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Search Results: 1 - 10 of 504904 matches for " David A. Cooper "
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αSynuclein and Mitochondrial Dysfunction: A Pathogenic Partnership in Parkinson’s Disease?
David Protter,Charmaine Lang,Antony A. Cooper
Parkinson's Disease , 2012, DOI: 10.1155/2012/829207
Abstract: Parkinson’s Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein αSynuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that αSynuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and αSynuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and αSynuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and αSynuclein Oligomerization. 1. Introduction Parkinson’s disease (PD) is a debilitating progressive neurodegenerative disorder for which there is no cure or long-term effective therapy. Classical symptoms include movement abnormalities such as postural instability and rigidity, tremors, and bradykinesia but more recently nonmotor symptoms have been ascribed to PD that include olfactory deficits, sleep disturbances, and gastrointestinal impairment. Although the molecular mechanisms underlying the disease are unknown, considerable evidence supports mitochondrial dysfunction and alpha-Synuclein (αSynuclein) as two of the major contributors to PD. This paper explores potential interrelationships between these two factors that may contribute to the initiation and/or progression of this disease. 2. Evidence for Dysfunctional Mitochondria Playing a Central Role in PD Mitochondria are essential for neuronal function and survival. Energy-demanding neurons require large numbers of functional mitochondria to provide most of their ATP via oxidative phosphorylation (OXPHOS), a process where electrons traversing the electron transport chain (complexes I–IV) are coupled to proton pumping to establish a mitochondrial membrane potential subsequently used to synthesize ATP (complex V). The involvement of mitochondrial dysfunction as a causal factor of PD is well supported by
Predictors of disease progression in HIV infection: a review
Simone E Langford, Jintanat Ananworanich, David A Cooper
AIDS Research and Therapy , 2007, DOI: 10.1186/1742-6405-4-11
Abstract: Elements of the immune response such as the diversity of HIV-specific cytotoxic lymphocyte responses and cell-surface CD38 expression correlate significantly with the control of viral replication. However, the relationship between soluble markers of immune activation and disease progression remains inconclusive. In patients on treatment, sustained virological rebound to >10 000 copies/mL is associated with poor clinical outcome. However, the same is not true of transient elevations of HIV RNA (blips). Another virological factor, drug resistance, is becoming a growing problem around the globe and monitoring must play a part in the surveillance and control of the epidemic worldwide. The links between chemokine receptor tropism and rate of disease progression remain uncertain and the clinical utility of monitoring viral strain is yet to be determined. The large number of confounding factors has made investigation of the roles of race and viral subtype difficult, and further research is needed to elucidate their significance.Host factors such as age, HLA and CYP polymorphisms and psychosocial factors remain important, though often unalterable, predictors of disease progression. Although gender and mode of transmission have a lesser role in disease progression, they may impact other markers such as viral load. Finally, readily measurable markers of disease such as total lymphocyte count, haemoglobin, body mass index and delayed type hypersensitivity may come into favour as ART becomes increasingly available in resource-limited parts of the world. The influence of these, and other factors, on the clinical progression of HIV infection are reviewed in detail, both preceding and following treatment initiation.Throughout the clinically latent period associated with Human Immunodeficiency Virus (HIV) infection the virus continues to actively replicate, usually resulting in symptomatic illness [1-3]. Highly variable disease progression rates between individuals are well-recogni
HIV research in Australia: linking basic research findings with clinical and public health outcomes
Sharon R Lewin, John M Kaldor, David A Cooper
Retrovirology , 2006, DOI: 10.1186/1742-4690-3-86
