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| 2. |
- Alzari, Pedro M., et al.
(författare)
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Implementation of semi-automated cloning and prokaryotic expression screening : the impact of SPINE
- 2006
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Ingår i: Acta Crystallographica Section D. - 0907-4449 .- 1399-0047. ; 62, s. 1103-1113
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Tidskriftsartikel (refereegranskat)abstract
- The implementation of high- throughput ( HTP) cloning and expression screening in Escherichia coli by 14 laboratories in the Structural Proteomics In Europe ( SPINE) consortium is described. Cloning efficiencies of greater than 80% have been achieved for the three non- ligation- based cloning techniques used, namely Gateway, ligation- indendent cloning of PCR products ( LIC- PCR) and In- Fusion, with LIC- PCR emerging as the most cost- effective. On average, two constructs have been made for each of the approximately 1700 protein targets selected by SPINE for protein production. Overall, HTP expression screening in E. coli has yielded 32% soluble constructs, with at least one for 70% of the targets. In addition to the implementation of HTP cloning and expression screening, the development of two novel technologies is described, namely library- based screening for soluble constructs and parallel small- scale high- density fermentation.
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| 3. |
- Glackin, C., et al.
(författare)
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A comparison of fuzzy strategies for corporate acquisition analysis
- 2007
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Ingår i: Fuzzy sets and systems (Print). - : Elsevier BV. - 0165-0114 .- 1872-6801. ; 158:18, s. 2039-2056
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Tidskriftsartikel (refereegranskat)abstract
- Analysing all prospective companies for acquisition in large market sectors is an onerous task. A strategy that results in a shortlist of companies that meet certain basic criteria is required. The short-listed companies can then be further investigated in more detail later if desired. Fuzzy logic systems (FLSs) imbued with the expertise of a focal organisation's financial experts can be of great assistance in this process. In this paper an investigation into the suitability of FLSs for acquisition analysis is presented. The nuances of training and tuning are discussed. In particular, the difficulty of obtaining suitable amounts of expert data is a recurring theme throughout the paper. A strategy for circumventing this issue is presented that relies on the design of a conventional fuzzy logic rule base with the assistance of a financial expert. With the rule base created, various scenarios such as the simulation of multiple experts and the creation of expert training data are investigated. In particular, two scenarios for the creation of simulated expert data are presented. In the first the responses from the different experts are averaged, and in the second scenario the responses from all the different experts are preserved in the training data. This paper builds on previous work with scalable membership functions, however, the use of fuzzy C-means clustering and backpropagation training, are new developments. Additionally, a type-2 FLS is developed and its potential advantages are discussed for this application. The type-2 system facilitates the inclusion of the opinions of multiple experts. Both the type-1 and type-2 FLSs were trained using the backpropagation algorithm with early stopping and verified with five-fold cross-validation. Multiple runs of the five-fold method were conducted with different random orderings of the data. For this particular application, the type-1 system performed comparably with the type-2 system despite the considerable amount of variation in the expert training data. The training results have proven the methods to be capable of efficient tuning of parameters, and of reliable ranking of prospective companies.
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| 4. |
- Gombert, Michael, et al.
(författare)
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CCL1-CCR8 interactions : an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation.
- 2005
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 174:8, s. 5082-91
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Tidskriftsartikel (refereegranskat)abstract
- Atopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10-20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1alpha) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.
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| 5. |
- Huhtaniemi, Ilpo T, et al.
(författare)
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Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats.
- 2009
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 94, s. 277-284
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Tidskriftsartikel (refereegranskat)abstract
- Context: The individual variability in the waning androgenic-anabolic functions of aging men may be influenced by the CAG repeat polymorphism in exon 1 of the androgen receptor (AR), affecting androgen sensitivity. However, findings on its phenotypic effects are inconclusive. Objective: To investigate the relationships between health status, various reproductive hormones and the AR CAG repeat length. Design: A multi-national prospective cohort observational study - cross-sectional baseline data. Setting: Population survey of community-dwelling men. Participants: Men (40-79-yr-old; n=3,369) randomly recruited from centers in eight European countries; CAG repeat analysis was performed in 2,878 men. Main outcome measures: The correlations of the CAG repeat length with selected endocrine, metabolic and phenotypic parameters related to aging and sex hormone action. Results: Only minor differences were found in CAG repeat lengths between the eight European countries. They showed significant positive association with total, free and bioavailable levels of testosterone (T) and estradiol (E2). FSH but not LH correlated inversely with CAG repeat length. Significant associations were found with bone ultrasound parameters at the calcaneus. Negative correlation was found with triglycerides, but not with other blood lipids, or with anthropometry, blood pressure, hemoglobin, insulin sensitivity, or sexual and prostatic functions. Conclusions: The AR CAG repeat length correlates significantly with serum T and E2 of aging men. Weaker transcriptional activity of the AR with longer CAG-encoded polyglutamine repeats appears to be totally or near-totally compensated for by higher T levels. The residual phenotypic correlations may reflect differences in estrogen levels/actions following aromatization of the higher T levels.
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| 6. |
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| 7. |
- Limer, Kate L., et al.
