Transmission Shifts Underlie Variability in Population Responses to Yersinia pestis Infection

Host populations for the plague bacterium, Yersinia pestis, are highly variable in their response to plague ranging from near deterministic extinction (i.e., epizootic dynamics) to a low probability of extinction despite persistent infection (i.e., enzootic dynamics). Much of the work to understand this variability has focused on specific host characteristics, such as population size and resistance, and their role in determining plague dynamics. Here, however, we advance the idea that the relative importance of alternative transmission routes may vary causing shifts from epizootic to enzootic dynamics. We present a model that incorporates host and flea ecology with multiple transmission hypotheses to study how transmission shifts determine population responses to plague. Our results suggest enzootic persistence relies on infection of an off-host flea reservoir and epizootics rely on transiently maintained flea infection loads through repeated infectious feeds by fleas. In either case, early-phase transmission by fleas (i.e., transmission immediately following an infected blood meal) has been observed in laboratory studies, and we show that it is capable of driving plague dynamics at the population level. Sensitivity analysis of model parameters revealed that host characteristics (e.g., population size and resistance) vary in importance depending on transmission dynamics, suggesting that host ecology may scale differently through different transmission routes enabling prediction of population responses in a more robust way than using either host characteristics or transmission shifts alone

Non-parametric clustering over user features and latent behavioral functions with dual-view mixture models

International audienceWe present a dual-view mixture model to cluster users based on their features and latent behavioral functions. Every component of the mixture model represents a probability density over a feature view for observed user attributes and a behavior view for latent behavioral functions that are indirectly observed through user actions or behaviors. Our task is to infer the groups of users as well as their latent behavioral functions. We also propose a non-parametric version based on a Dirichlet Process to automatically infer the number of clusters. We test the properties and performance of the model on a synthetic dataset that represents the participation of users in the threads of an online forum. Experiments show that dual-view models outperform single-view ones when one of the views lacks information

Possible pro-carcinogenic association of endotoxin on lung cancer among Shanghai women textile workers

Background: Endotoxin (lipopolysaccharide) is a widespread contaminant in many environmental settings. Since the 1970s, there has been generally consistent evidence indicating reduced risks for lung cancer associated with occupational endotoxin exposure. Methods: We updated a case–cohort study nested within a cohort of 267 400 female textile workers in Shanghai, China. We compared exposure histories of 1456 incident lung cancers cases diagnosed during 1989–2006 with those of a reference subcohort of 3022 workers who were free of lung cancer at the end of follow-up. We applied Cox proportional hazards modelling to estimate exposure–response trends, adjusted for age and smoking, for cumulative exposures lagged by 0, 10, and 20 years, and separately for time windows of ⩽15 and \u3e15 years since first exposure. Results: We observed no associations between cumulative exposure and lung cancer, irrespective of lag interval. In contrast, analyses by exposure time windows revealed modestly elevated, but not statistically significant relative risks (∼1.27) at the highest three exposure quintiles for exposures that occurred \u3e15 years since first exposure. Conclusions: The findings do not support a protective effect of endotoxin, but are suggestive of possible lung cancer promotion with increasing time since first exposure

BioTorrents: A File Sharing Service for Scientific Data

The transfer of scientific data has emerged as a significant challenge, as datasets continue to grow in size and demand for open access sharing increases. Current methods for file transfer do not scale well for large files and can cause long transfer times. In this study we present BioTorrents, a website that allows open access sharing of scientific data and uses the popular BitTorrent peer-to-peer file sharing technology. BioTorrents allows files to be transferred rapidly due to the sharing of bandwidth across multiple institutions and provides more reliable file transfers due to the built-in error checking of the file sharing technology. BioTorrents contains multiple features, including keyword searching, category browsing, RSS feeds, torrent comments, and a discussion forum. BioTorrents is available at http://www.biotorrents.net

A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila

Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens

A new molecular breast cancer subclass defined from a large scale real-time quantitative RT-PCR study

BACKGROUND: Current histo-pathological prognostic factors are not very helpful in predicting the clinical outcome of breast cancer due to the disease's heterogeneity. Molecular profiling using a large panel of genes could help to classify breast tumours and to define signatures which are predictive of their clinical behaviour. METHODS: To this aim, quantitative RT-PCR amplification was used to study the RNA expression levels of 47 genes in 199 primary breast tumours and 6 normal breast tissues. Genes were selected on the basis of their potential implication in hormonal sensitivity of breast tumours. Normalized RT-PCR data were analysed in an unsupervised manner by pairwise hierarchical clustering, and the statistical relevance of the defined subclasses was assessed by Chi2 analysis. The robustness of the selected subgroups was evaluated by classifying an external and independent set of tumours using these Chi2-defined molecular signatures. RESULTS: Hierarchical clustering of gene expression data allowed us to define a series of tumour subgroups that were either reminiscent of previously reported classifications, or represented putative new subtypes. The Chi2 analysis of these subgroups allowed us to define specific molecular signatures for some of them whose reliability was further demonstrated by using the validation data set. A new breast cancer subclass, called subgroup 7, that we defined in that way, was particularly interesting as it gathered tumours with specific bioclinical features including a low rate of recurrence during a 5 year follow-up. CONCLUSION: The analysis of the expression of 47 genes in 199 primary breast tumours allowed classifying them into a series of molecular subgroups. The subgroup 7, which has been highlighted by our study, was remarkable as it gathered tumours with specific bioclinical features including a low rate of recurrence. Although this finding should be confirmed by using a larger tumour cohort, it suggests that gene expression profiling using a minimal set of genes may allow the discovery of new subclasses of breast cancer that are characterized by specific molecular signatures and exhibit specific bioclinical features

