Foot-and-mouth disease (FMD) in the UK provides an ideal opportunity to explore optimal control measures for an infectious disease. The presence of fine-scale spatio-temporal data for the 2001 epidemic has allowed the development of epidemiological models that are more accurate than those generally created for other epidemics and provide the opportunity to explore a variety of alternative control measures. Vaccination was not used during the 2001 epidemic; however, the recent DEFRA (Department for Environment Food and Rural Affairs) contingency plan details how reactive vaccination would be considered in future. Here, using the data from the 2001 epidemic, we consider the optimal deployment of limited vaccination capacity in a complex heterogeneous environment. We use a model of FMD spread to investigate the optimal deployment of reactive ring vaccination of cattle constrained by logistical resources. The predicted optimal ring size is highly dependent upon logistical constraints but is more robust to epidemiological parameters. Other ways of targeting reactive vaccination can significantly reduce the epidemic size; in particular, ignoring the order in which infections are reported and vaccinating those farms closest to any previously reported case can substantially reduce the epidemic. This strategy has the advantage that it rapidly targets new foci of infection and that determining an optimal ring size is unnecessary.

We present a three-dimensional hybrid cellular automata (CA)/partial differential equation (PDE) model that allows for the study of morphogenesis in simple cellular systems. We apply the model to the cellular slime mold Dictyostelium discoideum ''from single cells to crawling slug''. Using simple local interactions we can achieve the basic morphogenesis with only three processes: production of and chemotaxis to cAMP and cellular adhesion. The interplay of these processes causes the amoebae to spatially self-organize leading to the complex behaviour of stream and mound formation, cell sorting and slug migration all without any change of parameters during the complete morphogenetic process.7 1997 Academic Press Limited

Despite considerable success elucidating important immunological and resource-based mechanisms that control the dynamics of infection in some diseases, little is known about how differences in these mechanisms result in strain differences in patterns of pathogenesis. Using a combination of data and theory, we disentangle the role of ecological factors (e.g., resource abundance) in the dynamics of pathogenesis for the malaria species Plasmodium chabaudi in CD4+ T cell-depleted mice. We build a series of nested models to systematically test a number of potential regulatory mechanisms and determine the "best" model using statistical techniques. The best-fit model is further tested using an independent data set from mixed-clone competition experiments. We find that parasites preferentially invade older red blood cells even when they are more fecund in younger reticulocytes and that inoculum size has a strong effect on burst size in reticulocytes. Importantly, the results suggest that strain-specific differences in virulence arise from differences in red blood cell age-specific invasion rates and burst sizes, since these are lower for the less virulent strain, as well as from differences in levels of erythropoesis induced by each strain. Our analyses highlight the importance of model selection and validation for revealing new biological insights.

Kinetoplastids are protists defined by one of the most complex mitochondrial genomes in nature, the kinetoplast. In the sleeping sickness parasite Trypanosoma brucei, the kinetoplast is a chain mail-like network of two types of interlocked DNA molecules: a few dozen ∼23-kb maxicircles (homologs of the mitochondrial genome of other eukaryotes) and thousands of ∼1-kb minicircles. Maxicircles encode components of respiratory chain complexes and the mitoribosome. Several maxicircle-encoded mRNAs undergo extensive post-transcriptional RNA editing via addition and deletion of uridines. The process is mediated by hundreds of species of minicircle-encoded guide RNAs (gRNAs), but the precise number of minicircle classes and gRNA genes was unknown. Here we present the first essentially complete assembly and annotation of the kinetoplast genome of T. brucei. We have identified 391 minicircles, encoding not only ∼930 predicted ‘canonical’ gRNA genes that cover nearly all known editing events (accessible via the web at http://hank.bio.ed.ac.uk), but also ∼370 ‘non-canonical’ gRNA genes of unknown function. Small RNA transcriptome data confirmed expression of the majority of both categories of gRNAs. Finally, we have used our data set to refine definitions for minicircle structure and to explore dynamics of minicircle copy numbers.

SummarySleeping sickness is characterized by waves of the extracellular parasite Trypanosoma brucei in host blood, with infections continuing for months or years until inevitable host death. These waves reflect the dynamic conflict between the outgrowth of a succession of parasite antigenic variants and their control by the host immune system. Although a contributor to these dynamics is the density-dependent differentiation from proliferative “slender forms” to transmissible “stumpy forms,” an absence of markers discriminating stumpy forms has prevented accurate parameterization of this component. Here, we exploit the stumpy-specific PAD1 marker, which functionally defines transmission competence, to quantitatively monitor stumpy formation during chronic infections. This allows reconstruction of the temporal events early in infection. Mathematical modeling of these data describes the parameters controlling trypanosome within-host dynamics and provides strong support for a quorum-sensing-like mechanism. Our data reveal the dominance of transmission stages throughout infection, a consequence being austere use of the parasite's antigen repertoire.

Two different RNA editing systems have been described in the kinetoplast-mitochondrion of trypanosomatid protists. The first involves the precise insertion and deletion of U residues mostly within the coding regions of maxicircle-encoded mRNAs to produce open reading frames. This editing is mediated by short overlapping complementary guide RNAs encoded in both the maxicircle and the minicircle molecules and involves a series of enzymatic cleavage-ligation steps. The second editing system is a C 34 to U34 modification in the anticodon of the imported tRNA Trp , thereby permitting the decoding of the UGA stop codon as tryptophan. U-insertion editing probably originated in an ancestor of the kinetoplastid lineage and appears to have evolved in some cases by the replacement of the original pan-edited cryptogene with a partially edited cDNA. The driving force for the evolutionary fixation of these retroposition events was postulated to be the stochastic loss of entire minicircle sequence classes and their encoded guide RNAs upon segregation of the single kinetoplast DNA network into daughter cells at cell division. A large plasticity in the relative abundance of minicircle sequence classes has been observed during cell culture in the laboratory. Computer simulations provide theoretical evidence for this plasticity if a random distribution and segregation model of minicircles is assumed. The possible evolutionary relationship of the C to U and U-insertion editing systems is discussed.

During their life cycle, trypanosomes must overcome conflicting demands to ensure their survival and transmission. First, they must evade immunity without overwhelming the host. Second, they must generate and maintain transmission stages at sufficient levels to allow passage into their tsetse vector. Finally, they must rapidly commit to onward development when they enter the tsetse fly. On the basis of recent quantification and modelling of Trypanosoma brucei infection dynamics, we propose that the interplay between immune evasion and development achieves both infection chronicity and transmissibility. Moreover, we suggest that a novel form of bistable regulation ensures developmental commitment on entry into the tsetse fly midgut.

International debate on the merits of vaccinating poultry against the H5N1 influenza A virus has raised concerns about the possibility of an increased risk of between-flock transmission before outbreaks are detected. Here we show that this 'silent spread' can occur because of incomplete protection at the flock level, even if a vaccine is effective in individual birds. The use of unvaccinated sentinels can mitigate, although not completely eliminate, the problem.