Beyond the Constitution? Englishness in a post-devolved Britain

The notion that we are currently witnessing a growing commitment to English nationalism and deeper and wider identification with Englishness, as opposed to Britishness, is becoming part of the political wisdom of the age. The suggestion that the English are beginning to think of themselves as a nation with a separate identity from the other nationalities within the United Kingdom feeds into a vexed debate among politicians and commentators about the identity and future of ‘Britishness’ itself. This paper argues for the adoption of a greater sense of historical proportion about these trends, and challenges the widely held presumption that the rise of Englishness signals the death-knell of values and identities associated with Britishness

Characterisation of Ga(1-x)In(x)Sb quantum wells (x~0.3) grown on GaAs using AlGaSb interface misfit buffer

GaInSb multiple quantum wells (MQW) grown on GaAs using an AlGaSb interface misfit (IMF) metamorphic buffer layer technique exhibit superior infrared photoluminescence (PL) at room temperature compared with MQW grown directly on GaSb. PL emission was obtained in the range from 1.7 μm (4 K) to 1.9 μm (300 K) from Ga1-xInxSb samples containing five compressively strained QW with In content x~0.3. Structural and optical characterisation confirms that the AlGaSb IMF growth technique is promising for the development of photonic devices operating at extended wavelengths based on GaAs substrates

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits

Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications

<p>Abstract</p> <p>Background</p> <p>This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ) against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for <it>Plasmodium falciparum </it>resistance against CQ and sulphadoxine/pyrimethamine (SP).</p> <p>Methods</p> <p>Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for <it>P. falciparum </it>chloroquine resistance transporter gene (<it>pfcrt</it>)-76 polymorphisms, mutation <it>pfcrt-</it>S163R and the antifolate resistance-associated mutations dihydrofolate reductase (<it>dhfr</it>)-C59R and dihydropteroate synthase (<it>dhps</it>)-K540E. Direct DNA sequencing of the <it>pfcrt </it>gene from three representative field samples was carried out after DNA amplification of the 13 exons of the <it>pfcrt </it>gene.</p> <p>Results</p> <p>Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant <it>pfcrt </it>T76 was 98% in 112 amplified pre-treatment samples. The presence of <it>pfcrt </it>T76 was poorly predictive of <it>in vivo </it>CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9). The prevalence of <it>dhfr </it>Arg-59 mutation in 99 amplified samples was 5%, while the <it>dhps </it>Glu-540 was not detected in any of 119 amplified samples. Sequencing the <it>pfcrt </it>gene confirmed that Yemeni CQ resistant <it>P. falciparum </it>carry the old world (Asian and African) CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371.</p> <p>Conclusion</p> <p>This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR <it>P. falciparum </it>parasites from Yemen. Mutant <it>pfcrt</it>T76 is highly prevalent but it is a poor predictor of treatment failure in the study population. The prevalence of mutation <it>dhfr</it>Arg59 is suggestive of emerging resistance to SP, which is currently a component of the recommended combination treatment of falciparum malaria in Yemen. More studies on these markers are recommended for surveillance of resistance in the study area.</p

Indels, structural variation, and recombination drive genomic diversity in Plasmodium falciparum.

The malaria parasite Plasmodium falciparum has a great capacity for evolutionary adaptation to evade host immunity and develop drug resistance. Current understanding of parasite evolution is impeded by the fact that a large fraction of the genome is either highly repetitive or highly variable and thus difficult to analyze using short-read sequencing technologies. Here, we describe a resource of deep sequencing data on parents and progeny from genetic crosses, which has enabled us to perform the first genome-wide, integrated analysis of SNP, indel and complex polymorphisms, using Mendelian error rates as an indicator of genotypic accuracy. These data reveal that indels are exceptionally abundant, being more common than SNPs and thus the dominant mode of polymorphism within the core genome. We use the high density of SNP and indel markers to analyze patterns of meiotic recombination, confirming a high rate of crossover events and providing the first estimates for the rate of non-crossover events and the length of conversion tracts. We observe several instances of meiotic recombination within copy number variants associated with drug resistance, demonstrating a mechanism whereby fitness costs associated with resistance mutations could be compensated and greater phenotypic plasticity could be acquired

Adaptive Copy Number Evolution in Malaria Parasites

Copy number polymorphism (CNP) is ubiquitous in eukaryotic genomes, but the degree to which this reflects the action of positive selection is poorly understood. The first gene in the Plasmodium folate biosynthesis pathway, GTP-cyclohydrolase I (gch1), shows extensive CNP. We provide compelling evidence that gch1 CNP is an adaptive consequence of selection by antifolate drugs, which target enzymes downstream in this pathway. (1) We compared gch1 CNP in parasites from Thailand (strong historical antifolate selection) with those from neighboring Laos (weak antifolate selection). Two percent of chromosomes had amplified copy number in Laos, while 72% carried multiple (2–11) copies in Thailand, and differentiation exceeded that observed at 73 synonymous SNPs. (2) We found five amplicon types containing one to greater than six genes and spanning 1 to >11 kb, consistent with parallel evolution and strong selection for this gene amplification. gch1 was the only gene occurring in all amplicons suggesting that this locus is the target of selection. (3) We observed reduced microsatellite variation and increased linkage disequilibrium (LD) in a 900-kb region flanking gch1 in parasites from Thailand, consistent with rapid recent spread of chromosomes carrying multiple copies of gch1. (4) We found that parasites bearing dhfr-164L, which causes high-level resistance to antifolate drugs, carry significantly (p = 0.00003) higher copy numbers of gch1 than parasites bearing 164I, indicating functional association between genes located on different chromosomes but linked in the same biochemical pathway. These results demonstrate that CNP at gch1 is adaptive and the associations with dhfr-164L strongly suggest a compensatory function. More generally, these data demonstrate how selection affects multiple enzymes in a single biochemical pathway, and suggest that investigation of structural variation may provide a fast-track to locating genes underlying adaptation

Genome-Wide Compensatory Changes Accompany Drug- Selected Mutations in the Plasmodium falciparum crt Gene

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well in culture, which may reflect adaptive changes in the parasite genome to compensate for the mutations in PfCRT. Using three isogenic clones that have different drug resistance profiles corresponding to unique mutations in the pfcrt gene (106/1K76, 106/176I, and 106/76I-352K), we investigated changes in gene expression in these parasites grown with and without CQ. We also conducted hybridizations of genomic DNA to identify copy number (CN) changes in parasite genes. RNA transcript levels from 45 genes were significantly altered in one or both mutants relative to the parent line, 106/1K76. Most of the up-regulated genes are involved in invasion, cell growth and development, signal transduction, and transport activities. Of particular interest are genes encoding proteins involved in transport and/or regulation of cytoplasmic or compartmental pH such as the V-type H+ pumping pyrophosphatase 2 (PfVP2), Ca2+/H+ antiporter VCX1, a putative drug transporter and CN changes in pfmdr1. These changes may represent adaptations to altered functionality of PfCRT, a predicted member of drug/metabolite transporter superfamily found on the parasite food vacuole (FV) membrane. Further investigation of these genes may shed light on how the parasite compensates for functional changes accompanying drug resistance mutations in a gene coding for a membrane/drug transporter