| 1. |
- Hudson, Lawrence N, et al.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 4. |
- Brady, Lauren, et al.
(författare)
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Correlation of integrated ERG/PTEN assessment with biochemical recurrence in prostate cancer
- 2021
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Ingår i: Cancer Treatment and Research Communications. - : Elsevier. - 2468-2942. ; 29
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Prostate cancer is a heterogeneous disease, with a complex molecular landscape that evolves throughout disease progression. Common alterations in genes such as ERG and PTEN have been attributed to worse prognosis. This study aimed to further examine the clinical relevance of PTEN and ERG expression in a cohort of patients with prostate cancer post radical prostatectomy.METHODS: Tissue microarrays were constructed from 132 patients with prostate cancer from the Irish Prostate Cancer Research Consortium and University Hospital of Orebro, Sweden. Patients were divided into three groups - Group 1: biochemical recurrence, Group 2: no biochemical recurrence and Group 3: immediate progression after surgery. PTEN and ERG immunohistochemical analysis was performed and the association between expression levels and clinical parameters were compared.RESULTS: Pathological stage pT3 tumours were more common at borderline significantly higher levels amongst patients who biochemically recurred when compared to patients who did not recur after radical prostatectomy (p = 0.05). ERG and PTEN expression levels were compared separately and concurrently across all three patient groups. Lack of ERG expression was strongly associated with immediate progression after surgery (p = 0.029). Loss of/low PTEN trended towards an association with immediate progression, however this was not statistically significant (p = 0.066).CONCLUSION: In this study, negative ERG expression was strongly associated with immediate biochemical progression after radical prostatectomy. Moreover, a trend towards a relationship between aberrant PTEN expression and progression was observed. Additional studies with long-term follow up data may provide further clinical insight into the genomic heterogeneity in this population.
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| 5. |
- Chen, Song, et al.
(författare)
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Compressive fatigue limit of four types of dental restorative materials
- 2016
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Ingår i: Journal of The Mechanical Behavior of Biomedical Materials. - : Elsevier BV. - 1751-6161 .- 1878-0180. ; 61, s. 283-289
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the quasi-static compressive strength and the compressive fatigue limit of four different dental restorative materials, before and after aging in distilled water for 30 days. A conventional glass ionomer cement (Fuji IX GP; IG), a zinc-reinforced glass ionomer cement (Chemfil rock; CF), a light curable resin-reinforced glass ionomer cement (Fuji II LC; LC) and a resin-based composite (Quixfil; QF) were investigated. Cylindrical specimens (4 mm in diameter and 6 mm in height) were prepared according to the manufacturer's instructions. The compressive fatigue limit was obtained using the staircase method. Samples were tested in distilled water at 37 degrees C, at a frequency of 10 Hz with 10(5) cycles set as run-out. 17 fatigue samples were tested for each group. Two-way ANOVA and one-way ANOVA followed by Tukey's post-hoc test were used to analyze the results. Among the four types of materials, the resin-based composite exhibited the highest compressive strength (244 +/- 13.0 MPa) and compressive fatigue limit (134 +/- 7.8 MPa), followed by the light-cured resin reinforced glass ionomer cement (168 +/- 8.5 MPa and 92 +/- 6.6 MPa, respectively) after one day of storage in distilled water. After being stored for 30 days, all specimens showed an increase in compressive strength. Aging showed no effect on the compressive fatigue limit of the resin-based composite and the light-cured resin reinforced glass ionomer cement, however, the conventional glass ionomer cements showed a drastic decrease (37% for IG, 31% for CF) in compressive fatigue limit. In conclusion, in the present study, resin modified GIC and resin-based composite were found to have superior mechanical properties to conventional GIC.
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| 6. |
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| 7. |
- Curtis, Bruce A., et al.
