An Altered Immune Response, but Not Individual Cationic Antimicrobial Peptides, Is Associated with the Oral Attenuation of Ara4N-Deficient Salmonella enterica Serovar Typhimurium in Mice

Salmonella enterica serovar Typhimurium (S. Typhimurium) uses two-component regulatory systems (TCRS) to respond to stimuli in the local microenvironment. Upon infection, the Salmonella TCRSs PhoP-PhoQ (PhoPQ) and PmrA-PmrB (PmrAB) are activated by environmental signals in the intestinal lumen and within host cells. TCRS-mediated gene expression results in lipopolysaccharide (LPS) modification and cationic antimicrobial peptide resistance. The PmrA-regulated pmrHFIJKLM operon mediates 4-amino-4-deoxy-L-arabinose (Ara4N) production and attachment to the lipid A of LPS. A ΔpmrF S. Typhimurium strain cannot produce Ara4N, exhibits increased sensitivity to cationic antimicrobial peptide (CAMP)-mediated killing, and attenuated virulence in mice upon oral infection. CAMPs are predicted to play a role in elimination of Salmonella, and may activate PhoPQ and PmrAB in vivo, which could increase bacterial resistance to host defenses. Competition experiments between wild type (WT) and ΔpmrF mutant strains of S. Typhimurium indicated that selection against this mutant first occurs within the intestinal lumen early during infection. However, CRAMP and active cryptdins alone are not responsible for elimination of Ara4N-deficient bacteria in vivo. Investigation into the early immune response to ΔpmrF showed that it differed slightly from the early immune response to WT S. Typhimurium. Further investigation into the early immune response to infection of Peyer's patches suggests a role for IL-13 in the attenution of the ΔpmrF mutant strain. Thus, prominent CAMPs present in the mouse intestine are not responsible for the selection against the ΔpmrF strain in this location, but limited alterations in innate immune induction were observed that affect bacterial survival and virulence

Gold in the Dalradian terrane : a review of previous work

The Dalradian Supergroup comprises a Late Precambrian sequence of marine clastic sedimentary rocks and minor basic volcanic rocks which was folded and metamorphosed during the early Palaeozoic Caledonian Orogeny. Intrusive igneous rocks are widespread throughout the Dalradian terrane. The most important in terms of gold metallogenesis are the post-tectonic granites which comprise a diverse suite of calc-alkaline intrusions emplaced between 420 and 395 Ma. Numerous occurrences of gold in bedrock and alluvium are documented in the Dalradian terrane of Scotland. Mesothermal vein occurrences are the most important and include the Cononish deposit, near Tyndrum in Perthshire, where planning permission for mining has been granted. Gold mineralisation of several other styles, including intrusion-related, epithermal, stratiform and occurrences associated with mafic-ultramafic intrusions, is also present. This report has been compiled for the BGS Core Programme project ‘Sedimentary Basin Resources: Gold in orogenic extensional basins – the Dalradian’. This project, carried out between 1997–2000, was designed to investigate the factors controlling the distribution of gold in the Dalradian and to develop a predictive metallogenic model for gold mineralisation in this terrane. This report provides a` review of known gold occurrences and the results of past mineral exploration activity in the Dalradian terrane. The latter has been compiled from records held in BGS archives and the available data are summarised in a series of appendices. Exploration for metalliferous mineralisation has been carried out widely in the Dalradian terrane by commercial mining companies and by BGS. In the 1970s most work focused on Cu, Pb, Zn, Ni and Mo, while more recently, from 1981 onwards, precious metals (Au and PGE) were the prime target. Between 1972 and 1984 the DTI sought to encourage private-sector mineral exploration by the provision of grants under the Mineral Exploration and Investment Grants Act (MEIGA). About 150 reports derived from these projects are available on open-file at BGS. Exploration by BGS was carried out mainly through the DTI-funded Mineral Reconnaissance Programme (MRP), which ran between 1972 and 1997. Nearly 150 reports and associated data releases were produced by the MRP. Together the MEIGA and MRP reports have been the major sources of information used in this report. The combination of improved genetic models for gold deposits, the increased availability of multidisciplinary digital geoscience data and the information on previous exploration summarised in this report provides a sound basis for research on gold mineralisation in the Dalradian terrane. Potential exists in a range of settings that may host economic gold deposits

Role of Salmonella enterica serovar typhimurium two-component system PreA/PreB in modulating PmrA-regulated gene transcription

