| 1. |
- Ryden, Mikael, et al.
(författare)
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Transplanted Bone Marrow-Derived Cells Contribute to Human Adipogenesis
- 2015
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:3, s. 408-417
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Tidskriftsartikel (refereegranskat)abstract
- Because human white adipocytes display a high turnover throughout adulthood, a continuous supply of precursor cells is required to maintain adipogenesis. Bone marrow (BM)-derived progenitor cells may contribute to mammalian adipogenesis; however, results in animal models are conflicting. Here we demonstrate in 65 subjects who underwent allogeneic BM or peripheral blood stem cell (PBSC) transplantation that, over the entire lifespan, BM/PBSC-derived progenitor cells contribute similar to 10% to the subcutaneous adipocyte population. While this is independent of gender, age, and different transplantation-related parameters, body fat mass exerts a strong influence, with up to 2.5-fold increased donor cell contribution in obese individuals. Exome and whole-genome sequencing of single adipocytes suggests that BM/PBSC-derived progenitors contribute to adipose tissue via both differentiation and cell fusion. Thus, at least in the setting of transplantation, BM serves as a reservoir for adipocyte progenitors, particularly in obese subjects.
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| 2. |
- Arner, Erik, et al.
(författare)
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Adipocyte Turnover : Relevance to Human Adipose Tissue Morphology
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:1, s. 105-109
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Adipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia). We investigated factors of putative importance for adipose tissue morphology. RESEARCH DESIGN AND METHODS-Subcutaneous adipocyte size and total fat mass were compared in 764 subjects with BMI 18-60 kg/m(2). A morphology value was defined as tire difference between the measured adipocyte volume and the expected volume given by a curved-line fit for a given body fat mass and was related to insulin values. In 35 subjects, in vivo adipocyte turnover was measured by exploiting incorporation of atmospheric C-14 into DNA. RESULTS-Occurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but con-elated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (beta-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = -0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (similar to 10% per year) or mean age of adipocytes (similar to 10 years) was not correlated with morphology. CONCLUSIONS-Adipose tissue morphology correlates with insulin measures and is linked to the total adipocyte number independently of sex and body fat level. Low generation rates of adipocytes associate with adipose tissue hypertrophy, whereas high generation rates associate with adipose hyperplasia. Diabetes 59:105-109, 2010
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| 3. |
- Arner, Peter, et al.
(författare)
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Dynamics of human adipose lipid turnover in health and metabolic disease
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 478:7367, s. 110-113
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes(1). Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring (14)C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.
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| 4. |
- Castillejo-Lopez, Casimiro, et al.
(författare)
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Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation
- 2019
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 20, s. 42-59
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Tidskriftsartikel (refereegranskat)abstract
- We combined CAGE sequencing in human adipocytes during differentiation with data from genome-wide association studies to identify an enhancer in the SNX10 locus on chromosome 7, presumably involved in body fat distribution. Using reporter assays and CRISPR-Cas9 gene editing in human cell lines, we characterized the role of the enhancer in adipogenesis. The enhancer was active during adipogenesis and responded strongly to insulin and isoprenaline. The allele associated with increased waist-hip ratio in human genetic studies was associated with higher enhancer activity. Mutations of the enhancer resulted in less adipocyte differentiation. RNA sequencing of cells with disrupted enhancer showed reduced expression of established adipocyte markers, such as ADIPOQ and LPL, and identified CHI3L1 on chromosome 1 as a potential gene involved in adipocyte differentiation. In conclusion, we identified and characterized an enhancer in the SNX10 locus and outlined its plausible mechanisms of action and downstream targets.
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| 5. |
- Ehrlund, A, et al.
(författare)
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Transcriptional Dynamics During Human Adipogenesis and Its Link to Adipose Morphology and Distribution
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 66:1, s. 218-230
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Tidskriftsartikel (refereegranskat)abstract
- White adipose tissue (WAT) can develop into several phenotypes with different pathophysiological impact on type 2 diabetes. To better understand the adipogenic process, the transcriptional events that occur during in vitro differentiation of human adipocytes were investigated and the findings linked to WAT phenotypes. Single-molecule transcriptional profiling provided a detailed map of the expressional changes of genes, enhancers, and long noncoding RNAs, where different types of transcripts share common dynamics during differentiation. Common signatures include early downregulated, transient, and late induced transcripts, all of which are linked to distinct developmental processes during adipogenesis. Enhancers expressed during adipogenesis overlap significantly with genetic variants associated with WAT distribution. Transiently expressed and late induced genes are associated with hypertrophic WAT (few but large fat cells), a phenotype closely linked to insulin resistance and type 2 diabetes. Transcription factors that are expressed early or transiently affect differentiation and adipocyte function and are controlled by several well-known upstream regulators such as glucocorticosteroids, insulin, cAMP, and thyroid hormones. Taken together, our results suggest a complex but highly coordinated regulation of adipogenesis.
