Evidence for a common role for the serine-type Plasmodium falciparum serine repeat antigen proteases : implications for vaccine and drug design

Serine repeat antigens (SERAs) are a family of secreted “cysteine-like” proteases of Plasmodium parasites. Several SERAs possess an atypical active-site serine residue in place of the canonical cysteine. The human malaria parasite Plasmodium falciparum possesses six “serine-type” (SERA1 to SERA5 and SERA9) and three “cysteine-type” (SERA6 to SERA8) SERAs. Here, we investigate the importance of the serine-type SERAs to blood-stage parasite development and examine the extent of functional redundancy among this group. We attempted to knock out the four P. falciparum serine-type SERA genes that have not been disrupted previously. SERA1, SERA4, and SERA9 knockout lines were generated, while only SERA5, the most strongly expressed member of the SERA family, remained refractory to genetic deletion. Interestingly, we discovered that while SERA4-null parasites completed the blood-stage cycle normally, they exhibited a twofold increase in the level of SERA5 mRNA. The inability to disrupt SERA5 and the apparent compensatory increase in SERA5 expression in response to the deletion of SERA4 provides evidence for an important blood-stage function for the serine-type SERAs and supports the notion of functional redundancy among this group. Such redundancy is consistent with our phylogenetic analysis, which reveals a monophyletic grouping of the serine-type SERAs across the genus Plasmodium and a predominance of postspeciation expansion. While SERA5 is to some extent further validated as a target for vaccine and drug development, our data suggest that the expression level of other serine-type SERAs is the only barrier to escape from anti-SERA5-specific interventions.

Differential rates of offspring provisioning in Gould’s petrels: are better feeders better breeders?

Procellariiformes (albatrosses and petrels) must accumulate substantial energy reserves to sustain them while incubating their single egg. They then produce a chick that is often more than 130% of their own body mass. Thus, despite the variable nature of resource availability in the marine environment, successful reproduction requires a considerable increase in foraging rates. Birds that are better foragers are, therefore, likely to be better parents. As surrogates of foraging ability, we assessed two parental traits that are separated temporally over the breeding season, body condition during incubation and provisioning performance, in Gould’s petrel (Pterodroma leucoptera). Although parental condition did not influence hatching success, we found significant positive correlations between the average body condition of a breeding pair and both the growth rate of chicks (g day^–1) and the body condition of chicks at peak mass. Provisioning rate also correlated positively with chick condition. Chick condition was positively correlated with haemoglobin concentration [Hb] at peak mass, which was positively correlated with [Hb] at fledging. Because the probability of survival after fledging may be influenced by chick body condition and [Hb], the ability of parents to acquire additional resources for breeding is likely to be an important determinant of reproductive success.

Factors affecting the site of investment, and the reliance on savings for arctic breeders : the capital–income dichotomy revisited

The extent to which migratory birds that breed in the Arctic and winter in southern biomes rely on residual body stores for reproduction is unresolved. The short arctic summer and the limited availability of food early in the season constrain the time available for successful reproduction. Birds that are able to bring sufficient endogenous reserves to the breeding ground to meet, at least partially, the demands of egg-laying can initiate clutch production soon after arrival, thereby shortening the length of the breeding season and improving the chances of reproductive success. The amount of reserves available will be influenced by body size, the increased energetic and predation costs associated with carrying large stores, distances between staging sites and the location of the breeding grounds within the Arctic. Birds need not fly directly to the breeding grounds from the established temperate staging sites. Extensive feeding by migrants may occur in the Arctic, even within a few kilometres of the breeding sites as the birds track the retreating snowline. Irrespective of their size, birds are thus able to store some resources necessary for egg laying at local or regional scales. It is thus important to make a distinction between local capital and distant capital breeding. The extent to which a bird is characterized as a distant capital, local capital, or an income breeder not only varies between species, but also between individuals and seasons.

Will they come again? A study of events and repeat visitation

Event organisers invest considerable effort in developing, promoting and conducting events with the expectation that not only will new participants be attracted to future events but also that those who have attended will make repeat visitations. This study addresses this issue by investigating the type of events that attract repeat visitation and the possible reasons for these repeat visitations. Getz's (1997) typology of events is used to classify the events, which were used in the data collection for this research. The study utilises data collected in an origin-based survey to explore which events attract repeat visitors and what motivates this repeat visitation. Whilst marketing literature, and to some degree, tourism literature, have examined repeat purchase and repeat visitation, events literature has not dealt with this to any great extent.

