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https://www.readbyqxmd.com/read/28350885/glutamate-dependent-ectodomain-shedding-of-neuregulin-1-type-ii-precursors-in-rat-forebrain-neurons
#1
Yuriko Iwakura, Ran Wang, Naoko Inamura, Kazuaki Araki, Shigeki Higashiyama, Nobuyuki Takei, Hiroyuki Nawa
The neurotrophic factor neuregulin 1 (NRG1) regulates neuronal development, glial differentiation, and excitatory synapse maturation. NRG1 is synthesized as a membrane-anchored precursor and is then liberated by proteolytic processing or exocytosis. Mature NRG1 then binds to its receptors expressed by neighboring neurons or glial cells. However, the molecular mechanisms that govern this process in the nervous system are not defined in detail. Here we prepared neuron-enriched and glia-enriched cultures from embryonic rat neocortex to investigate the role of neurotransmitters that regulate the liberation/release of NRG1 from the membrane of neurons or glial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28350872/rna-sequence-analysis-of-gene-expression-from-honeybees-apis-mellifera-infected-with-nosema-ceranae
#2
Bouabid Badaoui, André Fougeroux, Fabien Petit, Anna Anselmo, Chiara Gorni, Marco Cucurachi, Antonella Cersini, Anna Granato, Giusy Cardeti, Giovanni Formato, Franco Mutinelli, Elisabetta Giuffra, John L Williams, Sara Botti
Honeybees (Apis mellifera) are constantly subjected to many biotic stressors including parasites. This study examined honeybees infected with Nosema ceranae (N. ceranae). N. ceranae infection increases the bees energy requirements and may contribute to their decreased survival. RNA-seq was used to investigate gene expression at days 5, 10 and 15 Post Infection (P.I) with N. ceranae. The expression levels of genes, isoforms, alternative transcription start sites (TSS) and differential promoter usage revealed a complex pattern of transcriptional and post-transcriptional gene regulation suggesting that bees use a range of tactics to cope with the stress of N...
2017: PloS One
https://www.readbyqxmd.com/read/28350442/engineered-polymer-transferrin-conjugates-as-self-assembling-targeted-drug-delivery-systems
#3
Hiteshri Makwana, Francesca Mastrotto, Johannes Pall Magnusson, Darrell Sleep, Joanna Hay, Karl J Nicholls, Stephanie Allen, Cameron Alexander
Polymer-protein conjugates can be engineered to self-assemble into discrete and well-defined drug delivery systems which combine the advantages of receptor targeting and controlled drug release. We designed specific conjugates of the iron-binding and transport protein, transferrin (Tf), to combine the advantages of this serum-stable protein as a targeting agent for cancer cells with self-assembling polymers to act as carriers of cytotoxic drugs. Tf variants were expressed with cysteine residues at sites spanning different regions of the protein surface and the polymer conjugates grown from these variants were compared with polymer conjugates grown from non-selectively derivatised sites on native Tf...
March 28, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28346872/5-bromo-2-aryl-benzimidazole-derivatives-as-non-cytotoxic-potential-dual-inhibitors-of-%C3%AE-glucosidase-and-urease-enzymes
#4
Tanzila Arshad, Khalid Mohammed Khan, Najma Rasool, Uzma Salar, Shafqat Hussain, Humna Asghar, Mohammed Ashraf, Abdul Wadood, Muhammad Riaz, Shahnaz Perveen, Muhammad Taha, Nor Hadiani Ismail
On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC50=8.15±0.03-354.67±0.19μM) as compared to standard thiourea (IC50=21.25±0.15μM)...
March 20, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28346809/malat1-promotes-osteosarcoma-development-by-regulation-of-hmgb1-via-mir-142-3p-and-mir-129-5p
#5
Ke Liu, Jun Huang, Jiangdong Ni, Deye Song, Muliang Ding, Junjie Wang, Xianzhe Huang, Wenzhao Li
Recently, emerging evidence has demonstrated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long non-coding RNAs (lncRNAs), contributes to the initiation and development of tumors, including osteosarcoma (OS). Multiple studies have suggested an oncogenic role of MALAT1 and high-mobility group protein B1 (HMGB1) in OS tumorigenesis and metastasis, but the effects and mechanisms are not unanimous. Here, we showed that MALAT1 and HMGB1 were significantly increased in human OS cell lines and knockdown of MALAT1 reduced HMGB1 expression...
