NMR analysis of the dynamic exchange of the NS2B cofactor between open and closed conformations of the West Nile Virus NS2B-NS3 protease

BACKGROUND The two-component NS2B-NS3 proteases of West Nile and dengue viruses are essential for viral replication and established targets for drug development. In all crystal structures of the proteases to date, the NS2B cofactor is located far from the substrate binding site (open conformation) in the absence of inhibitor and lining the substrate binding site (closed conformation) in the presence of an inhibitor. METHODS In this work, nuclear magnetic resonance (NMR) spectroscopy of isotope and spin-labeled samples of the West Nile virus protease was used to investigate the occurrence of equilibria between open and closed conformations in solution. FINDINGS In solution, the closed form of the West Nile virus protease is the predominant conformation irrespective of the presence or absence of inhibitors. Nonetheless, dissociation of the C-terminal part of the NS2B cofactor from the NS3 protease (open conformation) occurs in both the presence and the absence of inhibitors. Low-molecular-weight inhibitors can shift the conformational exchange equilibria so that over 90% of the West Nile virus protease molecules assume the closed conformation. The West Nile virus protease differs from the dengue virus protease, where the open conformation is the predominant form in the absence of inhibitors. CONCLUSION Partial dissociation of NS2B from NS3 has implications for the way in which the NS3 protease can be positioned with respect to the host cell membrane when NS2B is membrane associated via N- and C-terminal segments present in the polyprotein. In the case of the West Nile virus protease, discovery of low-molecular-weight inhibitors that act by breaking the association of the NS2B cofactor with the NS3 protease is impeded by the natural affinity of the cofactor to the NS3 protease. The same strategy can be more successful in the case of the dengue virus NS2B-NS3 protease.The project was funded by the Australian Research Council (http://www.arc.gov.au), grant DP0877540

Constraining the HI-Halo Mass Relation From Galaxy Clustering

We study the dependence of galaxy clustering on atomic gas mass using a sample of $\sim$16,000 galaxies with redshift in the range of $0.0025<z<0.05$ and HI mass of $M_{\rm HI}>10^8M_{\odot}$, drawn from the 70% complete sample of the Arecibo Legacy Fast ALFA survey. We construct subsamples of galaxies with $M_{\rm HI}$ above different thresholds, and make volume-limited clustering measurements in terms of three statistics: the projected two-point correlation function, the projected cross-correlation function with respect to a reference sample selected from the Sloan Digital Sky Survey, and the redshift-space monopole moment. In contrast to previous studies, which found no/weak HI-mass dependence, we find both the clustering amplitude on scales above a few Mpc and the bias factors to increase significantly with increasing HI mass for subsamples with HI mass thresholds above $10^9M_{\odot}$. For HI mass thresholds below $10^9M_{\odot}$, while the measurements have large uncertainties caused by the limited survey volume and sample size, the inferred galaxy bias factors are systematically lower than the minimum halo bias factor from mass-selected halo samples. The simple halo model, in which galaxy content is only determined by halo mass, has difficulties in interpreting the clustering measurements of the HI-selected samples. We extend the simple model by including the halo formation time as an additional parameter. A model that puts HI-rich galaxies into halos that formed late can reproduce the clustering measurements reasonably well. We present the implications of our best-fitting model on the correlation of HI mass with halo mass and formation time, as well as the halo occupation distributions and HI mass functions for central and satellite galaxies. These results are compared with the predictions from semi-analytic galaxy formation models and hydrodynamic galaxy formation simulations.Comment: Accepted for publication in ApJ. The 2PCF measurements are available at http://sdss4.shao.ac.cn/guoh

Finite Temperature Casimir Effect and Dispersion in the Presence of Compactified Extra Dimensions

Finite temperature Casimir theory of the Dirichlet scalar field is developed, assuming that there is a conventional Casimir setup in physical space with two infinitely large plates separated by a gap R and in addition an arbitrary number q of extra compacified dimensions. As a generalization of earlier theory, we assume in the first part of the paper that there is a scalar 'refractive index' N filling the whole of the physical space region. After presenting general expressions for free energy and Casimir forces we focus on the low temperature case, as this is of main physical interest both for force measurements and also for issues related to entropy and the Nernst theorem. Thereafter, in the second part we analyze dispersive properties, assuming for simplicity q=1, by taking into account dispersion associated with the first Matsubara frequency only. The medium-induced contribution to the free energy, and pressure, is calculated at low temperatures.Comment: 25 pages, one figure. Minor changes in the discussion. Version to appear in Physica Script