Abstract: Australia is generally viewed as a success story in the global HIV epidemic, with its national strategic response in place since the late 1980s credited with delivering extremely low infection rates and high levels of treatment access. Perhaps less well known is the extent to which Australia has been able to contribute to the world's knowledge about HIV infection, particularly in the areas of pathogenesis and clinical medicine. A unique combination of a geographically and demographically focussed epidemic, specialised medical units, a history of outstanding research in basic immunology and virology and dedicated national resources for health care and research has given rise to a scientific output that is disproportionate to the size of Australia's HIV epidemic.Although Australia was one of the first countries in the Asia Pacific Region to report AIDS cases, and its epidemic curve rose sharply during the first half of the 1980s, it had begun to plateau by the early 1990s, and reached a peak even before the treatment revolution was under way. A rapid expansion of needle and syringe programs ensured that people who injected illicit drugs were largely protected from HIV infection, with prevalence consistently reported as being below 1% in this population. Nationally, the estimated prevalence is now among the lowest in the world, at around 0.1%By far the most common cause of HIV transmission has been male to male sex, which has been associated with most of the cumulative 22,000 diagnoses estimated to have occurred in Australia since the first case in 1982. In the first decade of the epidemic, the proportion was even higher, and cases of HIV infection were highly concentrated in the large urban centres, where vibrant gay communities had developed in the late 1970s. In several cities, these communities were located near teaching hospitals with an established track record in virology and clinical infectious diseases, such as the Fairfield Infectious Diseases Hospital in Mel
Scheme for implementing atomic multiport devices
Jessica J. Cooper,David W. Hallwood,Jacob A. Dunningham
Physics , 2007,
Abstract: Multiport generalizations of beam splitters are the key component in multipath interferometers, which are important in a range of quantum state engineering and precision measurement schemes. Here we propose a straightforward method for implementing multiport devices for atoms trapped in optical ring lattices. These devices are interesting as atoms have certain properties (such as mass) that photons do not and the ring configuration makes them useful for applications such as precision gyroscopes. We discuss how they could be employed in useful measurement schemes and investigate how practical considerations limit the size of the devices that can be achieved by this method.
Hybrid guiding-centre/full-orbit simulations in non-axisymmetric magnetic geometry exploiting general criterion for guiding-centre accuracy
David Pfefferlé,Jonathan P. Graves,Wilfred A. Cooper
Physics , 2014, DOI: 10.1088/0741-3335/57/5/054017
Abstract: To identify under what conditions guiding-centre or full-orbit tracing should be used, an estimation of the spatial variation of the magnetic field is proposed, not only taking into account gradient and curvature terms but also parallel currents and the local shearing of field-lines. The criterion is derived for general three-dimensional magnetic equilibria including stellarator plasmas. Details are provided on how to implement it in cylindrical coordinates, and in flux coordinates that rely on the geometric toroidal angle. A means of switching between guiding-centre and full-orbit equations at first order in Larmor radius with minimal discrepancy is shown. Techniques are applied to a MAST (Mega Amp Spherical Tokamak) helical core equilibrium in which the inner kinked flux-surfaces are tightly compressed against the outer axisymmetric mantle and where the parallel current peaks at the nearly rational surface. This is put in relation with the simpler situation $\vec{B}(x,y,z) = B_0 [\sin(kx) \vec{e_y} + \cos(kx)\vec{e_z}]$, for which full orbits and lowest order drifts are obtained analytically. In the kinked equilibrium, the full orbits of NBI fast ions are solved numerically and shown to follow helical drift surfaces. This result partially explains the off-axis redistribution of NBI fast particles in the presence of MAST Long-Lived Modes (LLM).
Variable and value elimination in binary constraint satisfaction via forbidden patterns
David A. Cohen,Martin C. Cooper,Guillaume Escamocher,Stanislav Zivny
Computer Science , 2015, DOI: 10.1016/j.jcss.2015.02.001
Abstract: Variable or value elimination in a constraint satisfaction problem (CSP) can be used in preprocessing or during search to reduce search space size. A variable elimination rule (value elimination rule) allows the polynomial-time identification of certain variables (domain elements) whose elimination, without the introduction of extra compensatory constraints, does not affect the satisfiability of an instance. We show that there are essentially just four variable elimination rules and three value elimination rules defined by forbidding generic sub-instances, known as irreducible existential patterns, in arc-consistent CSP instances. One of the variable elimination rules is the already-known Broken Triangle Property, whereas the other three are novel. The three value elimination rules can all be seen as strict generalisations of neighbourhood substitution.
