| 1. |
- Went, M, et al.
(author)
-
Author Correction: Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
- 2019
-
In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 213-
-
Journal article (peer-reviewed)abstract
- The original version of this Article contained an error in the spelling of a member of the PRACTICAL Consortium, Manuela Gago-Dominguez, which was incorrectly given as Manuela Gago Dominguez. This has now been corrected in both the PDF and HTML versions of the Article. Furthermore, in the original HTML version of this Article, the order of authors within the author list was incorrect. The PRACTICAL consortium was incorrectly listed after Richard S. Houlston and should have been listed after Nora Pashayan. This error has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication.
|
|
| 2. |
- Emonts, B., et al.
(author)
-
The Dragonfly Galaxy: II. ALMA unveils a triple merger and gas exchange in a hyper-luminous radio galaxy at z = 2
- 2015
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 584
-
Journal article (peer-reviewed)abstract
- The Dragonfly Galaxy (MRC 0152-209), at redshift z similar to 2, is one of the most vigorously star-forming radio galaxies in the Universe. What triggered its activity? We present ALMA Cycle 2 observations of cold molecular CO(6 5) gas and dust, which reveal that this is likely a gas-rich triple merger. It consists of a close double nucleus (separation similar to 4 kpc) and a weak CO-emitter at similar to 10 kpc distance, all of which have counterparts in HST/NICMOS imagery. The hyper-luminous starburst and powerful radio-AGN were triggered at this precoalescent stage of the merger. The CO(6-5) traces dense molecular gas in the central region, and complements existing CO(1-0) data, which reveal more widespread tidal debris of cold gas. We also find similar to 10(10) M-circle dot of molecular gas with enhanced excitation at the highest velocities. At least 20-50% of this high-excitation, high-velocity gas shows kinematics that suggests it is being displaced and redistributed within the merger, although with line-of-sight velocities of vertical bar v vertical bar < 500 km s(-1), this gas will probably not escape the system. The processes that drive the redistribution of cold gas are likely related to either the gravitational interaction between two kpc-scale discs, or starburst/AGN-driven outflows. We estimate that the rate at which the molecular gas is redistributed is at least. M similar to 1200 +/- 500 M-circle dot yr(-1), and could perhaps even approach the star formation rate of similar to 3000 +/- 800 M-circle dot yr(-1). The fact that the gas depletion and gas redistribution timescales are similar implies that dynamical processes can be important in the evolution of massive high-z galaxies.
|
|
| 3. |
- Gullberg, B., et al.
(author)
-
The mysterious morphology of MRC0943-242 as revealed by ALMA and MUSE
- 2016
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 586
-
Journal article (peer-reviewed)abstract
- © 2016 ESO. We present a pilot study of the z = 2.923 radio galaxy MRC0943-242, where we combine information from ALMA and MUSE data cubes for the first time. Even with modest integration times, we disentangle the AGN and starburst dominated components. These data reveal a highly complex morphology as the AGN, starburst, and molecular gas components show up as widely separated sources in dust continuum, optical continuum, and CO line emission observations. CO(1-0) and CO(8-7) line emission suggest that there is a molecular gas reservoir offset from both the dust and the optical continuum that is located ∼90 kpc from the AGN. The UV line emission has a complex structure in emission and absorption. The line emission is mostly due to a large scale ionisation cone energised by the AGN, and a Lyα emitting bridge of gas between the radio galaxy and a heavily star-forming set of components. Strangely, the ionisation cone has no Lyα emission. We find this is due to an optically thick layer of neutral gas with unity covering fraction spread out over a region of at least ∼100 kpc from the AGN. Other less thick absorption components are associated with Lyα emitting gas within a few tens of kpc from the radio galaxy and are connected by a bridge of emission. We speculate that this linear structure of dust, Lyα and CO emission, and the redshifted absorption seen in the circum nuclear region may represent an accretion flow feeding gas into this massive AGN host galaxy.
|
|
| 4. |
- Gullberg, Elisabet, et al.
