| 1. |
- Wang, Chuan, et al.
(författare)
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Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4
- 2013
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72:1, s. 96-103
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:The transcription factors interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are encoded by two of the strongest susceptibility genes for systemic lupus erythematosus (SLE).OBJECTIVE:To investigate the target genes and functional roles of IRF5 and STAT4 in human peripheral blood mononuclear cells (PBMCs).METHODS: Chromatin immunoprecipitation-sequencing (ChIP-seq) was performed in PBMCs stimulated to activate IRF5 and STAT4. The expression of the target genes of IRF5 and STAT4 was investigated in a publicly available dataset generated from PBMCs from patients with SLE and healthy controls. The genomic regions bound by the transcription complexes mediated by IRF5 and STAT4 were examined for transcription factor binding motifs and SLE-associated sequence variants.RESULTS: More than 7000 target genes for IRF5 and STAT4 were identified in stimulated PBMCs. These genes were enriched to functional pathways in the type I interferon system, and have key roles in the inflammatory response. The expression patterns of the target genes were characteristic for patients with SLE. The transcription factors high mobility group-I/Y, specificity protein 1, and paired box 4 may function cooperatively with IRF5 and STAT4 in transcriptional regulation. Eight of the target regions for IRF5 and STAT4 contain SLE-associated sequence variants.CONCLUSIONS:By participating in transcription complex with other co-factors, IRF5 and STAT4 harbour the potential of regulating a large number of target genes, which may contribute to their strong association with SLE.
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| 2. |
- Al-Emrani, Mohammad, 1967, et al.
(författare)
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Girders with Trapezoidally Corrugated Webs -- Under Patch Loading
- 2011
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Ingår i: EUROSTEEL 2011. - 9789291471034 ; 2, s. 620-625
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Konferensbidrag (refereegranskat)abstract
- This paper deals with the buckling and postbuckling behaviour of plate girders with corrugated web under a concentrated load on the top flange. A couple of design models and experiments from earlier studies are briefly reviewed.Further, six additional experimental tests have been performed on a girder with thin corrugated web. A FE-model of this girder is then developed and the behaviour of the girder is validated through comparisons with the girder used in the tests. The ultimate load and the postbuckling behaviour were determined by both laboratory tests and finite element simulations for three different positions of a narrow load strip across the flange, namely at: (1) an inclined fold, (2) the junction between two folds, (3) a longitudinal fold. Finally, a parametric study is performed using the FE-model where the influence of certain parameters on the ultimate load and buckling behaviour is investigated. The results from this parametric study are compared and evaluated together with two design models chosen to be the most suitable.
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| 3. |
- Alsmark, Cecilia M., et al.
(författare)
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The louse-borne human pathogen Bartonella quintana is a genomic derivative of the zoonotic agent Bartonella henselae
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:26, s. 9716-9721
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Tidskriftsartikel (refereegranskat)abstract
- We present the complete genomes of two human pathogens, Bartonella quintana (1,581,384 bp) and Bartonella henselae (1,931,047 bp). The two pathogens maintain several similarities in being transmitted by insect vectors, using mammalian reservoirs, infecting similar cell types (endothelial cells and erythrocytes) and causing vasculoproliferative changes in immunocompromised hosts. A primary difference between the two pathogens is their reservoir ecology. Whereas B. quintana is a specialist, using only the human as a reservoir, B. henselae is more promiscuous and is frequently isolated from both cats and humans. Genome comparison elucidated a high degree of overall similarity with major differences being B. henselae specific genomic islands coding for filamentous hemagglutinin, and evidence of extensive genome reduction in B. quintana, reminiscent of that found in Rickettsia prowazekii. Both genomes are reduced versions of chromosome I from the highly related pathogen Brucella melitensis. Flanked by two rRNA operons is a segment with similarity to genes located on chromosome II of B. melitensis, suggesting that it was acquired by integration of megareplicon DNA in a common ancestor of the two Bartonella species. Comparisons of the vector-host ecology of these organisms suggest that the utilization of host-restricted vectors is associated with accelerated rates of genome degradation and may explain why human pathogens transmitted by specialist vectors are outnumbered by zoonotic agents, which use vectors of broad host ranges.
