MEK1 and MEK2, the only known activators of ERK, are attractive therapeutic candidates for both cancer and autoimmune diseases. However, how MEK signaling finely regulates immune cell activation is ...only partially understood. To address this question, we specifically delete Mek1 in hematopoietic cells in the Mek2 null background. Characterization of an allelic series of Mek mutants reveals the presence of distinct degrees of spontaneous B cell activation, which are inversely proportional to the levels of MEK proteins and ERK activation. While Mek1 and Mek2 null mutants have a normal lifespan, 1Mek1 and 1Mek2 mutants retaining only one functional Mek1 or Mek2 allele in hematopoietic cell lineages die from glomerulonephritis and lymphoproliferative disorders, respectively. This establishes that the fine-tuning of the ERK/MAPK pathway is critical to regulate B and T cell activation and function and that each MEK isoform plays distinct roles during lymphocyte activation and disease development.
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•ERK activation in B and T cells is proportional to MEK protein levels•Mek1 and Mek2 play non-redundant roles during lymphocyte activation•1Mek1 mutant mice develop a lupus-like disease•1Mek2 mutant mice die from lymphoproliferative disorders
Houde et al. report that the kinases MEK1 and MEK2 play distinct roles in lymphocyte activation. Reduced Mek1/Mek2 expression led to reduced levels of ERK activation and to spontaneous B and T cell activation. Moreover, 1Mek1 mutant mice develop lupus-like disease, establishing Mek expression as a key gatekeeper of B cell tolerance.
Chloranthalactone B (CTB), a lindenane-type sesquiterpenoid, was obtained from the Chinese medicinal herb
, which is frequently used as a remedy for inflammatory diseases. However, the ...anti-inflammatory mechanisms of CTB have not been fully elucidated. In this study, we investigated the molecular mechanisms underlying these effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CTB strongly inhibited the production of nitric oxide and pro-inflammatory mediators such as prostaglandin E₂, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 in RAW264.7 cells stimulated with LPS. A reverse-transcription polymerase chain reaction assay and Western blot further confirmed that CTB inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β at the transcriptional level, and decreased the luciferase activities of activator protein (AP)-1 reporter promoters. These data suggest that inhibition occurred at the transcriptional level. In addition, CTB blocked the activation of p38 mitogen-activated protein kinase (MAPK) but not c-Jun N-terminal kinase or extracellular signal-regulated kinase 1/2. Furthermore, CTB suppressed the phosphorylation of MKK3/6 by targeting the binding sites via formation of hydrogen bonds. Our findings clearly show that CTB inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways. Therefore, CTB could potentially be used as an anti-inflammatory agent.
This meta-analysis reviews experimental and quasi-experimental studies in which students learned by constructing, modifying, or viewing node-link diagrams. Following an exhaustive search for studies ...meeting specified design criteria, 67 standardized mean difference effect sizes were extracted from 55 studies involving 5,818 participants. Students at levels ranging from Grade 4 to postsecondary used concept maps to learn in domains such as science, psychology, statistics, and nursing. Posttests measured recall and transfer. Across several instructional conditions, settings, and methodological features, the use of concept maps was associated with increased knowledge retention. Mean effect sizes varied from small to large depending on how concept maps were used and on the type of comparison treatment. Significant heterogeneity was found in most subsets.
•An effective chaotic color/grayscale image encryption algorithm is proposed.•The encryption algorithm has a simple structure, easy implementation, and more secure.•The proposed algorithm has a high ...degree of security level, and it can compete with other encryption algorithms.
Image encryption has become the essential way to secure image information with the high frequency of multimedia information exchange on the Internet. In this paper, an effective chaotic color/grayscale image encryption algorithm is proposed. The algorithm uses a hybrid 2D composite chaotic map combined with a sine–cosine cross-chaotic map for the transformation required to scramble the image as a confusion phase. As for the diffusion phase, a 1D combined Logistic-Tent chaotic map is used to generate a chaotic self-diffusion matrix that is bitwise XORed with the scrambled image to produce the final cipher image. The proposed algorithm combines the merits of both 1D and 2D chaotic maps; it has a simple structure, easy implementation, and excellent chaotic features making its chaotic orbits more unpredictable for introducing more security. The simulation and analysis results proved that the algorithm has a promising security performance and has a high ability to resist statistical and differential attacks.