March 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28346741/small-molecules-targeting-human-n-acetylmannosamine-kinase
#6
Stephan Hinderlich, Martin Neuenschwander, Paul-Robin Wratil, Andreas Oder, Michael Lisurek, Long D Nguyen, Jens Peter von Kries, Christian Hackenberger
N-Acetylmannosamine kinase (MNK) plays a key role in the biosynthesis of sialic acids and glycosylation of proteins. Sialylated glycoconjugates affect a large number of biological processes, including immune modulation and cancer transformation. For the search of effective inhibitors of MNK we applied high-throughput screening of drug-like small molecules. Applying different orthogonal assays for their validation we identified four potential MNK-specific inhibitors with IC50 values in the low micromolar range...
March 27, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28346407/insights-into-activity-and-inhibition-from-the-crystal-structure-of-human-o-glcnacase
#7
Nathaniel L Elsen, Sangita B Patel, Rachael E Ford, Dawn L Hall, Fred Hess, Hari Kandula, Maria Kornienko, John Reid, Harold Selnick, Jennifer M Shipman, Sujata Sharma, Kevin J Lumb, Stephen M Soisson, Daniel J Klein
O-GlcNAc hydrolase (OGA) catalyzes removal of βα-linked N-acetyl-D-glucosamine from serine and threonine residues. We report crystal structures of Homo sapiens OGA catalytic domain in apo and inhibited states, revealing a flexible dimer that displays three unique conformations and is characterized by subdomain α-helix swapping. These results identify new structural features of the substrate-binding groove adjacent to the catalytic site and open new opportunities for structural, mechanistic and drug discovery activities...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346406/diabetes-reversal-by-inhibition-of-the-low-molecular-weight-tyrosine-phosphatase
#8
Stephanie M Stanford, Alexander E Aleshin, Vida Zhang, Robert J Ardecky, Michael P Hedrick, Jiwen Zou, Santhi R Ganji, Matthew R Bliss, Fusayo Yamamoto, Andrey A Bobkov, Janna Kiselar, Yingge Liu, Gregory W Cadwell, Shilpi Khare, Jinghua Yu, Antonio Barquilla, Thomas D Y Chung, Tomas Mustelin, Simon Schenk, Laurie A Bankston, Robert C Liddington, Anthony B Pinkerton, Nunzio Bottini
Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases...
March 27, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28346356/microinjection-of-antibodies-targeting-the-lamin-a-c-histone-binding-site-blocks-mitotic-entry-and-reveals-separate-chromatin-interactions-with-hp1-cenpb-and-pml
#9
Charles R Dixon, Melpomeni Platani, Alexandr A Makarov, Eric C Schirmer
Lamins form a scaffold lining the nucleus that binds chromatin and contributes to spatial genome organization; however, due to the many other functions of lamins, studies knocking out or altering the lamin polymer cannot clearly distinguish between direct and indirect effects. To overcome this obstacle, we specifically targeted the mapped histone-binding site of A/C lamins by microinjecting antibodies specific to this region predicting that this would make the genome more mobile. No increase in chromatin mobility was observed; however, interestingly, injected cells failed to go through mitosis, while control antibody-injected cells did...
March 25, 2017: Cells
https://www.readbyqxmd.com/read/28346321/growth-arrest-and-dna-damage-inducible-protein-45%C3%AE-mediated-dna-demethylation-of-voltage-dependent-t-type-calcium-channel-3-2-subunit-enhances-neuropathic-allodynia-after-nerve-injury-in-rats
#10
Cheng-Yuan Lai, Ming-Chun Hsieh, Yu-Cheng Ho, An-Sheng Lee, Hsueh-Hsiao Wang, Jen-Kun Cheng, Yat-Pang Chau, Hsien-Yu Peng
BACKGROUND: Growth arrest and DNA-damage-inducible protein 45β reactivates methylation-silenced neural plasticity-associated genes through DNA demethylation. However, growth arrest and DNA-damage-inducible protein 45β-dependent demethylation contributes to neuropathic allodynia-associated spinal plasticity remains unclear. METHODS: Adult male Sprague-Dawley rats (654 out of 659) received a spinal nerve ligation or a sham operation with or without intrathecal application of one of the following: growth arrest and DNA-damage-inducible protein 45β messenger RNA-targeted small interfering RNA, lentiviral vector expressing growth arrest and DNA-damage-inducible protein 45β, Ro 25-6981 (an NR2B-bearing N-methyl-D-aspartate receptor antagonist), or KN-93 (a calmodulin-dependent protein kinase II antagonist) were used for behavioral measurements, Western blotting, immunofluorescence, dot blots, detection of unmodified cytosine enrichment at cytosine-phosphate-guanine site, chromatin immunoprecipitation quantitative polymerase chain reaction analysis, and slice recordings...