The PmrA/PmrB two-component system encoded by the pmrCAB operon regulates the modification of Salmonella enterica serovar Typhimurium lipopolysaccharide leading to polymyxin B resistance. PmrA and PhoP are the only known activators of pmrCAB. A transposon mutagenesis screen for additional regulators of a pmrC::MudJ fusion led to the identification of a two-component system, termed PreA/PreB (pmrCAB regulators A and B), that controls the transcription of the pmrCAB operon in response to unknown signals. The initial observations indicated that insertions in, or a deletion of, the preB sensor, but not the preA response regulator, caused upregulation of pmrCAB. Interestingly, the expression of pmrCAB was not upregulated in a preAB mutant grown in LB broth, implicating PreA in the increased expression of pmrCAB in the preB strain. This was confirmed by overexpression of preA+ in preAB or preB backgrounds, which resulted in significant upregulation or further upregulation of pmrCAB. No such effect was observed in any tested preB+ backgrounds. Additionally, an ectopic construct expressing a preA[D51A] allele also failed to upregulate pmrC in any of the pre backgrounds tested, which implies that there is a need for phosphorylation in the activation of the target genes. The observed upregulation of pmrCAB occurred independently of the response regulators PmrA and PhoP. Although a preB mutation led to increased transcription of pmrCAB, this did not result in a measurable effect on polymyxin B resistance. Our genetic data support a model of regulation whereby, in response to unknown signals, the PreB sensor activates PreA, which in turn indirectly upregulates pmrCAB transcription

The LBDS Hercules sample of mJy radio sources at 1.4 GHz - II. Redshift distribution, radio luminosity function, and the high-redshift cut-off

{Abridged} A combination of spectroscopy and broadband photometric redshifts has been used to find the complete redshift distribution of the Hercules sample of millijansky radio sources. These data have been used to examine the evolution of the radio luminosity function (RLF) and its high-redshift cut-off. New redshifts have been measured for eleven sources, and a further ten upper limits are given. The total number of sources with known redshifts in the sample is now 47 (65%). We calculated broadband photometric redshifts for the remaining one-third of the sample. For the luminosity range probed by the present study (P_1.4 > 10^24.5 W/Hz/sr), we use the V/V_max test to show conclusively that there is a deficit of high-redshift (z > 2-2.5) objects. Comparison with the model RLFs of Dunlop & Peacock (1990) shows that our data can now exclude pure luminosity evolution. Two of the models of DP90, and the RLF deduced by direct binning of the data, both favour a luminosity dependence for the high-redshift cut-off, with lower-luminosity sources (P_1.4 \simeq 10^24 W/Hz/sr) in decline by z \simeq 1-1.5 while higher-luminosity sources (P_1.4 \simeq 10^{25-26} W/Hz/sr) decline in comoving number density beyond z \simeq 2-2.5.Comment: Revised version submitted to MNRAS. 16 pages, 12 figure

Genome-wide analysis of the PreA/PreB (QseB/QseC) regulon of Salmonella enterica serovar Typhimurium

Background. The Salmonella PreA/PreB two-component system (TCS) is an ortholog of the QseBC TCS of Escherichia coli. In both Salmonella and E. coli, this system has been shown to affect motility and virulence in response to quorum-sensing and hormonal signals, and to affect the transcription of the Salmonella enterica serovar Typhimurium (S. Typhimurium) pmrAB operon, which encodes an important virulence-associated TCS. Results. To determine the PreA/PreB regulon in S. Typhimurium, we performed DNA microarrays comparing the wild type strain and various preA and/or preB mutants in the presence of ectopically expressed preA (qseB). These data confirmed our previous findings of the negative effect of PreB on PreA gene regulation and identified candidate PreA-regulated genes. A proportion of the activated loci were previously identified as PmrA-activated genes (yibD, pmrAB, cptA, etc.) or were genes located in the local region around preA, including the preAB operon. The transcriptional units were defined in this local region by RT-PCR, suggesting three PreA activated operons composed of preA-preB, mdaB-ygiN, and ygiW-STM3175. Several putative virulence-related phenotypes were examined for preAB mutants, resulting in the observation of a host cell invasion and slight virulence defect of a preAB mutant. Contrary to previous reports on this TCS, we were unable to show a PreA/PreB-dependent effect of the quorum-sensing signal AI-2 or of epinephrine on S. Typhimurium with regard to bacterial motility. Conclusion. This work further characterizes this unorthadox OmpR/EnvZ class TCS and provides novel candidate regulated genes for further study. This first in-depth study of the PreA/PreB regulatory system phenotypes and regulation suggests significant comparative differences to the reported function of the orthologous QseB/QseC in E. coli