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| 6. |
- Rydén, Mikael, et al.
(författare)
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Lipolysis defect in people with obesity who undergo metabolic surgery
- 2022
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Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell Publishing Inc.. - 0954-6820 .- 1365-2796. ; 292:4, s. 667-678
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cross-sectional studies demonstrate that catecholamine stimulation of fat cell lipolysis is blunted in obesity. We investigated whether this defect persists after substantial weight loss has been induced by metabolic surgery, and whether it is related to the outcome.DESIGN/METHODS: Patients with obesity not able to successfully reduce body weight by conventional means (n = 126) were investigated before and 5 years after Roux-en-Y gastric bypass surgery (RYGB). They were compared with propensity-score matched subjects selected from a control group (n = 1017), and with the entire group after adjustment for age, sex, body mass index (BMI), fat cell volume and other clinical parameters. Catecholamine-stimulated lipolysis (glycerol release) was investigated in isolated fat cells using noradrenaline (natural hormone) or isoprenaline (synthetic beta-adrenoceptor agonist).RESULTS: Following RYGB, BMI was reduced from 39.9 (37.5-43.5) (median and interquartile range) to 29.5 (26.7-31.9) kg/m2 (p < 0.0001). The post-RYGB patients had about 50% lower lipolysis rates compared with the matched and total series of controls (p < 0.0005). Nordrenaline activation of lipolysis at baseline was associated with the RYGB effect; those with high lipolysis activation (upper tertile) lost 30%-45% more in body weight, BMI or fat mass than those with low (bottom tertile) initial lipolysis activation (p < 0.0007).CONCLUSION: Patients with obesity requiring metabolic surgery have impaired ability of catecholamines to stimulate lipolysis, which remains despite long-term normalization of body weight by RYGB. Furthermore, preoperative variations in the ability of catecholamines to activate lipolysis may predict the long-term reduction in body weight and fat mass.
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| 7. |
- Andersson, Daniel P., et al.
(författare)
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Omentectomy in addition to gastric bypass surgery and influence on insulin sensitivity : A randomized double blind controlled trial
- 2014
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 33:6, s. 991-996
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Tidskriftsartikel (refereegranskat)abstract
- Background & aims: Accumulation of visceral adipose tissue is associated with insulin resistance and cardio-vascular disease. The aim of this study was to elucidate whether removal of a large amount of visceral fat by omentectomy in conjunction with Roux en-Y gastric bypass operation (RYGB) results in enhanced improvement of insulin sensitivity compared to gastric bypass surgery alone. Methods: Eighty-one obese women scheduled for RYGB were included in the study. They were randomized to RYGB or RYGB in conjunction with omentectomy. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp before operation and sixty-two women were also reexamined 2 years post-operatively. The primary outcome measure was insulin sensitivity and secondary outcome measures included cardio-metabolic risk factors. Results: Two-year weight loss was profound but unaffected by omentectomy. Before intervention, there were no clinical or metabolic differences between the two groups. The difference in primary outcome measure, insulin sensitivity, was not significant between the non-omentectomy (6.7 +/- 1.6 mg/kg body weight/minute) and omentectomy groups (6.6 +/- 1.5 mg/kg body weight/minute) after 2 years. Nor did any of the cardio-metabolic risk factors that were secondary outcome measures differ significantly. Conclusion: Addition of omentectomy to gastric bypass operation does not give an incremental effect on long term insulin sensitivity or cardio-metabolic risk factors. The clinical usefulness of omentectomy in addition to gastric bypass operation is highly questionable.
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| 8. |
- Andersson, Karl-Erik, et al.
(författare)
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Urinary bladder contraction and relaxation: Physiology and pathophysiology
- 2004
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Ingår i: Physiological Reviews. - : American Physiological Society. - 1522-1210 .- 0031-9333. ; 84:3, s. 935-986
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Forskningsöversikt (refereegranskat)abstract
- The detrusor smooth muscle is the main muscle component of the urinary bladder wall. Its ability to contract over a large length interval and to relax determines the bladder function during filling and micturition. These processes are regulated by several external nervous and hormonal control systems, and the detrusor contains multiple receptors and signaling pathways. Functional changes of the detrusor can be found in several clinically important conditions, e.g., lower urinary tract symptoms (LUTS) and bladder outlet obstruction. The aim of this review is to summarize and synthesize basic information and recent advances in the understanding of the properties of the detrusor smooth muscle, its contractile system, cellular signaling, membrane properties, and cellular receptors. Alterations in these systems in pathological conditions of the bladder wall are described, and some areas for future research are suggested.
