关键词： Phosphate glasses   Glass-ceramic   Solid electrolyte   Crystallization kinetic   Nasicon structure   Impedance spectroscopy  

摘要： Advancing energy density, enabling lithium metal anodes, and ensuring unparalleled safety and operational reliability in lithium batteries hinge on advancing inorganic solid-state electrolytes. To overcome current impediments, we present an innovative approach that integrates glass-ceramics with a pioneering new Nasicon strategy involving molybdenum doping. In the conducted study, a series of 14Li2O-9Al2O3-38TiO2-(39-x)P2O5xMoO3 glasses, denoted as LATPMox, along with their corresponding glass-ceramics (LATPMox-GC), have exhibited a promising characteristic as solid electrolytes. X-ray diffraction (XRD) analysis confirms the formation of the novel Mo-doped Nasicon phases in the glass-ceramics, as validated by Rietveld refinement. Examination of the crystallization kinetic behavior of the glasses reveals a three-dimensional nucleation process with spherical particle growth, featuring an activation energy of 165 kJ mol-1. Transmission Electron Microscopy TEM characterization aligns crystallization behavior with crystallite and distribution within the glass matrix, resulting in a compact and dense microstructure. The structural properties of the resultant phases are examined through FT-IR, Raman spectroscopy, and TEM-SEAD analysis. Vickers indentation tests were employed to assess the microscopic fracture toughness, and both the glass and glass-ceramics materials demonstrated favorable mechanical performance. Optical characterization using UV-visible absorption highlights the reduction of Mo6+ to Mo5+, likely occupying tetrahedral sites within the crystalline lattice. Impedance spectroscopy measurement showcases the effective promotion of ionic conductivity following Mo doping, reaching a total conductivity value of 5.50 x 10-5 Omega- 1 cm- 1 along with a high lithium transference number of 0.99 at room temperature for LATPMo2.6-GC glass-ceramic. This value is larger than that of many other glass-ceramics as well as that of the well-known lithium phosphorous oxy-nitrid

关键词： IQGAP1   B cell   MAPK   IQGAP1 signalosome  

摘要： IQGAP1 is a multi-functional scaffold protein. However, its role in B cell development and function is unknown. Here, we show IQGAP1 as an essential scaffold that regulates early B cell development and function. Iqgap1-/- mice contained significantly increased numbers of B220+ B, B220+IgM- pro/pre-B, and B220LowIgM+ immature-B cells in the bone marrow. In the spleens of the Iqgap1-/- mice, newly formed and follicular B cell numbers were increased, while the marginal zone B cell numbers were significantly reduced. Lack of IQGAP1 reduced T-dependent and T-independent humoral responses. Mechanistically, the lack of IQGAP1 considerably decreased the phosphorylation of Mek1/2, Erk1/2, and Jnk1/2. B cells from Iqgap1-/- mice failed to suppress IL-7R-mediated activation of Stat5a/b, an essential step for cell-cycle exit and initiate light-chain recombination, reducing RS rearrangement frequency. Our study provides the first evidence that IQGAP1-based signalosome is necessary for the development and functions of B cells.

关键词： apical protein endocytosis   epithelial cell polarity   IQGAP1   MDCK cells   polarity reorientation   Rac1   Tiam1   two-cell stage  

摘要： A single epithelial cell embedded in extracellular matrix (ECM) can proliferate to form an apical lumen-harboring cyst, whose formation is a fundamental step in epithelial organ development. At an early two-cell stage after cell division, the cell doublet typically displays "inverted" polarity, with apical and basolateral proteins being located to the ECM-facing and cell-cell-contacting plasma membranes, respectively. Correct cystogenesis requires polarity reorientation, a process containing apical protein endocytosis from the ECM-abutting periphery and subsequent apical vesicle delivery to a cell-cell contact site for lumen formation. Here, we show that downstream of the ECM-signal-transducer beta 1-integrin, Rac1, and its effector IQGAP1 promote apical protein endocytosis, contributing to polarity reorientation of mammalian epithelial Madin-Darby canine kidney (MDCK) cells at a later two-cell stage in three-dimensional culture. Rac1-GTP facilitates IQGAP1 interaction with the Rac-specific activator Tiam1, which also contributes to the endocytosis and enhances the effect of IQGAP1. These findings suggest that Tiam1 and IQGAP1 form a positive feedback loop to activate Rac1. With Rac1-GTP, IQGAP1 also binds to AP2 alpha, an adaptor protein subunit for clathrin-mediated endocytosis;depletion of the AP2 complex impairs apical protein endocytosis in MDCK doublets. Thus, Rac1 likely participates in polarity reorientation at the two-cell stage via its interaction with IQGAP1.

