotic expansions of the Hankel and Bessel functions

In this paper, we reconsider the large-argument asymptotic expansions of the Hankel, Bessel and modified Bessel functions and their derivatives. New integral representations for the remainder terms of these asymptotic expansions are found and used to obtain sharp and realistic error bounds. We also give re-expansions for these remainder terms and provide their error estimates. A detailed discussion on the sharpness of our error bounds and their relation to other results in the literature is given. The techniques used in this paper should also generalize to asymptotic expansions which arise from an application of the method of steepest descents.Comment: 32 pages, 2 figures, accepted for publication in Acta Applicandae Mathematica

The Science of Sungrazers, Sunskirters, and Other Near-Sun Comets

This review addresses our current understanding of comets that venture close to the Sun, and are hence exposed to much more extreme conditions than comets that are typically studied from Earth. The extreme solar heating and plasma environments that these objects encounter change many aspects of their behaviour, thus yielding valuable information on both the comets themselves that complements other data we have on primitive solar system bodies, as well as on the near-solar environment which they traverse. We propose clear definitions for these comets: We use the term near-Sun comets to encompass all objects that pass sunward of the perihelion distance of planet Mercury (0.307 AU). Sunskirters are defined as objects that pass within 33 solar radii of the Sun’s centre, equal to half of Mercury’s perihelion distance, and the commonly-used phrase sungrazers to be objects that reach perihelion within 3.45 solar radii, i.e. the fluid Roche limit. Finally, comets with orbits that intersect the solar photosphere are termed sundivers. We summarize past studies of these objects, as well as the instruments and facilities used to study them, including space-based platforms that have led to a recent revolution in the quantity and quality of relevant observations. Relevant comet populations are described, including the Kreutz, Marsden, Kracht, and Meyer groups, near-Sun asteroids, and a brief discussion of their origins. The importance of light curves and the clues they provide on cometary composition are emphasized, together with what information has been gleaned about nucleus parameters, including the sizes and masses of objects and their families, and their tensile strengths. The physical processes occurring at these objects are considered in some detail, including the disruption of nuclei, sublimation, and ionisation, and we consider the mass, momentum, and energy loss of comets in the corona and those that venture to lower altitudes. The different components of comae and tails are described, including dust, neutral and ionised gases, their chemical reactions, and their contributions to the near-Sun environment. Comet-solar wind interactions are discussed, including the use of comets as probes of solar wind and coronal conditions in their vicinities. We address the relevance of work on comets near the Sun to similar objects orbiting other stars, and conclude with a discussion of future directions for the field and the planned ground- and space-based facilities that will allow us to address those science topics