| 1. |
- Benedict, Christian, et al.
(författare)
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The fat mass and obesity gene is linked to reduced verbal fluency in overweight and obese elderly men
- 2011
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 32:6, s. 1159.e1-1159.e5
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Tidskriftsartikel (refereegranskat)abstract
- Humans carrying the prevalent rs9939609 A allele of the fat mass and obesity-associated (FTO) gene are more susceptible to developing obesity than noncarries. Recently, polymorphisms in the FTO gene of elderly subjects have also been linked to a reduced volume in the frontal lobe as well as increased risk for incident Alzheimer disease. However, so far there is no evidence directly linking the FTO gene to functional cognitive processes. Here we examined whether the FTO rs9939609 A allele is associated with verbal fluency performance in 355 elderly men at the age of 82 years who have no clinically apparent cognitive impairment. Retrieval of verbal memory is a good surrogate measure reflecting frontal lobe functioning. Here we found that obese and overweight but not normal weight FTO A allele carriers showed a lower performance on verbal fluency than non-carriers (homozygous for rs9939609 T allele). This effect was not observed for a measure of general cognitive performance (i.e., Mini-Mental State Examination score), thereby indicating that the FTO gene primarily affects frontal lobe-dependent cognitive processes in elderly men.
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| 2. |
- Cedernaes, Jonathan, et al.
(författare)
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Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract
- 2011
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 411:4, s. 702-707
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Tidskriftsartikel (refereegranskat)abstract
- Solute carriers (SLCs), the second largest super-family of membrane proteins in the human genome, transport amino acids, sugars, fatty acids, inorganic ions, essential metals and drugs over membranes. To date no study has provided a comprehensive analysis of SLC localization along the entire GI tract. The aim of the present study was to provide a comprehensive, segment-specific description of the localization of SLC genes along the rat Cl tract by employing bioinformatics and molecular biology methods. The Unigene database was screened for rat SLC entries in the intestinal tissue. Using qPCR we measured expression of the annotated genes in the Cl tract divided into the following segments: the esophagus, the corpus and the antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum. Our Unigene-derived gene pool was expanded with data from in-house tissue panels and a literature search. We found 44 out of 78 (56%) of gut SLC transcripts to be expressed in all Cl tract segments, whereas the majority of remaining SLCs were detected in more than five segments. SLCs are predominantly expressed in gut regions with absorptive functions although expression was also found in segments unrelated to absorption. The proximal jejunum had the highest number of differentially expressed SLCs. In conclusion, SLCs are a crucial molecular component of the Cl tract, with many of them expressed along the entire GI tract. This work presents the first overall road map of localization of transporter genes in the Cl tract.
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| 3. |
- Jacobsson, Josefin A., et al.
(författare)
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Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5, s. e20158-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution. Objective: To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans. Design: Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Results: Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women. Conclusions: Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender.
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| 4. |
- Nordström, Karl, et al.
(författare)
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Independent HHsearch, Needleman-Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families
- 2011
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 0737-4038 .- 1537-1719. ; 28:9, s. 2471-2480
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Tidskriftsartikel (refereegranskat)abstract
- Several families of G protein-coupled receptors (GPCR) show no significant sequence similarities and it has been debated which groups of GPCRs that share a common origin. We developed and performed integrated independent HHsearch, Needleman-Wunsch-based and motif analyses on almost 7000 unique GPCRs from twelve species. Moreover, we mined the evolutionary important Trichoplax adhaerens, Nematostella vectensis, Thalassiosira pseudonana and Strongylocentrotus purpuratus genomes, revealing remarkably rich vertebrate-like repertoires already in the early Metazoan species. We found strong evidence for that the Adhesion and Frizzled families are children to the cAMP family with HHsearch homology probabilities of 99.8% and 99.4%, respectively, also supported by the Needleman-Wunsch analysis and several motifs. We also found that the large Rhodopsin family is likely a child of the cAMP family with a HHsearch homology probability of 99.4% and conserved motifs. Therefore, we suggest that the Adhesion and Frizzled families originated from the cAMP family in an event close to that which gave rise to the Rhodopsin family. We also found convincing evidence that the Rhodopsin family is parent to the important sensory Taste 2, Vomeronasal type 1 and Nematode chemoreceptor families. The insect odorant, gustatory and Trehalose receptors, frequently referred to as GPCRs, form a separate cluster without relationship to the other families and we speculate, based on these and other’s results, that these families are ligand-gated ion channels rather than GPCRs. Overall, we suggest common descent of at least 97% of the GPCRs sequences found in humans, including all the main families.
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| 5. |
- Rask-Andersen, Mathias, et al.
