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https://www.readbyqxmd.com/read/28330327/role-of-gnb3-net-kcnj11-tcf7l2-and-grl-genes-single-nucleotide-polymorphism-in-the-risk-prediction-of-type-2-diabetes-mellitus
#1
REVIEW
Saliha Rizvi, Syed Tasleem Raza, Qamar Rahman, Farzana Mahdi
Type 2 diabetes (T2DM) is a polygenic metabolic disorder characterized by hyperglycemia occurring as a result of impaired insulin secretion or insulin resistance. Various environmental and genetic factors interact and increase the risk of T2DM and its complications. Among the various genetic factors associated with T2DM, single nucleotide polymorphism in different candidate genes have been studied intensively and the resulting genetic variants have been found to have either positive or negative association with T2DM thereby increasing or decreasing the risk of T2DM, respectively...
December 2016: 3 Biotech
https://www.readbyqxmd.com/read/28328290/cross-talk-between-rho-gtpases-and-pi3k-in-the-neutrophil
#2
Barry McCormick, Julia Y Chu, Sonja Vermeren
Neutrophils are short-lived, abundant peripheral blood leukocytes that provide a first line of defense against bacterial and fungal infections whilst also being a key part of the inflammatory response. Chemokines induce neutrophil recruitment to inflammatory sites, where neutrophils perform a number of diverse functions that are aimed at fighting infections. Neutrophil effector functions are tightly regulated processes that are governed by an array of intracellular signaling pathways and initiated by receptor-ligand binding events...
March 22, 2017: Small GTPases
https://www.readbyqxmd.com/read/28328248/-a8344g-mitochondrial-dna-mutation-observed-in-two-generations
#3
Anett Fekete, Kinga Hadzsiev, Judit Bene, Antónia Nászai, Petra Mátyás, Ágnes Till, Béla Melegh
This article presents the case of a 62-year-old mother and her 41-year-old daughter, who have had severe neurological symptoms for a few decades. After a long investigation period the definite diagnosis of MERRF syndrome was confirmed. After DNA isolation from our patient's blood sample we examined the mitochondrial DNA with direct sequencing. An adenine-guanine substitution was detected in the tRNA gene at position 8344, based on the sequence ferogram the heteroplasmy was over 90%. The clinical phenotype was not clearly characteristic for MERRF syndrome, adult-onset and lipomas are not typical in this disease...
March 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28326134/revaluation-of-biomass-derived-furfuryl-alcohol-derivatives-for-the-synthesis-of-carbocyclic-nucleoside-phosphonate-analogues
#4
Bemba Sidi Mohamed, Christian Périgaud, Christophe Mathé
The racemic synthesis of new carbocyclic nucleoside methylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using bio-sourced furfuryl alcohol derivatives. All compounds were prepared using a Mitsunobu coupling between the heterocyclic base and an appropriate carbocyclic precursor. After deprotection, the compounds were evaluated for their activity against a large number of viruses. However, none of them showed significant antiviral activity or cytotoxicity.
2017: Beilstein Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28325822/structural-basis-for-chemokine-recognition-by-a-g-protein-coupled-receptor-and-implications-for-receptor-activation
#5
Joshua J Ziarek, Andrew B Kleist, Nir London, Barak Raveh, Nicolas Montpas, Julien Bonneterre, Geneviève St-Onge, Crystal J DiCosmo-Ponticello, Chad A Koplinski, Ishan Roy, Bryan Stephens, Sylvia Thelen, Christopher T Veldkamp, Frederick D Coffman, Marion C Cohen, Michael B Dwinell, Marcus Thelen, Francis C Peterson, Nikolaus Heveker, Brian F Volkman
Chemokines orchestrate cell migration for development, immune surveillance, and disease by binding to cell surface heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). The array of interactions between the nearly 50 chemokines and their 20 GPCR targets generates an extensive signaling network to which promiscuity and biased agonism add further complexity. The receptor CXCR4 recognizes both monomeric and dimeric forms of the chemokine CXCL12, which is a distinct example of ligand bias in the chemokine family...
March 21, 2017: Science Signaling
https://www.readbyqxmd.com/read/28325821/phosphorylation-of-the-exocyst-protein-exo84-by-tbk1-promotes-insulin-stimulated-glut4-trafficking
#6
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/28325749/the-nca-1-and-nca-2-ion-channels-function-downstream-of-gq-and-rho-to-regulate-locomotion-in-caenorhabditis-elegans
#7
Irini Topalidou, Pin-An Chen, Kirsten Cooper, Shigeki Watanabe, Erik M Jorgensen, Michael Ailion
The heterotrimeric G protein Gq positively regulates neuronal activity and synaptic transmission. Previously, the Rho guanine nucleotide exchange factor Trio was identified as a direct effector of Gq that acts in parallel to the canonical Gq effector phospholipase C. Here we examine how Trio and Rho act to stimulate neuronal activity downstream of Gq in the nematode Caenorhabditis elegans Through two forward genetic screens, we identify the cation channels NCA-1 and NCA-2, orthologs of mammalian NALCN, as downstream targets of the Gq/Rho pathway...
