| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Iacopetta, B, et al.
(författare)
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Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.
- 2006
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. - : Elsevier BV. - 0923-7534. ; 17:5, s. 842-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.
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| 3. |
- Margulies, Elliott H, et al.
(författare)
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Analyses of deep mammalian sequence alignments and constraint predictions for 1% of the human genome
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 760-774
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Tidskriftsartikel (refereegranskat)abstract
- A key component of the ongoing ENCODE project involves rigorous comparative sequence analyses for the initially targeted 1% of the human genome. Here, we present orthologous sequence generation, alignment, and evolutionary constraint analyses of 23 mammalian species for all ENCODE targets. Alignments were generated using four different methods; comparisons of these methods reveal large-scale consistency but substantial differences in terms of small genomic rearrangements, sensitivity (sequence coverage), and specificity (alignment accuracy). We describe the quantitative and qualitative trade-offs concomitant with alignment method choice and the levels of technical error that need to be accounted for in applications that require multisequence alignments. Using the generated alignments, we identified constrained regions using three different methods. While the different constraint-detecting methods are in general agreement, there are important discrepancies relating to both the underlying alignments and the specific algorithms. However, by integrating the results across the alignments and constraint-detecting methods, we produced constraint annotations that were found to be robust based on multiple independent measures. Analyses of these annotations illustrate that most classes of experimentally annotated functional elements are enriched for constrained sequences; however, large portions of each class (with the exception of protein-coding sequences) do not overlap constrained regions. The latter elements might not be under primary sequence constraint, might not be constrained across all mammals, or might have expendable molecular functions. Conversely, 40% of the constrained sequences do not overlap any of the functional elements that have been experimentally identified. Together, these findings demonstrate and quantify how many genomic functional elements await basic molecular characterization.
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| 4. |
- Davidsson, Kent, 1967, et al.
(författare)
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Potassium, chlorine, and sulfur in ash, particles, deposits, and corrosion during wood combustion in a circulating fluidized-bed boiler
- 2007
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Ingår i: Energy & Fuels. - : American Chemical Society (ACS). - 1520-5029 .- 0887-0624. ; 21:1, s. 71-81
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Tidskriftsartikel (refereegranskat)abstract
- The effect of the addition of chlorine and/or sulfur to the fuel on fly ash composition, deposit formation, and superheater corrosion has been studied during biomass combustion in a circulating fluidized-bed boiler. The chlorine (HCl (aq)) and sulfur (SO2 (g)) were added in proportions of relevance for the potassium chemistry. The composition of the bottom and the fly ashes was analyzed. Gas and particle measurements were performed downstream of the cyclone before the convection pass and the flue gas composition was recorded in the stack with a series of standard instruments and an FTIR analyzer. At the position downstream of the cyclone, a deposit probe was situated, simulating a superheater tube. Deposits on the probe and initial corrosion were examined. It is concluded that addition of sulfur and chlorine increases the formation of submicron particles leading to deposition of potassium sulfate and chloride. The results compare well with earlier work based on laboratory-scale experiments concerning effects of chlorine and sulfur on potassium chemistry.
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| 5. |
- Elsik, Christine G., et al.
(författare)
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The Genome Sequence of Taurine Cattle : A Window to Ruminant Biology and Evolution
- 2009
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 324:5926, s. 522-528
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Tidskriftsartikel (refereegranskat)abstract
- To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
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| 6. |
- Emilsson, Kent, 1963-, et al.
(författare)
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Comparison between aortic, mitral and tricuspid annular velocities measured with quantitative two-dimensional color Doppler tissue imaging in healthy subjects.
