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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 13 April 2010, Vol.107(15), pp.6794-8
    Description: The key to understanding amyloid disease is the characterization of oligomeric species formed during the early stages of fibril assembly. Here we have used electrospray ionisation-ion mobility spectrometry-mass spectrometry to identify and structurally characterize the oligomers formed during amyloid assembly from beta(2)-microglobulin (beta(2)m). Beta(2)m oligomers are shown to have collision cross-sections consistent with monomeric units arranged in elongated assemblies prior to fibril formation. Direct observation, separation, and quantification of transient oligomeric species reveals that monomers to tetramers are populated through the lag phase with no evidence for the significant population of larger oligomeric species under the conditions employed. The dynamics of each oligomeric species were monitored directly within the ensemble at concentrations commensurate with amyloid formation by observing the subunit exchange of (14)N- and (15)N-labeled oligomers. Analysis of the data revealed a decrease in oligomer dynamics concomitant with increasing oligomer size and the copopulation of dynamic dimeric and trimeric species with more stable trimeric and tetrameric species. The results presented map the events occurring during the lag phase of fibril formation and give a clear insight into the structural characteristics and dynamic nature of the beta(2)m oligomers, demonstrating the existence of elongated assemblies arising from an intact amyloidogenic protein during fibril formation.
    Keywords: Amyloid -- Chemistry ; Spectrometry, Mass, Electrospray Ionization -- Methods ; Beta 2-Microglobulin -- Chemistry
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Biophysical Journal, 2011, Vol.101(5), pp.1238-1247
    Description: -Microglobulin is a 99-residue protein with a propensity to form amyloid-like fibrils in vitro which exhibit distinct morphologies dependent on the solution conditions employed. Here we have used ion mobility spectrometry-mass spectrometry to characterize the oligomeric species detected during the formation of worm-like fibrils of -microglobulin at pH 3.6. Immediately upon sample dissolution, -microglobulin monomer and oligomers—the latter ranging in size from dimer to hexamer—are present as a pool of rapidly interconverting species. Increasing the ionic strength of the solution initiates fibril formation without a lag-phase whereupon these oligomers become more stable and higher-order species (7-mer to 〉14-mer) are observed. The oligomers detected have collision cross-sectional areas consistent with a linearly stacked assembly comprising subunits of native-like volume. The results provide insights into the identity and properties of the transient, oligomeric intermediates formed during assembly of worm-like fibrils and identify species that differ significantly from the oligomers previously characterized during the nucleated assembly of long, straight fibrils. The data presented demonstrate the interrelationship between different fibril-forming pathways and identify their points of divergence.
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
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  • 3
    Language: English
    In: Behaviour Research and Therapy, 2015, Vol.69, p.100(11)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.brat.2015.04.008 Byline: David P. Smith, Malcolm W. Battersby, Peter W. Harvey, Rene G. Pols, Robert Ladouceur Abstract: Problem gambling-specific cognitive therapy (CT) and behavioural (exposure-based) therapy (ET) are two core cognitive-behavioural techniques to treating the disorder, but no studies have directly compared them using a randomised trial. Author Affiliation: (a) Flinders University, Department of Psychiatry, Flinders Human Behaviour and Health Research Unit, GPO Box 2100, Adelaide SA 2001, Australia (b) Universite Laval, School of Psychology, 2325, rue des Bibliotheques, Bureau 1328, Quebec, Quebec G1V 0A6, Canada Article History: Received 20 June 2014; Revised 18 March 2015; Accepted 13 April 2015
    Keywords: Cognitive Therapy – Research ; Clinical Trials – Research
    ISSN: 0005-7967
    Source: Cengage Learning, Inc.
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  • 4
    In: Ecology, January 2012, Vol.93(1), pp.17-23
    Description: Threshold detection methods are increasingly popular for assessing nonlinear responses to environmental change, but their statistical performance remains poorly understood. We simulated linear change in stream benthic macroinvertebrate communities and evaluated the performance of commonly used threshold detection methods based on model fitting (piecewise quantile regression [PQR]), data partitioning (nonparametric change point analysis [NCPA]), and a hybrid approach (significant zero crossings [SiZer]). We demonstrated that false detection of ecological thresholds (type I errors) and inferences on threshold locations are influenced by sample size, rate of linear change, and frequency of observations across the environmental gradient (i.e., sample–environment distribution, SED). However, the relative importance of these factors varied among statistical methods and between inference types. False detection rates were influenced primarily by user‐selected parameters for PQR (τ) and SiZer (bandwidth) and secondarily by sample size (for PQR) and SED (for SiZer). In contrast, the location of reported thresholds was influenced primarily by SED. Bootstrapped confidence intervals for NCPA threshold locations revealed strong correspondence to SED. We conclude that the choice of statistical methods for threshold detection should be matched to experimental and environmental constraints to minimize false detection rates and avoid spurious inferences regarding threshold location.
