"It Looks Good on Paper, But It Was Never Meant to Be Real": Mixed-Gender Events in the Paralympic Movement.

Although the Paralympic Games have been around for over 60 years, women remain underrepresented in almost all aspects of the Paralympic Movement. It has been suggested that a way to increase women's involvement is through the implementation of mixed-gender events. On paper, this approach makes sense. However, when it comes to the implementation of mixed-gender opportunities for women, it is less clear how effective these events are in increasing participation by women in Para sport. Through document analysis and interviews with athletes and organizers of mixed-gender Paralympic sport, we explore the various strategies that four mixed-gender sports have used to address the issue of gender parity. Using critical feminist theories, we illustrate how larger social, political, and cultural ideas about gender influence women's experiences within these events and discuss the potential of using mixed-gender initiatives to address gender parity within the Paralympic Movement.

Cultural influences on physical activity and exercise beliefs in patients with chronic kidney disease: 'The Culture-CKD Study'-a qualitative study.

OBJECTIVES: This study used a mixed-method approach to explore cultural and ethnic influences on the perception of, and decision to engage with or not to engage with, physical activity and exercise therapy in patients with chronic kidney disease (CKD). DESIGN: Qualitative research was conducted through the use of semistructured interviews and focus groups. Self-reported physical activity levels were measured using the General Practice Physical Activity Questionnaire (GPPAQ), and self-efficacy for exercise with Bandura's Self-Efficacy for Exercise Scale. SETTING: This study was conducted in a non-clinical setting of a single National Health Service Hospital Trust between April 2018 and July 2019. PARTICIPANTS: Participants >18 years of age with a diagnosis of CKD, from black African, black Caribbean, South Asian or white ethnicity were eligible for the study. 84 patients with a diagnosis of CKD (stages 2-5), aged 25-79 (mean age 57) were recruited. Semistructured interviews (n=20) and six single-sex, ethnic-specific focus group discussions were undertaken (n=36). OUTCOMES: Primary outcome was to explore the perceptions, attitudes and values about exercise and physical activity in different ethnic groups through qualitative interviews, analysed using an inductive thematic analysis approach. Questionnaires were analysed using Pearson correlation to determine if there was a significant relationship between the self-efficacy and GPPAQ levels. RESULTS: Qualitative analysis provided four primary themes: I am who I am, Change of identity, Influences to physical activity and exercise and Support and education. Quantitative analysis using Pearson correlation revealed a significant correlation between GPPAQ levels of activity and self-efficacy to regulate exercise behaviour (r=-0.40, p=0.001). CONCLUSION: Understanding the cultural, attitudes and beliefs of individuals with CKD from a variety of ethnic backgrounds is complex. Understanding of patients' experiences, thoughts and beliefs may be of relevance to clinicians when designing CKD exercise services. TRIAL REGISTRATION NUMBER: NCT03709212; Pre-results.

The Social Empowerment of Difference: The Potential Influence of Para sport.

This article explores the significance of parasport culture in highlighting an emancipatory understanding of difference and enhancing social empowerment. Disability studies are used to illuminate the influence of ableist ideology on people with impairments. Rather than being suppressed, difference should be recognized and valued in parasport practices and ideologies, leading to a pluralist culture, in which farther and wider social emancipation can be grounded. Acceptance of difference is an absolute and essential precondition for parasport cultures to promote positive social change for people with disabilities.

Repression of caspase-3 and RNA-binding protein HuR cleavage by cyclooxygenase-2 promotes drug resistance in oral squamous cell carcinoma.