While there has been increased examination of the motivation and behaviour of event visitors (Mohr, Backman et al. 1993; Uysal, Gahan et al. 1993; Crompton and McKay 1997; Tang and Turco 2001) there has been relatively little examination of repeat visitors to events. The emphasis within studies on repeat visitation has been on satisfaction with those events rather than a consideration of a wider range of influencing factors (Gitelson and Crompton 1984; O'Neill, Getz et al. 1999). Those factors may include an interest in a particular type of event, influence of family and friends, whether it is a local community event, the cost - value factor and a variety of other reasons.

Effect of insulin-like growth factor I on HIV type 1 long terminal repeat-driven chloramphenicol acetyltransferase expression

In this study, we have investigated the ability of insulin-like growth factor I (IGF-I) to inhibit HIV long terminal repeat (LTR)-driven gene expression. Using COS 7 cells cotransfected with tat and an HIV LTR linked to a chloramphenicol acetyltransferase (CAT) reporter, we observed that physiological levels of IGF-I (10-9 M) significantly inhibited CAT expression in a concentration- and time-dependent manner. IGF-I did not inhibit C AT expression in COS 7 cells transfected with pSVCAT, and did not affect CAT expression in the absence of cotransfection with tat . Transfection of HIV-1 proviral DNA into COS 7 cells +/- IGF-I resulted in a significant decrease ( p 0.05) in infectious virion production. Both IGF-I and Ro24-7429 inhibited LTR-driven C AT expression, while TNF- alpha -enhanced CAT expression was not affected by IGF-I. On the other hand, a plasmid encoding parathyroid hormone-related peptide exhibited dramatic additivity of inhibition of CAT expression in COS 7 cells. Finally, we show that in Jurkat or U937 cells cotransfected with HIVLTRCAT/tat, IGF-I significantly inhibited CAT expression. Further, interleukin 4 showed in U937 cells inhibition of CAT expression that was not additive to IGF-I induced inhibition. Our data demonstrate that IGF-I can specifically inhibit HIVLTRCAT expression. This inhibition may occur at the level of the tat /TAR interaction. Finally, this IGF-I effect is seen in target cell lines and similar paths of inhibition may be involved in the various cell types employed.

Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation

RUNX2 is an essential transcription factor required for skeletal development and cartilage formation. Haploinsufficiency of RUNX2 leads to cleidocranial displaysia (CCD) a skeletal disorder characterised by gross dysgenesis of bones particularly those derived from intramembranous bone formation. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Since none of the known mutations causing CCD characterised to date map in the glutamine repeat region, we hypothesised that Q-repeat mutations may be related to a more subtle bone phenotype. We screened subjects derived from four normal populations for Q-repeat variants. A total of 22 subjects were identified who were heterozygous for a wild type allele and a Q-repeat variant allele: (15Q, 16Q, 18Q and 30Q). Although not every subject had data for all measures, Q-repeat variants had a significant deficit in BMD with an average decrease of 0.7SD measured over 12 BMD-related parameters (p = 0.005). Femoral neck BMD was measured in all subjects (−0.6SD, p = 0.0007). The transactivation function of RUNX2 was determined for 16Q and 30Q alleles using a reporter gene assay. 16Q and 30Q alleles displayed significantly lower transactivation function compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency of about 0.4%. These mutations significantly alter BMD and display impaired transactivation function, introducing a new class of functionally relevant RUNX2 mutants.

‘Yes, no, maybe, can you repeat the question?’ : Is thinking like a lawyer different to thinking like a teacher?

Presentation at APLEC 2013. 
Kristoffer Greaves is researching how lawyers who teach lawyers’ skills in PLT engage in scholarly activities regarding their teaching work. This qualitative research involves cross-disciplinary exchanges between law, legal education, education theory and practice, sociology of law, and cultural theory. Data collected for the research includes 30+ hours semi-structured interviews with 35 PLT practitioners working with different PLT providers around Australia.
One question asked during the interviews - Is thinking like a lawyer different to thinking like a teacher? - elicited reflective and diverse responses and insights about how PLT practitioners reconcile ‘thinking like a lawyer’ with their teaching and mentoring work.
This presentation discusses the relevance and significance of these insights in the context of scholarship of teaching in PLT, and practical legal training’s ‘big picture’ purpose to improve protection of clients, protection of the administration of justice, and the assurance of the quality of legal services.

