Evasins: Therapeutic Potential of a New Family of Chemokine-Binding Proteins from Ticks

Blood sucking parasites such as ticks remain attached to their hosts for relatively long periods of time in order to obtain their blood meal without eliciting an immune response. One mechanism used to avoid rejection is the inhibition of the recruitment of immune cells, which can be achieved by a class of chemokine binding proteins (CKBPs) known as Evasins. We have identified three distinct Evasins produced by the salivary glands of the common brown dog tick, Rhipicephalus sanguineus. They display different selectivities for chemokines, the first two identified show a narrow selectivity profile, whilst the third has a broader binding spectrum. The Evasins showed efficacy in several animal models of inflammatory disease. Here we will discuss the potential of their development for therapeutic use, addressing both the advantages and disadvantages that this entails

In vivo evaluation of pathogenicity and transmissibility of influenza A(H1N1)pdm09 hemagglutinin receptor binding domain 222 intrahost variants isolated from a single immunocompromised patient

AbstractThe influenza A(H1N1)pdm09 virus has circulated worldwide and continued to cause complicated infections and deaths. Reports have identified an increased prevalence of the hemagglutinin receptor binding domain D222G mutation in viruses isolated from individuals who have suffered such severe infections, but this association is still unclear. Virus isolated from a nasopharyngeal wash of a severely ill immunocompromised patient at the time of diagnosis contained the D222, but isolates collected later in his course from a bronchoalveolar lavage contained primarily the G222 mutation and was mixed with a minor population of D222. These clinical isolates were compared to a G222 plaque purified virus in the ferret model. The G222 predominant clinical isolate was the most pathogenic in ferrets and developed the most diversity at the 222 amino acid position during infection, suggesting that increased diversity and not a specific polymorphism at HA 222 may be important in predicting pathogenic potential

Structural Basis of Chemokine Sequestration by a Tick Chemokine Binding Protein: The Crystal Structure of the Complex between Evasin-1 and CCL3

Chemokines are a subset of cytokines responsible for controlling the cellular migration of inflammatory cells through interaction with seven transmembrane G protein-coupled receptors. The blocking of a chemokine-receptor interaction results in a reduced inflammatory response, and represents a possible anti-inflammatory strategy, a strategy that is already employed by some virus and parasites. Anti-chemokine activity has been described in the extracts of tick salivary glands, and we have recently described the cloning and characterization of such chemokine binding proteins from the salivary glands, which we have named Evasins.We have solved the structure of Evasin-1, a very small and highly selective chemokine-binding protein, by x-ray crystallography and report that the structure is novel, with no obvious similarity to the previously described structures of viral chemokine binding proteins. Moreover it does not possess a known fold. We have also solved the structure of the complex of Evasin-1 and its high affinity ligand, CCL3. The complex is a 1:1 heterodimer in which the N-terminal region of CCL3 forms numerous contacts with Evasin-1, including prominent pi-pi interactions between residues Trp89 and Phe14 of the binding protein and Phe29 and Phe13 of the chemokine.However, these interactions do not appear to be crucial for the selectivity of the binding protein, since these residues are found in CCL5, which is not a ligand for Evasin-1. The selectivity of the interaction would appear to lie in the N-terminal residues of the chemokine, which form the "address" whereas the hydrophobic interactions in the rest of the complex would serve primarily to stabilize the complex. A thorough understanding of the binding mode of this small protein, and its other family members, could be very informative in the design of potent neutralizing molecules of pro-inflammatory mediators of the immune system, such as chemokines

A New Scintillator Tile/Fiber Preshower Detector for the CDF Central Calorimeter

A detector designed to measure early particle showers has been installed in front of the central CDF calorimeter at the Tevatron. This new preshower detector is based on scintillator tiles coupled to wavelength-shifting fibers read out by multi-anode photomultipliers and has a total of 3,072 readout channels. The replacement of the old gas detector was required due to an expected increase in instantaneous luminosity of the Tevatron collider in the next few years. Calorimeter coverage, jet energy resolution, and electron and photon identification are among the expected improvements. The final detector design, together with the R&D studies that led to the choice of scintillator and fiber, mechanical assembly, and quality control are presented. The detector was installed in the fall 2004 Tevatron shutdown and started collecting colliding beam data by the end of the same year. First measurements indicate a light yield of 12 photoelectrons/MIP, a more than two-fold increase over the design goals.Comment: 5 pages, 10 figures (changes are minor; this is the final version published in IEEE-Trans.Nucl.Sci.

Development of FTK architecture: a fast hardware track trigger for the ATLAS detector

The Fast Tracker (FTK) is a proposed upgrade to the ATLAS trigger system that will operate at full Level-1 output rates and provide high quality tracks reconstructed over the entire detector by the start of processing in Level-2. FTK solves the combinatorial challenge inherent to tracking by exploiting the massive parallelism of Associative Memories (AM) that can compare inner detector hits to millions of pre-calculated patterns simultaneously. The tracking problem within matched patterns is further simplified by using pre-computed linearized fitting constants and leveraging fast DSP's in modern commercial FPGA's. Overall, FTK is able to compute the helix parameters for all tracks in an event and apply quality cuts in approximately one millisecond. By employing a pipelined architecture, FTK is able to continuously operate at Level-1 rates without deadtime. The system design is defined and studied using ATLAS full simulation. Reconstruction quality is evaluated for single muon events with zero pileup, as well as WH events at the LHC design luminosity. FTK results are compared with the tracking capability of an offline algorithm.Comment: To be published in the proceedings of DPF-2009, Detroit, MI, July 2009, eConf C09072

The Evolution of FTK, a Real-Time Tracker for Hadron Collider Experiments

We describe the architecture evolution of the highly-parallel dedicated processor FTK, which is driven by the simulation of LHC events at high luminosity (1034 cm-2 s-1). FTK is able to provide precise on-line track reconstruction for future hadronic collider experiments. The processor, organized in a two-tiered pipelined architecture, execute very fast algorithms based on the use of a large bank of pre-stored patterns of trajectory points (first tier) in combination with full resolution track fitting to refine pattern recognition and to determine off-line quality track parameters. We describe here how the high luminosity simulation results have produced a new organization of the hardware inside the FTK processor core.Comment: 11th ICATPP conferenc