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71.
Background
HIV Pre-Exposure Prophylaxis (PrEP) has been found to be efficacious in preventing HIV acquisition among seronegative individuals in a variety of risk groups, including men who have sex with men and people who inject drugs. To date, however, it remains unclear how socio-cultural norms (e.g., attitudes towards HIV; social understandings regarding HIV risk practices) may influence the scalability of future PrEP interventions. The objective of this study is to assess how socio-cultural norms may influence the implementation and scalability of future HIV PrEP interventions in Vancouver, Canada.Methods
We conducted 50 interviews with young men (ages 18–24) with a variety of HIV risk behavioural profiles (e.g., young men who inject drugs; MSM). Interviews focused on participants’ experiences and perceptions with various HIV interventions and policies, including PrEP.Results
While awareness of PrEP was generally low, perceptions about the potential personal and public health gains associated with PrEP were interconnected with expressions of complex and sometimes conflicting social norms. Some accounts characterized PrEP as a convenient form of reliable protection against HIV, likening it to the female birth control pill. Other accounts cast PrEP as a means to facilitate ‘socially unacceptable’ behaviour (e.g., promiscuity). Stigmatizing rhetoric was used to position PrEP as a tool that could promote some groups’ proclivities to take ‘risks’.Conclusion
Stigma regarding ‘risky’ behaviour and PrEP should not be underestimated as a serious implementation challenge. Pre-implementation strategies that concomitantly aim to improve knowledge about PrEP, while addressing associated social prejudices, may be key to effective implementation and scale-up. 相似文献72.
Familial amyloidotic polyneuropathy (FAP) is an inherited autosomal dominant disease that is commonly caused by accumulation of deposits of transthyretin (TTR) amyloid around peripheral nerves. The only effective treatment for FAP is liver transplantation. However, recent studies on TTR aggregation provide clues to the mechanism of the molecular pathogenesis of FAP and suggest new avenues for therapeutic intervention. It is increasingly recognized that there are common features of a number of protein-misfolding diseases that can lead to neurodegeneration. As for other amyloidogenic proteins, the most toxic forms of aggregated TTR are likely to be the low-molecular-mass diffusible species, and there is increasing evidence that this toxicity is mediated by disturbances in calcium homeostasis. This article reviews what is already known about the mechanism of TTR aggregation in FAP and describes how recent discoveries in other areas of amyloid research, particularly Alzheimer's disease, provide clues to the molecular pathogenesis of FAP. 相似文献
73.
Small KM Brown KM Forbes SL Liggett SB 《The Journal of biological chemistry》2001,276(34):31596-31601
Depressed G-protein-coupled receptor (GPCR) signaling has been implicated as a component of the pathophysiology of a number of complex diseases including heart failure and asthma, and augmentation or restoration of signaling by various means has been shown to improve organ function. Because some properties of native GPCRs are disadvantageous for ectopic therapeutic expression, we utilized the beta(2)-adrenergic receptor (beta(2)AR) as a scaffold to construct a highly modified therapeutic receptor-effector complex (TREC) suitable for gene therapy. Altogether, 19 modifications were made to the receptor. The ligand-binding site was re-engineered in TM-3 so that a beta-hydroxylmethyl side chain acts as a proton donor for the binding of a novel ligand. In addition, sites critical for agonist-promoted down-regulation in the amino terminus and for phosphorylation by GPCR kinases, and protein kinases A and C, in the third intracellular loop and the carboxyl terminus of the receptor were altered. These modifications of the receptor resulted in depressed agonist-stimulated adenylyl cyclase activity (26.8 +/- 2.1 versus 41.4 +/- 8 pmol/min/mg for wild-type beta(2)AR). This was fully restored by fusing the carboxyl terminus of the modified receptor to G alpha(s) (43.3 +/- 2.7 pmol/min/mg). The fully modified fused receptor was not activated by beta-agonists but rather by a nonbiogenic amine agonist that itself failed to activate the wild-type beta(2)AR. This two-way selectivity thus provides targeted activation based on physiologic status. Furthermore, the TREC did not display tachyphylaxis to prolonged agonist exposure (desensitization was 1 +/- 5% versus 55 +/- 4% for wild-type beta(2)AR). Thus, despite extensive alterations in regions of conformational lability, the beta(2)AR can be tailored to have optimal signaling characteristics for gene therapy. As a general paradigm, TRECs for enhancement of other G-protein signaling appear to be feasible for modification of other pathologic states. 相似文献
74.