(author)
-
Identification of Cell Adhesion Molecules in the Human Follicle-Associated Epithelium That Improve Nanoparticle Uptake into the Peyer's Patches
- 2006
-
In: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 319:2, s. 632-639
-
Journal article (peer-reviewed)abstract
- The aim of this study was to identify cell adhesion molecules that could serve as targets of the human follicle-associated epithelium (FAE) overlying Peyer's patches and to assess nanoparticle uptake levels across this epithelium. We first studied the expression of the mouse M-cell marker beta(1)-integrin and used a model of human FAE derived from intestinal epithelial Caco-2 cells and Raji B-cells to identify additional potential targets by cDNA array. The protein expression of potential targets in the model FAE and in human ileal FAE tissues was quantified by immunofluorescence. Integrin targeting was studied by investigating the transport of Arg-Gly-Asp (RGD)-coated (integrin- binding), Arg-Gly-Glu (RGE)-coated (nonintegrin-binding), and uncoated nanoparticles across ileal specimens mounted in Ussing chambers. Both beta(1)-integrin and the cell adhesion molecule CD9 were more abundantly expressed in the model and human FAE compared with the Caco-2 control cells or villus epithelium (VE). Uncoated nanoparticles were not taken up across either FAE or VE. General integrin targeting with RGD improved the nanoparticle transport dramatically across the FAE and to a lower extent across the VE. Compared with RGE, RGD improved transport 4-fold across the FAE. There was no difference in the transport of RGD- and RGE-coated nanoparticles across the VE. In conclusion, beta(1)-integrin and CD9 were identified as targets in human FAE. The difference in RGD- and RGE-mediated transport across the FAE, but not the VE, suggests that a specific integrin interaction was the dominating mechanism for improved nanoparticle uptake across the FAE., whereas charge interaction contributed substantially to the improved VE uptake.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
- Wirfält, Elisabet, et al.
(author)
-
Food sources of carbohydrates in a European cohort of adults.
- 2002
-
In: Public Health Nutrition. - 1475-2727. ; 5:6B, s. 1197-1215
-
Journal article (peer-reviewed)abstract
- Objective: To describe the average consumption of carbohydrate-providing food groups among study centres of the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Of the 27 redefined EPIC study centres, 19 contributed subjects of both genders and eight centres female participants only (men, n=13 031; women, n=22 924, after exclusion of subjects under 35 and over 74 years of age from the original 36 900 total). Dietary data were obtained using the 24-hour recall methodology using the EPIC-SOFT software. The major sources of dietary carbohydrate were identified, and 16 food groups were examined. Results: The 10 food groups contributing most carbohydrate were bread; fruit; milk and milk products; sweet buns, cakes and pies; potato; sugar and jam; pasta and rice; vegetables and legumes; crispbread; and fruit and vegetable juices. Consumption of fruits as well as vegetables and legumes was higher in southern compared with northern centres, while soft drinks consumption was higher in the north. Italian centres had high pasta and rice consumption, but breakfast cereal, potato, and sweet buns, cakes and pies were higher in northern centres. In Sweden, lower bread consumption was balanced with a higher consumption of crispbread, and with sweet buns, cakes and pies. Overall, men consumed higher amounts of vegetables and legumes, bread, soft drinks, potatoes, pasta and rice, breakfast cereal and sugar and jam than women, but fruit consumption appeared more frequent in women. Conclusion: The study supports the established idea that carbohydrate-rich foods chosen in northern Europe are different from those in the Mediterranean region. When comparing and interpreting diet-disease relationships across populations, researchers need to consider all types of foods.
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Bergemalm, Daniel, 1977-, et al.