A well-studied RNA-binding protein Hu Antigen-R (HuR), controls post-transcriptional gene regulation and undergoes stress-activated caspase-3 dependent cleavage in cancer cells. The cleavage products of HuR are known to promote cell death; however, the underlying molecular mechanisms facilitating caspase-3 activation and HuR cleavage remains unknown. Here, we show that HuR cleavage associated with active caspase-3 in oral cancer cells treated with ionizing radiation and chemotherapeutic drug, paclitaxel. We determined that oral cancer cells overexpressing cyclooxygenase-2 (COX-2) limited the cleavage of caspase-3 and HuR, which reduced the rate of cell death in paclitaxel resistant oral cancer cells. Specific inhibition of COX-2 by celecoxib, promoted apoptosis through activation of caspase-3 and cleavage of HuR in paclitaxel-resistant oral cancer cells, both in vitro and in vivo. In addition, oral cancer cells overexpressing cellular HuR increased the half-life of COX-2 mRNA, promoted COX-2 protein expression and exhibited enhanced tumor growth in vivo in comparison with cells expressing a cleavable form of HuR. Finally, our ribonucleoprotein immunoprecipitation and sequencing (RIP-seq) analyses of HuR in oral cancer cells treated with ionizing radiation (IR), determined that HuR cleavage product-1 (HuR-CP1) bound and promoted the expression of mRNAs encoding proteins involved in apoptosis. Our results indicated that, cellular non-cleavable HuR controls COX-2 mRNA expression and enzymatic activity. In addition, overexpressed COX-2 protein repressed the cleavage of caspase-3 and HuR to promote drug resistance and tumor growth. Altogether, our observations support the use of the COX-2 inhibitor celecoxib, in combination with paclitaxel, for the management of paclitaxel resistant oral cancer cells.

Low dose resveratrol improves cerebrovascular function in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Progressive microvascular dysfunction in type 2 diabetes mellitus (T2DM) may impair the ability of cerebral vessels to supply blood to brain regions during local metabolic demand, thereby increasing risks of dementia. Having previously demonstrated that resveratrol can enhance vasodilator function in the systemic circulation, we hypothesised that resveratrol could similarly benefit the cerebral circulation. We aimed to determine the most efficacious dose of resveratrol to improve cerebral vasodilator responsiveness (CVR) in T2DM. METHODS AND RESULTS: In a double-blind, placebo-controlled, balanced crossover intervention, 36 dementia-free, non-insulin dependent T2DM older adults (49-78 years old) consumed single doses of synthetic trans-resveratrol (0, 75, 150, and 300 mg) at weekly intervals. Transcranial Doppler ultrasound was used to assess CVR to a hypercapnic stimulus, both before and 45 min after treatment. CVR, measured bilaterally in the middle cerebral arteries (MCA) and posterior cerebral arteries (PCA), was expressed as the percentage change in mean blood flow velocity from baseline to the peak velocity attained during hypercapnia. Resveratrol consumption increased CVR in the MCA; mean within-individual changes for each dose from placebo were 13.8 ± 3.5% for 75 mg (P = 0.001), 8.9 ± 3.5% for 150 mg (P = 0.016), and 13.7 ± 3.3% for 300 mg (P < 0.001); only the 75 mg dose was efficacious in the PCA (13.2 ± 4.5%, P = 0.016). CONCLUSIONS: Our results provide the first clinical evidence of an acute enhancement of vasodilator responsiveness in cerebral vessels following consumption of resveratrol in this population who are known to have endothelial dysfunction and sub-clinical cognitive impairment. Importantly, maximum improvement was observed with the lowest dose used. CLINICAL TRIAL REGISTRATION: ACTRN12614000891628 (www.anzctr.org.au).

Translational regulation of inhibin ßA by TGFß via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells.

The epithelial-to-mesenchymal transition (EMT) is a cellular process that functions during embryonic development and tissue regeneration, thought to be aberrantly activated in epithelial-derived cancer and has an important role in the process of metastasis. The transforming growth factor (TGF)-ß signaling pathway is a key inducer of EMT and we have elucidated a posttranscriptional mechanism by which TGFß modulates expression of select transcripts via the RNA-binding protein hnRNP E1 during EMT. One such transcript inhibin ßA is a member of the TGFß superfamily. Here, we show by polysome profiling that inhibin ßA is translationally regulated by TGFß via hnRNP E1. TGFß treatment or knockdown of hnRNP E1 relieves silencing of the inhibin ßA transcript, resulting in increased protein expression and secreted levels of the inhibin ßA homodimer, activin A. Our data indicate that the translational upregulation of inhibin ßA enhances the migration and invasion of cells that have undergone an EMT and promotes cancer progression in vivo.