Herscovitz H Derksen A Walsh MT McKnight CJ Gantz DL Hadzopoulou-Cladaras M Zannis V Curry C Small DM 《Journal of lipid research》2001,42(1):51-59
The N-terminal 17% of apolipoprotein B (apoB-17) readily associates with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) to form large (240-A diameter) discoidal particles. Because apoB is normally secreted with triacylglycerol (TAG)-rich lipoproteins, we studied the binding of apoB-17 to triolein-rich emulsions modeling nascent TAG-rich very low density-like lipoproteins. Emulsions with the following composition (by weight) were prepared: 85--89% triolein, 1.1--1.4% cholesterol, and 10--14% phosphatidylcholines (PC) including either egg yolk (EY)-, dimyristoyl (DM)-, or dipalmitoyl (DP)-PC representing (at 25 degrees C), respectively, a fluid surface, a surface at transition, and a mainly solid surface. The respective sizes were 1,260 +/- 500, 1,070 +/- 450, and 830 +/- 300 A mean diameter. The emulsions were incubated with conditioned medium containing apoB-17, and then reisolated by ultracentrifugation. Analysis of the emulsion-bound proteins by gel electrophoresis showed that all three emulsions bound primarily apoB-17. The DPPC emulsions bound more apoB-17 than EYPC or DMPC emulsions. Immunoaffinity-purified apoB-17 exhibited saturable, high affinity binding to EYPC and DPPC emulsions. The respective K(d) values were 32 +/- 23 and 85 +/- 27 nM and capacities (N) were 10 and 58 molecules of apoB-17 per particle. When apoB-17 bound to emulsions was incubated with DMPC MLV at 26 degrees C for 18 h, it remained bound to the emulsions, indicating that once bound to these emulsions it is unable to exchange off and solubilize DMPC into discs. In contrast, apoE-3 bound to emulsions dissociated from the emulsions when incubated with DMPC MLV and formed discs.Thus, apoB-17 binds strongly and irreversibly to emulsions modeling nascent lipoproteins. It therefore may play an important role in the stabilization of nascent VLDL and chylomicrons.- Herscovitz, H., A. Derksen, M. T. Walsh, C. J. McKnight, D. L. Gantz, M. Hadzopoulou-Cladaras, V. Zannis, C. Curry, and D. M. Small. The N-terminal 17% of apoB binds tightly and irreversibly to emulsions modeling nascent very low density lipoproteins. J. Lipid Res. 2001. 42: 51;-59. 相似文献
75.
76.
Insertion sequence (IS) elements are bacterial genes that are able to transpose to different locations in the genome. These elements are often used in molecular epidemiology as genetic markers that track the spread of pathogens. Transposable elements have frequently been described as "selfish DNA" because they facilitate their own transposition, causing damage when they insert into coding regions, while contributing little if anything to the bacterial host. According to this hypothesis, the expansion of copy number of insertion sequences is opposed by negative selection against high copy numbers. From an alternative point of view, we might expect IS elements to intrinsically regulate transposition within cells, thereby limiting damage to their bacterial host. Here, we report evidence that the copy number of IS6110 in Mycobacterium tuberculosis is controlled by selection against the element. We first construct 12 different models of marker change resulting from a combination of possible transposition functions and selective regimes. We then compute the Akaike Information Criterion for each model to identify the models that best explain data consisting of serial isolates of M. tuberculosis genotyped with IS6110. We find that the best performing models all include selection against the accumulation of copies. Specifically, our analysis points to the interaction of separate copies of the element causing lethal effects. We discuss the implications of these findings for genome evolution and molecular epidemiology. 相似文献
77.
