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https://www.readbyqxmd.com/read/28644070/particulate-matter-disrupts-human-lung-endothelial-cell-barrier-integrity-via-rho-dependent-pathways
#1
Ting Wang, Yuka Shimizu, Xiaomin Wu, Gabriel T Kelly, Xiaoyan Xu, Lichun Wang, Zhongqing Qian, Yin Chen, Joe G N Garcia
Increased exposure to ambient particulate matter (PM) is associated with elevated morbidity and mortality in patients with cardiopulmonary diseases and cancer. We and others have shown that PM induces lung microvascular barrier dysfunction which potentially enhances the systemic toxicity of PM. However, the mechanisms by which PM disrupts vascular endothelial integrity remain incompletely explored. We hypothesize that PM induces endothelial cell (EC) cytoskeleton rearrangement via Rho GTPase-dependent pathways to facilitate vascular hyperpermeability...
June 23, 2017: Pulmonary Circulation
https://www.readbyqxmd.com/read/28642160/a-novel-missense-variant-gln220arg-of-gnb4-encoding-guanine-nucleotide-binding-protein-subunit-beta-4-in-a-japanese-family-with-autosomal-dominant-motor-and-sensory-neuropathy
#2
Shiroh Miura, Takuya Morikawa, Ryuta Fujioka, Kazuhito Noda, Kengo Kosaka, Takayuki Taniwaki, Hiroki Shibata
Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy...
June 19, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28641529/irna-2methyl-identify-rna-2-o-methylation-sites-by-incorporating-sequence-coupled-effects-into-general-pseknc-and-ensemble-classifier
#3
Wang-Ren Qiu, Shi-Yu Jiang, Bi-Qian Sun, Xuan Xiao, Xiang Cheng, Kuo-Chen Chou
OBJECTIVE: Being a kind of post-transcriptional modification (PTCM) in RNA, the 2'-O-methylation modification occurs in the processes of life development and disease formation as well. Accordingly, from the angles of both basic research and drug development, we are facing a challenging problem: given an uncharacterized RNA sequence formed by many nucleotides of A (adenine), C (cytosine), G (guanine), and U (uracil), which one can be of 2-O-methylation modification, and which one cannot? Unfortunately, so far no computational method whatsoever has been developed to address such a problem...
June 22, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28641070/elmo-proteins-transduce-g-protein-coupled-receptor-signal-to-control-reorganization-of-actin-cytoskeleton-in-chemotaxis-of-eukaryotic-cells
#4
Xuehua Xu, Tian Jin
Chemotaxis, which is chemoattractant-guided directional cell migration, plays major roles in recruitment of neutrophils, the metastasis of cancer cells, and the development of the model organism Dictyostelium discoideum. These cells share remarkable similarities in the signaling pathways by which they control chemotaxis. They all use a G protein-coupled receptor (GPCR)-mediated signal transduction pathway to sense the chemotactic gradient to guide cell migration. Diverse chemokines activate Rac through conserved GPCR signaling pathways...
June 22, 2017: Small GTPases
https://www.readbyqxmd.com/read/28640851/ligand-mediated-and-tertiary-interactions-cooperatively-stabilize-the-p1-region-in-the-guanine-sensing-riboswitch
#5
Christian A Hanke, Holger Gohlke
Riboswitches are genetic regulatory elements that control gene expression depending on ligand binding. The guanine-sensing riboswitch (Gsw) binds ligands at a three-way junction formed by paired regions P1, P2, and P3. Loops L2 and L3 cap the P2 and P3 helices and form tertiary interactions. Part of P1 belongs to the switching sequence dictating the fate of the mRNA. Previous studies revealed an intricate relationship between ligand binding and presence of the tertiary interactions, and between ligand binding and influence on the P1 region...
