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Statin therapy and intensity: Analysis inside people using myocardial injuries.
Viral protein 9 (VP9) is a non-structural protein of white spot syndrome virus (WSSV) highly expressed during the early stage of infection. The crystal structure of VP9 suggests that the polymers of VP9 dimers resemble a DNA mimic, but its function remains elusive. In this study, we demonstrated that VP9 impedes histones binding to DNA via single-molecule manipulation. We established VP9 expression in HeLa cells due to the lack of a WSSV-susceptible cell line, and observed abundant VP9 in the nucleus, which mirrors its distribution in the hemocytes of WSSV-infected shrimp. VP9 expression increased the dynamics and rotational mobility of histones in stable H3-GFP HeLa cells as revealed by fluorescent recovery after photobleaching and fluorescence anisotropy imaging, which suggested a loosened compaction of chromatin structure. Successive salt fractionation showed that a prominent population of histones was solubilized in high salt concentrations, which implies alterations of bulk chromatin structure. Southern blotting identified that VP9 alters juxtacentromeric chromatin structures to be more accessible to micrococcal nuclease digestion. RNA microarray revealed that VP9 expression also leads to significant changes of cellular gene expression. Our findings provide evidence that VP9 alters the cellular higher-order chromatin structure, uncovering a potential strategy adopted by WSSV to facilitate its replication. © 2020 The Authors.Interactions between magnetic fields (MFs) and living cells may stimulate a large variety of cellular responses to a MF, while the underlying intracellular mechanisms still remain a great puzzle. On a fundamental level, the MF - cell interaction is affected by the two broken symmetries (a) left-right (LR) asymmetry of the MF and (b) chirality of DNA molecules carrying electric charges and subjected to the Lorentz force when moving in a MF. Here we report on the chirality-driven effect of static magnetic fields (SMFs) on DNA synthesis. This newly discovered effect reveals how the interplay between two fundamental features of symmetry in living and inanimate nature-DNA chirality and the inherent features of MFs to distinguish the left and right-manifests itself in different DNA synthesis rates in the upward and downward SMFs, consequently resulting in unequal cell proliferation for the two directions of the field. The interplay between DNA chirality and MF LR asymmetry will provide fundamental knowledge for many MF-induced biological phenotypes. © 2020 The Authors.The ubiquitin-proteasome system (UPS) governs the protein degradation process and balances proteostasis and cellular homeostasis. It is a well-controlled mechanism, in which removal of the damaged or excessive proteins is essential in driving signal pathways for cell survival or death. Accumulation of damaged proteins and failure in removal may contribute to disease initiation such as in cancers and neurodegenerative diseases. In this notion, specific protein-protein interaction is essential for the recognition of targeted proteins in UPS. WW domain plays an indispensable role in the protein-protein interactions during signaling. Among the 51 WW domain-containing proteins in the human proteomics, near one-quarter of them are involved in the UPS, suggesting that WW domains are crucial modules for driving the protein-protein binding and subsequent ubiquitination and degradation. Tiplaxtinin In this review, we detail a broad spectrum of WW domains in protein-protein recognition, signal transduction, and relevance to diseases. New perspectives in dissecting the molecular interactions are provided. © 2020 The Authors.In patients with macular edema due to ischemic retinopathy, aqueous levels of hepatocyte growth factor (HGF) correlate with edema severity. We tested whether HGF expression and activity in mice with oxygen-induced ischemic retinopathy supports a role in macular edema. In ischemic retina, HGF was increased in endogenous cells and macrophages associated with retinal neovascularization (NV). HGF activator was increased in and around retinal vessels potentially providing vascular targeting. One day after intravitreous injection of HGF, VE-cadherin was reduced and albumin levels in retina and vitreous were significantly increased indicating vascular leakage. Injection of VEGF caused higher levels of vitreous albumin than HGF, and co-injection of both growth factors caused significantly higher levels than either alone. HGF increased the number of macrophages on the retinal surface, which was blocked by anti-c-Met and abrogated in chemokine (C-C motif) ligand 2 (CCL2)-/- mice. Injection of anti-c-Met significantly decreased leakage within 24 hours and after 5 days it reduced retinal NV in mice with ischemic retinopathy, but had no effect on choroidal NV. These data indicate that HGF is a pro-permeability, pro-inflammatory, and pro-angiogenic factor and along with its activator is increased in ischemic retina providing support for a potential role of HGF in macular edema in ischemic retinopathies. © 2020 The Authors.Increased production of the osteoclastogenic cytokine RANKL is a common feature of pathologic bone loss, but the underlying cause of this increase is poorly understood. The unfolded protein response (UPR) is activated in response to accumulation of misfolded proteins in the endoplasmic reticulum (ER). Failure to resolve misfolding results in excess UPR signaling that stimulates cytokine production and cell death. We therefore investigated whether RANKL is one of the cytokines stimulated in response to elevated UPR in bone cells. Pharmacologic induction of UPR with tunicamycin (Tm)-stimulated RANKL expression in cultures of primary osteoblastic cells and in osteoblast and osteocyte cell lines. Pharmacologic inhibition of the UPR blunted Tm-induced RANKL production. Silencing Edem1 or Sel1l, proteins that aid in degradation of misfolded proteins, also induced UPR and increased RANKL mRNA. Moreover, Tm or hypoxia increased RANKL and bone resorption in cultures of neonatal murine calvaria. Administration of Tm to adult mice caused dilation of ER in osteoblasts and osteocytes, elevated the UPR, and increased RANKL expression and osteoclast number. These findings support the hypothesis that excessive UPR signaling stimulates the expression of RANKL by osteoblasts and osteocytes, and thereby facilitates excessive bone resorption and bone loss in pathologic conditions. © 2020 The Authors.
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