Magnetoelliptic Instabilities

We consider the stability of a configuration consisting of a vertical magnetic field in a planar flow on elliptical streamlines in ideal hydromagnetics. In the absence of a magnetic field the elliptical flow is universally unstable (the ``elliptical instability''). We find this universal instability persists in the presence of magnetic fields of arbitrary strength, although the growthrate decreases somewhat. We also find further instabilities due to the presence of the magnetic field. One of these, a destabilization of Alfven waves, requires the magnetic parameter to exceed a certain critical value. A second, involving a mixing of hydrodynamic and magnetic modes, occurs for all magnetic-field strengths. These instabilities may be important in tidally distorted or otherwise elliptical disks. A disk of finite thickness is stable if the magnetic fieldstrength exceeds a critical value, similar to the fieldstrength which suppresses the magnetorotational instability.Comment: Accepted for publication in Astrophysical Journa

In vivo imaging of protease activity by Probody therapeutic activation.

Probody™ therapeutics are recombinant, proteolytically-activated antibody prodrugs, engineered to remain inert until activated locally by tumor-associated proteases. Probody therapeutics exploit the fundamental dysregulation of extracellular protease activity that exists in tumors relative to healthy tissue. Leveraging the ability of a Probody therapeutic to bind its target at the site of disease after proteolytic cleavage, we developed a novel method for profiling protease activity in living animals. Using NIR optical imaging, we demonstrated that a non-labeled anti-EGFR Probody therapeutic can become activated and compete for binding to tumor cells in vivo with a labeled anti-EGFR monoclonal antibody. Furthermore, by inhibiting matriptase activity in vivo with a blocking-matriptase antibody, we show that the ability of the Probody therapeutic to bind EGFR in vivo was dependent on protease activity. These results demonstrate that in vivo imaging of Probody therapeutic activation can be used for screening and characterization of protease activity in living animals, and provide a method that avoids some of the limitations of prior methods. This approach can improve our understanding of the activity of proteases in disease models and help to develop efficient strategies for cancer diagnosis and treatment

Inhibition of a viral enzyme by a small-molecule dimer disruptor.

We identified small-molecule dimer disruptors that inhibit an essential dimeric protease of human Kaposi's sarcoma-associated herpesvirus (KSHV) by screening an alpha-helical mimetic library. Next, we synthesized a second generation of low-micromolar inhibitors with improved potency and solubility. Complementary methods including size exclusion chromatography and 1H-13C HSQC titration using selectively labeled 13C-Met samples revealed that monomeric protease is enriched in the presence of inhibitor. 1H-15N HSQC titration studies mapped the inhibitor binding site to the dimer interface, and mutagenesis studies targeting this region were consistent with a mechanism where inhibitor binding prevents dimerization through the conformational selection of a dynamic intermediate. These results validate the interface of herpesvirus proteases and other similar oligomeric interactions as suitable targets for the development of small-molecule inhibitors

Inhibitors of SARS-CoV entry--identification using an internally-controlled dual envelope pseudovirion assay.

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) emerged as the causal agent of an endemic atypical pneumonia, infecting thousands of people worldwide. Although a number of promising potential vaccines and therapeutic agents for SARS-CoV have been described, no effective antiviral drug against SARS-CoV is currently available. The intricate, sequential nature of the viral entry process provides multiple valid targets for drug development. Here, we describe a rapid and safe cell-based high-throughput screening system, dual envelope pseudovirion (DEP) assay, for specifically screening inhibitors of viral entry. The assay system employs a novel dual envelope strategy, using lentiviral pseudovirions as targets whose entry is driven by the SARS-CoV Spike glycoprotein. A second, unrelated viral envelope is used as an internal control to reduce the number of false positives. As an example of the power of this assay a class of inhibitors is reported with the potential to inhibit SARS-CoV at two steps of the replication cycle, viral entry and particle assembly. This assay system can be easily adapted to screen entry inhibitors against other viruses with the careful selection of matching partner virus envelopes

SmSP2: A serine protease secreted by the blood fluke pathogen Schistosoma mansoni with anti-hemostatic properties.

