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

Failure of vaccination to prevent outbreaks of foot-and-mouth disease

Outbreaks of foot-and-mouth disease persist in dairy cattle herds in Saudi Arabia despite revaccination at intervals of 4-6 months. Vaccine trials provide data on antibody responses following vaccination. Using this information we developed a mathematical model of the decay of protective antibodies with which we estimated the fraction of susceptible animals at a given time after vaccination. The model describes the data well, suggesting over 95% take with an antibody half-life of 43 days. Farm records provided data on the time course of five outbreaks. We applied a 'SLIR' epidemiological model to these data, fitting a single parameter representing disease transmission rate. The analysis provides estimates of the basic reproduction number R(0), which may exceed 70 in some cases. We conclude that the critical intervaccination interval which would provide herd immunity against FMDV is unrealistically short, especially for heterologous challenge. We suggest that it may not be possible to prevent foot-and-mouth disease outbreaks on these farms using currently available vaccines

Genetic and antigenic characterisation of serotype A FMD viruses from East Africa to select new vaccine strains

Vaccine strain selection for emerging foot-and-mouth disease virus (FMDV) outbreaks in enzootic countries can be addressed through antigenic and genetic characterisation of recently circulating viruses. A total of 56 serotype A FMDVs isolated between 1998 and 2012, from Central, East and North African countries were characterised antigenically by virus neutralisation test using antisera to three existing and four candidate vaccine strains and, genetically by characterising the full capsid sequence data. A Bayesian analysis of the capsid sequence data revealed the viruses to be of either African or Asian topotypes with subdivision of the African topotype viruses into four genotypes (Genotypes I, II, IV and VII). The existing vaccine strains were found to be least cross-reactive (good matches observed for only 5.4–46.4% of the sampled viruses). Three bovine antisera, raised against A-EA-2007, A-EA-1981 and A-EA-1984 viruses, exhibited broad cross-neutralisation, towards more than 85% of the circulating viruses. Of the three vaccines, A-EA-2007 was the best showing more than 90% in-vitro cross-protection, as well as being the most recent amongst the vaccine strains used in this study. It therefore appears antigenically suitable as a vaccine strain to be used in the region in FMD control programmes

Detection of Crab Giant Pulses Using the Mileura Widefield Array Low Frequency Demonstrator Field Prototype System

We report on the detection of giant pulses from the Crab Nebula pulsar at a frequency of 200 MHz using the field deployment system designed for the Mileura Widefield Array's Low Frequency Demonstrator (MWA-LFD). Our observations are among the first high-quality detections at such low frequencies. The measured pulse shapes are deconvolved for interstellar pulse broadening, yielding a pulse-broadening time of 670$\pm$100 $\mu$s, and the implied strength of scattering (scattering measure) is the lowest that is estimated towards the Crab nebula from observations made so far. The sensitivity of the system is largely dictated by the sky background, and our simple equipment is capable of detecting pulses that are brighter than $\sim$9 kJy in amplitude. The brightest giant pulse detected in our data has a peak amplitude of $\sim$50 kJy, and the implied brightness temperature is $10^{31.6}$ K. We discuss the giant pulse detection prospects with the full MWA-LFD system. With a sensitivity over two orders of magnitude larger than the prototype equipment, the full system will be capable of detecting such bright giant pulses out to a wide range of Galactic distances; from $\sim$8 to $\sim$30 kpc depending on the frequency. The MWA-LFD will thus be a highly promising instrument for the studies of giant pulses and other fast radio transients at low frequencies.Comment: 10 pages, 6 figures, Accepted for publication in the Astrophysical Journa

Bright Giant Pulses from the Crab Nebula Pulsar: Statistical Properties, Pulse Broadening and Scattering due to the Nebula

We report observations of Crab giant pulses made with the Australia Telescope Compact Array and a baseband recorder system, made simultaneously at two frequencies, 1300 and 1470 MHz. These observations were sensitive to pulses with amplitudes \ga 3 kJy and widths \ga 0.5 $\mu$s. Our analysis led to the detection of more than 700 such bright giant pulses over 3 hours, and using this large sample we investigate their amplitude, width, arrival time and energy distributions. The brightest pulse detected in our data has a peak amplitude of $\sim$ 45 kJy and a width of $\sim$ 0.5 $\mu$s, and therefore an inferred brightness temperature of $\sim 10^{35}$ K. The duration of giant-pulse emission is typically $\sim$1 $\mu$s, however it can also be as long as 10 $\mu$s. The pulse shape at a high time resolution (128 ns) shows rich diversity and complexity in structure and is marked by an unusually low degree of scattering. We discuss possible implications for scattering due to the nebula, and for underlying structures and electron densities.Comment: 8 pages, 8 figures, Accepted for publication in Ap

