Nonlinear pedagogy : implications for teaching games for understanding (TGfU)

Nonlinear Dynamics, provides a framework for understanding how teaching and learning processes function in Teaching Games for Understanding (TGfU). In Nonlinear Pedagogy, emergent movement behaviors in learners arise as a consequence of intrinsic self-adjusted processes shaped by interacting constraints in the learning environment. In a TGfU setting, representative, conditioned games provide ideal opportunities for pedagogists to manipulate key constraints so that self-adjusted processes by players lead to emergent behaviors as they explore functional movement solutions. The implication is that, during skill learning, functional movement variability is necessary as players explore different motor patterns for effective skill execution in the context of the game. Learning progressions in TGfU take into account learners’ development through learning stages and have important implications for organisation of practices, instructions and feedback. A practical application of Nonlinear Pedagogy in a national sports institute is shared to exemplify its relevance for TGfU practitioners.

Safeguarding rural Australia : addressing masculinity and violence in rural settings. Data report No. 4 - Risky behaviour - misuse of alcohol, illicit drugs, firearms use and abuse, other risky behaviour

This report focuses on our examination of extant data which have been sourced with respect to personally and socially risky behaviour associated with males living in regional and remote Australia . The AIHW (2008: PHE 97:89) defines personally risky behaviour, on the one hand, as working, swimming, boating, driving or operating hazardous machinery while intoxicated with alcohol or an illicit drug. Socially risky behaviour, on the other hand, is defined as creating a public disturbance, damaging property, stealing or verbally or physically abusing someone while intoxicated with alcohol or an illicit drug. Additional commentary resulting from exploration, examination and analyses of secondary data is published online in complementary reports in this series.

A preliminary investigation of the role of the Phenylalynine: Tyrosine Ratio in children with early and continuously treated phenylketonuria : toward identification of “safe” levels

Children with early and continuously treated phenylketonuria (ECT-PKU) remain at risk of developing executive function (EF) deficits. There is some evidence that a high phenylalanine to tyrosine ratio (phe:tyr) is more strongly associated with impaired EF development than high phenylalanine alone. This study examined EF in a sample of 11 adolescents against concurrent and historical levels of phenylalanine, phe:tyr, and tyrosine. Lifetime measures of phe:tyr were more strongly associated with EF than phenylalanine-only measures. Children with a lifetime phe:tyr less than 6 demonstrated normal EF, whereas children who had a lifetime phe:tyr above 6, on average, demonstrated clinically impaired EF.

Optimising figure of merit for phonetic spoken term detection

This paper introduces a novel technique to directly optimise the Figure of Merit (FOM) for phonetic spoken term detection. The FOM is a popular measure of sTD accuracy, making it an ideal candiate for use as an objective function. A simple linear model is introduced to transform the phone log-posterior probabilities output by a phe classifier to produce enhanced log-posterior features that are more suitable for the STD task. Direct optimisation of the FOM is then performed by training the parameters of this model using a non-linear gradient descent algorithm. Substantial FOM improvements of 11% relative are achieved on held-out evaluation data, demonstrating the generalisability of the approach.

Tyrosine monitoring in children with early and continuously treated phenylketonuria: Results of an international practice survey

Investigations into the biochemical markers associated with executive function (EF) impairment in children with early and continuously treated phenylketonuria (ECT-PKU) remain largely phenylalanine-only focused, despite experimental data showing that a high phenylalanine:tyrosine (phe:tyr) ratio is more strongly associated with EF deficit than phe alone. A high phe:tyr ratio is hypothesized to lead to a reduction in dopamine synthesis within the brain, which in turn results in the development of EF impairment. This paper provides a snapshot of current practice in the monitoring and/or treatment of tyrosine levels in children with PKU, across 12 countries from Australasia, North America and Europe. Tyrosine monitoring in this population has increased over the last 5 years, with over 80% of clinics surveyed reporting routine monitoring of tyrosine levels in infancy alongside phe levels. Twenty-five percent of clinics surveyed reported actively treating/managing tyrosine levels (with supplemental tyrosine above that contained in PKU formulas) to ensure tyrosine levels remain within normal ranges. Anecdotally, supplemental tyrosine has been reported to ameliorate symptoms of both attention deficit hyperactivity disorder and depression in this population. EF assessment of children with ECT-PKU was likewise highly variable, with 50% of clinics surveyed reporting routine assessments of intellectual function. However when function was assessed, test instruments chosen tended towards global measures of IQ prior to school entry, rather than specific assessment of EF development. Further investigation of the role of tyrosine and its relationship with phe and EF development is needed to establish whether routine tyrosine monitoring and increased supplementation is recommended.