- 2007
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961 .- 1475-097X. ; 27:5, s. 275-83
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To compare the systolic, early and late diastolic velocities of the aortic, mitral and tricuspid annuli in healthy subjects and to study the intraobserver and interobserver reproducibility (IIOR) of measuring the velocities at the aortic annulus.METHODS: Twenty healthy subjects with mean age 28 years were investigated with quantitative two-dimensional color Doppler tissue imaging and the systolic, early and late diastolic velocities were measured at the aortic, mitral and tricuspid annuli.RESULTS: The mitral annulus had significant higher systolic velocity and early diastolic velocity than the aortic annulus. The late diastolic velocity was significant lower at the aortic annulus compared with the both other annuli. At the different sites of the annuli the highest systolic velocity and early diastolic velocity were measured at the lateral site of the mitral annulus, whereas the lowest systolic velocity was measured at the septal site of the same annulus. The lowest early diastolic velocity was found at the septal site of the aortic annulus. The highest late diastolic velocity was measured at the lateral site of the tricuspid annulus and the lowest at the lateral site of the aortic annulus.CONCLUSIONS: The mitral annulus has statistical significant higher systolic and early diastolic velocities than the aortic annulus. There are significant differences in velocities between several of the different sites of the annuli. IIOR of measuring the systolic and early diastolic velocities of the aortic annulus is good.
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| 7. |
- Emilsson, Kent, 1963-, et al.
(författare)
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Comparison between maximal early diastolic velocity in long-axis direction obtained by M-mode echocardiography and by tissue Doppler in the assessment of right ventricular diastolic function
- 2005
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Ingår i: Clinical Physiology and Functional Imaging. - Oxford : Blackwell. - 1475-0961 .- 1475-097X. ; 25:3, s. 178-182
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Tidskriftsartikel (refereegranskat)abstract
- Recently the maximal early diastolic velocity in long-axis direction of the right ventricle (RV) obtained by tissue Doppler imaging (MDV TDI) has been introduced in the assessment of RV diastolic function (RVDF). There are reasons to think that also the maximal early diastolic velocity in long-axis direction of the RV obtained using M-mode echocardiography (MDV TAM) could be used to assess RVDF. Therefore, 29 patients were examined with echocardiography and MDV TAM and MDV TDI were measured and compared. A good correlation (r = 0.76, P< 0.001) was found between MDV TAM and MDV TDI indicating that MDV TAM might be used in the assessment of RVDF. However, the velocities obtained by MDV TDI (126.7 &PLUSMN; 38.9 mm s(-1)) were significantly (P< 0.001) higher than the velocities obtained by MDV TAM (78.3 &PLUSMN; 27.8 mm s(-1)) and the agreement between MDV TAM and MDV TDI was rather poor probably mainly due to differences in the measuring technique. This means that reference values cannot be used interchangeably between MDV TAM and MDV TDI. If MDV TAM is going to be used in the assessment of RVDF new reference values have to be produced if today's technique and recommendations to measure MDV TAM and MDV TDI are used. However, as most new echocardiographs are equipped with PW-TDI technology it seems preferable to use this technique and compare obtained values with already established reference values.
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| 8. |
- Mogensen, M, et al.
(författare)
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Maximal lipid oxidation in patients with type 2 diabetes is normal and shows an adequate increase in response to aerobic training.
- 2009
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Ingår i: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 11:9, s. 874-83
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Insulin resistance in subjects with type 2 diabetes (T2D) and obesity is associated with an imbalance between the availability and the oxidation of lipids. We hypothesized that maximal whole-body lipid oxidation during exercise (FATmax) is reduced and that training-induced metabolic adaptation is attenuated in T2D. METHODS: Obese T2D (n = 12) and control (n = 11) subjects matched for age, sex, physical activity and body mass index completed 10 weeks of aerobic training. Subjects were investigated before and after training with maximal and submaximal exercise tests and euglycaemic-hyperinsulinaemic clamps combined with muscle biopsies. RESULTS: Training increased maximal oxygen consumption (VO(2max)) and muscle citrate synthase activity and decreased blood lactate concentrations during submaximal exercise in both groups (all p < 0.01). FATmax increased markedly (40-50%) in both T2D and control subjects after training (all p < 0.001). There were no significant differences in these variables and lactate threshold (%VO(2max)) between groups before or after training. Insulin-stimulated glucose disappearance rate (Rd) was lower in T2D vs. control subjects both before and after training. Rd increased in response to training in both groups (all p < 0.01). There was no correlation between Rd and measures of oxidative capacity or lipid oxidation during exercise or the training-induced changes in these parameters. CONCLUSIONS: FATmax was not reduced in T2D, and muscle oxidative capacity increased adequately in response to aerobic training in obese subjects with and without T2D. These metabolic adaptations to training seem to be unrelated to changes in insulin sensitivity and indicate that an impaired capacity for lipid oxidation is not a major cause of insulin resistance in T2D.
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| 9. |
- Svane, Maria, 1957, et al.
(författare)
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Cesium as a tracer for alkali processes in a circulating fluidized bed reactor
- 2006
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Ingår i: Energy & Fuels. - : American Chemical Society (ACS). - 0887-0624 .- 1520-5029. ; 20:3, s. 979-985
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Tidskriftsartikel (refereegranskat)abstract
- Addition of cesium salt has been used to study the removal rate, transport, and fate of alkali components during combustion of a mixture of wood chips and pellets in a 12-MW circulating fluidized bed (CFB) reactor. The alkali concentration in the flue gas was monitored with a recently developed aerosol mass spectrometer to provide on-line measurements of alkali-containing submicron particles. Cs2CO3 was fed with the fuel during a 5.5-h period, and the Cs concentration in the flue gas and in ash samples was followed for 70 h. Cesium addition resulted in a 1000-fold increase in Cs concentrations, followed by a slow decay of the concentrations during the following days. Cs was concluded to bind strongly to the fluidized bed material and to be removed with the bed ash or by slow release to the gas phase. The apparent rate coefficient for Cs removal from the bed was approximately 0.03 h(-1). After 70 h, 33 +/- 10% of the added cesium had been removed with the bottom ash, 7 +/- 5% with secondary cyclone ash, and 45 +/- 10% with the bag-house filter ash. About 15% of the Cs remained in the facility at this time, either bound to the fluidized bed material or as deposits on surfaces. Cesium compounds released from the bed participate in the formation of new particles that are efficiently collected by the bag-house filters. A minor Cs fraction also condenses on fly ash particles that are removed by the secondary cyclone. The study shows that the results of cesium addition can be followed in detail under typical operation conditions, and the potential of the tracer method for studies of transformations and fate of alkali compounds in commercial scale boilers is discussed.
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| 10. |
- Wagner, M., et al.
(författare)
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Subgroup Analyses in Randomized Controlled Trials: The Need for Risk Stratification in Kidney Transplantation
- 2009
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Ingår i: American Journal of Transplantation. - : Elsevier BV. - 1600-6135. ; 9:10, s. 2217-2222
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Although randomized controlled trials (RCT) are the gold standard for establishing causation in clinical research, their aggregated results can be misleading when applied to individual patients. A treatment may be beneficial in some patients, but its harms may outweigh benefits in others. While conventional one-variable-at-a-time subgroup analyses have well-known limitations, multivariable risk-based analyses can help uncover clinically significant heterogeneity in treatment effects that may be otherwise obscured. Trials in kidney transplantation have yielded the finding that a reduction in acute rejection does not translate into a similar benefit in prolonging graft survival and improving graft function. This paradox might be explained by the variation in risk for acute rejection among included kidney transplant recipients varying the likelihood of benefit or harm from intense immunosuppressive regimens. Analyses that stratify patients by their immunological risk may resolve these otherwise puzzling results. Reliable risk models should be developed to investigate benefits and harms in rationally designed risk-based subgroups of patients in existing RCT data sets. These risk strata would need to be validated in future prospective clinical trials examining long-term effects on patient and graft survival. This approach may allow better individualized treatment choices for kidney transplant recipients.
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