Adiposity is related to decrements in cardiorespiratory fitness in obese and normal-weight children.

BACKGROUND: Obese children are typically less physically active than their normal-weight peers and are often assumed to be 'unfit'. OBJECTIVE: Investigate the relationships between adiposity, physical activity levels and cardiorespiratory fitness (CRF) in obese and normal-weight children. A secondary aim was to examine obese/normal-weight differences in CRF. METHODS: Obese (N = 107) and normal-weight (N = 132) 10-13-year-olds participated. Fat-free mass (FFM), percent fat, physical activity and peak oxygen uptake (VO2peak ) were assessed. Analyses were adjusted for socioeconomic status (SES). RESULTS: Higher percent fat was inversely associated with VO2peak normalized for mass (r = -0.780, P < 0.001) even after controlling for physical activity (r = -0.673, P < 0.001). While higher percent fat was also inversely associated with VO2peak normalized for FFM, this was only significant in males (r = -0.247, P = 0.004) and did not persist after controlling for physical activity (r = -0.059 P = 0.526). Compared with normal-weight children, obese children had higher absolute VO2peak , lower VO2peak corrected for mass (P ≤ 0.009) and lower VO2peak corrected for FFM (P = 0.041) that did not persist after controlling for SES (P = 0.086). CONCLUSION: Obesity-related inefficiencies in CRF were evident. Higher adiposity was associated with poorer CRF relative to mass, irrespective of physical activity levels. However, low physical activity levels may be responsible for associations between adiposity and CRF relative to FFM seen in boys, indicating the importance of encouraging physical activity.

Comparative sensitivity of the cnidarian Exaiptasia pallida and a standard toxicity test suite: testing whole effluents intended for ocean disposal.

The sea anemone Exaiptasia pallida (formally Aiptasia pulchella) has been identified as a valuable test species for tropical marine ecotoxicology. Here, the sensitivities of newly developed endpoints for E. pallida to two unidentified whole effluents were compared to a standard suite of temperate toxicity test species and endpoints that are commonly used in toxicological risk assessments for tropical marine environments. For whole effluent 1 (WE1), a 96-h lethal concentration 50 % (LC50) of 40 (95 % confidence intervals, 30-54) % v/v and a 12-day LC50 of 12 (9-15) % v/v were estimated for E. pallida, exhibiting a significantly higher sensitivity than standard sub-lethal endpoints in Allorchestes compressa (96-h effective concentration 50 % (EC50) of >100 % v/v for immobilisation) and Hormosira banksii (72-h EC50 of >100 % v/v for germination), and a similar sensitivity to Mytilus edulis galloprovincialis larval development with a 48-h LC50 of 29 (28-30) % v/v. Sub-lethal effects of whole effluent 2 (WE2) on E. pallida pedal lacerate development resulted in an 8-day EC50 of 7 (3-11) % v/v, demonstrating comparable sensitivity of this endpoint to standardised sub-lethal endpoints in H. banksii (72-h EC50 of 11 (10-11) % v/v for germination), M. edulis galloprovincialis (48-h EC50 for larval development of 12 (9-14) % v/v) and Heliocidaris tuberculata (1-h EC50 of 13 (12-14) % v/v for fertilisation; 72-h EC50 of 26 (25-27) % v/v for larval development) and a significantly higher sensitivity than A. compressa immobilisation (96-h EC50 of >100 % v/v). The sensitivity of E. pallida compared to a standard test species suite highlights the value in standardising the newly developed toxicity test methods for inclusion in routine toxicological risk assessment of complex whole effluents. Importantly, this species provides an additional taxonomic group to the test species that are currently available for tropical marine ecotoxicology and, being a cnidarian, may represent important tropical marine environments including coral reefs.

