| 1. |
- Novakova, Lenka, et al.
(author)
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Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers
- 2018
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 13:4
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Journal article (peer-reviewed)abstract
- Background Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization. Objective This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course. Methods This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: Patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: Cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction. Results Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration. Conclusions In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.
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| 2. |
- Andersen, Oluf, 1941, et al.
(author)
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Diffusion tensor imaging in multiple sclerosis at different final outcomes
- 2018
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In: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 137:2, s. 165-173
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Journal article (peer-reviewed)abstract
- OBJECTIVES:Methods to evaluate the relative contributions of demyelination vs axonal degeneration over the long-term course of MS are urgently needed. We used magnetic resonance diffusion tensor imaging (DTI) to estimate degrees of demyelination and axonal degeneration in the corpus callosum (CC) in cases of MS with different final outcomes.MATERIALS AND METHODS:We determined DTI measures mean diffusivity (MD), fractional anisotropy (FA), and axial (AD) and radial (RD) diffusivities in the CC of 31 MS patients, of whom 13 presented a secondary progressive course, 11 a non-progressive course, and seven a monophasic course. The study participants were survivors from an incidence cohort of 254 attack-onset MS patients with 50 years of longitudinal follow-up. As reference, we included five healthy individuals without significant morbidity.RESULTS:In patients with secondary progression, compared to all other groups, the corpus callosum showed increased RD and reduced FA, but no change in AD. None of the parameters exhibited differences among non-progressive and monophasic course groups and controls.CONCLUSION:Increased RD was observed in secondary progressive MS, indicating significant myelin loss. Normal RD values observed in the clinically isolated syndrome and non-progressive groups confirm their benign nature. AD was not a characterizing parameter for long-term outcome. Demyelination revealed by increased RD is a distinguishing trait for secondary progression.
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| 3. |
- Arne, Gabriella, et al.
(author)
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Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location, and poor prognosis.
- 2011
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In: International journal of cancer. Journal international du cancer. - : Wiley. - 1097-0215 .- 0020-7136. ; 129:5, s. 1149-1161
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Journal article (peer-reviewed)abstract
- In gastrointestinal stromal tumors (GISTs), KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profiles of GISTs carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Expression profiling was performed on 9 tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analyzed by meta-analysis. Expression of CD133 (prominin-1) protein was examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in western Sweden. Survival analysis was performed on patients subjected to R0 resection (n=180) using the Cox proportional hazards model. Gene expression profiling, meta-analysis, and qPCR showed up regulation of CD133 in GISTs carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was more frequent in gastric GISTs (48%) than in small intestinal GISTs (4%). CD133 positivity was also more frequent in GISTs with KIT exon 11 mutations (41%) than in tumors with mutations in KIT exon 9, PDGFRA, or wild-type tumors (0-17%). Univariate survival analysis showed a significant correlation between the presence of CD133 protein and shorter overall survival (hazard ratio=2.23, P=0.027). Multivariate analysis showed that CD133 provided additional information on patient survival compared to age, sex, NIH risk group and mutational status. CD133 is expressed in a subset of predominantly gastric GISTs with KIT exon 11 mutations and poor prognosis.
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| 4. |
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| 5. |
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| 6. |
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| 7. |
- Eliasdottir, Olöf, et al.
(author)
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A nationwide survey of the influence of month of birth on the risk of developing multiple sclerosis in Sweden and Iceland
- 2018
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 265:1, s. 108-114
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Journal article (peer-reviewed)abstract
- Previous studies have shown that the risk of multiple sclerosis (MS) is associated with season of birth with a higher proportion of MS patients being born in spring. However, this relationship has recently been questioned and may be due to confounding factors. Our aim was to assess the influence from season or month of birth on the risk of developing MS in Sweden and Iceland. Information about month of birth, gender, and phenotype of MS for patients born 1940-1996 was retrieved from the Swedish MS registry (SMSR), and their place of birth was retrieved from the Swedish Total Population Registry (TPR). The corresponding information was retrieved from medical journals of Icelandic MS patients born 1981-1996. The control groups consisted of every person born in Sweden 1940-1996, their gender and county of birth (TPR), and in Iceland all persons born between 1981 and 1996 and their gender (Statistics Iceland). We calculated the expected number of MS patients born during each season and in every month and compared it with the observed number. Adjustments were made for gender, birth year, and county of birth. We included 12,020 Swedish and 108 Icelandic MS patients in the analyses. There was no significant difference between expected and observed MS births related to season or month of birth in Sweden or Iceland. This was even the results before adjustments were made for birth year and birth place. No significant differences were found in subgroup analyses including data of latitude of birth, gender, clinical phenotype, and MS onset of 30 years or less. Our results do not support the previously reported association between season or month of birth and MS risk. Analysis of birth place and birth year as possible confounding factors showed no major influence of them on the seasonal MS risk in Sweden and Iceland.
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| 8. |
- Ericson, Elke, 1973, et al.
(author)
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Genetic pleiotropy in Saccharomyces cerevisiae quantified by high-resolution phenotypic profiling
- 2006
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In: Molecular Genetics and Genomics. - : Springer Science and Business Media LLC. - 1617-4615 .- 1617-4623. ; 275:6, s. 605-614
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Journal article (peer-reviewed)abstract
- Genetic pleiotropy, the ability of a mutation in a single gene to give rise to multiple phenotypic outcomes, constitutes an important but incompletely understood biological phenomenon. We used a highresolution and high-precision phenotypic profiling approach to quantify the fitness contribution of genes on the five smallest yeast chromosomes during different forms of environmental stress, selected to probe a wide diversity of physiological features. We found that the extent of pleiotropy is much higher than previously claimed; 17% of the yeast genes were pleiotropic whereof one-fifth were hyper-pleiotropic. Pleiotropic genes preferentially participate in functions related to determination of protein fate, cell growth and morphogenesis, signal transduction and transcription. Contrary to what has earlier been proposed we did not find experimental evidence for slower evolutionary rate of pleiotropic genes/proteins. We also refute the existence of phenotypic islands along chromosomes but report on a remarkable loss both of pleiotropy and of phenotypic penetrance towards chromosomal ends. Thus, the here reported features of pleiotropy both have implications on our understanding of evolutionary processes as well as the mechanisms underlying disease.
