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https://www.readbyqxmd.com/read/28436620/arginine-rich-peptide-based-mrna-nanocomplexes-efficiently-instigate-cytotoxic-t-cell-immunity-dependent-on-the-amphipathic-organization-of-the-peptide
#1
Vimal K Udhayakumar, Ans De Beuckelaer, Joanne McCaffrey, Cian M McCrudden, Jonathan L Kirschman, Daryll Vanover, Lien Van Hoecke, Kenny Roose, Kim Deswarte, Bruno G De Geest, Stefan Lienenklaus, Philip J Santangelo, Johan Grooten, Helen O McCarthy, Stefaan De Koker
To date, the mRNA delivery field has been heavily dominated by lipid-based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell-penetrating peptide containing the amphipathic RALA motif to deliver antigen-encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH-dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol...
April 24, 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28415752/correlation-between-facial-morphology-and-gene-polymorphisms-in-the-uygur-youth-population
#2
Huiyu He, Xue Mi, Jiayu Zhang, Qin Zhang, Yuan Yao, Xu Zhang, Feng Xiao, Chunping Zhao, Shutao Zheng
Human facial morphology varies considerably among individuals and can be influenced by gene polymorphisms. We explored the effects of single nucleotide polymorphisms (SNPs) on facial features in the Uygur youth population of the Kashi area in Xinjiang, China. Saliva samples were collected from 578 volunteers, and 10 SNPs previously associated with variations in facial physiognomy were genotyped. In parallel, 3D images of the subjects' faces were obtained using grating facial scanning technology. After delimitation of 15 salient landmarks, the correlation between SNPs and the distances between facial landmark pairs was assessed...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28363788/mesenchymal-stem-cell-fate-following-non-viral-gene-transfection-strongly-depends-on-the-choice-of-delivery-vector
#3
T Gonzalez-Fernandez, B N Sathy, C Hobbs, G M Cunniffe, H O McCarthy, N J Dunne, V Nicolosi, F J O'Brien, D J Kelly
Controlling the phenotype of mesenchymal stem cells (MSCs) through the delivery of regulatory genes is a promising strategy in tissue engineering (TE). Essential to effective gene delivery is the choice of gene carrier. Non-viral delivery vectors have been extensively used in TE, however their intrinsic effects on MSC differentiation remain poorly understood. The objective of this study was to investigate the influence of three different classes of non-viral gene delivery vectors: (1) cationic polymers (polyethylenimine, PEI), (2) inorganic nanoparticles (nanohydroxyapatite, nHA) and (3) amphipathic peptides (RALA peptide) on modulating stem cell fate after reporter and therapeutic gene delivery...
March 28, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28325821/phosphorylation-of-the-exocyst-protein-exo84-by-tbk1-promotes-insulin-stimulated-glut4-trafficking
#4
Maeran Uhm, Merlijn Bazuine, Peng Zhao, Shian-Huey Chiang, Tingting Xiong, Sheelarani Karunanithi, Louise Chang, Alan R Saltiel
Insulin stimulates glucose uptake through the translocation of the glucose transporter GLUT4 to the plasma membrane. The exocyst complex tethers GLUT4-containing vesicles to the plasma membrane, a process that requires the binding of the G protein (heterotrimeric guanine nucleotide-binding protein) RalA to the exocyst complex. We report that upon activation of RalA, the protein kinase TBK1 phosphorylated the exocyst subunit Exo84. Knockdown of TBK1 blocked insulin-stimulated glucose uptake and GLUT4 translocation; knockout of TBK1 in adipocytes blocked insulin-stimulated glucose uptake; and ectopic overexpression of a kinase-inactive mutant of TBK1 reduced insulin-stimulated glucose uptake in 3T3-L1 adipocytes...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28325291/systemic-rala-inos-nanoparticles-a-potent-gene-therapy-for-metastatic-breast-cancer-coupled-as-a-biomarker-of-treatment
#5
Cian M McCrudden, John W McBride, Joanne McCaffrey, Ahlam A Ali, Nicholas J Dunne, Vicky L Kett, Jonathan A Coulter, Tracy Robson, Helen O McCarthy
This study aimed to determine the therapeutic benefit of a nanoparticular formulation for the delivery of inducible nitric oxide synthase (iNOS) gene therapy in a model of breast cancer metastasis. Nanoparticles comprising a cationic peptide vector, RALA, and plasmid DNA were formulated and characterized using a range of physiochemical analyses. Nanoparticles complexed using iNOS plasmids and RALA approximated 60 nm in diameter with a charge of 25 mV. A vector neutralization assay, performed to determine the immunogenicity of nanoparticles in immunocompetent C57BL/6 mice, revealed that no vector neutralization was evident...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28283553/genome-wide-association-study-of-sepsis-in-extremely-premature-infants
#6
Lakshmi Srinivasan, Grier Page, Haresh Kirpalani, Jeffrey C Murray, Abhik Das, Rosemary D Higgins, Waldemar A Carlo, Edward F Bell, Ronald N Goldberg, Kurt Schibler, Beena G Sood, David K Stevenson, Barbara J Stoll, Krisa P Van Meurs, Karen J Johnson, Joshua Levy, Scott A McDonald, Kristin M Zaterka-Baxter, Kathleen A Kennedy, Pablo J Sánchez, Shahnaz Duara, Michele C Walsh, Seetha Shankaran, James L Wynn, C Michael Cotten
OBJECTIVE: To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. STUDY DESIGN: Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1...