关键词： Skin fibrosis   miR-3606-3p   ITGAV   GAB1   TGFBR2   Fibroblast abnormalities   SSc   Systemic sclerosis   AKT   Protein kinase B   p-AKT   phosphorylated AKT   PI3K   Phosphatidylinositol 3-kinase   ERK   Extracellular regulated protein kinase   p-ERK   phosphorylated ERK   SMAD2/3   SMAD family member 3/3   p-SMAD2/3   phosphorylated SMAD2/3   RTK   Receptor tyrosine kinases   NF-κB   Nuclear factor-kappaB   TGF-β   Transforming growth factor-beta   TGFBR1   Transforming growth factor beta receptor 1   TGFBR2   Transforming growth factor beta receptor II   ITGAV   Integrin subunit alpha V   GAB1   GRB2-associated binding protein 1   DOS   Daughter of Sevenless   si-ITGAV   small interfering RNAs of ITGAV   si-GAB1   small interfering RNAs of GAB1   si-TGFBR2   small interfering RNAs of TGFBR2   α-SMA   actin alpha 2, smooth muscle   COL1A1   collagen type I alpha 1 chain   COL1A2   collagen type I alpha 2 chain   COL3A1   collagen type III alpha 1 chain   GAPDH   glyceraldehyde-3-phosphate dehydrogenase   S100A4   S100 calcium binding protein A4   U6   RNA, U6 small nuclear 1   β-actin   actin beta   FAK   Focal adhesion kinase   PPP2CB   protein phosphatase 2 catalytic subunit beta   SRC   SRC proto-oncogene, non-receptor tyrosine kinase   ITGA4   integrin subunit alpha 4   CAPN7   calpain 7   PPP2R1B   protein phosphatase 2 scaffold subunit Abeta   CAV1   caveolin 1   ITGB8   integrin subunit beta 8   ZFYVE16   zinc finger FYVE-type containing 16   RPS6KB1   ribosomal protein S6 kinase B1   CRK   CRK proto-oncogene, adaptor protein   EGFR   epidermal growth factor receptor   SMURF2   SMAD specific E3 ubiquitin protein ligase 2   SKIL   SKI like proto-oncogene   MAP2K6   mitogen-activated protein kinase kinase 6   PIP4K2C   phosphatidylinositol-5-phosphate 4-kinase type 2 gamma   FRS2   fibroblast growth factor receptor substrate 2   XIAP   X-linked inhibitor of apoptosis   EIF2A   eukaryotic translation initiation factor 2A   SHC1   SHC adaptor protein 1   NC   Negative control   ADA1   Adenosine deaminase   NID2   Nidogen-2   CDKN1A   Cyclin-dependent kinase inhibitor 1A   CDK1   Cyclin dependent kinase 1   ECM   Extracellular matrix   CTGF   connective tissue growth factor   PDGF   platelet derived growth factor   TNF-α   tumor necrosi  