The Impact of Mutation and Gene Conversion on the Local Diversification of Antigen Genes in African Trypanosomes

. Abstract 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 role of transforming growth factor-beta (TGF-beta) during ovarian follicular development in sheep

BACKGROUND: Recently, several members of the transforming growth factor-beta (TGF-beta) superfamily have been shown to be essential for regulating the growth and differentiation of ovarian follicles and thus fertility. METHODS: Ovaries of neonatal and adult sheep were examined for expression of the TGF-betas 1–3 and their receptors (RI and RII) by in situ hybridization using ovine cDNAs. The effects of TGF-beta 1 and 2 on proliferation and differentiation of ovine granulosa cells in vitro were also studied. RESULTS: The expression patterns of TGF-beta 1 and 2 were similar in that both mRNAs were first observed in thecal cells of type 3 (small pre-antral) follicles. Expression of both mRNAs continued to be observed in the theca of larger follicles and was also present in cells within the stroma and associated with the vascular system of the ovary. There was no evidence for expression in granulosa cells or oocytes. Expression of TGF-beta 3 mRNA was limited to cells associated with the vascular system within the ovary. TGFbetaRI mRNA was observed in oocytes from the type 1 (primordial) to type 5 (antral) stages of follicular growth and granulosa and thecal cells expressed this mRNA at the type 3 (small pre-antral) and subsequent stages of development. The TGFbetaRI signal was also observed in the ovarian stroma and vascular cells. In ovarian follicles, mRNA encoding TGFbetaRII was restricted to thecal cells of type 3 (small pre-antral) and larger follicles. In addition, expression was also observed in some cells of the surface epithelium and in some stromal cells. In granulosa cells cultured for 6 days, both TGF-beta 1 and 2 decreased, in a dose dependent manner, both the amount of DNA and concentration of progesterone. CONCLUSION: In summary, mRNA encoding both TGF-beta 1 and 2 were synthesized by ovarian theca, stroma and cells of the vascular system whereas TGF-beta 3 mRNA was synthesized by vascular cells. Luteinizing granulosa cells also responded to both TGF-beta 1 and beta 2 in vitro. These findings in sheep are consistent with TGF-beta potentially being an important autocrine regulator of thecal cell function and possibly a paracrine regulator of ovarian cell function at various development stages

Predicting the public health benefit of vaccinating cattle against Escherichia coli O157

Identifying the major sources of risk in disease transmission is key to designing effective controls. However, understanding of transmission dynamics across species boundaries is typically poor, making the design and evaluation of controls particularly challenging for zoonotic pathogens. One such global pathogen is Escherichia coli O157, which causes a serious and sometimes fatal gastrointestinal illness. Cattle are the main reservoir for E. coli O157, and vaccines for cattle now exist. However, adoption of vaccines is being delayed by conflicting responsibilities of veterinary and public health agencies, economic drivers, and because clinical trials cannot easily test interventions across species boundaries, lack of information on the public health benefits. Here, we examine transmission risk across the cattle–human species boundary and show three key results. First, supershedding of the pathogen by cattle is associated with the genetic marker stx2. Second, by quantifying the link between shedding density in cattle and human risk, we show that only the relatively rare supershedding events contribute significantly to human risk. Third, we show that this finding has profound consequences for the public health benefits of the cattle vaccine. A naïve evaluation based on efficacy in cattle would suggest a 50% reduction in risk; however, because the vaccine targets the major source of human risk, we predict a reduction in human cases of nearly 85%. By accounting for nonlinearities in transmission across the human–animal interface, we show that adoption of these vaccines by the livestock industry could prevent substantial numbers of human E. coli O157 cases

Examining the Ethical Environment in Higher Education

Higher Education Institutions (HEIs) across the world have found themselves faced with new challenges on issues of ethics. Much of this has been centred on issues of assessment: plagiarism, buying essays, sharing/lending of previously passed work and the stealing of marked/returned work of others. Institutions still treat academic misconduct as largely a behavioural difficulty rather than an issue of ethics (or education), suggesting that academia places a far greater emphasis on combating new forms of dishonesty than it does on encouraging ethical habits and a healthy ethical environment. To date, the majority of research in this area has examined these forms of academic misconduct from the point of view of the student and/or the university, with the perspective of academics receiving very limited attention. Our hypothesis is that academics are perhaps best placed to provide the education needed to create and sustain an ethical environment, and we argue that being ‘ethically aware’ is a critical factor in the development of academic competence for all parties. This study adds to existing research in three ways: firstly, by highlighting the importance of an overall framework for an ethical environment within HEIs; secondly, by suggesting an ecological model of key parties (the university, students and academics) with responsibility for this environment in assessment; and thirdly, by including new evidence (generated by a survey of academics) to extend our understanding of their views on these issues