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| 23. |
- Do, DV, et al.
(författare)
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A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo
- 2013
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Ingår i: Genes & development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 27:12, s. 1378-1390
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Tidskriftsartikel (refereegranskat)abstract
- Although it is known that OCT4–NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4–NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.
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| 27. |
- Gu, Y, et al.
(författare)
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Strong association between nutritional markers and arterial stiffness in continuous ambulatory peritoneal dialysis patients
- 2008
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Ingår i: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 26:4, s. 340-346
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Malnutrition is a predictor of cardiovascular disease in dialysis patients, but the mechanisms remain unknown. We investigated links between nutritional markers and arterial stiffness in continuous ambulatory peritoneal dialysis patients. <i>Methods:</i> We evaluated the relationship between arterial stiffness evaluated by pulse-wave velocity (PWV) and four estimates of nutritional status (serum albumin, handgrip strength [HGS], subjective global assessment [SGA], and bioelectrical impedance analysis phase angle [PA]) in 124 PD patients. <i>Results:</i> Malnourished patients exhibited a significantly higher PWV than those classified as well-nourished by SGA (p < 0.05). Furthermore, PWV correlated negatively with albumin, HGS and PA (p < 0.001, respectively). PWV was also correlated with age, systolic blood pressure, and C-reactive protein. In multivariate regression analysis, albumin, HGS, SGA and PA were each independently associated with PWV after adjustment. <i>Conclusions:</i> The significant association between each nutritional marker and PWV in PD patients was independent of inflammation and diabetic state, suggesting that malnutrition may contribute to vascular dysfunction.
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| 29. |
- Guo, JP, et al.
(författare)
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Sequencing of the MHC region defines HLA-DQA1 as the major genetic risk for seropositive rheumatoid arthritis in Han Chinese population
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:6, s. 773-780
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Tidskriftsartikel (refereegranskat)abstract
- The strong genetic contribution of the major histocompatibility complex (MHC) region to rheumatoid arthritis (RA) has been generally attributed to human leukocyte antigen (HLA)-DRB1. However, due to the high polymorphisms and linkage disequilibrium within MHC, it is difficult to define novel and/or independent genetic risks using conventional HLA genotyping or chip-based microarray technology. This study aimed to identify novel RA risk variants by performing deep sequencing for MHC.MethodsWe first conducted target sequencing for the entire MHC region in 357 anticitrullinated protein antibodies (ACPA)-positive patients with RA and 1001 healthy controls, and then performed HLA typing in an independent case–control cohort consisting of 1415 samples for validation. All study subjects were Han Chinese. Genetic associations for RA susceptibility and severity were analysed. Comparative modelling was constructed to predict potential functions for the newly discovered RA association variants.ResultsHLA-DQα1:160D conferred the strongest and independent susceptibility to ACPA-positive RA (p=6.16×10−36, OR=2.29). DRβ1:37N had an independent protective effect (p=5.81×10−16, OR=0.49). As predicted by comparative modelling, the negatively charged DQα1:160D stabilises the dimer of dimers, thus may lead to an increased T cell activation. The negatively charged DRβ1:37N encoding alleles preferentially bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.ConclusionsWe provide the first evidence that HLA-DQα1:160D, instead of HLA-DRB1*0405, is the strongest and independent genetic risk for ACPA-positive RA in Han Chinese. Our study also illustrates the value of deep sequencing for fine-mapping disease risk variants in the MHC region.
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