(författare)
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Algal genomes reveal evolutionary mosaicism and the fate of nucleomorphs
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7427, s. 59-65
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Tidskriftsartikel (refereegranskat)abstract
- Cryptophyte and chlorarachniophyte algae are transitional forms in the widespread secondary endosymbiotic acquisition of photosynthesis by engulfment of eukaryotic algae. Unlike most secondary plastid-bearing algae, miniaturized versions of the endosymbiont nuclei (nucleomorphs) persist in cryptophytes and chlorarachniophytes. To determine why, and to address other fundamental questions about eukaryote-eukaryote endosymbiosis, we sequenced the nuclear genomes of the cryptophyte Guillardia theta and the chlorarachniophyte Bigelowiella natans. Both genomes have >21,000 protein genes and are intron rich, and B. natans exhibits unprecedented alternative splicing for a single-celled organism. Phylogenomic analyses and subcellular targeting predictions reveal extensive genetic and biochemical mosaicism, with both host-and endosymbiont-derived genes servicing the mitochondrion, the host cell cytosol, the plastid and the remnant endosymbiont cytosol of both algae. Mitochondrion-to-nucleus gene transfer still occurs in both organisms but plastid-to-nucleus and nucleomorph-to-nucleus transfers do not, which explains why a small residue of essential genes remains locked in each nucleomorph.
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| 8. |
- Gray, Steven, et al.
(författare)
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Purpose, processes, partnerships, and products : four Ps to advance participatory socio-environmental modeling
- 2018
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Ingår i: Ecological Applications. - : Wiley-Blackwell. - 1051-0761 .- 1939-5582. ; 28:1, s. 46-61
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Tidskriftsartikel (refereegranskat)abstract
- Including stakeholders in environmental model building and analysis is an increasingly popular approach to understanding ecological change. This is because stakeholders often hold valuable knowledge about socio-environmental dynamics and collaborative forms of modeling produce important boundary objects used to collectively reason about environmental problems. Although the number of participatory modeling (PM) case studies and the number of researchers adopting these approaches has grown in recent years, the lack of standardized reporting and limited reproducibility have prevented PM's establishment and advancement as a cohesive field of study. We suggest a four-dimensional framework (4P) that includes reporting on dimensions of (1) the Purpose for selecting a PM approach (the why); (2) the Process by which the public was involved in model building or evaluation (the how); (3) the Partnerships formed (the who); and (4) the Products that resulted from these efforts (the what). We highlight four case studies that use common PM software-based approaches (fuzzy cognitive mapping, agent-based modeling, system dynamics, and participatory geospatial modeling) to understand human-environment interactions and the consequences of ecological changes, including bushmeat hunting in Tanzania and Cameroon, agricultural production and deforestation in Zambia, and groundwater management in India. We demonstrate how standardizing communication about PM case studies can lead to innovation and new insights about model-based reasoning in support of ecological policy development. We suggest that our 4P framework and reporting approach provides a way for new hypotheses to be identified and tested in the growing field of PM.
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| 9. |
- Gray, Steven
(författare)
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The IGF-axis in liver disease : modulation of expression by histone deacetylase inhibitors
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Insulin-like growth factor (IGF) axis is composed of a family of ligands, receptors and binding proteins with important functions in the regulation of cell growth, apoptosis, survival, migration and development. The liver is a major provider of several of the IGF-axis members. Alterations to this axis may therefore be of importance in liver tumorigenesis. Enzymes that affect chromatin structure are increasingly being implicated in gene expression. One such group of enzymes are those which affect the acetylation status of the chromatin, histone acetyltransferases and histone deacetylases (HATs and HDACs respectively). The interplay between these enzymes is one of the means by which the cell can control gene transcription. The importance of these enzymes in the control of many cellular processes is only just being elucidated but the activities of these enzymes have been found to be important in transcription, cell cycle progression, gene silencing, lymphocyte and muscle differentiation, DNA replication and the cellular response to DNA damage. The role of histone deactylases in the regulation of gene expression can be examined experimentally using specific inhibitors, one of which is trichostatin A. This thesis is based on studies of the IGF-axis in both primary tumors and experimental manipulation of the axis by histone deacetylase inhibitors in an in vitro cell culture model. An examination of the gene expression profile for IGF-axis members in a series of hepatoblastomas (a pediatric liver tumor), reveals that the expression of many members of this axis are altered in liver tumors. Further investigations reveal that the expression of several important regulatory genes including histone deacetylases are also altered in these tumors. Investigations into the use of the histone deacetylase inhibitor trichostatin A (TSA) in a cell culture system revealed that the effect of this drug is dependent upon cell density. TSA was shown to affect the expression of members of the IGF-axis, in particular the expression of IGF2 and IGFBP-3. Expression of several important cell growth and regulatory genes, including p2l, p27 and TGFß1 were shown to be altered in this cell system upon treatment with TSA. Providing exogenous IGF2 peptide (IGF-II) could modulate the observed effects even further. It was also shown that IGF-II in the presence of IL-2 could affect TSA induced upregulation of HDAC1 mRNA expression.