March 10, 2017: Archives of Disease in Childhood. Fetal and Neonatal Edition
https://www.readbyqxmd.com/read/28116815/involvement-of-ralfuranones-in-the-quorum-sensing-signaling-pathway-and-virulence-of-ralstonia-solanacearum-strain-oe1-1
#7
Yuka Mori, Shiho Ishikawa, Hideyuki Ohnishi, Mika Shimatani, Yukino Morikawa, Kazusa Hayashi, Kouhei Ohnishi, Akinori Kiba, Kenji Kai, Yasufumi Hikichi
The soil-borne plant pathogenic Ralstonia solanacearum strain OE1-1 produces and secretes methyl 3-hydroxymyristate (3-OH MAME) as a quorum sensing (QS) signal, which contributes to its virulence. A global virulence regulator, PhcA, functioning through the QS system positively regulates the expression of ralA, which encodes furanone synthase, to produce aryl-furanone secondary metabolites, ralfuranones. A ralfuranone-deficient mutant (ΔralA) is weakly virulent when directly inoculated into tomato xylem vessels...
January 23, 2017: Molecular Plant Pathology
https://www.readbyqxmd.com/read/28042326/exosomes-derived-from-mir-140-5p-overexpressing-human-synovial-mesenchymal-stem-cells-enhance-cartilage-tissue-regeneration-and-prevent-osteoarthritis-of-the-knee-in-a-rat-model
#8
Shi-Cong Tao, Ting Yuan, Yue-Lei Zhang, Wen-Jing Yin, Shang-Chun Guo, Chang-Qing Zhang
OBJECTIVES: Osteoarthritis (OA) is the most common joint disease throughout the world. Exosomes derived from miR-140-5p-overexpressing synovial mesenchymal stem cells (SMSC-140s) may be effective in treating OA. We hypothesized that exosomes derived from SMSC-140 (SMSC-140-Exos) would enhance the proliferation and migration abilities of articular chondrocytes (ACs) without harming extracellular matrix (ECM) secretion. METHODS: SMSCs were transfected with or without miR-140-5p...
2017: Theranostics
https://www.readbyqxmd.com/read/27979747/dna-vaccination-for-cervical-cancer-a-novel-technology-platform-of-rala-mediated-gene-delivery-via-polymeric-microneedles
#9
Ahlam A Ali, Cian M McCrudden, Joanne McCaffrey, John W McBride, Grace Cole, Nicholas J Dunne, Tracy Robson, Adrien Kissenpfennig, Ryan F Donnelly, Helen O McCarthy
HPV subtypes (16, 18) are associated with the development of cervical cancer, with oncoproteins E6 and E7 responsible for pathogenesis. The goal of this study was to evaluate our 'smart system' technology platform for DNA vaccination against cervical cancer. The vaccination platform brings together two main components; a peptide RALA which condenses DNA into cationic nanoparticles (NPs), and a polymeric polyvinylpyrrolidone (PVP) microneedle (MN) patch for cutaneous delivery of the loaded NPs. RALA condensed E6/E7 DNA into NPs not exceeding 100nm in diameter, and afforded the DNA protection from degradation in PVP...
