Medicine (St Vincent's) - Research Publications
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ItemNo Preview AvailableMolecular Basis for Lysine Specificity in the Yeast Ubiquitin-Conjugating Enzyme Cdc34(AMER SOC MICROBIOLOGY, 2010-05-15)Ubiquitin (Ub)-conjugating enzymes (E2s) and ubiquitin ligases (E3s) catalyze the attachment of Ub to lysine residues in substrates and Ub during monoubiquitination and polyubiquitination. Lysine selection is important for the generation of diverse substrate-Ub structures, which provides versatility to this pathway in the targeting of proteins to different fates. The mechanisms of lysine selection remain poorly understood, with previous studies suggesting that the ubiquitination site(s) is selected by the E2/E3-mediated positioning of a lysine(s) toward the E2/E3 active site. By studying the polyubiquitination of Sic1 by the E2 protein Cdc34 and the RING E3 Skp1/Cul1/F-box (SCF) protein, we now demonstrate that in addition to E2/E3-mediated positioning, proximal amino acids surrounding the lysine residues in Sic1 and Ub are critical for ubiquitination. This mechanism is linked to key residues composing the catalytic core of Cdc34 and independent of SCF. Changes to these core residues altered the lysine preference of Cdc34 and specified whether this enzyme monoubiquitinated or polyubiquitinated Sic1. These new findings indicate that compatibility between amino acids surrounding acceptor lysine residues and key amino acids in the catalytic core of ubiquitin-conjugating enzymes is an important mechanism for lysine selection during ubiquitination.
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ItemDeterminants of the Specificity of Rotavirus Interactions with the α2β1 Integrin(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-02-25)The human α2β1 integrin binds collagen and acts as a cellular receptor for rotaviruses and human echovirus 1. These ligands require the inserted (I) domain within the α2 subunit of α2β1 for binding. Previous studies have identified the binding sites for collagen and echovirus 1 in the α2 I domain. We used CHO cells expressing mutated α2β1 to identify amino acids involved in binding to human and animal rotaviruses. Residues where mutation affected rotavirus binding were located in several exposed loops and adjacent regions of the α2 I domain. Binding by all rotaviruses was eliminated by mutations in the activation-responsive αC-α6 and αF helices. This is a novel feature that distinguishes rotavirus from other α2β1 ligands. Mutation of residues that co-ordinate the metal ion (Ser-153, Thr-221, and Glu-256 in α2 and Asp-130 in β1) and nearby amino acids (Ser-154, Gln-215, and Asp-219) also inhibited rotavirus binding. The importance of most of these residues was greatest for binding by human rotaviruses. These mutations inhibit collagen binding to α2β1 (apart from Glu-256) but do not affect echovirus binding. Overall, residues where mutation affected both rotavirus and collagen recognition are located at one side of the metal ion-dependent adhesion site, whereas those important for collagen alone cluster nearby. Mutations eliminating rotavirus and echovirus binding are distinct, consistent with the respective preference of these viruses for activated or inactive α2β1. In contrast, rotavirus and collagen utilize activated α2β1 and show an overlap in α2β1 residues important for binding.
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ItemHow effective are family-based and institutional nutrition interventions in improving children's diet and health? A systematic review(BMC, 2017-10-17)BACKGROUND: Effective strategies to improve dietary intake in young children are a priority to reduce the high prevalence of chronic non-communicable diseases in adulthood. This study aimed to assess the impact of family-based and school/preschool nutrition programs on the health of children aged 12 or younger, including the sustainability of these impacts and the relevance to socio-economic inequalities. METHODS: A systematic review of literature published from 1980 to December 2014 was undertaken. Randomised controlled trials involving families with children aged up to 12 years in high income countries were included. The primary outcomes were dietary intake and health status. Results were presented in a narrative synthesis due to the heterogeneity of the interventions and outcomes. RESULTS: The systematic search and assessment identified 39 eligible studies. 82% of these studies were set in school/preschools. Only one school study assessed the impact of involving parents systematically. The family-based programs which provided simple positive dietary advice to parents and regular follow-up reduced fat intake significantly. School and family-based studies, if designed and implemented well, increased F&V intake, particularly fruit. Effective school-based programs have incorporated role-models including peers, teachers and heroic figures, rewards and increased access to healthy foods. School nutrition programs in disadvantaged communities were as effective as programs in other communities. CONCLUSIONS: Family and school nutrition programs can improve dietary intake, however evidence of the long-term sustainability of these impacts is limited. The modest overall impact of even these successful programs suggest complementary nutrition interventions are needed to build a supportive environment for healthy eating generally.