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| 9. |
- Fernandez-Ricaud, Luciano, 1975, et al.
(author)
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PROPHECY - a database for high-resolution phenomics
- 2005
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 33
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Journal article (peer-reviewed)abstract
- The rapid recent evolution of the field phenomics—the genome-wide study of gene dispensability by quantitative analysis of phenotypes—has resulted in an increasing demand for new data analysis and visualization tools. Following the introduction of a novel approach for precise, genome-wide quantification of gene dispensability in Saccharomyces cerevisiae we here announce a public resource for mining, filtering and visualizing phenotypic data—the PROPHECY database. PROPHECY is designed to allow easy and flexible access to physiologically relevant quantitative data for the growth behaviour of mutant strains in the yeast deletion collection during conditions of environmental challenges. PROPHECY is publicly accessible at http://prophecy.lundberg.gu.se.
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| 10. |
- Fernandez-Ricaud, Luciano, 1975, et al.
(author)
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PROPHECY—a yeast phenome database, update 2006
- 2007
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 35
-
Journal article (peer-reviewed)abstract
- Connecting genotype to phenotype is fundamental in biomedical research and in our understanding of disease. Phenomics—the large-scale quantitative phenotypic analysis of genotypes on a genome-wide scale—connects automated data generation with the development of novel tools for phenotype data integration, mining and visualization. Our yeast phenomics database PROPHECY is available at http://prophecy.lundberg.gu.se. Via phenotyping of 984 heterozygous diploids for all essential genes the genotypes analysed and presented in PROPHECY have been extended and now include all genes in the yeast genome. Further, phenotypic data from gene overexpression of 574 membrane spanning proteins has recently been included. To facilitate the interpretation of quantitative phenotypic data we have developed a new phenotype display option, the Comparative Growth Curve Display, where growth curve differences for a large number of mutants compared with the wild type are easily revealed. In addition, PROPHECY now offers a more informative and intuitive first-sight display of its phenotypic data via its new summary page. We have also extended the arsenal of data analysis tools to include dynamic visualization of phenotypes along individual chromosomes. PROPHECY is an initiative to enhance the growing field of phenome bioinformatics
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| 11. |
- Fernandez-Ricaud, L., et al.
(author)
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Testing of Chromosomal Clumping of Gene Properties
- 2009
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In: Statistical Applications in Genetics and Molecular Biology. - 1544-6115. ; 8:1
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Journal article (peer-reviewed)abstract
- Clumping of gene properties like expression or mutant phenotypes along chromosomes is commonly detected using completely random null-models where their location is equally likely across the chromosomes. Interpretation of statistical tests based on these assumptions may be misleading if dependencies exist that are unequal between chromosomes or in different chromosomal parts. One such regional dependency is the telomeric effect, observed in several studies of Saccharomyces cerevisiae, under which e. g. essential genes are less likely to reside near the chromosomal ends. In this study we demonstrate that standard randomisation test procedures are of limited applicability in the presence of telomeric effects. Several extensions of such standard tests are here suggested for handling clumping simultaneously with regional differences in essentiality frequencies in sub-telomeric and central gene positions. Furthermore, a general non-homogeneous discrete Markov approach for combining parametrically modelled position dependent probabilities of a dichotomous property with a simple single parameter clumping is suggested. This Markov model is adapted to the observed telomeric effects and then simulations are used to demonstrate properties of the suggested modified randomisation tests. The model is also applied as a direct alternative tool for statistical analysis of the S. cerevisiae genome for clumping of phenotypes.
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| 12. |
- Gunnarsson, Lina-Maria, 1977, et al.
(author)
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Evolutionary conservation of human drug targets in organisms used for environmental risk assessments.
- 2008
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In: Environmental science & technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 42:15, s. 5807-13
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Journal article (peer-reviewed)abstract
- Pharmaceuticals are typically found in very low concentrations in the aquatic environment. Accordingly, environmental effects clearly assigned to residual drugs are consistent with high affinity interactions with conserved targets in affected wildlife species rather than with a general toxic effect. Thus, evolutionarily well-conserved targets in a given species are associated with an increased risk. In this study orthologs for 1318 human drug targets were predicted in 16 species of which several are relevant for ecotoxicity testing. The conservation of different functional categories of targets was also analyzed. Zebrafish had orthologs to 86% of the drug targets while only 61% were conserved in Daphnia and 35% in green alga. The predicted presence and absence of orthologs agrees well with published experimental data on the potential for specific drug target interaction in various species. Based on the conservation of targets we propose that aquatic environmental risk assessments for human drugs should always include comprehensive studies on aquatic vertebrates. Furthermore, individual targets, especially enzymes, are well conserved suggesting that tests on evolutionarily distant organisms would be highly relevant for certain drugs. We propose that the results can guide environmental risk assessments by improving the possibilities to identify species sensitive to certain types of pharmaceuticals or to other contaminants that act through well defined mechanisms of action. Moreover, we suggest that the results can be used to interpret the relevance of existing ecotoxicity data.
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| 13. |
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| 14. |
- Gunnarsson, Lina-Maria, 1977, et al.
