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Salt stress is a global environmental problem, which affects various biochemical and physiological processes in plants and significantly decreases the quantity and quality of the yield. NaCl is the main driver of NaCl-mediated effects because the accumulation of sodium ions (Na+) in plant tissues disrupts the homeostasis of other ions and may lead to secondary stresses. Two-component signalling (TCS) is an evolutionally conserved histidine-kinase based system utilised by many organisms to react to inner and environmental stimuli and stresses. In this review, we focus on the effect of NaCl on histidine-kinase based two-component signalling systems (TCS) in bacteria and its advanced form multi-step phosphorely (MSP) engaged in cytokinin signalling in plants. Further, we discuss available data on the sodium-sensing approach employed by bacteria and plants, current limitations, and future prospects in this area. Also, based on the analysed experimental and evolutional data, we suggested some potential directions for the future investigation of the salt-sensing mechanisms in plants.

Bacteria have evolved a large number of two‐component signalling systems (TCSs), which are typically composed of a histidine sensor kinase (HK) and a response regulator (RR), to sense environmental changes and modulate subsequent adaptive responses. Here, we describe the involvement of an orphan single‐domain RR named EmvR in the virulence, extracellular polysaccharide (EPS) production and cell motilities of the bacterial leaf streak pathogen Xanthomonas oryzae pv. oryzicola (Xoc), which infects rice leaves mainly via stomata and wounds. Deletion of emvR in Xoc reduced virulence when using spraying inoculation but not when using infiltration inoculation. The emvR deletion mutant displayed weakened spreading and enhanced twitching. Additionally, although deletion of emvR did not significantly affect EPS production, overexpression of emvR significantly increased EPS production. Several standard assays revealed that EmvR physically interacts with PilB and represses its ATPase activity. Combining our data with previous findings that PilB provides the energy for type IV pilus (T4P) biogenesis, we conclude that EmvR plays a vital role in modulating Xoc T4P synthesis and in the early stage of Xoc infection through rice stomata. Moreover, our data reveal that EmvR can also interact with the HK of the TCS ColSXOCgx_4036/ColRXOCgx_4037, which positively and negatively affects Xoc spreading and twitching, respectively. We propose a ‘one‐to‐two’ TCS working model for the role of ColSXOCgx_4036, ColRXOCgx_4037, and EmvR in modulating Xoc motility. An orphan single‐domain response regulator EmvR is co‐opted by a sensor kinase to form a branched two‐component system to modulate pili‐dependent motility.

In the contemporary era of drug discovery, herbal treatments have demonstrated an unparalleled ability to produce anticancer drugs. An important part of the therapy of cancer is the use of plants and their by-products via analogues, which alter the tumor microenvironment and several signaling pathways. The objective of the current investigation was to conclude the rate at which the herbal medications quercetin (QT) and sulforaphane (SFN) repressed the growth of breast carcinoma cells in MDA-MB-231 by preventing the ERK/MAPK signaling systems. The cells were assessed for several studies after being subjected to different concentrations (0–70 µM) of QT and SFN (QT + SFN) for duration of 24 h. We investigated the combination that QT + SFN generated cytotoxicity using the MTT assay. The DCFH-DA staining technique was utilized to assess ROS. The protein spectra of survival of cells, cell cycle progression, and apoptosis were evaluated employing flow cytometry and western blotting. The consequences illustrated that the relative cytotoxicity of QT and SFN was roughly 28.74 μM and 39.87 μM for MDA-MB-231 cells, respectively. Following the 24-h incubation period, MDA-MB-231 cells exhibit considerable cytotoxicity when QT and SFN are combined, with IC 50 values of 19.48 μM. Moreover, MCF-7 and MDA-MB-231 cells treated with QT and SFN concurrently showed substantial production of ROS and increased apoptotic signals. Consequently, because QT + SFN inhibit the production of ERK/MAPK/JNK/p38-based control of proliferation and cell cycle-regulating proteins, it has been considered a chemotherapeutic medication. To determine the extent to which the co-treatment induces apoptosis, more in vivo study will be required before they can be used commercially.

