Seleno-amino acids: A novel class of anti-tuberculosis compounds identified through modified culture screening conditions

Tuberculosis continues to be a major world health problem, causing more deaths than any other bacterial disease. Long treatment durations using a complex cocktail of drugs are often associated with patient non-adherence to therapy, and this has accelerated the development of drug resistant strains. Tuberculosis drug resistance has developed to the extent that some strains are resistant to all clinically used drugs. Therefore novel tuberculosis treatment drugs are urgently required to combat these resistant strains, sterilise latent infections and reduce lengthy treatment durations. This research developed and optimised a high-throughput assay to screen chemical libraries for compounds with anti-mycobacterial activity. The assay utilised fast growing tuberculosis model species M. smegmatis expressing foreign green fluorescent protein (GFP). GFP allowed bacterial growth inhibition to be measured both by fluorescence in addition to absorbance. The assay was expanded to four different culture conditions two of which were nutrient starvation that better mimicked environmental conditions M. tuberculosis is exposed to during infection. These differential culture conditions also revealed previously unidentified mycobacterial inhibitors. Three chemical libraries totaling over 5,000 compounds were screened in the different culture conditions. Seleno-amino acids (Se-AAs), a novel class of anti-tuberculosis compounds, were discovered through screens in nutrient starvation conditions. Based on traits of strong inhibitory activity towards mycobacteria, low human cell line cytotoxicity, structural novelty and known over-the-counter sale as a non-prescription dietary supplement, the Se-AAs were chosen as a promising pharmacophore for further study. Using evidence derived from anti-sense gene knockdown, transposon mutagenesis and biochemical enzyme assays, a pro-drug hypothesis of anti-mycobacterial activity was proposed that involved Se-AAs being transported into the mycobacterial cell by nutrient uptake transporters and subsequent cleavage into catalytically active methylselenium species by lyase enzymes used in mycobacterial sulphurous amino acid metabolism. The activated methylselenium is reduced by mycobacterial redox homeostasis enzymes involved in mycobacterial oxidative defence such as alkyl hydroperoxidases, generating reactive oxygen radical products that damage mycobacterial DNA, lipids and proteins. Reduced methylselenol can be cycled back to the oxidised state by cellular mycothiones, continuously generating damaging reactive oxygen species within the mycobacterial cell. Methylselenium species also disrupt essential mycobacterial processes, such as ketosteroid catabolism and iron-sulphur cluster protein function. In summary, this research has designed and implemented a novel dual label differential culture condition assay useful in the screening and detection of chemicals with anti-tuberculosis properties. A novel structural class of anti-tuberculosis compounds with therapeutic potential, the Se-AAs, was discovered using this assay, the structure-activity relationship of the Se-AAs was explored and a three-component model of Se-AA anti-tuberculosis activity is proposed

Polymicrobial oral biofilm models: simplifying the complex

Over the past century, numerous studies have used oral biofilm models to investigate growth kinetics, biofilm formation, structure and composition, antimicrobial susceptibility and host–pathogen interactions. In vivo animal models provide useful models of some oral diseases; however, these are expensive and carry vast ethical implications. Oral biofilms grown or maintained in vitro offer a useful platform for certain studies and have the advantages of being inexpensive to establish and easy to reproduce and manipulate. In addition, a wide range of variables can be monitored and adjusted to mimic the dynamic environmental changes at different sites in the oral cavity, such as pH, temperature, salivary and gingival crevicular fluid flow rates, or microbial composition. This review provides a detailed insight for early-career oral science researchers into how the biofilm models used in oral research have progressed and improved over the years, their advantages and disadvantages, and how such systems have contributed to our current understanding of oral disease pathogenesis and aetiology

LoCuSS: A Comparison of Sunyaev-Zel'dovich Effect and Gravitational Lensing Measurements of Galaxy Clusters

We present the first measurement of the relationship between the Sunyaev-Zel'dovich effect signal and the mass of galaxy clusters that uses gravitational lensing to measure cluster mass, based on 14 X-ray luminous clusters at z~0.2 from the Local Cluster Substructure Survey. We measure the integrated Compton y-parameter, Y, and total projected mass of the clusters (M_GL) within a projected clustercentric radius of 350 kpc, corresponding to mean overdensities of 4000-8000 relative to the critical density. We find self-similar scaling between M_GL and Y, with a scatter in mass at fixed Y of 32%. This scatter exceeds that predicted from numerical cluster simulations, however, it is smaller than comparable measurements of the scatter in mass at fixed T_X. We also find no evidence of segregation in Y between disturbed and undisturbed clusters, as had been seen with T_X on the same physical scales. We compare our scaling relation to the Bonamente et al. relation based on mass measurements that assume hydrostatic equilibrium, finding no evidence for a hydrostatic mass bias in cluster cores (M_GL = 0.98+/-0.13 M_HSE), consistent with both predictions from numerical simulations and lensing/X-ray-based measurements of mass-observable scaling relations at larger radii. Overall our results suggest that the Sunyaev-Zel'dovich effect may be less sensitive than X-ray observations to the details of cluster physics in cluster cores.Comment: Minor changes to match published version: 2009 ApJL 701:114-11

