HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine.

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism

A single amino acid substitution in the R3 domain of GLABRA1 leads to inhibition of trichome formation in Arabidopsis without affecting its interaction with GLABRA3

GLABRA1 (GL1) is an R2R3 MYB transcription factor that regulates trichome formation in Arabidopsis by interacting with the bHLH transcription factor GLABRA3 (GL3) or ENHANCER OF GL3 (EGL3). The conserved [D/E]L×2 [R/K]×3L×6L×3R amino acid signature in the R3 domain of MYB proteins has been shown to be required for the interaction of MYBs with R/B‐like bHLH transcription factors. By using genetic and molecular analyses, we show that the glabrous phenotype in the nph4‐1 mutant is caused by a single nucleotide mutation in the GL1 gene, generating a Ser to Phe substitution (S92F) in the conserved [D/E]L×2[R/K]×3L×6L×3R amino acid signature of GL1. Activation of the integrated GL2p:GUS reporter gene in protoplasts by cotransfection of GL1 and GL3 or EGL3 was abolished by this GL1‐S92F substitution. However, GL1‐S92F interacted successfully with GL3 or EGL3 in protoplast transfection assays. Unlike VPGL1GL3, the fusion protein VPGL1‐S92FGL3 failed to activate the integrated GL2p:GUS reporter gene in transfected protoplasts. These results suggested that the S92 in the conserved [D/E]L×2 [R/K]×3L×6L×3R amino acid signature of GL1 is not essential for the interaction of GL1 and GL3, but may play a role in the binding of GL1 to the promoters of its target genes.The R2R3 MYB transcription factor GL1 is a key regulator of trichome formation in Arabidopsis. The conserved [D/E]L×2[R/K]×3L×6L×3R amino acid signature in the R3 domain is required for the interaction of MYBs with R/B‐like bHLH transcription factors. S92F amino acid substantiation in the conserved [D/E]L×2[R/K]×3L×6L×3R signature in GL1 lead to loss‐of‐function mutation of GL1. However, our results indicate that Ser92 residue is not required for the interaction of GL1 with bHLH transcription factor GL3 or EGL3, but may required for binding of GL1 to its target genes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145310/1/pce12695_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145310/2/pce12695.pd

Institutional determinants of construction safety management strategies of contractors in Hong Kong

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Research Progress on Extraction, Structure, Functions and Mechanism of Action of Mesona Polysaccharide

Mesona is a special edible and medicinal food in China. The country has an abundant Mesona output and a large number of Mesona consumers. Polysaccharide is one of the important active components in Mesona, which has a variety of biological activities in disease prevention and treatment. Currently, Mesona polysaccharide has been widely used in Chinese Traditional medicine, herbal tea, as well as jelly. However, there are problems such as insufficient development of deep-processing products. In this paper, the domestic and foreign literature in the past recent years are retrieved and collected. This article comprehensively proposes the extraction, isolation and purification technologies of Mesona polysaccharide, as well as their characteristic structures, and rheological and gelling properties. Additionally, their functional activities and the underlying mechanism of action on antioxidant, regulation of gut flora, anti-hyperglycemia, anti-hyperlipidemia, liver protection and immunoregulation are systematically reviewed. This review provides useful ideas and guidance for the basic research as well as the commercialization of research on Mesona

Restoration of Cardiac Function After Myocardial Infarction by Long-Term Activation of the CNS Leptin-Melanocortin System

Heart failure has a high mortality rate, and current therapies offer limited benefits. The authors demonstrate that activation of the central nervous system leptin-melanocortin pathway confers remarkable protection against progressive heart failure following severe myocardial infarction. The beneficial cardiac-protective actions of leptin require activation of brain melanocortin-4 receptors and elicit improvements in cardiac substrate oxidation, cardiomyocyte contractility, C