Metapopulation structure for perpetuation of Francisella tularensis tularensis

<p>Abstract</p> <p>Background</p> <p>Outbreaks of Type A tularemia due to <it>Francisella tularensis tularensis </it>are typically sporadic and unstable, greatly hindering identification of the determinants of perpetuation and human risk. Martha's Vineyard, Massachusetts has experienced an outbreak of Type A tularemia which has persisted for 9 years. This unique situation has allowed us to conduct long-term eco-epidemiologic studies there. Our hypothesis is that the agent of Type A tularemia is perpetuated as a metapopulation, with many small isolated natural foci of transmission. During times of increased transmission, the foci would merge and a larger scale epizootic would occur, with greater likelihood that humans become exposed.</p> <p>Methods</p> <p>We sampled questing dog ticks from two natural foci on the island and tested them for tularemia DNA. We determined whether the force of transmission differed between the two foci. In addition, we examined the population structure of <it>F. tularensis </it>from ticks by variable number tandem repeat (VNTR) analysis, which allowed estimates of diversity, linkage disequilibrium, and eBURST analysis.</p> <p>Results</p> <p>The prevalence of tularemia DNA in ticks from our two field sites was markedly different: one site was stable over the course of the study yielding as many as 5.6% positive ticks. In contrast, infected ticks from the comparison site markedly increased in prevalence, from 0.4% in 2003 to 3.9% in 2006. Using 4 VNTR loci, we documented 75 different haplotypes (diversity = 0.91). eBURST analysis indicates that the stable site was essentially clonal, but the comparison site contained multiple unrelated lineages. The general bacterial population is evolving clonally (multilocus disequilibrium) and the bacteria in the two sites are reproductively isolated.</p> <p>Conclusion</p> <p>Even within an isolated island, tularemia natural foci that are no more than 15 km apart are uniquely segregated. One of our sites has stable transmission and the other is emergent. The population structure at the stable site is that of a clonal complex of circulating bacteria, whereas the emerging focus is likely to be derived from multiple founders. We conclude that the agent of tularemia may perpetuate in small stable natural foci and that new foci emerge as a result of spillover from such stable sites.</p

The genomic evolution of human prostate cancer.

Prostate cancers are highly prevalent in the developed world, with inheritable risk contributing appreciably to tumour development. Genomic heterogeneity within individual prostate glands and between patients derives predominantly from structural variants and copy-number aberrations. Subtypes of prostate cancers are being delineated through the increasing use of next-generation sequencing, but these subtypes are yet to be used to guide the prognosis or therapeutic strategy. Herein, we review our current knowledge of the mutational landscape of human prostate cancer, describing what is known of the common mutations underpinning its development. We evaluate recurrent prostate-specific mutations prior to discussing the mutational events that are shared both in prostate cancer and across multiple cancer types. From these data, we construct a putative overview of the genomic evolution of human prostate cancer

Disturbance and diversity at two spatial scales

The spatial scale of disturbance is a factor potentially influencing the relationship between disturbance and diversity. There has been discussion on whether disturbances that affect local communities and create a mosaic of patches in different successional stages have the same effect on diversity as regional disturbances that affect the whole landscape. In a microcosm experiment with metacommunities of aquatic protists, we compared the effect of local and regional disturbances on the disturbance–diversity relationship. Local disturbances destroyed entire local communities of the metacommunity and required reimmigration from neighboring communities, while regional disturbances affected the whole metacommunity but left part of each local community intact. Both disturbance types led to a negative relationship between disturbance intensity and Shannon diversity. With strong local disturbance, this decrease in diversity was due to species loss, while strong regional disturbance had no effect on species richness but reduced the evenness of the community. Growth rate appeared to be the most important trait for survival after strong local disturbance and dominance after strong regional disturbance. The pattern of the disturbance–diversity relationship was similar for both local and regional diversity. Although local disturbances at least temporally increased beta diversity by creating a mosaic of differently disturbed patches, this high dissimilarity did not result in regional diversity being increased relative to local diversity. The disturbance–diversity relationship was negative for both scales of diversity. The flat competitive hierarchy and absence of a trade-off between competition and colonization ability are a likely explanation for this pattern

Expression profile of the N-myc Downstream Regulated Gene 2 (NDRG2) in human cancers with focus on breast cancer