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| 9. |
- Arner, Erik
(författare)
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Solving repeat problems in shotgun sequencing
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Shotgun sequencing is the most powerful strategy for large scale sequencing. Two main approaches exist: clone-by-clone and whole genome shotgun (WGS). In the clone-by-clone strategy, overlapping clones are amplified and then sheared in a random fashion. In the WGS approach, a sufficient amount of cells from the target organism are obtained, and the random shearing is performed on extracted DNA. In both approaches, the resulting fragments are cloned and the fragment ends are subsequently sequenced, producing sequence reads. If a sufficient amount of sequence has been obtained, the reads will overlap in a way that makes it possible to deduce their correct order. A number of computer programs have been developed for this task. However, none of these programs are capable of producing correct assemblies if the target sequence contains repeats. This is because assembly algorithms in general are greedy, which means that when faced with different alternatives for the positioning of a read, the algorithm will fit the read at the first available position meeting the criteria for inclusion into the assembly. The resulting assemblies typically have the repeat regions degenerated, truncating the regions into a few copies with abnormally high shotgun coverage. This phenomenon occurs even when the repeat copies differ from each other, since the assembly programs are unable to distinguish the subtle differences between repeat elements from the sequencing errors produced by the sequencing apparatus. The work presented here is aimed at solving the repeat problem by detecting and utilizing single base differences between nearly identical repeats. In paper I, a statistical method for detecting repeat differences in the presence of sequencing errors was developed, implemented, and tested on simulated data. We showed that it is possible to obtain high specificity as well as sensitivity compared to other methods, by evaluating coinciding deviations from consensus in pairs of columns in multiple alignments. In paper II, a finishing tool (DNPTrapper) that visualizes the differences and enables manual and semi-automatic resolution of repeat regions was constructed and tested with simulated data as well as real data from the Trypanosoma cruzi WGS project. Results showed that using DNPTrapper, it is possible to resolve and analyze complicated repeat regions previously considered difficult or even impossible to resolve. Finally in paper III, five repeated genes in T. cruzi were analyzed using DNPTrapper. Different repeat characteristics in the parasite were described, and it was shown that thorough analysis of repeat regions is required for correcting erroneous consensus sequences of repeated genes in the assembly.
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| 10. |
- Arner, Peter, et al.
(författare)
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Variations in the size of the major omentum are primarily determined by fat cell number
- 2013
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:5, s. E897-E901
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Accumulation of visceral adipose tissue (VAT) is strongly linked to insulin resistance. Variations in the size of any adipose depot are determined by alterations in adipocyte volume and/or number. The individual contribution of each of the latter factors was determined in the major omentum, a fully resectable VAT depot.SUBJECTS: Total removal of the major omentum (omentectomy) was performed in conjunction with bariatric surgery in 55 obese patients. Tissue weight as well as mean adipocyte size and number in the omentum were determined. In subgroups, total VAT was estimated by computerized tomography (n = 17) or dual-energy x-ray absorptiometry (n = 34).RESULTS: The weight of the major omentum (on average 0.6 kg) correlated significantly with total VAT mass estimated by computerized tomography or dual-energy x-ray absorptiometry (r = 0.48-0.7; P < .01). Omental weight in relation to total body fat correlated with several features of the metabolic syndrome and inversely with serum-leptin (P < .001). Mean adipocyte size and total adipocyte number correlated strongly with omental weight (r = 0.6-0.8; P < .0001), irrespective of body mass index and total body fat mass, and accounted almost in total for interindividual variations in omental size. However, stepwise regression analysis demonstrated that adipocyte number was significantly (P < .0001) more important (62%) than adipocyte size (35%).CONCLUSION: The size of the major omentum is representative for VAT mass and correlates with a pernicious metabolic profile. Variations in omental weight are primarily determined by adipocyte number and to a lesser degree by adipocyte size, suggesting that increased VAT mass in obesity is predominantly dependent on adipocyte proliferation.
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| 11. |
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| 12. |
- Ekman, Mari, et al.
(författare)
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Receptor-induced phasic activity of newborn mouse bladders is inhibited by protein kinase C and involves T-type Ca channels.