April 2017: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/27846370/dissolving-microneedles-for-dna-vaccination-improving-functionality-via-polymer-characterization-and-rala-complexation
#10
Grace Cole, Joanne McCaffrey, Ahlam A Ali, John W McBride, Cian M McCrudden, Eva M Vincente-Perez, Ryan F Donnelly, Helen O McCarthy
DNA vaccination holds the potential to treat or prevent nearly any immunogenic disease, including cancer. To date, these vaccines have demonstrated limited immunogenicity in vivo due to the absence of a suitable delivery system which can protect DNA from degradation and improve transfection efficiencies in vivo. Recently, microneedles have been described as a novel physical delivery technology to enhance DNA vaccine immunogenicity. Of these devices, dissolvable microneedles promise a safe, pain-free delivery system which may simultaneously improve DNA stability within a solid matrix and increase DNA delivery compared to solid arrays...
January 2, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/27825764/synthesis-of-novel-ral-inhibitors-an-in-vitro-and-in-vivo-study
#11
Chao Yan, Dan Theodorescu, Bettina Miller, Amit Kumar, Vijay Kumar, David Ross, Michael F Wempe
Chemical synthesis was performed to produce a series of 6-amino-1,3-disubstituted-4-phenyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile compounds (14-57) which were characterized by (1)H NMR, (13)C NMR and LC/MS-MS. These compounds were assessed for their effect on the in vitro anchorage independent growth of human lung cancer cell line H2122 and IC50 values calculated. Two of the more potent compounds, BQU057 40 and BQU082 57 also displayed a dose dependent effect on RalA and RalB activity in H2122 spheroids using the common RalBP1 pull-down assay...
December 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27791178/structural-basis-of-recognition-of-farnesylated-and-methylated-kras4b-by-pde%C3%AE
#12
Srisathiyanarayanan Dharmaiah, Lakshman Bindu, Timothy H Tran, William K Gillette, Peter H Frank, Rodolfo Ghirlando, Dwight V Nissley, Dominic Esposito, Frank McCormick, Andrew G Stephen, Dhirendra K Simanshu
Farnesylation and carboxymethylation of KRAS4b (Kirsten rat sarcoma isoform 4b) are essential for its interaction with the plasma membrane where KRAS-mediated signaling events occur. Phosphodiesterase-δ (PDEδ) binds to KRAS4b and plays an important role in targeting it to cellular membranes. We solved structures of human farnesylated-methylated KRAS4b in complex with PDEδ in two different crystal forms. In these structures, the interaction is driven by the C-terminal amino acids together with the farnesylated and methylated C185 of KRAS4b that binds tightly in the central hydrophobic pocket present in PDEδ...
November 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27773821/tyrosine-phosphorylation-of-ralgds-by-c-met-receptor-blocks-its-interaction-with-ras
#13
Richard Wong, Larry Feig
RalGDS is a guanine nucleotide exchange factor that promotes the active GTP-bound form of Ral GTPases, RalA and RalB. GTP-bound Ras has the capacity to activate Ral GTPases at least in part by binding to the C-terminal Ras-binding domain (RBD) of RalGDS and directing the protein to Ral GTPases in the plasma membrane. In many cases, activation of Ral proteins complements other Ras effector pathways to carry out a cell function, but in others it opposes them. Moreover, in many cases activation of Ral proteins contributes to the oncogenic potential of Ras...
October 20, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27748916/dysregulation-of-micro-143-3p-and-balbp1-contributes-to-the-pathogenesis-of-the-development-of-ovarian-carcinoma
#14
Hongyan Zhang, Wanbin Li
The objective of the present study was to identify the association between mir-143-3p and RalA-binding protein 1 (RALBP1), and their roles in regulating the development of ovarian cancer. Overexpression of RALBP1 induced apoptosis of the ovarian cancer cells, and developed ovarian cancer. In silico analysis and luciferase assay were used to identify whether RALBP1 was the target of mir-143-3p. Subsequently, real‑time PCR and western blotting were used to determine the expression level of mir-143-3p, RALBP1 mRNA and protein in different groups, furthermore, MTT assay and flow cytometry were used to detect the viability and apoptosis of cells in different treatment groups...
