Incorporating heterogeneity in farmer disease control behaviour into a livestock disease transmission model.

Human behaviour is critical to effective responses to livestock disease outbreaks, especially with respect to vaccination uptake. Traditionally, mathematical models used to inform this behaviour have not taken heterogeneity in farmer behaviour into account. We address this by exploring how heterogeneity in farmers vaccination behaviour can be incorporated to inform mathematical models.

Health economic evaluation of strategies to eliminate gambiense human African trypanosomiasis in the Mandoul disease focus of Chad.

Human African trypanosomiasis, caused by the gambiense subspecies of Trypanosoma brucei (gHAT), is a deadly parasitic disease transmitted by tsetse. Partners worldwide have stepped up efforts to eliminate the disease, and the Chadian government has focused on the previously high-prevalence setting of Mandoul. In this study, we evaluate the economic efficiency of the intensified strategy that was put in place in 2014 aimed at interrupting the transmission of gHAT, and we make recommendations on the best way forward based on both epidemiological projections and cost-effectiveness.

Modelling to infer the role of animals in gambiense human African trypanosomiasis transmission and elimination in the DRC.

Gambiense human African trypanosomiasis (gHAT) has been targeted for elimination of transmission (EoT) to humans by 2030. Whilst this ambitious goal is rapidly approaching, there remain fundamental questions about the presence of non-human animal transmission cycles and their potential role in slowing progress towards, or even preventing, EoT. In this study we focus on the country with the most gHAT disease burden, the Democratic Republic of Congo (DRC), and use mathematical modelling to assess whether animals may contribute to transmission in specific regions, and if so, how their presence could impact the likelihood and timing of EoT.

Identifying regions for enhanced control of gambiense sleeping sickness in the Democratic Republic of Congo.

Gambiense human African trypanosomiasis (sleeping sickness, gHAT) is a disease targeted for elimination of transmission by 2030. While annual new cases are at a historical minimum, the likelihood of achieving the target is unknown. We utilised modelling to study the impacts of four strategies using currently available interventions, including active and passive screening and vector control, on disease burden and transmission across 168 endemic health zones in the Democratic Republic of the Congo.

Cost-effectiveness of sleeping sickness elimination campaigns in five settings of the Democratic Republic of Congo.

Gambiense human African trypanosomiasis (gHAT) is marked for elimination of transmission by 2030, but the disease persists in several low-income countries. We couple transmission and health outcomes models to examine the cost-effectiveness of four gHAT elimination strategies in five settings - spanning low- to high-risk - of the Democratic Republic of Congo. Alongside passive screening in fixed health facilities, the strategies include active screening at average or intensified coverage levels, alone or with vector control with a scale-back algorithm when no cases are reported for three consecutive years.

Update of transmission modelling and projections of gambiense human African trypanosomiasis in the Mandoul focus, Chad.

Background: In recent years, a programme of vector control, screening and treatment of gambiense human African trypanosomiasis (gHAT) infections led to a rapid decline in cases in the Mandoul focus of Chad. To represent the biology of transmission between humans and tsetse, we previously developed a mechanistic transmission model, fitted to data between 2000 and 2013 which suggested that transmission was interrupted by 2015. The present study outlines refinements to the model to: (1) Assess whether elimination of transmission has already been achieved despite low-level case reporting; (2) quantify the role of intensified interventions in transmission reduction; and (3) predict the trajectory of gHAT in Mandoul for the next decade under different strategies.

Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells.

The human CD8 T cell clone 6C5 has previously been shown to recognize the -butyl-modified Bax peptide LLSY(3-Bu)FGTPT presented by HLA-A*02:01. This nonnatural epitope was likely created as a by-product of fluorenylmethoxycarbonyl protecting group peptide synthesis and bound poorly to HLA-A*02:01. In this study, we used a systematic approach to identify and characterize natural ligands for the 6C5 TCR.

Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma.

Molecular mimicry is one of the leading mechanisms by which infectious agents can induce autoimmunity. Whether a similar mechanism triggers an antitumor immune response is unexplored, and the role of antiviral T cells infiltrating the tumor has remained anecdotal. To address these questions, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes.

Quantifying epidemiological drivers of gambiense human African Trypanosomiasis across the Democratic Republic of Congo.

Gambiense human African trypanosomiasis (gHAT) is a virulent disease declining in burden but still endemic in West and Central Africa. Although it is targeted for elimination of transmission by 2030, there remain numerous questions about the drivers of infection and how these vary geographically. In this study we focus on the Democratic Republic of Congo (DRC), which accounted for 84% of the global case burden in 2016, to explore changes in transmission across the country and elucidate factors which may have contributed to the persistence of disease or success of interventions in different regions.

GPU-Accelerated Discovery of Pathogen-Derived Molecular Mimics of a T-Cell Insulin Epitope.

