Plasticity in transmission strategies of the malaria parasite, Plasmodium chabaudi : environmental and genetic effects

Parasites may alter their behaviour to cope with changes in the within-host environment. In particular, investment in transmission may alter in response to the availability of parasite resources or host immune responses. However, experimental and theoretical studies have drawn conflicting conclusions regarding parasites' optimal (adaptive) responses to deterioration in habitat quality. We analyse data from acute infections with six genotypes of the rodent malaria species to quantify how investment in transmission (gametocytes) is influenced by the within-host environment. Using a minimum of modelling assumptions, we find that proportional investment in gametocytogenesis increases sharply with host anaemia and also increases at low parasite densities. Further, stronger dependence of investment on parasite density is associated with greater virulence of the parasite genotype. Our study provides a robust quantitative framework for studying parasites' responses to the host environment and whether these responses are adaptive, which is crucial for predicting the short-term and evolutionary impact of transmission-blocking treatments for parasitic diseases

A fundamental test for stellar feedback recipes in galaxy simulations

Direct comparisons between galaxy simulations and observations that both reach scales < 100 pc are strong tools to investigate the cloud-scale physics of star formation and feedback in nearby galaxies. Here we carry out such a comparison for hydrodynamical simulations of a Milky Way-like galaxy, including stochastic star formation, HII region and supernova feedback, and chemical post-processing at 8 pc resolution. Our simulation shows excellent agreement with almost all kpc-scale and larger observables, including total star formation rates, radial profiles of CO, HI, and star formation through the galactic disc, mass ratios of the ISM components, both whole-galaxy and resolved Kennicutt-Schmidt relations, and giant molecular cloud properties. However, we find that our simulation does not reproduce the observed de-correlation between tracers of gas and star formation on < 100 pc scales, known as the star formation 'uncertainty principle', which indicates that observed clouds undergo rapid evolutionary lifecycles. We conclude that the discrepancy is driven by insufficiently-strong pre-supernova feedback in our simulation, which does not disperse the surrounding gas completely, leaving star formation tracer emission too strongly associated with molecular gas tracer emission, inconsistent with observations. This result implies that the cloud-scale de-correlation of gas and star formation is a fundamental test for feedback prescriptions in galaxy simulations, one that can fail even in simulations that reproduce all other macroscopic properties of star-forming galaxies.Comment: 13 pages, 10 figures, accepted for publication in MNRA

Distinguishing low frequency mutations from RT-PCR and sequence errors in viral deep sequencing data

There is a high prevalence of coronary artery disease (CAD) in patients with left bundle branch block (LBBB); however there are many other causes for this electrocardiographic abnormality. Non-invasive assessment of these patients remains difficult, and all commonly used modalities exhibit several drawbacks. This often leads to these patients undergoing invasive coronary angiography which may not have been necessary. In this review, we examine the uses and limitations of commonly performed non-invasive tests for diagnosis of CAD in patients with LBBB

Investigating intra-host and intra-herd sequence diversity of foot-and-mouth disease virus

Due to the poor-fidelity of the enzymes involved in RNA genome replication, foot-and-mouth disease (FMD) virus samples comprise of unique polymorphic populations. In this study, deep sequencing was utilised to characterise the diversity of FMD virus (FMDV) populations in 6 infected cattle present on a single farm during the series of outbreaks in the UK in 2007. A novel RT–PCR method was developed to amplify a 7.6 kb nucleotide fragment encompassing the polyprotein coding region of the FMDV genome. Illumina sequencing of each sample identified the fine polymorphic structures at each nucleotide position, from consensus level changes to variants present at a 0.24% frequency. These data were used to investigate population dynamics of FMDV at both herd and host levels, evaluate the impact of host on the viral swarm structure and to identify transmission links with viruses recovered from other farms in the same series of outbreaks. In 7 samples, from 6 different animals, a total of 5 consensus level variants were identified, in addition to 104 sub-consensus variants of which 22 were shared between 2 or more animals. Further analysis revealed differences in swarm structures from samples derived from the same animal suggesting the presence of distinct viral populations evolving independently at different lesion sites within the same infected animal

The impact of within-herd genetic variation upon inferred transmission trees for foot-and-mouth disease virus

Full-genome sequences have been used to monitor the fine-scale dynamics of epidemics caused by RNA viruses. However, the ability of this approach to confidently reconstruct transmission trees is limited by the knowledge of the genetic diversity of viruses that exist within different epidemiological units. In order to address this question, this study investigated the variability of 45 foot-and-mouth disease virus (FMDV) genome sequences (from 33 animals) that were collected during 2007 from eight premises (10 different herds) in the United Kingdom. Bayesian and statistical parsimony analysis demonstrated that these sequences exhibited clustering which was consistent with a transmission scenario describing herd-to-herd spread of the virus. As an alternative to analysing all of the available samples in future epidemics, the impact of randomly selecting one sequence from each of these herds was used to assess cost-effective methods that might be used to infer transmission trees during FMD outbreaks. Using these approaches, 85% and 91% of the resulting topologies were either identical or differed by only one edge from a reference tree comprising all of the sequences generated within the outbreak. The sequence distances that accrued during sequential transmission events between epidemiological units was estimated to be 4.6 nucleotides, although the genetic variability between viruses recovered from chronic carrier animals was higher than between viruses from animals with acute-stage infection: an observation which poses challenges for the use of simple approaches to infer transmission trees. This study helps to develop strategies for sampling during FMD outbreaks, and provides data that will guide the development of further models to support control policies in the event of virus incursions into FMD free countries