    Keywords: Ecological Thresholds ; Nonparametric Change Point Analysis ; Piecewise Quantile Regression ; Sizer ; Stream Benthic Macroinvertebrates ; Type I Error
    ISSN: 0012-9658
    E-ISSN: 1939-9170
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  • 5
    In: The New England Journal of Medicine, 2013, Vol.368(15), pp.1460-1461
    Description: New guidelines for lung-cancer screening are appearing, but they seem to be based on the 2011 National Lung Screening Trial report of a 20% reduction in mortality with spiral CT scanning. This percentage may have been underestimated. To the Editor: The core result of the National Lung Screening Trial (NLST) (Aug. 10, 2011, issue)1 was this: “There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT [computed tomographic] group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI [confidence interval], 6.8 to 26.7; P=0.004).” Developers of practice guidelines for clinicians have taken that result to mean that “4 out of 5 who are going to die from lung cancer will die of it even if . . .
    Keywords: Medicine;
    ISSN: 0028-4793
    E-ISSN: 1533-4406
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  • 6
    Language: English
    In: Journal of Mammalogy, 1 April 2012, Vol.93(2), pp.390-398
    Description: Advances in the application of stable isotopes have allowed the quantitative evaluation of previously cryptic ecological processes. In particular, researchers have utilized the predictable spatial patterning in natural abundance of isotopes to better understand animal dispersal and migration. However, quantifying dispersal via natural abundance alone has proven to be of limited utility for species exhibiting short-or mid-distance dispersal events, including most mammalian species. In previous experimental work, we demonstrated that consumption of 1 dose of isotopically enriched baits elicited a distinct "mark" in hair of captive martens (Martes spp.). Herein, we report findings from a field test of our isotopie enrichment approach to mark freeranging animals and quantify dispersal of martens across forest stands at sites in southeastern Alaska and northern British Columbia. In the field, we supplemented bait used in single-capture hair traps with the amino acid glycine artificially enriched in ²H, ¹³C, or¹⁵N By applying unique combinations of artificially enriched isotopie markers within discrete forest stands, the isotopie signature of collected hair reflected the forest patch where the individual originated. From our isotopie marks, we were able to infer dispersal events between forested stands and, thus, estimate rates and approximate dispersal distances. Our findings demonstrate that isotopie enrichment can be a cost-effective method to mark the hair of midsized mammals for the quantification of dispersal.
    Keywords: Biological sciences -- Biology -- Zoology ; Biological sciences -- Biology -- Anatomy ; Physical sciences -- Physics -- Microphysics ; Biological sciences -- Biology -- Zoology ; Applied sciences -- Technology -- Tools ; Biological sciences -- Biology -- Zoology ; Physical sciences -- Chemistry -- Physical chemistry ; Linguistics -- Language -- Orthographies ; Physical sciences -- Chemistry -- Chemical elements ; Political science -- Military science -- Armed forces
    ISSN: 00222372
    E-ISSN: 15451542
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  • 7
    Language: English
    In: The Medical journal of Australia, 02 April 2012, Vol.196(6), pp.395-8
    Description: To describe values of serum prostate-specific antigen (PSA) in older men without diagnosed prostate cancer, categorised by age and country of birth, and to describe self-reported prostate cancer screening. A cohort study (the Concord Health and Ageing in Men Project) involving a representative sample of 1434 eligible community-dwelling men with no diagnosis of prostate cancer who were aged 70 years and over and living in a defined geographic area in Sydney, with baseline data collected between 28 January 2005 and 4 June 2007. Serum PSA levels and self-reported prostate cancer screening. 11% of men (155) had a PSA level of ≥6.5 ng/mL, increasing from 7.5% of men aged 70-74 years to 31.4% of men aged≥90 years. PSA levels varied with ethnicity, with Australian-born men (695) having the highest levels (median, 2.3 ng/mL; 5th-95th percentile, 0.4-10.1 ng/mL), followed by men born in China (n=42; 2.1 ng/mL; 0.4-12.4 ng/mL), United Kingdom and Ireland (n=70; 1.9 ng/mL; 0.3-8.9 ng/mL), Greece (n=59; 1.5 ng/mL; 0.2-6.1 ng/mL), and Italy (n=293; 1.4 ng/mL; 0.3-7.2 ng/mL). A PSA test in the previous 2 years was reported by 48% of participants, and a digital rectal examination (DRE) in the previous 2 years by 37%. A significant number of men aged over 70 years reported recent prostate cancer tests. The PSA level ranges reported in this cohort will help with interpreting serum PSA level findings in men aged over 70 years.
