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Close to the edge : how Yes's masterpiece defined prog rock
The author draws upon dozens of original and past interviews to argue that Close to the edge is the ultimage prog rock album.
Book
A community-sourced glossary of open scholarship terms
Open scholarship has transformed research, and introduced a host of new terms in the lexicon of researchers. The ‘Framework for Open and Reproducible Research Teaching’ (FORRT) community presents a crowdsourced glossary of open scholarship terms to facilitate education and effective communication between experts and newcomers.
Journal Article
Lactate Suppresses Macrophage Pro-Inflammatory Response to LPS Stimulation by Inhibition of YAP and NF-κB Activation via GPR81-Mediated Signaling
Recent evidence from cancer research indicates that lactate exerts a suppressive effect on innate immune responses in cancer. This study investigated the mechanisms by which lactate suppresses macrophage pro-inflammatory responses. Macrophages [Raw 264.7 and bone marrow derived macrophages (BMDMs)] were treated with LPS in the presence or absence of lactate. Pro-inflammatory cytokines, NF-κB and YAP activation and nuclear translocation were examined. Our results show that lactate significantly attenuates LPS stimulated macrophage TNF-α and IL-6 production. Lactate also suppresses LPS stimulated macrophage NF-κB and YAP activation and nuclear translocation in macrophages. Interestingly, YAP activation and nuclear translocation are required for LPS stimulated macrophage NF-κB activation and TNFα production. Importantly, lactate suppressed YAP activation and nuclear translocation is mediated by GPR81 dependent AMKP and LATS activation which phosphorylates YAP, resulting in YAP inactivation. Finally, we demonstrated that LPS stimulation induces an interaction between YAP and NF-κB subunit p65, while lactate decreases the interaction of YAP and NF-κB, thus suppressing LPS induced pro-inflammatory cytokine production. Our study demonstrates that lactate exerts a previously unknown role in the suppression of macrophage pro-inflammatory cytokine production
GPR81 mediated YAP inactivation, resulting in disruption of YAP and NF-κB interaction and nuclear translocation in macrophages.
Journal Article
A phosphotyrosine switch regulates organic cation transporters
Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition
in vivo
diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive ‘transporter-phosphoproteome’ with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.
Organic cation transporters are important drug transporters that influence therapeutic outcomes. Here, the authors find that these transporters are regulated by tyrosine phosphorylation and propose that tyrosine kinase inhibitors can influence drug transporter function through post-translational mechanisms.
Journal Article
Epithelial Expression of YAP and TAZ Is Sequentially Required in Lung Development
Abstract
TAZ (transcriptional coactivator with PDZ-binding motif) and YAP (Yes-associated protein) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their roles during lung development remain unknown. We aimed to investigate YAP and TAZ functions using lung epithelium–specific Taz and Yap conditional knockout mice. We generated lung epithelium–specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Shh (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)–SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-β (transforming growth factor-β) stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. Our results provide a novel insight into the molecular mechanisms underlying lung development and contribute to a better understanding of the characteristics of TAZ and YAP.
Journal Article
Curcumol inhibits ferritinophagy to restrain hepatocyte senescence through YAP/NCOA4 in non‐alcoholic fatty liver disease
Objectives In recent years, cellular senescence has attracted a lot of interest in researchers due to its involvement in non‐alcoholic fatty liver disease (NAFLD). However, the mechanism of cellular senescence is not clear. The purpose of this study was to investigate the effect of curcumol on hepatocyte senescence in NAFLD and the molecular mechanisms implicated. Materials and methods LVG Golden Syrian hamsters, C57BL/6J mice and human hepatocyte cell line LO2 were used. Cellular senescence was assessed by analyses of senescence marker SA‐β‐gal, p16 and p21, H3K9me3, γ‐H2AX and telomerase activity. Results The results showed that curcumol could inhibit hepatocyte senescence in both in vivo and in vitro NAFLD models, and the mechanism might be related to its regulation of ferritinophagy and subsequent alleviation of iron overload. Moreover, overexpression of nuclear receptor coactivator 4 (NCOA4) weakened the effect of curcumol on ferritinophagy‐mediated iron overload and cellular senescence. Furthermore, we demonstrated that curcumol reduced the expression of NCOA4 by Yes‐associated protein (YAP). In addition, depression of YAP could impair the effect of curcumol on iron overload and cellular senescence. Conclusion Our results clarified the mechanism of curcumol inhibition of hepatocyte senescence through YAP/NCOA4 regulation of ferritinophagy in NAFLD. These findings provided a promising option of curcumol to regulate cellular senescence by target YAP/NCOA4 for the treatment of NAFLD. Curcumol inhibited hepatocyte senescence by suppressing ferritinophagy‐mediated iron overload. Furthermore, this effect of curcumol is related to the regulation of YAP/NCOA4 in NAFLD models.
Journal Article
A gp130–Src–YAP module links inflammation to epithelial regeneration
Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
This study demonstrates the activation of a STAT3-independent healing pathway in response to mucosal injury which involves the co-receptor for IL-6 cytokines gp130 and downstream effectors Src, Yes, YAP and Notch.
Beneficial effects of inflammation
As well as activating innate and adaptive immunity, inflammation triggers tissue repair and regeneration through mechanisms that are largely unknown. This study demonstrates the activation of a STAT3-independent healing pathway in a mouse model of experimental colitis through a process involving gp130 (a co-receptor for interleukin-6 family cytokines) and the downstream effectors Src, Yes, YAP and Notch.
Journal Article
YAP is essential for TGF‐β‐induced retinal fibrosis in diabetic rats via promoting the fibrogenic activity of Müller cells
The purpose of this study was to investigate whether Yes‐associated protein (YAP) activation and proliferation of retinal Müller cells play a role in the development of TGF‐β‐induced retinal fibrosis. We studied the effects of YAP activation on retinal fibrosis in diabetic rats and human retinal Müller cells (hMCs) in vitro. The retinal expression of YAP and fibrogenic molecules in rats was detected using Western blotting and immunohistochemistry. After treatment with transforming growth factor‐β1 (TGF‐β1), the levels of fibrogenic molecules, and the activation of YAP and PI3K/Akt signalling pathway in hMCs were detected with Western blotting. The effect of YAP on retinal fibrotic changes was evaluated using YAP knockdown experiments and YAP inhibitors. Results showed that YAP expression was increased in the retina of diabetic rats along with increased retinal fibrosis. In cultured hMCs, YAP inhibition suppressed TGF‐β1‐stimulated hMC differentiation to myofibroblasts and extracellular matrix (ECM) production, while YAP activation promoted hMC differentiation and ECM production independent of TGF‐β1. Furthermore, hMCs cultured on a gel with greater stiffness differentiated into myofibroblasts in a YAP‐dependent manner. In diabetic rats, treatment with the YAP inhibitor verteporfin suppressed retinal fibrogenesis. In addition, the TGF‐β1‐induced PI3K/Akt signalling pathway mediated YAP activation as well as expression of fibrogenic molecules. The interaction between ECM stiffness and YAP forms a feed‐forward process leading to retinal fibrosis. Our work highlights YAP as an essential regulator of pro‐fibrotic responses in TGF‐β‐induced retinal fibrosis.
Journal Article
Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest
The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of an adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies, where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of >10,000 organoids, we systematically optimize parameters, including extracellular matrix (ECM), metabolic substrate, and growth factor conditions, that enhance cardiac tissue viability, function, and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions, hPSC-CMs were refractory to mitogenic stimuli, and we found that key proliferation pathways including β-catenin and Yes-associated protein 1 (YAP1) were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both β-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher-throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock therapeutic strategies.
Journal Article