| 1. |
- Nelander, Sven, 1974, et al.
(författare)
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Predictive screening for regulators of conserved functional gene modules (gene batteries) in mammals
- 2005
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Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The expression of gene batteries, genomic units of functionally linked genes which are activated by similar sets of cis- and trans-acting regulators, has been proposed as a major determinant of cell specialization in metazoans. We developed a predictive procedure to screen the mouse and human genomes and transcriptomes for cases of gene-battery-like regulation. RESULTS: In a screen that covered approximately 40 percent of all annotated protein-coding genes, we identified 21 co-expressed gene clusters with statistically supported sharing of cis-regulatory sequence elements. 66 predicted cases of over-represented transcription factor binding motifs were validated against the literature and fell into three categories: (i) previously described cases of gene battery-like regulation, (ii) previously unreported cases of gene battery-like regulation with some support in a limited number of genes, and (iii) predicted cases that currently lack experimental support. The novel predictions include for example Sox 17 and RFX transcription factor binding sites that were detected in approximately 10% of all testis specific genes, and HNF-1 and 4 binding sites that were detected in approximately 30% of all kidney specific genes respectively. The results are publicly available at http://www.wlab.gu.se/lindahl/genebatteries. CONCLUSION: 21 co-expressed gene clusters were enriched for a total of 66 shared cis-regulatory sequence elements. A majority of these predictions represent novel cases of potential co-regulation of functionally coupled proteins. Critical technical parameters were evaluated, and the results and the methods provide a valuable resource for future experimental design.
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| 2. |
- Jorswieck, Eduard A., 1975-, et al.
(författare)
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The MISO interference channel from a game-theoretic perspective : A combination of selfishness and altruism achieves Pareto optimality
- 2008
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Ingår i: 2008 IEEE International Conference On Acoustics, Speech And Signal Processing. - : IEEE. - 9781424414833 ; , s. 5364-5367
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Konferensbidrag (refereegranskat)abstract
- We study the MISO interference channel from a game-theoretic perspective. Recently, it was shown that the rates at the non-cooperative Nash equilibrium (NE) strategy are poor especially in the medium and high SNR regimes. A reasonable outcome of the cooperative approach, close to the Pareto boundary of the achievable rate region, was shown to be the zero-forcing (ZF) strategy. In this work, we prove that any point on the Pareto boundary can be achieved by a certain linear combination of the NE and ZF strategies. A scalar weight per user chooses between "selfish" (NE) and altruistic (ZF) behavior. Thereby, the difficult beamforming optimization is reduced to a simple weight optimization. Different optimal operating points, e.g. maximum weighted sum-rate, the Nash-bargaining solution, or the Egalitarian solution, can be obtained by a computationally efficient iterative algorithm. The results are characterized by instantaneous achievable rate regions and the corresponding operating points.
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| 3. |
- Larsson, Erik, 1975, et al.
(författare)
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Discovery of microvascular miRNAs using public gene expression data : miR-145 is expressed in pericytes and is a regulator of Fli1
- 2009
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Ingår i: Genome Medicine. - : Springer Science and Business Media LLC. - 1756-994X. ; 1:11, s. 108-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDA function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets.METHODSBioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber.RESULTSmiR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro.CONCLUSIONSmiR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature.
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| 4. |
- Larsson, Erik, 1975, et al.
(författare)
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Do two mutually exclusive gene modules define the phenotypic diversity of mammalian smooth muscle?
- 2008
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Ingår i: Molecular genetics and genomics : MGG. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 280:2, s. 127-37
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Tidskriftsartikel (refereegranskat)abstract
- Smooth muscle cells (SMCs) are key components of all hollow organs, where they perform contractile, synthetic and other functions. Unlike other muscle cells, SMCs are not terminally differentiated, but exhibit considerable phenotypic variation. Such variation is manifested both across disease states such as asthma and atherosclerosis, and physiological states such as pregnancy and wound healing. While there has been considerable investigation into the diversity of SMCs at the level of morphology and individual biomarkers, less is known about the diversity of SMCs at the level of the transcriptome. To explore this question, we performed an extensive statistical analysis that integrates 200 transcriptional profiles obtained in different SMC phenotypes and reference tissues. Our results point towards a non-trivial hypothesis: that transcriptional variation in different SMC phenotypes is characterized by coordinated differential expression of two mutually exclusive (anti-correlating) gene modules. The first of these modules (C) encodes 19 co-transcribed cell cycle associated genes, whereas the other module (E) encodes 41 co-transcribed extra-cellular matrix components. We propose that the positioning of smooth muscle cells along the C/E axis constitutes an important determinant of SMC phenotypes. In conclusion, our study introduces a new approach to assess phenotypic variation in smooth muscle cells, and is relevant as an example of how integrative bioinformatics analysis can shed light on not only terminal differentiated states but also subtler details in phenotypic variability. It also raises the broader question whether coordinated expression of gene modules is a common mechanism underlying phenotypic variability in mammalian cells.
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| 5. |
- Larsson, Erik, 1975, et al.
(författare)
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HeliCis: a DNA motif discovery tool for colocalized motif pairs with periodic spacing.
