Molecular Docking and NMR Binding Studies to Identify Novel Inhibitors of Human Phosphomevalonate Kinase

Phosphomevalonate kinase (PMK) phosphorylates mevalonate-5-phosphate (M5P) in the mevalonate pathway, which is the sole source of isoprenoids and steroids in humans. We have identified new PMK inhibitors with virtual screening, using autodock. Promising hits were verified and their affinity measured using NMR-based 1H–15N heteronuclear single quantum coherence (HSQC) chemical shift perturbation and fluorescence titrations. Chemical shift changes were monitored, plotted, and fitted to obtain dissociation constants (Kd). Tight binding compounds with Kd’s ranging from 6–60 μM were identified. These compounds tended to have significant polarity and negative charge, similar to the natural substrates (M5P and ATP). HSQC cross peak changes suggest that binding induces a global conformational change, such as domain closure. Compounds identified in this study serve as chemical genetic probes of human PMK, to explore pharmacology of the mevalonate pathway, as well as starting points for further drug development

Mass Profiles of the Typical Relaxed Galaxy Clusters A2199 and A496

We present maps and radial profiles of the gas temperature in the nearby galaxy clusters A2199 and A496, which have the most accurate ASCA spectral data for all hot clusters. These clusters are relaxed and can provide reliable X-ray mass measurements under the assumption of hydrostatic equilibrium. The cluster average temperatures corrected for the presence of cooling flows are 4.8+-0.2 keV and 4.7+-0.2 keV (90% errors), respectively. Outside the central cooling flow regions, the radial temperature profiles are similar to those of the majority of nearby relaxed clusters. They are accurately described by polytropic models with gamma=1.17+-0.07 for A2199 and gamma=1.24+-0.09 for A496. We use these polytropic models to derive accurate total mass profiles. Within r=0.5/h Mpc, which corresponds to a radius of overdensity 1000, the total mass values are 1.45+-0.15 10^14 /h Msun and 1.55+-0.15 10^14 /h Msun. These values are 10% lower than those obtained assuming constant temperature. The values inside a gas core radius (0.07-0.13/h Mpc) are a factor of >1.5 higher than the isothermal values. The gas mass fraction increases with radius (by a factor of 3 between the X-ray core radius and r_1000) and at r_1000 reaches values of 0.057+-0.005 and 0.056+-0.006 h^-3/2 for the two clusters, respectively. Our mass profiles within r_1000 are remarkably well approximated by the NFW "universal" profile. Since A2199 and A496 are typical relaxed clusters, the above findings should be relevant for most such systems. In particular, the similarity of the temperature profiles in nearby clusters appears to reflect the underlying "universal" dark matter profile. The upward revision of mass at small radii will resolve most of the discrepancy between the X-ray and strong lensing mass estimates. (Abridged)Comment: Latex, 9 pages, 6 figures, uses emulateapj.sty. Submitted to Ap

Imaging Active Infection in vivo Using D-Amino Acid Derived PET Radiotracers.

Occult bacterial infections represent a worldwide health problem. Differentiating active bacterial infection from sterile inflammation can be difficult using current imaging tools. Present clinically viable methodologies either detect morphologic changes (CT/ MR), recruitment of immune cells (111In-WBC SPECT), or enhanced glycolytic flux seen in inflammatory cells (18F-FDG PET). However, these strategies are often inadequate to detect bacterial infection and are not specific for living bacteria. Recent approaches have taken advantage of key metabolic differences between prokaryotic and eukaryotic organisms, allowing easier distinction between bacteria and their host. In this report, we exploited one key difference, bacterial cell wall biosynthesis, to detect living bacteria using a positron-labeled D-amino acid. After screening several 14C D-amino acids for their incorporation into E. coli in culture, we identified D-methionine as a probe with outstanding radiopharmaceutical potential. Based on an analogous procedure to that used for L-[methyl-11C]methionine ([11C] L-Met), we developed an enhanced asymmetric synthesis of D-[methyl-11C]methionine ([11C] D-Met), and showed that it can rapidly and selectively differentiate both E. coli and S. aureus infections from sterile inflammation in vivo. We believe that the ease of [11C] D-Met radiosynthesis, coupled with its rapid and specific in vivo bacterial accumulation, make it an attractive radiotracer for infection imaging in clinical practice