(author)
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Sensitive and robust gene expression changes in fish exposed to estrogen – a microarray approach
- 2007
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8:149
-
Journal article (peer-reviewed)abstract
- Background Vitellogenin is a well established biomarker for estrogenic exposure in fish. However, effects on gonadal differentiation at concentrations of estrogen not sufficient to give rise to a measurable vitellogenin response suggest that more sensitive biomarkers would be useful. Induction of zona pellucida genes may be more sensitive but their specificities are not as clear. The objective of this study was to find additional sensitive and robust candidate biomarkers of estrogenic exposure. Results Hepatic mRNA expression profiles were characterized in juvenile rainbow trout exposed to a measured concentration of 0.87 and 10 ng ethinylestradiol/L using a salmonid cDNA microarray. The higher concentration was used to guide the subsequent identification of generally more subtle responses at the low concentration not sufficient to induce vitellogenin. A meta-analysis was performed with data from the present study and three similar microarray studies using different fish species and platforms. Within the generated list of presumably robust responses, several well-known estrogen-regulated genes were identified. Two genes, confirmed by quantitative RT-PCR (qPCR), fulfilled both the criteria of high sensitivity and robustness; the induction of the genes encoding zona pellucida protein 3 and a nucleoside diphosphate kinase (nm23). Conclusion The cross-species, cross-platform meta-analysis correctly identified several robust responses. This adds confidence to our approach used for identifying candidate biomarkers. Specifically, we propose that analyses of an nm23 gene together with zona pellucida genes may increase the possibilities to detect an exposure to low levels of estrogenic compounds in fish.
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| 15. |
- Imberg, Henrik, 1991, et al.
(author)
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Optimization of Two-Phase Sampling Designs With Application to Naturalistic Driving Studies
- 2022
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In: IEEE Transactions on Intelligent Transportation Systems. - 1524-9050 .- 1558-0016. ; 23:4, s. 3575-88
-
Journal article (peer-reviewed)abstract
- Naturalistic driving studies (NDS) generate tremendous amounts of traffic data and constitute an important component of modern traffic safety research. However, analysis of the entire NDS database is rarely feasible, as it often requires expensive and time-consuming annotations of video sequences. We describe how automatic measurements, readily available in an NDS database, may be utilized for selection of time segments for annotation that are most informative with regards to detection of potential associations between driving behavior and a consecutive safety critical event. The methodology is illustrated and evaluated on data from a large naturalistic driving study, showing that the use of optimized instance selection may reduce the number of segments that need to be annotated by as much as 50%, compared to simple random sampling. IEEE
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| 16. |
- Jauhiainen, Alexandra, 1981, et al.
(author)
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Distinct cytoplasmic and nuclear functions of the stress induced protein DDIT3/CHOP/GADD153
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:4
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Journal article (peer-reviewed)abstract
- DDIT3, also known as GADD153 or CHOP, encodes a basic leucine zipper transcription factor of the dimer forming C/EBP family. DDIT3 is known as a key regulator of cellular stress response, but its target genes and functions are not well characterized. Here, we applied a genome wide microarray based expression analysis to identify DDIT3 target genes and functions. By analyzing cells carrying tamoxifen inducible DDIT3 expression constructs we show distinct gene expression profiles for cells with cytoplasmic and nuclear localized DDIT3. Of 175 target genes identified only 3 were regulated by DDIT3 in both cellular localizations. More than two thirds of the genes were downregulated, supporting a role for DDIT3 as a dominant negative factor that could act by either cytoplasmic or nuclear sequestration of dimer forming transcription factor partners. Functional annotation of target genes showed cell migration, proliferation and apoptosis/survival as the most affected categories. Cytoplasmic DDIT3 affected more migration associated genes, while nuclear DDIT3 regulated more cell cycle controlling genes. Cell culture experiments confirmed that cytoplasmic DDIT3 inhibited migration, while nuclear DDIT3 caused a G1 cell cycle arrest. Promoters of target genes showed no common sequence motifs, reflecting that DDIT3 forms heterodimers with several alternative transcription factors that bind to different motifs. We conclude that expression of cytoplasmic DDIT3 regulated 94 genes. Nuclear translocation of DDIT3 regulated 81 additional genes linked to functions already affected by cytoplasmic DDIT3. Characterization of DDIT3 regulated functions helps understanding its role in stress response and involvement in cancer and degenerative disorders.
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| 17. |
- Jauhiainen, Alexandra, 1981, et al.
(author)
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Transcriptional and metabolic data integration and modeling for identification of active pathways
- 2012
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In: Biostatistics. - : Oxford University Press (OUP). - 1465-4644 .- 1468-4357. ; 13:4, s. 748-761
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Journal article (peer-reviewed)abstract
- With the growing availability of omics data generated to describe different cells and tissues, the modeling and interpretation of such data has become increasingly important. Pathways are sets of reactions involving genes, metabolites, and proteins highlighting functional modules in the cell. Therefore, to discover activated or perturbed pathways when comparing two conditions, for example two different tissues, it is beneficial to use several types of omics data. We present a model that integrates transcriptomic and metabolomic data in order to make an informed pathway-level decision. Since metabolites can be seen as end-points of perturbations happening at the gene level, the gene expression data constitute the explanatory variables in a sparse regression model for the metabolite data. Sophisticated model selection procedures are developed to determine an appropriate model. We demonstrate that the transcript profiles can be used to informatively explain the metabolite data from cancer cell lines. Simulation studies further show that the proposed model offers a better performance in identifying active pathways than, for example, enrichment methods performed separately on the transcript and metabolite data.
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| 18. |
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| 19. |
- Jonsson, Viktor, 1987, et al.
