| 1. |
- Baghbanan, Alireza, 1971-
(författare)
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Scale and Stress Effects on Hydro-Mechanical Properties of Fractured Rock Masses
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, the effects of size and stress on permeability, deformability and strength of fractured rock masses are investigated. A comparison study was carried out to examine the effects of considering, or not considering, the correlation between distributions of fracture apertures and fracture trace lengths on the hydro-mechanical behavior of fractured rocks. The basic concepts used are the fundamental principles of the general theory of elasticity, Representative Elementary Volume (REV), the tensor of equivalent permeability, and the strength criteria of the fractured rocks. Due to the size and stress dependence of the hydro-mechanical properties of rock fractures, the overall effective (or equivalent) hydro-mechanical properties of the fractured rocks are also size and stress-dependent. However, such dependence cannot be readily investigated in laboratory using small samples, and so numerical modeling becomes a necessary tool for estimating their impacts. In this study, a closed-form relation is established for representing the correlation between a truncated lognormal distribution of fracture apertures and a truncated power law distribution of trace lengths, as obtained from field mapping. Furthermore, a new nonlinear algorithm is developed for predicting the relationship between normal stress and normal displacement of fractures, based on the Bandis model and the correlation between aperture and length. A large number of stochastic Discrete Fracture Network (DFN) models of varying sizes were extracted from some generated large-sized parent realizations based on a realistic fracture system description from a site investigation programme at Sellafield, UK, for calculating the REV of hydro-mechanical properties of fractured rocks. Rotated DFN models were also generated and used for evaluation of the distributions of directional permeabilities, such that tensors of equivalent permeability could be established based on stochastically established REVs. The stress-dependence of the permeability and the stress-displacement behaviour were then investigated using models of REV sizes. The Discrete Element Method (DEM) was used for numerical simulation of the fluid flow, deformability properties and mechanical strength behavior of fractured rocks. The results show significant scale-dependency of rock permeability, deformability and strength, and its variation when the correlation between aperture and trace length of fractures are concerned, with the overall permeability and deformability more controlled by dominating fractures with larger apertures and higher transmissivity and deformability, compared with fracture network models having uniform aperture. As the second moment of aperture distribution increases, a fractured rock mass shows more discrete behavior and an REV is established in smaller value of second moment with much larger model size, compared with the models with uniform fracture aperture. When the fracture aperture pattern is more scattered, the overall permeability, Young’s modulus and mechanical strength change significantly. The effect of stress on permeability and fluid flow patterns in fractured rock is significant and can lead to the existence or non-existence of a permeability tensor. Stress changes the fluid flow patterns and can cause significant channeling and the permeability tensor, and REV may be destroyed or re-established at different applied stress conditions. With an increase in the confining stress on the DEM models, the strength is increased. Compared with the Hoek-Brown criterion, the Mohr-Coulomb strength envelope provides a better fit to the results of numerical biaxial compression tests, with significant changes of the strength characteristic parameters occurring when the second moment of the aperture distribution is increased.
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| 2. |
- Holme, Petter, et al.
(författare)
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Exploring the assortativity-clustering space of a network's degree sequence
- 2007
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Ingår i: Physical Review E. - 1539-3755. ; 75:4
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Tidskriftsartikel (refereegranskat)abstract
- Nowadays there is a multitude of measures designed to capture different aspects of network structure. To be able to say if a measured value is expected or not, one needs to compare it with a reference model (null model). One frequently used null model is the ensemble of graphs with the same set of degrees as the original network. Here, we argue that this ensemble can give more information about the original network than effective values of network structural quantities. By mapping out this ensemble in the space of some low-level network structure-in our case, those measured by the assortativity and clustering coefficients-one can, for example, study where in the valid region of the parameter space the observed networks are. Such analysis suggests which quantities (or combination of quantities) are actively optimized during the evolution of the network. We use four very different biological networks to exemplify our method. Among other things, we find that high clustering might be a force in the evolution of protein interaction networks. We also find that all four networks are conspicuously robust to both random errors and targeted attacks.