Predictors of Limb Fat Gain in HIV Positive Patients Following a Change to Tenofovir-Emtricitabine or Abacavir-Lamivudine
Allison Martin, Janaki Amin, Sean Emery, David Baker, Andrew Carr, David A. Cooper, Mark Bloch
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026885
Abstract: Background Antiretroviral treatment (cART) in HIV causes lipoatrophy. We examined predictors of anthropometric outcomes over 96 weeks in HIV-infected, lipoatrophic adults receiving stable cART randomised to tenofovir-emtricitabine (TDF-FTC) or abacavir-lamivudine (ABC-3TC) fixed dose combinations. Methodology/Principal Findings The STEAL study was a prospective trial of virologically suppressed participants randomised to either TDF-FTC (n = 178) or ABC-3TC (n = 179). Anthropometric assessment was conducted at baseline, weeks 48 and 96. The analysis population included those with baseline and week 96 data remaining on randomised therapy. Distribution of limb fat change was divided into four categories (≤0%, >0–10%, >10–20%, >20%). Baseline characteristics [demographics, medical history, metabolic and cardiovascular biomarkers] were assessed as potential predictors of change in percent subcutaneous limb fat using linear regression. 303 participants (85% of STEAL population) were included. Baseline characteristics were: mean (±SD) age 45 (±8) years; thymidine analogue nucleoside reverse transcriptase inhibitor (tNRTI) duration 4 (±3) years; limb fat 5.4 (±3.0)kg; body mass index 24.7 (±3.5) kg/m2. Mean (SD) limb fat gain to week 48 and 96 was 7.6% (±22.4) and 13.2% (±27.3), respectively, with no significant difference between groups. 51.5% of all participants had >10% gain in limb fat. Predictors of greater limb fat gain at week 96 were baseline tNRTI (10.3, p = 0.001), glucose >6 mmol/L (16.1, p = 0.04), higher interleukin 6 (IL-6) (2.8, p = 0.004) and lower baseline limb fat (3.8–6.4 kg – 11.2; >6.4 kg – 15.7, p trend<0.001). Conclusions/Significance Modest peripheral fat gain occurred with both TDF-FTC and ABC-3TC. Baseline factors associated with more severe lipodystrophy (lipoatrophy, baseline tNRTI, raised IL6, and glucose) predicted greater limb fat recovery at 96 weeks.
Characterisation of a functional intronic polymorphism in the human growth hormone (GHI) gene
David S Millar, Martin Horan, Nadia A Chuzhanova, David N Cooper
Human Genomics , 2010, DOI: 10.1186/1479-7364-4-5-289
Abstract: Human growth hormone (GH) plays an important role in immune function and bone turnover, in addition to its well-documented influences on stature, muscle mass, lipid and carbohydrate metabolism and postnatal growth [1]. The specificity of GH action lies in promoting the homodimerisation of its cell surface receptor (GHR), resulting in the induction of post-receptor signalling pathways [2]. Human GH synthesis is directed by the pituitary-expressed GH1 gene, which is located on chromosome 17q23 within a gene cluster that includes three paralogous placentally expressed genes (CSH1, CSH2 and GH2). The control of GH1 gene expression is regulated by the pituitary-expressed transcription factor, PIT1, which drives GH expression by binding not only to the GH1 proximal promoter, but also to a locus control region (LCR) located between 14.5 kilobases (kb) and 32 kb upstream of the GH1 gene [3].The proximal region of the GH1 gene promoter exhibits a high level of sequence variation, with 15 single nucleotide polymorphisms (SNPs) occurring within a 450 base pair (bp) stretch of DNA [4,5]. This high level of sequence diversity is explicable in terms of a combination of gene conversion, recurrent mutations and selection [4,6,7] In the European population, these polymorphic variants manifest in at least 40 different haplotypes that display a 12-fold range of expression level in a reporter gene assay [6]. At least in this population, there is a tendency for those haplotypes associated with a markedly reduced level of reporter gene expression to be more prevalent than those haplotypes associated with an increased level, possibly as a consequence of selection [6].In addition to the promoter polymorphisms, an A/T SNP has been reported at nucleotide +90 within intron 4 of the GH1 gene (rs2665802; chromosome 17 coordinate, 59348761 -- termed 1663 by Hasegawa et al [8]. and here, termed +1169). The +1169A allele of this SNP has been associated with reduced levels of circulating GH and ins