(author)
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Modelling of zero-inflation improves inference of metagenomic gene count data
- 2019
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In: Statistical Methods in Medical Research. - : SAGE Publications. - 0962-2802 .- 1477-0334. ; 28:12, s. 3712-3728
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Journal article (peer-reviewed)abstract
- Metagenomics enables the study of gene abundances in complex mixtures of microorganisms and has become a standard methodology for the analysis of the human microbiome. However, gene abundance data is inherently noisy and contains high levels of biological and technical variability as well as an excess of zeros due to non-detected genes. This makes the statistical analysis challenging. In this study, we present a new hierarchical Bayesian model for inference of metagenomic gene abundance data. The model uses a zero-inflated overdispersed Poisson distribution which is able to simultaneously capture the high gene-specific variability as well as zero observations in the data. By analysis of three comprehensive datasets, we show that zero-inflation is common in metagenomic data from the human gut and, if not correctly modelled, it can lead to substantial reductions in statistical power. We also show, by using resampled metagenomic data, that our model has, compared to other methods, a higher and more stable performance for detecting differentially abundant genes. We conclude that proper modelling of the gene-specific variability, including the excess of zeros, is necessary to accurately describe gene abundances in metagenomic data. The proposed model will thus pave the way for new biological insights into the structure of microbial communities.
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| 20. |
- Jonsson, Viktor, 1987, et al.
(author)
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Statistical evaluation of methods for identification of differentially abundant genes in comparative metagenomics
- 2016
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In: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 17
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Journal article (peer-reviewed)abstract
- Background: Metagenomics is the study of microbial communities by sequencing of genetic material directly from environmental or clinical samples. The genes present in the metagenomes are quantified by annotating and counting the generated DNA fragments. Identification of differentially abundant genes between metagenomes can provide important information about differences in community structure, diversity and biological function. Metagenomic data is however high-dimensional, contain high levels of biological and technical noise and have typically few biological replicates. The statistical analysis is therefore challenging and many approaches have been suggested to date. Results: In this article we perform a comprehensive evaluation of 14 methods for identification of differentially abundant genes between metagenomes. The methods are compared based on the power to detect differentially abundant genes and their ability to correctly estimate the type I error rate and the false discovery rate. We show that sample size, effect size, and gene abundance greatly affect the performance of all methods. Several of the methods also show non-optimal model assumptions and biased false discovery rate estimates, which can result in too large numbers of false positives. We also demonstrate that the performance of several of the methods differs substantially between metagenomic data sequenced by different technologies. Conclusions: Two methods, primarily designed for the analysis of RNA sequencing data (edgeR and DESeq2) together with a generalized linear model based on an overdispersed Poisson distribution were found to have best overall performance. The results presented in this study may serve as a guide for selecting suitable statistical methods for identification of differentially abundant genes in metagenomes.
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| 21. |
- Jonsson, Viktor, 1987, et al.
(author)
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Variability in Metagenomic Count Data and Its Influence on the Identification of Differentially Abundant Genes.
- 2017
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In: Journal of Computational Biology. - : Mary Ann Liebert Inc. - 1066-5277 .- 1557-8666. ; 24:4, s. 311-326
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Journal article (peer-reviewed)abstract
- Metagenomics is the study of microorganisms in environmental and clinical samples using high-throughput sequencing of random fragments of their DNA. Since metagenomics does not require any prior culturing of isolates, entire microbial communities can be studied directly in their natural state. In metagenomics, the abundance of genes is quantified by sorting and counting the DNA fragments. The resulting count data are high-dimensional and affected by high levels of technical and biological noise that make the statistical analysis challenging. In this article, we introduce an hierarchical overdispersed Poisson model to explore the variability in metagenomic data. By analyzing three comprehensive data sets, we show that the gene-specific variability varies substantially between genes and is dependent on biological function. We also assess the power of identifying differentially abundant genes and show that incorrect assumptions about the gene-specific variability can lead to unacceptable high rates of false positives. Finally, we evaluate shrinkage approaches to improve the variance estimation and show that the prior choice significantly affects the statistical power. The results presented in this study further elucidate the complex variance structure of metagenomic data and provide suggestions for accurate and reliable identification of differentially abundant genes.
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| 22. |
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| 23. |
- Karimi, Mahssa, et al.
(author)
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A sleep apnea related risk of vehicle accident is reduced by CPAP - Swedish traffic accident data acquisition (STRADA) registry
- 2014
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In: 22nd Congress of the European Sleep Research Society, 16–20 September 2014, Tallinn, Estonia. Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 23:Suppl 1, s. 67-67
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Journal article (peer-reviewed)abstract
- Objectives: Obstructive sleep apnea (OSA) is associated with excessive daytime sleepiness (EDS) and two to seven times increased risk of motor vehicle accidents (MVAs) compared with the general population. The MVA rate in patients with suspected OSA, clinical features and the effect of treatment on risk prediction was investigated. Methods: Clinical sleep laboratory patients were cross-analyzed with a matched control group from the general population. The 10-year incidence of MVA among patients (n = 1478, 70.4% males, mean age 54 (13) years) and accidents (n = 21118) in the general population was analyzed. Risk factors associated with MVA risk were determined in patients with OSA. Results: Observed accidents among patients (n = 74) were compared with the expected number (n = 29.91, risk ratio 2.47, P < 0.001) predicted from the control population. Observed MVAs were more prevalent among younger (18–44 years) patiens but estimated OSA related excess accident risk was most prominent in elderly (65–80 years, risk ratio 3.5) drivers. Risk factors within the OSA patient cohort (high traffic exposure≥15 000 km/year, Epworth Sleepiness Score ≥16, habitual sleep time ≤5 h/night and use of hypnotics) were associated with increased accident risk (odds ratio 1.2, 2.1, 2.7 and 2.1, respectively, all P ≤ 0.03. Compliance with CPAP (≥4 h/night), was associated with a reduction of MVA frequency (7.6 to 2.5 accidents/1000 drivers/year). Conclusions: The motor vehicle accident risk in this large cohort of unselected sleep apnea patients suggests a need for accurate tools to identify individuals at risk. Conventional metrics of sleep apnea severity (e.g. apnea-hypopnea-index) failed to identify patients at risk.
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| 24. |
- Kneider, Maria, et al.
