Understanding the Dynamics of Gene Regulatory Systems : Characterisation and Clinical Relevance of cis-Regulatory Polymorphisms

Peer reviewedPublisher PD

Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones

This work was funded by The BBSRC (BB/D004659/1) the Wellcome Trust (080980/Z/06/Z) and the Medical Research Council (G0701003). Colin Hay was funded by the Chief Scientist Office, Scotland. Scott Davidson was funded by a BBSRC strategic studentship (BBS/S/2005/12001). Philip Cowie was funded by the Scottish Universities Life Sciences Alliance (SULCA).Peer reviewedPublisher PD

Disease associated polymorphisms within the conserved ECR1 enhancer differentially regulate the tissue specific activity of the cannabinoid‐1 receptor gene promoter; implications for cannabinoid pharmacogenetics

EH was funded by Medical Research Scotland (PhD-719-2013) and GW Pharmaceuticals. AMcE was funded by BBSRC project grant (BB/N017544/1). PB and DW are funded by the Scottish Government Rural and Environment Science and Analytical Services Division to the Rowett Institute. The authors declare no conflicts of interest.Peer reviewedPublisher PD

Bifidobacterium breve MRx0004 protects against airway inflammation in a severe asthma model by suppressing both neutrophil and eosinophil lung infiltration

All authors were employees of (or in the case of MID, seconded full-time to) 4D Pharma Research Ltd while engaged in the research project. This work was supported by funding provided by 4D Pharma PLC. 4D Pharma Research Ltd owns a family of patent applications which are pending internationally which are derived from International Patent Publication No. WO2016/203223 which protect the treatment of severe asthma using MRx0004. George Grant, Angela Patterson, Imke Mulder, Seanin McCluskey and Emma Raftis are named as inventors for this patent family. The authors declare no other competing interests.Peer reviewedPublisher PD

Predicting dust extinction from the stellar mass of a galaxy

We investigate how the typical dust extinction of H-alpha luminosity from a star-forming galaxy depends upon star formation rate (SFR), metallicity and stellar mass independently, using a sample of ~90,000 galaxies from Data Release 7 of the Sloan Digital Sky Survey (SDSS). We measure extinctions directly from the Balmer decrement of each source, and while higher values of extinction are associated with an increase in any of the three parameters, we demonstrate that the fundamental property that governs extinction is stellar mass. After this mass-dependent relationship is removed, there is very little systematic dependence of the residual extinctions with either SFR or metallicity, and no significant improvement is obtained from a more general parameterisation. In contrast to this, if either a SFR-dependent or metallicity-dependent extinction relationship is applied, the residual extinctions show significant trends that correlate with the other parameters. Using the SDSS data, we present a relationship to predict the median dust extinction of a sample of galaxies from its stellar mass, which has a scatter of ~0.3 mag. The relationship was calibrated for H-alpha emission, but can be more generally applied to radiation emitted at other wavelengths. These results have important applications for studies of high-redshift galaxies, where individual extinction measurements are hard to obtain but stellar mass estimates can be relatively easily estimated from long-wavelength data.Comment: Accepted for publication in MNRAS. 12 pages. Dedicated to the memory of Timothy Gar

Keck telescope constraint on cosmological variation of the proton-to-electron mass ratio

Molecular transitions recently discovered at redshift z_abs=2.059 toward the bright background quasar J2123-0050 are analysed to limit cosmological variation in the proton-to-electron mass ratio, mu=m_p/m_e. Observed with the Keck telescope, the optical echelle spectrum has the highest resolving power and largest number (86) of H_2 transitions in such analyses so far. Also, (seven) HD transitions are used for the first time to constrain mu-variation. These factors, and an analysis employing the fewest possible free parameters, strongly constrain mu's relative deviation from the current laboratory value: dmu/mu =(+5.6+/-5.5_stat+/-2.9_sys)x10^{-6}, indicating an insignificantly larger mu in the absorber. This is the first Keck result to complement recent null constraints from three systems at z_abs>2.5 observed with the Very Large Telescope. The main possible systematic errors stem from wavelength calibration uncertainties. In particular, distortions in the wavelength solution on echelle order scales are estimated to contribute approximately half the total systematic error component, but our estimate is model dependent and may therefore under or overestimate the real effect, if present. To assist future mu-variation analyses of this kind, and other astrophysical studies of H_2 in general, we provide a compilation of the most precise laboratory wavelengths and calculated parameters important for absorption-line work with H_2 transitions redwards of the hydrogen Lyman limit.Comment: 15 pages, 8 figures (8 EPS files), 3 tables. Accepted by MNRAS. ArXiv copy includes full version of Fig. 1 (additional 8 pages, 7 EPS files). Complete version of Table 1 available at http://astronomy.swin.edu.au/~mmurphy/pub.htm