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| 3. |
- Li, Jing, et al.
(författare)
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CYP3A phenotyping approach to predict systemic exposure to EGFR tyrosine kinase inhibitors
- 2006
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 98:23, s. 1714-1723
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gefitinib is an orally active inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) with activity in non-small-cell lung cancer. The response to gefitinib is variable, possibly because of interindividual variation in the activity of cytochrome P450 3A (CYP3A), the principal enzyme that metabolizes gefitinib. We prospectively assessed the influence of CYP3A activity on gefitinib disposition and toxicity. Methods: Twenty-seven patients with advanced cancer were treated with daily oral gefitinib at 250 mg (n = 13) or 500 mg (n = 14) for 28 days. Concentration-time profiles of midazolam and geftinib were constructed based on measurement of their concentration in serial blood samples using high-performance liquid chromatography and mass spectroscopy. CYP3A activity was determined at baseline by assessment of midazolam apparent oral clearance. Pharmacokinetic studies were performed for a period of 28 days, and population modeling was performed using NONMEM software. A structural pharmacokinetic model was developed to describe the concentration-time profiles of unbound and total gefitinib plasma concentrations, and patient-specific covariates were added to the model to account for unexplained interindividual variability in pharmacokinetic parameters. Statistical tests were two-sided. Results: Gefitinib pharmacokinetics exhibited wide interindividual variability (interindividual variability on total and unbound gefitinib apparent oral clearance was 79% and 74%, respectively). Midazolam clearance (mean = 40 L/h, range = 10-111) was highly correlated with that of total and unbound gefitinib (R2 = .60 and R2 = .68, respectively) and with steady-state plasma through concentrations of gefitinib (R2 = .58 and R2 = .60, respectively), and it accounted for approximately 40% of interindividual variability in gefitinib clearance in the pharmacokinetic model. Both total and unbound gefitinib steady-state plasma trough concentrations were associated with the development of diarrhea (P <.05), but not skin rash. At a dose of 250 mg gefitinib, 11 of 13 patients achieved steady-state plasma trough concentrations above the IC 50 for inhibition of mutant EGFR in vitro (0.015 μM), but only one achieved a steady-state plasma trough concentration above the IC 50 for inhibition of wild-type EGFR (0.1 μM). Conclusions: As an in vivo phenotypic probe of CYP3A, midazolam oral clearance may have utility for prediction of gefitinib exposure and dose selection. A pharmacokinetic model incorporating this indicator of CYP3A activity has potential for optimization of treatment with gefitinib and other TK inhibitors that are metabolized in a similar manner.
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| 4. |
- Lindgren, Cecilia M, et al.
(författare)
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Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
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Tidskriftsartikel (refereegranskat)abstract
- To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
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| 5. |
- Loos, Ruth J. F., et al.
(författare)
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Common variants near MC4R are associated with fat mass, weight and risk of obesity
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:6, s. 768-775
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Tidskriftsartikel (refereegranskat)abstract
- To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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| 6. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 7. |
- Ong, Ken K., et al.
(författare)
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Genetic variation in LIN28B is associated with the timing of puberty
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:6, s. 729-733
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Tidskriftsartikel (refereegranskat)abstract
- The timing of puberty is highly variable(1). We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 x 10(-8)). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08-0.16; P = 2.8 x 10(-10); combined P = 3.6 x 10(-16)). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 x 10(-7); N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing(2), as the first genetic determinant regulating the timing of human pubertal growth and development.
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| 8. |
- Prokopenko, Inga, et al.
(författare)
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Variants in MTNR1B influence fasting glucose levels
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 77-81
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Tidskriftsartikel (refereegranskat)abstract
- To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.
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| 9. |
- van Erp, Nielka P, et al.
(författare)
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Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:24, s. 7394-7400
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) mu g.h/mL and 41.2 (32.1-53.1) mu g.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 mu mol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.
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| 10. |
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