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| 4. |
- Andersson, Siv G E, et al.
(författare)
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Comparative genomics of microbial pathogens and symbionts.
- 2002
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Ingår i: Bioinformatics. - 1367-4803 .- 1367-4811. ; 18 Suppl 2, s. S17-
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Tidskriftsartikel (refereegranskat)abstract
- We are interested in quantifying the contribution of gene acquisition, loss, expansion and rearrangements to the evolution of microbial genomes. Here, we discuss factors influencing microbial genome divergence based on pair-wise genome comparisons of closely related strains and species with different lifestyles. A particular focus is on intracellular pathogens and symbionts of the genera Rickettsia, Bartonella and BUCHNERA: Extensive gene loss and restricted access to phage and plasmid pools may provide an explanation for why single host pathogens are normally less successful than multihost pathogens. We note that species-specific genes tend to be shorter than orthologous genes, suggesting that a fraction of these may represent fossil-orfs, as also supported by multiple sequence alignments among species. The results of our genome comparisons are placed in the context of phylogenomic analyses of alpha and gamma proteobacteria. We highlight artefacts caused by different rates and patterns of mutations, suggesting that atypical phylogenetic placements can not a priori be taken as evidence for horizontal gene transfer events. The flexibility in genome structure among free-living microbes contrasts with the extreme stability observed for the small genomes of aphid endosymbionts, in which no rearrangements or inflow of genetic material have occurred during the past 50 millions years (1). Taken together, the results suggest that genomic stability correlate with the content of repeated sequences and mobile genetic elements, and thereby indirectly with bacterial lifestyles.
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| 5. |
- Andersson, Siv, et al.
(författare)
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On the origin of mitochondria: a genomics perspective.
- 2003
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Ingår i: Philosophical Transactions of the Royal Society B: Biological Sciences. - : The Royal Society. - 1471-2970. ; 358:1429, s. 165-177
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Tidskriftsartikel (refereegranskat)abstract
- The availability of complete genome sequence data from both bacteria and eukaryotes provides information about the contribution of bacterial genes to the origin and evolution of mitochondria. Phylogenetic analyses based on genes located in the mitochondrial genome indicate that these genes originated from within the f-proteobacteria. A number of ancestral bacterial genes have also been transferred from the mitochondrial to the nuclear genome, as evidenced by the presence of orthologous genes in the mitochondrial genome in some species and in the nuclear genome of other species. However, a multitude of mitochondrial proteins encoded in the nucleus display no homology to bacterial proteins, indicating that these originated within the eukaryotic cell subsequent to the acquisition of the endosymbiont. An analysis of the expression patterns of yeast nuclear genes coding for mitochondrial proteins has shown that genes predicted to be of eukaryotic origin are mainly translated on polysomes that are free in the cytosol whereas those of putative bacterial origin are translated on polysomes attached to the mitochondrion. The strong relationship with f-proteobacterial genes observed for some mitochondrial genes, combined with the lack of such a relationship for others, indicates that the modern mitochondrial proteome is the product of both reductive and expansive processes.
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| 6. |
- Bergholdt, Regine, et al.
(författare)
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Integrative analysis for finding genes and networks involved in diabetes and other complex diseases
- 2007
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-7596 .- 1465-6906. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- We have developed an integrative analysis method combining genetic interactions, identified using type l diabetes genome scan data, and a high-confidence human protein interaction network. Resulting networks were ranked by the significance of the enrichment of proteins from interacting regions. We identified a number of new protein network modules and novel candidate genes/ proteins for type 1 diabetes. We propose this type of integrative analysis as a general method for the elucidation of genes and networks involved in diabetes and other complex diseases.
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| 7. |
- Bill-Axelson, Anna, et al.
(författare)
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Radical prostatectomy versus watchful waiting in localized prostate cancer : the Scandinavian prostate cancer group-4 randomized trial
- 2008
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:16, s. 1144-1154
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
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| 8. |
- Boussau, Bastien, et al.