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| 10. |
- Halliday, Alison, et al.
(författare)
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10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1) : A multicentre randomised trial
- 2010
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 376:9746, s. 1074-1084
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Tidskriftsartikel (refereegranskat)abstract
- Background If carotid artery narrowing remains asymptomatic (ie, has caused no recent stroke or other neurological symptoms), successful carotid endarterectomy (CEA) reduces stroke incidence for some years. We assessed the long-term effects of successful CEA. Methods Between 1993 and 2003, 3120 asymptomatic patients from 126 centres in 30 countries were allocated equally, by blinded minimised randomisation, to immediate CEA (median delay 1 month, IQR 0·3-2·5) or to indefinite deferral of any carotid procedure, and were followed up until death or for a median among survivors of 9 years (IQR 6-11). The primary outcomes were perioperative mortality and morbidity (death or stroke within 30 days) and non-perioperative stroke. Kaplan-Meier percentages and logrank p values are from intention-to-treat analyses. This study is registered, number ISRCTN26156392. Findings 1560 patients were allocated immediate CEA versus 1560 allocated deferral of any carotid procedure. The proportions operated on while still asymptomatic were 89·7 versus 4·8 at 1 year (and 92·1 vs 16·5 at 5 years). Perioperative risk of stroke or death within 30 days was 3·0 (95 CI 2·4-3·9; 26 non-disabling strokes plus 34 disabling or fatal perioperative events in 1979 CEAs). Excluding perioperative events and non-stroke mortality, stroke risks (immediate vs deferred CEA) were 4·1 versus 10·0 at 5 years (gain 5·9, 95 CI 4·0-7·8) and 10·8 versus 16·9 at 10 years (gain 6·1, 2·7-9·4); ratio of stroke incidence rates 0·54, 95 CI 0·43-0·68, p<0·0001. 62 versus 104 had a disabling or fatal stroke, and 37 versus 84 others had a non-disabling stroke. Combining perioperative events and strokes, net risks were 6·9 versus 10·9 at 5 years (gain 4·1, 2·0-6·2) and 13·4 versus 17·9 at 10 years (gain 4·6, 1·2-7·9). Medication was similar in both groups; throughout the study, most were on antithrombotic and antihypertensive therapy. Net benefits were significant both for those on lipid-lowering therapy and for those not, and both for men and for women up to 75 years of age at entry (although not for older patients). Interpretation Successful CEA for asymptomatic patients younger than 75 years of age reduces 10-year stroke risks. Half this reduction is in disabling or fatal strokes. Net benefit in future patients will depend on their risks from unoperated carotid lesions (which will be reduced by medication), on future surgical risks (which might differ from those in trials), and on whether life expectancy exceeds 10 years. Funding UK Medical Research Council, BUPA Foundation, Stroke Association.
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| 11. |
- Jordan, Rebecca, et al.