(author)
-
Systemic Inflammation in Preclinical Ulcerative Colitis
- 2021
-
In: Gastroenterology. - : AGA Institute. - 0016-5085 .- 1528-0012. ; 161:5, s. 1526-1539.e9
-
Journal article (peer-reviewed)abstract
- Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
|
|
| 14. |
- Do, Anh-Tri, 1978-
(author)
-
Regulation of Heparan Sulfate 6-O-Sulfation Patterns
- 2006
-
Doctoral thesis (other academic/artistic)abstract
- Heparan sulfates (HSs) are linear, negatively charged polysaccharides composed of alternating hexuronic acid (glucuronic acid or iduronic acid) and glucosamine residues that can be substituted to varying degrees with sulfate groups. HS, localized in the extracellular matrix and on the surface of most cells, interacts with a large number of proteins. The actions of HS largely depend on the amount and distribution of its sulfate groups, that provide binding sites for proteins. This thesis focuses on the regulation of the structural diversity in HS, in particular the regulation of its 6-O-sulfation patterns that are generated by the combined action of 6-O-sulfotransferases (6OSTs) during biosynthesis, and 6-O-endosulfatases (Sulfs) after completed biosynthesis. In addition, a new model organism is introduced that offers good prospects for investigating the evolutional aspects of HS structural heterogeneity.Our studies showed that the three mouse 6OSTs (6OST1-3) exhibit similar substrate specificities in vitro, with minor differences in target preferences. Overexpression of the 6OSTs in cells resulted in increased 6-O-sulfation of both N-sulfated and N-acetylated glucosamine residues. The changes were independent of enzyme isoform but positively correlated to the level of enzyme expressed.Quail Sulf1 and Sulf2 enzymes were shown to be cell surface HS 6-O-endosulfatases with preference towards a subset of trisulfated disaccharides within HS chains. The Sulfs contain a “hydrophilic domain” that was shown to be essential for binding of HS, anchorage to the cell surface and endosulfatase activity. QSulf1 was also shown to promote Wnt-Frizzled signaling in cells. An HS-like polysaccharide was isolated from the sea anemone Nematostella vectensis and characterized, and all the enzyme families involved in HS biosynthesis and modification in mammalian model systems were also identified. Our results suggest that Nematostella may be a useful tool for understanding the role of evolution in generating HS structural diversity.
|
|
| 15. |
|
|
| 16. |
- Ferrari, P., et al.
(author)
-
A bivariate measurement error model for nitrogen and potassium intakes to evaluate the performance of regression calibration in the European Prospective Investigation into Cancer and Nutrition study
- 2009
-
In: European Journal of Clinical Nutrition. - : Springer Science and Business Media LLC. - 1476-5640 .- 0954-3007. ; 63:4s, s. 179-187
-
Journal article (peer-reviewed)abstract
- Objectives: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, the performance of 24-h dietary recall (24-HDR) measurements as reference measurements in a linear regression calibration model is evaluated critically at the individual (within-centre) and aggregate (between-centre) levels by using unbiased estimates of urinary measurements of nitrogen and potassium intakes. Methods: Between 1995 and 1999, 1072 study subjects (59% women) from 12 EPIC centres volunteered to collect 24-h urine samples. Log-transformed questionnaire, 24-HDR and urinary measurements of nitrogen and potassium intakes were analysed in a multivariate measurement error model to estimate the validity of coefficients and error correlations in self-reported dietary measurements. In parallel, correlations between means of 24-HDR and urinary measurements were computed. Linear regression calibration models were used to estimate the regression dilution (attenuation) factors. Results: After adjustment for sex, centre, age, body mass index and height, the validity coefficients for 24-HDRs were 0.285 (95% confidence interval: 0.194, 0.367) and 0.371 (0.291, 0.446) for nitrogen and potassium intakes, respectively. The attenuation factors estimated in a linear regression calibration model were 0.368 (0.228, 0.508) for nitrogen and 0.500 (0.361, 0.639) for potassium intakes; only the former was different from the estimate obtained using urinary measurements in the measurement error model. The aggregate-level correlation coefficients between means of urinary and 24-HDR measurements were 0.838 (0.637, 0.932) and 0.756 (0.481, 0.895) for nitrogen and potassium intakes, respectively. Conclusions: This study suggests that 24-HDRs can be used as reference measurements at the individual and aggregate levels for potassium intake, whereas, for nitrogen intake, good performance is observed for between-centre calibration, but some limitations are apparent at the individual level. European Journal of Clinical Nutrition (2009) 63, S179-S187; doi: 10.1038/ejcn.2009.80
|
|
| 17. |
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Gullberg, Elisabet, et al.
