Antigenic variation in <i>Trypanosoma brucei</i>: joining the DOTs

African trypanosomes, such as &lt;i&gt;Trypanosoma brucei&lt;/i&gt;, are protistan parasites that cause sleeping sickness. Though first described more than a century ago, trypanosomes remain a blight on the health of the human population and on the economy of sub-Saharan Africa. &lt;i&gt;T. brucei&lt;/i&gt; replicates in the bloodstream of infected mammals and traverses the blood-brain barrier to enter the central nervous system in the late, frequently fatal, stages of the disease. Because of its extracellular lifestyle, &lt;i&gt;T. brucei&lt;/i&gt; is continuously exposed to antibody challenge. To circumvent this, the parasite uses antigenic variation of a surface protein named the variant surface glycoprotein (VSG). Around 107 VSG molecules are expressed on the parasite's cell surface, creating a dense coat that prevents adaptive immunity from detecting or accessing invariant antigens. However, antibodies against the expressed VSG are generated, and periodic switches to an immunologically distinct VSG coat are necessary for parasite survival. Such switches are pre-emptive of the immune response and contribute to the pattern of trypanosome growth seen in an infected host (Figure 1): parasite numbers increase, but then drop as VSG-specific antibodies are raised by the host. Cells that have switched to another VSG coat survive this killing and seed the outgrowth of a subsequent peak of parasites, which is again decimated by anti-VSG immune killing. As a survival strategy, antigenic variation succeeds by prolonging the time that the parasite

3D Morphometric and Posture Study of Felid Scapulae Using Statistical Shape Modelling

We present a three dimensional (3D) morphometric modelling study of the scapulae of Felidae, with a focus on the correlations between forelimb postures and extracted scapular shape variations. Our shape modelling results indicate that the scapular infraspinous fossa becomes larger and relatively broader along the craniocaudal axis in larger felids. We infer that this enlargement of the scapular fossa may be a size-related specialization for postural support of the shoulder joint

<i>VSG</i> Switching Hierarchy in T. brucei

<p>The graph is adapted from [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060185#pbio-0060185-b009" target="_blank">9</a>] and shows the numbers of T. brucei cells (parasitaemia) measured in a cow for up to 70 days post-infection (this measurement is depicted by inversely plotting the prepatent period, in days, that a 0.2-ml inoculum of cattle blood achieves a parasitaemia of 1 × 10^8.1 trypanosomes ml⁻¹ units in an immunosuppressed mouse). Below the graph is a depiction of <i>VSG</i> gene activation timing (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060185#pbio-0060185-g002" target="_blank">Figure 2</a> for details of the switch mechanisms). During <i>VSG</i> switches driven by recombination, silent <i>VSG</i>s at a telomere are, in general, activated more frequently that subtelomeric array <i>VSG</i>s, which are activated more frequently than <i>VSG</i> pseudogenes (pseudo). It is unclear (indicated by a question mark) if transcriptional switches between <i>VSG</i> bloodstream expression sites (BES) occur predominantly at the start of an infection or continue throughout.</p

Mechanisms of <i>VSG</i> Switching during Antigenic Variation in T. brucei

<p>The <i>VSG</i> gene expressed prior to a switch (indicated by a blue box) is transcribed from an expression site (ES) that is found at the telomere (vertical black line) of a chromosome (horizontal black line); active transcription of the ES is indicated by a dotted arrow, <i>ESAG</i>s are depicted by black boxes, and 70-bp repeat sequence is shown as a hatched box. Gene conversion to generate a <i>VSG</i> switch can occur by copying a silent <i>VSG</i> (red box) from a subtelomeric array into the ES, replacing the resident <i>VSG</i>; the amount of sequence copied during gene conversion is illustrated, and normally encompasses the <i>VSG</i> ORF and extends upstream to the 70-bp repeats. The silent <i>VSG</i> donor can also be telomeric (either in a mini chromosome or in an inactive ES); here, the downstream limit of conversion can extend to the telomere repeats, while the upstream limit can either be in the 70-bp repeats or the <i>ESAG</i>s (if the donor is in an ES). Segmental <i>VSG</i> conversion involves the copying of sequence from multiple, normally nonfunctional <i>VSG</i>s (pink, red, or green boxes) to generate a novel mosaic <i>VSG</i> in the ES. In transcriptional <i>VSG</i> switching, recombination appears not to be involved; instead, limited transcription at a silent <i>VSG</i> ES (indicated by a small arrow) becomes activated to generate fully active transcription, while the previously active ES is silenced.</p

Functions of Dot1-Mediated Histone H3 Methylation

<p>Two models for the role of Dot1-mediated methylation of histone H3 are diagrammed, comparing a Dot1 mutant (ΔDot1) and a wild-type cell. The repulsion model is derived from [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060185#pbio-0060185-b021" target="_blank">21</a>]. Methylation of histone H3 is indicated by “me”, and the level of transcription of a chromosome (black line) is indicated by a shaded gray bar (a thick bar indicates active transcription, a thin bar indicates silenced transcription). Silencing factors (such as Sir proteins in yeast; light blue circles) are indicated localised to the telomere (vertical line) in wild-type cells, being excluded from elsewhere by H3K79 methylation. Mutation of Dot1 removes H3K79 methylation, de-repressing transcription of the telomeric region. The recruitment model is based on [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0060185#pbio-0060185-b032" target="_blank">32</a>], and shows the same region of chromosome after suffering a DNA double-strand break (gap in the line). Here, histone H3K79 methylation recruits a checkpoint signalling factor (Rad9 in yeast; dark blue circle), and in the absence of histone H3K79 methylation processing of the DNA break to yield single stranded DNA is increased, amplifying the DNA damage signalling cascade.</p

Preparation for commissioning of materials detritiation facility at Culham Science Centre

The Materials Detritiation Facility has been designed to thermally treat solid non-combustible radioactive waste produced during operations of the Joint European Torus (JET) that is classified as Intermediate Level Waste in the UK due to its tritium inventory (> 12 kBq/g). The waste will be thermally treated in a retort furnace at temperatures up to 1000 degrees C under a flowing air atmosphere to reduce its tritium inventory sufficiently to allow its disposal at a lower waste category via existing disposal routes. The gaseous flow from the furnace will be processed via a bubbler system, where released tritium will be trapped in water. Commissioning of the facility will be divided into two main parts: inactive and active. The main purpose of the inactive commissioning is to verify that all components and safety systems of the facility are installed, tested and operated properly and within their operational limits. Several trials of the furnace with non-radioactive materials will be performed to verify its temperature profile, and to verify operation of the gaseous process line. During the active commissioning, small amounts of tritium-contaminated material will be introduced into the facility and used for active trials. The tritium inventory in this material has been selected based on the As low as reasonably practicable (ALARP) principle, to ensure that the activity levels are sufficient to fully test the control instrumentation and pose minimal risk to operators during commissioning. Overall, four active trials will be performed with carbon-based and Inconel materials with total tritium inventories of 1MBq, 3GBq, 20GBq and 26GBq. Tritium levels in the bubblers as well as in aerial discharge from the facility will be monitored. Furthermore, all materials used in the active trials will be sampled and analyzed to verify the performance of the process and confirm that a major part of tritium inventory can be removed from materials by the process