March 27, 2017: Anesthesiology
https://www.readbyqxmd.com/read/28346102/phage-display-derived-ligand-for-mucosal-transcytotic-receptor-gp-2-promotes-antigen-delivery-to-m-cells-and-induces-antigen-specific-immune-response
#11
Inam Ullah Khan, Jiansheng Huang, Rui Liu, Jingbo Wang, Jun Xie, Naishuo Zhu
Successful oral immunization depends on efficient delivery of antigens (Ags) to the mucosal immune induction site. Glycoprotein-2 (GP-2) is an integral membrane protein that is expressed specifically on M cells within follicle-associated epithelium (FAE) and serves as transcytotic receptor for luminal Ags. In this study, we selected peptide ligands against recombinant human GP-2 by screening a phage display library and evaluated their interaction with GP-2 in vitro and ex vivo. Selected peptides were conjugated to the C-terminal of enhanced green fluorescence protein (EGFP) and evaluated for their ability to induce an immune response in mice...
February 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28345916/molecular-mechanism-of-nucleotide-dependent-allosteric-regulation-in-amp-activated-protein-kinase
#12
Navjeet Ahalawat, Rajesh Kumar Murarka
The AMP-activated protein kinase (AMPK), a central enzyme in the regulation of energy homeostasis, is an important drug target for type 2 diabetes, obesity and cancer. Binding of adenosine nucleotides to the regulatory γ-subunit tightly regulates the activity of this enzyme. Though recent crystal structures of AMPK have provided important insights into the allosteric activation of AMPK, molecular details of the regulatory mechanism of AMPK activation is still elusive. Here, we have performed extensive all-atom molecular dynamics (MD) simulations and shown that the kinase domain (KD) and γ-subunit comes closer resulting in a more compact heterotrimeric AMPK complex in AMP-bound state compared to the ATP-bound state...
March 27, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28345889/ape1-accelerates-turnover-of-hogg1-by-preventing-retrograde-binding-to-the-abasic-site-product
#13
Alexandre Esadze, Gaddiel Rodriguez, Shannen Lee Cravens, James T Stivers
A major product of oxidative DNA damage is 8-oxoguanine. In humans, 8-oxoguanine DNA Glycosylase (hOGG1) facilitates removal of these lesions, producing an abasic (AP) site in the DNA that is subsequently incised by AP-endonuclease 1 (APE1). APE1 stimulates turnover of several glycosylases by accelerating rate-limiting product release. However, there have been conflicting accounts of whether hOGG1 follows a similar mechanism. In pre-steady state kinetic measurements, we found that addition of APE1 had no effect on the rapid burst phase of 8-oxoguanine excision by hOGG1, but accelerated steady-state turnover (kcat) by ~10-fold...
March 27, 2017: Biochemistry
https://www.readbyqxmd.com/read/28345882/covalent-allosteric-inactivation-of-ptp1b-by-an-inhibitor-electrophile-conjugate
#14
Puminan Punthasee, Adrian R Laciak, Andrea Hicks Cummings, Kasi Viswanatharaju Ruddraraju, Sarah M Lewis, Roman Hillebrand, Harkewal Singh, John J Tanner, Kent S Gates
Protein tyrosine phosphatase 1B (PTP1B) is a validated drug target but it has proven difficult to develop medicinally-useful, reversible inhibitors of this enzyme. Here we explored covalent strategies for the inactivation of PTP1B using a conjugate composed of an active site-directed 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide inhibitor connected via a short linker to an electrophilic α-bromoacetamide moiety. The inhibitor-electrophile conjugate 5a caused time-dependent loss of PTP1B activity consistent with a covalent inactivation mechanism...
