Roles of Coagulation Proteases and PARs (Protease-Activated Receptors) in Mouse Models of Inflammatory Diseases

Activation of the blood coagulation cascade leads to fibrin deposition and platelet activation that are required for hemostasis. However, aberrant activation of coagulation can lead to thrombosis. Thrombi can cause tissue ischemia, and fibrin degradation products and activated platelets can enhance inflammation. In addition, coagulation proteases activate cells by cleavage of PARs (protease-activated receptors), including PAR1 and PAR2. Direct oral anticoagulants have recently been developed to specifically inhibit the coagulation proteases FXa (factor Xa) and thrombin. Administration of these inhibitors to wild-type mice can be used to determine the roles of FXa and thrombin in different inflammatory diseases. These results can be compared with the phenotypes of mice with deficiencies of either Par1 (F2r) or Par2 (F2rl1). However, inhibition of coagulation proteases will have effects beyond reducing PAR signaling, and a deficiency of PARs will abolish signaling from all proteases that activate these receptors. We will summarize studies that examine the roles of coagulation proteases, particularly FXa and thrombin, and PARs in different mouse models of inflammatory disease. Targeting FXa and thrombin or PARs may reduce inflammatory diseases in humans

kt Effects in Direct-Photon Production

We discuss the phenomenology of initial-state parton-kt broadening in direct-photon production and related processes in hadron collisions. After a brief summary of the theoretical basis for a Gaussian-smearing approach, we present a systematic study of recent results on fixed-target and collider direct-photon production, using complementary data on diphoton and pion production to provide empirical guidance on the required amount of kt broadening. This approach provides a consistent description of the observed pattern of deviation of next-to-leading order QCD calculations relative to the direct-photon data, and accounts for the shape and normalization difference between fixed-order perturbative calculations and the data. We also discuss the uncertainties in this phenomenological approach, the implications of these results on the extraction of the gluon distribution of the nucleon, and the comparison of our findings to recent related work.Comment: LaTeX, uses revtex and epsf, 37 pages, 15 figure

Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies

Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated clinical efficacy against influenza A and B virus infections. In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log(10) 50% tissue culture infective doses compared to a placebo, with no reemergence of virus after the completion of therapy. Paired isolates (n = 41) obtained before and during therapy with zanamivir demonstrated no shifts in susceptibility to zanamivir when measured by NA assays, although for a few isolates NA activity was too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility of isolates to zanamivir was extremely variable even at baseline and did not correlate with the speed of resolution of virus shedding. Isolates with apparent limited susceptibility to zanamivir by plaque reduction proved highly susceptible in vivo in the ferret model. Further sequence analysis of paired isolates revealed no changes in the hemagglutinin and NA genes in the majority of isolates. The few changes observed were all natural variants. No amino acid changes that had previously been identified in vitro as being involved with reduced susceptibility to zanamivir were observed. These studies highlighted problems associated with monitoring susceptibility to NA inhibitors in the clinic, in that no reliable cell-based assay is available. At present the NA assay is the best available predictor of susceptibility to NA inhibitors in vivo, as measured in the validated ferret model of infection

High-p_T pion and kaon production in relativistic nuclear collisions

High-p_T pion and kaon production is studied in relativistic proton-proton, proton-nucleus, and nucleus-nucleus collisions in a wide energy range. Cross sections are calculated based on perturbative QCD, augmented by a phenomenological transverse momentum distribution of partons (``intrinsic k_T''). An energy dependent width of the transverse momentum distribution is extracted from pion and charged hadron production data in proton-proton/proton-antiproton collisions. Effects of multiscattering and shadowing in the strongly interacting medium are taken into account. Enhancement of the transverse momentum width is introduced and parameterized to explain the Cronin effect. In collisions between heavy nuclei, the model over-predicts central pion production cross sections (more significantly at higher energies), hinting at the presence of jet quenching. Predictions are made for proton-nucleus and nucleus-nucleus collisions at RHIC energies.Comment: 26 pages in Latex, 19 EPS figure