Prevalence of Tidal Interactions among Local Seyfert Galaxies

No mechanisms have hitherto been conclusively demonstrated to be responsible for initiating optically-luminous nuclear (Seyfert) activity in local disk galaxies. Only a small minority of such galaxies are visibly disturbed in optical starlight, with the observed disturbances being at best marginally stronger than those found in matched samples of inactive galaxies. Here, we report the first systematic study of an optically-selected sample of twenty-three active galaxies in atomic hydrogen (HI) gas, which is the most sensitive and enduring tracer known of tidal interactions. Eighteen of these galaxies are (generally) classified as Seyferts, with over half (and perhaps all) having [OIII] luminosities within two orders of magnitude of Quasi-Stellar Objects. Only ~28% of these Seyfert galaxies are visibly disturbed in optical DSS2 images. By contrast, ~94% of the same galaxies are disturbed in HI, in nearly all cases not just spatially but also kinematically on galactic (>~20 kpc) scales. In at least ~67% and perhaps up to ~94% of cases, the observed HI disturbances can be traced to tidal interactions with neighboring galaxies detected also in HI. The majority of these neighboring galaxies have projected separations of <~ 100 kpc and differ in radial velocities by <~100 km/s from their respective Seyfert galaxies, and many have optical luminosities ranging from the Small to Large Magellanic Clouds. In a companion paper, we show that only ~15% of a matched control sample of inactive galaxies display comparable HI disturbances. Our results suggest that: i) most Seyfert galaxies (with high nuclear luminosities) have experienced tidal interactions in the recent past; ii) in most cases, these tidal interactions are responsible for initiating events that lead to their nuclear activity.Comment: 64 pages, 44 figures, accepted for publication in ApJ. Changes: Nothing is changed except that the paper was compiled differently to reduce the number of pages. To be friendly to the Earth forest, you could also choose to only print the text part of the paper and view images on line. (see http://www.astro.virginia.edu/~ck2v/paper/

EEG reinvestigations of visual statistical learning for faces, scenes, and objects

The objective of this ongoing, replication study is to understand temporal and spatial patterns in our environment by using the technique of electroencephalography (EEG). Visual statistical learning (VSL) helps us to understand conditional probabilities from our environments. This concept is why we know that chairs are located under tables, not above. The goal of this study is to understand whether participants can unconsciously associate pairs of items (faces, scenes, and objects) from their short-term memory. Strong pairs become more similar to each other, as compared to weak pairs, which become less similar. In the main task, participants saw items appear on the screen, on at a time, for 100ms each. Items directly followed each other without transitions. In the post-task, participants were asked to rate how familiar pairs of items were, using a sliding scale. There were three types of pairs presented: strong pairs where item B followed item A 100% of the time; weak pairs where item B followed item A 11% of the time; and foil pairs where item B followed item A 0% of the time. In conclusion, results are similar to the current study (n = 10) in that there are behavioral differences between strong vs. foil and strong vs. weak pairs

Finite Temperature Casimir Effect in Randall-Sundrum Models

The finite temperature Casimir effect for a scalar field in the bulk region of the two Randall-Sundrum models, RSI and RSII, is studied. We calculate the Casimir energy and the Casimir force for two parallel plates with separation $a$ on the visible brane in the RSI model. High-temperature and low-temperature cases are covered. Attractiveness versus repulsiveness of the temperature correction to the force is discussed in the typical special cases of Dirichlet-Dirichlet, Neumann-Neumann, and Dirichlet-Neumann boundary conditions at low temperature. The Abel-Plana summation formula is made use of, as this turns out to be most convenient. Some comments are made on the related contemporary literature.Comment: 33 pages latex, 2 figures. Some changes in the discussion. To appear in New J. Phy

Quantitative 3D analysis of complex single border cell behaviors in coordinated collective cell migration

Understanding the mechanisms of collective cell migration is crucial for cancer metastasis, wound healing and many developmental processes. Imaging a migrating cluster in vivo is feasible, but the quantification of individual cell behaviours remains challenging. We have developed an image analysis toolkit, CCMToolKit, to quantify the Drosophila border cell system. In addition to chaotic motion, previous studies reported that the migrating cells are able to migrate in a highly coordinated pattern. We quantify the rotating and running migration modes in 3D while also observing a range of intermediate behaviours. Running mode is driven by cluster external protrusions. Rotating mode is associated with cluster internal cell extensions that could not be easily characterized. Although the cluster moves slower while rotating, individual cells retain their mobility and are in fact slightly more active than in running mode. We also show that individual cells may exchange positions during migration