March 21, 2017: Genetics
https://www.readbyqxmd.com/read/28325114/complexes-of-dna-bases-and-watson-crick-base-pairs-interaction-with-neutral-silver-agn-n-8-10-12-clusters-a-dft-and-tddft-study
#8
Ruby Srivastava
We study the binding of the neutral Agn (n = 8, 10, 12) to the DNA base- adenine (A), guanine (G) and Watson-Crick -adenine-thymine (AT), guanine-cytosine (GC) pairs. Geometries of complexes were optimized at the DFT level using the hybrid B3LYP functional. LANL2DZ effective core potential (ECP) was used for silver and 6-31+G(**) was used for all other atoms. NBO charges were analyzed using the Natural population analysis. The absorption properties of Agn-A,G/WC complexes were also studied using time-dependent density functional theory (TDDFT)...
March 21, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28324509/human-telomeric-g-quadruplex-structures-and-g-quadruplex-interactive-compounds
#9
Clement Lin, Danzhou Yang
G-quadruplexes are noncanonical secondary structures formed in DNA sequences containing consecutive runs of guanines. It has been shown that the 3' G-rich single-stranded overhangs of human telomeres can form G-quadruplex structures, and the human telomeric DNA G-quadruplexes are considered attractive targets for anticancer drugs. G-quadruplex-interactive compounds have been shown to inhibit telomerase access as well as telomere capping. Nuclear magnetic resonance (NMR) spectroscopy is a powerful method in determining the G-quadruplex structures under physiologically relevant conditions...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28323387/induction-of-tumor-regression-by-intratumoral-sting-agonists-combined-with-anti-programmed-death-l1-blocking-antibody-in-a-preclinical-squamous-cell-carcinoma-model
#10
Shekhar K Gadkaree, Juan Fu, Rupashree Sen, Michael J Korrer, Clint Allen, Young J Kim
BACKGROUND: Cyclic dinucleotides (CDNs) are bacterial intracellular messengers that have demonstrated antitumor activity in melanoma and breast tumors, although their role in immunotherapy of head and neck squamous cell cancers (HNSCCs) has not been well investigated. METHODS: We measured primary tumor growth rates, mechanism of antitumor activity, and efficacy of programmed death-L1 blockade combinatorial therapy in SCCFVII tumor-bearing C3H/HeOUJ mice undergoing intratumoral injections with RR-cyclic-di-guanine (synthetic CDG), CDG (natural cyclic-di-guanine), R848 (TLR 7/8 agonist), or phosphate buffered saline (PBS, control)...
March 21, 2017: Head & Neck
https://www.readbyqxmd.com/read/28323226/herc1-mutations-in-idiopathic-intellectual-disability
#11
G Eda Utine, Ekim Z Taşkıran, Can Koşukcu, Beren Karaosmanoğlu, Naz Güleray, Özlem Akgün Doğan, P Özlem Şimşek Kiper, Koray Boduroğlu, Mehmet Alikaşifoğlu
HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1. Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition...
March 16, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28319837/kalirin-reduction-rescues-psychosis-associated-behavioral-deficits-in-appswe-psen1de9-transgenic-mice
#12
Josh M Krivinko, Susan L Erickson, Eric E Abrahamson, Zachary P Wills, Milos D Ikonomovic, Peter Penzes, Robert A Sweet
Psychosis in Alzheimer's disease (AD+P) represents a distinct clinical and neurobiological AD phenotype and is associated with more rapid cognitive decline, higher rates of abnormal behaviors, and increased caregiver burden compared with AD without psychosis. On a molecular level, AD+P is associated with greater reductions in the protein kalirin, a guanine exchange factor which has also been linked to the psychotic disease, schizophrenia. In this study, we sought to determine the molecular and behavioral consequences of kalirin reduction in APPswe/PSEN1dE9 mice...
February 16, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28318223/high-throughput-dual-screening-method-for-ras-activities-and-inhibitors
#13
Kari Kopra, Arjan J van Adrichem, Outi M H Salo-Ahen, Juha Peltonen, Krister Wennerberg, Harri J Härmä
Ras GTPases act as "molecular switches", alternating between inactive GDP-bound and active GTP-bound conformation. Ras-oncogenes were discovered over three decades ago, but there are still no effective therapies for Ras-driven cancers. Drug discovery strategies have so far been unsuccessful, due to a lack of suitable screening methodologies and well-defined binding pockets on the Ras proteins. Here, we addressed the former by introducing a homogeneous quenching resonance energy transfer (QRET) technique based screening strategy for Ras interfacial and competitive inhibitors...