Aspects of χ\chi and ψ\psi Production in Polarized Proton-Proton Collisions

Several topics of relevance to low transverse momentum $\psi$ and $\chi_{1,2}(c\overline{c})$ production in polarized proton-proton collisions are discussed. The leading ${\cal O}(\alpha_S^3)$ contributions to the low $p_T$ $\chi_1$ production cross-sections via $gg$, $qg$, and $q\overline{q}$ initial states are calculated as well as the corresponding spin-spin asymmetries. We find that $\chi_1$ production increases relative to direct $\psi$ and $\chi_2$ production, providing up to $25\%$ of the observable $e^+e^-$ pairs arising from $\psi$ decays in $pp$ collisions at $\sqrt{s} = 500\,GeV$. The spin-dependence of $\chi_1$ production, however, is much smaller than for either direct $\psi$ or $\chi_2$ production and so will likely be far less useful than either process in probing the polarized gluon structure function of the proton. A subset of the ${\cal O}(\alpha_S^3)$ radiative corrections to $\chi_2$ production involving initial state quarks are also performed and compared to leading order $gg \rightarrow \chi_2$ predictions.Comment: 21 pages + 5 postscript figures (included), OCIP/C-94-

An investigation of the potential application of chitosan/aloe-based membranes for regenerative medicine

A significant number of therapeutics derived from natural polymers and plants have been developed to replace or to be used in conjunction with existing dressing products. The use of the therapeutic properties of aloe vera could be very useful in the creation of active wound dressing materials. The present work was undertaken to examine issues concerning structural features, topography, enzymatic degradation behavior, antibacterial activity and cellular response of chitosan/aloe vera-based membranes. The chitosan/aloe vera-based membranes that were developed displayed satisfactory degradation, roughness, wettability and mechanical properties. A higher antibacterial potency was displayed by the blended membranes. Moreover, in vitro assays demonstrated that these blended membranes have good cell compatibility with primary human dermal fibroblasts. The chitosan/aloe vera-based membranes might be promising wound dressing materials.The authors acknowledge financial support from the Portuguese Foundation for Science and Technology (grants SFRH/BPD/45307/2008 and SFRH/BD/64601/2009), the "Fundo Social Europeu", and the "Programa Diferencial de Potencial Humano". This work was partially supported by the FEDER through POCTEP 0330_IBEROMARE_1_P

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Human antigen R as a therapeutic target in pathological cardiac hypertrophy

RNA binding proteins represent an emerging class of proteins with a role in cardiac dysfunction. We show that activation of the RNA binding protein human antigen R (HuR) is increased in the failing human heart. To determine the functional role of HuR in pathological cardiac hypertrophy, we created an inducible cardiomyocyte-specific HuR-deletion mouse and showed that HuR deletion reduces left ventricular hypertrophy, dilation, and fibrosis while preserving cardiac function in a transverse aortic constriction (TAC) model of pressure overload-induced hypertrophy. Assessment of HuR-dependent changes in global gene expression suggests that the mechanistic basis for this protection occurs through a reduction in fibrotic signaling, specifically through a reduction in TGF-β (Tgfb) expression. Finally, pharmacological inhibition of HuR at a clinically relevant time point following the initial development of pathological hypertrophy after TAC also yielded a significant reduction in pathological progression, as marked by a reduction in hypertrophy, dilation, and fibrosis and preserved function. In summary, this study demonstrates a functional role for HuR in the progression of pressure overload-induced cardiac hypertrophy and establishes HuR inhibition as a viable therapeutic approach for pathological cardiac hypertrophy and heart failure

Quantum walks: a comprehensive review

Quantum walks, the quantum mechanical counterpart of classical random walks, is an advanced tool for building quantum algorithms that has been recently shown to constitute a universal model of quantum computation. Quantum walks is now a solid field of research of quantum computation full of exciting open problems for physicists, computer scientists, mathematicians and engineers. In this paper we review theoretical advances on the foundations of both discrete- and continuous-time quantum walks, together with the role that randomness plays in quantum walks, the connections between the mathematical models of coined discrete quantum walks and continuous quantum walks, the quantumness of quantum walks, a summary of papers published on discrete quantum walks and entanglement as well as a succinct review of experimental proposals and realizations of discrete-time quantum walks. Furthermore, we have reviewed several algorithms based on both discrete- and continuous-time quantum walks as well as a most important result: the computational universality of both continuous- and discrete- time quantum walks.Comment: Paper accepted for publication in Quantum Information Processing Journa

Measurement of the Isolated Photon Cross Section in p-pbar Collisions at sqrt{s}=1.96 TeV

The cross section for the inclusive production of isolated photons has been measured in p anti-p collisions at sqrt{s}=1.96 TeV with the D0 detector at the Fermilab Tevatron Collider. The photons span transverse momenta 23 to 300 GeV and have pseudorapidity |eta|<0.9. The cross section is compared with the results from two next-to-leading order perturbative QCD calculations. The theoretical predictions agree with the measurement within uncertainties.Comment: 7 pages, 5 figures, submitted to Phys.Lett.