March 27, 2017: Biochemistry
https://www.readbyqxmd.com/read/28345816/germline-variation-in-the-3-untranslated-region-of-the-pou2af1-gene-is-associated-with-susceptibility-to-lymphoma
#15
Kan Zhai, Jiang Chang, Jinlong Hu, Chen Wu, Dongxin Lin
Genetic variations in certain genes may alter the susceptibility to lymphoma. We searched electronic databases and selected candidate single-nucleotide polymorphisms (SNPs) located within 3'-untranslated regions (3'-UTRs) that might affect miRNA-binding ability in the 50 most dysregulated genes in lymphoma for further study. We found that rs1042752-located in the 3'-UTR of POU2AF1, which plays a vital role in lymphomagenesis-was significantly associated with lymphoma risk in a case-control study with 793 patients and 939 controls...
March 27, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/28345670/domain-dependent-effects-of-insulin-and-igf-1-receptors-on-signalling-and-gene-expression
#16
Weikang Cai, Masaji Sakaguchi, Andre Kleinridders, Gonzalo Gonzalez-Del Pino, Jonathan M Dreyfuss, Brian T O'Neill, Alfred K Ramirez, Hui Pan, Jonathon N Winnay, Jeremie Boucher, Michael J Eck, C Ronald Kahn
Despite a high degree of homology, insulin receptor (IR) and IGF-1 receptor (IGF1R) mediate distinct cellular and physiological functions. Here, we demonstrate how domain differences between IR and IGF1R contribute to the distinct functions of these receptors using chimeric and site-mutated receptors. Receptors with the intracellular domain of IGF1R show increased activation of Shc and Gab-1 and more potent regulation of genes involved in proliferation, corresponding to their higher mitogenic activity. Conversely, receptors with the intracellular domain of IR display higher IRS-1 phosphorylation, stronger regulation of genes in metabolic pathways and more dramatic glycolytic responses to hormonal stimulation...
March 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28345656/structure-and-function-of-the-zika-virus-full-length-ns5-protein
#17
Baoyu Zhao, Guanghui Yi, Fenglei Du, Yin-Chih Chuang, Robert C Vaughan, Banumathi Sankaran, C Cheng Kao, Pingwei Li
The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 Å resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site...
March 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28345603/pja2-ubiquitinates-the-hiv-1-tat-protein-with-atypical-chain-linkages-to-activate-viral-transcription
#18
Tyler B Faust, Yang Li, Gwendolyn M Jang, Jeffrey R Johnson, Shumin Yang, Amit Weiss, Nevan J Krogan, Alan D Frankel
Transcription complexes that assemble at the HIV-1 promoter efficiently initiate transcription but generate paused RNA polymerase II downstream from the start site. The virally encoded Tat protein hijacks positive transcription elongation factor b (P-TEFb) to phosphorylate and activate this paused polymerase. In addition, Tat undergoes a series of reversible post-translational modifications that regulate distinct steps of the transcription cycle. To identify additional functionally important Tat cofactors, we performed RNAi knockdowns of sixteen previously identified Tat interactors and found that a novel E3 ligase, PJA2, ubiquitinates Tat in a non-degradative manner and specifically regulates the step of HIV transcription elongation...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28345600/the-structure-of-zika-virus-ns5-reveals-a-conserved-domain-conformation
#19
Boxiao Wang, Xiao-Feng Tan, Stephanie Thurmond, Zhi-Min Zhang, Asher Lin, Rong Hai, Jikui Song
The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health. Here we report the crystal structure of the ZIKV NS5 protein in complex with S-adenosyl-L-homocysteine, in which the tandem methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains stack into one of the two alternative conformations of flavivirus NS5 proteins. The activity of this NS5 protein is verified through a de novo RdRp assay on a subgenomic ZIKV RNA template. Importantly, our structural analysis leads to the identification of a potential drug-binding site of ZIKV NS5, which might facilitate the development of novel antivirals for ZIKV...
March 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28345465/demethoxycurcumin-inhibited-human-epithelia-ovarian-cancer-cells-growth-via-up-regulating-mir-551a
#20
Zhenhua Du, Xianqun Sha
Curcumin is a natural agent that has ability to dampen tumor cells' growth. However, the natural form of curcumin is prone to degrade and unstable in vitro. Here, we demonstrated that demethoxycurcumin (a curcumin-related demethoxy compound) could inhibit cell proliferation and induce apoptosis of ovarian cancer cells. Moreover, IRS2/PI3K/Akt axis was inactivated in cells treated with demethoxycurcumin. Quantitative real-time reverse transcription polymerase chain reaction demonstrated that miR-551a was down-regulated in ovarian cancer tissues and ovarian cancer cell lines...
March 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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