(author)
-
Peyer's patches and M cells as potential sites of the inflammatory onset in Crohn's disease
- 2006
-
In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1072, s. 218-232
-
Journal article (peer-reviewed)abstract
- Clinical observations suggest that the sites of initial inflammation in ileal Crohn's disease (CD) are the lymphoid follicles, where the aphtoid lesions originate from small erosions of the follicle-associated epithelium (FAE). Lymphoid follicles and Peyer's patches (PPs) consist of a number of B-cell follicles with intervening T cell areas. The T cell follicular area is also populated by dendritic cells (DCs) and macrophages. A single layer of epithelial cells covering each follicle forms a dome between the surrounding villi. This FAE differs from normal villus epithelium in several ways that make the epithelial cells of the FAE more exposed to the luminal contents, more accessible to antigens, and in closer contact with the immune system. The most prominent feature is the presence of specialized M cells, which are optimized for antigen adherence and transport. M cells play an important role in the surveillance of the intestinal lumen, but also provide a route of entry for various pathogens. In this article we review the current knowledge on the epithelial phenotype of the human FAE, and changes of the FAE and M cells in intestinal inflammation, leading to a hypothesis of the role of the FAE and M cells in the pathogenesis of CD.
|
|
| 31. |
- Gullberg, Elisabet, et al.
(author)
-
Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
- 2008
-
In: Laboratory investigation; a journal of technical methods and pathology. - New York, USA : Elsevier BV. - 1530-0307 .- 0023-6837. ; 88:11, s. 1215-26
-
Journal article (peer-reviewed)abstract
- Crohn's disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv+ Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P<0.01) and ileal mucosa (268+/-47% of control; P<0.01), whereas inv bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size- and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
- Gullberg, Joanna, et al.
(author)
-
The challenge of applying digital image processing software on intraoral radiographs for osteoporosis risk assessment
- 2022
-
In: Dentomaxillofacial Radiology. - : British Institute of Radiology. - 0250-832X .- 1476-542X. ; 51:1
-
Journal article (peer-reviewed)abstract
- Objectives: The purpose of this study was to evaluate rater agreement and the accuracy of a semi-automated software and its fully automated tool for osteoporosis risk assessment in intraoral radiographs. Methods: A total of 567 intraoral radiographs was selected retrospectively from women aged 75-80 years participating in a large population based study (SUPERB) based in Gothenburg, Sweden. Five raters assessed participants' risk of osteoporosis in the intraoral radiographs using a semi-automated software. Assessments were repeated after 4 weeks on 121 radiographs (20%) randomly selected from the original 567. Radiographs were also assessed by the soft wares' fully automated tool for analysis. Results: Overall interrater agreement for the five raters was 0.37 (95% CI 0.32-0.41), and for the five raters with the fully automated tool included as 'sixth rater' the overall Kappa was 0.34 (0.30-0.38). Intrarater agreement varied from moderate to substantial according to the Landis and Koch interpretation scale. Diagnostic accuracy was calculated in relation to reference standard for osteoporosis diagnosis which is T score values for spine, total hip and femoral neck and presented in form of sensitivities, specificities, predictive values, likelihood ratios and odds ratios. All raters' mean sensitivity, including the fully automated tool, was 40,4% (range 14,3%-57,6%). Corresponding values for specificity was 69,5% (range 59,7%-90,4%). The diagnostic odds ratios ranged between 1 and 2.7. Conclusion: The low diagnostic odds ratio and agreement between raters in osteoporosis risk assessment using the software for analysis of the trabecular pattern in intraoral radiographs shows that more work needs to be done to optimise the automation of trabecular pattern analysis in intraoral radiographs.
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
- Keita, Åsa V, et al.
(author)
-
Characterization of antigen and bacterial transport in the follicle-associated epithelium of human ileum
- 2006
-
In: Laboratory investigation. - : Elsevier BV. - 0023-6837 .- 1530-0307. ; 86:5, s. 504-516
-
Journal article (peer-reviewed)abstract
- The follicle-associated epithelium (FAE), covering Peyer's patches, provides a route of entry for antigens and microorganisms. Animal studies showed enhanced antigen and bacterial uptake in FAE, but no study on barrier function of human FAE has been reported. Our aim was to characterize the normal barrier properties of human FAE. Specimens of normal ileum were taken from 30 patients with noninflammatory colonic disease. Villus epithelium (VE) and FAE were identified and mounted in Ussing chambers. Permeability to 51Cr-EDTA, transmucosal flux of the protein antigen, horseradish peroxidase (HRP), and transport of fluorescent Escherichia coli (chemically killed K-12 and live HB101) were measured. Uptake mechanisms were studied by confocal- and transmission electron microscopy, and by using pharmacological inhibitors in an in vitro coculture model of FAE and in human ileal FAE. HRP flux was substantially higher in FAE than in VE, and was reduced by an amiloride analog. Electron microscopy showed HRP-containing endosomes. Transport of E. coli K-12 and HB101 was also augmented in FAE and was confirmed by confocal microscopy. In vitro coculture experiments and electron microscopy revealed actin-dependent, mainly transcellular, uptake of E. coli K-12 into FAE. 51Cr-EDTA permeability was equal in FAE and VE. Augmented HRP flux and bacterial uptake but similar paracellular permeability, suggest functional variations of transcellular transport in the FAE. We show for the first time that FAE of human ileum is functionally distinct from regular VE, rendering the FAE more prone to bacterial–epithelial cell interactions and delivery of antigens to the mucosal immune system.