- 2007
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Ingår i: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Correct temporal and spatial gene expression during metazoan development relies on combinatorial interactions between different transcription factors. As a consequence, cis-regulatory elements often colocalize in clusters termed cis-regulatory modules. These may have requirements on organizational features such as spacing, order and helical phasing (periodic spacing) between binding sites. Due to the turning of the DNA helix, a small modification of the distance between a pair of sites may sometimes drastically disrupt function, while insertion of a full helical turn of DNA (10-11 bp) between cis elements may cause functionality to be restored. Recently, de novo motif discovery methods which incorporate organizational properties such as colocalization and order preferences have been developed, but there are no tools which incorporate periodic spacing into the model. RESULTS: We have developed a web based motif discovery tool, HeliCis, which features a flexible model that allows de novo detection of motifs with periodic spacing. Depending on the parameter settings it may also be used for discovering colocalized motifs without periodicity or motifs separated by a fixed gap of known or unknown length. We show on simulated data that it can efficiently capture the synergistic effects of colocalization and periodic spacing to improve detection of weak DNA motifs. It provides a simple to use web interface which interactively visualizes the current settings and thereby makes it easy to understand the parameters and the model structure. CONCLUSIONS: HeliCis provides simple and efficient de novo discovery of colocalized DNA motif pairs, with or without periodic spacing. Our evaluations show that it can detect weak periodic patterns which are not easily discovered using a sequential approach, i.e. first finding the binding sites and second analyzing the properties of their pairwise distances.
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| 6. |
- Larsson, Erik, 1975
(författare)
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Regulation of gene expression in the vascular wall
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Blood vessel growth and function are closely related to a number of pathological conditions, including tumor angiogenesis, wound healing and atherosclerosis. Smooth muscle cells (SMC) and endothelial cells (EC), the two major constituents of the vascular wall, are both characterized by the expression of unique phenotypic marker genes, many of which have vital roles in blood vessel development and disease. We therefore sought to obtain a more complete picture of vascular-specific gene expression, gene regulation and genetic variation. We performed an unbiased computational screen to identify cases of transcriptional coregulation in mammalian cell differentiation. This generated a number of novel hypotheses, one of them being that the SMC marker gene lipoma-preferred partner (LPP) could be activated by serum response factor (SRF), a known master regulator of SMC differentiation. Using chromatin immunoprecipitation, gel shift assays, reporter assays and transgenic mouse models, we showed that LPP belongs to the category of SMC-specific genes that are regulated by SRF, an important insight because LPP has a role in the control of SMC migration. By combining in-house and public genome-wide expression data, we identified 32 novel EC-specific mRNAs. A number of these, such as the G-protein coupled receptors Gpr116 and Ramp2, represent putative drug targets. By integrating our results with data from published genome-wide association studies, we investigated if genetic variation in EC-specific genes contributes to human disease. Independent replication of selected SNPs in 10,505 individuals revealed that a variant in one of the novel EC markers, DRAM, is associated with the development of essential hypertension. Finally, the role of microRNAs (miRNA), an abundant class of small regulatory RNAs, was evaluated in the microvasculature. Through screening of public expression data, we identified a novel microvascular-enriched miRNA, miR-145, and showed that overexpression of this molecule leads to reduced cell migration. In conclusion, we identified novel vascular marker genes and provided insights into the regulation of such genes. In addition, we showed that genetic variation in a novel EC marker gene contributes to the development of hypertension in the human population.
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| 7. |
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| 8. |
- Larsson, Erik, 1966-, et al.
(författare)
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What Impacts Course Evaluation?
- 2007
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Ingår i: 12th SIGCSE Conf. on Innovation and Technology in Computer Science Education,2007. - New York, NY, USA : ACM. - 9781595936103 ; , s. 333-333
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Konferensbidrag (refereegranskat)abstract
- Today most universities are using course evaluations. However, course evaluations are often discussed and questioned. This paper reports on a survey where we aim at finding out (1) if students have a preconceived notion of a course, (2) if course evaluation scores can be predicted early in a course, (3) if exam throughput impacts course evaluation, and (4) if web-based evaluation reflects the general opinion from students. The results from the study indicate that students do not let preconceived notion impact nor does exam throughput matter to course evaluation. Further, the final web-based results seem to correlate with opinion of students attending lectures. However, the evaluation grades tend to be defined early in the course; hence first impression lasts.
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| 9. |
- Lindskog, Henrik, 1977, et al.
(författare)
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New insights to vascular smooth muscle cell and pericyte differentiation of mouse embryonic stem cells in vitro.
- 2006
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 26:7, s. 1457-64
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The molecular mechanisms that regulate pericyte differentiation are not well understood, partly because of the lack of well-characterized in vitro systems that model this process. In this article, we develop a mouse embryonic stem (ES) cell-based angiogenesis/vasculogenesis assay and characterize the system for vascular smooth muscle cell (VSMC) and pericyte differentiation. METHODS AND RESULTS: ES cells that were cultured for 5 days on OP9 stroma cells upregulated their transcription of VSMC and pericyte selective genes. Other SMC marker genes were induced at a later time point, which suggests that vascular SMC/pericyte genes are regulated by a separate mechanism. Moreover, sequence analysis failed to identify any conserved CArG elements in the vascular SMC and pericyte gene promoters, which indicates that serum response factor is not involved in their regulation. Gleevec, a tyrosine kinase inhibitor that blocks platelet-derived growth factor (PDGF) spell-receptor signaling, and a neutralizing antibody against transforming growth factor (TGF) beta1, beta2, and beta3 failed to inhibit the induction of vascular SMC/pericyte genes. Finally, ES-derived vascular sprouts recruited cocultured MEF cells to pericyte-typical locations. The recruited cells activated expression of a VSMC- and pericyte-specific reporter gene. CONCLUSIONS: We conclude that OP9 stroma cells induce pericyte differentiation of cocultured mouse ES cells. The induction of pericyte marker genes is temporally separated from the induction of SMC genes and does not require platelet-derived growth factor B or TGFbeta1 signaling.
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| 10. |
- Lundgren, Anna, 1974, et al.
(författare)
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Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients
- 2005
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Ingår i: Infect Immun. ; 73:1, s. 523-31
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4(+) CD25(high) T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4(+) CD25(low) and CD4(+) CD25(-) cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4(+) CD25(high) T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4(+) CD25(high) cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections.
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