- 2009
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Ingår i: BJU International. - 1464-4096 .- 1464-410X. ; 104:5, s. 690-697
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To investigate the mechanisms involved in the phasic contractile activity after muscarinic receptor activation of newborn urinary bladders and to compare neonatal and adult bladders. MATERIALS AND METHODS Detrusor muscle strips were isolated from newborn mice (aged 0-2 days) and compared with preparations from adult mice (aged 10-12 weeks). The effects of an activator (phorbol 12,13-dibutyrate, PDBu) and an inhibitor (GF109203X) of protein kinase C (PKC) on contractions were investigated. T-type Ca(2+) channels were blocked with NiCl(2). RESULTS The newborn urinary bladders responded with prominent phasic contractile activity in response to carbachol (1 microm). GF109203X (3 microm) reduced carbachol-induced force by approximately 60% in the newborn, compared with 30% in the adult. PDBu (1 microm) enhanced the muscarinic receptor-mediated contraction in adult bladder muscle, whereas it completely abolished the responses in the newborn. There was no inhibition after activation with depolarization (high-K(+)) or purinergic agonists (ATP, alpha,beta-methylene ATP). NiCl(2) (>30 microm) inhibited the peak responses to carbachol in the newborn and at 300 microm it completely abolished the phasic contractile response. The responses of the adult bladder muscle were only marginally affected by NiCl(2). CONCLUSIONS Muscarinic receptor stimulation recruits the PKC signalling pathway in both the adult and neonatal urinary bladder. Potent PKC activation is inhibitory on carbachol-induced activation in the newborn and stimulatory in the adult bladder. Furthermore, muscarinic receptor stimulation activates T-type Ca(2+) channels in the newborn, but not the adult bladder.
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| 13. |
- Ekman, Mari, et al.
(författare)
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Signal transduction pathways of muscarinic receptor mediated activation in the newborn and adult mouse urinary bladder.
- 2009
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Ingår i: BJU International. - 1464-4096. ; 103:1, s. 90-97
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE To study the role of M(2) and M(3) muscarinic receptor subtypes, sources of activator Ca(2+), and mechanisms involved in increased force oscillations in muscarinic contractions in the bladders of newborn and adult mice, as in the adult bladder muscarinic M(3) receptors are considered to mediate the main part of bladder contraction, and this has not been established in the newborn bladder. MATERIALS AND METHODS Bladder preparations from newborn (0-2 days) and adult (10-12 weeks) mice were mounted for in vitro force registration and activated with carbachol and high-K(+) solution in the presence of M(3) (4-DAMP 30 nm) or M(2) (methoctramine, 100 nm) receptor antagonists. Thapsigargin (1 microm) or ryanodine (10 microm) were used to inhibit sarcoplasmic reticulum Ca(2+) release. L-NAME (300 microm) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microm) were used to inhibit nitric oxide synthase and guanylyl cyclase, respectively. Gap-junction function was inhibited with by 18-beta-glycyrrhetinic acid (18-beta-GA; 0.1-100 microm). Big-conductance (BK) and small-conductance (SK) K(+) channels were inhibited by apamine and charybdotoxin (0.3 microm), respectively. RESULTS Concentration-response relations for carbachol in the presence of 4-DAMP and methoctramine showed that M(3) receptors are the main activating pathway also in the newborn bladder. Neither thapsigargin nor ryanodine influenced the muscarinic responses of the newborn and adult bladders. Carbachol-induced contractions were not influenced by L-NAME or ODQ. The 18-beta-GA inhibited carbachol-induced contractions in both newborn and adult tissue in a similar manner. Apamine and charybdotoxin slightly increased the amplitude of the contractile responses. CONCLUSION These results suggest that in the newborn mouse bladder, as in adult bladders, the M(3) muscarinic receptor subtype is mainly responsible for carbachol-induced contractile responses. The main mechanism for muscarinic receptor-induced activation is influx of Ca(2+) from the extracellular medium, and there seems to be no major contribution of Ca(2+) release from intracellular stores. The phasic contractile activity induced by carbachol in the newborn bladder is not influenced by gap junction inhibition and does not involve SK and BK channels.
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| 14. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 15. |
- Franzen, Oscar, et al.
(författare)
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The Short Non-Coding Transcriptome of the Protozoan Parasite Trypanosoma cruzi
- 2011
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Ingår i: PLoS Neglected Tropical Diseases. - : Public Library of Science (PLoS). - 1935-2727 .- 1935-2735. ; 5:8, s. e1283-
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Tidskriftsartikel (refereegranskat)abstract
- The pathway for RNA interference is widespread in metazoans and participates in numerous cellular tasks, from gene silencing to chromatin remodeling and protection against retrotransposition. The unicellular eukaryote Trypanosoma cruzi is missing the canonical RNAi pathway and is unable to induce RNAi-related processes. To further understand alternative RNA pathways operating in this organism, we have performed deep sequencing and genome-wide analyses of a size-fractioned cDNA library (16-61 nt) from the epimastigote life stage. Deep sequencing generated 582,243 short sequences of which 91% could be aligned with the genome sequence. About 95-98% of the aligned data (depending on the haplotype) corresponded to small RNAs derived from tRNAs, rRNAs, snRNAs and snoRNAs. The largest class consisted of tRNA-derived small RNAs which primarily originated from the 3' end of tRNAs, followed by small RNAs derived from rRNA. The remaining sequences revealed the presence of 92 novel transcribed loci, of which 79 did not show homology to known RNA classes.