Microevolution of Pandemic Vibrio parahaemolyticus Assessed by the Number of Repeat Units in Short Sequence Tandem Repeat Regions

The emergence of the pandemic strain Vibrio parahaemolyticus O3:K6 in 1996 caused a large increase of diarrhea outbreaks related to seafood consumption in Southeast Asia, and later worldwide. Isolates of this strain constitutes a clonal complex, and their effectual differentiation is possible by comparison of their variable number tandem repeats (VNTRs). The differentiation of the isolates by the differences in VNTRs will allow inferring the population dynamics and microevolution of this strain but this requires knowing the rate and mechanism of VNTRs' variation. Our study of mutants obtained after serial cultivation of clones showed that mutation rates of the six VNTRs examined are on the order of 10−4 mutant per generation and that difference increases by stepwise addition of single mutations. The single stepwise mutation (SSM) was deduced because mutants with 1, 2, 3, or more repeat unit deletions or insertions follow a geometric distribution. Plausible phylogenetic trees are obtained when, according to SSM, the genetic distance between clusters with different number of repeats is assessed by the absolute differences in repeats. Using this approach, mutants originated from different isolates of pandemic V. parahaemolyticus after serial cultivation are clustered with their parental isolates. Additionally, isolates of pandemic V. parahaemolyticus from Southeast Asia, Tokyo, and northern and southern Chile are clustered according their geographical origin. The deepest split in these four populations is observed between the Tokyo and southern Chile populations. We conclude that proper phylogenetic relations and successful tracing of pandemic V. parahaemolyticus requires measuring the differences between isolates by the absolute number of repeats in the VNTRs considered

Entry of Yersinia pestis into the Viable but Nonculturable State in a Low-Temperature Tap Water Microcosm

Yersinia pestis, the causative agent of plague, has caused several pandemics throughout history and remains endemic in the rodent populations of the western United States. More recently, Y. pestis is one of several bacterial pathogens considered to be a potential agent of bioterrorism. Thus, elucidating potential mechanisms of survival and persistence in the environment would be important in the event of an intentional release of the organism. One such mechanism is entry into the viable but non-culturable (VBNC) state, as has been demonstrated for several other bacterial pathogens. In this study, we showed that Y. pestis became nonculturable by normal laboratory methods after 21 days in a low-temperature tap water microcosm. We further show evidence that, after the loss of culturability, the cells remained viable by using a variety of criteria, including cellular membrane integrity, uptake and incorporation of radiolabeled amino acids, and protection of genomic DNA from DNase I digestion. Additionally, we identified morphological and ultrastructural characteristics of Y. pestis VBNC cells, such as cell rounding and large periplasmic spaces, by electron microscopy, which are consistent with entry into the VBNC state in other bacteria. Finally, we demonstrated resuscitation of a small number of the non-culturable cells. This study provides compelling evidence that Y. pestis persists in a low-temperature tap water microcosm in a viable state yet is unable to be cultured under normal laboratory conditions, which may prove useful in risk assessment and remediation efforts, particularly in the event of an intentional release of this organism

Genome-Wide Modeling of Transcription Preinitiation Complex Disassembly Mechanisms using ChIP-chip Data

Apparent occupancy levels of proteins bound to DNA in vivo can now be routinely measured on a genomic scale. A challenge in relating these occupancy levels to assembly mechanisms that are defined with biochemically isolated components lies in the veracity of assumptions made regarding the in vivo system. Assumptions regarding behavior of molecules in vivo can neither be proven true nor false, and thus is necessarily subjective. Nevertheless, within those confines, connecting in vivo protein-DNA interaction observations with defined biochemical mechanisms is an important step towards fully defining and understanding assembly/disassembly mechanisms in vivo. To this end, we have developed a computational program PathCom that models in vivo protein-DNA occupancy data as biochemical mechanisms under the assumption that occupancy levels can be related to binding duration and explicitly defined assembly/disassembly reactions. We exemplify the process with the assembly of the general transcription factors (TBP, TFIIB, TFIIE, TFIIF, TFIIH, and RNA polymerase II) at the genes of the budding yeast Saccharomyces. Within the assumption inherent in the system our modeling suggests that TBP occupancy at promoters is rather transient compared to other general factors, despite the importance of TBP in nucleating assembly of the preinitiation complex. PathCom is suitable for modeling any assembly/disassembly pathway, given that all the proteins (or species) come together to form a complex