March 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28318029/computational-study-of-the-reactivity-of-cytosine-derivatives
#14
Jihène Jerbi, Michael Springborg
The aim of the present study is to provide computational insight using dispersion-corrected density-functional calculations into the reactivity properties of modified cytosine in the gas phase and in aqueous solution, whereby special emphasis is put on systems that are obtained through demethylation and methylation. Since this field is relatively incipient, our goal is to identify relationships between reactivity and stability for the modified compounds to understand their biological functionalities. Our results show that addition of a methyl, hydroxylmethyl, formyl, or carboxyl group reduces the length of the nearest hydrogen bond between the cytosine-guanine (CG) base pair and increases the length of the longest hydrogen bond of the DNA base pair...
March 20, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28317975/exposing-the-g-quadruplex-to-electric-fields-the-role-played-by-telomeres-in-the-propagation-of-dna-errors
#15
José Pedro Cerón-Carrasco, Denis Jacquemin
To protect their core machinery from the attack of exogenous agents, cells locate DNA in their nucleus. Nevertheless, some reactive chemical species and physical agents might reach DNA and alter its natural double helix structure. For instance, pulsed electric fields can be used to selectively rewrite the stored genetic information. However, for such modification to be effective, one needs, as a prerequisite, that the replication mechanism is not stopped by the field, so that the changes propagate over the following generations...
March 20, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28315520/fail-safe-control-of-translation-initiation-by-dissociation-of-eif2%C3%AE-phosphorylated-ternary-complexes
#16
Martin D Jennings, Christopher J Kershaw, Tomas Adomavicius, Graham D Pavitt
Phosphorylation of eIF2α controls translation initiation by restricting the levels of active eIF2-GTP-Met-tRNAi ternary complexes (TC). This modulates the expression of all eukaryotic mRNAs and contributes to the cellular integrated stress response. Key to controlling the activity of eIF2 are translation factors eIF2B and eIF5, thought to primarily function with eIF2-GDP and TC respectively. Using a steady-state kinetics approach with purified proteins we demonstrate that eIF2B binds to eIF2 with equal affinity irrespective of the presence or absence of competing guanine nucleotides...
March 18, 2017: ELife
https://www.readbyqxmd.com/read/28306504/targeting-of-polycomb-repressive-complex-2-to-rna-by-short-repeats-of-consecutive-guanines
#17
Xueyin Wang, Karen J Goodrich, Anne R Gooding, Haroon Naeem, Stuart Archer, Richard D Paucek, Daniel T Youmans, Thomas R Cech, Chen Davidovich
Polycomb repressive complex 2 (PRC2) is a histone methyltransferase that trimethylates H3K27, a mark of repressed chromatin. Mammalian PRC2 binds RNA promiscuously, with thousands of target transcripts in vivo. But what does PRC2 recognize in these RNAs? Here we show that purified human PRC2 recognizes G > C,U ≫ A in single-stranded RNA and has a high affinity for folded guanine quadruplex (G4) structures but little binding to duplex RNAs. Importantly, G-tract motifs are significantly enriched among PRC2-binding transcripts in vivo...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28304276/scaffold-mediated-gating-of-cdc42-signaling-flux
#18
Péter Rapali, Romain Mitteau, Craig Ronald Braun, Aurèlie Massoni-Laporte, Caner Ünlü, Laure Bataille, Floriane Saint Arramon, Steven P Gygi, Derek McCusker
Scaffold proteins modulate signaling pathway activity spatially and temporally. In budding yeast, the scaffold Bem1 contributes to polarity axis establishment by regulating the GTPase Cdc42. While different models have been proposed for Bem1 function, there is little direct evidence for an underlying mechanism. Here, we find that Bem1 directly augments the Guanine Exchange Factor (GEF) activity of Cdc24. Bem1 also increases GEF phosphorylation by the p21-activated kinase (PAK), Cla4. Phosphorylation abrogates the scaffold-dependent stimulation of GEF activity, rendering Cdc24 insensitive to additional Bem1...
March 17, 2017: ELife
https://www.readbyqxmd.com/read/28304230/modular-regulation-of-rho-family-gtpases-in-development
#19
Marlis Denk-Lobnig, Adam C Martin
Rho family GTPase signaling regulates the actin cytoskeleton and is critical for behaviors that range from the cell to tissue-scale. A theme in Rho GTPase biology is that there are many more regulators, such as guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), than GTPases themselves. Here, we review different, modular cases where GEFs and GAPs function together to elicit precise spatial and temporal control of signaling. We focus on examples from metazoan development, where precise regulation of Rho GTPases is critical for proper tissue form and function...
March 17, 2017: Small GTPases
https://www.readbyqxmd.com/read/28303227/analysis-of-cordyceps-by-multi-column-liquid-chromatography
#20
Zhengming Qian, Shaoping Li
Cordyceps is a famous traditional Chinese medicine (TCM) that has been used in China for hundreds of years. In the present study a multi-column liquid chromatography (MC-LC) system was developed for the qualitative analysis of macromolecules and micromolecules in Cordyceps. The MC-LC system includes a size exclusion pre-column, a size exclusion column (SEC) and a reversed phase column (RP) which were controlled by column-switching valves. The sample was separated by the size exclusion pre-column into two fractions (macromolecules and micromolecules)...
March 2017: Acta Pharmaceutica Sinica. B
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