| 1. |
- van Es, Michael A, et al.
(författare)
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Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis
- 2009
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:10, s. 1083-1087
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
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| 2. |
- van Es, Michael A, et al.
(författare)
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Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
- 2008
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:1, s. 29-31
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Tidskriftsartikel (refereegranskat)abstract
- We identified a SNP in the DPP6 gene that is consistently strongly associated with susceptibility to amyotrophic lateral sclerosis (ALS) in different populations of European ancestry, with an overall P value of 5.04 x 10(-8) in 1,767 cases and 1,916 healthy controls and with an odds ratio of 1.30 (95% confidence interval (CI) of 1.18-1.43). Our finding is the first report of a genome-wide significant association with sporadic ALS and may be a target for future functional studies.
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| 3. |
- Van Es, Michael A, et al.
(författare)
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Analysis of FGGY as a risk factor for sporadic amyotrophic lateral sclerosis
- 2009
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Ingår i: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders. - : Informa UK Limited. - 1466-0822 .- 1743-4483. ; 10:5-6, s. 441-447
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Tidskriftsartikel (refereegranskat)abstract
- A genome-wide association study (GWAS) using pooled DNA samples from 386 sporadic ALS patients and 542 controls from the USA, identified genetic variation in FGGY (FLJ10986) as a risk factor, as well as 66 additional candidate SNPs. Considering the large number of hypotheses that are tested in GWAS, independent replication of associations is crucial for identifying true-positive genetic risk factors for disease. The primary aim of this study was to study the association between FGGY and sporadic ALS in large, homogeneous populations from northern Europe. Genotyping experiments were performed using Illumina Beadchips, Sequenom iPLEX assays and Taqman technology on large case-control series from The Netherlands, Belgium, Sweden and Ireland (total: 1883 sporadic ALS patients and 2063 controls). No significant association between sporadic ALS and the six previously reported associated SNPs in FGGY was observed: rs6700125 (p =0.56), rs6690993 (p =0.30), rs10493256 (p =0.68), rs6587852 (p =0.64), rs1470407 (p =0.28) and rs333662 (p =0.44). Screening of the additional candidate loci did not yield significant associations either, with the lowest p-value in joint analysis for rs7772593 (p =0.14). We concluded that common genetic variation in FGGY is not associated with susceptibility to sporadic ALS in genetically homogeneous populations from northern Europe.
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| 6. |
- Slater, Graham J., et al.
(författare)
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Evolutionary History of the Falklands Wolf
- 2009
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Ingår i: Current Biology. - : Elsevier BV. - 0960-9822 .- 1879-0445. ; 19:20, s. R937-R938
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Berger, E., et al.
(författare)
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An Intermediate Luminosity Transient in NGC 300 : The Eruption of a Dust-Enshrouded Massive Star
- 2009
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 699, s. 1850-1865
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Tidskriftsartikel (refereegranskat)abstract
- We present multi-epoch high-resolution optical spectroscopy, UV/radio/X-ray imaging, and archival Hubble and Spitzer observations of an intermediate luminosity optical transient recently discovered in the nearby galaxy NGC 300. We find that the transient (NGC 300 OT2008-1) has a peak absolute magnitude of M bol ≈ -11.8 mag, intermediate between novae and supernovae, and similar to the recent events M85 OT2006-1 and SN 2008S. Our high-resolution spectra, the first for this event, are dominated by intermediate velocity (~200-1000 km s-1) hydrogen Balmer lines and Ca II emission and absorption lines that point to a complex circumstellar environment, reminiscent of the yellow hypergiant IRC+10420. In particular, we detect asymmetric Ca II H&K absorption with a broad red wing extending to ~103 km s-1, indicative of gas inflow at high velocity (possibly the wind of a massive binary companion). The low luminosity, intermediate velocities, and overall similarity to a known eruptive star indicate that the event did not result in a complete disruption of the progenitor. We identify the progenitor in archival Spitzer observations, with deep upper limits from Hubble data. The spectral energy distribution points to a dust-enshrouded star with a luminosity of about 6 × 104 L sun, indicative of a ~10-20 M sun progenitor (or binary system). This conclusion is in good agreement with our interpretation of the outburst and circumstellar properties. The lack of significant extinction in the transient spectrum indicates that the dust surrounding the progenitor was cleared by the outburst. We thus predict that the progenitor should be eventually visible with Hubble if the transient event marks an evolutionary transition to a dust-free state, or with Spitzer if the event marks a cyclical process of dust formation.
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| 8. |
- Beurskens, M. N. A., et al.