Sample convection in liquid-state NMR: why it is always with us, and what we can do about it.

Many NMR experiments on liquids suffer if the sample convects. This is particularly true for applications, such as the measurement of diffusion, that rely on spatial labelling of spins. It is widely assumed that, in most well-conducted experiments with stable temperature regulation, samples do not convect. Unfortunately this is not the case. It is shown here that typical NMR samples show measurable convective flow for all but a very narrow range of temperatures; convection is seen both above and below this range, which can be as small as a degree or so for a mobile solvent such as chloroform. This convection is driven by both vertical and horizontal temperature gradients. Measurements of convection velocity are presented for a range of samples, sample tubes, probes, and temperatures. Both decreasing sample tube inner diameter and changing sample tube material from glass to sapphire can slow convection markedly, with sapphire tubes being particularly effective. Such tubes are likely to be particularly helpful for accurate measurement of diffusion by NMR.

Day-to-day physical functioning and disability in obese 10- to 13-year-olds.

UNLABELLED: What is already known about this subject? Compared with their healthy-weight peers, children with obesity have; impaired physical health-related quality of life reduced physical activity levels reduced capacity to perform certain weight-bearing tasks in field-based fitness tests What this study adds? First investigation of obesity-related disability in children using the International Classification for Functioning, Disability and Health framework for Children and Youth. Obesity in children appears to be associated with disability impacting basic locomotor skills and physical health-related quality of life. Children's participation in key life areas related to physical functioning appears to be minimally impacted by obesity. OBJECTIVE: The aim of this study was to investigate whether obesity is related to impaired day-to-day physical functioning and disability in children. METHODS: An observational case-control study was conducted in three Australian states. Obese (n = 107) and healthy-weight (n = 132) 10- to 13-year-olds (132 male, 107 female) were recruited via media advertisements. Assessment of body composition (dual energy X-ray absorptiometry), locomotor capacity (six-minute walk test [6MWT], timed up and down stairs test [TUDS] and timed up and go [TUG]) and child-reported physical health-related quality of life (HRQoL) were undertaken. Participants wore an accelerometer for 8 days and completed two use-of-time telephone interviews to assess participation in key life areas. RESULTS: Compared with their healthy-weight counterparts, obese children had lower physical HRQoL scores (P < 0.01) and reduced locomotor capacity (TUDS z-score, TUG and 6MWT; P < 0.01). Higher percent body fat was significantly related to lower physical HRQoL scores (r = -0.48, P < 0.01), slower performance times for the TUDS and TUG (r = 0.59 and 0.26 respectively, P < 0.01), shorter 6MWT distances (r = -0.51, P < 0.01) and reduced time spent in community participation activities (r = -0.23, P < 0.01). CONCLUSIONS: As anticipated, obesity appears to undermine physical functioning in children, including the capacity to perform basic locomotor skills yet, unexpectedly, participation in key life areas related to physical functioning appeared largely unaffected.

Proximal correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum.

