Leprosy is a chronic, dermatological and neurological disease that results from infection with the unculturable pathogen Mycobacterium leprae 1 and causes nerve damage that can lead to severe disabilities. There is no known reservoir for M. leprae other than human beings. New opportunities for understanding the transmission of the leprosy bacillus and its phylogeny have arisen following the determination of the complete 3.3-Mb genome sequence of the TN strain, from Tamil Nadu, India 2 .A notable feature of the M. leprae genome is the exceptionally large number of pseudogenes, which occupy almost half of the TN chromosome 2 . The resulting loss of function most likely accounts for the exceptionally slow growth rate of the bacillus and for researchers' failure to culture it in vitro. Given this extensive genome decay, one might expect to find more genetic variability between different isolates of M. leprae, but initial analysis of SNPs demonstrated that these were very rare, occurring roughly once every 28 kb. RESULTS Complete genome sequence of Br4923The Br4923 strain of M. leprae was chosen for complete genome analysis because it was originally isolated from a patient in Brazil, the country with the second highest leprosy burden, and because Brazil is geographically remote from India Recombination between dispersed repeats?The SNPs associated with dispersed repeats deserve some comment, as they provide evidence for genome plasticity in M. leprae. Variation between different copies of repeat family members had previously been reported 18, 19 , but analysis of two complete genomes provided a richer, more comprehensive dataset. Although all four repeat families (RLEP, REPLEP, LEPRPT and LEPREP) were present in the same copy number and location in both genomes, roughly half of the family members displayed sequence polymorphisms when pair-wise comparisons were performed (Fig. 1). The number of polymorphic sites ranged from one in LEPRPT and REPLEP to six in RLEP. With one exception, these resulted from G-A transitions in the RLEP, LEPRPT and LEPREP elements or single-base indels in LEPREP or REPLEP. The polymorphic sites tend to be occupied by A in the TN strain and by G in Br4923. Variation in REPLEP occurs at position 636, which is occupied either by GGG or GG (Fig. 1). Almost 25% of the total SNPs (38/155) occur in these repeats, which account for a mere 1.16% of the genome. The over-representation of SNPs in these elements may indicate that recombination events between different copies of the repetitive elements result in the dispersal of a particular SNP. This interpretation is supported by the strain-specific bias for A and G in the TN and Br4923 strains, respectively, and the finding that more differences are found toward the center of the element rather than near its ends. In turn, these combined findings render polymorphic sites in repetitive DNA unattractive as potential epidemiological tools. Search for informative SNPsFor phylogenetic and phylogeographic purposes, we determined which SNPs had been inhe...

Summary Background Artemisinin-resistant Plasmodium falciparum has been reported in Pailin, western Cambodia, detected as a slow parasite clearance rate in vivo. Emergence of this phenotype in western Thailand and possibly elsewhere threatens to compromise the effectiveness of all artemisinin-based combination therapies. Parasite genetics is associated with parasite clearance rate but does not account for all variation. We investigated contributions of both parasite genetics and host factors to the artemisinin-resistance phenotype in Pursat, western Cambodia. Methods Between June 19 and Nov 28, 2009, and June 26 and Dec 6, 2010, we enrolled patients aged 10 years or older with uncomplicated falciparum malaria, a density of asexual parasites of at least 10 000 per μL of whole blood, no symptoms or signs of severe malaria, no other cause of febrile illness, and no chronic illness. We gave participants 4 mg/kg artesunate at 0, 24, and 48 h, 15 mg/kg mefloquine at 72 h, and 10 mg/kg mefloquine at 96 h. We assessed parasite density on thick blood films every 6 h until undetectable. The parasite clearance half-life was calculated from the parasite clearance curve. We genotyped parasites with 18 microsatellite markers and patients for haemoglobin E, α-thalassaemia, and a mutation of G6PD, which encodes glucose-6-phosphate dehydrogenase. To account for the possible effects of acquired immunity on half-life, we used three surrogates for increased likelihood of exposure to P falciparum: age, sex, and place of residence. This study is registered with ClinicalTrials.gov, number NCT00341003. Findings We assessed 3504 individuals from all six districts of Pursat province seeking treatment for malaria symptoms. We enrolled 168 patients with falciparum malaria who met inclusion criteria. The geometric mean half-life was 5.85 h (95% CI 5.54–6.18) in Pursat, similar to that reported in Pailin (p=0.109). We identified two genetically different parasite clone groups: parasite group 1 (PG1) and parasite group 2 (PG2). Non-significant increases in parasite clearance half-life were seen in patients with haemoglobin E (0.55 h; p=0.078), those of male sex (0.96 h; p=0.064), and in 2010 (0.68 h; p=0.068); PG1 was associated with a significant increase (0.79 h; p=0.033). The mean parasite heritability of half-life was 0.40 (SD 0.17). Interpretation Heritable artemisinin resistance is established in a second Cambodian province. To accurately identify parasites that are intrinsically susceptible or resistant to artemisinins, future studies should explore the effect of erythrocyte polymorphisms and specific immune responses on half-life variation. Funding Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).

Antimalarial drugs impose strong pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome 1,2. Search for signals of selection may lead to genes encoding drug or immune targets 3. The lack of high-throughput genotyping methods, inadequate knowledge of parasite population history, and time-consuming adaptations of parasites to in vitro culture have hampered genome-wide association studies (GWAS) of parasite traits. Here we report genotyping of DNA from 189 culture-adapted P. falciparum parasites using a custom-built array with thousands of single nucleotide polymorphisms (SNPs). Population structure, variation in recombination rate, and loci under recent positive selection were detected. Parasite half maximum inhibitory concentrations (IC50) to seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. The SNP array and genome-wide parameters provide valuable tools and information for new advances in P. falciparum genetics.

Using nationally representative samples for public school teachers and principals, the authors inquired into whether principal background and school processes are related to teacher job satisfaction. Employing hierarchical linear modeling (HLM), the authors were able to control for background characteristics at both the teacher and school levels. They found that 17% of the total variance in teacher job satisfaction is between schools, a statistically significant amount that indicates schools can make a difference in teacher job satisfaction. The authors found that school processes—particularly career and working conditions, staff collegiality, administrative support, and to a lesser extent, positive student behavior and teacher empowerment—are positively associated with teacher job satisfaction. Although two principal background variables—the experience of being a department head or an athletic coach/director—are statistically significant, the authors found the block of school process variables explains far more variance than the block of principal background variables. Based on the findings, the authors discussed issues such as the complexity of the phenomenon of teacher job satisfaction, the role of school process versus principal background, and monetary versus cultural factors.