BackgroundSerine proteases are important virulence factors for many pathogens. Recently, we discovered a group of trypsin-like serine proteases with domain organization unique to flatworm parasites and containing a thrombospondin type 1 repeat (TSR-1). These proteases are recognized as antigens during host infection and may prove useful as anthelminthic vaccines, however their molecular characteristics are under-studied. Here, we characterize the structural and proteolytic attributes of serine protease 2 (SmSP2) from Schistosoma mansoni, one of the major species responsible for the tropical infectious disease, schistosomiasis.Methodology/principal findingsSmSP2 comprises three domains: a histidine stretch, TSR-1 and a serine protease domain. The cleavage specificity of recombinant SmSP2 was determined using positional scanning and multiplex combinatorial libraries and the determinants of specificity were identified with 3D homology models, demonstrating a trypsin-like endopeptidase mode of action. SmSP2 displayed restricted proteolysis on protein substrates. It activated tissue plasminogen activator and plasminogen as key components of the fibrinolytic system, and released the vasoregulatory peptide, kinin, from kininogen. SmSP2 was detected in the surface tegument, esophageal glands and reproductive organs of the adult parasite by immunofluorescence microscopy, and in the excretory/secretory products by immunoblotting.Conclusions/significanceThe data suggest that SmSP2 is secreted, functions at the host-parasite interface and contributes to the survival of the parasite by manipulating host vasodilatation and fibrinolysis. SmSP2 may be, therefore, a potential target for anti-schistosomal therapy

A model-independent Dalitz plot analysis of B±→DK± with D→K0Sh+h− (h=π,K) decays and constraints on the CKM angle γ

A binned Dalitz plot analysis of B ±→DK ± decays, with D→KS0π+π- and D→KS0K+K-, is performed to measure the CP-violating observables x ± and y ± which are sensitive to the CKM angle γ. The analysis exploits 1.0 fb -1 of data collected by the LHCb experiment. The study makes no model-based assumption on the variation of the strong phase of the D decay amplitude over the Dalitz plot, but uses measurements of this quantity from CLEO-c as input. The values of the parameters are found to be x -=(0.0±4.3±1.5±0.6)×10 -2, y -=(2.7±5.2±0.8±2.3)×10 -2, x +=(-10.3±4.5±1.8±1.4)×10 -2 and y +=(-0.9±3.7±0.8±3.0)×10 -2. The first, second, and third uncertainties are the statistical, the experimental systematic, and the error associated with the precision of the strong-phase parameters measured at CLEO-c, respectively. These results correspond to γ=(44-38+43)°, with a second solution at γ→γ+180°, and r B=0.07±0.04, where r B is the ratio between the suppressed and favoured B decay amplitudes

First observation of the decay B0s→ϕK∗0

The first observation of the decay B0s→ϕK∗0 is reported. The analysis is based on a data sample corresponding to an integrated luminosity of 1.0 fb−1 of pp collisions at s√=7 TeV, collected with the LHCb detector. A yield of 30 ± 6 B0s→(K+K−)(K−π+) decays is found in the mass windows 1012.5 < M (K + K −) < 1026.5 MeV/c 2 and 746 < M(K − π +) < 1046 MeV/c 2. The signal yield is found to be dominated by B0s→ϕK∗0 decays, and the corresponding branching fraction is measured to be B(B0s→ϕK∗0) = (1.10 ± 0.24 (stat) ± 0.14 (syst) ± 0.08 (f d /f s )) × 10−6, where the uncertainties are statistical, systematic and from the ratio of fragmentation fractions f d /f s which accounts for the different production rate of B 0 and B0s mesons. The significance of B0s→ϕK∗0 signal is 6.1 standard deviations. The fraction of longitudinal polarization in B0s→ϕK∗0 decays is found to be f 0 = 0.51 ± 0.15 (stat) ± 0.07 (syst)