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| 16. |
- Li, Mei, et al.
(författare)
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Development and prevention of ischemic contracture (“stone heart”) in the pig heart
- 2023
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Ingår i: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs. Following cessation of ventilation, circulatory death (systolic pressure <8 mmHg) occurred within 13.1 ± 1.2 min; and a stone heart, manifested with asystole, increased left ventricular wall thickness and stiffness, established after a further 17 ± 6 min. Adenosine triphosphate and phosphocreatine levels decreased by about 50% in the stone heart. Electron microscopy showed deteriorated structure with contraction bands, Z-line streaming and swollen mitochondria. Synchrotron based small angle X-ray scattering of trabecular samples from stone hearts revealed attachment of myosin to actin, without volume changes in the sarcomeres. Ca2+ sensitivity, determined in permeabilized muscle, was increased in stone heart samples. An in vitro model for stone heart, using isolated trabecular muscle exposed to hypoxia/zero glucose, exhibited the main characteristics of stone heart in whole animals, with a fall in high-energy phosphates and development of muscle contracture. The stone heart condition in vitro was significantly attenuated by the myosin inhibitor MYK-461 (Mavacamten). In conclusion, the stone heart is a hypercontracted state associated with myosin binding to actin and increased Ca2+ sensitivity. The hypercontractile state, once developed, is poorly reversible. The myosin inhibitor MYK-461, which is clinically approved for other indications, could be a promising venue for prevention.
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| 17. |
- Miliara, Sophia, et al.
(författare)
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The biological and prognostic role of long non-coding RNA NEAT1 in acute myeloid leukemia
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Nuclear paraspeckle assembly transcript 1 (NEAT1) is a long non-coding RNA localized in the cell nucleus that has been associated to promote several malignant solid tumors. Its role in acute myeloid leukemia (AML) remains largely elusive. Therefore, the aim of this study was to define the role of NEAT1 in AML compared to normal hematopoiesis. During normal hematopoiesis, it was identified that NEAT1 expression was low in early progenitors but increased in more differentiated cells, especially in monocytes. NEAT1 expression was increased in AML as a whole compared to normal bone marrow (NBM). It was specifically high in AML with inv(16) and t(8;21), while it was lower in patients with t(15;17). Further, NEAT1 expression correlated positively with ASXL1, KRAS and NRAS mutations and negatively with TP53 mutant AML. Higher NEAT expression was associated to better overall survival in AML, independent of other known risk factors. Antisense oligo-mediated knockdown of NEAT1 in AML cells significantly increased expression of the monocytic marker CD14 while granulocytic markers did not change. Genes affected by NEAT1-knockdown using CAGE-sequencing were significantly enriched for genes involved in glucose metabolism. By investigating genome-wide RNA and DNA interactions using RADICL-sequencing, it was revealed that NEAT1 binds to the loci of key hematopoietic regulator RUNX2 as well as the chromatin regulators KMT2A, KMT5B and CHD7. The results suggest that lncRNA NEAT1 has a potential role in hematopoietic and AML cell differentiation and could be a potential new biomarker in AML.
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| 18. |
- Pillon, Nicolas J., et al.
(författare)
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Distinctive exercise-induced inflammatory response and exerkine induction in skeletal muscle of people with type 2 diabetes
- 2022
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Ingår i: Science Advances. - : NLM (Medline). - 2375-2548. ; 8:36
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Tidskriftsartikel (refereegranskat)abstract
- Mechanistic insights into the molecular events by which exercise enhances the skeletal muscle phenotype are lacking, particularly in the context of type 2 diabetes. Here, we unravel a fundamental role for exercise-responsive cytokines (exerkines) on skeletal muscle development and growth in individuals with normal glucose tolerance or type 2 diabetes. Acute exercise triggered an inflammatory response in skeletal muscle, concomitant with an infiltration of immune cells. These exercise effects were potentiated in type 2 diabetes. In response to contraction or hypoxia, cytokines were mainly produced by endothelial cells and macrophages. The chemokine CXCL12 was induced by hypoxia in endothelial cells, as well as by conditioned medium from contracted myotubes in macrophages. We found that CXCL12 was associated with skeletal muscle remodeling after exercise and differentiation of cultured muscle. Collectively, acute aerobic exercise mounts a noncanonical inflammatory response, with an atypical production of exerkines, which is potentiated in type 2 diabetes.
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| 19. |
- Reitzner, Stefan M., et al.