(författare)
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Twelve Questions for the Participatory Modeling Community
- 2018
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Ingår i: Earth's Future. - : American Geophysical Union (AGU). - 2328-4277. ; 6:8, s. 1046-1057
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Tidskriftsartikel (refereegranskat)abstract
- Participatory modeling engages the implicit and explicit knowledge of stakeholders to create formalized and shared representations of reality and has evolved into a field of study as well as a practice. Participatory modeling researchers and practitioners who focus specifically on environmental resources met at the National Socio-Environmental Synthesis Center (SESYNC) in Annapolis, Maryland, over the course of 2 years to discuss the state of the field and future directions for participatory modeling. What follows is a description of 12 overarching groups of questions that could guide future inquiry.
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| 12. |
- Kagaayi, Joseph, et al.
(författare)
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Uptake and retention on HIV pre-exposure prophylaxis among key and priority populations in South-Central Uganda
- 2020
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Ingår i: Journal of the International AIDS Society. - : Wiley. - 1758-2652. ; 23:8
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionPre‐exposure prophylaxis (PrEP) programmes have been initiated in sub‐Saharan Africa to prevent HIV acquisition in key populations at increased risk. However, data on PrEP uptake and retention in high‐risk African communities are limited. We evaluated PrEP uptake and retention in HIV hyperendemic fishing villages and trading centres in south‐central Uganda between April 2018 and March 2019.MethodsPrEP eligibility was assessed using a national risk screening tool. Programme data were used to evaluate uptake and retention over 12 months. Multivariable modified Poisson regression estimated adjusted prevalence ratios (aPR) and 95% Confidence intervals (CIs) of uptake associated with covariates. We used Kaplan–Meier analysis to estimate retention and multivariable Cox regression to estimate adjusted relative hazards (aRH) and 95% CIs of discontinuation associated with covariates.Results and discussionOf the 2985 HIV‐negative individuals screened; 2750 (92.1 %) were eligible; of whom 2,536 (92.2%) accepted PrEP. Male (aPR = 0.91, 95% CI = 0.85 to 0.97) and female (aPR = 0.85, 95% CI = 0.77 to 0.94) fisher folk were less likely to accept compared to HIV‐discordant couples. Median retention was 45.4 days for both men and women, whereas retention was higher among women (log rank, p < 0.001) overall. PrEP discontinuation was higher among female sex workers (aRH = 1.42, 95% CI = 1.09 to 1.83) and female fisher folk (aRH = 1.99, 95% CI = 1.46 to 2.72), compared to women in discordant couples. Male fisher folk (aRH = 1.37, 95% CI = 1.07 to 1.76) and male truck drivers (aRH = 1.49, 95% CI = 1.14 to 1.94) were more likely to discontinue compared to men in discordant couples. Women 30 to 34 years tended to have lower discontinuation rates compared to adolescents 15 to 19 years (RH = 0.78 [95% CI = 0.63 to 0.96]).ConclusionsPrEP uptake was high, but retention was very low especially among those at the highest risk of HIV: fisher folk, sex workers and truck drivers and adolescent girls. Research on reasons for PrEP discontinuation could help optimize retention.
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| 13. |
- Loughman, Tony, et al.
(författare)
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Analytical Validation of a Novel 6-Gene Signature for Prediction of Distant Recurrence in Estrogen Receptor-Positive, HER2-Negative, Early-Stage Breast Cancer
- 2022
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 68:6, s. 837-847
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOncoMasTR is a recently developed multigene prognostic test for early-stage breast cancer. The test has been developed in a kit-based format for decentralized deployment in molecular pathology laboratories. The analytical performance characteristics of the OncoMasTR test are described in this study.MethodsExpression levels of 6 genes were measured by 1-step reverse transcription-quantitative PCR on RNA samples prepared from formalin-fixed, paraffin-embedded (FFPE) breast tumor specimens. Assay precision, reproducibility, input range, and interference were determined using FFPE-derived RNA samples representative of low and high prognostic risk scores. A pooled RNA sample derived from 6 FFPE breast tumor specimens was used to establish the linear range, limit of detection, and amplification efficiency of the individual gene expression assays.ResultsThe overall precision of the OncoMasTR test was high with an SD of 0.16, which represents less than 2% of the 10-unit risk score range. Test results were reproducible across 4 testing sites, with correlation coefficients of 0.94 to 0.96 for the continuous risk score and concordance of 86% to 96% in low-/high-risk sample classification. Consistent risk scores were obtained across a > 100-fold RNA input range. Individual gene expression assays were linear up to quantification cycle values of 36.0 to 36.9, with amplification efficiencies of 80% to 102%. Test results were not influenced by agents used during RNA isolation, by low levels of copurified genomic DNA, or by moderate levels of copurified adjacent nontumor tissue.ConclusionThe OncoMasTR prognostic test displays robust analytical performance that is suitable for deployment by local pathology laboratories for decentralized use.
