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131.
132.
Malaria kills close to a million people every year, mostly children under the age of five. In the drive towards the development of an effective vaccine and new chemotherapeutic targets for malaria, field-based studies on human malaria infection and laboratory-based studies using animal models of malaria offer complementary opportunities to further our understanding of the mechanisms behind malaria infection and pathology. We outline here the parallels between the Plasmodium chabaudi mouse model of malaria and human malaria. We will highlight the contribution of P. chabaudi to our understanding of malaria in particular, how the immune response in malaria infection is initiated and regulated, its role in pathology, and how immunological memory is maintained. We will also discuss areas where new tools have opened up potential areas of exploration using this invaluable model system. 相似文献
133.
Walter P Maksymowych Anthony S Russell Peter Chiu Alex Yan Niall Jones Tracey Clare Robert GW Lambert 《Arthritis research & therapy》2012,14(5):1-7
Introduction
Inflammation associated with synovial expression of TNFα is a recognised feature of osteoarthritis (OA), although no studies have yet reported beneficial effects of anti-TNFα therapy on clinical manifestations of inflammation in OA.Methods
We conducted an open-label evaluation of adalimumab over 12 weeks in 20 patients with OA of the knee and evidence of effusion clinically. Inclusion criteria included daily knee pain for the month preceding study enrolment and a summed pain score of 125 to 400 mm visual analogue scale on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale. The primary outcome was the Osteoarthritis Research Society International/Outcome Measures in Rheumatology Clinical Trials (OARSI/OMERACT) response criterion at week 12. Secondary outcomes included the WOMAC pain score 20% and 50% improvement, WOMAC stiffness and function scores, patient and physician global visual analogue scale, as well as target joint swelling.Results
Treatment was well tolerated and completed by 17 patients with withdrawals unrelated to lack of efficacy or adverse events. By intention to treat, an OARSI/OMERACT response was recorded in 14 (70%) patients. WOMAC pain 20% and 50% responses were recorded in 14 (70%) patients and eight (40%) patients, respectively. Significant improvement was observed in mean WOMAC pain, stiffness, function, physician and patient global, as well as target joint swelling at 12 weeks (P < 0.0001 for all). After treatment discontinuation, 16 patients were available for assessment at 22 weeks and OARSI/OMERACT response compared with baseline was still evident in 10 (50%) patients.Conclusion
Targeting TNFα may be of therapeutic benefit in OA and requires further evaluation in controlled trials.Trial registration
ClinicalTrials.gov: . NCT00686439相似文献134.
The proto-oncogene, pleomorphic adenoma gene-like 2 (PLAGL2), is implicated in a variety of cancers including acute myeloid
leukemia (AML), malignant glioma, colon cancer, and lung adenocarcinoma. There is additional evidence that PLAGL2 can function
as a tumor suppressor by initiating cell cycle arrest and apoptosis. Interestingly, PLAGL2 has also been implicated in human
myelodysplastic syndrome, a disease that is characterized by ineffective hematopoiesis and can lead to fatal cytopenias (low
blood counts) as a result of increased apoptosis in the marrow, or, in about one-third of cases, can progress to AML. To gain
a better understanding of the actions of PLAGL2 in human myeloid cells, we generated a stable PLAGL2-inducible cell line,
using human promonocytic U937 cells. PLAGL2 expression inhibited cell proliferation which correlated with an accumulation
of cells in G1, apoptotic DNA-laddering, an increase in caspase 3, 8, and 9 activity, and a loss of mitochondrial transmembrane
potential. There was significant increase in the p53 homologue, p73, with PLAGL2 expression, and consistent with mechanisms
of p73-regulated cell cycle control and apoptosis, there was increased expression of known p73 target genes p21, DR5, TRAIL,
and Bax. PLAGL2-induced cell cycle block was abolished in the presence of p73 siRNA. Together, these data support a role for
PLAGL2 in cell cycle regulation and apoptosis via activation of p73. 相似文献
135.
Heather J. M. Weir Tracey K. Murray Patrick G. Kehoe Seth Love Eric M. Verdin Michael J. O’Neill Jon D. Lane Nina Balthasar 《PloS one》2012,7(11)
Progressive mitochondrial dysfunction contributes to neuronal degeneration in age-mediated disease. An essential regulator of mitochondrial function is the deacetylase, sirtuin 3 (SIRT3). Here we investigate a role for CNS Sirt3 in mitochondrial responses to reactive oxygen species (ROS)- and Alzheimer’s disease (AD)-mediated stress. Pharmacological augmentation of mitochondrial ROS increases Sirt3 expression in primary hippocampal culture with SIRT3 over-expression being neuroprotective. Furthermore, Sirt3 expression mirrors spatiotemporal deposition of β-amyloid in an AD mouse model and is also upregulated in AD patient temporal neocortex. Thus, our data suggest a role for SIRT3 in mechanisms sensing and tackling ROS- and AD-mediated mitochondrial stress. 相似文献
136.
Decision-making is defined as selection amongst options based on their utility, in a flexible and context-dependent manner. Oviposition site selection by the female fly, Drosophila melanogaster, has been suggested to be a simple and genetically tractable model for understanding the biological mechanisms that implement decisions. Paradoxically, female Drosophila have been found to avoid oviposition on sugar which contrasts with known Drosophila feeding preferences. Here we demonstrate that female Drosophila prefer egg laying on sugar, but this preference is sensitive to the size of the egg laying substrate. With larger experimental substrates, females preferred to lay eggs directly on sugar containing media over other (plain, bitter or salty) media. This was in contrast to smaller substrates with closely spaced choices where females preferred non-sweetened media. We show that in small egg laying chambers newly hatched first instar larvae are able to migrate along a diffusion gradient to the sugar side. In contrast, in contexts where females preferred egg laying directly on sugar, larvae were unable to migrate to find the sucrose if released on the sugar free side of the chamber. Thus, where larval foraging costs are high, female Drosophila choose to lay their eggs directly upon the nutritious sugar substrate. Our results offer a powerful model for female decision-making. 相似文献
137.