(författare)
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Functional coupling analysis suggests link between the obesity gene FTO and the BDNF-NTRK2 signaling pathway
- 2011
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Ingår i: BMC Neuroscience. - : Springer Science and Business Media LLC. - 1471-2202. ; 12, s. 117-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Fat mass and obesity gene (FTO) has been identified through genome wide association studies as an important genetic factor contributing to a higher body mass index (BMI). However, the molecular context in which this effect is mediated has yet to be determined. We investigated the potential molecular network for FTO by analyzing co-expression and protein-protein interaction databases, Coxpresdb and IntAct, as well as the functional coupling predicting multi-source database, FunCoup. Hypothalamic expression of FTO-linked genes defined with this bioinformatics approach was subsequently studied using quantitative real time-PCR in mouse feeding models known to affect FTO expression.Results: We identified several candidate genes for functional coupling to FTO through database studies and selected nine for further study in animal models. We observed hypothalamic expression of Profilin 2 (Pfn2), cAMP-dependent protein kinase catalytic subunit beta (Prkacb), Brain derived neurotrophic factor (Bdnf), neurotrophic tyrosine kinase, receptor, type 2 (Ntrk2), Signal transducer and activator of transcription 3 (Stat3), and Btbd12 to be co-regulated in concert with Fto. Pfn2 and Prkacb have previously not been linked to feeding regulation.Conclusions: Gene expression studies validate several candidates generated through database studies of possible FTO-interactors. We speculate about a wider functional role for FTO in the context of current and recent findings, such as in extracellular ligand-induced neuronal plasticity via NTRK2/BDNF, possibly via interaction with the transcription factor CCAAT/enhancer binding protein beta (C/EBP beta)
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| 6. |
- Rask-Andersen, Mathias, et al.
(författare)
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Trends in the exploitation of novel drug targets
- 2011
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Ingår i: Nature reviews. Drug discovery. - : Springer Science and Business Media LLC. - 1474-1776 .- 1474-1784. ; 10:8, s. 579-590
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Tidskriftsartikel (refereegranskat)abstract
- The discovery and exploitation of new drug targets is a key focus for both the pharmaceutical industry and academic biomedical research. To provide an insight into trends in the exploitation of new drug targets, we have analysed the drugs that were approved by the US Food and Drug Administration during the past three decades and examined the interactions of these drugs with therapeutic targets that are encoded by the human genome, using the DrugBank database and extensive manual curation. We have identified 435 effect-mediating drug targets in the human genome, which are modulated by 989 unique drugs, through 2,242 drug-target interactions. We also analyse trends in the introduction of drugs that modulate previously unexploited targets, and discuss the network pharmacology of the drugs in our data set.
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| 7. |
- Sreedharan, Smitha, et al.
(författare)
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The G protein coupled receptor Gpr153 shares common evolutionary origin with Gpr162 and is highly expressed in central regions including the thalamus, cerebellum and the arcuate nucleus
- 2011
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 278:24, s. 4881-4894
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Tidskriftsartikel (refereegranskat)abstract
- The Rhodopsin family of G protein-coupled receptors (GPCRs) includes the phylogenetic α-group consisting of about 100 human members. The α-group is the only group of GPCRs that has many receptors for biogenic amines which are major drug targets. Several members of this group are orphan receptors and their functions are elusive. In this study we present a detailed phylogenetic and anatomical characterization of the Gpr153 receptor and also attempted to study its functional role. We identified the homologue of GPR153 in the elephant shark genome and phylogenetic and synteny analyses revealed that Gpr162 originated from Gpr153, through a duplication event before the radiation of the amphibian lineage. Quantitative real time PCR study reveals wide spread expression of GPR153 in the CNS and all the peripheral tissues investigated. Detailed in situ hybridization on mouse brain showed specifically high expression in the thalamus, cerebellum and the arcuate nucleus. The antisense oligodeoxynucleotide knockdown of GPR153 caused a slight reduction in food intake and the elevated plus maze test showed significant reduction in the percentage of time spent in the centre square, which points towards a probable role in decision making. This report provides the first detailed characterization of the evolution, expression and as well as primary functional properties of the GPR153 gene.
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| 8. |
- Västermark, Åke, et al.
(författare)
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Functional specialization in nucleotide sugar transporters occurred through differentiation of the gene cluster EamA (DUF6) before the radiation of Viridiplantae
- 2011
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Ingår i: BMC Evolutionary Biology. - : Springer Science and Business Media LLC. - 1471-2148. ; 11, s. 123-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The drug/metabolite transporter superfamily comprises a diversity of protein domain families with multiple functions including transport of nucleotide sugars. Drug/metabolite transporter domains are contained in both solute carrier families 30, 35 and 39 proteins as well as in acyl-malonyl condensing enzyme proteins. In this paper, we present an evolutionary analysis of nucleotide sugar transporters in relation to the entire superfamily of drug/metabolite transporters that considers crucial intra-protein duplication events that have shaped the transporters. We use a method that combines the strengths of hidden Markov models and maximum likelihood to find relationships between drug/metabolite transporter families, and branches within families. Results: We present evidence that the triose-phosphate transporters, domain unknown function 914, uracil-diphosphate glucose-N-acetylglucosamine, and nucleotide sugar transporter families have evolved from a domain duplication event before the radiation of Viridiplantae in the EamA family (previously called domain unknown function 6). We identify previously unknown branches in the solute carrier 30, 35 and 39 protein families that emerged simultaneously as key physiological developments after the radiation of Viridiplantae, including the "35C/E" branch of EamA, which formed in the lineage of T. adhaerens (Animalia). We identify a second cluster of DMTs, called the domain unknown function 1632 cluster, which has non-cytosolic N- and C-termini, and thus appears to have been formed from a different domain duplication event. We identify a previously uncharacterized motif, G-X(6)-G, which is overrepresented in the fifth transmembrane helix of C-terminal domains. We present evidence that the family called fatty acid elongases are homologous to transporters, not enzymes as had previously been thought. Conclusions: The nucleotide sugar transporters families were formed through differentiation of the gene cluster EamA (domain unknown function 6) before Viridiplantae, showing for the first time the significance of EamA.
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