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| 14. |
- Luepker, Russell V., et al.
(författare)
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Community education for cardiovascular disease prevention. Morbidity and mortality results from the Minnesota Heart Health Program
- 1996
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Ingår i: American Journal of Epidemiology. - 0002-9262. ; 144:4, s. 351-362
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Tidskriftsartikel (refereegranskat)abstract
- The Minnesota Heart Health Program was a community trial of cardiovascular disease prevention methods that was conducted from 1980 to 1990 in three Upper Midwestern communities with three matched comparison communities. A 5- to 6-year intervention program used community-wide and individual health education in an attempt to decrease population risk. A major hypothesis was that the incidence of validated fatal and nonfatal coronary heart disease and stroke in 30- to 74-year-old men and women would decline differentially in the education communities after the health promotion program was introduced. This hypothesis was investigated using mixed-model regression. The intervention effect was modeled as a series of annual departures from a linear secular trend after a 2-year lag from the start of the intervention program. In the education communities, 2,394 cases of coronary heart disease and 818 cases of stroke occurred, with 2,526 and 739 cases, respectively, being seen in the comparison communities. The overall decline in coronary heart disease incidence was 1.8 percent per year in men (p = 0.03) and 3.6 percent per year in women (p = 0.007). For stroke, there were no significant secular trends. The authors recently published findings showing minimal effects of sustained intervention on risk factor levels. In the current report, there was no evidence of a significant intervention effect on morbidity or mortality, either for coronary heart disease or for stroke.
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| 15. |
- Mandel, Ronald J, et al.
(författare)
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Novel oligodendroglial alpha synuclein viral vector models of multiple system atrophy : studies in rodents and nonhuman primates
- 2017
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 5:1, s. 47-47
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Tidskriftsartikel (refereegranskat)abstract
- Multiple system atrophy (MSA) is a horrible and unrelenting neurodegenerative disorder with an uncertain etiology and pathophysiology. MSA is a unique proteinopathy in which alpha-synuclein (α-syn) accumulates preferentially in oligodendroglia rather than neurons. Glial cytoplasmic inclusions (GCIs) of α-syn are thought to elicit changes in oligodendrocyte function, such as reduced neurotrophic support and demyelination, leading to neurodegeneration. To date, only a murine model using one of three promoters exist to study this disease. We sought to develop novel rat and nonhuman primate (NHP) models of MSA by overexpressing α-syn in oligodendroglia using a novel oligotrophic adeno-associated virus (AAV) vector, Olig001. To establish tropism, rats received intrastriatal injections of Olig001 expressing GFP. Histological analysis showed widespread expression of GFP throughout the striatum and corpus callosum with >95% of GFP+ cells co-localizing with oligodendroglia and little to no expression in neurons or astrocytes. We next tested the efficacy of this vector in rhesus macaques with intrastriatal injections of Olig001 expressing GFP. As in rats, we observed a large number of GFP+ cells in gray matter and white matter tracts of the striatum and the corpus callosum, with 90-94% of GFP+ cells co-localizing with an oligodendroglial marker. To evaluate the potential of our vector to elicit MSA-like pathology in NHPs, we injected rhesus macaques intrastriatally with Olig001 expressing the α-syn transgene. Histological analysis 3-months after injection demonstrated widespread α-syn expression throughout the striatum as determined by LB509 and phosphorylated serine-129 α-syn immunoreactivity, all of which displayed as tropism similar to that seen with GFP. As in MSA, Olig001-α-syn GCIs in our model were resistant to proteinase K digestion and caused microglial activation. Critically, demyelination was observed in the white matter tracts of the corpus callosum and striatum of Olig001-α-syn but not Olig001-GFP injected animals, similar to the human disease. These data support the concept that this vector can provide novel rodent and nonhuman primate models of MSA.