Sandra Larson Germán Comina Robert H. Gilman Brian H. Tracey Marjory Bravard José W. López 《PloS one》2012,7(10)
Background
A laboratory-free test for assessing recovery from pulmonary tuberculosis (TB) would be extremely beneficial in regions of the world where laboratory facilities are lacking. Our hypothesis is that analysis of cough sound recordings may provide such a test. In the current paper, we present validation of a cough analysis tool.Methodology/Principal Findings
Cough data was collected from a cohort of TB patients in Lima, Peru and 25.5 hours of recordings were manually annotated by clinical staff. Analysis software was developed and validated by comparison to manual scoring. Because many patients cough in bursts, coughing was characterized in terms of cough epochs. Our software correctly detects 75.5% of cough episodes with a specificity of 99.6% (comparable to past results using the same definition) and a median false positive rate of 4 false positives/hour, due to the noisy, real-world nature of our dataset. We then manually review detected coughs to eliminate false positives, in effect using the algorithm as a pre-screening tool that reduces reviewing time to roughly 5% of the recording length. This cough analysis approach provides a foundation to support larger-scale studies of coughing rates over time for TB patients undergoing treatment. 相似文献138.
Young CM He R Emlet RB Li Y Qian H Arellano SM Van Gaest A Bennett KC Wolf M Smart TI Rice ME 《Integrative and comparative biology》2012,52(4):483-496
Using data on ocean circulation with a Lagrangian larval transport model, we modeled the potential dispersal distances for seven species of bathyal invertebrates whose durations of larval life have been estimated from laboratory rearing, MOCNESS plankton sampling, spawning times, and recruitment. Species associated with methane seeps in the Gulf of Mexico and/or Barbados included the bivalve "Bathymodiolus" childressi, the gastropod Bathynerita naticoidea, the siboglinid polychaete tube worm Lamellibrachia luymesi, and the asteroid Sclerasterias tanneri. Non-seep species included the echinoids Cidaris blakei and Stylocidaris lineata from sedimented slopes in the Bahamas and the wood-dwelling sipunculan Phascolosoma turnerae, found in Barbados, the Bahamas, and the Gulf of Mexico. Durations of the planktonic larval stages ranged from 3 weeks in lecithotrophic tubeworms to more than 2 years in planktotrophic starfish. Planktotrophic sipunculan larvae from the northern Gulf of Mexico were capable of reaching the mid-Atlantic off Newfoundland, a distance of more than 3000?km, during a 7- to 14-month drifting period, but the proportion retained in the Gulf of Mexico varied significantly among years. Larvae drifting in the upper water column often had longer median dispersal distances than larvae drifting for the same amount of time below the permanent thermocline, although the shapes of the distance-frequency curves varied with depth only in the species with the longest larval trajectories. Even species drifting for >2 years did not cross the ocean in the North Atlantic Drift. 相似文献
139.
Rycroft-Malone J McCormack B Hutchinson AM Decorby K Bucknall TK Kent B Schultz A Snelgrove-Clarke E Stetler CB Titler M Wallin L Wilson V 《Implementation science : IS》2012,7(1):33
ABSTRACT: BACKGROUND: Realist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question 'what interventions and strategies are effective in enabling evidence-informed healthcare?' The strengths and challenges of conducting realist review are also considered. METHODS: The realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses. RESULTS: Based on key terms and concepts related to various interventions to promote evidenceinformed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area. CONCLUSIONS: Realist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review. 相似文献
140.
Jin W. Kim Seong-Tae Kim Aubrey R. Turner Tracey Young Shelly Smith Wennuan Liu Johan Lindberg Lars Egevad Henrik Gronberg William B. Isaacs Jianfeng Xu 《PloS one》2012,7(10)
Many differentially methylated genes have been identified in prostate cancer (PCa), primarily using candidate gene-based assays. Recently, several global DNA methylation profiles have been reported in PCa, however, each of these has weaknesses in terms of ability to observe global DNA methylation alterations in PCa. We hypothesize that there remains unidentified aberrant DNA methylation in PCa, which may be identified using higher resolution assay methods. We used the newly developed Illumina HumanMethylation450 BeadChip in PCa (n = 19) and adjacent normal tissues (n = 4) and combined these with gene expression data for identifying new DNA methylation that may have functional consequences in PCa development and progression. We also confirmed our methylation results in an independent data set. Two aberrant DNA methylation genes were validated among an additional 56 PCa samples and 55 adjacent normal tissues. A total 28,735 CpG sites showed significant differences in DNA methylation (FDR adjusted P<0.05), defined as a mean methylation difference of at least 20% between PCa and normal samples. Furthermore, a total of 122 genes had more than one differentially methylated CpG site in their promoter region and a gene expression pattern that was inverse to the direction of change in DNA methylation (e.g. decreased expression with increased methylation, and vice-versa). Aberrant DNA methylation of two genes, AOX1 and SPON2, were confirmed via bisulfate sequencing, with most of the respective CpG sites showing significant differences between tumor samples and normal tissues. The AOX1 promoter region showed hypermethylation in 92.6% of 54 tested PCa samples in contrast to only three out of 53 tested normal tissues. This study used a new BeadChip combined with gene expression data in PCa to identify novel differentially methylated CpG sites located within genes. The newly identified differentially methylated genes may be used as biomarkers for PCa diagnosis. 相似文献