Mining microbial genomes for new natural products and biosynthetic pathways

Analyses of microbial genome sequences have revealed numerous examples of ‘cryptic’ or ‘orphan’ biosynthetic gene clusters, with the potential to direct the production of novel, structurally complex natural products. This article summarizes the various methods that have been developed for discovering the products of cryptic biosynthetic gene clusters in microbes and gives an account of my group's discovery of the products of two such gene clusters in the model actinomycete Streptomyces coelicolor M145. These discoveries hint at new mechanisms, roles and specificities for natural product biosynthetic enzymes. Our efforts to elucidate these are described. The identification of new secondary metabolites of S. coelicolor raises the question: what is their biological function? Progress towards answering this question is also summarized

3D Integral Field Observations of Ten Galactic Winds - I. Extended phase (>10 Myr) of mass/energy injection before the wind blows

We present 3D spectroscopic observations of a sample of 10 nearby galaxies with the AAOmega-SPIRAL integral field spectrograph on the 3.9m AAT, the largest survey of its kind to date. The double-beam spectrograph provides spatial maps in a range of spectral diagnostics: [OIII] 5007, H-beta, Mg-b, NaD, [OI] 6300, H-alpha, [NII] 6583, [SII] 6717, 6731. All of the objects in our survey show extensive wind-driven filamentation along the minor axis, in addition to large-scale disk rotation. Our sample can be divided into either starburst galaxies or active galactic nuclei (AGN), although some objects appear to be a combination of these. The total ionizing photon budget available to both classes of galaxies is sufficient to ionise all of the wind-blown filamentation out to large radius. We find however that while AGN photoionisation always dominates in the wind filaments, this is not the case in starburst galaxies where shock ionisation dominates. This clearly indicates that after the onset of star formation, there is a substantial delay (> 10 Myr) before a starburst wind develops. We show why this behavior is expected by deriving ``ionisation'' and dynamical timescales for both AGNs and starbursts. We establish a sequence of events that lead to the onset of a galactic wind. The clear signature provided by the ionisation timescale is arguably the strongest evidence yet that the starburst phenomenon is an impulsive event. A well-defined ionisation timescale is not expected in galaxies with a protracted history of circumnuclear star formation. Our 3D data provide important templates for comparisons with high redshift galaxies.[Abridged]Comment: 43 pages, 30 figures, Accepted for publication in ApJ Jan-2010, Full resolution figures available from: http://www.aao.gov.au/AAO/local/www/rgs/work/winds/public/papers/SPIRAL_WINDS_hi-res.htm

GMASS Ultradeep Spectroscopy of Galaxies at redshift z~2. I. The stellar metallicity

Context: Galaxy metallicities have been measured to redshift z~2 by gas-phase oxygen abundances of the interstellar medium using the R23 and N2 methods. Galaxy stellar metallicities provide crucial data for chemical evolution models but have not been assessed reliably much outside the local Universe. Aims: We determine the iron-abundance, stellar metallicity of star-forming galaxies (SFGs) at redshift z~2, observed as part of the Galaxy Mass Assembly ultra-deep Spectroscopic Survey (GMASS). Methods: We compute the equivalent width of a rest-frame mid-ultraviolet, photospheric absorption-line index, the 1978 index found to vary monotonically with stellar metallicity by Rix and collaborators. We normalise and combine 75 SFG spectra from the GMASS survey to produce a spectrum corresponding to a total integration time 1652.5 hours (and a signal-to-noise ratio ~100 for our 1.5 angstrom binning) of FORS2 spectroscopic observations at the Very Large Telescope. Results: We measure an iron-abundance, stellar metallicity of log (Z/Zsolar) = -0.574+/-0.159 for our spectrum representative of a galaxy of stellar mass 9.4 x 10^9 Msolar assuming a Chabrier IMF. We find that the R04 model SFG spectrum for log (Z/Zsolar) = -0.699 solar metallicity provides the best description of our GMASS coadded spectrum. For similar galaxy stellar mass, our stellar metallicity is ~0.25 dex lower than the oxygen-abundance, gas-phase metallicity quantified by Erb and collaborators for UV-selected star-forming galaxies at z=2. Conclusions: We conclude that we are witnessing the establishment of a light-element overabundance in galaxies as they are being formed at redshift z~2. Our measurements are reminiscent of the alpha-element enhancement seen in low-redshift, galactic bulges and early-type galaxies. (Abridged)Comment: Accepted for publication in Astronomy and Astrophysics on 18 December 2007, 9 pages, 8 figures, aa.bst and aa.cls A&A style file

Observations and modelling of a clumpy galaxy at z=1.6: Spectroscopic clues to the origin and evolution of chain galaxies