The China comprehensive inspection train (CIT) is designed for evaluating railway infrastructure to ensure safe railway operations. The CIT integrates an array of inspection devices, capable of simultaneously assessing railway health condition parameters. The CIT450, representing the second generation, can reach a top speed of 450 km/h with inspection on the infrastructure. This paper begins by outlining the global evolution of inspection trains. It then focuses on the critical technologies underlying the CIT450, which include: (1) real-time inspection data acquisition with spatial and temporal synchronization; (2) intelligent fusion and centralized management of multi-source inspection data, enabling remote supervision of the inspection process; (3) technologies in inspecting track, train–track interaction, catenary, signalling systems, and train operating environment; and (4) AI-driven analysis and correlation of inspection data. The future developmental directions for comprehensive inspection trains are discussed finally. The CIT450’s approach to real-time railway health monitoring can enrich traditional inspection means, operational, and maintenance methods by enhancing inspection efficiency and automating railway maintenance.

The combination of a BRAF inhibitor (dabrafenib) and a MEK inhibitor (trametinib) in patients with metastatic melanoma produced a significantly higher response rate than dabrafenib alone. Median progression-free survival was 9.4 months, as compared with 5.8 months with dabrafenib alone. Pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) pathway has proved to be a major advance in the treatment of metastatic melanoma. The use of vemurafenib and dabrafenib, agents that block MAPK signaling in patients with melanoma and the BRAF V600E mutation, has been associated with prolonged survival and progression-free survival, respectively, in randomized phase 3 trials involving patients with previously untreated melanoma. 1 – 6 Trametinib mediates blockade of MAPK kinase (MEK), which is downstream of BRAF in the MAPK pathway and has been associated with improved progression-free and overall survival in BRAF V600 melanoma (comprising both V600E and V600K mutations). . . .

Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl 4 -induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B hi F4/80 int Ly-6C lo macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter–diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C hi monocytes, a common origin with profibrotic Ly-6C hi macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C lo subset, compared with Ly-6C hi macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process.

Abstract The Cpx-envelope stress system coordinates the expression and assembly of surface structures important for the virulence of Gram-negative pathogenic bacteria. It is comprised of the membrane-anchored sensor kinase CpxA, the cytosolic response regulator CpxR and the accessory protein CpxP. Characteristic of the group of two-component systems, the Cpx system responds to a broad range of stimuli including pH, salt, metals, lipids and misfolded proteins that cause perturbation in the envelope. Moreover, the Cpx system has been linked to inter-kingdom signalling and bacterial cell death. However, although signal specificity has been assumed, for most signals the mechanism of signal integration is not understood. Recent structural and functional studies provide the first insights into how CpxP inhibits CpxA and serves as sensor for misfolded pilus subunits, pH and salt. Here, we summarize and reflect on the current knowledge on signal integration by the Cpx-envelope stress system.

G protein-independent, arrestin-dependent signaling is a paradigm that broadens the signaling scope of G protein-coupled receptors (GPCRs) beyond G proteins for numerous biological processes. However, arrestin signaling in the collective absence of functional G proteins has never been demonstrated. Here we achieve a state of “zero functional G” at the cellular level using HEK293 cells depleted by CRISPR/Cas9 technology of the Gs/q/12 families of Gα proteins, along with pertussis toxin-mediated inactivation of Gi/o. Together with HEK293 cells lacking β-arrestins (“zero arrestin”), we systematically dissect G protein- from arrestin-driven signaling outcomes for a broad set of GPCRs. We use biochemical, biophysical, label-free whole-cell biosensing and ERK phosphorylation to identify four salient features for all receptors at “zero functional G”: arrestin recruitment and internalization, but—unexpectedly—complete failure to activate ERK and whole-cell responses. These findings change our understanding of how GPCRs function and in particular of how they activate ERK1/2. Arrestins terminate signaling from GPCRs, but several lines of evidence suggest that they are also able to transduce signals independently of G proteins. Here, the authors systematically ablate G proteins in cell lines, and show that arrestins are unable to act as genuine signal initiators.

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-β-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.