Evan Wood Thomas Kerr Will Small Kathy Li David C. Marsh Julio S.G. Montaner Mark W. Tyndall 《CMAJ》2004,171(7):731-734
Background
North America''s first medically supervised safer injecting facility for illicit injection drug users was opened in Vancouver on Sept. 22, 2003. Although similar facilities exist in a number of European cities and in Sydney, Australia, no standardized evaluations of their impact have been presented in the scientific literature.Methods
Using a standardized prospective data collection protocol, we measured injection-related public order problems during the 6 weeks before and the 12 weeks after the opening of the safer injecting facility in Vancouver. We measured changes in the number of drug users injecting in public, publicly discarded syringes and injection-related litter. We used Poisson log-linear regression models to evaluate changes in these public order indicators while considering potential confounding variables such as police presence and rainfall.Results
In stratified linear regression models, the 12-week period after the facility''s opening was independently associated with reductions in the number of drug users injecting in public (p < 0.001), publicly discarded syringes (p < 0.001) and injection-related litter (p < 0.001). The predicted mean daily number of drug users injecting in public was 4.3 (95% confidence interval [CI] 3.5–5.4) during the period before the facility''s opening and 2.4 (95% CI 1.9–3.0) after the opening; the corresponding predicted mean daily numbers of publicly discarded syringes were 11.5 (95% CI 10.0–13.2) and 5.4 (95% CI 4.7–6.2). Externally compiled statistics from the city of Vancouver on the number of syringes discarded in outdoor safe disposal boxes were consistent with our findings.Interpretation
The opening of the safer injecting facility was independently associated with improvements in several measures of public order, including reduced public injection drug use and public syringe disposal.Many cities are experiencing epidemics of bloodborne diseases as a result of illicit injection drug use,1,2,3 and drug overdoses have become a leading cause of death in many urban areas.4,5,6 Public drug use also plagues many inner city neighbourhoods, and the unsafe disposal of syringes in these settings is a major community concern.7,8,9,10,11,12,13In over 2 dozen European cities and, more recently, in Sydney, Australia, medically supervised safer injecting facilities, where injection drug users (IDUs) can inject previously obtained illicit drugs under the supervision of medical staff, have been established in an effort to reduce the community and public health impacts of illicit drug use.14 Inside these facilities IDUs are typically provided with sterile injecting equipment, emergency care in the event of overdose, as well as primary care services and referral to addiction treatment.13,15 Although anecdotal reports have suggested that such sites may improve public order,12 reduce the number of deaths from overdose16 and improve access to care,17 no standardized evaluations of their impact are available in the scientific literature.18On Sept. 22, 2003, health officials in Vancouver opened a government-sanctioned safer injecting facility as pilot project. The facility, the first in North America, is centrally located in Vancouver''s Downtown Eastside, which is the most impoverished urban neighbourhood in Canada and home to well-documented overdose and HIV epidemics among the estimated 5000 IDUs who reside there.19,20 Federal approval for the 3-year project was granted on the condition that the health and social impacts of the facility be rigorously evaluated. Although evaluation of the facility''s impact on certain outcomes (e.g., HIV incidence) is ongoing and will take several years, it is now possible to examine the impacts of the site on public order. Therefore, we conducted this study to test the hypothesis that changes in improperly discarded syringes and public drug use would be observed after the opening of the safer injecting facility. 相似文献78.
