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https://www.readbyqxmd.com/read/28932835/a-multi-functional-guanine-derivative-for-studying-the-dna-g-quadruplex-structure
#1
Takumi Ishizuka, Pei-Yan Zhao, Hong-Liang Bao, Yan Xu
In the present study, we developed a multi-functional guanine derivative, (8F)G, as a G-quadruplex stabilizer, a fluorescent probe for the detection of G-quadruplex formation, and a (19)F sensor for the observation of the G-quadruplex. We demonstrate that the functional nucleoside bearing a 3,5-bis(trifluoromethyl)benzene group at the 8-position of guanine stabilizes the DNA G-quadruplex structure and fluoresces following the G-quadruplex formation. Furthermore, we show that the functional sensor can be used to directly observe DNA G-quadruplexes by (19)F-NMR in living cells...
September 21, 2017: Analyst
https://www.readbyqxmd.com/read/28930674/a-protein-scaffold-coordinates-src-mediated-jnk-activation-in-response-to-metabolic-stress
#2
Shashi Kant, Claire L Standen, Caroline Morel, Dae Young Jung, Jason K Kim, Wojciech Swat, Richard A Flavell, Roger J Davis
Obesity is a major risk factor for the development of metabolic syndrome and type 2 diabetes. How obesity contributes to metabolic syndrome is unclear. Free fatty acid (FFA) activation of a non-receptor tyrosine kinase (SRC)-dependent cJun NH2-terminal kinase (JNK) signaling pathway is implicated in this process. However, the mechanism that mediates SRC-dependent JNK activation is unclear. Here, we identify a role for the scaffold protein JIP1 in SRC-dependent JNK activation. SRC phosphorylation of JIP1 creates phosphotyrosine interaction motifs that bind the SH2 domains of SRC and the guanine nucleotide exchange factor VAV...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28928363/an-autism-spectrum-disorder-related-de-novo-mutation-hotspot-discovered-in-the-gef1-domain-of-trio
#3
Anastasiia Sadybekov, Chen Tian, Cosimo Arnesano, Vsevolod Katritch, Bruce E Herring
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac1. Recent studies suggest that autism spectrum disorder (ASD)-related behavioral phenotypes in animal models of ASD can be produced by dysregulation of Rac1's control of actin polymerization at glutamatergic synapses. Here, in humans, we discover a large cluster of ASD-related de novo mutations in Trio's Rac1 activating domain, GEF1. Our study reveals that these mutations produce either hypofunctional or hyperfunctional forms of Trio in rodent neurons in vitro...
September 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28927665/fgd5-sustains-vascular-endothelial-growth-factor-a-vegfa-signaling-through-inhibition-of-proteasome-mediated-vegf-receptor-2-degradation
#4
Johan Heldin, Paul O'Callaghan, Rodrigo Hernández Vera, Peder Fredlund Fuchs, Pär Gerwins, Johan Kreuger
The complete repertoire of endothelial functions elicited by FGD5, a guanine nucleotide exchange factor activating the Rho GTPase Cdc42, has yet to be elucidated. Here we explore FGD5's importance during vascular endothelial growth factor A (VEGFA) signaling via VEGF receptor 2 (VEGFR2) in human endothelial cells. In microvascular endothelial cells, FGD5 is located at the inner surface of the cell membrane as well as at the outer surface of EEA1-positive endosomes carrying VEGFR2. The latter finding prompted us to explore if FGD5 regulates VEGFR2 dynamics...
September 16, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28927343/a-triple-stranded-g-quadruplex-formation-in-the-promoter-region-of-human-myosin-%C3%AE-myh7-gene
#5
Anju Singh, Shrikant Kukreti
Regulatory regions in human genome, enriched in guanine-rich DNA sequences have the propensity to fold into G-quadruplex structures. On exploring the genome for search of G-tracts, it was interesting to find that promoter of Human Myosin Gene (MYH7) contains a conserved 23-mer G-rich sequence (HM-23). Mutations in this gene are associated with familial cardiomyopathy. Enrichment of MYH7 gene in G-rich sequences could possibly play a critical role in its regulation. We used polyacrylamide gel electrophoresis (PAGE), UV-Thermal denaturation (UV-Tm) and Circular Dichroism (CD), to demonstrate the formation of a G-quadruplex by 23-mer G-rich sequence HM23 in promoter location of MYH7 gene...