(author)
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Upper Respiratory Infections and MRI Activity in Relapsing-Remitting Multiple Sclerosis
- 2015
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In: Neuroepidemiology. - : S. Karger AG. - 0251-5350 .- 1423-0208. ; 45:2, s. 83-89
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Journal article (peer-reviewed)abstract
- Background: Although clinical reports have suggested a relationship between systemic infections and multiple sclerosis (MS) relapses, MRI evidence supporting an association is conflicting. Here we evaluated the temporal relationship between upper respiratory infections (URIs) and MRI activity in relapsing-remitting (RR) MS. Methods: We combined individual data on URI with data on active lesions in pre-scheduled MRI examinations performed every 4 weeks for 28 weeks in 69 patients. A 4-week at-risk (AR) period started, by definition, 1 week before the onset of a URI. We recorded the relationship between the number of active lesions in each MRI with (1) the number of days of AR time in the immediately preceding 4-week period and (2) the number of days passed since the onset of a preceding URI. Results: Average MRI lesions/day showed no difference between AR (0.0764) and not-AR (0.0774) periods. The number of lesions in 483 pre-scheduled MRI examinations did not correlate with the AR proportion in the prior 4-week period (rho = -0.03), and time from URI onset did not correlate with lesion number on the next MRI examination (rho = 0.003). Conclusion: The occurrence of a URI did not increase the risk of MRI activity evaluated in an adjacent 4-week window in RRMS.
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| 25. |
- Kristiansson, Erik, 1978, et al.
(author)
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A novel method for cross-species gene expression analysis
- 2013
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 14
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Journal article (peer-reviewed)abstract
- Background Analysis of gene expression from different species is a powerful way to identify evolutionarily conserved transcriptional responses. However, due to evolutionary events such as gene duplication, there is no one-to-one correspondence between genes from different species which makes comparison of their expression profiles complex. Results In this paper we describe a new method for cross-species meta-analysis of gene expression. The method takes the homology structure between compared species into account and can therefore compare expression data from genes with any number of orthologs and paralogs. A simulation study shows that the proposed method results in a substantial increase in statistical power compared to previously suggested procedures. As a proof of concept, we analyzed microarray data from heat stress experiments performed in eight species and identified several well-known evolutionarily conserved transcriptional responses. The method was also applied to gene expression profiles from five studies of estrogen exposed fish and both known and potentially novel responses were identified. Conclusions The method described in this paper will further increase the potential and reliability of meta-analysis of gene expression profiles from evolutionarily distant species. The method has been implemented in R and is freely available at http://bioinformatics.math.chalmers.se/Xspecies/ webcite.
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| 26. |
- Kristiansson, Erik, 1978, et al.
(author)
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Evolutionary Forces Act on Promoter Length: Identification of Enriched Cis-Regulatory Elements
- 2009
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In: Molecular Biology and Evolution. ; 26:6, s. 1299-1307
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Journal article (peer-reviewed)abstract
- Transcription factors govern gene expression by binding to short DNA sequences called cis-regulatory elements. These sequences are typically located in promoters, which are regions of variable length upstream of the open reading frames of genes. Here, we report that promoter length and gene function are related in yeast, fungi, and plants. In particular, the promoters for stress-responsive genes are in general longer than those of other genes. Essential genes have, on the other hand, relatively short promoters. We utilize these findings in a novel method for identifying relevant cis-regulatory elements in a set of coexpressed genes. The method is shown to generate more accurate results and fewer false positives compared with other common procedures. Our results suggest that genes with complex transcriptional regulation tend to have longer promoters than genes responding to few signals. This phenomenon is present in all investigated species, indicating that evolution adjust promoter length according to gene function. Identification of cis-regulatory elements in Saccharomyces cerevisiae can be done with the web service located at http://enricher.zool.gu.se.
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| 27. |
- Kristiansson, Erik, 1978, et al.
(author)
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Quality Optimised Analysis of General Paired Microarray Experiments
- 2006
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In: Statistical Applications in Genetics and Molecular Biology. - : Walter de Gruyter GmbH. - 1544-6115. ; 5:1
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Journal article (peer-reviewed)abstract
- In microarray experiments, several steps may cause sub-optimal quality and the need for quality control is strong. Often the experiments are complex, with several conditions studied simultaneously. A linear model for paired microarray experiments is proposed as a generalisation of the paired two-sample method by Kristiansson et al. (2005). Quality variation is modelled by different variance scales for different (pairs of) arrays, and shared sources of variation are modelled by covariances between arrays. The gene-wise variance estimates are moderated in an empirical Bayes approach. Due to correlations all data is typically used in the inference of any linear combination of parameters. Both real and simulated data are analysed. Unequal variances and strong correlations are found in real data, leading to further examination of the fit of the model and of the nature of the datasets in general. The empirical distributions of the test-statistics are found to have a considerably improved match to the null distribution compared to previous methods, which implies more correct p-values provided that most genes are non-differentially expressed. In fact, assuming independent observations with identical variances typically leads to optimistic p-values. The method is shown to perform better than the alternatives in the simulation study.
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Lind, Marcus, 1976, et al.
(author)
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Changes in HbA(1c) and frequency of measuring HbA(1c) and adjusting glucose-lowering medications in the 10 years following diagnosis of type 2 diabetes: a population-based study in the UK
- 2014
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In: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 57:8, s. 1586-1594
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Journal article (peer-reviewed)abstract
- Aim/hypothesis The aim of this work was to study levels of HbA(1c) and patterns of adjusting glucose-lowering drugs in patients with impaired glycaemic control over 10 years after diagnosis of type 2 diabetes. Methods We studied 4,529 individuals in The Health Improvement Network Database newly diagnosed with type 2 diabetes in the year 2000. Results From 6 months to 10 years after diagnosis, the HbA(1c) increased from 7.04% (53.4 mmol/mol) to 7.49% (58.3 mmol/mol) (average annual change: 0.047% [0.51 mmol/mol]). The greatest annual change occurred between 6 months and 2 years (0.21% [2.30 mmol/mol] increase per year, p < 0.001), followed by the 2-5 year time period (0.033% [0.36 mmol/mol] increase per year, p < 0.001). No significant increase in HbA(1c) occurred between 5 and 10 years (p = 0.20). In multivariable analyses, patients who were younger (p < 0.001), with higher BMI (p = 0.033) and who were current insulin users (p = 0.024) at diagnosis had greater increases in HbA(1c) between 6 months and 2 years. For individuals with HbA(1c) above 7.0% (53 mmol/mol) the mean time to next measurement of HbA(1c) was 0.53 years and increase in doses or changes to other glucose-lowering medications were performed in 26% of cases. Conclusions/interpretation HbA(1c) increases by approximately 0.5% (5 mmol/mol) over 10 years after diagnosis of type 2 diabetes, with the main increase appearing in the first years after diagnosis. More frequent monitoring of HbA(1c) and adjustments of glucose-lowering drugs may be essential to prevent the decline.