Mingkui?CaoEmail author Stephen D.?Prince Jennifer?Small Scott J.?Goetz 《Ecosystems》2004,7(3):233-242
Spatial and temporal variations in net primary production (NPP) are of great importance to ecological studies, natural resource management, and terrestrial carbon sink estimates. However, most of the existing estimates of interannual variation in NPP at regional and global scales were made at coarse resolutions with climate-driven process models. In this study, we quantified global NPP variation at an 8 km and 10-day resolution from 1981 to 2000 based on satellite observations. The high resolution was achieved using the GLObal Production Efficiency Model (GLO-PEM), which was driven with variables derived almost entirely from satellite remote sensing. The results show that there was an increasing trend toward enhanced terrestrial NPP that was superimposed on high seasonal and interannual variations associated with climate variability and that the increase was occurring in both northern and tropical latitudes. NPP generally decreased in El Niño season and increased in La Niña seasons, but the magnitude and spatial pattern of the response varied widely between individual events. Our estimates also indicate that the increases in NPP during the period were caused mainly by increases in atmospheric carbon dioxide and precipitation. The enhancement of NPP by warming was limited to northern high latitudes (above 50°N); in other regions, the interannual variations in NPP were correlated negatively with temperature and positively with precipitation. 相似文献
79.
American marten (Martes americana) have a close association with mature temperate forests, a habitat that expanded throughout the Pacific Northwest as glaciers receded at the end of the Pleistocene. Similar to several other forest-associated mammals in North America (e.g. black bear), genetic analysis of the marten shows a deep phylogeographical subdivision that reflects populations with distinctive evolutionary histories. Using a suite of 14 microsatellite markers, we explored the genetic structure of marten populations in two reciprocally monophyletic clades in the Pacific Northwest identified previously as M. caurina and M. americana by mitochondrial haplotypes and morphology. Microsatellite phylogeographical patterns were congruent with mitochondrial analyses. These independent data sets shed light upon hybridization patterns, population structure and evolutionary histories. Hybridization between M. caurina and M. americana individuals was documented in two regions of sympatry (Kuiu Island in southeastern Alaska and southern Montana). Northern insular populations of M. caurina exhibited higher differentiation and lower variability relative to northern populations of M. americana. Greater divergence among M. caurina populations may reflect longer isolation and persistence in coastal forest habitat that was fragmented by rising sea level in the early Holocene. Lower differentiation among northern M. americana populations and close relationship to other continental M. americana populations may reflect more recent expansion into the Pacific Northwest and/or continued gene flow among populations. Differentiation among M. caurina populations was attributed to habitat fragmentation (i.e. rising sea level), as opposed to isolation-by-distance; oceanic straits pose significant barriers to gene flow among M. caurina populations and between populations of M. caurina and M. americana. 相似文献
80.
Subasinghe S Unabia S Barrow CJ Mok SS Aguilar MI Small DH 《Journal of neurochemistry》2003,84(3):471-479
Accumulation of beta amyloid (Abeta) in the brain is central to the pathogenesis of Alzheimer's disease. Abeta can bind to membrane lipids and this binding may have detrimental effects on cell function. In this study, surface plasmon resonance technology was used to study Abeta binding to membranes. Abeta peptides bound to synthetic lipid mixtures and to an intact plasma membrane preparation isolated from vascular smooth muscle cells. Abeta peptides were also toxic to vascular smooth muscle cells. There was a good correlation between the toxic effect of Abeta peptides and their membrane binding. 'Ageing' the Abeta peptides by incubation for 5 days increased the proportion of oligomeric species, and also increased toxicity and the amount of binding to lipids. The toxicities of various Abeta analogs correlated with their lipid binding. Significantly, binding was influenced by the concentration of cholesterol in the lipid mixture. Reduction of cholesterol in vascular smooth muscle cells not only reduced the binding of Abeta to purified plasma membrane preparations but also reduced Abeta toxicity. The results support the view that Abeta toxicity is a direct consequence of binding to lipids in the membrane. Reduction of membrane cholesterol using cholesterol-lowering drugs may be of therapeutic benefit because it reduces Abeta-membrane binding. 相似文献