OBJECTIVE: To examine the social and behavioural correlates of metabolic phenotypes during 'at-risk' and 'case' stages of the metabolic disease continuum. DESIGN: Cross-sectional study of a random population sample. PARTICIPANTS: A total of 718 community-dwelling adults (57% female), aged 18-92 years from a regional South Australian city. MEASUREMENTS: Total body fat and lean mass and abdominal fat mass were assessed by dual energy x-ray absorptiometry. Fasting venous blood was collected in the morning for assessment of glycated haemoglobin, plasma glucose, serum triglycerides, cholesterol lipoproteins and insulin. Seated blood pressure (BP) was measured. Physical activity and smoking, alcohol and diet (96-item food frequency), sleep duration and frequency of sleep disordered breathing (SDB) symptoms, and family history of cardiometabolic disease, education, lifetime occupation and household income were assessed by questionnaire. Current medications were determined by clinical inventory. RESULTS: 36.5% were pharmacologically managed for a metabolic risk factor or had known diabetes ('cases'), otherwise were classified as the 'at-risk' population. In both 'at-risk' and 'cases', four major metabolic phenotypes were identified using principal components analysis that explained over 77% of the metabolic variance between people: fat mass/insulinemia (FMI); BP; lipidaemia/lean mass (LLM) and glycaemia (GLY). The BP phenotype was uncorrelated with other phenotypes in 'cases', whereas all phenotypes were inter-correlated in the 'at-risk'. Over and above other socioeconomic and behavioural factors, medications were the dominant correlates of all phenotypes in 'cases' and SDB symptom frequency was most strongly associated with FMI, LLM and GLY phenotypes in the 'at-risk'. CONCLUSION: Previous research has shown FMI, LLM and GLY phenotypes to be most strongly predictive of diabetes development. Reducing SDB symptom frequency and optimising the duration of sleep may be important concomitant interventions to standard diabetes risk reduction interventions. Prospective studies are required to examine this hypothesis.

Combined use of filtered and edited 1 H NMR spectroscopy to detect 13 C-enriched compounds in complex mixtures.

In conventional metabolism and pharmacokinetic studies, radioactive isotopes are used to identify and quantify the breakdown products of xenobiotics. However, the stable isotope (13) C provides a cheaper and less hazardous alternative. Metabolites of (13) C-enriched xenobiotics can be detected, quantified and identified by (13) C-filtered NMR spectroscopy. However, one obstacle to using (13) C is its 1.1% natural abundance that produces a background signal in (13) C-filtered NMR spectra of crude biological extracts. The signal makes it difficult to distinguish between (13) C-enriched xenobiotics resonances from endogenous metabolites unrelated to the xenobiotic. This study proposes that the (13) C background signal can be distinguished from resonances of (13) C-enriched xenobiotics by the absence of a (12) C component in the xenobiotic. This is detected by combined analysis of (13) C-filtered and -edited NMR spectra. The theory underlying the approach is described and the method is demonstrated by the detection of sub-microgram amounts of (13) C-enriched phenacetin in crude extracts of hepatocyte microsomes.

Difference, adapted physical activity and human development: potential contribution of capabilities approach.

This paper is a call to Adapted Physical Activity (APA) professionals to increase the reflexive nature of their practice. Drawing upon Foucault's concept of governmentality (1977) APA action may work against its own publicized goals of empowerment and self-determination. To highlight these inconsistencies, we will draw upon historical and social factors that explain the implicit dangers of practice not following policy. We propose that APA practitioners work according to ethical guidelines, based upon a capabilities approach (Nussbaum, 2006, 2011; Sen, 2009) to counteract possible adverse effects of APA practitioner action. A capabilities approach is conducive to the development of each individual's human potential, by holistically considering the consequences of physical activity (i.e., biological, cultural, social, and psychological dimensions). To conclude, this paper will offer suggestions that may lead to an ethical reflection aligned with the best interest of APA's users.

Obesity: the new childhood disability?

This review addresses the impact of obesity on paediatric physical functioning utilizing the World Health Organization International Classification of Functioning, Disability and Health Framework (ICF). The ICF encompasses functioning (as it relates to all body functions and structures), activities (undertaking a particular task) and participation (in a life situation) with disability referring to impairments in body functions/structures, activity restrictions or participation limitations. Electronic databases were searched for peer-reviewed studies published in English prior to May 2009 that examined aspects of physical functioning in children (≤18 years). Eligible studies (N = 104) were ranked by design and synthesized descriptively. Childhood obesity was found to be associated with deficits in function, including impaired cardiorespiratory fitness and performance of motor tasks; and there was some limited evidence of increased musculoskeletal pain and decrements in muscle strength, gait and balance. Health-related quality of life and the subset of physical functioning was inversely related to weight status. However, studies investigating impacts of obesity on wider activity and participation were lacking. Further research utilizing the ICF is required to identify and better characterize the effects of paediatric obesity on physical function, activity and participation, thereby improving targets for intervention to reduce disability in this population.

