Structural Studies on Microneme proteins from Toxoplasma gondii

Toxoplasma gondii is a polyxenous parasite of the phylum Apicomplexa and the etiological agent of the coccidian disease Toxoplasmosis. Toxoplasma gondii is characterized by its unique gliding motility as well as its ability to infect virtually all nucleated cells. The micronemes are a group of secretory organelles that contribute to the ability of the parasite to recognize the surface of the host-cell prior to parasite invasion via the secretion of adhesive protein complexes. Previous attempts at obtaining structural data for several microneme proteins from Toxoplasma gondii such as microneme protein TgMIC 2, 3 and 4 have so far been unsuccessful due to the inability to produce soluble protein samples using the prokaryotic expression system, Escherichia coli. This work is focussed upon the adaptation of a eukaryotic expression system, Pichia pastoris, to producing Apicomplexan microneme proteins which can cause problems in prokaryotic expression systems due to its eukaryotic origin as well as its high cysteine content. Modifications to the fermenter medium and standard screening protocols allowed for the expression of microneme protein domain constructs in Pichia pastoris with yields ranging from 0.1 to 1.2 mg/L in fermenter culture. Soluble protein samples were produced for several constructs expressed in Pichia pastoris including full length samples of TgMIC3 and TgMIC4 as well as the TSR56 pair in TgMIC2. In addition, isotopically enriched soluble and folded protein samples were successfully produced with a yield of 0.02 to 0.12 mg/L and were successfully subjected to analysis via 2D NMR. Full length TgMIC4 was also successfully crystallized and resulted in crystals which diffracted to 8.0Å. Pichia pastoris has been successful in producing soluble microneme protein samples and has the potential to alleviate the long-standing bottleneck in our efforts to understand the mechanisms involved in Toxoplasma gondii host-cell invasion

Cortical activation to action perception is associated with action production abilities in young infants

The extent to which perception and action share common neural processes is much debated in cognitive neuroscience. Taking a developmental approach to this issue allows us to assess whether perceptual processing develops in close association with the emergence of related action skills within the same individual. The current study used functional near-infrared spectroscopy (fNIRS) to investigate the perception of human action in 4- to 6-month-old human infants. In addition, the infants' manual dexterity was assessed using the fine motor component of The Mullen Scales of Early Learning and an in-house developed Manual Dexterity task. Results show that the degree of cortical activation, within the posterior superior temporal sulcus—temporoparietal junction (pSTS-TPJ) region, to the perception of manual actions in individual infants correlates with their own level of fine motor skills. This association was not fully explained by either measures of global attention (i.e., looking time) or general developmental stage. This striking concordance between the emergence of motor skills and related perceptual processing within individuals is consistent with experience-related cortical specialization in the developing brain

Projecting the Health and Economic Burden of Cardiovascular Disease Among People with Type 2 Diabetes, 2022–2031

Objective: The aim was to project the health and economic outcomes of cardiovascular disease (CVD) among people with type 2 diabetes from Australian public healthcare and societal perspectives over the next decade. Methods: A dynamic multistate model with yearly cycles was developed to project cardiovascular events among Australians with type 2 diabetes aged 40–89 years from 2022 to 2031. CVD risk (myocardial infarction [MI] and stroke) in the type 2 diabetes population was estimated using the 2013 pooled cohort equation, and recurrent cardiovascular event rates in the type 2 diabetes with established CVD population were obtained from the global Reduction of Atherothrombosis for Continued Health (REACH) registry. Costs and utilities were derived from published sources. Outcomes included fatal and non-fatal MI and stroke, years of life lived, quality-adjusted life years (QALYs), total healthcare costs, and total productivity losses. The annual discount rate was 5%, applied to outcomes and costs. Results: Between 2022 and 2031, a total of 83,618 non-fatal MIs (95% uncertainty interval [UI] 83,170–84,053) and 58,774 non-fatal strokes (95% UI 58,458–59,013) were projected. Total years of life lived and QALYs (discounted) were projected to be 9,549,487 (95% UI 9,416,423–9,654,043) and 6,632,897 (95% UI 5,065,606–7,591,679), respectively. Total healthcare costs and total lost productivity costs (discounted) were projected to be 9.59 billion Australian dollars (AU$) (95$9.07 billion (95% UI 663.53 million–33.19 billion), respectively. Conclusions: CVD in people with type 2 diabetes will substantially impact the Australian healthcare system and society over the next decade. Future work to investigate different strategies to optimize the control of risk factors for the prevention and treatment of CVD in type 2 diabetes in Australia is warranted

Developmental Paths to Anxiety in an Autism-Enriched Infant Cohort: The Role of Temperamental Reactivity and Regulation

The aim of this study was to explore the associations between temperamental reactivity and regulation and the emergence of anxiety traits in a longitudinal sample of infants enriched for later ASD. Parents of 143 infants who were at high- and low-risk for ASD rated their child’s temperament traits when they were 9, 15 and 24 months old; they rated anxiety and ASD traits when they were 36 months old. The findings suggest that behavioural inhibition may be an early predictor of later anxiety in children with and without ASD and that lower levels of effortful control in children who later develop ASD may contribute to the higher expression of anxiety within this population