We investigate the properties of a clump-cluster galaxy at redshift 1.57. The morphology of this galaxy is dominated by eight star-forming clumps in optical observations, and has photometric properties typical of most clump-cluster and chain galaxies. Its complex asymmetrical morphology has led to the suggestion that this system is a group merger of several initially separate proto-galaxies. We performed H_alpha integral field spectroscopy of this system using SINFONI on VLT UT4. These observations reveal a large-scale velocity gradient throughout the system, but with large local kinematic disturbances. Using a numerical model of gas-rich disk fragmentation, we find that clump interactions and migration can account for the observed disturbed rotation. On the other hand, the global rotation would not be expected for a multiply merging system. We further find that this system follows the stellar mass vs. metallicity, star formation rate and size relations expected for a disk at this redshift, and exhibits a disk-like radial metallicity gradient, so that the scenario of internal disk fragmentation is the most likely one. A red and metallic central concentration appears to be a bulge in this proto-spiral clumpy galaxy. A chain galaxy at redshift 2.07 in the same field also shows disk-like rotation. Such systems are likely progenitors of the present-day bright spiral galaxies, forming their exponential disks through clump migration and disruption and fueling their bulges. Our present results show that disturbed morphologies and kinematics are not necessarily signs of galaxy mergers and interactions, and can instead result from the internal evolution of primordial disks.Comment: A&A, accepted. Version with full resolution figures available at http://aramis.obspm.fr/~bournaud/udfr2.pdf -- Animation of clumpy galaxy models available at http://aramis.obspm.fr/~bournaud/cc/cc.htm

Massive star formation in Wolf-Rayet galaxies. V: Star formation rates, masses and the importance of galaxy interactions

(Abridged) We have performed a comprehensive analysis of a sample of 20 starburst galaxies, most of them classified as Wolf-Rayet galaxies. In this paper, the last of the series, we analyze the global properties of our galaxy sample using multiwavelength data (X-ray, FUV, optical, NIR, FIR, and radio). The agreement between our Ha-based SFR and those provided by indicators at other wavelengths is remarkable, but we consider that the new Ha-based calibration provided by Calzetti et al. (2007) should be preferred over older calibrations. The FUV-based SFR provides a powerful tool to analyze the star-formation activity in both global and local scales independently to the Ha emission. We provide empirical relationships between the ionized gas mass, neutral gas mass, dust mass, stellar mass, and dynamical mass with the B-luminosity. Although all mass estimations increase with increasing luminosity, we find important deviations to the general trend in some objects, that seem to be consequence of their particular evolutionary histories. We investigate the mass-metallicity relations and conclude that both the nature and the star-formation history are needed to understand the relationships between both properties. The majority of the galaxies follow a Schmidt-Kennicutt scaling law of star-formation that agrees with that reported in individual star-forming regions within M~51 but not with that found in normal spiral galaxies. We found a relation between the reddening coefficient and the warm dust mass indicating that the extinction is mainly internal to the galaxies. Considering all data, we found that 17 up to 20 galaxies are clearly interacting or merging with low-luminosity dwarf objects or HI clouds. We conclude that interactions do play a fundamental role in the triggering mechanism of the strong star-formation activity observed in dwarf starburst galaxies.Comment: 33 pages, 21 figures, accepted for publication by A&

Brain/blood ratios of methadone and ABCB1 polymorphisms in methadone-related deaths

Methadone is an opioid that often leads to fatalities. Interpretation of toxicological findings can be challenging if no further information about the case history is available. The aims of this study were (1) to determine whether brain/blood ratios can assist in the interpretation of methadone findings in fatalities; (2) to examine whether polymorphisms in the gene encoding the P-glycoprotein (also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1)), which functions as a multispecific efflux pump in the blood-brain barrier, affect brain/blood ratios of methadone. Femoral venous blood and brain tissue (medulla oblongata and cerebellum) from 107 methadone-related deaths were analysed for methadone by gas chromatography-mass spectrometry. In addition, all the samples were genotyped for three common ABCB1 single nucleotide polymorphisms (SNPs rs1045642, rs1128503, and rs2032582) using ion-pair reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry (ICEMS). In nearly all cases, methadone concentrations were higher in the brain than in the blood. Inter-individual brain/blood ratios varied (0.6-11.6); the mean ratio was 2.85 (standard deviation 1.83, median 2.35). Moreover, significant differences in mean brain/blood ratios were detected among the synonymous genotypes of rs1045642 in ABCB1 (p = 0.001). Cases with the T/T genotype had significantly higher brain/blood ratios than cases with the other genotypes (T/T vs. T/C difference (d) = 1.54, 95% CI [1.14, 2.05], p = 0.002; T/T vs. C/C d = 1.60, 95% CI [1.13, 2.29], p = 0.004). Our results suggest that the rs1045642 polymorphisms in ABCB1 may affect methadone concentrations in the brain and its site of action and may be an additional factor influencing methadone toxicity