(författare)
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Computational inference of scenarios for alpha-proteobecterial genome evolution
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:26, s. 9722-9727
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Tidskriftsartikel (refereegranskat)abstract
- The alpha-proteobacteria, from which mitochondria are thought to have originated, display a 10-fold genome size variation and provide an excellent model system for studies of genome size evolution in bacteria. Here, we use computational approaches to infer ancestral gene sets and to quantify the flux of genes along the branches of the alpha-proteobacterial species tree. Our study reveals massive gene expansions at branches diversifying plant-associated bacteria and extreme losses at branches separating intracellular bacteria of animals and humans. Alterations in gene numbers have mostly affected functional categories associated with regulation, transport, and small-molecule metabolism, many of which are encoded by paralogous gene families located on auxiliary chromosomes. The results suggest that the alpha-proteobacterial ancestor contained 3,000-5,000 genes and was a free-living, aerobic, and motile bacterium with pili and surface proteins for host cell and environmental interactions. Approximately one third of the ancestral gene set has no homologs among the eukaryotes. More than 40% of the genes without eukaryotic counterparts encode proteins that are conserved among the alpha-proteobacteria but for which no function has yet been identified. These genes that never made it into the eukaryotes but are widely distributed in bacteria may represent bacterial drug targets and should be prime candidates for future functional characterization.
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| 9. |
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| 10. |
- Ericsson, Olle, et al.
(författare)
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Clinical validation of a novel automated cell-free DNA screening assay for trisomies 21, 13, and 18 in maternal plasma.
- 2019
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Ingår i: Prenatal diagnosis. - : Wiley. - 1097-0223 .- 0197-3851. ; 39:11, s. 1011-1015
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate clinical performance of a new automated cell-free (cf)DNA assay in maternal plasma screening for trisomies 21, 18, and 13, and to determine fetal sex.Maternal plasma samples from 1200 singleton pregnancies were analyzed with a new non-sequencing cfDNA method, which is based on imaging and counting specific chromosome targets. Reference outcomes were determined by either cytogenetic testing, of amniotic fluid or chorionic villi, or clinical examination of neonates.The samples examined included 158 fetal aneuploidies. Sensitivity was 100% (112/112) for trisomy 21, 89% (32/36) for trisomy 18, and 100% (10/10) for trisomy 13. The respective specificities were 100%, 99.5%, and 99.9%. There were five first pass failures (0.4%), all in unaffected pregnancies. Sex classification was performed on 979 of the samples and 99.6% (975/979) provided a concordant result.The new automated cfDNA assay has high sensitivity and specificity for trisomies 21, 18, and 13 and accurate classification of fetal sex, while maintaining a low failure rate. The study demonstrated that cfDNA testing can be simplified and automated to reduce cost and thereby enabling wider population-based screening.
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| 11. |
- Helldin, Jan Olof, et al.
(författare)
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Assessment of traffic noise impact in important bird sites in Sweden : A practical method for the regional scale
- 2013
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Ingår i: Oecologia Australis. - : Oecologia Australis. - 2177-6199. ; 17:1, s. 48-62
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Tidskriftsartikel (refereegranskat)abstract
- Previous research has pointed out the negative impact of traffic noise on wildlife adjacent to major roads, but despite the scientific evidence, the impact of traffic noise in natural environments is rarely assessed, and even more rarely mitigated, in road planning, in Sweden as well as in most other countries. It has been argued that the reason to this shortcoming is the lack of a practical method to assess this impact on natural environments. We developed a desktop method for assessing the traffic noise impact on areas of importance for nature conservation, with special emphasis on important bird sites. The method output is a calculation of the effective habitat loss due to traffic noise for each site, based on dose-effect relationships presented in literature, available GIS data on selected habitat types, official road data, and a simplified model for noise distribution. The method has a dual purpose; to estimate the impact of traffic noise on birds at larger geographic scales, and to identify priority sites for mitigation efforts. We applied the method in two Swedish regions with relatively low or moderate road and traffic densities. The results from these case studies pointed out that i) at regional level, the impact zone covers a small part of the land area (0.6 and 3.3% of lower and higher density regions, respectively), ii) for certain important bird habitat types, >10% of sites are within the impact zone, iii) the impact from traffic noise represents an effective loss of 0.02-1.7% of the total area of the selected habitat types. The latter figures can be taken as estimates of the present conservation debt of traffic noise. The results indicate that traffic noise may have a disproportionate impact on some important bird habitats. Because bird sites are often rich also in other taxa, and in addition tend to be important areas for outdoor recreation, we argue that traffic noise may have a broad impact on nature conservation, and that mitigation efforts should be made to minimize this impact. We discuss the general applicability of the method.