The Combination of BH3-Mimetic ABT-737 with the Alkylating Agent Temozolomide Induces Strong Synergistic Killing of Melanoma Cells Independent of p53
Steven N. Reuland, Nathaniel B. Goldstein, Katie A. Partyka, David A. Cooper, Mayumi Fujita, David A. Norris, Yiqun G. Shellman
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024294
Abstract: Metastatic melanoma has poor prognosis and is refractory to most conventional chemotherapies. The alkylating agent temozolomide (TMZ) is commonly used in treating melanoma but has a disappointing response rate. Agents that can act cooperatively with TMZ and improve its efficacy are thus highly sought after. The BH3 mimetic ABT-737, which can induce apoptosis by targeting pro-survival Bcl-2 family members, has been found to enhance the efficacy of many conventional chemotherapeutic agents in multiple cancers. We found that combining TMZ and ABT-737 induced strong synergistic apoptosis in multiple human melanoma cell lines. When the drugs were used in combination in a mouse xenograft model, they drastically reduced tumor growth at concentrations where each individual drug had no significant effect. We found that TMZ treatment elevated p53 levels, and that the pro-apoptotic protein Noxa was elevated in TMZ/ABT-737 treated cells. Experiments with shRNA demonstrated that the synergistic effect of TMZ and ABT-737 was largely dependent on Noxa. Experiments with nutlin-3, a p53 inducer, demonstrated that p53 induction was sufficient for synergistic cell death with ABT-737 in a Noxa-dependent fashion. However, p53 was not necessary for TMZ/ABT-737 synergy as demonstrated by a p53-null line, indicating that TMZ and ABT-737 together induce Noxa in a p53-independent fashion. These results demonstrate that targeting anti-apoptotic Bcl-2 members is a promising method for treating metastatic melanoma, and that clinical trials with TMZ and Bcl-2 inhibitors are warranted.
A Co-Evolution Model for Dynamic Social Network and Behavior  [PDF]
Liping Tong, David Shoham, Richard S. Cooper
Open Journal of Statistics (OJS) , 2014, DOI: 10.4236/ojs.2014.49072
Abstract: Individual behaviors, such as drinking, smoking, screen time, and physical activity, can be strongly influenced by the behavior of friends. At the same time, the choice of friends can be influenced by shared behavioral preferences. The actor-based stochastic models (ABSM) are developed to study the interdependence of social networks and behavior. These methods are efficient and useful for analysis of discrete behaviors, such as drinking and smoking; however, since the behavior evolution function is in an exponential format, the ABSM can generate inconsistent and unrealistic results when the behavior variable is continuous or has a large range, such as hours of television watched or body mass index. To more realistically model continuous behavior variables, we propose a co-evolution process based on a linear model which is consistent over time and has an intuitive interpretation. In the simulation study, we applied the expectation maximization (EM) and Markov chain Monte Carlo (MCMC) algorithms to find the maximum likelihood estimate (MLE) of parameter values. Additionally, we show that our assumptions are reasonable using data from the National Longitudinal Study of Adolescent Health (Add Health).
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