http://hdl.handle.net/1842/3413 Wed, 22 May 2013 18:30:00 GMT 2013-05-22T18:30:00Z http://hdl.handle.net/1842/4442 Title: Construction of a large scale integrated map of macrophage pathogen recognition and effector systems Authors: Raza, S.; McDerment, N.; Lacaze, P. A.; Robertson, K.; Watterson, S.; Chen, Y.; Chisholm, M.; Eleftheriadis, G.; Monk, S.; O'Sullivan, M.; Turnbull, A.; Roy, D.; Theocharidis, A.; Ghazal, P.; Freeman, T. C. Abstract: Background: In an effort to better understand the molecular networks that underpin macrophage activation we have been assembling a map of relevant pathways. Manual curation of the published literature was carried out in order to define the components of these pathways and the interactions between them. This information has been assembled into a large integrated directional network and represented graphically using the modified Edinburgh Pathway Notation (mEPN) scheme. Results: The diagram includes detailed views of the toll-like receptor (TLR) pathways, other pathogen recognition systems, NF-kappa-B, apoptosis, interferon signalling, MAP-kinase cascades, MHC antigen presentation and proteasome assembly, as well as selected views of the transcriptional networks they regulate. The integrated pathway includes a total of 496 unique proteins, the complexes formed between them and the processes in which they are involved. This produces a network of 2,170 nodes connected by 2,553 edges. Conclusions: The pathway diagram is a navigable visual aid for displaying a consensus view of the pathway information available for these systems. It is also a valuable resource for computational modelling and aid in the interpretation of functional genomics data. We envisage that this work will be of value to those interested in macrophage biology and also contribute to the ongoing Systems Biology community effort to develop a standard notation scheme for the graphical representation of biological pathways. Sat, 01 May 2010 00:00:00 GMT http://hdl.handle.net/1842/4442 2010-05-01T00:00:00Z http://hdl.handle.net/1842/4009 Title: Regulation of gene expression during M-G1-phase in fission yeast through Plo1p and forkhead transcription factors Authors: Papadopoulou, Kyriaki; Ng, Szu Shien; Ohkura, Hiroyuki; Geymonat, Marco; Sedgwick, Steven G.; McInerny, Christopher J. Abstract: In fission yeast the expression of several genes during M-G1 phase is controlled by binding of the PCB binding factor (PBF) transcription factor complex to Pombe cell cycle box ( PCB) promoter motifs. Three components of PBF have been identified, including two forkhead-like proteins Sep1p and Fkh2p, and a MADS-box-like protein, Mbx1p. Here, we examine how PBF is controlled and reveal a role for the Polo kinase Plo1p.plo1(+) shows genetic interactions with sep1(+), fkh2(+) and mbx1(+), and overexpression of a kinase-domain mutant of plo1 abolishes M-G1-phase transcription. Plo1p binds to and directly phosphorylates Mbx1p, the first time a Polo kinase has been shown to phosphorylate a MADS box protein in any organism. Fkh2p and Sep1p interact in vivo and in vitro, and Fkh2p, Sep1p and Plo1p contact PCB promoters in vivo. However, strikingly, both Fkh2p and Plo1p bind to PCB promoters only when PCB-controlled genes are not expressed during S- and G2-phase, whereas by contrast Sep1p contacts PCBs coincident with M-G1-phase transcription. Thus, Plo1p, Fkh2p and Sep1p control M-G1-phase gene transcription through a combination of phosphorylation and cell-cycle-specific DNA binding to PCBs. Tue, 01 Apr 2008 00:00:00 GMT http://hdl.handle.net/1842/4009 2008-04-01T00:00:00Z http://hdl.handle.net/1842/3032 Title: Direct estimation of the mitochondrial DNA mutation rate in Drosophila melanogaster Authors: Keightley P.D.; Charlesworth B.; Haag-Liautard C.; Coffey N.; Houle D.; Lynch M. Abstract: Mitochondrial DNA (mtDNA) variants are widely used in evolutionary genetics as markers for population history and to estimate divergence times among taxa. Inferences of species history are generally based on phylogenetic comparisons, which assume that molecular evolution is clock-like. Between-species comparisons have also been used to estimate the mutation rate, using sites that are thought to evolve neutrally. We directly estimated the mtDNA mutation rate by scanning the mitochondrial genome of Drosophila melanogaster lines that had undergone approximately 200 generations of spontaneous mutation accumulation (MA). We detected a total of 28 point mutations and eight insertion-deletion (indel) mutations, yielding an estimate for the single-nucleotide mutation rate of 6.2 x 10(-8) per site per fly generation. Most mutations were heteroplasmic within a line, and their frequency distribution suggests that the effective number of mitochondrial genomes transmitted per female per generation is about 30. We observed repeated occurrences of some indel mutations, suggesting that indel mutational hotspots are common. Among the point mutations, there is a large excess of G -> A mutations on the major strand (the sense strand for the majority of mitochondrial genes). These mutations tend to occur at nonsynonymous sites of protein-coding genes, and they are expected to be deleterious, so do not become fixed between species. The overall mtDNA mutation rate per base pair per fly generation in Drosophila is estimated to be about 10x higher than the nuclear mutation rate, but the mitochondrial major strand G -> A mutation rate is about 70x higher than the nuclear rate. Silent sites are substantially more strongly biased towards A and T than nonsynonymous sites, consistent with the extreme mutation bias towards A+T. Strand-asymmetric mutation bias, coupled with selection to maintain specific nonsynonymous bases, therefore provides an explanation for the extreme base composition of the mitochondrial genome of Drosophila. Fri, 01 Aug 2008 00:00:00 GMT http://hdl.handle.net/1842/3032 2008-08-01T00:00:00Z http://hdl.handle.net/1842/2836 Title: Porcine cysticercosis in southeast Uganda: seroprevalence in Kamuli and Kaliro districts Authors: Waiswa, C; Fèvre, E M; Nsadha, Z; Sikasunge, C S; Willingham III, A L Abstract: The recent recognition of neurocysticercosis as a major cause of epilepsy in Uganda and changes in pig demography have lead to a need to better understand the basic epidemiology of Taenia solium infections in pigs and humans. Human exposure is a function of the size of the animal reservoir of this zoonosis. This is the first field survey for porcine cysticercosis to investigate the prevalence of antigen-positive pigs across an entire rural district of south-east Uganda. In our field surveys, 8.6% of 480 pigs screened were sero-positive for the parasite by B158/B60 Ag-ELISA. In addition, of the 528 homesteads surveyed 138 (26%) did not have pit latrines indicating a high probability of pigs having access to human faeces and thus T. solium eggs. This study thus indicates the need for better data on this neglected zoonotic disease in Uganda, with a particular emphasis on the risk factors for infection in both pigs and humans. In this regard, further surveys of pigs, sero-prevalence surveys in humans and an understanding of cysticercosis-related epilepsy are required, together with risk-factor studies for human and porcine infections. Thu, 01 Jan 2009 00:00:00 GMT http://hdl.handle.net/1842/2836 2009-01-01T00:00:00Z