摘要： Introduction Fibroblast abnormalities are crucial causes of skin fibrosis, including systemic sclerosis (SSc) and keloids. However, their mechanisms, including underlying microRNA regulatory mechanisms, remain elusive. Objectives This study aimed to evaluate the roles, mechanisms, and therapeutic potential of miR-3606-3p in regulating multiple fibroblast abnormalities. Methods The miR-3606-3p levels were evaluated in skin tissues and primary fibroblasts. RNA-seq and luciferase assays were employed to identify miR-3606-3p targets. Collagen contraction, western blotting, in vivo imaging, and real-time cellular analysis were used to assess fibroblast abnormalities. The therapeutic potential of miR-3606-3p was evaluated in mice. Results MiR-3606-3p decreased in skin tissues (SSc: Fold Change (FC) =  − 2.95, P = 0.0101; keloid: FC =  − 3.42, P < 0.0001) and primary fibroblasts (SSc: FC =  − 12.74, P = 0.0278; keloid: FC =  − 2.08, P = 0.0021) from skin fibrosis patients, and negatively correlated with disease severity. Mechanistically, miR-3606-3p targeted the 3′-untranslated regions (3′-UTRs) of Integrin αV ( ITGAV ), GRB2-associated binding protein 1 ( GAB1 ), and transforming growth factor beta receptor 2 ( TGFBR2 ), all of these three targets increased in skin fibrosis. Simultaneously, miR-3606-3p inhibited fibroblast’s fibrogenesis, migration, inflammation, and proliferation by inhibiting ITGAV/integrin/FAK, GAB1/p-AKT/p-ERK, and TGFBR2/p-SMAD2/3 signaling. ITGAV-mediated integrin/FAK signaling unidirectionally activated the p-AKT/p-ERK and p-SMAD2/3 pathways. Knockdown of GAB1 and TGFRB2 reduced ITGAV-induced p-AKT/p-ERK and p-SMAD2/3 activities. MiR-3606-3p, si-ITGAV , si-GAB1 , and si-TGFBR2 exhibited significant inhibition of fibrogenesis and migration. Inflammation was primarily inhibited by si-ITGAV and si-GAB1, while proliferation was primarily inhibited by si-TGFBR2 . Moreover , miR-3606-3p significantly attenuates skin fibrosis in keloid-bearing mice. Concl

关键词： IQGAP   EGFR   fluorescence imaging   protein oligomerization   cell signaling  

摘要： IQGAP1 is a large, multi-domain scaffold that connects and modulates different signaling networks including the one initiated by epidermal growth factor (EGF). In this study, we have used live cell fluorescence imaging methods along with other biochemical techniques to follow the mechanisms used by IQGAP1 to enhance EGF signaling. We show that IQGAP1 enhances EGF signaling by promoting the oligomerization of its receptor, EGFR, upon EGF addition along with concurrent IQGAP oligomerization. Using cellular markers, we find that IQGAP1 promotes the plasma membrane localization of EGFR and promotes association to one of its phosphoinositide lipid pathway ligands, PI(3,4,5)P3. Additionally, we find that binding of EGFR to IQGAP1 protects EGFR from lysosomal degradation. Taken together, our results show that IQGAP1 enhances EGF-mediated pathway progression through mechanisms that augment simple scaffolding activities.

关键词： Glioblastoma   Scaffold proteins   Precision medicine   IQGAP1  

摘要： Glioblastoma (GB) is a highly heterogeneous type of incurable brain cancer with a low survival rate. Intensive ongoing research has identified several potential targets;however, GB is marred by the activation of multiple pathways, and thus common targets are highly sought. The signal regulatory scaffold IQGAP1 is an oncoprotein implicated in GB. IQGAP1 nucleates a myriad of pathways in a contextual manner and modulates many of the targets altered in GB like MAPK, NF-kappa B, and mTOR/PI3K/Akt1, thus positioning it as a plausible common therapeutic target. Here, we review the targets that are subjects of GB treatment clinical trials and the commonly used animal models that facilitate target identification. We propose a model in which the dysfunction of various IQGAP1 pathways can explain to a larger extent some of the GB heterogeneity and offer a platform for personalized medicine.

摘要： (no summary available)

关键词： IQGAP1   Mycobacteria   Phthiocerol dimycocerosate (PDIM)   VEGF   Granuloma  

摘要： Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or ***), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-alpha production by repressing the MKK3 signal and reducing NF-kappa Bp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by *** infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-kappa Bp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases.