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- Ihre, Johan, 1707-1780
(författare)
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Dissertatio politica, de necessitate subordinationis in republica; quam, consentiente et adprob. ampl. senatu Philos. in Regia Academia Upsaliensi, sub præsidio ... Johannis Ihre, .. pro gradu publice ventilandam modeste sistit, stipendiarius regius, Laurentius L. Björkegren Ostro-Gothus, in Audit. Carol. Maj. ad diem XI Martii, Horis ante meridiem solitis.
- 1743
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Björkegren, Johan L M, et al.
(författare)
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Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
- 2014
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.
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| 3. |
- Björkegren, Johan
(författare)
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Triglyceride-rich lipoproteins : postprandial metabolism and composition in relation to atherosclerosis
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A relationship between postprandial lipaemia and coronary heart disease (CHD) was established as early as the 1950s. Since then, most attention has been paid to postprandial triglyceride-rich lipoproteins (TRLs) of intestinal origin, i.e. chylomicrons and chylomicron remnants, whereas TRLs of hepatic origin, i.e. very low density lipoproteins (VLDL) and their remnants have not been examined in detail in relation to CHD. This is surprising since an increase of VLDL particles of Svedberg flotation rate (Sf) 60-400 is the major alteration of lipoprotein particle number occurring in the postprandial state, accounting for 90% of the total cholesterol increase in the TRL fractions. The present research programme was set up to investigate alterations in metabolism and composition of TRL particles of different origin in relation to atherosclerosis. Healthy human volunteers were challenged with either an oral or an intravenous fat load, and TRLs in plasma samples were separated according to particle size (cumulative flotation in a density gradient ) and origin (immunoaffinity purification of VLDL particles from chylomicron-like lipid emulsion particles or chylomicron remnant particles). To separate VLDL from chylomicron and chylomicron remnants, specific monoclonal antibodies directed towards the C-terminus of apo B-100 were used. The apolipoprotein and lipid composition of isolated TRL particles was determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), urea gel electrophoresis, and enzymatic lipid measurements. The receptor and non-receptor mediated binding and uptake of VLDL particles was evaluated on fibroblasts in vitro. The metabolic fate of VLDL particles in the postprandial state was further investigated by isotope kinetic studies. The presence of early atherosclerosis as reflected by the carotid intima-media thickness was assessed by B-mode carotid ultrasound in asymptomatic 50-year-old men. During transient triglyceridaemia like that normally seen after a mixed meal, healthy nor molipidaemic men were found to accumulate large VLDL secondary to competition between these particles and chylomicron-like particles for lipoprotein lipase (LPL). This rendered the VLDL particles enriched with apo E, apo C-l and cholesterol, and depleted of apo C-II. These compositional alterations increased the binding affinity of large VLDL particles to fibroblasts in vitro. Chylomicron remnant particles were relatively enriched with apo C-II and phospholipids compared with VLDL particles of similar size. Furthermore, whereas VLDL particles exhibited an early increase of apo C-III in response to an oral fat load, chylomicron remnant particles simultaneously were depleted of apo C-III. In addition, the cholesterol to triglyceride ratio of large VLDL particles was found to increase transiently, whereas the cholesterol to triglyceride ratio of large chylomicrons and small TRLs increased throughout the entire postprandial period. TRL remnant particles isolated at the end of the postprandial period from asymptomatic healthy 50-year-old men with signs of early atherosclerosis were enriched with apo C-l and cholesterol in particular. Thus, TRL remnant particles undergo specific metabolic and compositional alterations during transient triglyceridaemia which would facilitate their clearance and provide an explanation for differences in metabolism between the two TRL species. In addition, in normolipidaemic men with signs of early atherosclerosis the postprandial composition of TRL particles seems to be perturbed in a way that favours formation of potentially atherogenic TRL remnants, particularly of endogenous origin. This latter finding supports the contention that lipoprotein remnant particle composition may be a more sensitive predictor of the future risk of CHD than lipoprotein remnant particle number.
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| 4. |
- Eriksson, Olivia, et al.
(författare)
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Deconstructing the core dynamics from a complex time-lagged regulatory biological circuit
- 2009
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Ingår i: IET systems biology. - : Institution of Engineering and Technology (IET). - 1751-8849 .- 1751-8857. ; 3:2, s. 113-129
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Tidskriftsartikel (refereegranskat)abstract
- Complex regulatory dynamics is ubiquitous in molecular networks composed of genes and proteins. Recent progress in computational biology and its application to molecular data generate a growing number of complex networks. Yet, it has been difficult to understand the governing principles of these networks beyond graphical analysis or extensive numerical simulations. Here the authors exploit several simplifying biological circumstances which thereby enable to directly detect the underlying dynamical regularities driving periodic oscillations in a dynamical nonlinear computational model of a protein-protein network. System analysis is performed using the cell cycle, a mathematically well-described complex regulatory circuit driven by external signals. By introducing an explicit time delay and using a -tearing-and-zooming- approach the authors reduce the system to a piecewise linear system with two variables that capture the dynamics of this complex network. A key step in the analysis is the identification of functional subsystems by identifying the relations between state-variables within the model. These functional subsystems are referred to as dynamical modules operating as sensitive switches in the original complex model. By using reduced mathematical representations of the subsystems the authors derive explicit conditions on how the cell cycle dynamics depends on system parameters, and can, for the first time, analyse and prove global conditions for system stability. The approach which includes utilising biological simplifying conditions, identification of dynamical modules and mathematical reduction of the model complexity may be applicable to other well-characterised biological regulatory circuits.
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| 7. |
- Hallén, Kristofer, 1977-, et al.
(författare)
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Detection of compound mode of action by computational integration of whole-genome measurements and genetic perturbations
- 2006
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundA key problem of drug development is to decide which compounds to evaluate further in expensive clinical trials (Phase I- III). This decision is primarily based on the primary targets and mechanisms of action of the chemical compounds under consideration. Whole-genome expression measurements have shown to be useful for this process but current approaches suffer from requiring either a large number of mutant experiments or a detailed understanding of the regulatory networks.ResultsWe have designed an algorithm, CutTree that when applied to whole-genome expression datasets identifies the primary affected genes (PAGs) of a chemical compound by separating them from downstream, indirectly affected genes. Unlike previous methods requiring whole-genome deletion libraries or a complete map of gene network architecture, CutTree identifies PAGs from a limited set of experimental perturbations without requiring any prior information about the underlying pathways. The principle for CutTree is to iteratively filter out PAGs from other recurrently active genes (RAGs) that are not PAGs. The in silico validation predicted that CutTree should be able to identify 3–4 out of 5 known PAGs (~70%). In accordance, when we applied CutTree to whole-genome expression profiles from 17 genetic perturbations in the presence of galactose in Yeast, CutTree identified four out of five known primary galactose targets (80%). Using an exhaustive search strategy to detect these PAGs would not have been feasible (>1012 combinations).ConclusionIn combination with genetic perturbation techniques like short interfering RNA (siRNA) followed by whole-genome expression measurements, CutTree sets the stage for compound target identification in less well-characterized but more disease-relevant mammalian cell systems.
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| 8. |
- Hallén, Kristofer, et al.
(författare)
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Identification of active gene networks by filtering co-occurence text mining networks with whole genome expression measurements
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Since biological networks are believed to govern the cellular behavior under normal and diseased conditions there is a large interest in developing methods that can identify the underlying structure of those networks There has been an explosion of studies using text mining to extract useful biological information from the published biomedical literature as accessed through PubMed. Co-occurrence of gene symbols in abstracts have been proposed as a method to reconstruct gene networks. On the other hand, rapid progress in micro-array technology have produced extensive data-sets of the activity of the entire genome under different biological conditions. Yet, it is not clear how to validate and assess the quality of these inferred networks beyond visual inspection and case studies and it is not feasible to reconstruct gene networks directly from whole genome wide expression data . Here we present a novel method which integrates prior knowledge in the form of published articles with whole-genome wide expression measurements.Results: We have developed a benchmark system, using a Yeast gene network as a reference network. which enables us to determine the optimal parameters for how to integrate the information from both abstracts and full texts of published articles with whole genome wide expression data sets. We investigate how the quality of the network reconstruction depends on the number of articles used, whether only using abstracts as compared to full text articles. We develop a comprehensive network reconstruction algorithm that utilizes several criteria, including the frequency of co-occurrences in abstracts and full texts, to rank which edges that are most likely to be present in the network.Conclusions: Our method is a practical tool to effectively identify as many reliable edges as possible in a gene network combining text mining and whole-genome expression data. Our scheme could easily be integrated with other methods and other data types, such as sequence information, in order to find putative interactions between genes.
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| 9. |
- Hägg, Sara, 1977-, et al.
(författare)
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Carbon-14 Dating to Determine Carotid Plaque Age : Carbon-14 Dating of Carotid Plaques
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Rationale: The exact nature of atherosclerotic plaque development and the molecular mechanisms that lead to clinical manifestations of carotid stenosis are unclear. After nuclear bomb tests in the 1950s, atmospheric 14C concentrations rapidly increased. Since then, the concentrations have been declining, and the curve of declination can be used to date biological samples synthesized during the last five to six decades. Objective: To investigate plaque age as a novel characteristic of atherosclerotic plaques in patients with carotid stenosis. Methods and Results: Carotid plaques from 29 well-characterized endarterectomy patients with symptomatic carotid stenosis were analyzed by accelerator mass spectrometry, and global gene expression of 25 plaque samples was profiled with HG-U133 Plus 2.0 arrays. The average plaque age was 9.3 years, and inter- and intrasample standard variations were low (1–3.5 years); thus, most of the plaques were generated 5–15 years before surgery. Plaque age was not associated with patient age or plaque size, determined by intima-media thickness, but was inversely related to plasma insulin levels (P=0.0014). A cluster of functionally related genes enriched with genes involved in immune responses was activated in plaques with low plaque age, as were oxidative phosphorylation genes. Conclusion: Patients with mild insulin resistance have increased immune and inflammatory gene activity in their carotid plaques causing them to become instable, rapidly progressing into clinical manifestations at a relatively young age. These results show that plaque age, determined by 14C dating, is a novel and important characteristic of atherosclerotic plaques that will improve our understanding of the clinical significance and molecular underpinnings of atherosclerosis.
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| 10. |
- Hägg, Sara, et al.
(författare)
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Carotid Plaque Age Is a Feature of Plaque Stability Inversely Related to Levels of Plasma Insulin
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4, s. e18248-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric C-14-declination curve (a result of the atomic bomb tests in the 1950s and 1960s) to determine the average biological age of carotid plaques. Methodology/Principal Finding: The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for C-14 content by accelerator mass spectrometry. The average plaque age (i.e. formation time) was 9.6+/-3.3 years. All but two plaques had formed within 5-15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p=0.0014). Most plaques were echo-lucent rather than echo-rich (2.2460.97, range 1-5). However, plaques in the lowest tercile of plaque age (most recently formed) were characterized by further instability with a higher content of lipids and macrophages (67.8+/-12.4 vs. 50.4+/-6.2, p=0.00005; 57.6+/-26.1 vs. 39.8+/-25.7, p<0.0005, respectively), less collagen (45.3+/-6.1 vs. 51.1+/-9.8, p<0.05), and fewer smooth muscle cells (130+/-31 vs. 141+/-21, p<0.05) than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation. Conclusions/Significance: Our results show, for the first time, that plaque age, as judge by relative incorporation of C-14, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.
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