    Keywords: Biomarkers, Tumor -- Blood ; Prostate-Specific Antigen -- Blood ; Prostatic Neoplasms -- Blood
    ISSN: 0025729X
    E-ISSN: 1326-5377
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  • 8
    In: Nature, 2010, Vol.465(7296), p.342
    Description: The current and potential future impact of climate change on malaria is of major public health interest (1,2). The proposed effects of rising global temperatures on the future spread and intensification of the disease (3-5), and on existing malaria morbidity and mortality rates (3), substantively influence global health policy (6,7). The contemporary spatial limits of Plasmodium falciparum malaria and its endemicity within this range (8), when compared with comparable historical maps, offer unique insights into the changing global epidemiology of malaria over the last century. It has long been known that the range of malaria has contracted through a century of economic development and disease control (9). Here, for the first time, we quantify this contraction and the global decreases in malaria endemicity since approximately 1900. We compare the magnitude of these changes to the size of effects on malaria endemicity proposed under future climate scenarios and associated with widely used public health interventions. Our findings have two key and often ignored implications with respect to climate change and malaria. First, widespread claims that rising mean temperatures have already led to increases in worldwide malaria morbidity and mortality are largely at odds with observed decreasing global trends in both its endemicity and geographic extent. Second, the proposed future effects of rising temperatures on endemicity are at least one order of magnitude smaller than changes observed since about 1900 and up to two orders of magnitude smaller than those that can be achieved by the effective scale-up of key control measures. Predictions of an intensification of malaria in a warmer world, based on extrapolated empirical relationships or biological mechanisms, must be set against a context of a century of warming that has seen marked global declines in the disease and a substantial weakening of the global correlation between malaria endemicity and climate.
    Keywords: Malaria -- Risk Factors ; Malaria -- Research ; Disease Transmission -- Research ; Global Temperature Changes -- Health Aspects ; Global Temperature Changes -- Research;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 9
    Language: English
    In: BJU International, 2015, Vol.116(S3), p.18(8)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/bju.13152/abstract Byline: Manish I. Patel, Albert Bang, David Gillatt, David P. Smith Keywords: bladder cancer; cystectomy; population; survival; volume Objective To determine the contemporary survival outcomes from a whole population and identify significant predictors of survival, as contemporary population-based survival outcomes after radical cystectomy (RC) for the treatment of bladder cancer (BC) are sparse. Reports suggest a large disparity between population outcomes and those of centres of excellence. Patients and Methods All invasive BC cases diagnosed between 2001 and 2007 in New South Wales, Australia, were identified from the Central Cancer Registry. Records of treatment and death were electronically linked. All patients who underwent RC between 2001 and 2009 were selected for this study (804 patients). Follow-up was to the end of 2009. Outcomes assessed were disease-specific survival (DSS) and overall survival (OS). Multivariable Cox regression and log-rank analysis were used to model and compare survival within groups. Results Of 804 patients diagnosed during the study period 420 (52.2%) died during follow-up. The 5-year DSS and OS for all patients was 59.6% and 53.2%, respectively. The 5-year DSS for patients with localised, regional and distant disease, undergoing RC was 72%, 51% and 10%, respectively. Age (P 〈 0.001) and stage (P 〈 0.001) were associated with 5-year DSS and OS after adjusting for all other variables. High-volume centres had significantly better 5-year DSS compared with low-volume centres (P 〈 0.05). The 30-day mortality for high- vs low-volume centres was 1.8% and 3.6%, respectively. Perioperative mortality improved over time for high- and moderate-volume centres but not for low-volume centres. Conclusion Contemporary survival outcomes after RC are much improved compared with older studies and appear close to results from academic centres of excellence. High-volume centres report better 5-year DSS outcomes than lower volume centres. Article Note: Funding: M.I.P. was supported by a Fellowship from the NSW Cancer Institute (10/ECF/2-29).
    Keywords: Mortality – Analysis ; Cancer Research – Analysis ; Cancer Patients – Patient Outcomes ; Cancer Patients – Care and Treatment ; Cancer Patients – Analysis
    ISSN: 1464-4096
    E-ISSN: 1464410X
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  • 10
    Language: English
    In: 2012, Vol.7(9), p.e46221
    Description: G-protein-coupled receptors (GPCRs) are prime drug targets and targeted by approximately 60% of current therapeutic drugs such as β-blockers, antipsychotics and analgesics. However, no biophysical methods are available to quantify their interactions with ligand binding in a native environment. Here, we use ellipsometry to quantify specific interactions of receptors within native cell membranes. As a model system, the GPCR-ligand CXCL12α and its receptor CXCR4 are used. Human-derived Ishikawa cells were deposited onto gold coated slides via Langmuir-Schaefer film deposition and interactions between the receptor CXCR4 on these cells and its ligand CXCL12α were detected via total internal reflection ellipsometry (TIRE). This interaction could be inhibited by application of the CXCR4-binding drug AMD3100. Advantages of this approach are that it allows measurement of interactions in a lipid environment without the need for labelling, protein purification or reconstitution of membrane proteins. This technique is potentially applicable to a wide variety of cell types and their membrane receptors, providing a novel method to determine ligand or drug interactions targeting GPCRs and other membrane proteins.
    Keywords: Research Article ; Biology ; Physics ; Biotechnology ; Biophysics ; Physics ; Biochemistry
    E-ISSN: 1932-6203
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