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| 12. |
- Jansson, Kjell, 1956-, et al.
(författare)
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The value of repeated echocardiographic evaluation in patients with idiopathic dilated cardiomyopathy during treatment with metoprolol or captopril
- 2000
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Ingår i: Scandinavian Cardiovascular Journal. - 1401-7431 .- 1651-2006. ; 34:3, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- Serial echocardiographic investigations were carried out on patients with idiopathic dilated cardiomyopathy, to evaluate treatment effects on left ventricular (LV) performance during therapy with either metoprolol or captopril. Thirty-two patients (23 males and 9 females) with mild to moderate symptoms of heart failure (NYHA II-III) and a mean age of 49 years were included in the investigation. The patients were investigated with Doppler echocardiography before treatment, after 3 and 6 months of treatment (either metoprolol or captopril) and 1 month after withdrawal of treatment. Intra- and inter-investigator reproducibility was acceptable, with a coefficient of variation of less than 5% for LV dimensions. A reduction in LV dimensions was seen in both treatment groups. In the metoprolol group there was also an increase in LV stroke volume and fractional shortening. The non-invasive data were in accordance with invasive measurements of stroke volume and LV filling pressure. In patients with idiopathic dilated cardiomyopathy and mild to moderate symptoms of heart failure, echocardiography seemed to be sufficiently reproducible to be used for determination of treatment effects in a longitudinal heart failure study. Both metoprolol and captopril were well tolerated and had favourable effects on LV performance.
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| 13. |
- Karlberg, Olof, 1975-
(författare)
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Mitochondrial Evolution : Turning Bugs into Features
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The bacterial origin of mitochondria from an ancient endosymbiosis is now widely accepted and the mitochondrial ancestor is generally believed to belong to the bacterial subdivision α-proteobacteria. The high fraction of mitochondrial proteins encoded in the nucleus has commonly been explained with a massive transfer of genes from the genome of the ancestral mitochondrion.The aim of this work was to get a better understanding of the mitochondrial origin and evolution by comparative genomics and phylogenetic analyses on mitochondria and α-proteobacteria. To this end, we sequenced the genomes of the intracellular parasites Bartonella henselae and Bartonella quintana, the causative agents of cat-scratch disease and trench fever, and compared them with other α-proteobacteria as well as mitochondrial eukaryotes. Our results suggest that the adaptation to an intracellular life-style is coupled to an increased rate of genome degradation and a reduced ability to accommodate environmental changes. Reconstruction of the α-proteobacterial ancestor and phylogenetic analyses of the mitochondrial proteome in yeast revealed that only a small fraction of the proteins used for mitochondrial functions could be traced to the α-proteobacteria. Furthermore, a substantial fraction of the mitochondrial proteins was of eukaryotic origin and while most of the genes of the α-proteobacterial ancestor have been lost, many of those that have been transferred to the nuclear genome seem to encode non-mitochondrial proteins.
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| 14. |
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| 15. |
- Kiialainen, Anna, et al.
(författare)
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Performance of Microarray and Liquid Based Capture Methods for Target Enrichment for Massively Parallel Sequencing and SNP Discovery
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2, s. e16486-
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Tidskriftsartikel (refereegranskat)abstract
- Targeted sequencing is a cost-efficient way to obtain answers to biological questions in many projects, but the choice of the enrichment method to use can be difficult. In this study we compared two hybridization methods for target enrichment for massively parallel sequencing and single nucleotide polymorphism (SNP) discovery, namely Nimblegen sequence capture arrays and the SureSelect liquid-based hybrid capture system. We prepared sequencing libraries from three HapMap samples using both methods, sequenced the libraries on the Illumina Genome Analyzer, mapped the sequencing reads back to the genome, and called variants in the sequences. 74-75% of the sequence reads originated from the targeted region in the SureSelect libraries and 41-67% in the Nimblegen libraries. We could sequence up to 99.9% and 99.5% of the regions targeted by capture probes from the SureSelect libraries and from the Nimblegen libraries, respectively. The Nimblegen probes covered 0.6 Mb more of the original 3.1 Mb target region than the SureSelect probes. In each sample, we called more SNPs and detected more novel SNPs from the libraries that were prepared using the Nimblegen method. Thus the Nimblegen method gave better results when judged by the number of SNPs called, but this came at the cost of more over-sampling.