(författare)
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Genetic Variation in Sex Hormone Genes Influences Heel Ultrasound Parameters in Middle-Aged and Elderly Men: Results From the European Male Aging Study (EMAS)
- 2009
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Ingår i: Journal of Bone and Mineral Research. - 1523-4681. ; 24:2, s. 314-323
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Tidskriftsartikel (refereegranskat)abstract
- Genes involved in sex hormone pathways are candidates for influencing bone strength. Polymorphisms in these genes were tested for association with heel quantitative ultrasound (QUS) parameters in middle-aged and elderly European men. Men 40-79 yr of age were recruited from population registers in eight European centers for the European Male Aging Study (EMAS). Polymorphisms were genotyped in AR, ESR1, ESR2, CYP19A1, CYP17A1, SHBG, SRD5A2, LHB, and LHCGR. QUS parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured in the heel and used to derive BMD. The relationships between Q US parameters and polymorphisms were assessed using linear regression adjusting for age and center. A total of 2693 men, with a mean age of 60.1 +/- 11.1 (SD) yr were included in the analysis. Their mean BUA was 80.0 +/- 18.9 dB/Mhz, SOS was 1550.2 +/- 34.1. m/s, and BMD was 0.542 +/- 0.141 g/cm(2). Significant associations were observed between multiple SNPs in a linkage disequilibrium (LD) block within CYP19A1, peaking at the TCT indel with the deletion allele associating with reduced ultrasound BMD in heterozygotes (beta = -0.016, p = -0.005) and homozygotes (beta = -0.029, p = 0.001). The results for BUA and SOS were similar. Significant associations with QUS parameters were also observed for the CAG repeat in AR and SNPs in CYP17A1, LHCGR, and ESR1 Our data confirm evidence of association between bone QUS parameters and polymorphisms in CYP79A1, as well as modest associations with polymorphisms in CYP17A1, ESR1, LHCGR, and AR in a population sample of European men; this supports a role for genetically determined sex hormone actions in influencing male bone health.
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| 8. |
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| 9. |
- Spicer, R.A., et al.
(författare)
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The Late Cretaceous continental interior of Siberia: A challenge to climate models
- 2008
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 1385-013X .- 0012-821X. ; 267:1-2, s. 228-235
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Tidskriftsartikel (refereegranskat)abstract
- Geological evidence from the Late Cretaceous continental interior of the Vilui Basin, Siberia suggests a far wetter, warmer, and more equable annual climate than General Circulation Models (GCMs) can reproduce. The disparity cannot be bridged by the uncertainties inherent in either the models or the geological climate proxies. This implies the mismatch is genuine and that either 1) we have systematic errors in the interpretation/calibration of the climate proxies, and/or 2) lack of full knowledge of the boundary conditions needed for GCM models simulations of this period, and/or 3) an insufficient understanding of the nature of the coupled atmosphere–ocean–biosphere system and its representation within climate models during warm climate epochs. If it is the third explanation, this would have important implications for the prediction of future climates and would suggest that we may currently be underestimating future climate change in such regions.
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| 10. |
- Sturve, Joachim, 1966, et al.
(författare)
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Effects of North Sea oil and alkylphenols on biomarker responses in juvenile Atlantic cod (Gadus morhua)
- 2006
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Ingår i: Aquatic Toxicology. - : Elsevier BV. - 0166-445X. ; 78
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Tidskriftsartikel (refereegranskat)abstract
- A consequence of oil drilling at sea is the release of produced water contaminated with e.g. polycyclic aromatic hydrocarbons (PAH) and alkylphenols. In the present study, juvenile Atlantic cod were exposed to North Sea oil, nonylphenol and a combination of the North Sea oil and an alkylphenol mixture in a flow-through system. A suite of hepatic biomarkers were analysed. Exposure to North Sea oil resulted in strong induction of CYPIA protein levels and EROD activities. Exposure to nonylphenol, on the other hand, resulted in decreased CYPIA levels and EROD activities. Thus, nonylphenol appears to down-regulate CYPIA expression in Atlantic cod. Combined exposure to North Sea oil with an alkylphenol mixture resulted in lower EROD induction, compared to that in fish exposed to North Sea oil alone. This difference was not statistically significant. but still we believe that the alkylphenols have inhibited CYPIA activities in the fish which may have compromised CYPIA mediated metabolism of other xenobiotics, including PAH. CYP3A protein levels were lower, compared to controls, in fish exposed to nonylphenol and the combination of North Sea oil and alkylphenol mixture. In contrast. the oil alone had no effect on CYP3A protein content. North Sea oil exposure, alone or in combination with alkylphenols, caused oxidative stress observed as elevated levels of GSSG content and GR and CAT activities. Interestingly. exposure to nonylphenol resulted in a marked depletion of total glutathione levels. This apparent depletion may be a consequence of increased conjugation of glutathione to nonylphenol followed by excretion. An increase in conjugation enzyme GST activity was observed in the nonylphenol exposed group, although the difference was not significant. No sign of oxidative damage, measured as lipid peroxidation, was observed in any of the exposures experiments. This study suggests that North Sea oil may lead to oxidative stress and altered CYP1A and CYP3A expression. Alkylphenols, present in produced water, resulted in decreased CYP1A and CYP3A protein expression in Atlantic cod. (c) 2006 Elsevier B.V. All rights reserved.
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