(författare)
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Pedestal width and ELM size identity studies in JET and DIII-D; implications for ITER
- 2009
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Ingår i: Plasma Physics and Controlled Fusion. - : IOP Publishing. - 0741-3335 .- 1361-6587. ; 51:12, s. 124051-
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Tidskriftsartikel (refereegranskat)abstract
- The dependence of the H-mode edge transport barrier width on normalized ion gyroradius (rho* = rho/a) in discharges with type I ELMs was examined in experiments combining data for the JET and DIII-D tokamaks. The plasma configuration as well as the local normalized pressure (beta), collisionality (nu*), Mach number and the ratio of ion and electron temperature at the pedestal top were kept constant, while rho* was varied by a factor of four. The width of the steep gradient region of the electron temperature (T-e) and density (n(e)) pedestals normalized to machine size showed no or only a weak trend with rho*. A rho(1/2) or rho(1) dependence of the pedestal width, given by some theoretical predictions, is not supported by the current experiments. This is encouraging for the pedestal scaling towards ITER as it operates at lower rho* than existing devices. Some differences in pedestal structure and ELM behaviour were, however, found between the devices; in the DIII-D discharges, the n(e) and T-e pedestal were aligned at high rho* but the ne pedestal shifted outwards in radius relative to T-e as rho* decreases, while on JET the profiles remained aligned while rho* was scanned by a factor of two. The energy loss at an ELM normalized to the pedestal energy increased from 10% to 40% as rho* increased by a factor of two in the DIII-D discharges but no such variation was observed in the case of JET. The measured pedestal pressures and widths were found to be consistent with the predictions from modelling based on peeling-ballooning stability theory, and are used to make projections towards ITER
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| 9. |
- Fransson, Claes, et al.
(författare)
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Hubble Space Telescope and Ground-based Observations of SN 1993J and SN 1998S : CNO Processing in the Progenitors
- 2005
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 622, s. 991-1007
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Tidskriftsartikel (refereegranskat)abstract
- Ground-based and Hubble Space Telescope observations are presented for SN 1993J and SN 1998S. SN 1998S shows strong, relatively narrow circumstellar emission lines of N III-V and C III-IV, as well as broad lines from the ejecta. Both the broad ultraviolet and optical lines in SN 1998S indicate an expansion velocity of ~7000 km s-1. The broad emission components of Lyα and Mg II are strongly asymmetrical after day 72 past the explosion and differ in shape from Hα. Different models based on dust extinction from dust in the ejecta or shock region, in combination with Hα from a circumstellar torus, are discussed. It is concluded, however, that the double-peaked line profiles are more likely to arise as a result of optical depth effects in the narrow, cool, dense shell behind the reverse shock than in a torus-like region. The ultraviolet lines of SN 1993J are broad, with a boxlike shape, coming from the ejecta and a cool, dense shell. The shapes of the lines are well fitted by a shell with inner velocity ~7000 km s-1 and outer velocity ~10,000 km s-1. For both SN 1993J and SN 1998S a strong nitrogen enrichment is found, with N/C~12.4 in SN 1993J and N/C~6.0 in SN 1998S. From a compilation of all supernovae with determined CNO ratios, we discuss the implications of these observations for the structure of the progenitors of Type II supernovae. Based in part on observations obtained with the Hubble Space Telescope, which is operated by AURA, Inc., under NASA contract NAS 5-26555.
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| 16. |
- Rockabrand, David M, et al.
(författare)
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Enterotoxigenic Escherichia coli colonization factor types collected from 1997 to 2001 in US military personnel during operation Bright Star in northern Egypt.
- 2006
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Ingår i: Diagnostic microbiology and infectious disease. - : Elsevier BV. - 0732-8893. ; 55:1, s. 9-12
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Tidskriftsartikel (refereegranskat)abstract
- Operation Bright Star (OBS) is a biennial, multinational exercise in Egypt involving 15000 US troops. Consistent with past observations in deployed troops, diarrhea is the most significant cause of morbidity. Focused efforts are ongoing to develop vaccines against the most common pathogens affecting our troops. As part of these efforts, diarrhea surveillance was conducted during OBS to monitor pathogens associated with illness and to identify new vaccine targets. A retrospective review was conducted of prior studies with similar methods. Soldiers with diarrhea presenting to the OBS clinic provided a stool sample that was inoculated into Carey-Blair transport media. Within 3 days, the Cary-Blair tubes were transported to the Naval Medical Research Unit no. 3 in Cairo where bacterial culture was performed. As part of the evaluation, 5 Escherichia coli-like colonies were collected and tested for toxin production using the GM1-ELISA. Toxin-positive isolates were further tested for colonization factors (CF) by a dot-blot assay using a standardized panel of monoclonal antibodies against CFA/I, CS1-CS7, CS17, CS8 (CFA/III), CS12 (PCFO159), and CS14 (PCFO166). Enterotoxigenic E. coli (ETEC) was the most frequently isolated pathogen during each OBS from which data were collected. The rate of ETEC-associated diarrhea ranged from 22% to 58%. Over time, there were dramatic shifts in the frequency and distribution of CFs. Over the 5 years of study, an increasing number of ETEC isolates had no known CF identified, and in 2001, only 40% of ETEC was associated with known CFs. The most commonly identified CF was CS6. Diarrheal disease, particularly ETEC, continues to be a common malady among US military personnel deployed to Egypt. We have identified ETEC CF types, especially CS6, which should be considered potential vaccine candidates. However, despite intensive testing, CFs could not be identified in most of the ETEC isolated, highlighting the need for further studies to identify novel CFs and alternative vaccine targets.
