Sydney, Australia

University of New South Wales
Sydney, Australia

The University of New South Wales is an Australian public research university located in the Sydney suburbs of Kensington and Paddington. Established in 1949, it is ranked among the top 50 universities in the world, according to the 2014 QS World University Rankings, and among the top 5 in Australia. It is also the first university in the world to be awarded the QS 5 Star Plus badge for excellence. UNSW currently has more than 50,000 students from over 120 countries.The main UNSW campus is located on a modern 38-hectare site at Kensington, seven kilometres from the centre of Sydney and close to local beaches including Coogee and Bondi. Other campuses are UNSW Art & Design in Paddington, UNSW Canberra at the Australian Defence Force Academy, and sub-campuses at Randwick and Coogee in Sydney, as well as research stations around New South Wales.UNSW is a founding member of the prestigious Group of Eight, a coalition of Australian research-intensive universities, and of Universitas 21, a leading global network of research universities. It has international exchange and research partnerships with over 200 universities around the world.UNSW graduates hold more chief executive positions of ASX 200 listed companies than those of any other university in Australia. Wikipedia.

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Sinclair D.A.,Harvard University | Sinclair D.A.,University of New South Wales | Guarente L.,Massachusetts Institute of Technology
Annual Review of Pharmacology and Toxicology | Year: 2014

The mammalian sirtuins (SIRT1-7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans. © 2014 by Annual Reviews.

Agency: European Commission | Branch: H2020 | Program: RIA | Phase: SC1-PM-21-2016 | Award Amount: 7.58M | Year: 2017

STRENGTHS aims to provide effective community-based health care implementation strategies to scale-up the delivery and uptake of effective mental health interventions in different country contexts. The current refugee crisis across Europe and the Middle East effects both individual refugees psychological well-being, as they face extreme stressors in their flight from their home country, but also has large effects on the healthcare systems of countries housing refugees. In reponse to this crisis, the STRENGTHS project aims to provide a framework for scaling-up the delivery and uptake of effective community-based mental health strategies to address the specific needs of refugees within and outside Europes borders. STRENGTHS will outline necessary steps needed to integrate evidence based low-intensity psychological interventions for common mental disorders into health systems in Syrias surrounding countries taking up the majority of refugees (Turkey, Lebanon and Jordan), a LMIC (Egypt) and European countries (Germany, Switzerland the Netherlands and Sweden). The consortium is a unique partnership between academics, non-governmental organisations (NGOs), international agencies and local partners with the responsibility to provide and scale-up evidence-based mental health and psychosocial support interventions for refugees. Key preparatory steps in the local political, regulatory and governance processes for uptake and scaling-up of the intervention and key contextual and system-related factors for integration will be validated for the real-life impact on the responsiveness of the system. The low-intensity interventions and training materials will be adapted and implemented in Syrian refugees within Syrias surrounding countries taking up the majority of refugees (Turkey, Lebanon and Jordan), a LMIC (Egypt) and European countries (Germany, Switzerland the Netherlands and Sweden). STRENGTHS will disseminate and promote buy-in of a validated framework for large-scale implementation of the low intensity interventions to providers of health and social services, policy makers and funding agencies.

Mcnally G.P.,University of New South Wales
Neuropharmacology | Year: 2014

Extinction training can reduce drug seeking behavior. This article reviews the neural circuits that contribute to extinction and approaches to enhancing the efficacy of extinction. Extinction of drug seeking depends on cortical-striatal-hypothalamic and cortical-hypothalamic-thalamic pathways. These pathways interface, in the hypothalamus and thalamus respectively, with the neural circuits controlling reinstatement of drug seeking. The actions of these pathways at lateral hypothalamic orexin neurons, and of perifornical/dorsomedial hypothalamic derived opioid peptides at kappa opioid receptors in the paraventricular thalamus, are important for inhibiting drug seeking. Despite effectively reducing or inhibiting drug seeking in the short term, extinguished drug seeking is prone to relapse. Three different strategies to augment extinction learning or retrieval are reviewed: pharmacological augmentation, retrieval - extinction training, and provision of extinction memory retrieval cues. These strategies have been used in animal models and with human drug users to enhance extinction or cue exposure treatments. They hold promise as novel strategies to promote abstinence from drug seeking. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. © 2013 Elsevier Ltd. All rights reserved.