Neuropsychological development in children with early and continuously treated phenylketonuria : association with biochemical markers

PKU is a genetically inherited inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. The failure of this enzyme causes incomplete metabolism of protein ingested in the diet, specifically the conversion of one amino acid, phenylalanine, to tyrosine, which is a precursor to the neurotransmitter dopamine. Rising levels of phenylalanine is toxic to the developing brain, disrupting the formation of white matter tracts. The impact of tyrosine deficiency is not as well understood, but is hypothesized to lead to a low dopamine environment for the developing brain. Detection in the newborn period and continuous treatment (a low protein phe-restricted diet supplemented with phenylalanine-free protein formulas) has resulted in children with early and continuously treated PKU now developing normal I.Q. However, deficits in executive function (EF) are common, leading to a rate of Attention Deficit Hyperactivity Disorder (ADHD) up to five times the norm. EF worsens with exposure to higher phenylalanine levels, however recent research has demonstrated that a high phenylalanine to tyrosine ratio (phenylalanine:tyrosine ratio), which is hypothesised to lead to poorer dopamine function, has a more negative impact on EF than phenylalanine levels alone. Research and treatment of PKU is currently phenylalanine-focused, with little investigation of the impact of tyrosine on neuropsychological development. There is no current consensus as to the veracity of tyrosine monitoring or treatment in this population. Further, the research agenda in this population has demonstrated a primary focus on EF impairment alone, even though there may be additional neuropsychological skills compromised (e.g., mood, visuospatial deficits). The aim of this PhD research was to identify residual neuropsychological deficits in a cohort of children with early and continuously treated phenylketonuria, at two time points in development (early childhood and early adolescence), separated by eight years. In addition, this research sought to determine which biochemical markers were associated with neuropsychological impairments. A clinical practice survey was also undertaken to ascertain the current level of monitoring/treatment of tyrosine in this population. Thirteen children with early and continuously treated PKU were tested at mean age 5.9 years and again at mean age 13.95 years on several neuropsychological measures. Four children with hyperphenylalaninemia (a milder version of PKU) were also tested at both time points and provide a comparison group in analyses. Associations between neuropsychological function and biochemical markers were analysed. A between groups analysis in adolescence was also conducted (children with PKU compared to their siblings) on parent report measures of EF and mood. Minor EF impairments were evident in the PKU group by age 6 years and these persisted into adolescence. Life-long exposure to high phenylalanine:tyrosine ratio and/or low tyrosine independent of phenylalanine were significantly associated with EF impairments at both time points. Over half the children with PKU showed severe impairment on a visuospatial task, and this was associated only with concurrent levels of tyrosine in adolescence. Children with PKU also showed a statistically significant decline in a language comprehension task from 6 years to adolescence (going from normal to subnormal), this deficit was associated with lifetime levels of phenylalanine. In comparison, the four children with hyperphenylalaninemia demonstrated normal function at both time points, across all measures. No statistically significant differences were detected between children with PKU and their siblings on the parent report of EF and mood. However, depressive symptoms were significantly correlated with: EF; long term high phe:tyr exposure; and low tyrosine levels independent of phenylalanine. The practice survey of metabolic clinics from 12 countries indicated a high level of variability in terms of monitoring/treatment of tyrosine in this population. Whilst over 80% of clinics surveyed routinely monitored tyrosine levels in their child patients, 25% reported treatment strategies to increase tyrosine (and thereby lower the phenylalanine:tyrosine ratio) under a variety of patient presentation conditions. Overall, these studies have shown that EF impairments associated with PKU provide support for the dopamine-deficiency model. A language comprehension task showed a different trajectory, serving a timely reminder that non-EF functions also remain vulnerable in this population; and that normal function in childhood does not guarantee normal function by adolescence. Mood impairments were associated with EF impairments as well as long term measures of phenylalanine:tyrosine and/or tyrosine. The implications of this research for enhanced clinical guidelines are discussed given varied current practice.

Catalytic properties of 26 S and 20 S proteasomes and radiolabeling of MB1, LMP7, and C7 subunits associated with trypsin-like and chymotrypsin-like activities*