Polyalanine repeat polymorphism in RUNX2 is associated with site-specific fracture in post-menopausal femals

Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within the RUNX2 gene have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18 bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of distal radius and bones of intramembranous origin compared to bones of endochondral origin (p = 0.0001). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p = 0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele showed a minor quantitative decrease. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.

Rewind, repeat: TV’s fame machine is oh-so retro

As much as the contemporary talent show appears to be different, there are qualities that relate to earlier versions of televised talent contests internationally and domestically. This article explores how the past iterations inform the present and its production of an internal - almost studio system - of fame.

Fracture prediction from repeat BMD measurements in clinical practice

Summary: We investigated whether repeat BMD measurements in clinical populations are useful for fracture risk assessment. We report that repeat BMD measurements are a robust predictor of fracture in clinical populations; this is not affected by preceding BMD change or recent osteoporosis therapy. Introduction: In clinical practice, many patients selectively undergo repeat bone mineral density (BMD) measurements. We investigated whether repeat BMD measurements in clinical populations are useful for fracture risk assessment and whether this is affected by preceding change in BMD or recent osteoporosis therapy. Methods: We identified women and men aged ≥50 years who had a BMD measurement during 1990–2009 from a large clinical BMD database for Manitoba, Canada (n = 50,215). Patient subgroups aged ≥50 years at baseline with repeat BMD measures were identified. Data were linked to an administrative data repository, from which osteoporosis therapy, fracture outcomes, and covariates were extracted. Using Cox proportional hazards models, we assessed covariate-adjusted risk for major osteoporotic fracture (MOF) and hip fracture according to BMD (total hip, lumbar spine, femoral neck) at different time points. Results: Prevalence of osteoporosis therapy increased from 18 % at baseline to 55 % by the fourth measurement. Total hip BMD was predictive of MOF at each time point. In the patient subgroup with two repeat BMD measurements (n = 13,481), MOF prediction with the first and second measurements was similar: adjusted-hazard ratio (HR) per SD 1.45 (95 % CI 1.34–1.56) vs. 1.64 (95 % CI 1.48–1.81), respectively. No differences were seen when the second measurement results were stratified by preceding change in BMD or osteoporosis therapy (both p-interactions >0.2). Similar results were seen for hip fracture prediction and when spine and femoral neck BMD were analyzed. Conclusion: Repeat BMD measurements are a robust predictor of fracture in clinical populations; this is not affected by preceding BMD change or recent osteoporosis therapy.

Accounting for uncertainty in volumes of seabed change measured with repeat multibeam sonar surveys

Seafloors of unconsolidated sediment are highly dynamic features; eroding or accumulating under the action of tides, waves and currents. Assessing which areas of the seafloor experienced change and measuring the corresponding volumes involved provide insights into these important active sedimentation processes. Computing the difference between Digital Elevation Models (DEMs) obtained from repeat Multibeam Echosounders (MBES) surveys has become a common technique to identify these areas, but the uncertainty in these datasets considerably affects the estimation of the volumes displaced. The two main techniques used to take into account uncertainty in volume estimations are the limitation of calculations to areas experiencing a change in depth beyond a chosen threshold, and the computation of volumetric confidence intervals. However, these techniques are still in their infancy and, as a result, are often crude, seldom used or poorly understood. In this article, we explored a number of possible methodological advances to address this issue, including: (1) using the uncertainty information provided by the MBES data processing algorithm CUBE, (2) adapting fluvial geomorphology techniques for volume calculations using spatially variable thresholds and (3) volumetric histograms. The nearshore seabed off Warrnambool harbour - located in the highly energetic southwest Victorian coast, Australia - was used as a test site. Four consecutive MBES surveys were carried out over a four-months period. The difference between consecutive DEMs revealed an area near the beach experiencing large sediment transfers - mostly erosion - and an area of reef experiencing increasing deposition from the advance of a nearby sediment sheet. The volumes of sediment displaced in these two areas were calculated using the techniques described above, both traditionally and using the suggested improvements. We compared the results and discussed the applicability of the new methodological improvements. We found that the spatially variable uncertainty derived from the CUBE algorithm provided the best results (i.e. smaller confidence intervals), but that similar results can be obtained using as a fixed uncertainty value derived from a reference area under a number of operational conditions.