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ItemSugar-sweetened beverage (SSB) consumption, correlates and interventions among Australian Aboriginal and Torres Strait Islander communities: a scoping review(BMJ PUBLISHING GROUP, 2019-06)OBJECTIVES: Sugar-sweetened beverage (SSB) consumption in Australian Aboriginal and Torres Strait Islander people is reported to be disproportionally high compared with the general Australian population. This review aimed to scope the literature documenting SSB consumption and interventions to reduce SSB consumption among Australian Aboriginal and Torres Strait Islander people. Findings will inform strategies to address SSB consumption in Aboriginal and Torres Strait Islander communities. METHODS: PubMed, SCOPUS, CINAHL, Informit, Joanna Briggs Institute EBP, Mura databases and grey literature were searched for articles published between January 1980 and June 2018. Studies were included if providing data specific to an Australian Aboriginal and/or Torres Strait Islander population's SSB consumption or an intervention that focused on reducing SSB consumption in this population. DESIGN: Systematic scoping review. RESULTS: 59 articles were included (1846 screened). While reported SSB consumption was high, there were age-related and community-related differences observed in some studies. Most studies were conducted in remote or rural settings. Implementation of nutrition interventions that included an SSB component has built progressively in remote communities since the 1980s with a growing focus on community-driven, culturally sensitive approaches. More recent studies have focused exclusively on SSB consumption. Key SSB-related intervention elements included incentivising healthier options; reducing availability of less-healthy options; nutrition education; multifaceted or policy implementation (store nutrition or government policy). CONCLUSIONS: There was a relatively large number of studies reporting data on SSB consumption and/or sales, predominantly from remote and rural settings. During analysis it was subjectively clear that the more impactful studies were those which were community driven or involved extensive community consultation and collaboration. Extracting additional SSB-specific consumption data from an existing nationally representative survey of Aboriginal and Torres Strait Islander people could provide detailed information for demographic subgroups and benchmarks for future interventions. It is recommended that a consistent, culturally appropriate, set of consumption measures be developed.
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ItemJAK2 is dispensable for maintenance of JAK2 mutant B-cell acute lymphoblastic leukemias(COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT, 2018-06-01)Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
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ItemPeripheral neuropathy in the hands of people with diabetes mellitus(ELSEVIER IRELAND LTD, 2016-09)AIMS: Peripheral sensorimotor neuropathy is a recognised complication of diabetes mellitus however little attention has been given to its development in the hands. The aim of this study was to determine the prevalence of sensory impairment in the hands of participants with diabetes, the agreement between two measurement tools for assessing sensation and the association between hand sensibility, age, glycaemic control and end-organ damage. METHODS: A total of 162 participants were recruited and divided into two cohorts based on a diagnosis of diabetes. Participants were tested for the presence of hand neuropathy using Semmes-Weinstein monofilaments and the AsTex™. Medical records of participants with diabetes were accessed retrospectively to determine glycaemic control and diabetes complications. RESULTS: A highly statistically significant association was found between neuropathy and diabetes status (P<0.001) on monofilament testing. The prevalence of neuropathy was 64% compared to ∼10% amongst participants without diabetes. Age, male gender and diabetic retinopathy were associated with neuropathy. The AsTex™ identified participants with diminished protective sensation on monofilament testing. CONCLUSIONS: This study demonstrates a relationship between diabetes and upper limb neuropathy. Age, male gender and retinopathy were associated with diminished hand sensation. The AsTex™ may have a role as a screening tool for identifying clinically significant hand neuropathy.
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ItemIL-23 costimulates antigen-specific MAIT cell activation and enables vaccination against bacterial infection(AMER ASSOC ADVANCEMENT SCIENCE, 2019-11-01)Mucosal-associated invariant T (MAIT) cells are activated in a TCR-dependent manner by antigens derived from the riboflavin synthesis pathway, including 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), bound to MHC-related protein-1 (MR1). However, MAIT cell activation in vivo has not been studied in detail. Here, we have found and characterized additional molecular signals required for optimal activation and expansion of MAIT cells after pulmonary Legionella or Salmonella infection in mice. We show that either bone marrow–derived APCs or non–bone marrow–derived cells can activate MAIT cells in vivo, depending on the pathogen. Optimal MAIT cell activation in vivo requires signaling through the inducible T cell costimulator (ICOS), which is highly expressed on MAIT cells. Subsequent expansion and maintenance of MAIT-17/1-type responses are dependent on IL-23. Vaccination with IL-23 plus 5-OP-RU augments MAIT cell–mediated control of pulmonary Legionella infection. These findings reveal cellular and molecular targets for manipulating MAIT cell function under physiological conditions.