September 19, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28924219/mesoscopic-model-for-dna-g-quadruplex-unfolding
#6
A E Bergues-Pupo, I Gutiérrez, J R Arias-Gonzalez, F Falo, A Fiasconaro
Genomes contain rare guanine-rich sequences capable of assembling into four-stranded helical structures, termed G-quadruplexes, with potential roles in gene regulation and chromosome stability. Their mechanical unfolding has only been reported to date by all-atom simulations, which cannot dissect the major physical interactions responsible for their cohesion. Here, we propose a mesoscopic model to describe both the mechanical and thermal stability of DNA G-quadruplexes, where each nucleotide of the structure, as well as each central cation located at the inner channel, is mapped onto a single bead...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28923977/prepatterning-by-rhogefs-governs-rho-gtpase-spatiotemporal-dynamics-during-wound-repair
#7
Mitsutoshi Nakamura, Jeffrey M Verboon, Susan M Parkhurst
Like tissues, single cells are subjected to continual stresses and damage. As such, cells have a robust wound repair mechanism comprised of dynamic membrane resealing and cortical cytoskeletal remodeling. One group of proteins, the Rho family of small guanosine triphosphatases (GTPases), is critical for this actin and myosin cytoskeletal response in which they form distinct dynamic spatial and temporal patterns/arrays surrounding the wound. A key mechanistic question, then, is how these GTPase arrays are formed...
September 18, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28923919/multiple-interactions-between-an-arf-gef-complex-and-charged-lipids-determine-activation-kinetics-on-the-membrane
#8
Deepti Karandur, Agata Nawrotek, John Kuriyan, Jacqueline Cherfils
Lipidated small GTPases and their regulators need to bind to membranes to propagate actions in the cell, but an integrated understanding of how the lipid bilayer exerts its effect has remained elusive. Here we focused on ADP ribosylation factor (Arf) GTPases, which orchestrate a variety of regulatory functions in lipid and membrane trafficking, and their activation by the guanine-nucleotide exchange factor (GEF) Brag2, which controls integrin endocytosis and cell adhesion and is impaired in cancer and developmental diseases...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28923883/microtubules-associated-rac-regulation-of-endothelial-barrier-a-role-of-asef-in-acute-lung-injury
#9
Pratap Karki, Anna A Birukova
The endothelial barrier function regulated by the cytoskeletal reorganizations has been implicated in the pathogenesis of multiple lung diseases including asthma, sepsis, edema, and acute respiratory distress syndrome. The extensive studies have established that activation of small GTPase Rac is a key mechanism in endothelial barrier protection but the role of microtubules-associated Rac in the endothelial functions remains poorly understood. With the emerging evidences that microtubules disassembly also plays a critical role in actin cytoskeleton remodeling leading to endothelial permeability, the knowledge on microtubules-mediated regulation of endothelial barrier is imperative to better understand the etiology of lung injuries as well as to develop novel therapeutics against these disorders...
September 18, 2017: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
https://www.readbyqxmd.com/read/28921499/synthesis-of-the-phosphoramidite-units-for-benzene-glycol-nucleic-acid
#10
Yusuke Maeda, Nazuki Niwa, Yoshihito Ueno
Benzene-glycol nucleic acid-DNA chimeras form thermally and thermodynamically stable duplexes with complementary RNAs, and have base-discriminating abilities. This unit describes the synthesis of four nucleoside analogs, an adenine, cytosine, thymine, and guanine analogs with base-benzene-glycol structure. The synthesis starts with conversion of (S)-mandelic acid in arylboronic acid derivative, common intermediate. Nucleobase coupling of the intermediate and phosphitylation afford to phosphoroamidite units...