Acute resveratrol supplementation improves flow-mediated dilatation in overweight/obese individuals with mildly elevated blood pressure.

BACKGROUND AND AIMS: Flow-mediated dilatation of the brachial artery (FMD) is a biomarker of endothelial function and cardiovascular health. Impaired FMD is associated with several cardiovascular risk factors including hypertension and obesity. Various food ingredients such as polyphenols have been shown to improve FMD. We investigated whether consuming resveratrol, a polyphenol found in red wine, can enhance FMD acutely and whether there is a dose-response relationship for this effect. METHODS AND RESULTS: 19 overweight/obese (BMI 25-35 kg m(-2)) men or post-menopausal women with untreated borderline hypertension (systolic BP: 130-160 mmHg or diastolic BP: 85-100 mmHg) consumed three doses of resveratrol (resVida™ 30, 90 and 270 mg) and a placebo at weekly intervals in a double-blind, randomized crossover comparison. One hour after consumption of the supplement, plasma resveratrol and FMD were measured. Data were analyzed by linear regression versus log(10) dose of resveratrol. 14 men and 5 women (age 55 ± 2 years, BMI 28.7 ± 0.5 kg m(-2), BP 141 ± 2/89 ± 1 mmHg) completed this study. There was a significant dose effect of resveratrol on plasma resveratrol concentration (P < 0.001) and on FMD (P < 0.01), which increased from 4.1 ± 0.8% (placebo) to 7.7 ± 1.5% after 270 mg resveratrol. FMD was also linearly related to log(10) plasma resveratrol concentration (P < 0.01). CONCLUSION: Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine.

A multi-criteria weight of evidence approach for deriving ecological benchmarks for radioactive substances.

Dose rate benchmarks are required in the tiered approaches used to screen out benign exposure scenarios in radiological ecological risk assessment. Such screening benchmarks, namely the predicted no-effect dose rates (PNEDR), have been derived by applying, as far as possible, the European guidance developed for chemicals. To derive the ecosystem level (or generic) PNEDR, radiotoxicity EDR(10) data (dose rates giving a 10% effect in comparison with the control) were used to fit a species sensitivity distribution (SSD) and estimate the HDR(5) (the hazardous dose rate affecting 5% of species with a 10% effect). Then, a multi-criteria approach was developed to justify using an assessment factor (AF) to apply to the HDR(5) for estimating a PNEDR value. Several different statistical data treatments were considered which all gave reasonably similar results. The suggested generic screening value of 10 microGy h(-1) (incremental dose rate) was derived using the lowest available EDR(10) value per species, an unweighted SSD, and an AF of 2 applied to the estimated HDR(5). Consideration was also given to deriving screening benchmark values for organism groups but this was not thought to be currently appropriate due to few relevant data being currently available.

Protection of the environment from ionising radiation in a regulatory context--an overview of the PROTECT coordinated action project.

The outcome of the PROTECT project (Protection of the Environment from Ionising Radiation in a Regulatory Context) is summarised, focusing on the protection goal and derivation of dose rates which may detrimentally affect wildlife populations. To carry out an impact assessment for radioactive substances, the estimated dose rates produced by assessment tools need to be compared with some form of criteria to judge the level of risk. To do this, appropriate protection goals need to be defined and associated predefined dose rate values, or benchmarks, derived and agreed upon. Previous approaches used to estimate dose rates at which there may be observable changes in populations or individuals are described and discussed, as are more recent derivations of screening benchmarks for use in regulatory frameworks. We have adopted guidance and procedures used for assessment and regulation of other chemical stressors to derive benchmarks. On the basis of consultation with many relevant experts, PROTECT has derived a benchmark screening dose rate, using data on largely reproductive effects to derive species sensitivity distributions, of 10 microGy h(-1) which can be used to identify situations which are below regulatory concern with a high degree of confidence.