2017: PloS One
https://www.readbyqxmd.com/read/28637664/expanded-repertoire-of-rasgrp2-variants-responsible-for-platelet-dysfunction-and-severe-bleeding
#6
Sarah K Westbury, Matthias Canault, Daniel Greene, Emilse Bermejo, Katharine Hanlon, Michele P Lambert, Carolyn M Millar, Paquita Nurden, Samya G Obaji, Shoshana Revel-Vilk, Chris Van Geet, Kate Downes, Sofia Papadia, Salih Tuna, Christopher Watt, Nihr BioResource-Rare Diseases Consortium, Kathleen Freson, Michael A Laffan, Willem H Ouwehand, Marie-Christine Alessi, Ernest Turro, Andrew D Mumford
Heritable platelet function disorders (PFDs) are genetically heterogeneous and poorly characterised. Pathogenic variants in RASGRP2, which encodes calcium and diacylglycerol-regulated guanine exchange factor I (CalDAG-GEFI), have been reported previously in three pedigrees with bleeding and reduced platelet aggregation responses. To better define the phenotype associated with pathogenic RASGRP2 variants, we compared high-throughput sequencing and phenotype data from 2,042 cases in pedigrees with unexplained bleeding or platelet disorders to data from 5,422 controls...
June 21, 2017: Blood
https://www.readbyqxmd.com/read/28634209/genetic-evidence-that-%C3%AE-arrestins-are-dispensable-for-the-initiation-of-%C3%AE-2-adrenergic-receptor-signaling-to-erk
#7
Morgan O'Hayre, Kelsie Eichel, Silvia Avino, Xuefeng Zhao, Dana J Steffen, Xiaodong Feng, Kouki Kawakami, Junken Aoki, Karen Messer, Roger Sunahara, Asuka Inoue, Mark von Zastrow, J Silvio Gutkind
The β2-adrenergic receptor (β2AR) has provided a paradigm to elucidate how G protein-coupled receptors (GPCRs) control intracellular signaling, including the discovery that β-arrestins, which bind to ligand-activated GPCRs, are central for GPCR function. We used genome editing, conditional gene deletion, and small interfering RNAs (siRNAs) to determine the roles of β-arrestin 1 (β-arr1) and β-arr2 in β2AR internalization, trafficking, and signaling to ERK. We found that only β-arr2 was essential for β2AR internalization...
June 20, 2017: Science Signaling
https://www.readbyqxmd.com/read/28633570/enantioselective-light-switch-effect-of-%C3%AE-and-%C3%AE-ru-phenanthroline-2-dipyrido-3-2-a-2-3-c-phenazine-2-bound-to-g-quadruplex-dna
#8
Jin Ha Park, Hyun Suk Lee, Myung Duk Jang, Sung Wook Han, Seog K Kim, Young-Ae Lee
The interaction of Δ- and Λ-[Ru(phen)2DPPZ](2+) (DPPZ = dipyrido[3,2-a:2', 3'-c]phenazine, phen = phenanthroline) with a G-quadruplex formed from 5'-G2T2G2TGTG2T2G2-3'(15-mer) was investigated. The well-known enhancement of luminescence intensity (the 'light-switch' effect) was observed for the [Ru(phen)2DPPZ](2+) complexes upon formation of an adduct with the G-quadruplex. The emission intensity of the G-quadruplex-bound Λ-isomer was 3-fold larger than that of the Δ-isomer when bound to the G-quadruplex, which is opposite of the result observed in the case of double stranded DNA (dsDNA); the light switch effect is larger for the dsDNA-bound Δ-isomer...
June 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28630934/ligand-binding-to-a-g-protein-coupled-receptor-captured-in-a-mass-spectrometer
#9
Hsin-Yung Yen, Jonathan T S Hopper, Idlir Liko, Timothy M Allison, Ya Zhu, Dejian Wang, Monika Stegmann, Shabaz Mohammed, Beili Wu, Carol V Robinson
G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors belong to the largest family of membrane-embedded cell surface proteins and are involved in a diverse array of physiological processes. Despite progress in the mass spectrometry of membrane protein complexes, G protein-coupled receptors have remained intractable because of their low yield and instability after extraction from cell membranes. We established conditions in the mass spectrometer that preserve noncovalent ligand binding to the human purinergic receptor P2Y1...