Protein-coated corrole nanoparticles for the treatment of prostate cancer cells

Development of novel therapeutic strategies to eradicate malignant tumors is of paramount importance in cancer research. In a recent study, we have introduced a facile protocol for the preparation of corrole-protein nanoparticles (NPs). These NPs consist of a corrole-core coated with protein. We now report that a novel lipophilic corrole, (2)Ga, delivered as human serum albumin (HSA)-coated NPs, displayed antineoplastic activity towards human prostate cancer DU-145 cells. Cryo-TEM analysis of these NPs revealed an average diameter of 50.2 ± 8.1 nm with a spherical architecture exhibiting low polydispersity. In vitro cellular uptake of (2)Ga/albumin NPs was attributable to rapid internalization of the corrole through ligand binding-dependent extracellular release and intercalation of the corrole cargo into the lipid bilayer of the plasma membrane. This finding is in contrast with a previously reported study on corrole-protein NPs that displayed cellular uptake via endocytosis. Investigation of the non-light-induced mechanism of action of (2)Ga suggested the induction of necrosis through plasma membrane destabilization, impairment of calcium homeostasis, lysosomal stress and rupture, as well as formation of reactive oxygen species (ROS). (2)Ga also exhibited potent light-induced cytotoxicity through ROS generation. These findings demonstrate a rapid cellular uptake of (2)Ga/protein NPs along with targeted induction of tumor cell necrosis

Protein-coated corrole nanoparticles for the treatment of prostate cancer cells

Development of novel therapeutic strategies to eradicate malignant tumors is of paramount importance in cancer research. In a recent study, we have introduced a facile protocol for the preparation of corrole-protein nanoparticles (NPs). These NPs consist of a corrole-core coated with protein. We now report that a novel lipophilic corrole, (2)Ga, delivered as human serum albumin (HSA)-coated NPs, displayed antineoplastic activity towards human prostate cancer DU-145 cells. Cryo-TEM analysis of these NPs revealed an average diameter of 50.2 ± 8.1 nm with a spherical architecture exhibiting low polydispersity. In vitro cellular uptake of (2)Ga/albumin NPs was attributable to rapid internalization of the corrole through ligand binding-dependent extracellular release and intercalation of the corrole cargo into the lipid bilayer of the plasma membrane. This finding is in contrast with a previously reported study on corrole-protein NPs that displayed cellular uptake via endocytosis. Investigation of the non-light-induced mechanism of action of (2)Ga suggested the induction of necrosis through plasma membrane destabilization, impairment of calcium homeostasis, lysosomal stress and rupture, as well as formation of reactive oxygen species (ROS). (2)Ga also exhibited potent light-induced cytotoxicity through ROS generation. These findings demonstrate a rapid cellular uptake of (2)Ga/protein NPs along with targeted induction of tumor cell necrosis

Prevalence of Tidal Interactions among Local Seyfert Galaxies: The Control Experiment

We test whether there is a relation between the observed tidal interactions and Seyfert activity by imaging in HI twenty inactive galaxies at the same spatial resolution and detection threshold as the Seyfert sample. This control sample of inactive galaxies were closely matched in Hubble type, range in size and inclination, and have roughly comparable galaxy optical luminosity to the Seyfert galaxies. We find that only ~15% of the galaxies in our control sample are disturbed in HI, whereas the remaining ~85% show no disturbances whatsoever in HI. Even at a spatial resolution of ~10 kpc, none of the latter galaxies show appreciable HI disturbances reminiscent of tidal features. In a companion paper (Kuo et al. 2008), we report results from the first systematic imaging survey of Seyfert galaxies in atomic hydrogen (HI) gas. We find that only ~28% of the eighteen Seyfert galaxies in that sample are visibly disturbed in optical starlight. By contrast, ~94% of the same Seyfert galaxies are disturbed spatially and usually also kinematically in HI gas on galactic scales of >~20 kpc. In at least ~67% and up to perhaps ~94% of cases, the observed disturbances can be traced to tidal interactions with neighboring galaxies detected also in HI. The dramatic contrast between the observed prevalence of HI disturbances in the Seyfert and control samples implicates tidal interactions in initiating events that lead to luminous Seyfert activity in a large fraction of local disk galaxies.Comment: 38 pages, 27 figures, Accepted for publication in ApJ. Changes from previous version: The title of the previous version of this paper appeared in Astroph was incorrect. It has been replaced with the correct on