The host galaxies of luminous quasars

We present results of a deep HST/WFPC2 imaging study of 17 quasars at z~0.4, designed to determine the properties of their host galaxies. The sample consists of quasars with absolute magnitudes in the range -24>M_V>-28, allowing us to investigate host galaxy properties across a decade in quasar luminosity, but at a single redshift. We find that the hosts of all the RLQs, and all the RQQs with nuclear luminosities M_V<-24, are massive bulge-dominated galaxies, confirming and extending the trends deduced from our previous studies. From the best-fitting model host galaxies we have estimated spheroid and black-hole masses, and the efficiency (with respect to Eddington luminosity) with which each quasar is radiating. The largest inferred black-hole mass in our sample is \~3.10^9 M_sun, comparable to those at the centres of M87 and Cygnus A. We find no evidence for super-Eddington accretion in even the most luminous objects. We investigate the role of scatter in the black-hole:spheroid mass relation in determining the ratio of quasar to host-galaxy luminosity, by generating simulated populations of quasars lying in hosts with a Schechter mass function. Within the subsample of the highest luminosity quasars, the observed variation in nuclear-host luminosity ratio is consistent with being the result of the scatter in the black-hole:spheroid relation. Quasars with high nuclear-host ratios can be explained by sub-Eddington accretion onto black holes in the high-mass tail of the black-hole:spheroid relation. Our results imply that, owing to the Schechter cutoff, host mass should not continue to increase linearly with quasar luminosity, at the very highest luminosities. Any quasars more luminous than M_V=-27 should be found in massive elliptical hosts which at the present day would have M_V ~ -24.5.Comment: Accepted for publication in MNRAS. 18 pages; 7 figures and 17 greyscale images are reproduced here at low quality due to space limitations. High-resolution figures are available from ftp://ftp.roe.ac.uk/pub/djef/preprints/floyd2004

The UV-Optical Color Dependence of Galaxy Clustering in the Local Universe

We measure the UV-optical color dependence of galaxy clustering in the local universe. Using the clean separation of the red and blue sequences made possible by the NUV - r color-magnitude diagram, we segregate the galaxies into red, blue and intermediate "green" classes. We explore the clustering as a function of this segregation by removing the dependence on luminosity and by excluding edge-on galaxies as a means of a non-model dependent veto of highly extincted galaxies. We find that \xi (r_p, \pi) for both red and green galaxies shows strong redshift space distortion on small scales -- the "finger-of-God" effect, with green galaxies having a lower amplitude than is seen for the red sequence, and the blue sequence showing almost no distortion. On large scales, \xi (r_p, \pi) for all three samples show the effect of large-scale streaming from coherent infall. On scales 1 Mpc/h < r_p < 10 Mpc/h, the projected auto-correlation function w_p(r_p) for red and green galaxies fits a power-law with slope \gamma ~ 1.93 and amplitude r_0 ~ 7.5 and 5.3, compared with \gamma ~ 1.75 and r_0 ~ 3.9 Mpc/h for blue sequence galaxies. Compared to the clustering of a fiducial L* galaxy, the red, green, and blue have a relative bias of 1.5, 1.1, and 0.9 respectively. The w_p(r_p) for blue galaxies display an increase in convexity at ~ 1 Mpc/h, with an excess of large scale clustering. Our results suggest that the majority of blue galaxies are likely central galaxies in less massive halos, while red and green galaxies have larger satellite fractions, and preferentially reside in virialized structures. If blue sequence galaxies migrate to the red sequence via processes like mergers or quenching that take them through the green valley, such a transformation may be accompanied by a change in environment in addition to any change in luminosity and color.Comment: accepted by MNRA

Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

Background: Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR). Objective: We investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR. Methods: Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR. Results: We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR. Conclusions: Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice

Using inferred residue contacts to distinguish between correct and incorrect protein models

Motivation: The de novo prediction of 3D protein structure is enjoying a period of dramatic improvements. Often, a remaining difficulty is to select the model closest to the true structure from a group of low-energy candidates. To what extent can inter-residue contact predictions from multiple sequence alignments, information which is orthogonal to that used in most structure prediction algorithms, be used to identify those models most similar to the native protein structure

What determines the spatial pattern in summer upwelling trends on the U.S. West Coast?

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C08012, doi:10.1029/2012JC008016.Analysis of sea surface temperature (SST) from coastal buoys suggests that the summertime over-shelf water temperature off the U.S. West Coast has been declining during the past 30 years at an average rate of −0.19°C decade−1. This cooling trend manifests itself more strongly off south-central California than off Oregon and northern California. The variability and trend in the upwelling north of off San Francisco are positively correlated with those of the equatorward wind, indicating a role of offshore Ekman transport in the north. In contrast, Ekman pumping associated with wind stress curls better explains the stronger and statistically more significant cooling trend in the south. While the coast-wide variability and trend in SST are strongly correlated with those of large-scale modes of climate variability, they in general fail to explain the southward intensification of the trend in SST and wind stress curl. This result suggests that the local wind stress curl, often topographically forced, may have played a role in the upwelling trend pattern.H.S. acknowledges the WHOI supports from the Coastal Research Fund in Support of Scientific Staff, the Penzance Endowed Fund in Support of Assistant Scientists, and the Andrew W. Mellon Foundation Endowed Fund for Innovative Research. K.B. and C.E. acknowledge support by the National Science Foundation through grants OCE-1059632 and OCE 1061434.2013-03-0