June 2017: Science Advances
https://www.readbyqxmd.com/read/28630924/capturing-the-radical-ion-pair-intermediate-in-dna-guanine-oxidation
#10
Jialong Jie, Kunhui Liu, Lidan Wu, Hongmei Zhao, Di Song, Hongmei Su
Although the radical ion pair has been frequently invoked as a key intermediate in DNA oxidative damage reactions and photoinduced electron transfer processes, the unambiguous detection and characterization of this species remain formidable and unresolved due to its extremely unstable nature and low concentration. We use the strategy that, at cryogenic temperatures, the transient species could be sufficiently stabilized to be detectable spectroscopically. By coupling the two techniques (the cryogenic stabilization and the time-resolved laser flash photolysis spectroscopy) together, we are able to capture the ion-pair transient G(+•)⋯Cl(-) in the chlorine radical-initiated DNA guanine (G) oxidation reaction, and provide direct evidence to ascertain the intricate type of addition/charge separation mechanism underlying guanine oxidation...
June 2017: Science Advances
https://www.readbyqxmd.com/read/28630045/structure-based-analysis-of-the-guanine-nucleotide-exchange-factor-smggds-reveals-armadillo-repeat-motifs-and-key-regions-for-activity-and-gtpase-binding
#11
Hikaru Shimizu, Sachiko Toma-Fukai, Shinya Saijo, Nobutaka Shimizu, Kenji Kontani, Toshiaki Katada, Toshiyuki Shimizu
Small GTPases are molecular switches that have critical biological roles and are controlled by GTPase-activating proteins and guanine-nucleotide exchange factors (GEFs). The smg GDP dissociation stimulator (SmgGDS) protein functions as a GEF for the RhoA and RhoC small GTPases. SmgGDS has various regulatory roles, including small GTPase trafficking and localization and as a molecular chaperone, and interacts with many small GTPases possessing polybasic regions. Two SmgGDS splice variants, SmgGDS-558 and SmgGDS-607, differ in GEF activity and binding affinity for RhoA depending on the lipidation state, but the reasons for these differences are unclear...
June 19, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28629775/8-oxo-7-8-dihydroguanine-friend-and-foe-epigenetic-like-regulator-versus-initiator-of-mutagenesis
#12
REVIEW
Aaron M Fleming, Cynthia J Burrows
A high flux of reactive oxygen species during oxidative stress results in oxidative modification of cellular components including DNA. Oxidative DNA "damage" to the heterocyclic bases is considered deleterious because polymerases may incorrectly read the modifications causing mutations. A prominent member in this class is the oxidized guanine base 8-oxo-7,8-dihydroguanine (OG) that is moderately mutagenic effecting G→T transversion mutations. Recent reports have identified that formation of OG in G-rich regulatory elements in the promoters of the VEGF, TNFα, and SIRT1 genes can increase transcription via activation of the base excision repair (BER) pathway...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28628332/watson-crick-base-pair-radical-cation-as-a-model-for-oxidative-damage-in-dna
#13
Linda Feketeova, Bun Chan, George N Khairallah, Vincent Steinmetz, Philippe Maître, Leo Radom, Richard A J O'Hair
The deleterious cellular effects of ionizing radiation are well known but the mechanisms causing DNA damage are poorly understood. The accepted molecular events involve initial oxidation and deprotonation at guanine sites, triggering hydrogen-atom-abstraction reactions from the sugar moieties, causing DNA strand breaks. Probing the chemistry of the initially formed radical cation has been challenging. Here we generate, spectroscopically characterise and examine the reactivity of the Watson-Crick nucleobase-pair radical cation in the gas-phase...
June 19, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28628320/dynamics-of-charge-injection-and-charge-recombination-in-dna-mini-hairpins
#14
Ashutosh Kumar Mishra, Michelle A Harris, Ryan M Young, Michael R Wasielewski, Frederick D Lewis
Steady state spectroscopy, femtosecond transient absorption spectroscopy (fsTA), and femtosecond stimulated Raman spectroscopy (FSRS) of DNA mini-hairpins possessing a diphenylacetylenedicarboxamide (DPA) linker and 1-3 adenine-thymine (A-T) or guanine-cytosine (G-C) base pairs have been investigated. Ultraviolet and circular dichroism (UV and CD) spectra are consistent with ground state conformations that are predominantly base-paired and -stacked for conjugates possessing two or three base pairs; however, they offer no information concerning the conformation of conjugates possessing a single base pair...