20 and 26 S proteasomes were isolated from rat liver. The procedure developed for the 26 S proteasome resulted in greatly improved yields compared with previously published methods. A comparison of the kinetic properties of 20 and 26 S proteasomes showed significant differences in the kinetic characteristics with certain substrates and differences in the effects of a protein substrate on peptidase activity. Observed differences in the kinetics of peptidylglutamyl peptide hydrolase activity suggest that the 26 S complex cannot undergo the conformational changes of 20 S proteasomes at high concentrations of the substrate benzyloxycarbonyl (Z) -Leu-Leu-Glu-b-naphthylamide. Various inhibitors that differentially affect the trypsin-like and chymotrypsin-like activities have been identified. Ala-Ala-Phe-chloromethyl (CH2Cl) inhibits chymotrypsin-like activity assayed with succinyl (Suc) -Leu-Leu-Val-Tyr-AMC, but surprisingly not hydrolysis of Ala-Ala-Phe-7-amido-4-methylcoumarin (AMC). Tyr-Gly-Arg-CH2Cl inhibits Suc-Leu-Leu-Val-Tyr-AMC hydrolysis as well as trypsinlike activity measured with t-butoxycarbonyl (Boc) -Leu-Ser-Thr-Arg-AMC, while Z-Phe-Gly-Tyr-diazomethyl (CHN2) was found to inhibit only the two chymotrypsin- like activities. Radiolabeled forms of peptidyl chloromethane and peptidyl diazomethane inhibitors, [3H]acetyl-Ala-Ala-Phe-CH2Cl, [3H]acetyland radioiodinated Tyr-Gly-Arg-CH2Cl, and Z-Phe-Gly- Tyr-(125I-CHN2), have been used to identify catalytic components associated with each of the three peptidase activities. In each case, incorporation of the label could be blocked by prior treatment of the proteasomes with known active site-directed inhibitors, calpain inhibitor 1 or 3,4-dichloroisocoumarin. Subunits of labeled proteasomes were separated either by reverse phase-HPLC and SDS-polyacrylamide gel electrophoresis or by twodimensional polyacrylamide gel electrophoresis followed by autoradiography/fluorography and immunoblotting with subunit-specific antibodies. In each case, label was found to be incorporated into subunits C7, MB1, and LMP7 but in different relative amounts depending on the inhibitor used, consistent with the observed effects on the different peptidase activities. The results strongly suggest a relationship between trypsin-like activity and chymotrypsin-like activity. They also help to relate the different subunits of the complex to the assayed multicatalytic endopeptidase activities

Osteopenia in a teenage boy presenting with previously undiagnosed guanidinoacetate methyltransferase (GAMT) deficiency and response to creatine supplementation

A 16 y.o. fully ambulant boy born to consanguineous Indian parents, presented for assessment of a fragility femoral neck fracture sustained against a background of autism and moderately severe intellectual disability. He had a past history of infantile eczema, and epilepsy treated with anticonvulsants from 2 to 10 years of age, with no further seizures following cessation of anticonvulsants. He had a thin body habitus (see Table 1) with long fingers and a high arched palate. He had no speech and negligible social interaction, but physical examination was otherwise unremarkable. Positive investigations revealed an undetectable serum creatinine and a urinary metabolic screen which showed an elevated GUA:Phe of 160 (< 36) and a decreased creatinine of 0.3 mmol/l (1.2–29.5) consistent with the diagnosis of guanidinoacetate methyltransferase(GAMT) deficiency. He was commenced on oral creatine 5 g three times daily. Despite improvement in physical activity, height and bone density, there was no discernable improvement in his intellectual functioning. Proton and phosphorous brain and leg magnetic resonance spectroscopy(MRS) was performed at baseline and showed an increased inorganic phosphorus peak and decreased phosphocreatine synthesis in brain and decreased creatine concentration in muscle. Following creatine treatment total brain creatine(1H-MRS) and phosphocreatine/ATP ratio (31P-MRS) content increased to 30% and 60% of control values, respectively. Brain GUA returned to normal levels.

Porohyperelastic analysis to explore mechanical properties of chondrocytes using numerical modeling and experiments : a finite element study

There are many continuum mechanical models have been developed such as liquid drop models, solid models, and so on for single living cell biomechanics studies. However, these models do not give a fully approach to exhibit a clear understanding of the behaviour of single living cells such as swelling behaviour, drag effect, etc. Hence, the porohyperelastic (PHE) model which can capture those aspects would be a good candidature to study cells behaviour (e.g. chondrocytes in this study). In this research, an FEM model of single chondrocyte cell will be developed by using this PHE model to simulate Atomic Force Microscopy (AFM) experimental results with the variation of strain rate. This material model will be compared with viscoelastic model to demonstrate the advantages of PHE model. The results have shown that the maximum value of force applied of PHE model is lower at lower strain rates. This is because the mobile fluid does not have enough time to exude in case of very high strain rate and also due to the lower permeability of the membrane than that of the protoplasm of chondrocyte. This behavior is barely observed in viscoelastic model. Thus, PHE model is the better model for cell biomechanics studies.

Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility

Background The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1) underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP) protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. Methods The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program. Results Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. Conclusion This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S) to Phe (F)) changes a hydrophilic residue (S) to a hydrophobic residue (F) and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5' near gene), and rs746429 (synonymous (Ala (A) to Ala (A)), did not show significant associations with breast cancer incidence, yet were associated with lymph node metastasis in the previous study. This suggests that SIPA1 may be involved in different stages of breast carcinogenesis and since this study replicates a previous study of the associated SNP, it implicates variants of the SIPA1 gene as playing a potential role in breast cancer.

Porohyperelastic analysis of single osteocyte using AFM and inverse FEA

Osteocytes are the mature cells and perform as mechanosensors within the bone. The mechanical property of osteocytes plays an important role to fulfill these functions. However, little researches have been done to investigate the mechanical deformation properties of single osteocytes. Atomic Force Microscopy (AFM) is a state-of-art experimental facility for high resolution imaging of tissues, cells and any surfaces as well as for probing mechanical properties of the samples both qualitatively and quantitatively. In this paper, the experimental study based on AFM is firstly used to obtain forceindentation curves of single round osteocytes. The porohyperelastic (PHE) model of a single osteocyte is then developed by using the inverse finite element analysis (FEA) to identify and extract mechanical properties from the experiment results. It has been found that the PHE model is a good candidature for biomechanics studies of osteocytes.

Porohyperelastic analysis of single chondrocyte using AFM and inverse FEA

The aim of this paper is to determine the creep and relaxation responses of single chondrocytes in vitro. Firstly, Atomic Force Microscopy (AFM) was used to obtain the force-indentation curves of single chondrocytes at the strain-rate of 7.05 s-1. This result was then employed in inverse finite element analysis (FEA) using porohyperelastic (PHE) idealization of the cells to determine their mechanical properties. The PHE model results agreed well with AFM experimental data. This PHE model was then utilized to study chondrocyte’s creep and relaxation behaviors. The results revealed that the effect of fluid was predominant for cell’s mechanical behaviors and that the PHE is a good model for biomechanics studies of chondrocytes.

Analysis of strain-rate dependent mechanical behavior of single chondrocyte : a finite element study

Various studies have been conducted to investigate the effects of impact loading on cartilage damage and chondrocyte death. These have shown that the rate and magnitude of the applied strain significantly influence chondrocyte death, and that cell death occurred mostly in the superficial zone of cartilage suggesting the need to further understand the fundamental mechanisms underlying the chondrocytes death induced at certain levels of strain-rate. To date there is no comprehensive study providing insight on this phenomenon. The aim of this study is to examine the strain-rate dependent behavior of a single chondrocyte using a computational approach based on Finite Element Method (FEM). An FEM model was developed using various mechanical models, which were Standard Neo-Hookean Solid (SnHS), porohyperelastic (PHE) and poroviscohyperelastic (PVHE) to simulate Atomic Force Microscopy (AFM) experiments of chondrocyte. The PVHE showed, it can capture both relaxation and loading rate dependent behaviors of chondrocytes, accurately compared to other models.

Exploration of mechanisms underlying the strain-rate-dependent mechanical property of single chondrocytes

Based on the characterization by Atomic Force Microscopy (AFM), we report that the mechanical property of single chondrocytes has dependency on the strain-rates. By comparing the mechanical deformation responses and the Young’s moduli of living and fixed chondrocytes at four different strain-rates, we explore the deformation mechanisms underlying this dependency property. We found that the strain-rate-dependent mechanical property of living cells is governed by both of the cellular cytoskeleton (CSK) and the intracellular fluid when the fixed chondrocytes is mainly governed by their intracellular fluid which is called the consolidation-dependent deformation behavior. Finally, we report that the porohyperelastic (PHE) constitutive material model which can capture the consolidation-dependent behavior of both living and fixed chondrocytes is a potential candidature to study living cell biomechanics.

Stress relaxation analysis of single chondrocytes using porohyperelastic model based on AFM experiments

The aim of this study is to investigate the stress relaxation behavior of single chondrocytes using the Porohyperelastic (PHE) model and inverse Finite Element Analysis (FEA). Firstly, based on Atomic Force Microscopy (AFM) technique, we have found that the chondrocytes exhibited stress relaxation behavior. We explored the mechanism of this stress relaxation behavior and concluded that the intracellular fluid exuding out from the cells during deformation plays the most important role in the stress relaxation. Next, we have applied the inverse FEA technique to determine necessary material parameters for PHE model to simulate this stress relaxation behavior as this model is proven capable of capturing the non-linear behavior and the fluid-solid interaction during the stress relaxation of the single chondrocytes. It is observed that this PHE model can precisely capture the stress relaxation behavior of single chondrocytes and would be a suitable model for cell biomechanics.