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| 17. |
- van Es, Michael A, et al.
(författare)
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ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis : a genome-wide association study.
- 2007
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 6:10, s. 869-77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease characterised by progressive degeneration of motor neurons in the brain and spinal cord. ALS is thought to be multifactorial, with both environmental and genetic causes. Our aim was to identify genetic variants that predispose for sporadic ALS. METHODS: We did a three-stage genome-wide association study in 461 patients with ALS and 450 controls from The Netherlands, using Illumina 300K single-nucleotide polymorphism (SNP) chips. The SNPs that were most strongly associated with ALS were analysed in a further 876 patients and 906 controls in independent sample series from The Netherlands, Belgium, and Sweden. We also investigated the possible pathological functions of associated genes using expression data from whole blood of patients with sporadic ALS and of control individuals who were included in the genome-wide association study. FINDINGS: A genetic variant in the inositol 1,4,5-triphosphate receptor 2 gene (ITPR2) was associated with ALS (p=0.012 after Bonferroni correction). Combined analysis of all samples (1337 patients and 1356 controls) confirmed this association (p=3.28x10(-6), odds ratio 1.58, 95% CI 1.30-1.91). ITPR2 expression was greater in the peripheral blood of 126 ALS patients than in that of 126 healthy controls (p=0.00016). INTERPRETATION: Genetic variation in ITPR2 is a susceptibility factor for ALS. ITPR2 is a strong candidate susceptibility gene for ALS because it is involved in glutamate-mediated neurotransmission, is one of the main regulators of intracellular calcium concentrations, and has an important role in apoptosis.
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| 20. |
- Csenki, Leonard, et al.
(författare)
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Proof of principle of a generalized fuzzy Hough transform approach to peak alignment of one-dimensional 1H NMR data
- 2007
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Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 389:3, s. 875-885
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Tidskriftsartikel (refereegranskat)abstract
- In metabolic profiling, multivariate data analysis techniques are used to interpret one-dimensional (1D) 1H NMR data. Multivariate data analysis techniques require that peaks are characterised by the same variables in every spectrum. This location constraint is essential for correct comparison of the intensities of several NMR spectra. However, variations in physicochemical factors can cause the locations of the peaks to shift. The location prerequisite may thus not be met, and so, to solve this problem, alignment methods have been developed. However, current state-of-the-art algorithms for data alignment cannot resolve the inherent problems encountered when analysing NMR data of biological origin, because they are unable to align peaks when the spatial order of the peaks changes—a commonly occurring phenomenon. In this paper a new algorithm is proposed, based on the Hough transform operating on an image representation of the NMR dataset that is capable of correctly aligning peaks when existing methods fail. The proposed algorithm was compared with current state-of-the-art algorithms operating on a selected plasma dataset to demonstrate its potential. A urine dataset was also processed using the algorithm as a further demonstration. The method is capable of successfully aligning the plasma data but further development is needed to address more challenging applications, for example urine data.
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| 21. |
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| 22. |
- Ferapontova, Elena, et al.
(författare)
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Direct electrochemistry of proteins and enzymes
- 2005
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Ingår i: Electrochemistry of nucleic acids and proteins : towards electrochemical sensors for genomic and proteomics. - 044452150X
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
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| 23. |
- Haller, Daniel G, et al.
(författare)
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Potential regional differences for the tolerability profiles of fluoropyrimidines.
- 2008
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 26:13, s. 2118-23
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability. METHODS: Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study). RESULTS: In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR. CONCLUSION: Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
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| 24. |
- Lambrechts, Diether, et al.
(författare)
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Meta-analysis of VEGF variations in ALS : increased susceptibility in male carriers of the -2578AA genotype
- 2008
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Ingår i: Journal of Medical Genetics. - London : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 46:12, s. 840-846
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Tidskriftsartikel (refereegranskat)abstract
- Background: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. Methods and findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (−2578C/A, −1154G/A and −634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the −2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. Conclusions: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF −2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.
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| 25. |
- Lelliott, Christopher J., et al.
(författare)
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Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance
- 2006
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Ingår i: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 4:11
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Tidskriftsartikel (refereegranskat)abstract
- The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) has been implicated in important metabolic processes. A mouse lacking PGC-1beta (PGC1betaKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1betaKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1beta ablation was partially compensated by up-regulation of PGC-1alpha in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1betaKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1beta was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1betaKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1betaKO mice have impaired mitochondrial function. Lack of PGC-1beta also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1beta plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.
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