December 2016: Oncology Reports
https://www.readbyqxmd.com/read/27629377/distinct-roles-for-the-n-and-c-terminal-regions-of-m-sec-in-plasma-membrane-deformation-during-tunneling-nanotube-formation
#15
Shunsuke Kimura, Masami Yamashita, Megumi Yamakami-Kimura, Yusuke Sato, Atsushi Yamagata, Yoshihiro Kobashigawa, Fuyuhiko Inagaki, Takako Amada, Koji Hase, Toshihiko Iwanaga, Hiroshi Ohno, Shuya Fukai
The tunneling nanotube (TNT) is a structure used for intercellular communication, and is a thin membrane protrusion mediating transport of various signaling molecules and cellular components. M-Sec has potent membrane deformation ability and induces TNT formation in cooperation with the Ral/exocyst complex. Here, we show that the N-terminal polybasic region of M-Sec directly binds phosphatidylinositol (4,5)-bisphosphate for its localization to the plasma membrane during the initial stage of TNT formation. We further report a crystal structure of M-Sec, which consists of helix bundles arranged in a straight rod-like shape, similar to the membrane tethering complex subunits...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27595930/kras-related-proteins-in-pancreatic-cancer
#16
REVIEW
Karen M Mann, Haoqiang Ying, Joseph Juan, Nancy A Jenkins, Neal G Copeland
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, including cellular proliferation, migration, cellular metabolism and autophagy. 90% of pancreatic cancer patients harbor somatic oncogenic point mutations in KRAS, which lead to constitutive activation of the molecule...
December 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27566179/rala-is-overactivated-in-medulloblastoma
#17
Kevin F Ginn, Ben Fangman, Kaoru Terai, Amanda Wise, Daniel Ziazadeh, Kushal Shah, Robyn Gartrell, Brandon Ricke, Kyle Kimura, Sharad Mathur, Emma Borrego-Diaz, Faris Farassati
Medulloblastoma (MDB) represents a major form of malignant brain tumors in the pediatric population. A vast spectrum of research on MDB has advanced our understanding of the underlying mechanism, however, a significant need still exists to develop novel therapeutics on the basis of gaining new knowledge about the characteristics of cell signaling networks involved. The Ras signaling pathway, one of the most important proto-oncogenic pathways involved in human cancers, has been shown to be involved in the development of neurological malignancies...
October 2016: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/27510034/phosphatidic-acid-produced-by-rala-activated-pld2-stimulates-caveolae-mediated-endocytosis-and-trafficking-in-endothelial-cells
#18
Ying Jiang, Maria S Sverdlov, Peter T Toth, Long Shuang Huang, Guangwei Du, Yiyao Liu, Viswanathan Natarajan, Richard D Minshall
Caveolae are the primary route for internalization and transendothelial transport of macromolecules, such as insulin and albumin. Caveolae-mediated endocytosis is activated by Src-dependent caveolin-1 (Cav-1) phosphorylation and subsequent recruitment of dynamin-2 and filamin A (FilA), which facilitate vesicle fission and trafficking, respectively. Here, we tested the role of RalA and phospholipase D (PLD) signaling in the regulation of caveolae-mediated endocytosis and trafficking. The addition of albumin to human lung microvascular endothelial cells induced the activation of RalA within minutes, and siRNA-mediated down-regulation of RalA abolished fluorescent BSA uptake...
September 23, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27473470/rlip76-depletion-enhances-autophagic-flux-in-u251-cells
#19
Chenran Zhang, Zheng Cai, Qiang Liang, Qi Wang, Yicheng Lu, Liuhua Hu, Guohan Hu
Our previous study showed that RalA-binding protein 1 (RLIP76) is overexpressed in gliomas and is associated with higher tumour grade and decreased patient survival. Furthermore, RLIP76 downregulation increases chemosensitivity of glioma cells to temozolomide by inducing apoptosis. However, other mechanisms underlying RLIP76-associated chemoresistance are unknown. In this study, we investigated the effect of RLIP76 depletion on autophagy. RLIP76 was knocked down in U251 glioma cells using shRNA and autophagy-related proteins, and PI3K/Akt signalling components were evaluated...
April 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/27376061/probing-functional-changes-in-exocyst-configuration-with-monoclonal-antibodies
#20
Shivangi M Inamdar, Shu-Chan Hsu, Charles Yeaman
Spatial regulation of exocytosis relies on the exocyst, a hetero-octameric protein complex that tethers vesicles to fusion sites at the plasma membrane. Nevertheless, our understanding of mechanisms regulating exocyst assembly/disassembly, localization, and function are incomplete. Here, we have exploited a panel of anti-Sec6 monoclonal antibodies (mAbs) to probe possible configurational changes accompanying transitions in exocyst function in epithelial MDCK cells. Sec6 is quantitatively associated with Sec8 in high molecular weight complexes, as shown by gel filtration and co-immunoprecipitation studies...
2016: Frontiers in Cell and Developmental Biology
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