Studies Related to Chemical Mechanisms of Gas Formation in Hanford High- Level Nuclear Wastes

The objective of this work is to develop a detailed mechanistic understanding of the thermal reactions that lead to gas production in certain high-level waste storage tanks at the Hanford, Washington site. Prediction of the combustion hazard for these wastes and engineering parameters for waste processing depend upon both a knowledge of the composition of stored wastes and the changes that they undergo as a result of thermal and radiolytic decomposition. Since 1980 when Delagard first demonstrated that gas production (H{sub 2} and N{sub 2}O initially, later N{sub 2} and NH{sub 3}) in the affected tanks was related to oxidative degradation of metal complexants present in the waste, periodic attempts have been made to develop detailed mechanisms by which the gases were formed. These studies have resulted in the postulation of a series of reactions that account for many of the observed products, but which involve several reactions for which there is limited, or no, precedent. For example, Al(OH){sub 4}{sup -} has been postulated to function as a Lewis acid to catalyze the reaction of nitrite ion with the metal complexants, NO{sup -} is proposed as an intermediate, and the ratios of gaseous products may be a result of the partitioning of NO{sup -} between two or more reactions. These reactions and intermediates have been the focus of this project since its inception in 1996

Constraining q_0 with Cluster Gas Mass Fractions: A Feasibility Study

As the largest gravitationally bound objects in the universe, clusters of galaxies may contain a fair sample of the baryonic mass fraction of the universe. Since the gas mass fraction from the hot ICM is believed to be constant in time, the value of the cosmological deceleration parameter $q_0$ can be determined by comparing the calculated gas mass fraction in nearby and distant clusters (Pen 1997). To test the potential of this method, we compare the gas fractions derived for a sample of luminous ($L_X > 10^{45}$erg s$^{-1}$), nearby clusters with those calculated for eight luminous, distant ($0.3 < z < 0.6$) clusters using ASCA and ROSAT observations. For consistency, we evaluate the gas mass fraction at a fixed physical radius of 1 $h_{50}^{-1}$ Mpc (assuming $q_0=0.0$). We find a best fit value of $q_0 = 0.07$ with -0.47 < q_0 < 0.67 at 95% confidence. We also determine the gas fraction using the method of Evrard, Metzler, & Navarro (1997) to find the total mass within $r_{500}$, the radius where the mean overdensity of matter is 500 times the critical density. In simulations, this method reduces the scatter in the determination of gravitational mass without biasing the mean. We find that it also reduces the scatter in actual observations for nearby clusters, but not as much as simulations suggest. Using this method, the best fit value is $q_0 = 0.04$ with -0.50 < q_0 < 0.64. The excellent agreement between these two methods suggests that this may be a useful technique for determining $q_0$. The constraints on $q_0$ should improve as more distant clusters are studied and precise temperature profiles are measured to large radii.Comment: 8 pages, 4 figures, uses emulateapj.sty, onecolfloat.st

Singularities and Topology of Meromorphic Functions

We present several aspects of the "topology of meromorphic functions", which we conceive as a general theory which includes the topology of holomorphic functions, the topology of pencils on quasi-projective spaces and the topology of polynomial functions.Comment: 21 pages, 1 figur

The mass profile of A1413 observed with XMM-Newton: implications for the M-T relation

We present an XMM-Newton observation of A1413, a hot (kT = 6.5 keV) galaxy cluster at z=0.143. We construct gas and temperature profiles up to ~1700 kpc, equivalent to ~0.7 r_200. The gas distribution is well described by a beta model in the outer regions, but is more concentrated in the inner ~250 kpc. We introduce a new parameterisation for the inner regions, allowing a steeper gas density distribution. The projected radial temperature profile declines gradually towards the outer regions, by ~20% between 0.1 r_200 and 0.5 r_200, and is well described by a polytropic model with gamma = 1.07+/-0.01. We find that neither projection nor PSF effects change substantially the form of the temperature profile. Assuming hydrostatic equilibrium (HE) and spherical symmetry, we use the observed temperature profile and the new parametric form for the gas density profile to produce the total mass distribution. The mass profile is remarkably well fitted with the Moore et al. (1999) parameterisation with a concentration parameter in the range expected from numerical simulations. There are several indications that beyond a density contrast delta \~600, the gas may no longer be in HE. There is an offset with respect to adiabatic numerical simulations in the virialised part of the cluster, in that the predicted mass for the cluster temperature is ~40% too high. The gas distribution is peaked in the centre primarily as a result of the cusp in the dark matter profile. The X-ray gas to total mass ratio rises with increasing radius to f_gas ~ 0.2. These data strongly support the validity of the current approach for the modelling of the dark matter collapse, but confirm that understanding the gas specific physics is essential. (Abridged)Comment: To appear in A&