September 18, 2017: Current Protocols in Nucleic Acid Chemistry
https://www.readbyqxmd.com/read/28918301/mathematical-fundamentals-for-the-noise-immunity-of-the-genetic-code
#11
Elena Fimmel, Lutz Strüngmann
Symmetry is one of the essential and most visible patterns that can be seen in nature. Starting from the left-right symmetry of the human body, all types of symmetry can be found in crystals, plants, animals and nature as a whole. Similarly, principals of symmetry are also some of the fundamental and most useful tools in modern mathematical natural science that play a major role in theory and applications. As a consequence, it is not surprising that the desire to understand the origin of life, based on the genetic code, forces us to involve symmetry as a mathematical concept...
September 13, 2017: Bio Systems
https://www.readbyqxmd.com/read/28917843/rapgef2-a-guanine-nucleotide-exchange-factor-for-rap1-small-gtpases-plays-a-crucial-role-in-adherence-junction-aj-formation-in-radial-glial-cells-through-erk-mediated-upregulation-of-the-aj-constituent-protein-expression
#12
Maged Ibrahim Farag, Yoko Yoshikawa, Kazuhiro Maeta, Tohru Kataoka
Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap1, characterized by possession of the Ras/Rap-associating domains and implicated in the etiology of schizophrenia. We previously found that dorsal telencephalon-specific Rapgef2 conditional knockout mice exhibits severe defects in formation of apical surface adherence junctions (AJs) and localization of radial glial cells (RGCs). In this study, we analyze the underlying molecular mechanism by using primary cultures of RGCs established from the developing cerebral cortex...
September 13, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28916096/the-preparation-of-a-poly-pentaerythritol-tetraglycidyl-ether-co-poly-ethylene-imine-organic-monolithic-capillary-column-and-its-application-in-hydrophilic-interaction-chromatography-for-polar-molecules
#13
Ye Chen, Yan Shu, Zihui Yang, Xumei Lv, Wangming Tan, Yingzhuang Chen, Ming Ma, Bo Chen
An easy single-step thermal treatment "one-pot" approach for the preparation of poly (pentaerythritol tetraglycidyl ether-co-poly ethylene imine) organic monolithic capillary columns was developed successfully. The column was prepared by the epoxy-amine ring-opening polymerization of pentaerythritol tetraglycidyl ether (PTE) with poly (ethylene imine) (PEI) using acetonitrile (ACN) and polyethylene glycol 600 (PEG 600) as the porogenic system at 60 °C for 12 h. The obtained monolith was homogeneous and permeable...
October 2, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28915409/androgen-receptor-cytosine-adenine-and-guanine-trinucleotide-repeat-polymorphism-in-korean-patients-with-endometriosis-a-case-control-study
#14
Jae Jun Shin, Young Min Choi, Hwa Young Choi, Soo Jin Chae, Kyuri Hwang, Jin Ju Kim, Gyoung Hoon Lee, Jong Mi Kim
STUDY OBJECTIVE: To investigate the association between the androgen receptor (AR) cytosine, adenine, and guanine (CAG) repeat polymorphisms and endometriosis. STUDY DESIGN: A prospective case-control, genetic association study was performed on women with surgically proven endometriosis (n=421) and controls free of endometriosis (n=349). AR CAG repeat lengths were determined from peripheral blood samples. The difference in the frequency of each alleles were compared in patients with endometriosis and controls using Chi-square test...
September 8, 2017: European Journal of Obstetrics, Gynecology, and Reproductive Biology
https://www.readbyqxmd.com/read/28914317/a-bifunctional-nanomodulator-for-boosting-cpg-mediated-cancer-immunotherapy
#15
Zhenzhen Wang, Yan Zhang, Zhen Liu, Kai Dong, Chaoqun Liu, Xiang Ran, Fang Pu, Enguo Ju, Jinsong Ren, Xiaogang Qu
Unmethylated cytosine-phosphate-guanine (CpG) oligonucleotides (ODNs) possess high immunostimulatory activity and represent attractive tools for cancer treatment. However, their success in eliminating large solid tumors was hampered by the immunosuppressive tumor microenvironment. Herein, we report that the design of a novel MnO2-CpG-silver nanoclusters (AgNCs)-doxorubicin (DOX) conjugate for enhanced cancer immunotherapy, in which MnO2 nanosheets function as unique supports to integrate the chemotherapy drug DOX and the immunotherapeutic agent CpG-AgNCs...
