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121.
Darwin V. Lee Dongmei Li Qingyun Yan Yimin Zhu Bryan Goodwin Roberto Calle Martin B. Brenner Saswata Talukdar 《PloS one》2014,9(11)
Fibroblast growth factor 21 (FGF21) has evolved as a major metabolic regulator, the pharmacological administration of which causes weight loss, insulin sensitivity and glucose control in rodents and humans. To understand the molecular mechanisms by which FGF21 exerts its metabolic effects, we developed a human in vitro model of adipocytes to examine crosstalk between FGF21 and insulin signaling. Human adipose stem cell-derived (hASC) adipocytes were acutely treated with FGF21 alone, insulin alone, or in combination. Insulin signaling under these conditions was assessed by measuring tyrosine phosphorylation of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), and serine 473 phosphorylation of Akt, followed by a functional assay using 14C-2-deoxyglucose [14C]-2DG to measure glucose uptake in these cells. FGF21 alone caused a modest increase of glucose uptake, but treatment with FGF21 in combination with insulin had a synergistic effect on glucose uptake in these cells. The presence of FGF21 also effectively lowered the insulin concentration required to achieve the same level of glucose uptake compared to the absence of FGF21 by 10-fold. This acute effect of FGF21 on insulin signaling was not due to IR, IGF-1R, or IRS-1 activation. Moreover, we observed a substantial increase in basal S473-Akt phosphorylation by FGF21 alone, in contrast to the minimal shift in basal glucose uptake. Taken together, our data demonstrate that acute co-treatment of hASC-adipocytes with FGF21 and insulin can result in a synergistic improvement in glucose uptake. These effects were shown to occur at or downstream of Akt, or separate from the canonical insulin signaling pathway. 相似文献
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Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleases 总被引:6,自引:0,他引:6
Doyon Y McCammon JM Miller JC Faraji F Ngo C Katibah GE Amora R Hocking TD Zhang L Rebar EJ Gregory PD Urnov FD Amacher SL 《Nature biotechnology》2008,26(6):702-708
We describe the use of zinc-finger nucleases (ZFNs) for somatic and germline disruption of genes in zebrafish (Danio rerio), in which targeted mutagenesis was previously intractable. ZFNs induce a targeted double-strand break in the genome that is repaired to generate small insertions and deletions. We designed ZFNs targeting the zebrafish golden and no tail/Brachyury (ntl) genes and developed a budding yeast-based assay to identify the most active ZFNs for use in vivo. Injection of ZFN-encoding mRNA into one-cell embryos yielded a high percentage of animals carrying distinct mutations at the ZFN-specified position and exhibiting expected loss-of-function phenotypes. Over half the ZFN mRNA-injected founder animals transmitted disrupted ntl alleles at frequencies averaging 20%. The frequency and precision of gene-disruption events observed suggest that this approach should be applicable to any loci in zebrafish or in other organisms that allow mRNA delivery into the fertilized egg. 相似文献
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Andrew Curtright Micaela Rosser Shamii Goh Bailey Keown Erinn Wagner Jasmine Sharifi David W. Raible Ajay Dhaka 《PloS one》2015,10(1)
Acute and chronic pain conditions are often debilitating, inflicting severe physiological, emotional and economic costs and affect a large percentage of the global population. However, the development of therapeutic analgesic agents based primarily on targeted drug development has been largely ineffective. An alternative approach to analgesic development would be to develop low cost, high throughput, untargeted animal based behavioral screens that model complex nociceptive behaviors in which to screen for analgesic compounds. Here we describe the development of a behavioral based assay in zebrafish larvae that is effective in identifying small molecule compounds with analgesic properties. In a place aversion assay, which likely utilizes supraspinal neuronal circuitry, individually arrayed zebrafish larvae show temperature-dependent aversion to increasing and decreasing temperatures deviating from rearing temperature. Modeling thermal hyperalgesia, the addition of the noxious inflammatory compound and TRPA1 agonist allyl isothiocyanate sensitized heat aversion and reversed cool aversion leading larvae to avoid rearing temperature in favor of otherwise acutely aversive cooler temperatures. We show that small molecules with known analgesic properties are able to inhibit acute and/or sensitized temperature aversion. 相似文献
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Shanta Banerjee Jasmine Jakupovic Ferdinand Bohlmann Robert M. King Harold Robinson 《Phytochemistry》1985,24(11):2681-2683
The reinvestigation of the roots and aerial parts of Ageratina riparia afforded ten new chromenes, their structures being determined by spectral data and chemical transfomrations. 相似文献
129.
Immunocytochemical localization of alpha-protein kinase C in rat pancreatic beta-cells during glucose-induced insulin secretion
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S Ganesan R Calle K Zawalich K Greenawalt W Zawalich G I Shulman H Rasmussen 《The Journal of cell biology》1992,119(2):313-324
To investigate the role of protein kinase C (PKC) in the regulation of insulin secretion, we visualized changes in the intracellular localization of alpha-PKC in fixed beta-cells from both isolated rat pancreatic islets and the pancreas of awake unstressed rats during glucose-induced insulin secretion. Isolated, perifused rat islets were fixed in 4% paraformaldehyde, detergent permeabilized, and labeled with a mAb specific for alpha-PKC. The labeling was visualized by confocal immunofluorescent microscopy. In isolated rat pancreatic islets perifused with 2.75 mM glucose, alpha-PKC immunostaining was primarily cytoplasmic in distribution throughout the beta-cells. In islets stimulated with 20 mM glucose, there was a significant redistribution of alpha-PKC to the cell periphery. This glucose-induced redistribution was abolished when either mannoheptulose, an inhibitor of glucose metabolism, or nitrendipine, an inhibitor of calcium influx, were added to the perifusate. We also examined changes in the intracellular distribution of alpha-PKC in the beta-cells of awake, unstressed rats that were given an intravenous infusion of glucose. Immunocytochemical analysis of pancreatic sections from these rats demonstrated a glucose-induced translocation of alpha-PKC to the cell periphery of the beta-cells. These results demonstrate that the metabolism of glucose can induce the redistribution of alpha-PKC to the cell periphery of beta-cells, both in isolated islets and in the intact animal, and suggest that alpha-PKC plays a role in mediating glucose-induced insulin secretion. 相似文献
130.
The landrace sweet cherry (Prunus avium L.) cultivar ‘Cristobalina’ is a useful resource for sweet cherry breeding due to several important traits, including low chilling requirement, early maturity date, and self-compatibility. In this work, three families (N?=?325), derived from ‘Cristobalina’, were used to develop high-density genetic maps using the RosBREED 6K Illumina Infinium® cherry SNP array. Two of the families were derived from self-pollination, which allowed construction of the first F2 genetic maps in the species. The other map developed was from an interspecific cross of cultivars ‘Vic’?×?‘Cristobalina’. The maps developed include 511 to 816 mapped SNPs covering 622.4 to 726.0 cM. Mapped SNP marker order and position were compared to the sweet cherry and peach genome sequences, and a high degree of synteny was observed. However, inverted and small translocated regions between peach and sweet cherry genomes were observed with the most noticeable inversion at the top of LG5. The progeny resulting from self-pollination also revealed a high level of homozygosity, as large presumably homozygous regions as well as entire homozygous LGs were observed. These maps will be used for genetic analysis of relevant traits in sweet cherry breeding by QTL analysis, and self-pollination populations will be useful for investigating inbreeding depression in a naturally outbreeding species. 相似文献