Evolution of star formation in the UKIDSS ultra deep survey field-I. Luminosity functions and cosmic star formation rate out to z = 1.6

We present new results on the cosmic star formation history in the Subaru/XMM-Newton Deep Survey (SXDS)-Ultra Deep Survey (UDS) field out to z = 1.6. We compile narrowband data from the Subaru Telescope and the Visible and Infrared Survey Telescope forAstronomy (VISTA) in conjunction with broad-band data from the SXDS and UDS, to makea selection of 5725 emission-line galaxies in 12 redshift slices, spanning 10 Gyr of cosmictime. We determine photometric redshifts for the sample using 11-band photometry, and usea spectroscopically confirmed subset to fine tune the resultant redshift distribution. We usethe maximum-likelihood technique to determine luminosity functions in each redshift slice and model the selection effects inherent in any narrow-band selection statistically, to obviatethe retrospective corrections ordinarily required. The deep narrow-band data are sensitive tovery low star formation rates (SFRs), and allow an accurate evaluation of the faint end slopeof the Schechter function, α We find that a is particularly sensitive to the assumed faintest broad-band magnitude of a galaxy capable of hosting an emission line, and propose thatthis limit should be empirically motivated. For this analysis, we base our threshold on thelimiting observed equivalent widths of emission lines in the local Universe. We compute thecharacteristic SFR of galaxies in each redshift slice, and the integrated SFR density,ρ SFR. Wefind our results to be in good agreement with the literature and parametrize the evolution of the SFR density as ρ SFR α(1 + z)4.58 confirming a steep decline in star formation activity since z ~ 1.6.Peer reviewe

Constraining fundamental constants of physics with quasar absorption line systems

We summarize the attempts by our group and others to derive constraints on variations of fundamental constants over cosmic time using quasar absorption lines. Most upper limits reside in the range 0.5-1.5x10-5 at the 3sigma level over a redshift range of approximately 0.5-2.5 for the fine-structure constant, alpha, the proton-to-electron mass ratio, mu, and a combination of the proton gyromagnetic factor and the two previous constants, gp(alpha^2/mu)^nu, for only one claimed variation of alpha. It is therefore very important to perform new measurements to improve the sensitivity of the numerous methods to at least <0.1x10-5 which should be possible in the next few years. Future instrumentations on ELTs in the optical and/or ALMA, EVLA and SKA pathfinders in the radio will undoutedly boost this field by allowing to reach much better signal-to-noise ratios at higher spectral resolution and to perform measurements on molecules in the ISM of high redshift galaxies.Comment: 11 pages, 3 figure

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems

A physical model for the origin of the diffuse cosmic infrared background

We present a physical model for origin of the cosmic diffuse infrared background (CDIRB). By utilizing the observed stellar mass function and its evolution as input to a semi-empirical model of galaxy formation, we isolate the physics driving diffuse IR emission. The model includes contributions from three primary sources of IR emission: steady-state star formation owing to isolated disk galaxies, interaction-driven bursts of star formation owing to close encounters and mergers, and obscured active galactic nuclei (AGN). We find that most of the CDIRB is produced by equal contributions from objects at z=0.5-1 and z>1, as suggested by recent observations. Of those sources, the vast majority of the emission originates in systems with low to moderate IR luminosities (L_{IR}<10^{12} $L_sun); the most luminous objects contribute significant flux only at high-redshifts (z>2). All star formation in ongoing mergers accounts for <10% of the total at all wavelengths and redshifts, while emission directly attributable to the interaction-driven burst itself accounts for <5%. We furthermore find that obscured AGN contribute <1-2% of the CDIRB at all wavelengths and redshifts, with a strong upper limit of less than 4% of the total emission. Finally, since electron-positron pair production interactions with the CDIRB represent the primary source of opacity to very high energy (VHE: E_\gamma > 1 TeV) \gamma-rays, the model provides predictions for the optical depth of the Universe to the most energetic photons. We find that these predictions agree with observations of high-energy cutoffs at TeV energies in nearby blazars, and suggest that while the Universe is extremely optically thick at >10 TeV, the next generation of VHE \gamma-ray telescopes can reasonably expect detections from out to 50-150 Mpc.Comment: 14 pages, 13 figures, submitted to MNRA