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| 16. |
- Källström, Elisabeth, et al.
(författare)
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Identification of vibration properties of heavy duty machine driveline parts as a base for adequate condition monitoring: Torque converter
- 2016
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Ingår i: ICSV 2016 - 23rd International Congress on Sound and Vibration. - : INT INST ACOUSTICS & VIBRATION. - 9789609922623
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Konferensbidrag (refereegranskat)abstract
- Improving uptime is paramount in the heavy duty construction equipment business. Failure ofcritical components in the heavy duty machine may lead to unnecessary stops and expensive downtime. The torque converter, a complex omponent of the driveline, transmits and multiplies torque from the engine to the gearbox, and its failure may not only lead to the machine standing still but may also lead to damage of other parts of the automatic transmission. For adequate condition monitoring of the torque converter, different sensor data are measured on a construction equipment machine during controlled driving sessions. Vibration has been measured on the torque converter. An initial investigation of the vibration measured on the torque converter has been carried out to identify its vibration properties in order to enable its health monitoring to prevent failure. Initial signal analysis of the data have been carried out using Order Power Spectrum and Order Modulation Spectrum methods. The results indicate that the torque converter vibration properties contain information relevant for early fault detection.
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| 17. |
- Källström, Elisabeth, et al.
(författare)
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Identification of Vibration Properties of Wheel Loader Driveline Parts as a Base for Adequate Condition Monitoring: Bearings
- 2017
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Ingår i: 24th International Congress on Sound and Vibration 2017 (ICSV 24). - : International Institute of Acoustics and Vibration. - 9781510845855 ; , s. 312-319
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Konferensbidrag (refereegranskat)abstract
- In order to reduce costly downtime, adequate condition monitoring of the automatic transmission components in heavy duty construction equipment is necessary. The transmission in such equipment enables to change the gear ratio automatically. Further, the bearings in an automatic transmission provide low friction support to its rotating parts and act as an interface separating stationary from rotating components. Wear or other bearing faults may lead to an increase in energy consumption as well as failure of other related components in the automatic transmission, and thus costly downtime. In this study, different sensor data (particularly vibration) was collected on the automatic transmission during controlled test cycles in an automatic transmission test rig to enable adequate condition monitoring.An analysis of the measured vibration data was carried out using signal processing methods. The results indicate that predictive maintenance information related to the automatic transmission bearings may be extracted from vibrations measured on an automatic transmission. This information may be used for early fault detection, thus improving uptime and availability of heavy duty construction equipment.
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| 18. |
- Lage, Kasper, et al.
(författare)
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A human phenome-interactome network of protein complexes implicated in genetic disorders
- 2007
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 25:3, s. 309-316
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Tidskriftsartikel (refereegranskat)abstract
- We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.
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| 19. |
- Lappalainen, Tuuli, et al.
(författare)
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Transcriptome and genome sequencing uncovers functional variation in humans
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 501:7468, s. 506-511
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Tidskriftsartikel (refereegranskat)abstract
- Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.
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| 20. |
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| 21. |
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| 22. |
- Madrigal, Irene, et al.
(författare)
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A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability.
- 2016
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 24:8, s. 1117-1123
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Tidskriftsartikel (refereegranskat)abstract
- The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co-segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases.
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| 23. |
- Madrigal, Irene, et al.
(författare)
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Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes
- 2014
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 67:12, s. 1099-1103
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Tidskriftsartikel (refereegranskat)abstract
- Aims The causes of intellectual disability, which affects 1%-3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases. Methods Whole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes. Results We present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose. Conclusions The accessibility to next-generation sequencing allows clinicians to save much time and cost in identifying the aetiology of rare diseases. The presented cases are excellent examples that demonstrate the efficacy of next-generation sequencing in rare disease diagnosis.
