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| 12. |
- Loyfer, N, et al.
(författare)
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A DNA methylation atlas of normal human cell types
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:79447943, s. 355-
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2–5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.
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| 13. |
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| 14. |
- Garey, J, et al.
(författare)
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Genetic contributions to generalized arousal of brain and behavior
- 2003
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 100:19, s. 11019-11022
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Tidskriftsartikel (refereegranskat)abstract
- We have identified a generalized arousal component in the behavior of mice. Analyzed by mathematical/statistical approaches across experiments, investigators, and mouse populations, it accounts for about 1/3 of the variance in arousal-related measures. Knockout of the gene coding for the classical estrogen receptor (ER-α), a ligand-activated transcription factor, greatly reduced arousal responses. In contrast, disrupting the gene for a likely gene duplication product, ER-β, did not have these effects. A combination of mathematical and genetic approaches to arousal in an experimentally tractable mammal opens up analysis of a CNS function of considerable theoretical and practical significance.
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| 15. |
- La Merrill, Michele A, et al.
(författare)
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Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification
- 2020
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Ingår i: Nature Reviews Endocrinology. - : Nature Publishing Group. - 1759-5029 .- 1759-5037. ; 16:1, s. 45-57
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Tidskriftsartikel (refereegranskat)abstract
- Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.
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| 16. |
- Moss, J, et al.
(författare)
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Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 5068-
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Tidskriftsartikel (refereegranskat)abstract
- Methylation patterns of circulating cell-free DNA (cfDNA) contain rich information about recent cell death events in the body. Here, we present an approach for unbiased determination of the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types. The method is validated using in silico simulations as well as in vitro mixes of DNA from different tissue sources at known proportions. We show that plasma cfDNA of healthy donors originates from white blood cells (55%), erythrocyte progenitors (30%), vascular endothelial cells (10%) and hepatocytes (1%). Deconvolution of cfDNA from patients reveals tissue contributions that agree with clinical findings in sepsis, islet transplantation, cancer of the colon, lung, breast and prostate, and cancer of unknown primary. We propose a procedure which can be easily adapted to study the cellular contributors to cfDNA in many settings, opening a broad window into healthy and pathologic human tissue dynamics.
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| 17. |
- Archer, A, et al.
(författare)
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Skeletal muscle as a target of LXR agonist after long-term treatment: focus on lipid homeostasis
- 2014
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 306:5, s. E494-E502
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Tidskriftsartikel (refereegranskat)abstract
- The liver X receptors (LXR)α and LXRβ are transcription factors belonging to the nuclear receptor family, which play a central role in metabolic homeostasis, being master regulators of key target genes in the glucose and lipid pathways. Wild-type (WT), LXRα−/−, and LXRβ−/−mice were fed a chow diet with (treated) or without (control) the synthetic dual LXR agonist GW3965 for 5 wk. GW3965 raised intrahepatic triglyceride (TG) level but, surprisingly, reduced serum TG level through the activation of serum lipase activity. The serum TG reduction was associated with a repression of both catecholamine-stimulated lipolysis and relative glucose incorporation into lipid in isolated adipocytes through activation of LXRβ. We also demonstrated that LXRα is required for basal (nonstimulated) adipocyte metabolism, whereas LXRβ acts as a repressor of lipolysis. On the contrary, in skeletal muscle (SM), the lipogenic and cholesterol transporter LXR target genes were markedly induced in WT and LXRα−/−mice and to a lesser extent in LXRβ−/−mice following treatment with GW3965. Moreover, TG content was reduced in SM of LXRβ−/−mice, associated with increased expression of the main TG-lipase genes Hsl and Atgl. Energy expenditure was increased, and a switch from glucose to lipid oxidation was observed. In conclusion, we provide evidence that LXR might be an essential regulator of the lipid balance between tissues to ensure appropriate control of the flux of fuel. Importantly, we show that, after chronic treatment with GW3965, SM becomes the target tissue for LXR activation, as opposed to liver, in acute treatment.
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| 19. |
- Korach-Andre, M, et al.