|
|
| 39. |
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
- McGinn, Steven, et al.
(author)
-
New Technologies for DNA analysis-A review of the READNA Project.
- 2016
-
In: New Biotechnology. - : Elsevier BV. - 1876-4347 .- 1871-6784.
-
Research review (peer-reviewed)abstract
- The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 4 1/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3(rd) and 4(th) generation of sequencing methods with nanopores and in situ sequencing, respectively.
|
|
| 45. |
|
|
| 46. |
- Pedrosa-Domellöf, Fatima, et al.
(author)
-
Laminin chains in developing and adult human myotendinous junctions.
- 2000
-
In: Journal of Histochemistry and Cytochemistry. - 0022-1554 .- 1551-5044. ; 48:2, s. 201-10
-
Journal article (peer-reviewed)abstract
- In addition to being the specialized site for transmission of force from the muscle to the tendon, the myotendinous junction (MTJ) also plays an important role in muscle splitting during morphogenesis. An early event in the formation of the MTJ is a regional deposition of basement membranes. We used immunocytochemistry to investigate the distribution of laminin chains during the development of MTJs in human limb muscle at 8-22 weeks of gestation (wg) and in adult MTJs. We used polyclonal antibodies and a new monoclonal antibody (MAb) against the human laminin alpha1 G4/G5 domains. At 8-10 wg, laminin alpha1 and laminin alpha5 chains were specifically localized to the MTJ. Laminin alpha1 chain remained restricted to the MTJ at 22 wg as the laminin beta2 chain had appeared, whereas the laminin alpha5 chain became deposited along the entire length of the myotubes from 12 wg. In the adult MTJ, only vestigial amounts of laminin alpha1 and laminin alpha5 chains could be detected. On the basis of co-distribution data, we speculate that laminin alpha1 chain in the forming MTJ undergoes an isoform switch from laminin 1 to laminin 3. Our data indicate a potentially important role for laminin alpha1 chain in skeletal muscle formation.
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
- Saltó, C, et al.
(author)
-
Ablation of TRalpha2 and a concomitant overexpression of alpha1 yields a mixed hypo- and hyperthyroid phenotype in mice.
- 2001
-
In: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 0888-8809. ; 15:12, s. 2115-28
-
Journal article (peer-reviewed)abstract
- Thyroid hormone governs a diverse repertoire of physiological functions through receptors encoded in the receptor genes alpha and beta, which each generate variant proteins. In mammals, the alpha gene generates, in addition to the normal receptor TRalpha1, a non-hormone-binding variant TRalpha2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TRalpha2 expression. Selective ablation of TRalpha2 resulted in an inevitable, concomitant overexpression of TRalpha1. Both TRalpha2 +/- and -/- mice show a complex phenotype with low levels of free T3 and free T4, and have inappropriately normal levels of TSH. The thyroid glands exhibit mild morphological signs of dysfunction and respond poorly to TSH, suggesting that the genetic changes affect the ability of the gland to release thyroid hormones. However, the phenotype of the mutant mice also has features of hyperthyroidism, including decreased body weight, elevated heart rate, and a raised body temperature. Furthermore, TRalpha2-/- and TRalpha2+/- mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the overexpression of TRalpha1 and the concomitant decrease in TRalpha2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied. The phenotypes suggest that the balance of TRalpha1:TRalpha2 expressed from the TRalpha gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.
|
|
