| 1. |
- Akerblad, P, et al.
(författare)
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Gene expression analysis suggests that EBF-1 and PPAR gamma 2 induce adipogenesis of NIH-3T3 cells with similar efficiency and kinetics
- 2005
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 23:2, s. 206-216
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Tidskriftsartikel (refereegranskat)abstract
- Differentiation of multipotent mesenchymal stem cells into lipid-accumulating adipocytes is a physiological process induced by transcription factors in combination with hormonal stimulation. We have used Affymetrix microarrays to compare the adipogenic differentiation pathways of NIH-3T3 fibroblasts induced to undergo in vitro differentiation by ectopic expression of early B cell factor (EBF)-1 or peroxisome proliferator-activated receptor (PPAR)gamma 2. These experiments revealed that commitment to the adipogenic pathway in the NIH-3T3 cells was not reflected in gene expression until 4 days after induction of differentiation. Furthermore, gene expression patterns at the earlier time points after stimulation indicated that EBF-1 and PPAR gamma 2 induced different sets of genes, while the similarities increased upon differentiation, and that several genes linked to adipocyte differentiation were also transiently induced in the vector-transduced cells. These data suggest that the initial activation of genes associated with adipocyte development is independent of commitment to the adipogenic pathway and that EBF-1 and PPAR gamma 2 induce adipocyte differentiation with comparable kinetics and efficiency.
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| 2. |
- Banduseela, Varuna C., et al.
(författare)
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Gene expression and muscle fiber function in a porcine ICU model
- 2009
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 39:3, s. 141-159
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.
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| 3. |
- Blizard, David A., et al.
(författare)
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Blood pressure and heart rate QTL in mice of the B6/D2 lineage sex differences and environmental influences
- 2009
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 36:3, s. 158-166
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Tidskriftsartikel (refereegranskat)abstract
- A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F(2) adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F(2) data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F(2) mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.
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| 4. |
- Fischer, M Dominik, et al.
(författare)
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Definition of the unique human extraocular muscle allotype by expression profiling.
- 2005
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Ingår i: Physiol Genomics. - : American Physiological Society. - 1531-2267. ; 22:3, s. 283-91
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Tidskriftsartikel (refereegranskat)abstract
- The extraocular muscles (EOMs) are a unique group of specialized muscles that are anatomically and physiologically distinct from other skeletal muscles. Perhaps the most striking characteristic of the EOMs is their differential sensitivity to disease. EOMs are spared in Duchenne's muscular dystrophy (DMD) despite widespread involvement of other skeletal muscles. Conversely, they are early and prominent targets in myasthenia gravis and mitochondrial myopathies. It is unclear how EOMs achieve such specialization or a differential response to diseases; however, this has been attributed to a unique, group-specific pattern of gene expression or "allotype." To begin to address these issues as well as define the human EOM allotype, we analyzed the human EOM transcriptome using oligonucleotide-based expression profiling. Three hundred thirty-eight genes were found to be differentially expressed in EOM compared with quadriceps femoris limb muscle, using a twofold cutoff. Functional characterization revealed expression patterns corresponding to known metabolic and structural properties of EOMs such as expression of EOM-specific myosin heavy chain (MYH13) and high neural, vascular, and mitochondrial content, suggesting that the profiling was sensitive and specific. Genes related to myogenesis, stem cells, and apoptosis were detected at high levels in normal human EOMs, suggesting that efficient and continuous regeneration and/or myogenesis may be a mechanism by which the EOMs remain clinically and pathologically spared in diseases such as DMD. Taken together, this study provides insight into how human EOMs achieve their unique structural, metabolic, and pathophysiological properties.
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| 5. |
- Fuller, Jessica, et al.
(författare)
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Genetic Dissection Reveals Diabetes Loci Proximal to the Gimap5 Lymphopenia Gene.
- 2009
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 38, s. 89-97
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Tidskriftsartikel (refereegranskat)abstract
- Congenic DRF.(f/f) rats are protected from type 1 diabetes (T1D) by 34 Mb of F344 DNA introgressed proximal to the Gimap5 lymphopenia gene. To dissect the genetic factor(s) that confer protection from T1D in the DRF.(f/f) rat line, DRF.(f/f) rats were crossed to inbred BBDR or DR.(lyp/lyp) rats to generate congenic sublines that were genotyped, monitored for T1D and positional candidate genes sequenced. All (100%) DR.(lyp/lyp) rats developed T1D by 83 days of age. Reduction of the DRF.(f/f) F344 DNA fragment by 26 Mb (42.52 Mb-68.51 Mb) retained complete T1D protection. Further dissection revealed that a 2 Mb interval of F344 DNA (67.41-70.17 Mb) (Region 1) resulted in 47% protection and significantly delayed onset (p<0.001 compared to DR.(lyp/lyp)). Retaining <1 Mb of F344 DNA at the distal end (76.49-76.83 Mb) (Region 2) resulted in 28% protection and also delayed onset (p<0.001 compared to DR.(lyp/lyp)). Comparative analysis of diabetes frequency in the DRF.(f/f) congenic sublines further refined the RNO4 Region 1 interval to approximately 670 Kb and Region 2 to the 340 Kb proximal to Gimap5. All congenic DRF.(f/f) sublines were prone to low-grade pancreatic mononuclear cell infiltration around ducts and vessels but less than 20% of islets in non-diabetic rats showed islet infiltration. Coding sequence analysis revealed TCR Vbeta 8E, 12 and 13 as candidate genes in Region 1 and Znf467 and Atp6v0e2 as candidate genes in Region 2. Our results show that spontaneous T1D is controlled by at least two genetic loci 7 Mb apart on rat chromosome 4. Key words: Type 1 diabetes, BB rat, T cell receptor, autoimmune.