June 19, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28628279/acyclic-nucleoside-phosphonates-containing-9-deazahypoxanthine-and-a-5-membered-heterocycle-as-selective-inhibitors-of-plasmodial-6-oxopurine-phosphoribosyltransferases
#15
Martin Maxmilian Kaiser, Ondřej Baszczyňski, Dana Hocková, Lenka Poštová-Slavětínská, Martin Dračínský, Dianne T Keough, Luke W Guddat, Zlatko Janeba
Acyclic nucleoside phosphonates (ANPs) are an important class of therapeutic drugs that act as antiviral agents by inhibiting viral DNA polymerases and reverse transcriptases. ANPs containing a 6-oxopurine instead of 6-aminopurine or pyrimidine bases are inhibitors of the purine salvage enzyme, hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase (HG[X]PRT). Such compounds, and their prodrugs, are able to arrest the growth of Plasmodium falciparum (Pf) in cell culture. A new series of ANPs has been synthesized and tested as inhibitors of human HGPRT, PfHGXPRT and Plasmodium vivax (Pv) HGPRT...
June 19, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28628209/nucleobase-protection-of-deoxyribo-and-ribonucleosides
#16
Geeta Meher, Nabin K Meher, Radhakrishnan P Iyer
Oligonucleotides carrying a variety of chemical modifications including conjugates are finding increasing applications in therapeutics, diagnostics, functional genomics, proteomics, and as research tools in chemical and molecular biology. The successful synthesis of oligonucleotides primarily depends on the use of appropriately protected nucleoside building blocks including the exocyclic amino groups of the nucleobases, the hydroxyl groups at the 2'-, 3'-, and 5'-positions of the sugar moieties, and the internucleotide phospho-linkage...
June 19, 2017: Current Protocols in Nucleic Acid Chemistry
https://www.readbyqxmd.com/read/28627546/theoretical-study-of-gas-and-solvent-phase-stability-and-molecular-adsorption-of-noncanonical-guanine-bases-on-graphene
#17
Nabanita Saikia, Shashi P Karna, Ravindra Pandey
The gas and solvent phase stability of noncanonical (Gua)n nucleobases is investigated in the framework of dispersion-corrected density functional theory (DFT). The calculated results strongly support the high tendency for the dimerization of (Gua)n bases in both gas and solvent phases. An interplay between intermolecular and bifurcated H-bonds is suggested to govern the stability of (Gua)n bases which bears a correlation with the description of dispersion correction terms employed in the DFT calculations. For example, a higher polarity is predicted for (Gua)n bases by the dispersion-corrected DFT in contrast to the non-polar nature of (Gua)3 and (Gua)4 predicted by the hybrid meta-GGA calculations...
June 19, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28627018/the-nucleotide-free-state-of-heterotrimeric-g-proteins-%C3%AE-subunit-adopts-a-highly-stable-conformation
#18
Sai Krishna Andhirka, Ravichandran Vignesh, Gopala Krishna Aradhyam
Deciphering the mechanism of activation of heterotrimeric G proteins by their cognate receptors continues to be an intriguing area of research. The recently solved crystal structure of the ternary complex captured the receptor-bound α-subunit in an open conformation, without bound nucleotide has improved our understanding of the activation process. Despite these advancements, the mechanism by which the receptor causes GDP release from the α-subunit remains elusive. To elucidate the mechanism of activation, we studied guanine nucleotide-induced structural stability of the α-subunit (in response to thermal/chaotrope-mediated stress)...
June 19, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28626984/biologically-controlled-morphology-and-twinning-in-guanine-crystals
#19
Anna Hirsch, Benjamin A Palmer, Nadav Elad, Dvir Gur, Stephen Weiner, Lia Addadi, Leeor Kronik, Leslie Leiserowitz
Guanine crystals are widely used in nature as components of multilayer reflectors. Guanine-based reflective systems found in the copepod cuticle and in the mirror of the scallop eye are unique in that the multilayered reflectors are tiled to form a contiguous packed array. In the copepod cuticle, hexagonal crystals are closely packed to produce brilliant colors. In the scallop eye, square crystals are tiled to obtain an image-forming reflecting mirror. The tiles are about 1μm in size and 70 nm thick. According to analysis of their electron diffraction patterns the hexagon and square tiles are not single crystals...
June 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28625885/dock8-deficiency-insights-into-pathophysiology-clinical-features-and-management
#20
REVIEW
Catherine M Biggs, Sevgi Keles, Talal A Chatila
Dedicator of Cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8, encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3...
June 15, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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