(författare)
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Molecular profiling of high-level athlete skeletal muscle after acute endurance or resistance exercise : A systems biology approach
- 2024
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Ingår i: Molecular Metabolism. - : Elsevier GmbH. - 2212-8778. ; 79
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Long-term high-level exercise training leads to improvements in physical performance and multi-tissue adaptation following changes in molecular pathways. While skeletal muscle baseline differences between exercise-trained and untrained individuals have been previously investigated, it remains unclear how training history influences human multi-omics responses to acute exercise. Methods: We recruited and extensively characterized 24 individuals categorized as endurance athletes with >15 years of training history, strength athletes or control subjects. Timeseries skeletal muscle biopsies were taken from M. vastus lateralis at three time-points after endurance or resistance exercise was performed and multi-omics molecular analysis performed. Results: Our analyses revealed distinct activation differences of molecular processes such as fatty- and amino acid metabolism and transcription factors such as HIF1A and the MYF-family. We show that endurance athletes have an increased abundance of carnitine-derivates while strength athletes increase specific phospholipid metabolites compared to control subjects. Additionally, for the first time, we show the metabolite sorbitol to be substantially increased with acute exercise. On transcriptional level, we show that acute resistance exercise stimulates more gene expression than acute endurance exercise. This follows a specific pattern, with endurance athletes uniquely down-regulating pathways related to mitochondria, translation and ribosomes. Finally, both forms of exercise training specialize in diverging transcriptional directions, differentiating themselves from the transcriptome of the untrained control group. Conclusions: We identify a “transcriptional specialization effect” by transcriptional narrowing and intensification, and molecular specialization effects on metabolomic level Additionally, we performed multi-omics network and cluster analysis, providing a novel resource of skeletal muscle transcriptomic and metabolomic profiling in highly trained and untrained individuals.
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| 20. |
- Rosqvist, Fredrik, et al.
(författare)
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Overfeeding Polyunsaturated and Saturated Fat Causes Distinct Effects on Liver and Visceral Fat Accumulation in Humans
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:7, s. 2356-2368
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Tidskriftsartikel (refereegranskat)abstract
- Excess ectopic fat storage is linked to type 2 diabetes. The importance of dietary fat composition for ectopic fat storage in humans is unknown. We investigated liver fat accumulation and body composition during overfeeding saturated (SFA) or polyunsaturated (PUFA) fat. LIPOGAIN was a double-blind, parallel-group, randomized trial. Thirty-nine young and normal-weight individuals were overfed muffins high in SFA (palm oil) or n-6 PUFA (sunflower oil) for 7 weeks. Liver fat, visceral (VAT), subcutaneous abdominal (SAT), and total adipose tissue (TAT), pancreatic fat, and lean tissue was assessed by MRI. Transcriptomics were performed in SAT. Both groups gained similar weight. SFA however markedly increased liver fat compared with PUFA and caused 2-fold larger increase in VAT than PUFA. Conversely, PUFA caused a nearly 3-fold larger increase in lean tissue than SFA. Increase in liver fat directly correlated with changes in plasma SFA and inversely with PUFA. Genes involved in regulating energy dissipation, insulin resistance, body composition and fat cell differentiation in SAT were differentially regulated between diets, and associated with increased PUFA in SAT. In conclusion, overeating SFA promotes hepatic and visceral fat storage whereas excess energy from PUFA may instead promote lean tissue in healthy humans.
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| 21. |
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| 22. |
- Szekeres, Ferenc L. M., et al.
(författare)
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A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia–reperfusion in the mouse heart
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia–reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart.
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| 23. |
- Tabrizi, Fara, et al.
(författare)
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P117. Predicting Genetic Risk for Depression and Anxiety Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPolygenic scores (PGSs) harness the potential to provide an overall measure of individuals’ genetic liability to develop a disease (Torkamani et al., 2018), though much research is still needed. The aim of the present study was to predict prescription of pharmacological treatment of anxiety or depression from PGSs.MethodsThe target sample comprised two cohorts of genotyped Swedish twins (n = 11037). Cases were defined as individuals prescribed pharmacological treatment of depression (n = 1129) or anxiety (n = 1446). We constructed 6 PGSs based on GWAS on MDD diagnosis, Anxiety, Schizophrenia, Neuroticism scores, the GAD-7 scale, and the PHQ-9. Data were analyzed by logistic regression models with change in pseudo-R2 (above the baseline model with sex, age, cohort, and 20 ancestral PCs) following the inclusion of PGSs to predict the risk of anxiety or depression medication. All results corrected for multiple comparisons.ResultsPredictive performance was estimated to ΔR2depression = 0.028; ΔR2anxiety = 0.025 when all PGSs were included in the same model, with PGS for MDD being the single best predictor for both anxiety and depression. Individuals in the top 10% of the PGS distribution had greater odds of drug prescription (ORdepression = 1.82; CI95% = 1.53—2.17; ORanxiety = 1.65; CI95% = 1.40—1.95), while the bottom 10% had decreased risk (ORanxiety = 0.56; CI95% = 0.45—0.70; ORdepression = 0.58; CI95% = 0.45—0.74) compared to the remaining 90% of the distribution.ConclusionsPGSs can predict drug prescription for anxiety and depression in an independent sample.