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| 6. |
- Grundberg, Elin, et al.
(författare)
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Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells
- 2008
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 33:3, s. 301-11
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Tidskriftsartikel (refereegranskat)abstract
- Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.
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| 7. |
- Hägg Samuelsson, Ulrika, 1973, et al.
(författare)
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Gene expression profile and aortic vessel distensibility in voluntarily exercised spontaneously hypertensive rats: potential role of heat shock proteins
- 2005
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Ingår i: Physiol Genomics. - 1531-2267 .- 1094-8341. ; 22:3, s. 319-26
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Tidskriftsartikel (refereegranskat)abstract
- Physical exercise is considered to be beneficial for cardiovascular health. Nevertheless, the underlying specific molecular mechanisms still remain unexplored. In this study, we aimed to investigate the effects of voluntary exercise on vascular mechanical properties and gene regulation patterns in spontaneously hypertensive rats. By using ultrasound biomicroscopy in an ex vivo perfusion chamber, we studied the distensibility of the thoracic aorta. Furthermore, exercise-induced gene regulation was studied in aortae, using microarray analysis and validated with real-time PCR. We found that distensibility was significantly improved in aortas from exercising compared with control rats (P < 0.0001). Exercising rats demonstrated a striking pattern of coordinated downregulation of genes belonging to the heat shock protein family. In conclusion, voluntary exercise leads to improved vessel wall distensibility and reduced gene expression of heat shock protein 60 and 70, which may indicate decreased oxidative stress in the aortic vascular wall.
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| 8. |
- Karlsson, Göran, et al.
(författare)
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Gene expression profiling demonstrates that TGF-{beta}1 signals exclusively through receptor complexes involving Alk5 and identifies targets of TGF-{beta} signaling.
- 2005
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 21:3, s. 396-403
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor-β 1 (TGF-β) regulates cellular functions like proliferation, differentiation, and apoptosis. On the cell surface, TGF-β binds to receptor complexes consisting of TGF-β receptor type II (Tβ RII) and activin-like kinase receptor-5 (Alk5), and the downstream signaling is transduced by Smad and MAPK proteins. Recent data have shown that alternative receptor combinations aside from the classical pairing of Tβ RII/Alk5 can be relevant for TGF-β signaling. We have screened for alternative receptors for TGF-β and also for gene targets of TGF-β signaling, by performing functional assays and microarray analysis in murine embryonic fibroblast (MEF) cell lines lacking Alk5. Data from TGF-β-stimulated Alk5(-/-) cells show them to be completely unaffected by TGF-β. Additionally, 465 downstream targets of Alk5 signaling were identified when comparing Alk5(-/-) or TGF-β-stimulated Alk5(+/+) MEFs with unstimulated Alk5(+/+) cells. Our results demonstrate that, in MEFs, TGF-β signals exclusively through complexes involving Alk5, and give insight to its downstream effector genes.
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| 9. |
- Lionikas, A., et al.
(författare)
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Genetic determinants of weight of fast- and slow-twitch skeletal muscle in 500-day-old mice of the C57BL/6J and DBA/2J lineage.
- 2005
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 21:2, s. 184-192
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Tidskriftsartikel (refereegranskat)abstract
- C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141-152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13-22% greater (P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2 population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.
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| 10. |
- Nilsen, A.J., et al.
(författare)
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Comparative hepatic gene expression profiling of rats treated with 1H,1H,2H,2H-heptadecafluorodecan-1-ol or with pentadecafluorooctanoic acid
- 2008
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Ingår i: Physiol. Genomics. - : American Physiological Society. ; 34, s. 285-303
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Tidskriftsartikel (refereegranskat)abstract
- Pentadecafluorooctanoic acid is an established peroxisome proliferator. Little is known about effects of treatment with 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol, which is metabolized to pentadecafluorooctanoic acid. We compared effects of various dosages (3, 10, or 25 mg/kg body wt) of each of these compounds on hepatic gene expression in rats with microarrays. Microarray data were validated by real-time RT-PCR. Expression data were also correlated with hepatic activities of selected enzymes and with hepatic levels of pentadecafluorooctanoic acid and 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol. Pentadecafluorooctanoic acid caused the more powerful change in gene expression, in terms of both number of genes affected and extent of change in expression. Across the dosages used pentadecafluorooctanoic acid and 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol caused significant ( P ≤ 0.05) changes in expression for 441 and 105 genes, respectively. With 1 H,1 H,2 H,2 H-heptadecafluorodecan-1-ol ∼38% of the 105 genes exhibited decreased expression with a dose of 25 mg/kg body wt, these genes also appearing less responsive to treatment at the lower dosages. Bioinformatic analysis suggested that these genes are associated with regulatory functions. With pentadecafluorooctanoic acid, increasing dosage up to 10 mg/kg body wt brought about progressive increase in expression of affected genes. Pathways analysis suggested similar effects of the two compounds on lipid and amino acid metabolism. Marked differences were also found, particularly with respect to effects on genes related to oxidative phosphorylation, oxidative metabolism, free radical scavenging, xenobiotic metabolism, and complement and coagulation cascades.
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