Molecular epidemiology of African sleeping sickness

Human sleeping sickness in Africa, caused by Trypanosoma brucei spp. raises a number of questions. Despite the widespread distribution of the tsetse vectors and animal trypanosomiasis, human disease is only found in discrete foci which periodically give rise to epidemics followed by periods of endemicity A key to unravelling this puzzle is a detailed knowledge of the aetiological agents responsible for different patterns of disease--knowledge that is difficult to achieve using traditional microscopy. The science of molecular epidemiology has developed a range of tools which have enabled us to accurately identify taxonomic groups at all levels (species, subspecies, populations, strains and isolates). Using these tools, we can now investigate the genetic interactions within and between populations of Trypanosoma brucei and gain an understanding of the distinction between human- and nonhuman-infective subspecies. In this review, we discuss the development of these tools, their advantages and disadvantages and describe how they have been used to understand parasite genetic diversity, the origin of epidemics, the role of reservoir hosts and the population structure. Using the specific case of T.b. rhodesiense in Uganda, we illustrate how molecular epidemiology has enabled us to construct a more detailed understanding of the origins, generation and dynamics of sleeping sickness epidemics

The system of genetic exchange in <i>Trypanosoma brucei</i> and other trypanosomatids

In this chapter, we discuss our current understanding of the systems of genetic exchange in trypanosomatids and the im-pact the recent genome projects have had on this area of research. We focus mainly on the details of Trypanosoma brucei as it is the most extensively studied of the “trityps”, but will also refer to a recently discovered novel mechanism of genetic exchange in T. cruzi and the apparent rarity of genetic ex-change in Leishmania sp.The system of genetic exchange in Trypanosoma brucei has been known to exist since the late eighties when a genetic cross between different strains was carried out by co-transmission through the tsetse fly. We discuss the segregation of nuclear, chromosomal and kDNA markers and outline the two current models for the mechanism of genetic exchange. We also present how the completion of the genome project has allowed the identification of polymorphic micro and minisatel-lite markers distributed throughout the genome, which have been used to prove formally that meiosis, independent assortment and crossing over occur in this para-site, as would be predicted in a conventional Mendelian system. Such data have been used to construct the first genetic map of T. brucei, which opens up the use of genetic analysis, coupled with positional cloning and the genome sequence, as a tool to identify the genes involved in a range of traits relevant to the disease

Pictorial Socratic dialogue and conceptual change

Counter-examples used in a Socratic dialogue aim to provoke reflection to effect conceptual changes. However, natural language forms of Socratic dialogues have their limitations. To address this problem, we propose an alternative form of Socratic dialogue called the pictorial Socratic dialogue. A Spring Balance System has been designed to provide a platform for the investigation of the effects of this pedagogy on conceptual changes. This system allows learners to run and observe an experiment. Qualitative Cartesian graphs are employed for learners to represent their solutions. Indirect and intelligent feedback is prescribed through two approaches in the pictorial Socratic dialogue which aim to provoke learners probe through the perceptual structural features of the problem and solution, into the deeper level of the simulation where Archimedes’ Principle governs

Distributed resource discovery using a context sensitive infrastructure

Distributed Resource Discovery in a World Wide Web environment using full-text indices will never scale. The distinct properties of WWW information (volume, rate of change, topical diversity) limits the scaleability of traditional approaches to distributed Resource Discovery. An approach combining metadata clustering and query routing can, on the other hand, be proven to scale much better. This paper presents the Content-Sensitive Infrastructure, which is a design building on these results. We also present an analytical framework for comparing scaleability of different distribution strategies

Calcium signalling links MYC to NUAK1

NUAK1 is a member of the AMPK-related family of kinases. Recent evidence suggests that NUAK1 is an important regulator of cell adhesion and migration, cellular and organismal metabolism, and regulation of TAU stability. As such, NUAK1 may play key roles in multiple diseases ranging from neurodegeneration to diabetes and metastatic cancer. Previous work revealed a crucial role for NUAK1 in supporting viability of tumour cells specifically when MYC is overexpressed. This role is surprising, given that NUAK1 is activated by the tumour suppressor LKB1. Here we show that, in tumour cells lacking LKB1, NUAK1 activity is maintained by an alternative pathway involving calcium-dependent activation of PKCα. Calcium/PKCα-dependent activation of NUAK1 supports engagement of the AMPK-TORC1 metabolic checkpoint, thereby protecting tumour cells from MYC-driven cell death, and indeed, MYC selects for this pathway in part via transcriptional regulation of PKCα and ITPR. Our data point to a novel role for calcium in supporting tumour cell viability and clarify the synthetic lethal interaction between NUAK1 and MYC