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| 24. |
- Tabrizi, Fara, et al.
(författare)
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Prediction of anxiety and depression from polygenic scores in Swedish twins
- 2021
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Ingår i: Abstracts of the WASAD Congress 2021. - : Springer. ; , s. 1802-1803
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Konferensbidrag (refereegranskat)abstract
- Recent genome-wide association studies (GWAS) have identified several common variants associated with depression (Howard et al. 2019; Levey et al. 2021) and anxiety disorders (Levey et al. 2020; Meier et al. 2019; Purves et al. 2020), and these findings have been harnessed to develop polygenic scores (PGS) in order to provide an overall measure of individuals’ genetic liability to develop a disease (Torkamani et al. 2018). Research on the utility of PGSs as predictors of risk for disease is gaining traction, with studies on somatic illness showing that disease risk increases sharply in the right tail of the PGS distribution (Khera et al. 2018). Thus, PGS stratification could be of clinical relevance if it provides an opportunity to target those in need of preventive interventions with increased precision. The current potential of PGS stratification for depression and anxiety disorders remains an open question. In the current study, we applied 36 predefined PGSs from the polygenic index repository (Becker et al. 2021) on a target sample of 11,210 genotyped twins. Cases were defined as those with prescribed medication, where the prescription explicitly stated that a drug was ordinated for indication of depression or anxiety, respectively. Drugs included antidepressants (SSRI and SNRI), Benzodiazepines, Antihistamines, Buspirone, and Betablockers.
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| 25. |
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| 26. |
- Tammi, Martti, et al.
(författare)
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Separation of Nearly Identical Repeats in Shotgun Assemblies using Defined Nucloetide Positions, DNPs
- 2002
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 18:3, s. 379-388
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Tidskriftsartikel (refereegranskat)abstract
- An increasingly important problem in genome sequencing is the failure of the commonly used shotgun assembly programs to correctly assemble repetitive sequences. The assembly of non-repetitive regions or regions containing repeats considerably shorter than the average read length is in practice easy to solve, while longer repeats have been a difficult problem. We here present a statistical method to separate arbitrarily long, almost identical repeats, which makes it possible to correctly assemble complex repetitive sequence regions. The differences between repeat units may be as low as 1% and the sequencing error may be up to ten times higher. The method is based on the realization that a comparison of only a part of all overlapping sequences at a time in a data set does not generate enough information for a conclusive analysis. Our method uses optimal multi-alignments consisting of all the overlaps of each read. This makes it possible to determine defined nucleotide positions, DNPs, which constitute the differences between the repeat units. Differences between repeats are distinguished from sequencing errors using statistical methods, where the probabilities of obtaining certain combinations of candidate DNPs are calculated using the information from the multi-alignments. The use of DNPs and combinations of DNPs will allow for optimal and rapid assemblies of repeated regions. This method can solve repeats that differ in only two positions in a read length, which is the theoretical limit for repeat separation. We predict that this method will be highly useful in shotgun sequencing in the future.
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| 27. |
- Tammi, Martti, et al.
(författare)
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TRAP : Tandem Repeat Assembly Program produces improved shotgun assemblies of repetitive sequences
- 2003
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Ingår i: Computer Methods and Programs in Biomedicine. - 0169-2607 .- 1872-7565. ; 70:1, s. 47-59
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Tidskriftsartikel (refereegranskat)abstract
- The software commonly used for assembly of shotgun sequence data has several limitations. One such limitation becomes obvious when repetitive sequences are encountered. Shotgun assembly is a difficult task, even for non-repetitive regions, but the use of quality assessments of the data and efficient matching algorithms have made it possible to assemble most sequences efficiently. In the case of highly repetitive sequences, however, these algorithms fail to distinguish between sequencing errors and single base differences in regions containing nearly identical repeats. None of the currently available fragment assembly programs are able to correctly assemble highly similar repetitive data, and we, therefore, present a novel shotgun assembly program, Tandem Repeat Assembly Program (TRAP). The main feature of this program is the ability to separate long repetitive regions from each other by distinguishing single base substitutions as well as insertions/deletions from sequencing errors. This is accomplished by using a novel multiple-alignment based analysis method. Since repeats are a common complication in most sequencing projects, this software should be of use for the whole sequencing community.
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| 28. |
- van Harmelen, Vanessa, et al.