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ItemEvidence-Practice Gaps in Postdischarge Initiation With Oral Anticoagulants in Patients With Atrial Fibrillation.(Ovid Technologies (Wolters Kluwer Health), 2019-12-17)Background Oral anticoagulant (OAC) therapy reduces the risk of stroke in people with atrial fibrillation (AF), and is considered best practice; however, there is little Australian evidence around the uptake of OACs in this population. Methods and Results We used linked hospital admissions, pharmaceutical dispensing claims, medical services, and mortality data for people in Australia's 2 most populous states (July 2010 to June 2015). Among OAC-naïve people hospitalized with AF, we estimated initiation of OAC therapy within 30 days of discharge, and persistence with therapy in the first year. We analyzed both outcomes using multivariable Cox regression. In 71 184 people with AF (median age 78 years, 49% female), 22.7% initiated OAC therapy. Initiation was lowest in July to December 2011 (17.0%) and highest in July to December 2014 (30.1%) after subsidy of the direct OACs. In adjusted analyses, initiation was most likely in people with a CHA2DS2-VA score ≥7 (versus 0) (hazard ratio=6.25, 95% CI 5.08-7.69), and a history of venous thromboembolism (hazard ratio=2.65, 95% CI 2.49-2.83). Of the people who initiated OAC therapy, 39.9% discontinued within 1 year; a lower risk of discontinuation was associated with a CHA2DS2-VA score ≥7 (versus 0) (hazard ratio=0.22, 95% CI 0.14-0.35), or initiation on a direct OAC (versus warfarin) (hazard ratio=0.55, 95% CI 0.50-0.60). Conclusions We found that OAC therapy was severely underutilized in people hospitalized with AF, even among high-risk individuals. Reasons for this underuse, whether patient, prescriber, or hospital related, should be identified and addressed to reduce stroke-related morbidity and mortality in people with AF.
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ItemDevelopment and pilot feasibility study of a health information technology tool to calculate mortality risk for patients with asymptomatic carotid stenosis: the Carotid Risk Assessment Tool (CARAT)(BIOMED CENTRAL LTD, 2015-03-24)BACKGROUND: Patients with no history of stroke but with stenosis of the carotid arteries can reduce the risk of future stroke with surgery or stenting. At present, a physicians' ability to recommend optimal treatments based on an individual's risk profile requires estimating the likelihood that a patient will have a poor peri-operative outcomes and the likelihood that the patient will survive long enough to gain benefit from the procedure. We describe the development of the CArotid Risk Assessment Tool (CARAT) into a 2-year mortality risk calculator within the electronic medical record, integrating the tool into the clinical workflow, training the clinical team to use the tool, and assessing the feasibility and acceptability of the tool in one clinic setting. METHODS: We modified an existing clinical flowsheet with the local electronic medical record for the CARAT risk model. To understand how CARAT would fit into the existing clinical workflow, we observed the clinic and talked with the clinical staff to develop a process map for the existing clinical workflow. CARAT was completed by the clinic nurse for patients identified on the clinic schedule as having carotid narrowing. We analyzed post-implementation assessment in two ways: quantifying the proportion of eligible patients with whom CARAT was utilized, and surveying surgeons to understand the impact of CARAT on decision-making and clinical workflow. RESULTS: With minimum investment of institutional resources, we were able to produce a workable tool and pilot the tool in our clinic within a 6 month time period. Over 4 months, 287 patients were seen in the clinic with carotid narrowing, and clinic staff completed CARAT for 195 (68%). Per-surgeon completion rates ranged from 29 to 81%. Most patients (191 of 195, 98%) patients had a low 2-year calculated mortality risk. Most surgeons believed the risk assessment aligned with their expectations of patient predicted risk. CONCLUSIONS: We successfully integrated CARAT into the existing electronic medical record and have preliminary evidence that CARAT can be a valuable tool for evaluating mortality risk for patients with diseased carotid arteries. Accuracy of the risk calculations must be evaluated in larger, multi-center studies.
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ItemAlterations in Retinal Microvascular Geometry in Young Type 1 Diabetes(AMER DIABETES ASSOC, 2010-06)OBJECTIVE: To describe retinal microvascular geometric parameters in young patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (aged 12-20 years) had clinical assessments and retinal photography following standardized protocol at a tertiary-care hospital in Sydney. Retinal microvascular geometry, including arteriolar and venular tortuosity, branching angles, optimality deviation, and length-to-diameter ratio (LDR), were measured from digitized photographs. Associations of these geometric characteristics with diabetes duration, A1C level, systolic blood pressure (SBP), and other risk factors were assessed. RESULTS: Of 1,159 patients enrolled, 944 (81.4%) had gradable photographs and 170 (14.7%) had retinopathy. Older age was associated with decreased arteriolar (P = 0.024) and venular (P = 0.002) tortuosity, and female subjects had larger arteriolar branching angle than male subjects (P = 0.03). After adjusting for age and sex, longer diabetes duration was associated with larger arteriolar branching angle (P 8.5 vs.