(författare)
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Liver X receptors regulate de novo lipogenesis in a tissue-specific manner in C57BL/6 female mice
- 2011
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 301:1, s. E210-E222
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Tidskriftsartikel (refereegranskat)abstract
- The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRαβ−/−mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRαβ−/−mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRαβ−/−mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRαβ−/−mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from V̇o2and V̇co2was significantly higher in LXRαβ−/−than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRαβ−/−mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRαβ−/−mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRαβ−/−mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRαβ−/−mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development.
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| 20. |
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| 21. |
- Ogawa, S, et al.
(författare)
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Estrogen increases locomotor activity in mice through estrogen receptor alpha: specificity for the type of activity
- 2003
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 144:1, s. 230-239
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Tidskriftsartikel (refereegranskat)abstract
- Estrogens are known to increase running wheel activity of rodents primarily by acting on the medial preoptic area (mPOA). The mechanisms of this estrogenic regulation of running wheel activity are not completely understood. In particular, little is known about the separate roles of two types of estrogen receptors, ERα and ERβ, both of which are expressed in mPOA neurons. In the present study the effects of continuous estrogen treatment on running wheel activity were examined in male and female mice specifically lacking either the ERα (αERKO) or the ERβ (βERKO) gene. Mice were gonadectomized and 1 wk later implanted with either a low dose (16 ng/d) or a high dose (160 ng/d) of estradiol benzoate (EB) or with a placebo control pellet. Home cage running wheel activity was recorded for 9 d starting 10 d after EB implants. The same mice were also tested for open field activity before and after EB implants. In both female and male αERKO mice, running wheel activity was not different from that in corresponding wild-type (αWT) mice in placebo control groups. In both females and males it was increased by EB only in αWT, not αERKO, mice. In βERKO mice, on the other hand, both doses of EB equally increased running wheel activity in both sexes just as they did in βWT mice. Absolute numbers of daily revolutions of EB-treated groups, however, were significantly lower in βERKO females compared with βWT females. Before EB treatment, gonadectomized αERKO female were significantly less active than αWT mice in open field tests, whereas βERKO females tended to be more active than βWT mice. In male mice there were no effect of ERα or ERβ gene knockout on open field activity. Unlike its effect on running wheel activity, EB treatment induced only a small increase in open field activity in female, but not male, mice. These findings indicate that 1) in both sexes estrogenic regulation of running wheel activity is primarily mediated through the ERα, not the ERβ; and 2) hormone/genotype effects are specific to the type of locomotor activity (i.e. home cage running wheel activity and open field activity) measured.
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| 22. |
- Ogawa, S, et al.
(författare)
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Survival of reproductive behaviors in estrogen receptor beta gene-deficient (betaERKO) male and female mice
- 1999
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 96:22, s. 12887-12892
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Tidskriftsartikel (refereegranskat)abstract
- Previously, it was shown that the lack of a functional estrogen receptor (ER) α gene (ERα) greatly affects reproduction-related behaviors in both female and male mice. However, widespread expression of a novel second ER gene, ERβ, demanded that we examine the possible participation of ERβ in regulation of these behaviors. In dramatic contrast to our results with ERα knockout (αERKO) males, βERKO males performed at least as well as wild-type controls in sexual behavior tests. Moreover, not only did βERKO males exhibit normal male-typical aggressive behavior, including offensive attacks, but they also showed higher levels of aggression than wild-type mice under certain conditions of social experience. These data revealed a significant interaction between genotype and social experience with respect to aggressive behavior. Finally, females lacking a functional β isoform of the ER gene showed normal lordosis and courtship behaviors, extending in some cases beyond the day of behavioral estrus. These results highlight the importance of ERα for the normal expression of natural reproductive behaviors in both sexes and also provide a background for future studies evaluating ERβ gene contributions to other, nonreproductive behaviors.
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| 23. |
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| 24. |
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| 25. |
- Stegmayr, Bernd, et al.
(författare)
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World apheresis registry
- 2005
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Ingår i: Journal of clinical apheresis. - New York : Allen R. Liss. - 0733-2459 .- 1098-1101. ; 20:2, s. 126-127
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Tidskriftsartikel (refereegranskat)
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