Lowe A.B.,University of New South Wales
Polymer Chemistry | Year: 2014

This contribution serves as an update to a previous review (Polym. Chem. 2010, 1, 17-36) and highlights recent applications of thiol-ene 'click' chemistry as an efficient tool for both polymer/materials synthesis as well as modification. This current contribution covers examples from the literature published up to ca. mid 2013. It is not intended to be exhaustive but rather serves to highlight many of the new and exciting applications where researchers have applied thiol-ene chemistry in advanced macromolecular engineering and materials chemistry. This journal is © the Partner Organisations 2014.

Thordarson P.,University of New South Wales
Chemical Society Reviews | Year: 2011

The most common approach for quantifying interactions in supramolecular chemistry is a titration of the guest to solution of the host, noting the changes in some physical property through NMR, UV-Vis, fluorescence or other techniques. Despite the apparent simplicity of this approach, there are several issues that need to be carefully addressed to ensure that the final results are reliable. This includes the use of non-linear rather than linear regression methods, careful choice of stoichiometric binding model, the choice of method (e.g., NMR vs. UV-Vis) and concentration of host, the application of advanced data analysis methods such as global analysis and finally the estimation of uncertainties and confidence intervals for the results obtained. This tutorial review will give a systematic overview of all these issues - highlighting some of the key messages herein with simulated data analysis examples. © 2011 The Royal Society of Chemistry.

There is growing enthusiasm for increasing coverage of antiretroviral treatment among HIV-infected people for the purposes of preventing ongoing transmission. Treatment as prevention will face a number of barriers when implemented in real world populations, which will likely lead to the effectiveness of this strategy being lower than proposed by optimistic modelling scenarios or ideal clinical trial settings. Some settings, as part of their prevention and treatment strategies, have already attained rates of HIV testing and use of antiretroviral therapy-with high levels of viral suppression-that many countries would aspire to as targets for a treatment-as-prevention strategy. This review examines a number of these "natural experiments", namely, British Columbia, San Francisco, France, and Australia, to provide commentary on whether treatment as prevention has worked in real world populations. This review suggests that the population-level impact of this strategy is likely to be considerably less than as inferred from ideal conditions. © 2012 David P. Wilson.

Genome-wide combinatorial binding patterns for key transcription factors (TFs) have not been reported for primary human hematopoietic stem and progenitor cells (HSPCs), and have constrained analysis of the global architecture of molecular circuits controlling these cells. Here we provide high-resolution genome-wide binding maps for a heptad of key TFs (FLI1, ERG, GATA2, RUNX1, SCL, LYL1, and LMO2) in human CD34(+) HSPCs, together with quantitative RNA and microRNA expression profiles. We catalog binding of TFs at coding genes and microRNA promoters, and report that combinatorial binding of all 7 TFs is favored and associated with differential expression of genes and microRNA in HSPCs. We also uncover a previously unrecognized association between FLI1 and RUNX1 pairing in HSPCs, we establish a correlation between the density of histone modifications that mark active enhancers and the number of overlapping TFs at a peak, we demonstrate bivalent histone marks at promoters of heptad target genes in CD34(+) cells that are poised for later expression, and we identify complex relationships between specific microRNAs and coding genes regulated by the heptad. Taken together, these data reveal the power of integrating multifactor sequencing of chromatin immunoprecipitates with coding and noncoding gene expression to identify regulatory circuits controlling cell identity.

Background Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen. Methods We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with, number NCT00931463. Findings We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal. Interpretation The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy. Copyright © 2013 Elsevier B.V.

Don A.S.,University of New South Wales
Acta neuropathologica communications | Year: 2014

BACKGROUND: The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis.RESULTS: We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD.CONCLUSIONS: This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.

Bonduriansky R.,University of New South Wales
Trends in Ecology and Evolution | Year: 2012

The refutation of 'soft' inheritance and establishment of Mendelian genetics as the exclusive model of heredity is widely portrayed as an iconic success story of scientific progress. Yet, we are witnessing a re-emergence of debate on the role of soft inheritance in heredity and evolution. I argue that this reversal reflects not only the weight of new evidence but also an important conceptual change. I show that the concept of soft inheritance rejected by 20th-century genetics differs fundamentally from the current concept of 'nongenetic inheritance'. Moreover, whereas it has long been assumed that heredity is mediated by a single, universal mechanism, a pluralistic model of heredity is now emerging, based on a recognition of multiple, parallel mechanisms of inheritance. © 2012 Elsevier Ltd.

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