SIMPEL: Circuit model for photonic spike processing laser neurons

We propose an equivalent circuit model for photonic spike processing laser neurons with an embedded saturable absorber---a simulation model for photonic excitable lasers (SIMPEL). We show that by mapping the laser neuron rate equations into a circuit model, SPICE analysis can be used as an efficient and accurate engine for numerical calculations, capable of generalization to a variety of different laser neuron types found in literature. The development of this model parallels the Hodgkin--Huxley model of neuron biophysics, a circuit framework which brought efficiency, modularity, and generalizability to the study of neural dynamics. We employ the model to study various signal-processing effects such as excitability with excitatory and inhibitory pulses, binary all-or-nothing response, and bistable dynamics.Comment: 16 pages, 7 figure

Evolution and diversity of secretome genes in the apicomplexan parasite Theileria annulata

&lt;b&gt;BACKGROUND&lt;/b&gt;: Little is known about how apicomplexan parasites have evolved to infect different host species and cell types. Theileria annulata and Theileria parva invade and transform bovine leukocytes but each species favours a different host cell lineage. Parasite-encoded proteins secreted from the intracellular macroschizont stage within the leukocyte represent a critical interface between host and pathogen systems. Genome sequencing has revealed that several Theileria-specific gene families encoding secreted proteins are positively selected at the inter-species level, indicating diversification between the species. We extend this analysis to the intra-species level, focusing on allelic diversity of two major secretome families. These families represent a well-characterised group of genes implicated in control of the host cell phenotype and a gene family of unknown function. To gain further insight into their evolution and function, this study investigates whether representative genes of these two families are diversifying or constrained within the T. annulata population. &lt;b&gt;RESULTS&lt;/b&gt;: Strong evidence is provided that the sub-telomerically encoded SVSP family and the host-nucleus targeted TashAT family have evolved under contrasting pressures within natural T. annulata populations. SVSP genes were found to possess atypical codon usage and be evolving neutrally, with high levels of nucleotide substitutions and multiple indels. No evidence of geographical sub-structuring of allelic sequences was found. In contrast, TashAT family genes, implicated in control of host cell gene expression, are strongly conserved at the protein level and geographically sub-structured allelic sequences were identified among Tunisian and Turkish isolates. Although different copy numbers of DNA binding motifs were identified in alleles of TashAT proteins, motif periodicity was strongly maintained, implying conserved functional activity of these sites. &lt;b&gt;CONCLUSIONS&lt;/b&gt;: This analysis provides evidence that two distinct secretome genes families have evolved under contrasting selective pressures. The data supports current hypotheses regarding the biological role of TashAT family proteins in the management of host cell phenotype that may have evolved to allow adaptation of T. annulata to a specific host cell lineage. We provide new evidence of extensive allelic diversity in representative members of the enigmatic SVSP gene family, which supports a putative role for the encoded products in subversion of the host immune response

Human infectivity trait in <i>Trypanosoma brucei</i>: stability, heritability and relationship to sra expression

Some Trypanosoma brucei lines infect humans whereas others do not because the parasites are lysed by human serum. We have developed a robust, quantitative in vitro assay based on differential uptake of fluorescent dyes by live and dead trypanosomes to quantify the extent and kinetics of killing by human serum. This method has been used to discriminate between 3 classes of human serum resistance; sensitive, resistant and intermediate. TREU 927/4, the parasite used for the T. brucei genome project, is intermediate. The phenotype is expressed in both bloodstream and metacyclic forms, is stably expressed during chromic infections and on cyclical transmission through tsetse flies. Trypanosomes of intermediate phenotype are distinguished from sensitive populations of cells by the slower rate of lysis and by the potential to become fully resistant to killing by human serum as a result of selection or long-term serial passaging in mice, and to pass on full resistance phenotype to its progeny in a genetic cross. The sra gene has been shown previously to determine human serum resistance in T. brucei but screening for the presence and expression of this gene indicated that it is not responsible for the human serum resistance phenotype in the trypanosome lines that we have examined, indicating that an alternative mechanism for HSR exists in these stocks. Examination of the inheritance of the phenotype in F1 hybrids for both bloodstream and metacyclic stages from 2 genetic crosses demonstrated that the phenotype is co-inherited in both life-cycle stages in a manner consistent with being a Mendelian trait, determined by only one or a few genes