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| 32. |
- Lind, Marcus, 1976, et al.
(author)
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Historical hba1c values may explain the type 2 diabetes legacy effect: Ukpds 88
- 2021
-
In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:10, s. 2231-2237
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Type 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glycemic legacy effects have not been explained. We examined their relationships with prior individual HbA1c values and explored the potential impact of instituting earlier, compared with delayed, glucose-lowering therapy. RESEARCH DESIGN AND METHODS: Twenty-year ACM and MI hazard functions were estimated from diagnosis of type 2 diabetes in 3,802 UK Prospective Diabetes Study participants. Impact of HbA1c values over time was analyzed by weighting them according to their influence on downstream ACM and MI risks. RESULTS: Hazard ratios for a one percentage unit higher HbA1c for ACM were 1.08 (95% CI 1.07–1.09), 1.18 (1.15–1.21), and 1.36 (1.30–1.42) at 5, 10, and 20 years, respectively, and for MI was 1.13 (1.11–1.15) at 5 years, increasing to 1.31 (1.25–1.36) at 20 years. Imposing a one percentage unit lower HbA1c from diagnosis generated an 18.8% (95% CI 21.1–16.0) ACM risk reduction 10–15 years later, whereas delaying this reduction until 10 years after diagnosis showed a sevenfold lower 2.7% (3.1–2.3) risk reduction. Corresponding MI risk reductions were 19.7% (22.4–16.5) when lowering HbA1c at diagnosis, and threefold lower 6.5% (7.4–5.3%) when imposed 10 years later. CONCLUSIONS: The glycemic legacy effects seen in type 2 diabetes are explained largely by historical HbA1c values having a greater impact than recent values on clinical outcomes. Early detection of diabetes and intensive glucose control from the time of diagnosis is essential to maximize reduction of the long-term risk of glycemic complications.
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| 33. |
- Lind, Marcus, 1976, et al.
(author)
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The Association between HbA1c, Fasting Glucose, 1-Hour Glucose and 2-Hour Glucose during an Oral Glucose Tolerance Test and Cardiovascular Disease in Individuals with Elevated Risk for Diabetes
- 2014
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10
-
Journal article (peer-reviewed)abstract
- Objective: To determine the association between HbA1c, fasting plasma glucose (FPG), 1-hour (1 hPG) and 2-hour (2 hPG) glucose after an oral glucose tolerance test (OGTT) and cardiovascular disease in individuals with elevated risk for diabetes. Design: We studied the relationship between baseline, updated mean and updated (last) value of HbA1c, FPG, 1 hPG and 2 hPG after an oral 75 g glucose tolerance test (OGTT) and acute CVD events in 504 individuals with impaired glucose tolerance (IGT) at baseline enrolled in the Finnish Diabetes Prevention Study. Participants: 504 individuals with IGT were followed with yearly evaluations with OGTT, FPG and HbA1c. Results: Over a median follow-up of 9.0 years 34 (6.7%) participants had a CVD event, which increased to 52 (10.3%) over a median follow-up of 13.0 years when including events that occurred among participants following a diagnosis of diabetes. Updated mean HbA1c, 1 hPG and 2 hPG, HR per 1 unit SD of 1.57 (95% CI 1.16 to 2.11), p = 0.0032, 1.51 (1.03 to 2.23), p = 0.036 and 1.60 (1.10 to 2.34), p = 0.014, respectively, but not FPG (p = 0.11), were related to CVD. In analyses of the last value prior to the CVD event the same three glycaemic measurements were associated with the CVD events, with HRs per 1 unit SD of 1.45 (1.06 to 1.98), p = 0.020, 1.55 (1.04 to 2.29), p = 0.030 and 2.19 (1.51 to 3.18), p < 0.0001, respectively but only 2 hPG remained significant in pairwise comparisons. Including the follow-up period after diabetes onset updated 2 hPG (p = 0.003) but not updated mean HbA1c (p = 0.08) was related to CVD. Conclusions and Relevance: Current 2 hPG level in people with IGT is associated with increased risk of CVD. This supports its use in screening for prediabetes and monitoring glycaemic levels of people with prediabetes.
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| 34. |
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| 35. |
- Molin, Claes, 1977, et al.
(author)
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mRNA stability changes precede changes in steady-state mRNA amounts during hyperosmotic stress
- 2009
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In: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 15:4, s. 600-614
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Journal article (peer-reviewed)abstract
- Under stress, cells need to optimize the activity of a wide range of gene products during the response phases: shock, adaptation, and recovery. This requires coordination of several levels of regulation, including turnover and translation efficiencies ofmRNAs. Mitogen-activated protein (MAP) kinase pathways are implicated in many aspects of the environmental stress response,including initiation of transcription, translation efficiency, and mRNA turnover. In this study, we analyze mRNA turnover ratesand mRNA steady-state levels at different time points following mild hyperosmotic shock in Saccharomyces cerevisiae cells. Theregulation of mRNA stability is transient and affects most genes for which there is a change in transcript level. These changesprecede and prepare for the changes in steady-state levels, both regarding the initial increase and the later decline of stressinducedmRNAs. The inverse is true for stress-repressed genes, which become stabilized during hyperosmotic stress inpreparation of an increase as the cells recover. The MAP kinase Hog1 affects both steady-state levels and stability of stressresponsivetranscripts, whereas Rck2 influences steady-state levels without a major effect on stability. Regulation of mRNAstability is a wide-spread, but not universal, effect on stress-responsive transcripts during transient hyperosmotic stress. Bydestabilizing stress-induced mRNAs when their steady-state levels have reached a maximum, the cell prepares for thesubsequent recovery phase when these transcripts are to return to normal levels. Conversely, stabilization of stress-repressedmRNAs permits their rapid accumulation in the recovery phase. Our results show that mRNA turnover is coordinated withtranscriptional induction.