September 15, 2017: Nanoscale
https://www.readbyqxmd.com/read/28913561/conformational-rearrangement-of-1-2-d-gg-intrastrand-cis-diammineplatinum-crosslinked-dna-is-driven-by-counter-ion-penetration-within-the-minor-groove-of-the-modified-site
#16
Tsvetan G Gantchev, Peicho St Petkov, Darel J Hunting
The major structural aberrations of DNA induced by a cis-diammineplatinum (II) 1,2-d(GG) intrastrand cross-link (CPT) have been known for decades. To gain deeper insights into the structural dynamics of the sequence-dependent DNA distortions adjacent to the CPT adduct, we employed molecular modeling and molecular dynamics (MD) simulations. The structural dynamics of native (N-DNA) and cisPt 1,2-d(GG) crosslinked (CPT-DNA) in the form of symmetric 36 nt d(G2T15G*G*T15G2)●C2A15CCA15C2) oligonucleotide duplexes is compared...
September 14, 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28912101/importance-of-the-rem-ras-exchange-domain-for-membrane-interactions-by-rasgrp3
#17
Agnes Czikora, Noemi Kedei, Heather Kalish, Peter M Blumberg
RasGRP comprises a family of guanine nucleotide exchange factors, regulating the dissociation of GDP from Ras GTPases to enhance the formation of the active GTP-bound form. RasGRP1 possesses REM (Ras exchange), GEF (catalytic), EF-hand, C1, SuPT (suppressor of PT), and PT (plasma membrane-targeting) domains, among which the C1 domain drives membrane localization in response to diacylglycerol or phorbol ester and the PT domain recognizes phosphoinositides. The homologous family member RasGRP3 shows less plasma membrane localization...
September 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28910418/the-effect-of-s-substitution-at-the-o6-guanine-site-on-the-structure-and-dynamics-of-a-dna-oligomer-containing-a-g-t-mismatch
#18
Elaine Ann Moore, Yao-Zhong Xu
The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with S-substitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T...
2017: PloS One
https://www.readbyqxmd.com/read/28904386/skewed-x-inactivation-in-lesch-nyhan-disease-carrier-females
#19
Rosa J Torres, Juan G Puig
X chromosome inactivation (XCI) ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In several X-linked disorders, female carriers present skewed X inactivation. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked disorder. Males are affected and present with the complete Lesch-Nyhan disease (LND) or with a partial phenotype (Lesch-Nyhan variant, LNV). Female carriers are usually asymptomatic. The aim of the present study was to analyze the XCI pattern of HPRT-deficiency carrier females...
September 14, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28904242/the-g-quadruplex-dna-stabilizing-drug-pyridostatin-promotes-dna-damage-and-downregulates-transcription-of-brca1-in-neurons
#20
Jose F Moruno-Manchon, Edward C Koellhoffer, Jayakrishnan Gopakumar, Shashank Hambarde, Nayun Kim, Louise D McCullough, Andrey S Tsvetkov
The G-quadruplex is a non-canonical DNA secondary structure formed by four DNA strands containing multiple runs of guanines. G-quadruplexes play important roles in DNA recombination, replication, telomere maintenance, and regulation of transcription. Small molecules that stabilize the G-quadruplexes alter gene expression in cancer cells. Here, we hypothesized that the G-quadruplexes regulate transcription in neurons. We discovered that pyridostatin, a small molecule that specifically stabilizes G-quadruplex DNA complexes, induced neurotoxicity and promoted the formation of DNA double-strand breaks (DSBs) in cultured neurons...
September 12, 2017: Aging
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