Genome wide interactions of wild-type and activator bypass forms of σ54

Enhancer-dependent transcription involving the promoter specificity factor σ54 is widely distributed amongst bacteria and commonly associated with cell envelope function. For transcription initiation, σ54-RNA polymerase yields open promoter complexes through its remodelling by cognate AAA+ ATPase activators. Since activators can be bypassed in vitro, bypass transcription in vivo could be a source of emergent gene expression along evolutionary pathways yielding new control networks and transcription patterns. At a single test promoter in vivo bypass transcription was not observed. We now use genome-wide transcription profiling, genome-wide mutagenesis and gene over-expression strategies in Escherichia coli, to (i) scope the range of bypass transcription in vivo and (ii) identify genes which might alter bypass transcription in vivo. We find little evidence for pervasive bypass transcription in vivo with only a small subset of σ54 promoters functioning without activators. Results also suggest no one gene limits bypass transcription in vivo, arguing bypass transcription is strongly kept in check. Promoter sequences subject to repression by σ54 were evident, indicating loss of rpoN (encoding σ54) rather than creating rpoN bypass alleles would be one evolutionary route for new gene expression patterns. Finally, cold-shock promoters showed unusual σ54-dependence in vivo not readily correlated with conventional σ54 binding-sites.

Control of wild rubber extraction in the forests of northeast India, 1850-1880

This paper uses the history of rubber extraction to explore competing attempts to control the forest environments of Assam and beyond in the second half of the nineteenth century. Forest communities faced rival efforts at environmental control from both European and Indian traders, as well as from various centres of authority within the Raj. Government attempts to regulate rubber collection were undermined by the weak authority of the Raj in these regions, leading to widespread smuggling. Partly in response to the disruptive influence of rubber traders on the frontier, the Raj began to restrict the presence of outsiders in tribal regions, which came to be understood as distinct areas outside British control. When rubber yields from the forests nearest the Brahmaputra fell in the wake of intensive exploitation, India's scientific foresters demanded and from 1870 obtained the ability to regulate the Assamese forests, blaming indigenous rubber tapping strategies for the declining yields and arguing that Indian rubber could be ‘equal [to] if not better' than Amazonian rubber if only tappers would change their practices. The knowledge of the scientific foresters was fundamentally flawed, however, and their efforts to establish a new type of tapping practice failed. By 1880, the government had largely abandoned attempts to regulate wild Indian rubber, though wild sources continued to dominate the supply of global rubber until after 1910.

A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

PURPOSE: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique.

RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes.

CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

Ecological differences and coexistence in a guild of microparasites: Bartonella in wild rodents

The study of ecological differences among coexisting microparasites has been largely neglected, but it addresses important and unusual issues because there is no clear distinction in such cases between conventional (resource) and apparent competition. Here patterns in the population dynamics are examined for four species of Bartonella (bacterial parasites) coexisting in two wild rodent hosts, bank voles (Clethrionomys glareolus) and wood mice (Apodemus sylvaticus). Using generalized linear modeling and mixed effects models, we examine, for these four species, seasonal patterns and dependencies on host density (both direct and delayed) and, having accounted for these, any differences in prevalence between the two hosts. Whereas previous studies had failed to uncover species differences, here all four were different. Two, B. doshiae and B. taylorii, were more prevalent in wood mice, and one, B. birtlesii, was more prevalent in bank voles. B. birtlesii, B. grahamii, and B. taylorii peaked in prevalence in the fall, whereas B. doshiae peaked in spring. For B. birtlesii in bank voles, density dependence was direct, but for B. taylorii in wood mice density dependence was delayed. B. birtlesii prevalence in wood mice was related to bank vole density. The implications of these differences for species coexistence are discussed.

The dynamics of murid gammaherpesvirus 4 within wild, sympatric populations of bank voles and wood mice

Murid gammaherpesvirus 4 (MuHV-4) is widely used as a small animal model for understanding gammaherpesvirus infections in man. However, there have been no epidemiological studies of the virus in wild populations of small mammals. As MuHV-4 both infects cells associated with the respiratory and immune systems and attempts to evade immune control via various molecular mechanisms, infection may reduce immunocompetence with potentially serious fitness consequences for individuals. Here we report a longitudinal study of antibody to MuHV-4 in a mixed assemblage of bank voles (Clethrionomys glareolus) and wood mice (Apodemus sylvaticus) in the UK. The study was conducted between April 2001 and March 2004. Seroprevalence was higher in wood mice than bank voles, supporting earlier work that suggested wood mice were the major host even though the virus was originally isolated from a bank vole. Analyses of both the probability of having antibodies and the probability of initial seroconversion indicated no clear seasonal pattern or relationship with host density. Instead, infection risk was most closely associated with individual characteristics, with heavier males having the highest risk. This may reflect individual variation in susceptibility, potentially related to variability in the ability to mount an effective immune response.