<p>Abstract</p> <p>Background</p> <p>Several studies have shown that <it>NDRG2 </it>mRNA is down-regulated or undetectable in various human cancers and cancer cell-lines. Although the function of <it>NDRG2 </it>is currently unknown, high <it>NDRG2 </it>expression correlates with improved prognosis in high-grade gliomas, gastric cancer and hepatocellular carcinomas. Furthermore, <it>in vitro </it>studies have revealed that over-expression of NDRG2 in cell-lines causes a significant reduction in their growth. The aim of this study was to examine levels of <it>NDRG2 </it>mRNA in several human cancers, with focus on breast cancer, by examining affected and normal tissue.</p> <p>Methods</p> <p>By labelling a human Cancer Profiling Array with a radioactive probe against <it>NDRG2</it>, we evaluated the level of <it>NDRG2 </it>mRNA in 154 paired normal and tumor samples encompassing 19 different human cancers. Furthermore, we used quantitative real-time RT-PCR to quantify the levels of <it>NDRG2 </it>and <it>MYC </it>mRNA in thyroid gland cancer and breast cancer, using a distinct set of normal and tumor samples.</p> <p>Results</p> <p>From the Cancer Profiling Array, we saw that the level of <it>NDRG2 </it>mRNA was reduced by at least 2-fold in almost a third of the tumor samples, compared to the normal counterpart, and we observed a marked decreased level in colon, cervix, thyroid gland and testis. However, a Benjamini-Hochberg correction showed that none of the tissues showed a significant reduction in <it>NDRG2 </it>mRNA expression in tumor tissue compared to normal tissue. Using quantitative RT-PCR, we observed a significant reduction in the level of <it>NDRG2 </it>mRNA in a distinct set of tumor samples from both thyroid gland cancer (p = 0.02) and breast cancer (p = 0.004), compared with normal tissue. <it>MYC </it>mRNA was not significantly altered in breast cancer or in thyroid gland cancer, compared with normal tissue. In thyroid gland, no correlation was found between <it>MYC </it>and <it>NDRG2 </it>mRNA levels, but in breast tissue we found a weakly significant correlation with a positive r-value in both normal and tumor tissues, suggesting that <it>MYC </it>and <it>NDRG2 </it>mRNA are regulated together.</p> <p>Conclusion</p> <p>Expression of <it>NDRG2 </it>mRNA is reduced in many different human cancers. Using quantitative RT-PCR, we have verified a reduction in thyroid cancer and shown, for the first time, that <it>NDRG2 </it>mRNA is statistically significantly down-regulated in breast cancer. Furthermore, our observations indicate that other tissues such as cervix and testis can have lower levels of <it>NDRG2 </it>mRNA in tumor tissue compared to normal tissue.</p

TEV GAMMA-RAYS FROM PROTON BLAZARS

Proton acceleration in nearby blazars can be diagnosed measuring their intense TeV $\gamma$-ray emission. Flux predictions for 1101+384 (Mrk421) and 1219+285 (ON231), both strong EGRET sources (0.1-10 GeV), are obtained from model spectra of unsaturated synchrotron pair cascades fitted to publicly available multifrequency data. An experimental effort to confirm the predicted emission in the range 1-10 TeV would be of great importance for the problems of the origin of cosmic rays, the era of galaxy formation and the cosmological distance scale.Comment: 10 pages of latex using Kluwer spacekap.sty, to appear in Space Science Review

Psychosocial family factors and glycemic control among children aged 1-15 years with type 1 diabetes: a population-based survey

Background: Being the parents of children with diabetes is demanding. Jay Belsky’s determinants of parenting model emphasizes both the personal psychological resources, the characteristics of the child and contextual sources such as parents’ work, marital relations and social network support as important determinants for parenting. To better understand the factors influencing parental functioning among parents of children with type 1 diabetes, we aimed to investigate associations between the children’s glycated hemoglobin (HbA1c) and 1) variables related to the parents’ psychological and contextual resources, and 2) frequency of blood glucose measurement as a marker for diabetes-related parenting behavior. Methods: Mothers (n = 103) and fathers (n = 97) of 115 children younger than 16 years old participated in a population-based survey. The questionnaire comprised the Life Orientation Test, the Oslo 3-item Social Support Scale, a single question regarding perceived social limitation because of the child’s diabetes, the Relationship Satisfaction Scale and demographic and clinical variables. We investigated associations by using regression analysis. Related to the second aim hypoglycemic events, child age, diabetes duration, insulin regimen and comorbid diseases were included as covariates. Results: The mean HbA1c was 8.1%, and 29% had HbA1c ≤ 7.5%. In multiple regression analysis, lower HbA1c was associated with higher education and stronger perceptions of social limitation among the mothers. A higher frequency of blood glucose measurement was significantly associated with lower HbA1c in bivariate analysis. Higher child age was significantly associated with higher HbA1c both in bivariate and multivariate analysis. A scatterplot indicated this association to be linear. Conclusions: Most families do not reach recommended treatment goals for their child with type 1 diabetes. Concerning contextual sources of stress and support, the families who successfully reached the treatment goals had mothers with higher education and experienced a higher degree of social limitations because of the child’s diabetes. The continuous increasing HbA1c by age, also during the years before puberty, may indicate a need for further exploring the associations between child characteristics, context-related variables and parenting behavior such as factors facilitating the transfer of parents’ responsibility and motivation for continued frequent treatment tasks to their growing children

TOPOLOGICAL DEFECTS AND HIGHEST ENERGY COSMIC AND GAMMA RAYS

In this paper we review the hypothesis that a considerable part of the cosmic ray flux observed above about 10^{19}\eV may be produced by decaying or annihilating topological defects left over from phase transitions in the early universe at grand unification energy scales (\approx10^{16}\GeV). Possible signatures of cosmic ray producing defect models are discussed which could be tested experimentally in the near future. We thereby focus on model independent universal spectral properties of the predicted particle fluxes.Comment: 11 pages of uuencoded compressed postscript, including 3 figures, to be published in Space Science Reviews

Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2’s unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family