The strong links between (Human Leukocyte Antigen) HLA, infection and autoimmunity combine to implicate T-cells as primary triggers of autoimmune disease (AD). T-cell crossreactivity between microbially-derived peptides and self-peptides has been shown to break tolerance and trigger AD in experimental animal models. Detailed examination of the potential for T-cell crossreactivity to trigger human AD will require means of predicting which peptides might be recognised by autoimmune T-cell receptors (TCRs).

PeTTSy: a computational tool for perturbation analysis of complex systems biology models.

Background: Over the last decade sensitivity analysis techniques have been shown to be very useful to analyse complex and high dimensional Systems Biology models. However, many of the currently available toolboxes have either used parameter sampling, been focused on a restricted set of model observables of interest, studied optimisation of a objective function, or have not dealt with multiple simultaneous model parameter changes where the changes can be permanent or temporary.

Results: Here we introduce our new, freely downloadable toolbox, PeTTSy (Perturbation Theory Toolbox for Systems).

Identification of human viral protein-derived ligands recognized by individual MHCI-restricted T-cell receptors.

Evidence indicates that autoimmunity can be triggered by virus-specific CD8(+) T cells that crossreact with self-derived peptide epitopes presented on the cell surface by major histocompatibility complex class I (MHCI) molecules. Identification of the associated viral pathogens is challenging because individual T-cell receptors can potentially recognize up to a million different peptides. Here, we generate peptide length-matched combinatorial peptide library (CPL) scan data for a panel of virus-specific CD8(+) T-cell clones spanning different restriction elements and a range of epitope lengths.

CSI: a nonparametric Bayesian approach to network inference from multiple perturbed time series gene expression data.

Here we introduce the causal structure identification (CSI) package, a Gaussian process based approach to inferring gene regulatory networks (GRNs) from multiple time series data. The standard CSI approach infers a single GRN via joint learning from multiple time series datasets; the hierarchical approach (HCSI) infers a separate GRN for each dataset, albeit with the networks constrained to favor similar structures, allowing for the identification of context specific networks. The software is implemented in MATLAB and includes a graphical user interface (GUI) for user friendly inference.

Modeling meiotic chromosomes indicates a size dependent contribution of telomere clustering and chromosome rigidity to homologue juxtaposition.

Meiosis is the cell division that halves the genetic component of diploid cells to form gametes or spores. To achieve this, meiotic cells undergo a radical spatial reorganisation of chromosomes. This reorganisation is a prerequisite for the pairing of parental homologous chromosomes and the reductional division, which halves the number of chromosomes in daughter cells.

Quantitative analysis of regulatory flexibility under changing environmental conditions.

The circadian clock controls 24-h rhythms in many biological processes, allowing appropriate timing of biological rhythms relative to dawn and dusk. Known clock circuits include multiple, interlocked feedback loops. Theory suggested that multiple loops contribute the flexibility for molecular rhythms to track multiple phases of the external cycle.

Robustness from flexibility in the fungal circadian clock.

Background: Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle.

Prediction of photoperiodic regulators from quantitative gene circuit models.

Photoperiod sensors allow physiological adaptation to the changing seasons. The prevalent hypothesis is that day length perception is mediated through coupling of an endogenous rhythm with an external light signal. Sufficient molecular data are available to test this quantitatively in plants, though not yet in mammals.

Luciferases as reporter genes.

Luciferase is the ideal reporter gene to provide temporal and spatial information on promoter activity in Arabidopsis and other eukaryotes; the noninvasive detection of luminescence and short half-life of luciferase activity allow repeated measurements of individual seedlings over several days to assay dynamic changes in gene expression. Transgenic or transiently transformed plants with a luciferase gene under the control of a promoter of interest are required. Detection of the low level of luminescence produced by the luciferase gene in Arabidopsis requires the use of low light detecting charge-coupled device (CCD) cameras or scintillation counters.

Extension of a genetic network model by iterative experimentation and mathematical analysis.

Circadian clocks involve feedback loops that generate rhythmic expression of key genes. Molecular genetic studies in the higher plant Arabidopsis thaliana have revealed a complex clock network. The first part of the network to be identified, a transcriptional feedback loop comprising TIMING OF CAB EXPRESSION 1 (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1), fails to account for significant experimental data.

Analysis of phase of LUCIFERASE expression reveals novel circadian quantitative trait loci in Arabidopsis.

In response to exogenous rhythms of light and temperature, most organisms exhibit endogenous circadian rhythms (i.e. cycles of behavior and gene expression with a periodicity of approximately 24 h).

Use of fluorescent DNA-intercalating dyes in the analysis of DNA via ion-pair reversed-phase denaturing high-performance liquid chromatography.

SYBR Green 1 is an asymmetrical cyanine DNA-binding dye that provides an opportunity for increasing the sensitivity of nucleic acid detection when used in conjunction with gel electrophoresis. In this paper, we summarize the general properties and specific uses of SYBR green 1 in ion-pair reversed-phase denaturing high-performance liquid chromatography (IP DHPLC). We describe several applications for the WAVE DHPLC platform that illustrate the generic potential of such intercalating dyes in mutation detection and gene expression profiling.