Risk Prediction of Coronary Heart Disease Based on Retinal Vascular Caliber (from the Atherosclerosis Risk In Communities [ARIC] Study)

Recent studies show that retinal vascular signs such as quantitative retinal vascular caliber are associated with an increased risk of incident coronary heart disease (CHD), but whether these retinal vascular signs add to the prediction of CHD over and above traditional CHD risk factors has not been addressed. We investigated whether these signs add to the prediction of CHD over and above the Framingham risk score amongst people (n=9,155) without diabetes selected from the Atherosclerosis Risk in Communities (ARIC) study. Incident CHD was ascertained using standardized methods and retinal vascular caliber and other retinal signs were measured from retinal photographs. After a mean of 8.8 years of follow up, there were 700 incident CHD events. Women with wider retinal venular caliber (hazard ratio 1.27 per 1 standard deviation increase [95% confidence interval, 1.08, 1.50]) and narrower retinal arteriolar caliber (1.31 per 1 standard deviation decrease [1.10, 1.56]) had a higher risk of incident CHD after adjusting for the Framingham risk score variables. The area under the receiver operator characteristic curve increased from 0.695 to 0.706 (1.7% increase) with the addition of retinal vascular caliber to the Framingham risk model. The risk prediction models with and without the retinal vascular caliber both fitted the data and were well calibrated for women. In men, retinal vascular caliber was not associated with CHD risk after adjustment. Other retinal vascular signs were not associated with 10-year incident CHD in men or women. In conclusion, although retinal vascular caliber independently predicts CHD risk in women, the incremental predictive ability over that of the Framingham model is modest, and unlikely to translate meaningfully into clinical practice

Developmental change in look durations predicts later effortful control in toddlers at familial risk for ASD

Background: Difficulties with Executive Functioning (EF) are common in individuals with a range of developmental disorders, including Autism Spectrum Disorder (ASD). Interventions that target underlying mechanisms of EF early in development could be broadly beneficial, but require infant markers of such mechanisms in order to be feasible. Prospective studies of infants at high familial risk (HR) for ASD have revealed a surprising tendency for HR toddlers to show longer epochs of attention to faces than low-risk (LR) controls. In typical development, decreases in look durations towards the end of the first year of life are driven by the development of executive attention – a foundational component of EF. Here, we test the hypothesis that prolonged attention to visual stimuli (including faces) in HR toddlers reflects early differences in the development of executive attention. Methods: In a longitudinal prospective study, we used eye-tracking to record HR and LR infants’ looking behaviour to social and non-social visual stimuli at ages 9 and 15 months. At age 3 years we assessed children with a battery of clinical research measures and collected parental report of Effortful Control (EC) – a temperament trait closely associated with EF and similarly contingent on executive attention. Results: Consistent with previous studies, we found an attenuated reduction in peak look durations to faces between 9 and 15 months for the HR group compared with the LR group, and lower EC amongst the HR-ASD group. In line with our hypothesis, change in peak look duration to faces between 9 and 15 months was negatively associated with EC at age 3. Conclusions: We suggest that for HR toddlers, disruption to the early development of executive attention results in an attenuated reduction in looking time to faces. Effects may be more apparent for faces due to early biases to orient towards them; further, attention difficulties may interact with earlier-emerging differences in social information processing. Our finding that prolonged attention to faces may be an early indicator of disruption to the executive attention system is of potential value in screening for infants at risk for later EF difficulties and for evaluation of intervention outcomes

Joint-level energetics differentiate isoinertial from speed-power resistance training—a Bayesian analysis

Background There is convincing evidence for the benefits of resistance training on vertical jump improvements, but little evidence to guide optimal training prescription. The inability to detect small between modality effects may partially reflect the use of ANOVA statistics. This study represents the results of a sub-study from a larger project investigating the effects of two resistance training methods on load carriage running energetics. Bayesian statistics were used to compare the effectiveness of isoinertial resistance against speed-power training to change countermovement jump (CMJ) and squat jump (SJ) height, and joint energetics. Methods Active adults were randomly allocated to either a six-week isoinertial (n = 16; calf raises, leg press, and lunge), or a speed-power training program (n = 14; countermovement jumps, hopping, with hip flexor training to target pre-swing running energetics). Primary outcome variables included jump height and joint power. Bayesian mixed modelling and Functional Data Analysis were used, where significance was determined by a non-zero crossing of the 95% Bayesian Credible Interval (CrI). Results The gain in CMJ height after isoinertial training was 1.95 cm (95% CrI [0.85–3.04] cm) greater than the gain after speed-power training, but the gain in SJ height was similar between groups. In the CMJ, isoinertial training produced a larger increase in power absorption at the hip by a mean 0.018% (equivalent to 35 W) (95% CrI [0.007–0.03]), knee by 0.014% (equivalent to 27 W) (95% CrI [0.006–0.02]) and foot by 0.011% (equivalent to 21 W) (95% CrI [0.005–0.02]) compared to speed-power training. Discussion Short-term isoinertial training improved CMJ height more than speed-power training. The principle adaptive difference between training modalities was at the level of hip, knee and foot power absorption