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| 24. |
- Nordlund, Jessica, et al.
(författare)
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Digital gene expression profiling of primary acute lymphoblastic leukemia cells
- 2012
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Ingår i: Leukemia. - : Nature Publishing Group. - 0887-6924 .- 1476-5551. ; 26:6, s. 1218-1227
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Tidskriftsartikel (refereegranskat)abstract
- We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of `second-generation sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of similar to 50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (Pless than1 x 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.
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| 25. |
- Orsini, Nicola, et al.
(författare)
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Long-term physical activity and lower urinary tract symptoms in men
- 2006
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Ingår i: Journal of Urology. - Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden. Univ Hosp Orebro, Dept Urol, Orebro, Sweden. Univ Hosp Orebro, Ctr Assessment Med Technol, Orebro, Sweden. Vasteras Hosp, Dept Urol, Vasteras, Sweden. : ELSEVIER SCIENCE INC. - 0022-5347 .- 1527-3792. ; 176:6, s. 2546-2550
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We assessed the association between physical activity, and the risk of moderate and severe lower urinary tract symptoms. Materials and Methods: A cross-sectional representative sample of 30,377 men 45 to 79 years old in central Sweden who completed a self-administered life-style questionnaire, including International Prostate Symptom Score questions, physical activity currently and recalled at age 30 years (total, work/occupation, walking/bicycling, inactivity and exercise) and demographic data. A total of 6,905 men (23%) who scored 8 or more points on International Prostate Symptom Score questions were considered to have moderate or severe lower urinary tract symptoms. Results: After controlling for subject age, waist-to-hip ratio, diabetes, smoking and drinking status, and educational level total physical activity was significantly inversely related to moderate and severe lower urinary tract symptoms (highest vs lowest quartile OR 0.72, 95% CI 0.66 to 0.79, p trend < 0.001). Men who were physically active at work as well as during leisure time were at half the risk of lower urinary tract symptoms compared to inactive men (OR 0.49, 95% CI 0.40 to 0.60). Long-term high inactivity (5 hours daily at age 30 years plus currently) was associated with a 2-fold increased risk compared with the risk in men who were more active at the 2 periods (OR 1.90, 95% CI 1.41 to 2.59). Conclusions: Our results suggest that physical activity in young and late adulthood may be associated with a lower risk of moderate and severe lower urinary tract symptoms.
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| 26. |
- Rhomberg, Thomas A., et al.
(författare)
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Proteomic analysis of the sarcosine-insoluble outer membrane fraction of the bacterial pathogen Bartonella henselae
- 2004
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Ingår i: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 4:10, s. 3021-3033
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Tidskriftsartikel (refereegranskat)abstract
- Bartonella henselae is an emerging zoonotic pathogen causing a wide range of disease manifestations in humans. In this study, we report on the analysis of the sarcosine-insoluble outer membrane fraction of B. henselae ATCC 49882 Houston-1 by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (1-D SDS-PAGE) and two-dimensional nonequilibrium pH gradient polyacrylamide gel electrophoresis (2-D NEPHGE). Protein species were identified by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) and subsequent database query against the B. henselae genome sequence. Subcellular fractionation, application of the ionic detergent lauryl sarcosine, assessment of trypsin sensitivity, and heat modifiability of surface-exposed proteins represented valuable tools for the analysis of the outer membrane subproteome of B. henselae. 2-D NEPHGE was applied to display and catalogue a substantial number of proteins associated with the B. henselae sarcosine-insoluble outer membrane fraction, resulting in the establishment of a first 2-D reference map of this compartment. Thus, 53 distinct protein species associated with the outer membrane subproteome fraction were identified. This study provides novel insights into the membrane biology and the associated putative virulence factors of this pathogen of increasing medical importance.
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| 27. |
- Rodrigues De Miranda, Joachim, et al.