Color-guided depth enhancement is used to refine depth maps according to the assumption that the depth edges and the color edges at the corresponding locations are consistent. In methods on such ...low-level vision tasks, the Markov random field (MRF), including its variants, is one of the major approaches that have dominated this area for several years. However, the assumption above is not always true. To tackle the problem, the state-of-the-art solutions are to adjust the weighting coefficient inside the smoothness term of the MRF model. These methods lack an explicit evaluation model to quantitatively measure the inconsistency between the depth edge map and the color edge map, so they cannot adaptively control the efforts of the guidance from the color image for depth enhancement, leading to various defects such as texture-copy artifacts and blurring depth edges. In this paper, we propose a quantitative measurement on such inconsistency and explicitly embed it into the smoothness term. The proposed method demonstrates promising experimental results compared with the benchmark and state-of-the-art methods on the Middlebury ToF-Mark, and NYU data sets.
Mitogen-activated protein kinases/Extracellular signal-regulated kinase (MAPK/ERK) pathway is essential for migration and invasion of malignant glioma. It is efficient to inhibit migration and ...invasion of glioma cells by targeting this pathway. Oleanolic acid (OA) has been well demonstrated to suppress survival, growth and angiogenesis of glioma cells. However, it is still unknown if OA affects the migration and invasion of glioma cells. We utilized U-87 MG glioma cell lines and primary glioma cells from patients to study the effect of OA on migration and invasion of glioma cells with multidisciplinary approaches. In this study, we found that OA significantly decreased the ability of glioma cells to migrate and invade. Epithelial-mesenchymal transition (EMT) of glioma cells was also suppressed by OA treatment. Furthermore, MAPK/ERK pathway was greatly inhibited in glioma cells under OA treatment. MAPK/ERK reactivation induced by a recombinant lentiviral vector, Lv-MEK, was able to rescue the inhibitory effect of OA on migration and invasion of glioma cells. Taken together, we provided evidences that OA was a MAPK/ERK pathway-targeting anti-tumor agent. Although the concentrations we used exceeded its physiological level, OA may be used to prevent migration and invasion of glioma cells by developing its derivatives with enhanced bioactivity.
This volume offers the author’s central articles on the medieval and early modern history of cartography for the first time in English translation. A first group of essays gives an overview of ...medieval cartography, illustrating the methods of cartographers. Another analyzes world maps and travel accounts in relation to mapped spaces. A third examines land surveying, cartographical practices of exploration, and the production of Portolan atlases.
Selumetinib: First Approval Markham, Anthony; Keam, Susan J
Drugs (New York, N.Y.),
06/2020, Letnik:
80, Številka:
9
Journal Article
Recenzirano
Selumetinib (KOSELUGO
; AZD6244, ARRY-142886) is a mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor being developed by AstraZeneca for the treatment of tumours associated with ...neurofibromatosis and various cancers. Selumetinib has been granted orphan drug status as adjuvant treatment for thyroid cancer (in the USA) and as treatment for neurofibromatosis type 1 (in the USA and the EU) and, based on the results of the phase II SPRINT trial, was recently approved in the USA in paediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. This article summarizes the milestones in the development of selumetinib leading to this first approval for the treatment of paediatric patients aged ≥ 2 years with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas.
Melatonin enhances pathogen resistance by inducing the expression of a number of plant defense‐related genes. To examine whether the melatonin‐mediated pathogen resistance is associated with ...mitogen‐activated protein kinase (MAPK) cascades, Arabidopsis and tobacco leaves were treated with melatonin and investigated for MAPK activation using an antiphospho‐p44/42 MAPK (Erk1/2) monoclonal antibody. Two MAPKs, MPK3 and MPK6, were activated rapidly and transiently by 1 μm melatonin treatment in Arabidopsis. Its tobacco ortholog MAPKs were also activated. The activation of MPK3 and MPK6 by 2‐hydroxymelatonin and N‐acetylserotonin was also observed, albeit to a lesser degree than that by melatonin. Furthermore, MAPK activation by melatonin was uncoupled from G‐protein signaling, because melatonin efficiently activated two MAPKs in a G‐protein β knockout mutant (agb1). Suppression of both MPK3 and MPK6 in transgenic Arabidopsis exhibited significant decreases in the induction of defense‐related gene expression and pathogen resistance relative to wild‐type plants. Using an array of MAP kinase kinase (MKK) knockout mutants, we found that four MKKs, namely MKK4, MKK5, MKK7, and MKK9, are responsible for the activation of MPK3 and MPK6 by melatonin, indicating that melatonin‐mediated innate immunity is triggered by MAPK signaling through MKK4/5/7/9‐MPK3/6 cascades.
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