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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
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
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
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...
December 12, 2016: Nanomedicine: Nanotechnology, Biology, and Medicine
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
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
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
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
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
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
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
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...
August 26, 2016: Journal of Neuro-oncology
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
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
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
Jitian Li, Liping Dai, Ningjing Lei, Mengtao Xing, Pei Li, Chenglin Luo, Carlos A Casiano, Jian-Ying Zhang
Autoantibodies against intracellular tumor-associated antigens (TAAs) are commonly found in human cancers. In this study, we characterized the serum autoantibody response to the RalA, Ras-like GTPase, in patients with prostate cancer (PCa). The autoantibodies were detected by immunofluorescence assay in PCa cell lines, ELISA, and immunoblotting in 339 serum samples from patients with PCa and benign prostatic hyperplasia (BPH), and in normal human sera (NHS). The expression of RalA in prostate tumor tissues was evaluated by immunohistochemistry (IHC) in tumor microarrays...
July 12, 2016: Oncotarget
Archana Pawar, Jeremy A Meier, Anwesha Dasgupta, Neha Diwanji, Neha Deshpande, Kritika Saxena, Natasha Buwa, Siddhi Inchanalkar, Martin Alexander Schwartz, Nagaraj Balasubramanian
Integrin dependent regulation of growth factor signalling confers anchorage dependence that is deregulated in cancers. Downstream of integrins and oncogenic Ras the small GTPase Ral is a vital mediator of adhesion dependent trafficking and signalling. This study identifies a novel regulatory crosstalk between Ral and Arf6 that controls Ral function in cells. In re-adherent mouse fibroblasts (MEFs) integrin dependent activation of RalA drives Arf6 activation. Independent of adhesion constitutively active RalA and RalB could both however activate Arf6...
September 2016: Cellular Signalling
Mei Zheng, Xiaohan Zhang, NingNing Sun, Chengchun Min, Xiaowei Zhang, Kyeong-Man Kim
Filamin A (FLNA) is known to act as platform for the signaling and intracellular trafficking of various GPCRs including dopamine D2 and D3 receptors (D2R, D3R). To understand molecular mechanisms involved in the FLNA-mediated regulation of D2R and D3R, comparative studies were conducted on the signaling and intracellular trafficking of the D2R and D3R in FLNA-knockdown cells, with a specific focus on the roles of the proteins that interact with FLNA and the D2R and D3R. Lowering the level of cellular FLNA caused an elevation in RalA activity and resulted in selective interference with the normal intracellular trafficking and signaling of the D2R and D3R, through GRK2 and β-arrestins, respectively...
August 2016: Biochimica et Biophysica Acta
Takahiro Kodama, Emilie A Bard-Chapeau, Justin Y Newberg, Michiko Kodama, Roberto Rangel, Kosuke Yoshihara, Jerrold M Ward, Nancy A Jenkins, Neal G Copeland
BACKGROUND & AIMS: High-throughput sequencing technologies have identified thousands of infrequently mutated genes in hepatocellular carcinomas (HCCs). However, high intratumor and intertumor heterogeneity, combined with large numbers of passenger mutations, have made it difficult to identify driver mutations that contribute to the development of HCC. We combined transposon mutagenesis with a high-throughput screen of a small-hairpin RNA (shRNA) library to identify genes and pathways that contribute to HCC development...
August 2016: Gastroenterology
Zhi Yi Wan, Johann Shane Tian, Hayden Weng Siong Tan, Ai Lee Chow, Arthur Yi Loong Sim, Kenneth Hon Kim Ban, Yun Chau Long
UNLABELLED: Fibroblast growth factor 19 (FGF19) is an important postprandial enterokine which regulates liver metabolism and hepatocyte proliferation. However, the precise mechanism by which FGF19 regulates these cellular effects is poorly understood. Given that mechanistic target of rapamycin complex 1 (mTORC1) regulates numerous postprandial adaptations, we investigated the potential role of mTORC1 in FGF19 action. We found that FGF19 activated mTORC1 in HepG2 and HuH7 human hepatoma cells, differentiated 3T3-L1 adipocytes and mouse liver...
October 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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