An uncertainty principle for star formation -- III. The characteristic emission time-scales of star formation rate tracers

We recently presented a new statistical method to constrain the physics of star formation and feedback on the cloud scale by reconstructing the underlying evolutionary timeline. However, by itself this new method only recovers the relative durations of different evolutionary phases. To enable observational applications, it therefore requires knowledge of an absolute 'reference time-scale' to convert relative time-scales into absolute values. The logical choice for this reference time-scale is the duration over which the star formation rate (SFR) tracer is visible because it can be characterised using stellar population synthesis (SPS) models. In this paper, we calibrate this reference time-scale using synthetic emission maps of several SFR tracers, generated by combining the output from a hydrodynamical disc galaxy simulation with the SPS model SLUG2. We apply our statistical method to obtain self-consistent measurements of each tracer's reference time-scale. These include H${\alpha}$ and 12 ultraviolet (UV) filters (from GALEX, Swift, and HST), which cover a wavelength range 150-350 nm. At solar metallicity, the measured reference time-scales of H${\alpha}$ are ${4.32^{+0.09}_{-0.23}}$ Myr with continuum subtraction, and 6-16 Myr without, where the time-scale increases with filter width. For the UV filters we find 17-33 Myr, nearly monotonically increasing with wavelength. The characteristic time-scale decreases towards higher metallicities, as well as to lower star formation rate surface densities, owing to stellar initial mass function sampling effects. We provide fitting functions for the reference time-scale as a function of metallicity, filter width, or wavelength, to enable observational applications of our statistical method across a wide variety of galaxies.Comment: 24 pages, 18 figures, 7 tables (including Appendices); published in MNRA

The impact of mutation and gene conversion on the local diversification of antigen genes in African trypanosomes

Patterns of genetic diversity in parasite antigen gene families hold important information about their potential to generate antigenic variation within and between hosts. The evolution of such gene families is typically driven by gene duplication, followed by point mutation and gene conversion. There is great interest in estimating the rates of these processes from molecular sequences for understanding the evolution of the pathogen and its significance for infection processes. In this study, a series of models are constructed to investigate hypotheses about the nucleotide diversity patterns between closely related gene sequences from the antigen gene archive of the African trypanosome, the protozoan parasite causative of human sleeping sickness in Equatorial Africa. We use a hidden Markov model approach to identify two scales of diversification: clustering of sequence mismatches, a putative indicator of gene conversion events with other lower-identity donor genes in the archive, and at a sparser scale, isolated mismatches, likely arising from independent point mutations. In addition to quantifying the respective probabilities of occurrence of these two processes, our approach yields estimates for the gene conversion tract length distribution and the average diversity contributed locally by conversion events. Model fitting is conducted using a Bayesian framework. We find that diversifying gene conversion events with lower-identity partners occur at least five times less frequently than point mutations on variant surface glycoprotein (VSG) pairs, and the average imported conversion tract is between 14 and 25 nucleotides long. However, because of the high diversity introduced by gene conversion, the two processes have almost equal impact on the per-nucleotide rate of sequence diversification between VSG subfamily members. We are able to disentangle the most likely locations of point mutations and conversions on each aligned gene pair

The prevalences of Salmonella Genomic Island 1 variants in human and animal Salmonella Typhimurium DT104 are distinguishable using a Bayesian approach

Throughout the 1990s, there was an epidemic of multidrug resistant Salmonella Typhimurium DT104 in both animals and humans in Scotland. The use of antimicrobials in agriculture is often cited as a major source of antimicrobial resistance in pathogenic bacteria of humans, suggesting that DT104 in animals and humans should demonstrate similar prevalences of resistance determinants. Until very recently, only the application of molecular methods would allow such a comparison and our understanding has been hindered by the fact that surveillance data are primarily phenotypic in nature. Here, using large scale surveillance datasets and a novel Bayesian approach, we infer and compare the prevalence of Salmonella Genomic Island 1 (SGI1), SGI1 variants, and resistance determinants independent of SGI1 in animal and human DT104 isolates from such phenotypic data. We demonstrate differences in the prevalences of SGI1, SGI1-B, SGI1-C, absence of SGI1, and tetracycline resistance determinants independent of SGI1 between these human and animal populations, a finding that challenges established tenets that DT104 in domestic animals and humans are from the same well-mixed microbial population