A Weak Gravitational Lensing and X-ray Analysis of Abell 2163

We report on the detection of dark matter in the cluster of galaxies Abell~2163 using the weak gravitational distortion of background galaxies, and an analysis of the cluster X-ray emission. We find that while the qualitative distributions of the cluster light and the dark matter are similar -- shallow and extended, with significant substructure -- the X-ray morphology shows a more regular overall appearance. We interpret the joint lensing and X-ray observations as a signature of a merger event in the cluster. We present new ROSAT/HRI data and reanalyze ROSAT/PSPC data, accounting for the effect of a varying background to determine the best fit parameters in the $\beta$-model formalism. We combine the surface brightness fits with two determinations of the radial temperature profile to determine the total mass. Although there are slight variations in the total mass determinations introduced by the uncertainties in the $\beta$-fit, the main contributor to the error arises from the uncertainties in the temperature determinations. Even though the morphologies of the dark matter/light and X-ray gas are quite different, we find that the total mass determined from the X-ray and weak lensing estimates are consistent with each other within the $2\sigma$ error bars, with the X-ray inferred mass a factor of $\simeq 2$ larger. However, as the lensing mass estimates are differential (the surface density at any point is determined relative to the mean in a control annulus), the shallow, extended nature of the mass profile biases the lensing inferred mass downwards. We estimate the correction for this effect and find very good agreement between the corrected lensing and X-ray results. We determine the gas mass fraction and find $f_g \simeq 0.07h^{-3/2}$ at all radii and a constant mass-to-light ratio of $M/L_VComment: 30 pages, latex file. Postscript file also available at ftp://magicbean.berkeley.edu/pub/squires/a2163/a2163_paper.ps.g

A Mosaic of the Coma Cluster of Galaxies with XMM-Newton

The Coma cluster of galaxies was observed with XMM-Newton in 12 partially overlapping pointings. We present here the resulting X-ray map in different energy bands and discuss the large scale structure of this cluster. Many point sources were found throughout the observed area, at least 11 of them are coincident with bright galaxies. We also give a hardness ratio map at the so far highest angular resolution obtained for a cluster of galaxies. In this map we found soft regions at the position of bright galaxies, little variation in the central 15 arcmin, but some harder regions north of the line NGC 4874 - NGC 4889.Comment: 6 pages, 3 figures, accepetd for publication in the A&A special issue on XMM-Newton result

A deep wide survey of faint low surface brightness galaxies in the direction of the Coma cluster of galaxies

We report on a search for faint (R total magnitude fainter than 21) and low surface brightness galaxies (R central surface brightness fainter than ~24) (fLSBs) in a 0.72x0.82 deg2 area centered on the Coma cluster. We analyzed deep B and R band CCD imaging obtained using the CFH12K camera at CFHT and found 735 fLSBs. The total B magnitudes, at the Coma cluster redshift, range from -13 to -9 with B central surface brightness as faint as 27 mag/arcsec2. Using empty field comparisons, we show that most of these fLSBs are probably inside the Coma cluster. We present the results of comparing the projected fLSB distributions with the distributions of normal galaxies and with known X-ray over densities. We also investigate their projected distribution relative to their location in the color magnitude relation. Colors of fLSBs vary between B-R~0.8 and ~1.4 for 2/3 of the sample and this part is consistent with the known CMR red-sequence for bright (R<18) ellipticals in Coma. These fLSBs are likely to have followed the same evolution as giant ellipticals, which is consistent with a simple feedback/collapse formation and a passive evolution. These fLSBs are mainly clustered around NGC4889. We found two other distinct fLSB populations. These populations have respectively redder and bluer colors compared to the giant elliptical red-sequence and possibly formed from stripped faint ellipticals and material stripped from spiral in-falling galaxies.Comment: To be published in A&A, 3 jpeg figures, data and full resolution article can be retrieved from http://cencosw.oamp.fr/. Updated CFHT ackowledgement