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| 36. |
- Nelander, Sven, 1974, et al.
(author)
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Predictive screening for regulators of conserved functional gene modules (gene batteries) in mammals
- 2005
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In: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 6:1
-
Journal article (peer-reviewed)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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| 37. |
- Nerman, Olle, 1951
(author)
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BRANCHING PROCESSES AND NEUTRAL MUTATIONS
- 2020
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In: Proceedings of the 1st World Congress of the Bernoulli Society. - : De Gruyter. ; , s. 683-692
-
Book chapter (other academic/artistic)
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| 38. |
- Nerman, Olle, 1951
(author)
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Discussion of “human life is unlimited-but short” by H Rootzén and D Zholud
- 2018
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In: Extremes. - : Springer Science and Business Media LLC. - 1386-1999 .- 1572-915X. ; 21:3, s. 411-413
-
Journal article (peer-reviewed)abstract
- The statistical paper human life is short-but unlimited is briefly discussed. The possibilities and limitations of statistical inference concerning very long human life spans are considered. The restricted models of tail distributions that arise from assumption of renormalized convergence of max- or conditional peaks over thresholds-distributions are questioned in the application context of the reviewed paper. The restrictions of natural systems designs on possibilities of extreme life spans, and the potential to adopt modified extreme value models, allowing seasonal variation of death rates, are also pointed out.
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| 39. |
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| 40. |
- Nilsson, Sven, et al.
(author)
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Rat–Mouse and Rat–Human Comparative Maps Based on Gene Homology and High-Resolution Zoo-FISH
- 2001
-
In: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 74:3, s. 287-98
-
Journal article (peer-reviewed)abstract
- The laboratory rat, Rattus norvegicus, and the laboratory mouse, Mus musculus, are key animal models in biomedical research. A deeper understanding of the genetic interrelationsships between Homo sapiens and these two rodent species is desirable for extending the usefulness of the animal models. We present comprehensive rat–human and rat–mouse comparative maps, based on 1090 gene homology assignments available for rat genes. Radiation hybrid, FISH, and zoo-FISH mapping data have been integrated to produce comparative maps that are estimated to comprise 83–100% of the conserved regions between rat and mouse and 66–82% of the conserved regions between rat and human. The rat–mouse zoo-FISH analysis, supported by data for individual genes, revealed nine previously undetected conserved regions compared to earlier reports. Since there is almost complete genome coverage in the rat–mouse comparative map, we conclude that it is feasible to make accurate predictions of gene positions in the rat based on gene locations in the mouse.
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| 41. |
- Sjögren, Anders, 1979, et al.
(author)
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Weighted Analysis of General Microarray Experiments
- 2007
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 8
-
Journal article (peer-reviewed)abstract
- Background In DNA microarray experiments, measurements from different biological samples are often assumed to be independent and to have identical variance. For many datasets these assumptions have been shown to be invalid and typically lead to too optimistic p-values. A method called WAME has been proposed where a variance is estimated for each sample and a covariance is estimated for each pair of samples. The current version of WAME is, however, limited to experiments with paired design, e.g. two-channel microarrays. Results The WAME procedure is extended to general microarray experiments, making it capable of handling both one- and two-channel datasets. Two public one-channel datasets are analysed and WAME detects both unequal variances and correlations. WAME is compared to other common methods: fold-change ranking, ordinary linear model with t-tests, LIMMA and weighted LIMMA. The p-value distributions are shown to differ greatly between the examined methods. In a resampling-based simulation study, the p-values generated by WAME are found to be substantially more correct than the alternatives when a relatively small proportion of the genes is regulated. WAME is also shown to have higher power than the other methods. WAME is available as an R-package. Conclusion The WAME procedure is generalized and the limitation to paired-design microarray datasets is removed. The examined other methods produce invalid p-values in many cases, while WAME is shown to produce essentially valid p-values when a relatively small proportion of genes is regulated. WAME is also shown to have higher power than the examined alternative methods.
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| 42. |
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| 43. |
- Skoog, Bengt, et al.
(author)
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Short-term prediction of secondary progression in a sliding window: A test of a predicting algorithm in a validation cohort
- 2019
-
In: Multiple Sclerosis Journal - Experimental, Translational and Clinical. - : SAGE Publications. - 2055-2173. ; 5:3
-
Journal article (peer-reviewed)abstract
- Introduction: The Multiple Sclerosis Prediction Score (MSPS, www.msprediction.com) estimates, for any month during the course of relapsing–remitting multiple sclerosis (MS), the individual risk of transition to secondary progression (SP) during the following year. Objective: Internal verification of the MSPS algorithm in a derivation cohort, the Gothenburg Incidence Cohort (GIC, n = 144) and external verification in the Uppsala MS cohort (UMS, n = 145). Methods: Starting from their second relapse, patients were included and followed for 25 years. A matrix of MSPS values was created. From this matrix, a goodness-of-fit test and suitable diagnostic plots were derived to compare MSPS-calculated and observed outcomes (i.e. transition to SP). Results: The median time to SP was slightly longer in the UMS than in the GIC, 15 vs. 11.5 years (p = 0.19). The MSPS was calibrated with multiplicative factors: 0.599 for the UMS and 0.829 for the GIC; the calibrated MSPS provided a good fit between expected and observed outcomes (chi-square p = 0.61 for the UMS), which indicated the model was not rejected. Conclusion: The results suggest that the MSPS has clinically relevant generalizability in new cohorts, provided that the MSPS was calibrated to the actual overall SP incidence in the cohort.