Dose-related effects of flavanol-rich cocoa on blood pressure.

Consumption of flavanol-containing cocoa products has been shown to lower blood pressure (BP), but the minimum dose required to reduce BP is not known. This study aimed to examine the effect of three different doses of cocoa flavanols (CF) on 24-h mean arterial BP. Twenty four hour ambulatory BP (24-ABP) monitoring was performed in 32 men and 20 postmenopausal women with untreated mild hypertension (seated clinic BP >130/85 and <160/100 mm Hg). Participants were randomized and instructed to consume daily a reconstituted cocoa beverage containing 33, 372, 712 or 1052 mg day(-1) of CF for 6 weeks in a double-blind, parallel comparison. Seated clinic BP and 24-h ABP were measured at 0, 3 and 6 weeks. Seated clinic BP did not change during the study period. There were significant reductions in 24-h systolic (5.3+/-5.1 mm Hg; P=0.001), diastolic (3+/-3.2 mm Hg; P=0.002) and mean arterial BP (3.8+/-3.2 mm Hg; P=0.0004) at the 1052 mg day(-1) CF only. No reduction in BP was seen at any other dose. No evidence of dose-response was seen in this experiment. The highest dose of 1052 mg CF per day was found to significantly lower BP. These results support previous evidence for CF to lower BP, however more research is needed to establish the most effective dose and food matrix.

Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing protein phosphatase 1 (PP1)-Axin interactions.

Wnt/beta-catenin signaling plays a pivotal role in modulating cellular proliferation, differentiation, tissue organization and embryonic development. Earlier, we found that the endocytic adaptor disabled-2 (Dab2) could attenuate Wnt/beta-catenin signaling by stabilizing Axin and preventing its translocation to the membrane. Recently, protein phosphatase 1 (PP1) has been shown to interact with, and dephosphorylate Axin, leading to its destabilization. Here, we show that Dab2 functions upstream of PP1 to block the interaction between Axin and PP1, inhibiting Axin dephosphorylation and thereby stabilizing its expression, ultimately leading to inhibition of Wnt/beta-catenin. We show that Dab2 acts as a competitive inhibitor of PP1 by binding to the same C-terminal domain of Axin. Both PP1 and Axin bind to the N-terminus of Dab2 and a Dab2 truncation mutant consisting of the N-terminal phosphotyrosine binding domain blocks PP1-Axin interactions and inhibits Wnt signaling. We confirm the inhibitory effect of Dab2 on Wnt/beta-catenin signaling in zebrafish embryos, showing that its ectopic expression phenocopies Axin overexpression resulting in altered dorsoventral patterning. We conclude that Dab2 stabilizes Axin and attenuates Wnt/beta-catenin signaling by preventing PP1 from binding Axin.

Do estuaries pose a toxic contamination risk for wading birds?

The impact of potentially toxic chemicals on wildlife is commonly assessed by comparing the intake of the contaminant with the "no observable effects level" (NOAEL) of intake. It is known, however, that there are considerable uncertainties inherent in this method. This study presents a Monte-Carlo based model to assess the degree of risk posed to birds (dunlin, Calidris alpina) from important estuarine habitats, and to show the limitations of such risk assessments, particularly with regard to data availability. The model was applied to predict the uptake of metals (Hg, Pb) in this shorebird species in Poole Harbour and the Severn Estuary/Bristol Channel, UK, two internationally important shorebird habitats. The results show that in both areas, Pb and Hg concentrations may pose an ecologically relevant toxic risk to wading birds. For Pb, uncertainty in NOAEL values dominates the overall uncertainty. Use of lethal toxicity data (LD50/100) was investigated as a method for assessing sub-lethal impacts from Hg. It was found that this method led to a significant under-estimate of the potential impact of Hg contamination, compared with direct estimation of NOAEL.