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| 16. |
- Marmion, David J., et al.
(författare)
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Viral-based rodent and nonhuman primate models of multiple system atrophy : Fidelity to the human disease
- 2021
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 148
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Tidskriftsartikel (refereegranskat)abstract
- Multiple system atrophy (MSA) is a rare and extremely debilitating progressive neurodegenerative disease characterized by variable combinations of parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal dysfunction. MSA is a unique synucleinopathy, in which alpha synuclein-rich aggregates are present in the cytoplasm of oligodendroglia. The precise origin of the alpha synuclein (aSyn) found in the glial cytoplasmic inclusions (GCIs) as well the mechanisms of neurodegeneration in MSA remain unclear. Despite this fact, cell and animal models of MSA rely on oligodendroglial overexpression of aSyn. In the present study, we utilized a novel oligotrophic AAV, Olig001, to overexpress aSyn specifically in striatal oligodendrocytes of rats and nonhuman primates in an effort to further characterize our novel viral vector-mediated MSA animal models. Using two cohorts of animals with 10-fold differences in Olig001 vector titers, we show a dose-dependent formation of MSA-like pathology in rats. High titer of Olig001-aSyn in these animals were required to produce the formation of pS129+ and proteinase K resistant aSyn-rich GCIs, demyelination, and neurodegeneration. Using this knowledge, we injected high titer Olig001 in the putamen of cynomolgus macaques. After six months, histological analysis showed that oligodendroglial overexpression of aSyn resulted in the formation of hallmark GCIs throughout the putamen, demyelination, a 44% reduction of striatal neurons and a 12% loss of nigral neurons. Furthermore, a robust inflammatory response similar to MSA was produced in Olig001-aSyn NHPs, including microglial activation, astrogliosis, and a robust infiltration of T cells into the CNS. Taken together, oligodendroglial-specific viral vector-mediated overexpression of aSyn in rats and nonhuman primates faithfully reproduces many of the pathological disease hallmarks found in MSA. Future studies utilizing these large animal models of MSA would prove extremely valuable as a pre-clinical platform to test novel therapeutics that are so desperately needed for MSA.
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| 17. |
- Sterjovski, Jasminka, et al.
(författare)
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Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS
- 2007
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Ingår i: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively. Results: Compared to PA-R5 Envs, A-R5 Envs had enhanced fusogenicity in quantitative cell-cell fusion assays, and reduced sensitivity to inhibition by the fusion inhibitor T-20. Sequence analysis identified the presence of Asn 362 (N362), a potential N-linked glycosylation site immediately N-terminal to CD4-binding site (CD4bs) residues in the C3 region of gp120, more frequently in AR5 Envs than PA-R5 Envs. N362 was associated with enhanced fusogenicity, faster entry kinetics, and increased sensitivity of Env-pseudotyped reporter viruses to neutralization by the CD4bs-directed Env mAb IgG1b12. Mutagenesis studies showed N362 contributes to enhanced fusogenicity of most A-R5 Envs. Molecular models indicate N362 is located adjacent to the CD4 binding loop of gp120, and suggest N362 may enhance fusogenicity by promoting greater exposure of the CD4bs and/or stabilizing the CD4-bound Env structure. Conclusion: Enhanced fusogenicity is a phenotype of the A-R5 Envs studied, which was associated with the presence of N362, enhanced HIV-1 entry kinetics and increased CD4bs exposure in gp120. N362 contributes to fusogenicity of R5 Envs in a strain dependent manner. Our studies suggest enhanced fusogenicity of A-R5 Envs may contribute to CD4+ T-cell loss in subjects who progress to AIDS whilst harbouring R5 HIV-1 variants. N362 may contribute to this effect in some individuals.
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