(författare)
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Characterization of a Novel RNA Virus Discovered in the Autumnal Moth Epirrita autumnata in Sweden
- 2017
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Ingår i: Viruses. - : MDPI AG. - 1999-4915. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- A novel, 10 kb RNA virus-tentatively named 'Abisko virus'-was discovered in the transcriptome data of a diseased autumnal moth (Epirrita autumnata) larva, as part of a search for the possible causes of the cyclical nature and mortality associated with geometrid moth dynamics and outbreaks in northern Fennoscandia. Abisko virus has a genome organization similar to that of the insect-infecting negeviruses, but phylogenetic and compositional bias analyses also reveal strong affiliations with plant-infecting viruses, such that both the primary host origin and taxonomic identity of the virus remain in doubt. In an extensive set of larval, pupal, and adult autumnal moth and winter moth (Operophtera brumata) outbreak samples, the virus was only detected in a few adult E. autumnata moths as well as the single larval transcriptome. The Abisko virus is therefore unlikely to be a factor in the Fennoscandia geometrid population dynamics.
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| 28. |
- 't Hoen, Peter A C, et al.
(författare)
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Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories
- 2013
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 31:11, s. 1015-1022
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Tidskriftsartikel (refereegranskat)abstract
- RNA sequencing is an increasingly popular technology for genome-wide analysis of transcript sequence and abundance. However, understanding of the sources of technical and interlaboratory variation is still limited. To address this, the GEUVADIS consortium sequenced mRNAs and small RNAs of lymphoblastoid cell lines of 465 individuals in seven sequencing centers, with a large number of replicates. The variation between laboratories appeared to be considerably smaller than the already limited biological variation. Laboratory effects were mainly seen in differences in insert size and GC content and could be adequately corrected for. In small-RNA sequencing, the microRNA (miRNA) content differed widely between samples owing to competitive sequencing of rRNA fragments. This did not affect relative quantification of miRNAs. We conclude that distributing RNA sequencing among different laboratories is feasible, given proper standardization and randomization procedures. We provide a set of quality measures and guidelines for assessing technical biases in RNA-seq data.
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| 29. |
- Tyden, Eva, et al.
(författare)
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Deep amplicon sequencing of preselected isolates of Parascaris equorum in beta-tubulin codons associated with benzimidazole resistance in other nematodes
- 2014
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Ingår i: Parasites & Vectors. - : Springer Science and Business Media LLC. - 1756-3305. ; 7, s. 410-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The development of anthelmintic resistance (AR) to macrocyclic lactones in the equine roundworm Parascaris equorum has resulted in benzimidazoles now being the most widely used substance to control Parascaris infections. However, over-reliance on one drug class is a risk factor for the development of AR. Consequently, benzimidazole resistance is widespread in several veterinary parasites, where it is associated with single nucleotide polymorphisms (SNPs) in drug targets encoded by the beta-tubulin genes. The importance of these SNPs varies between different parasitic nematodes, but it has been hypothesised that they occur, at low allele frequencies, even in unselected populations. This study investigated whether these SNPs exist in the P. equorum population and tested the hypothesis that BZ resistance can develop from pre-existing SNPs in codons 167, 198 and 200 of the beta-tubulin isotype 1 and 2 genes, reported to be associated with AR in strongylids. The efficacy of the oral paste formula fenbendazole on 11 farms in Sweden was also assessed. Methods: Two isotype-specific primer pairs were designed, one on either side of the codon 167 and one on either side of codons 198 and 200. A pool of 100 000 larvae was sequenced using deep amplicon sequencing by Illumina HiSeq. Faecal egg count reduction test was used to assess the efficacy of fenbendazole. Results: No SNPs were observed in codons 167, 198 or 200 of the beta-tubulin isotype 1 or 2 genes of P. equorum, even though 100 000 larvae were sequenced. Faecal egg count reduction testing of fenbendazole showed that this anthelmintic was still 100% effective, meaning that the likelihood of finding high allele frequency of SNPs associated with benzimidazoles resistance in P. equorum was low. Unexpectedly, the allele frequencies observed in single worms were comparable to those in pooled samples. Conclusions: We concluded that fenbendazole does not exert selection pressure on the beta-tubulin genes of isotypes 1 and 2 in P. equorum. The fact that no pre-existing SNPs were found in codons 167, 198 and 200 in P. equorum also illustrates the difficulties in generalising about AR mechanisms between different taxonomic groups of nematodes.
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