(författare)
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The vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 57:2, s. 378-386
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTAT-Visceral obesity increases risk of insulin resistance and type 2 diabetes. This may partly be due to a region-specific resistance to insulin's antilipolytic effect in visceral adipocytes. We investigated whether adipose tissue releases the vascular peptide endothelin-1 (ET-1) and whether ET-1 could account for regional differences in lipolysis. RESEARCH DESIGN AND METHODS-One group consisted of eleven obese and eleven nonobese subjects in whom ET-1 levels were compared between abdominal subcutaneous and arterialized blood samples. A second group included subjects undergoing anti-obesity surgery. Abdominal subcutaneous and visceral adipose tissues were obtained to study the effect of ET-1 on differentiated adipocytes regarding lipolysis and gene and protein expression. RESULTS-Adipose tissue had a marked net release of ET-1 in vivo, which was 2.5-fold increased in obesity. In adipocytes treated with ET-1, the antilipolytic effect of insulin was attenuated in Visceral but not in subcutaneous adipocytes, which could not be explained by effects of ET-1 on adipocyte differentiation. ET-1 decreased the expression of insulin receptor, insulin receptor substrate-1 and phosphodiesterase-3B and increased the expression of endothelin receptor-B (ETBR) in visceral but not in subcutaneous adipocytes. These effects were mediated via ETBR with signals through protein kinase C and calmodulin pathways. The effect of ET-1 could be mimicked by knockdown of IRS-1. CONCLUSIONS-ET-1 is released front human adipose tissue and links fat accumulation to insulin resistance. It selectively counteracts insulin inhibition of visceral adipocyte lipolysis via ETBR signaling pathways, which affect multiple steps in insulin signaling.
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| 29. |
- Wållberg, Helena, et al.
(författare)
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HER2-Positive Tumors Imaged Within 1 Hour Using a Site-Specifically C-11-Labeled Sel-Tagged Affibody Molecule
- 2012
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Ingår i: Journal of Nuclear Medicine. - Stockholm : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:9, s. 1446-1453
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Tidskriftsartikel (refereegranskat)abstract
- A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for individualizing therapy and predicting prognoses. In vivo imaging methods are available but not yet in clinical practice; new methodologies improving speed, sensitivity, and specificity are required. Methods: A HER2-binding Affibody molecule, Z(HER2:342), was recombinantly fused with a C-terminal selenocysteine-containing tetrapeptide Sel-tag, allowing site-specific labeling with either C-11 or Ga-68, followed by biodistribution studies with small-animal PET. Dosimetry data for the 2 radiotracers were compared. Imaging of HER2-expressing human tumor xenografts was performed using the C-11-labeled Affibody molecule. Results: Both the C-11- and Ga-68-labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4-5 percentage injected dose per gram of tissue at 1 h. Final retention in the kidneys was much lower (>5-fold) for the C-11-labeled protein, and its overall absorbed dose was considerably lower. C-11-Z(HER2:342) showed excellent tumor-targeting capability, with almost 10 percentage injected dose per gram of tissue in HER2-expressing tumors within 1 h. Specificity was demonstrated by preblocking binding sites with excess ligand, yielding significantly reduced radiotracer uptake (P = 0.002), comparable to uptake in tumors with low HER2 expression. Conclusion: To our knowledge, the Sel-tagging technique is the first that enables site-specific C-11-radiolabeling of proteins. Here we present the finding that, in a favorable combination between radionuclide half-life and in vivo pharmacokinetics of the Affibody molecules, C-11-labeled Set-tagged Z(HER2:342) can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.
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| 30. |
- Wållberg, Helena, et al.
(författare)
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Specific in vivo imaging of HER2-positive tumors within one hour using a site-specifically 11C-labeled Sel-tagged Affibody molecule
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for improvement of cancer care. In v ivo imaging methods are available, but are not yet in clinical practice; new methodologies improving speed, sensitivity and specificity are required. Here we describe promising results with a HER2‐binding Affibody molecule, ZHER2:342, recombinantly fused with a C‐terminal selenocysteine‐containing tetrapeptide Sel‐tag and site‐specifically labeled with either 11C or 68Ga for molecular imaging applications with positron emissiontomography (PET). In mice, both the 11C‐ and 68Ga‐labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4‐5 %ID/g at 1 h. Final uptake in kidneys was much lower (> 5‐fold) for the 11C‐labeled protein, leading to markedly reduced background radioactivity in the abdomen. Furthermore, 11C‐labeled Sel‐tagged ZHER2:342 showed excellent tumor targeting capability, with almost 10 %ID/g in HER2 expressing tumors within the first hour. High specificity was demonstrated by preblocking the binding sites with excess ligand, which yielded low radiotracer uptakes, comparable to those in tumors with low endogenous HER2 expression. To our knowledge the Sel‐tagging technique is the first that enables site‐specific 11C radiolabelingof proteins. Here we present that, in a favorable combination between radionuclide half‐life and in vivo pharmacokinetics of the Affibody molecules, 11C‐labeled Sel taggedZHER2:342 can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.
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