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| 44. |
- Tedeholm, Helen, 1978, et al.
(author)
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The outcome spectrum of multiple sclerosis: disability, mortality, and a cluster of predictors from onset
- 2015
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 262:5, s. 1148-1163
-
Journal article (peer-reviewed)abstract
- Interest in the long-term natural history of multiple sclerosis (MS) is being revived, as disability endpoints become increasingly important with the advent of highly efficacious long range but potentially harmful drugs. MS had an increasingly benign course, probably due to better assessment and changing diagnostic criteria. Incidence cohorts reduce inclusion bias, capturing both extreme benign and severe cases. We conducted a 50-year follow-up of an incidence cohort of Gothenburg residents with MS onset in 1950-1964 (n = 254; 212 with an initial relapsing-remitting course and 42 with a monophasic course, diagnostic criteria according to Poser). Patients were followed longitudinally until censoring, death, or study termination in 2012 and evaluated using Kaplan-Meier estimates and Cox regression analysis. Median time to secondary progression was 15 years. Median time to EDSS6 and EDSS7 was 26 and 48 years (n = 254), respectively. The cumulative risk of reaching EDSS6 was 50 % at 55 years of age and 80 % at 80 years of age (n = 212). A score based on a cluster of clinical features at onset predicted secondary progression, EDSS6, EDSS7, and EDSS10 (hazard ratio 1.6-2.3 per score unit for women, 0.99-1.49 for men). This score predicted the disease course during five decades indirectly, by predicting time to secondary progression. Age at onset predicted the course in men, with 3-6 % yearly increase in the risk of reaching disability milestones. The present incidence cohort provided hard outcome data in untreated patients over several decades.
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| 45. |
- Tedeholm, Helen, 1978, et al.
(author)
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Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs
- 2013
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In: Multiple Sclerosis Journal. - : SAGE Publications (UK and US). - 1352-4585 .- 1477-0970. ; 19:6, s. 765-774
-
Journal article (peer-reviewed)abstract
- Background: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). less thanbrgreater than less thanbrgreater thanObjective: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. less thanbrgreater than less thanbrgreater thanMethods: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. less thanbrgreater than less thanbrgreater thanResults: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). less thanbrgreater than less thanbrgreater thanConclusion: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.
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| 46. |
- Thorsen, Michael, 1974, et al.
(author)
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Genetic basis of arsenite and cadmium tolerance in Saccharomyces cerevisiae.
- 2009
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In: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 10
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Arsenic and cadmium are widely distributed in nature and pose serious threats to the environment and human health. Exposure to these nonessential toxic metals may result in a variety of human diseases including cancer. However, arsenic and cadmium toxicity targets and the cellular systems contributing to tolerance acquisition are not fully known. RESULTS: To gain insight into metal action and cellular tolerance mechanisms, we carried out genome-wide screening of the Saccharomyces cerevisiae haploid and homozygous diploid deletion mutant collections and scored for reduced growth in the presence of arsenite or cadmium. Processes found to be required for tolerance to both metals included sulphur and glutathione biosynthesis, environmental sensing, mRNA synthesis and transcription, and vacuolar/endosomal transport and sorting. We also identified metal-specific defence processes. Arsenite-specific defence functions were related to cell cycle regulation, lipid and fatty acid metabolism, mitochondrial biogenesis, and the cytoskeleton whereas cadmium-specific defence functions were mainly related to sugar/carbohydrate metabolism, and metal-ion homeostasis and transport. Molecular evidence indicated that the cytoskeleton is targeted by arsenite and that phosphorylation of the Snf1p kinase is required for cadmium tolerance. CONCLUSION: This study has pin-pointed core functions that protect cells from arsenite and cadmium toxicity. It also emphasizes the existence of both common and specific defence systems. Since many of the yeast genes that confer tolerance to these agents have homologues in humans, similar biological processes may act in yeast and humans to prevent metal toxicity and carcinogenesis.
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| 47. |
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| 48. |
- Thorsen, Michael, 1974, et al.
(author)
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Quantitative transcriptome, proteome and sulfur metabolite profiling of the Saccharomyces cerevisiae response to arsenite
- 2007
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In: Physiological Genomics. ; 30, s. 35-43
-
Journal article (peer-reviewed)abstract
- Arsenic is ubiquitously present in nature, and various mechanisms have evolved enabling cells to evade toxicity and acquire tolerance. Herein, we explored how Saccharomyces cerevisiae (budding yeast) respond to trivalent arsenic (arsenite) by quantitative transcriptome, proteome, and sulfur metabolite profiling. Arsenite exposure affected transcription of genes encoding functions related to protein biosynthesis, arsenic detoxification, oxidative stress defense, redox maintenance, and proteolytic activity. Importantly, we observed that nearly all components of the sulfate assimilation and glutathione biosynthesis pathways were induced at both gene and protein levels. Kinetic metabolic profiling evidenced a significant increase in the pools of sulfur metabolites as well as elevated cellular glutathione levels. Moreover, the flux in the sulfur assimilation pathway as well as the glutathione synthesis rate strongly increased with a concomitant reduction of sulfur incorporation into proteins. By combining comparative genomics and molecular analyses, we pinpointed transcription factors that mediate the core of the transcriptional response to arsenite. Taken together, our data reveal that arsenite-exposed cells channel a large part of assimilated sulfur into glutathione biosynthesis, and we provide evidence that the transcriptional regulators Yap1p and Met4p control this response in concert.
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| 49. |
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